THE JOURNAL OF TEHRAN UNIVERSITY HEART CENTER

Editor-in-Chief ABBASALI KARIMI, MD PROFESSOR OF CARDIAC SURGERY TEHRAN UNIVERSITY OF MEDICAL SCIENCES Managing Editor SEYED HESAMEDDIN ABBASI, MD TEHRAN HEART CENTER TEHRAN UNIVERSITY OF MEDICAL SCIENCES International Editors Zohair Yousef Al-halees, MD , FRCSC, FACS Fred Morady, MD King Faisal Heart Institute, Saudi Arabia University of Michigan, U. S. A Yadolah Dodge, PhD Mohammed T. Numan, MD University of Neuchâtel, Switzerland University of Texas, U. S. A Ali Dodge–Khatami, MD, PhD Ahmand S. Omran, MD, FACC, FASE University of Zürich, Switzerland King Abdulaziz Cardiac Center, Saudi Arabia Iradj Gandjbakhch, MD Fausto J. Pinto, MD, PhD, FESC, FACC, FASA, FSCAI, Hopital Pitie, France FASE Omer Isik, MD Lisbon University, Portugal Yeditepe University, School of Medicine, Turkey Mehrdad Rezaee, MD, PhD Sami S. Kabbani, MD Stanford University, School of Medicine, U. S. A Damascus University Cardiovascular Surgical Center, Syria Gregory S. Thomas, MD, MPH, FACC, FACP, FASNC Kayvan Kamalvand, MD, FRCP, FACC University of California, U. S. A William Harvey Hospital, United Kingdom Lee Samuel Wann, MD Jean Marco, MD, FESC Wisconsin Heart Hospital, U. S. A Centre Cardio- Thoracique de Monaco, France Hein J. Wellens, MD Ali Massumi, MD Cardiovascular Research Institute, Maastricht, The Netherlands Texas Heart Institute, U. S. A Douglas P. Zipes, MD Carlos-A. Mestres, MD Indiana University, School of medicine, U. S. A University of Barcelona, Spain Editorial Board Hossien Ahmadi, MD Seyed Rasoul Mirsharifi, MD Tehran University of Medical Sciences Tehran University of Medical Sciences Shahin Akhondzadeh, PhD Ahmad Mohebi, MD Tehran University of Medical Sciences Iran University of Medical Sciences Mohammad Alidoosti, MD Mohammad-Hasan Namazi Tehran University of Medical Sciences Shaheed beheshti University of Medical Sciences Mohammad Ali Boroumand, MD Ebrahim Nematipour, MD Tehran University of Medical Sciences Tehran University of Medical Sciences Ahmad Reza Dehpour, PhD Rezayat Parvizi, MD Tehran University of Medical Sciences Tabriz University of Medical Sciences Abbasali Karimi, MD Masoud Pezeshkian Tehran University of Medical Sciences Tabriz University of Medical Sciences Seyed Ebrahim Kassaian, MD Hassan Radmehr, MD Tehran University of Medical Sciences Tehran University of Medical Sciences Davood Kazemi Saleh, MD Saeed Sadeghian, MD Baghiatallah University of Medical Sciences Tehran University of Medical Sciences Majid Maleki, MD Mojtaba Salarifar, MD Iran University of Medical Sciences Tehran University of Medical Sciences Mehrab Marzban, MD Nizal Sarraf –Zadegan, MD Tehran University of Medical Sciences Isfahan University of Medical Sciences Mansor Moghadam, MD Ahmad Yaminisharif, MD Tehran University of Medical Sciences Tehran University of Medical Sciences Sina Moradmand Badie, MD Mohammad Reza Zafarghandi, MD Tehran University of Medical Sciences Tehran University of Medical Sciences Seyed Mahmood Mirhoseini, MD, DSc, FACC, FAES Aliakbar Zeinaloo, MD Tehran University of Medical Sciences Tehran University of Medical Sciences Advisory Board Kiyomars Abbasi, MD Elise Langdon- Neuner Tehran University of Medical Sciences The editor of The Write Stuff, Austria Seifollah Abdi, MD Jalil Majd Ardekani, MD Iran University of Medical Sciences Tehran University of Medical Sciences Alireza Amirzadegan, MD Fardin Mirbolook, MD Tehran University of Medical Sciences Gilan University of Medical Sciences Naser Aslanabadi, MD Mehdi Najafi, MD Tabriz University of Medical Sciences Tehran University of Medical Sciences Sirous Darabian, MD Younes Nozari, MD Tehran University of Medical Sciences Tehran University of Medical Sciences Gholamreza Davoodi, MD Hamid Reza Pour Hosseini, MD Tehran University of Medical Sciences Tehran University of Medical Sciences Saeed Davoodi, MD Hakimeh Sadeghian, MD Tehran University of Medical Sciences Tehran University of Medical Sciences Iraj Firoozi, MD Mohammad Saheb Jam, MD & PT Iran University of Medical Sciences Tehran University of Medical Sciences Seyed Khalil Foroozannia, MD Abbas Salehi Omran, MD Shaheed Sadoghi University of Medical Sciences Tehran University of Medical Sciences Armen Gasparyan MD, PhD Mahmood Shabestari, MD Armenia Mashhad University of Medical Sciences Ali Ghaemian, MD Shapour Shirani, MD Mazandaran University of Medical Sciences Tehran University of Medical Sciences Namvar Ghasemi Movahedi, MD Abbas Soleimani, MD Tehran University of Medical Sciences Kerman University of Medical Sciences Abbas Ghiasi, MD Seyed Abdolhosein Tabatabaei, MD Tehran University of Medical Sciences Tehran University of Medical Sciences Ali Kazemi Saeed, MD Murat Ugurlucan, MD Tehran University of Medical Sciences Rostock University Medical Faculty Seyed Kianoosh Hoseini Arezou Zoroufian, MD Tehran University of Medical Sciences Tehran University of Medical Sciences Mohammad Jafar Hashemi, MD Iran University of Medical Sciences Statistical Consultant Mahmood Sheikh Fathollahi Technical Editors Pedram Amouzadeh Office Fatemeh Esmaeili Darabi

The Journal of Tehran University Heart Center is indexed in EMBASE, CAB Abstracts, Global Health, Chemical Abstract Service, Cinahl, Google Scholar, DOAJ, Geneva Foundation for Medical Education and Research, Index Copernicus, Index Medicus for the WHO Eastern Mediterranean Region (IMEMR), ISC, SID, Iranmedex and Magiran Address North Kargar Street, Tehran Heart Center, Tehran, Iran 1411713138. Tel: +98-21-88029720. Fax: +98-21-88029702. Web Site: http://jthc.tums.ac.ir. E-mail: [email protected]. TEHRAN HEART CENTER Content

Volume: 5 Number: 2 Spring 2010

The Journal of Tehran University Heart Center

Review Article

Monitoring of Anticoagulant Therapy in Heart Disease: Considerations for the Current Assays Mohammadali Boroumand, Hamidreza Goodarzynejad ……………...... 57

Original Articles

Is the Peak-to-Mean Pressure Gradient Ratio Useful for Assessment of Aortic Valve Prosthesis Obstruction? Maryam Esmaeilzadeh, Ahmad Mirdamadi, Mozhgan Parsaee, Anita Sadeghpour, Majid Maleki, Hooman Bakhshandeh Abkenar …...... 69

Measurement of Atrial Septal Defect Size: A Comparative Study Between Transesophageal Echocardiography and Balloon Occlusive Diameter Method Hakimeh Sadeghian, Alimohammad Hajizeinali, Bahareh Eslami, Masoumeh Lotfi-Tokaldany, Mahmood Sheikhfathollahi, Mohammad Sahebjam, Elham Hakki, Arezou Zoroufian, Seyed Ebrahim Kassaian, Mohammad Alidosti ...... 74

Relationship Between Calcium-Phosphorus Product and Severity of Valvular Heart Insufficiency in Patients Undergoing Chronic Hemodialysis Masoumeh Kahnooj, Mohammad Masoomi, Ali Naderinasab, Akram Zaeem, Mehrdad Sheikhvatan ...... 78

Sonographic Prediction of Body Fat Volume (Subcutaneousand Visceral Fat) in Cardiovascular Patients Mir Hatef Shojaei, Shapour Shirani, Mohammad Reza Eshraghian, Maryam Soleymanzadeh ...... 83

Radiofrequency Catheter Ablation of Atrioventricular Nodal Reentrant Tachycardia: Success Rates and Complications During 14 Years of Experience Ahmad Yaminisharif, Gholamreza Davoodi, Ali Kazemisaeid, Ali Vasheghani Farahani, Fatemeh Ghazanchai, Mansour Moghaddam ...... 87

Case Reports

Single Stage Aortic Valve Replacement and Splenectomy in a Patient with Severe Aortic Stenosis Rezayat Parvizi, Rasoul Ibrahim Abdulrahman, Rezvaneh Salehi, Ghader Shah Mohamadi ……....……...... 92

Quadricuspid Aortic Valve Diagnosed by Transesophageal Echocardiography: A Case Report Farahnaz Nikdoust, Hakimeh Sadeghian, Bahareh Eslami, Shahla Majidi, Dariush Javidi ……..…...... 95

Perivalvular Abscess of Tricuspid Valve: A Rare Complication of Infective Endocarditis Ali Reza Moaref, Yadallah Mahmoody, Khallil Zarrabie ……………...... 98

The Journal of Tehran University Heart Center

TEHRAN HEART CENTER

Review Article Monitoring of Anticoagulant Therapy in Heart Disease: Considerations for the Current Assays

Mohammadali Boroumand, MD*, Hamidreza Goodarzynejad, MD

Tehran Heart Center, Tehran University of Medical Sciences, Iran.

Abstract

Clinicians should be aware of new developments to familiarize themselves with pharmacokinetic and pharmacodynamic characteristics of new anticoagulant agents to appropriately and safely use them. For the moment, cardiologists and other clinicians also require to master currently available drugs, realizing the mechanism of action, side effects, and laboratory monitoring to measure their anticoagulant effects. Warfarin and heparin have narrow therapeutic window with high inter- and intra-patient variability, thereby the use of either drug needs careful laboratory monitoring and dose adjustment to ensure proper antithrombotic protection while minimizing the bleeding risk. The prothrombin time (PT) and the activated partial thromboplastin time (aPTT) are laboratory tests commonly used to monitor warfarin and heparin, respectively. These two tests depend highly on the combination of reagent and instrument utilized. Results for a single specimen tested in different laboratories are variable; this is mostly attributable to the specific reagents and to a much lesser degree to the instrument used. The PT stands alone as the single coagulation test that has undergone the most extensive attempt at assay standardization. The international normalized ratio (INR) was introduced to ‘‘normalize’’ all PT reagents to a World Health Organization (WHO) reference thromboplastin preparation standard, such that a PT measured anywhere in the world would result in an INR value similar to that which would have been achieved had the WHO reference thromboplastin been utilized. However, INRs are reproducible between laboratories for only those patients who are stably anticoagulated with vitamin K antagonists (VKAs) (i.e., at least 6 weeks of VKA therapy), and are not reliable or reproducible between laboratories for patients for whom VKA therapy has recently been started or any other clinical conditions associated with a prolonged PT such as liver disease, disseminated intravascular coagulation, and congenital factor deficiencies. In contrast to marked progress in the standardization of PT reagents for INR reporting, no standardization system has been globally adopted for standardization of PTT reagents. Recently College of American Pathologists recommend that individual laboratories establish their own therapeutic range by using aPTT values calibrated against accepted therapeutic unfractionated heparin (UFH) levels calibrated against accepted therapeutic UFH levels performing anti-Xa test (which is the most accurate assay for monitoring UFH therapy). Herein, we review recent data on the monitoring of conventional anticoagulant agents. Marked interlaboratory variability still exists for PT, INR, and PTT tests. Further research should be focused on improving the standardization and calibration of these assays.

J Teh Univ Heart Ctr 2 (2010) 57-68

Keywords: Anticoagulants • Heart • International normalized ratio • Partial thromboplastin • Prothrombin time

*Corresponding Author: Mohammad Ali Boroumand, Associate Professor of Pathology, Tehran Heart Center, North Kargar Street, Tehran, Iran. 1411713138. Tel: +98 21 88029231. Fax: +98 21 88029231. E-mail: [email protected].

The Journal of Tehran University Heart Center 57 The Journal of Tehran University Heart Center Mohammadali Boroumand et al

Introduction sensitive to pre-analytic variables related to the quality of patients’ citrated plasma samples than most other laboratory The final effect of the coagulation cascade is to produce assays. Pre-analytic variables have significant impacts on thrombin, which acts on fibrinogen to generate the the coagulation protein-enzymatic reactions occurring in fibrin clot. Thrombin, factor IIa (FIIa), is produced from prothrombin time (PT) and activated partial thromboplastin prothrombin by the action of activated factor X (FXa). time (aPTT) assays. Pre-analytic variables may be due Anticoagulants are frequently prescribed for patients with to phlebotomy (time for tourniquet application optimally a variety of cardiovascular diseases to prevent thrombosis, < 1 minute), collection tubes (standardized tubes and to treat present thrombosis, or to reduce the recurrence of ensure the appropriate blood-to anticoagulant agent ratio), thromboembolic events after a first episode of thrombosis. specimen transportation (as soon as possible), centrifugation For decades, two main classes of anticoagulants have been conditions (time and speed to ensure obtaining platelet poor widely used by cardiologists: orally administered vitamin K plasma < 10,000/ul), and processing.1, 7, 8 Since the accuracy antagonists (VKAs), in particular warfarin, or parenterally of coagulation results is directly associated with the sample administered unfractionated heparin (UFH). Since their quality influenced by these pre-analytic variables, it is introduction into clinical practice in the late 1980s, low- essential to recognize applicable pre-analytic variables molecular-weight heparins (LMWHs) have replaced UFH that could have occurred before actual coagulation testing for many indications; however, UHF remains the drug of beginning at the time of phlebotomy. choice in selected patient groups due to its short half-life, its higher safety among patients with renal failure, and the fact that its anticoagulant effects are typically reversible with Warfarin therapy protamine sulfate.1 Currently available anticoagulants have several drawbacks. Warfarin is the most frequently used VKA and the only UFH and LMWHs, for example, must be given parenterally, oral anticoagulant available in Iran. VKAs act indirectly and which limits their usage in the outpatient setting and causes inhibit the gamma carboxylation of the vitamin K-dependent a rare but potentially fatal complication of heparin-induced coagulation factors II (prothrombin), VII, IX, and X.9 The thrombocytopenia.2 Warfarin offers the convenience of mechanism of the action of warfarin justifies its delayed oral administration but its antithrombotic effect takes hold onset and offset of action; synthesized coagulation factors only during the following three to five days and is subject prior to warfarin intake would continue to function until to interaction with a host of foods and other drugs,3 often degraded and replaced by inadequately carboxylated making anticoagulant control hard to obtain. Finally, warfarin molecules, leading to a slow onset of action whereas the long and heparin have narrow therapeutic window with high inter- half-life of warfarin explains the slow offset of action.9 As and intra-patient variability; thus, the use of either drug needs a result, in most circumstances, warfarin must be initiated careful laboratory monitoring and dose adjustment to ensure in conjunction with a rapidly acting anticoagulant such as proper antithrombotic protection while minimizing the heparin; it also must be discontinued several days before bleeding risk. Therefore, there has been a desire for simple, surgeries to reduce the likelihood of excessive bleeding. safer, fixed dosing new oral anticoagulation drugs with high bioavailability and predictable pharmacokinetics without Laboratory control need for monitoring. There are now several new oral agents targeting multiple points in the coagulation cascade that have The complex pharmacokinetics and pharmacodynamics the potential to alter the nature of anticoagulant therapy.4 of warfarin necessitate the inconvenience of frequent Clinicians should be aware of new developments to familiarize coagulation monitoring and dose adjustment. The PT has themselves with the pharmacokinetic and pharmacodynamic been applied for monitoring warfarin since the introduction characteristics of these agents to appropriately and safely of this drug in 1941. First emerged in the early 1900s, PT is use them. For the moment, cardiologists and other clinicians a commonly used screening test which assesses the global also require to master currently available drugs, realizing the function of the extrinsic clotting pathway, and specific mechanism of action, side effects, and laboratory monitoring cause of abnormal PT needs more specific and specialized to measure their anticoagulant effects. coagulation tests. The PT is performed by adding a reagent More importantly, for achieving best quality, laboratories known as thromboplastin to citrated plasma. Thromboplastin require to concentrate not only on analytical steps but also is a mixture of tissue factor, phospholipid, and calcium ions, on other steps in laboratory testing i.e. pre-analytic and post- and is used to initiate clotting as measured in the PT assay. analytic ones. Analyzing the causes of laboratory errors, Initially, the tests were performed by the manual clotting Plebani and Carraro ascribed 68% of laboratory errors techniques (e.g., tilt-tube method) and reagents prepared by to pre-analytic phase.5 Several other studies have shown individual laboratories, causing a wide variability of results. similar results.5, 6 In vitro coagulation test results are more In the late 1960s, commercially prepared reagents and

58 Monitoring of Anticoagulant Therapy in Heart Disease: Considerations ... TEHRAN HEART CENTER instrumentation for detecting the end point of the PT became PT measured anywhere in the world would result in an INR popular and decreased the degree of variability up to a point. value similar to that which would have been achieved had However, manufacturers' reagents differed from one another, the WHO reference thromboplastin been utilized. Therefore, and the same lot numbers from an individual manufacturer INRs from a given laboratory would be comparable to that revealed similar variability.10 The PT stands alone as the from any other laboratory across the world.19 single coagulation assay which has undergone major efforts In order to account for PT reagent responsiveness, an for standardization. The desire to standardize PTs began in International Sensitivity Index (ISI) is assigned to each the mid-1960s and the process was developed methodically commercial lot number of thromboplastin reagent. The ISI during the 1970s and 1980s.11-15 One must note that the impetus is a calibration parameter that defines the sensitivity of the for PT reagent standardization was to improve therapy for reagent as compared to a WHO International Reference one particular group of patients chronically anticoagulated Preparation (IRP) which, by definition, has an ISI of 1.0. with VKA therapy. This PT standardization was required The more sensitive the reagent, the lower the ISI value.20 due to the narrow therapeutic index of warfarin and the high Highly sensitive thromboplastins (ISI, approximately 1.0) risk of clotting or bleeding because of underdosage and produced by recombinant technology are now available. It overdosage, respectively. An influential study demonstrated was speculated that the use of low-ISI reagent could improve that reduced warfarin dosing and as a result low incidence the laboratory monitoring of oral anticoagulant therapy.21 of bleeding in countries using sensitive thromboplastin Unfortunately; however, low-ISI reagent, either tissue- or reagents dramatically accelerated the international interest to recombinantly-originated, would not improve INR precision standardize PT results and underscored the impetus for the or reproducibility between laboratories.22 The INR is a rapid clinical adoption of the international normalized ratio mathematical conversion of the PT measured as follows: (INR).16 Poller and Taberner17 also brought the importance of both the degree and the nature of this variability into attention in an epidemiologic study which showed that both the rate INR=( Patient PT )ISI of hemorrhagic complications and the dosage of warfarin Mean Normal PT differed in various regions of the world. This difference was attributed to the varied sensitivities of the thromboplastin Where Patient PT = measured prothrombin time, Mean reagents used to perform the PT. Normal PT = geometric mean PT of the reference range, ISI = International Sensitivity Index, specific to each International Normalized Ratio reagent-instrument combination. To determine an INR or establishing a local ISI, geometric, not arithmetic, mean Thromboplastin reagent can be produced by a variety PT is recommended based on the fact that PT values in a of methods, including tissue extraction, tissue culture, and ‘‘normal’’ population are distributed log-normally.23 The molecular biological (genetic) technologies. Thromboplastins mean normal PT is the geometric mean of the PT of almost from various sources and methods of manufacture contain 20 healthy individuals obtained via the blood-collection various concentrations and mixtures of components, and this system in use locally and tested with the same make and result in the fact that thromboplastins vary in responsiveness lot of thromboplastin as that of the ISI in use. Even though to a decrease in the vitamin K-dependent coagulation the INR system has improved PT reporting, it is still related factors. An unresponsive (insensitive) thromboplastin causes to unexpectedly high degrees of inconsistency in values less prolongation of the PT for a given decrease in vitamin between laboratories and even within one laboratory between K-dependent clotting factors than a responsive (sensitive) two different instruments. one. In 1983, the world health organization (WHO) An important source of variation in the INR system is produced a ‘gold standard’ in an attempt to offset variation the manufacturer-assigned ISI value as compared to the in thromboplastin reagent responsiveness and enhance "actual" ISI value according to the local calibration of standardization of PT reporting.18, 19 The INR was rapidly the thromboplastin against an IRP. The INR system of accepted of in Europe and other regions of the world to such PT standardization was originally on the basis of manual an extent that it was nearly universally used by the end of PT determination, and a single ISI value for each batch the 1980s; however, the acceptance in the United States was of thromboplastin reagent was assigned18, 24.Although slower and it came almost a decade later. At the time the INR many laboratories in Iran still detect PT manually, in all was developed, PT reagents in the United States (originated accredited centers worldwide and in ours, the manual PT typically from rabbit) were relatively insensitive to factor has been replaced by fully automated coagulometers , and deficiencies as compared to those consumed in Europe or many studies have revealed that the ISIs of thromboplastin Canada (originated typically from bovine or ovine). The reagents vary based on the type of instrument used.25-28 Some INR was intended to ‘‘normalize’’ all PT reagents to a WHO manufacturers have developed ‘instrument-specific’ ISIs; reference thromboplastin preparation standard, such that a nevertheless, this does not solve the problem completely

The Journal of Tehran University Heart Center 59 The Journal of Tehran University Heart Center Mohammadali Boroumand et al due to many possible instrument/reagent combinations and reproducible INRs > 4.5 are between laboratories, and no because ISIs are often different even among individual types certified or calibrator material exists to detect the accuracy of instruments with the same thromboplastin. Causes for why of INRs more than this value. Also, to our knowledge, there the ISI value of the thromboplastin reagent in a particular is no study on the variability of INRs > 4.5 in association laboratory on a particular instrument may be different from with using different thromboplastin reagents or instruments. the "actual" ISI value (variation in local ISI) include, but are On the other hand, laboratories should report INRs more than not restricted to, imprecision in the assignment of ISI by the 4.5 because international guidelines recommend different manufacturer, incorrect ISI value used by the laboratory in reversal VKA treatments to be undertaken when the INR is the INR calculation, and the local effect of the coagulation > 5 vs. > 9.9 Although the accuracy of INRs reported in this instrument on the ISI. range is not known, clinicians are relying on these values for For various reasons, including the need for manual PT particular therapies for the different ranges. testing with a WHO reference standard thromboplastin, Furthermore, theoretically, determination of the highest and that WHO standard thromboplastin is not readily INR a laboratory could report is dependent on the upper available routinely, ISI calibration by using the WHO- limit of the PT measurable range. Using INR equation recommended procedure is not always possible in routine simply converts the upper limit of the PT measurable range hospital laboratories. Moreover, the WHO procedure into an INR. For instance, if the PT limit is 125 seconds, needs a sample of 60 fresh plasmas from stabilized orally the geometric mean PT is 12.5 seconds and the reagent ISI anticoagulated patients and 20 fresh plasmas from normal is 1, with the highest INR the laboratory could report being individuals. Thus, thromboplastin reagents that are used in (125/12.5)1.0 = 10. If the same measured PT and geometric the laboratory are not calibrated directly against the IRP; mean PT are applicable, but the reagent ISI is 1.4, the highest they are instead calibrated against secondary standards held INR the laboratory could report is (125/12.5)1.4 = 15.9. The by the manufacturers. In fact, these reagents may be three or practice of reporting INRs greater than 10 is questioned and more calibration steps away from the IRP. A definite amount some laboratories simply report their INR at ‘‘greater than of imprecision in the ISI value occurs and is allowed with or equal to 10’’. each calibration. If a thromboplastin reagent is three steps Therefore, it seems vital for any individual laboratory to away from the IRP, up to 15% variation in the ISI value in verify the ISI assignment for its own unique local PT system, comparison with that determined against the IRP may be i.e., thromboplastin/coagulometer combination.30, 31 Although observed. This imprecision in the ISI of the thromboplastin such plasmas are not yet available in Iran, certified plasmas used locally is merely one reason for the difference in the are well-characterized plasmas that have INR values assigned INR system. to them in order to verify that the ISI used locally is correct. Another reason for variation is that different coagulation If the INR values of the certified plasmas determined locally instruments can have significant effects on the ISI of vary from the assigned INR values of these plasmas, this thromboplastins. ISI values are, thus, instrument- and reagent- suggests that local INR calibration is necessary or perhaps a specific. Variation in ISI values between apparently identical different thromboplastin reagent should be applied. coagulation instruments using the same thromboplastin may To overcome the aforementioned restrictions and to provide occur. ISI values are considered "generic" if the ISI determined guidance to both suppliers (manufacturers or reference for a thromboplastin is provided for a group of instruments laboratories) and laboratories as consumers of the certified that use the same general method for end-point detection, plasmas, a working group of the International Society of such as manual, photo-optical, or mechanical methods. This Thrombosis and Haemostasis, Subcommittee on Control of general scheme of assigning an ISI is problematic because not Anticoagulation, has recently produced guidelines on ISI all instruments within a group (i.e., not all optical systems) calibration and INR determination.32 The reader is referred function in the same way. Whenever possible, laboratories to this guideline for a detailed discussion on preparation, should use thromboplastin reagents with instrument-specific certification ,and use of certified plasmas for INR detection ISI values, as this improves INR accuracy. and internal quality control for INR performances .External For a more detailed review of variations in local ISI, quality control for INR performances is also available with a the reader is referred to CLSI document H54 Procedures number of national and international schemes ,including that for Validation of INR and Local Calibration of PT/INR from the WHO. Systems.23 Notably, INR results between instruments or between Is INR reliable in all clinical situations? laboratories show increased variation in values, even as high as 20%, when the therapeutic range of INR (i.e., INR One must keep in mind that INRs are reproducible 2-4.5) is exceeded.29 This variability occurs due to the fact between laboratories for only those patients who are stably that above this value INR, results become very sensitive to anticoagulated (i.e., at least 6 weeks of VKA therapy), and changes in PT as determined in seconds. It is unknown how are not reliable or reproducible between laboratories for

60 Monitoring of Anticoagulant Therapy in Heart Disease: Considerations ... TEHRAN HEART CENTER patients for whom VKA therapy has recently been started or drug therapy, close monitoring of anticoagulation is any other clinical conditions associated with a prolonged PT recommended.42 such as liver disease, disseminated intravascular coagulation, 3. Although biologic variables such as age, gender, and congenital factor deficiencies.31, 33-35 It is specifically genetic differences influence warfarin metabolism and INR suggested that PT numbers, in seconds, be used instead results, these factors are not of clinical importance and are of the INR for reporting PT results for patients with liver only responsible for a total approximate 10% INR coefficient disease.36 of variability (CV).43 4. Clinicians should be aware of pre-analytic variables, PT/INR Point-of-care testing including the system of blood drawing, the tubes and citrate concentrations in use, the amount of blood collected, Considering the large number of patients on chronic the tendency to reject unsuitable specimens, the storage anticoagulant therapy, there has been an increasing interest temperatures, and the times between collection and analysis, to determine the INR at the point of care. The Point of Care as potentially important factors for having a direct influence Testing (POCT) is defined as: "Diagnostic testing performed on the quality of results and on their clinical reliability. near to or at the site of the patient care which results in 5. In contrast to the concept that the PT reagents are only possible change in the care of the patient". As compared to sensitive to VKAs, the well-known interference of heparin testing performed in the clinical laboratory, it would be more with INR has been reported.44, 45 When PT reagents sensitive convenient for patients to perform testing at home or at a to heparin are used in a patient treated concurrently with local community clinic. Such a system would also generally heparin and warfarin, the INR values obtained are falsely provide savings of time and transportation costs. Moreover, elevated. Nonetheless, fortunately, most of the current PT a growing body of evidence has revealed that PT/INR self- reagents are not affected by therapeutic levels of heparin testing is a trusted method for monitoring long-term oral (concentrations of heparin as high as 1 U/ml). anticoagulation therapy, and it improves patient outcomes.37 6. According to the data from the leading manufacturers As the safety and effectiveness of VKAs therapy is and suppliers of reagents-coagulometers in Iran, only a small dependent on having patients within the target INR ranges number of laboratories provide routinely performing and (thromboembolic events rise at INR < 2.0 and bleeding evaluating daily quality control; this may result in variety in risk at INR > 4.5, disproportionately), the POCT must PT results in different laboratories. yield reliable INR values. The INR variability between two 7. One must keep in mind that INRs are reproducible methods, POCT vs. clinical laboratory, is not significantly between laboratories for only those patients who are stably different from previously documented interlaboratory INR anticoagulated (i.e., at least 6 weeks of VKA therapy) and variability, and POCT testing does not impose additional are not reliable or reproducible between laboratories for variability to INR results.9 However, optimal calibration patients for whom VKA therapy has recently been started or and quality control systems as well as reference with expert any other clinical conditions associated with a prolonged PT centers are required to achieve and maintain an acceptable such as liver disease, disseminated intravascular coagulation, quality standard. and congenital factor deficiencies.31, 33-35 It is specifically suggested that PT numbers, in seconds, be used instead What clinicians need to know about PT/INR of the INR for reporting PT results for patients with liver laboratory monitoring disease.36 8. INR is the only important and reliable parameter for the 1. Despite the fact that the PT coagulation test has undergone monitoring of patients who are stably anticoagulated (i.e., at the most extensive attempt for assay standardization, progress least 6 weeks of VKA therapy). in INR standardization of thromboplastins and calibration of coagulometers have not completely eliminated the variability in reagent/instrument within and between laboratories. Antithrombin (AT) therapy: UFH and LMWH A national quality control program and accreditation of laboratories by the Iranian Society of Pathology may solve Heparin products are a heterogeneous mixture of highly the problem in the interpretation of the PT results. negatively charged and sulfated polysaccharide units. The 2. Factors such as dietary vitamin K intake, dietary factors prototype of all heparin derivatives, UFH, has been used as other than vitamin K, alcohol use, concomitantly taken anticoagulant in a wide variety of clinical setting, especially drugs, herbal medicines, or supplements influence warfarin in patients with hematologic and cardiovascular disorders, for metabolism and INR results and are of clinical importance almost a century; the reader is referred to an excellent review for warfarin-treated patients (Table 1).3, 38-41 Therefore, in on this subject for more detail.1 LMWHs came into popular the case of remarkable dietary and lifestyle changes and use in the late 1980s because of their relative superiority to at commencement and discontinuation of concomitant UFH. They are synthetically derived from standard heparin

The Journal of Tehran University Heart Center 61 The Journal of Tehran University Heart Center Mohammadali Boroumand et al

Table1. Overview of interactions of the selected food and drugs with warfarin (Coumadin) Food, drug or drug class Effect Mechanism of action Recommendations Antibiotics Most agents, but specially trimethoprim- ↑ INR Reduction in synthesis of vitamin K by Select alternative antimicrobial therapy sulfamethoxazole, metronidazole, intestinal flora for patients who are taking warfarin ciprofloxacin, clarithromycin , erythromycin

Rifampin ↓ INR Induction of cytochrome P450 isoenzyme 2C9 Select alternative antibiotics

Antifungals

Fluconazole, miconazole ↑ INR Inhibition of cytochrome P450 isoenzyme 2C9 Select alternative antifungals Acetaminophen ↑ INR Direct interference with vitamin K cycle Prescribe lowest possible dosage of acetaminophen and monitor INR Antiplatelet agents Acetylsalicylic acid (ASA), ↑ INR Altering platelet function Limit the dosage (e.g., ASA<100 mg/ clopidogrel, ticlopidine day) and monitor INR NSAIDs ↑ INR Direct mucosal injury, If concomitant use is necessary, use Altering platelet function ? a cyclooxygenase-2 inhibitor and monitor INR Antidepressants

SSRIs ↑ INR Interference with primary hemostasis; some Select alternative antidepressants such as fluoxetine also inhibit cytochrome P450 isoenzyme 2C9 Levothyroxine ↑ INR Increasing the catabolism of clotting factors Prescribe lowest possible dosage of levothyroxine and monitor INR Alternative remedies Gingko biloba, dong quai, fenugreek, ↑ INR Unknown Avoid concomitant use chamomile St. John’s wort ↓ INR Unknown Avoid concomitant use

Vitamin K containing food/supplements

Leafy vegetables, certain legumes, ↓ INR Main dietary source of phylloquinone Control dietary vitamin K content

cauliflower, and some vegetable oils (e.g., (vitamin K1) rapeseed and soyabean )

Liver of animals and some fermented foods ↓ INR Main dietary source of menaquinone Control dietary vitamin K content

including cheese (vitamin K2)

Foods with antiplatelet effects

Garlic, and onion ↑ INR Antiplatelet effects? Control dietary intake

Grapefruit ↑ INR Inhibition of cytochrome P450 isoenzyme 1A2 - and 3A4

Cranberry ↑ INR Unknown -

Alcohol intake Acute binges (>3 drinks daily) ↑ INR Induction of the hepatic metabolism of Preferably avoid alcohol consumption anticoagulants? or limit intake to 1-2 drinks per day.

Chronic alcohol ingestion ↓ INR potential to increase the clearance of warfarin Preferably avoid alcohol consumption or limit intake to 1-2 drinks per day. Coenzyme Q10 (an herbal supplement) ↓ INR Having chemical structure similar to vitamin K Either be avoided or used consistently while on warfarin therapy Caffeinated beverages Cola, coffee, tea, hot chocolate, chocolate milk ↑ INR Unknown These foods should be avoided or limited NSAIDS, nonsteroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors

62 Monitoring of Anticoagulant Therapy in Heart Disease: Considerations ... TEHRAN HEART CENTER by either filtration or controlled depolymerization, which and AT, but too short to bridge to and bind thrombin, and yields chains with lower mean molecular weights. Standard their activity is predominantly directed at the inactivation heparins (UFH preparations) have molecular weights of of FXa.1 Therefore, UFH has roughly equivalent AT and 5,000 to 30,000 daltons, while LMWHs weigh ranging from anti-Xa effect, whereas the AT activity of each individual 1,000 to 10,000 daltons. commercially available LMWH products is dependent on The longer chain lengths and the dense negative the relative proportion of molecules containing 18 or more charge surrounding the molecules result in considerable monosaccharides. nonselective binding of UFH to cells and proteins, which reduces its anticoagulant effect. UFH is also limited by Laboratory monitoring of UFH inter-patient variability, unstable pharmacokinetics, and potential side effects such as hemorrhage and heparin- The aPTT is laboratory test commonly used to monitor induced thrombocytopenia.46 LMWH interacts less readily UFH anticoagulant effect. Nearly four decades ago, Basu with platelet factor 4, decreasing the risk of heparin-induced et al. at McMaster University51 in a retrospective analysis thrombocytopenia.47 of patient data suggested that an aPTT equal to 1.5 to 2.5 Based on these limitations, UFH therapy is usually times the mean control could reduce the risk of recurrent restricted to the hospital setting, where it can be laboratory thromboembolism. A subsequent experimental study by the monitored to guide its dosage properly. As compared to UFH, same group (McMaster group) on a rabbit model, using the the products of LMWH bind significantly less to plasma same aPTT reagents of thrombus extension, supported the 1.5 proteins, have enhanced bioavailability, interact less with to 2.5 therapeutic range.52 Based on these studies, an aPTT platelets, and yield a predictable pharmacokinetics. LWMH is ratio (measured by dividing the reported therapeutic range administered typically by subcutaneous abdominal injections of aPTT by the control value for the reagent) of 1.5 to 2.5 without need for laboratory monitoring; it can, therefore, was widely adopted as the UFH therapeutic range. Still, the be administered either in-hospital or out of the hospital. correlation of this therapeutic PTT values with the clinical However, these drugs have their own shortcomings, such that outcome is uncertain because it has not been validated in the anticoagulant effects of LMWHs cannot be sufficiently prospective studies and due to the fact that over the years the neutralized48 and that it is currently impossible to monitor new aPTT reagents and instruments have been available. their serum levels by point-of-care clinical methods. Given the lack of monitoring and blood level control, LMWHs are The aPTT and clinical outcome unsuitable for patients in emergency situation such as those with acute coronary syndrome taking LMWHs who are at Early clinical studies supported a relationship between an high risk of bleeding complications after the occurrence of aPTT ratio< 1.5 within the 24 or 48 hours of starting UFH and an urgent surgical intervention.49 recurrent thrombosis.53-55 Despite the fact that the data were In contrast to direct thrombin inhibitors such as hirudin less secure, the relationship between UFH concentrations which bind directly to thrombin and are able to inactivate more than 0.7 or 0.8 anti-Xa IU/ml with bleeding was also clot-bound thrombin,50 both UFH and LMWH inhibit reported.56, 57 Consequently, it seemed that the aPTT had a thrombin formation through binding to AT, a naturally well-defined association with clinical outcome (recurrent occurring plasma protein with anticoagulant properties. thrombosis and bleeding). However, the heparin/AT complex does not effect on clot- However, in later prospective studies comparing UFH with bound thrombin; instead, by inducing conformational LMWH in the treatment of thrombotic disease, it became changes in the AT molecule, heparin accelerates AT ability to clear that UFH was effective for the treatment of venous inactivate thrombin and factor Xa and dramatically increase thromboembolism, only if the therapy was commenced with the anticoagulant activity of AT. In other words, coagulation is an proper dosage (initiated as a bolus of at least 5,000 IU, suppressed by AT-dependent inactivation of serine proteases followed by a continuous intravenous infusion of at least involved in the coagulation cascade-particularly thrombin 30,000 IU/24 h).58-60 In addition, as various aPTT reagents (FIIa) and activated factor X (FXa). The ability of heparin were used to monitor the UFH dose, the anticoagulant effects to bind to FXa and FIIa is directly associated with the size related to a target aPTT ratio of 1.5 to 2.5 would have varied of the heparin. Any size heparin will bind to AT to inactivate markedly among studies.61 Accordingly, to re-examine Xa, but in order to inactivate thrombin the heparin molecules the relationship between the risk of recurrent venous with at least 18 polysaccharide units are only large enough thromboembolism and the aPTT response to adequate dose to bridge and bind both AT and thrombin simultaneously. It of UFH, a meta-analysis was performed on five studies that is believed that merely one third of the administered dosage provided data in this regard that showed the total recurrence of UFH binds all three factors to exert an anticoagulant rate was 6.3% in patients whose aPTT ratios were < 1.5 effect.1 LMWHs with a polysaccharide chain of shorter within the first 24 to 48 hours as compared to 7% in patients than 18 monosaccharides are large enough to bind both FXa whose aPTT ratios were higher than the lower limit of the

The Journal of Tehran University Heart Center 63 The Journal of Tehran University Heart Center Mohammadali Boroumand et al therapeutic range; thus, this result brought into question the guidelines by both the College of American Pathologists findings of early studies. (CAP)7 and the American College of Chest Physicians,1 It is not surprising for the aPTT to be of limited value which recommended a 0.3 to 0.7 IU/ml therapeutic range for for predicting clinical outcome in patients receiving UFH UFH using an anti-Xa assay. However, by contrast to the because it has been estimated that below 50% of the marked progress in the standardization of PT reagents for variation in the UFH serum concentration is reflected by the INR reporting, prolonged efforts by the medical community aPTT,7, 62, 63 with the remaining variability explained by the to establish a method of standardization for PTT reagents variables that are independent of the anticoagulant effect of has achieved little success and no standardization system has UFH, including pre-analytic variables such as the sample been globally adopted thus far.1, 66-69 collection methods and processing; analytic variables, in In an attempt to improve the precision of the assay, the most particular the combination of the reagent and instrument recent CAP recommendations for the laboratory monitoring used for calculating the aPTT; and biologic variables, which of UFH using the aPTT are that individual laboratories include clotting factor levels and variables that influence establish their own therapeutic range using aPTT values the pharmacokinetics of UFH and the dose-response of the calibrated against accepted therapeutic UFH levels using the aPTT to UFH.1, 7 Thus, the dosage of UFH seems to be more anti-Xa test (which is the most accurate assay for monitoring reliable than the aPTT in predicting clinical efficacy. UFH therapy). To produce a therapeutic range for the first time, the CAP The aPTT accuracy and standardization for reagents recommends firstly a collection of plasma samples from among laboratories patients receiving IV heparin therapy (ex vivo samples) and secondly analysis via the aPTT and heparin assay.70 A In 1953, the aPTT test was first introduced as a two-stage therapeutic aPTT range can be measured by determining assay to differentiate hemophilic from normal plasma. The the PTT values corresponding to anti-Xa levels of 0.3 and test was modified to a one-stage assay in 1958 and was 0.7 IU/ml. Changes in reagent lots and/or instrumentation further modified, as the test which is used today, in 1961. To should be accompanied by a revalidation of the therapeutic perform the test, a surface activator and diluted phospholipid range. Laboratories may consider repeating the same are mixed into citrated plasma, after which calcium is added validation process or analyzing and comparing the results and the clotting time is measured. The aPTT is primarily with the original PTT reagent lot (or method) versus the a measure of the function of the intrinsic and common new PTT lot on the samples from patients administered IV pathways of coagulation. The test is regularly used for the heparin therapy to determine clinically equivalent response. monitoring of treatment with UFH. The mean difference between the two lots must not be The McMaster group suggested a PTT ratio of 1.5 to 2.5 more than 7 seconds. Because each subsequent reagent lot by using their aPTT reagent matched to a heparin level of is compared against the preceding one, laboratories must 0.2 to 0.4 IU/ml as measured by a protamine sulfate titration monitor the total of differences from the reagent lot used in assay.64 At the time of this study, the wide variability in the original validation to be certain that the cumulative mean different aPTT reagents and test methods was not considered. PTT difference is not over 7 seconds.7 Be that as it may, with the availability of further aPTT If this type of standardization cannot be feasible, the use of reagents (and coagulometers), it became clear that each an aPTT ratio ranging from 2.0 to 3.0 or 3.5 may be preferable reagents demonstrated different sensitivities for the PTT to with most modern aPTT reagents and instruments in use than heparin; and as was mentioned before, the use of aPTT is an aPTT ratio of 1.5 to 2.5, which frequently demonstrates complicated by the variable response of various methods inadequate UFH concentrations.61, 71 and commercially available reagents to heparin (analytic Direct measures of UFH concentration with enzymatic variables).65 In other words, PTT therapeutic ranges derived assays such as the anti-Xa assay are of interest because these from heparin levels of 0.2 to 0.4 IU/ml via the protamine assays are not influenced by most pre-analytic variables (e.g. sulfate assay are reagent specific. under-filled collection tube which is a common problem) Once it was proven that the aPTT failed to accurately and biologic variables that interfere with the aPTT and may reflect the plasma heparin level, efforts focused on improving be suitable for automation but are nonetheless complex, the assay precision by creating reagent-specific therapeutic expensive, and reagent-intense. Furthermore, there are ranges. The use of therapeutic ratios was widely supplanted limited published data on the safety and effectiveness of by PTT therapeutic ranges calibrated using anti-Xa heparin anti-Xa assays for a routine monitoring and managing of measurements. On account of the fact that the data from the UFH therapy. One recent study demonstrated that there were McMaster group studies revealing a heparin level of 0.2 patients on intravenous UFH therapy in a medical intensive to 0.4 IU/ml via the protamine assay were equivalent to a care unit in whom no measurable heparin levels by 3 different level of 0.35 to 0.70 IU/ml by a factor Xa heparin assay,64 anti-Xa assays were identified.72 this association formed the basis for the development of

64 Monitoring of Anticoagulant Therapy in Heart Disease: Considerations ... TEHRAN HEART CENTER

Monitoring LMWH: When and how? them.78-80 In addition, the results of LMWH in a single anti-Xa assay vary, including marked variability from LMWHs have better bioavailability, substantially longer various LMWH lots from an individual manufacturer.81 half-life, dose-independent clearance, and decreased Considering the composition of the varying commercial protein-binding than UFH and these are factors that render LMWHs and related variable performance in laboratory their anticoagulant response more predictable. These assays, laboratories need to calibrate the chromogenic anti- characteristics obviate the need for laboratory monitoring for Xa assays against an international standard when using the the vast majority of the cases on LMWH therapy. However, a new dispensed LMWH.73 There is limited evidence that a in special groups for whom it is desirable to measure the single LMWH calibration curve can be used for a variety of circulating level of LMWH, including pregnant patients different LMWHs.82 (whose weight is constantly changing); those with renal Finally, it is notable that there is no readily available bedside failure; and neonates or other low-weight patients for whom assay such as the application of the Activated Clotting Time weight-based dosing may not be accurate, anti-Xa activity (ACT) with UFH to evaluate the anticoagulant effect of assays are recommended.73 The aPTT is not practical for LMWHs. This makes the safety and efficacy of the utility monitoring patients receiving LMWH, because LMWHs of LMWHs problematic, particularly in the catheterization specifically inhibit factor Xa, and to a lesser degree thrombin laboratory. as compared to standard heparin74, 75 and as a result have only little if any effect on the aPTT. Moreover, the anti-thrombin Role of Activated Clotting Time (ACT) in UFH activity of LMWH is much less than its anti-factor Xa activity monitoring and the aPTT prolongation largely depends on low thrombin activity.76 Hence, only anti-Xa activity assays can be used to The ACT was first introduced in 1966 and has been monitor LMWH. demonstrated to be insensitive to lower UFH concentrations Anti-Xa activity assays detect the amount of anti-Xa activity ever since.83 The ACT is essentially a POCT of coagulation in a sample. The functional activity of heparin (any UFH, that is used to monitor the anticoagulant effect of UFH on- LMWH or fondaparinux) is evaluated through adding enough site in patients when higher-intensity anticoagulation is antithrombin (AT) to bind all the available heparin and then needed. The test has several limitations, including the fact the ability of the AT-heparin complex to neutralize activated that it is not as accurate as other assays and that clotting clotting factors, FXa ,or FIIa is tested in a chromogenic or times achieved by the various activated clotting time devices clotting assay.51 Between two major methodologies, clot- cannot be used interchangeably.7, 84 The fact that the ACT, based versus chromogenic substrate assays, chromogenic alongside UFH, is prolonged by antiplatelet agents including anti-Xa activity assays are the methodology of choice and abciximab has supported the limited specificity of this test.85 recommended for LMWH monitoring.73 The cost of the anti- In spite of these limitations, the ACT is common in clinical factor Xa assay is about three times the cost of aPTT, but it is practice, particularly when evaluating anticoagulation related available for monitoring LMWH and UFH and is much less to interventional cardiology procedures and cardiopulmonary costly and easier to perform than protamine sulfate titration. bypass surgery. Errors in ACT measurements can also There are other clinical situations in which the determination occur due to technical causes; thus, standardization or of plasma anti-factor Xa activity may be more appropriate calibration of the ACT is required.86 To improve test results as the monitoring test; for instance, the actual concentration and concomitantly physicians’ reliance on the ACT, quality of heparin is hard to measure in patients on heparin therapy control systems are required to be carefully constructed and in whom the aPTT is raised above 180 s - often related to tracked. The control program must be easy to use and precise underlying liver disease and not related to heparin therapy. and be utilized in conjunction with very reliable, stable, and Among patients with an aPTT > 180 s, patients with an anti- reproducible control material; if the control is not within Xa activity < 1 IU/ml in comparison with those with an acceptable range, patient testing must not be performed. anti-factor Xa activity > 1 IU/ml have a significantly lower bleeding risk (23% versus 57%).77 The second example is in Summary of what clinicians need to know about heparin resistance once high doses of UFH fail to elevate the aPTT laboratory monitoring aPTT into the therapeutic range. In this situation, the anti- factor Xa assay is a safe and effective method for tracking 1. Like PT, aPTT results are highly dependent on the the patient, rather than further increasing the dosage in combination of reagent and instrumentation and type response to unchanged aPTT value, which adds to the risk of heparin brand used. Thus, depending on the reagent/ of bleedings.64 instrument and commercial preparations of heparin used, There are many different commercially available anti-Xa each laboratory needs to standardize and calibrate its unique activity assays which unfortunately are not standardized, therapeutic dose for heparin therapy. and considerable interassay result variability exists among 2. It is noteworthy that according to the leading importing

The Journal of Tehran University Heart Center 65 The Journal of Tehran University Heart Center Mohammadali Boroumand et al firms and suppliers of reagents-coagulometers in Iran, almost of these approaches would have the effect of raising the none of the laboratories in the country requests control imprecision of the estimated therapeutic range. Anti-Xa reagents of the ACT test, indicating that there is a lack of assays represent an attractive surrogate for the PTT in order adequate control program for this test. to track UFH; limited outcomes and high cost, however, 3. There are limited outcomes data with regard to anti-Xa restrict the utilization. heparin monitoring; however, as the tariff for this test is not Clinicians should bear in mind that a well-known too high in Iran, on the basis of the present outcomes and interference of heparin with INR has been reported. On the data currently available it is recommended that laboratories other hand, warfarin may increase the aPTT. Consequently, switch to anti-Xa heparin monitoring on most occasions. either of these tests may overestimate the effect of continuing 4. Warfarin may increase the aPTT; thereby collecting therapy after the discontinuation of the other medication. samples from patients taking warfarin and heparin simultaneously should be used only if the INR is < 1.3.87 References

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Ginsberg J, Turpie AG, Demers C, Kovacs M. A comparison of patients on therapeutic low molecular weight heparin (dalteparin) low-molecular-weight heparin administered primarily at home with or unfractionated heparin. Clin Lab Haematol 1999;21:55-60. unfractionated heparin administered in the hospital for proximal 79. Kitchen S, Iampietro R, Woolley AM, Preston FE. Anti Xa deep-vein thrombosis. N Engl J Med 1996;334:677-681. monitoring during treatment with low molecular weight 60. No authors listed. Low-molecular-weight heparin in the treatment heparin or danaparoid: inter-assay variability. Thromb Haemost of patients with venous thromboembolism. The Columbus 1999;82:1289-1293. investigators. N Engl J Med 1997;337:657-662. 80. Kitchen S, Theaker J, Preston FE. Monitoring unfractionated heparin 61. Raschke R, Hirsh J, Guidry JR. Suboptimal monitoring and therapy: relationship between eight anti-Xa assays and a protamine dosing of unfractionated heparin in comparative studies with low- titration assay. Blood Coagul Fibrinolysis 2000;11:137-144. molecular-weight heparin. Ann Intern Med 2003;138:720-723. 81. Gosselin RC, King JH, Janatpour KA, Dager WE, Larkin EC, 62. van den Besselaar AM, Sturk A, Reijnierse GL. Monitoring of Owings JT. Variability of plasma anti-Xa activities with different unfractionated heparin with the activated partial thromboplastin lots of enoxaparin. Ann Pharmacother 2004;38:563-568. time: determination of therapeutic ranges. Thromb Res 82. Robertson JD, Brandao L, Williams S, Ing C, Chan AK. Use 2002;107:235-240. of a single anti-Xa calibration curve is adequate for monitoring 63. Rapaport SI, Vermylen J, Hoylaerts M, Saito H, Hirsh J, Bates enoxaparin and tinzaparin levels in children. Thromb Res S, Dahlback B, Poller L. The multiple faces of the partial 2008;122:867-869. thromboplastin time APTT. J Thromb Haemost 2004;2:2250-2259. 83. Despotis GJ, Summerfield AL, Joist JH, Goodnough LT, Santoro 64. Levine MN, Hirsh J, Gent M, Turpie AG, Cruickshank M, Weitz J, SA, Spitznagel E, Cox JL, Lappas DG. Comparison of activated Anderson D, Johnson M. A randomized trial comparing activated coagulation time and whole blood heparin measurements with thromboplastin time with heparin assay in patients with acute laboratory plasma anti-Xa heparin concentration in patients having venous thromboembolism requiring large daily doses of heparin. cardiac operations. J Thorac Cardiovasc Surg 1994;108:1076-1082. Arch Intern Med 1994;154:49-56. 84. Avendano A, Ferguson JJ. Comparison of Hemochron and 65. Kitchen S, Preston FE. The therapeutic range for heparin therapy: HemoTec activated coagulation time target values during relationship between six activated partial thromboplastin time percutaneous transluminal coronary angioplasty. J Am Coll Cardiol reagents and two heparin assays. Thromb Haemost 1996;75:734-739. 1994;23:907-910. 66. Brandt JT, Triplett DA. Laboratory monitoring of heparin. Effect 85. Ammar T, Scudder LE, Coller BS. In vitro effects of the platelet of reagents and instruments on the activated partial thromboplastin glycoprotein IIb/IIIa receptor antagonist c7E3 Fab on the activated time. Am J Clin Pathol 1981;76:530-537. clotting time. Circulation 1997;95:614-617. 67. Brandt JT, Arkin CF, Bovill EG, Rock WA, Triplett DA. Evaluation 86. Jobes DR, Ellison N, Campbell FW. Limit(ation)s for ACT. Anesth of APTT reagent sensitivity to factor IX and factor IX assay Analg 1989;69:142-144. performance. Results from the college of American pathologists 87. Kearon C, Johnston M, Moffat K, McGinnis J, Ginsberg JS. Effect survey program. Arch Pathol Lab Med 1990;114:135-141. of warfarin on activated partial thromboplastin time in patients 68. Hales SC, Johnson GS, Wagner D. Comparison of six activated receiving heparin. Arch Intern Med 1998;158:1140-1143. partial thromboplastin time reagents: intrinsic system factors’ sensitivity and responsiveness. Clin Lab Sci 1990;3:194-196. 69. Spinler SA, Wittkowsky AK, Nutescu EA, Smythe MA. Anticoagulation monitoring part 2: unfractionated heparin and low- molecular-weight heparin. Ann Pharmacother 2005;39:1275-1285. 70. College of American Pathologists 2007 Hematology and Coagulation Laboratory Accreditation Checklist. http://www.cap. org/apps/docs/laboratory_accreditation/checklists/hematology_ coagulation_sep07.pdf (22 January 2010). 71. Bates SM, Weitz JI, Johnston M, Hirsh J, Ginsberg JS. Use of a fixed activated partial thromboplastin time ratio to establish a therapeutic range for unfractionated heparin. Arch Intern Med 2001;161:385-391. 72. Lehman CM, Rettmann JA, Wilson LW, Markewitz BA. Comparative performance of three anti-factor Xa heparin assays in patients in a medical intensive care unit receiving intravenous, unfractionated heparin. Am J Clin Pathol 2006;126:416-421. 73. Laposata M, Green D, van Cott EM, Barrowcliffe TW, Goodnight SH, Sosolik RC. College of American pathologists conference XXXI on laboratory monitoring of anticoagulant therapy: the clinical use and laboratory monitoring of low-molecular- weight heparin, danaparoid, hirudin and related compounds, and argatroban. Arch Pathol Lab Med 1998;122:799-807. 74. Rosenberg RD. Biochemistry and pharmacology of low molecular weight heparin. Semin Hematol 1997;34:2-8. 75. Fenton JW, Ofosu FA, Brezniak DV, Hassouna HI. Thrombin and antithrombotics. Semin Thromb Hemost 1998;24:87-91. 76. Houbouyan L, Boutiere B, Contant G, Dautzenberg MD, Fievet P, Potron G, Vassault A, Gourmelin Y. Validation protocol of analytical hemostasis systems: measurement of anti-Xa activity of low-molecular-weight heparins. Clin Chem 1996;42:1223-1230. 77. Haliassos A, Melita-Manolis H, Aggelaki D, Tassi D, Terzoglou G. Use of anti-X a activity as a marker for heparin-induced bleeding in patients with APTT > 180 s. Clin Chem 1997;43:1781-1782. 78. Kovacs MJ, Keeney M, MacKinnon K, Boyle E. Three different chromogenic methods do not give equivalent anti-Xa levels for

68 TEHRAN HEART CENTER

Original Article Is the Peak-to-Mean Pressure Gradient Ratio Useful for Assessment of Aortic Valve Prosthesis Obstruction?

Maryam Esmaeilzadeh, MD, FACC, FCAPSC*, Ahmad Mirdamadi, MD, Mozhgan Parsaee, MD, Anita Sadeghpour, MD, FASE, FACC, Majid Maleki, MD, FACC, FCAPSC, Hooman Bakhshandeh Abkenar, MD

Echocardiography Research Center of Shaheed Rajaei Cardiovascular Medical and Research Center, Tehran, Iran.

Received 11 August 2009; Accepted 28 January 2010

Abstract

Background: The evaluation of prosthetic valves is very difficult with two-dimensional transthoracic echocardiography alone. Doppler and color flow imaging as well as transesophageal echocardiography are more reliable to detect prosthetic valve dysfunction. However, Doppler study sometimes tends to be misleading due to the load-depending characteristics of peak and mean pressure gradients. The peak-to-mean pressure decrease ratio is a load-independent measure, which was previously used for the detecting and grading of aortic valve stenosis. We assessed the usefulness of this method for the evaluation of aortic valve prosthesis obstruction. Methods: One hundred fifty-four patients with aortic valve prostheses were included in this study. Transthoracic and transesophageal echocardiographic examinations were performed in all the patients. Peak velocity and velocity time integral of the aortic valve and left ventricular outflow tract, peak and mean aortic valve pressure gradients, peak-to-mean pressure gradient ratio, and time velocity integral (TVI) index were measured. Results: There was a significant relation between the TVI index (p value < 0.001) and aortic prosthesis obstruction. A TVI index < 0.2 had a sensitivity of 71% and specificity of 100% for the detection of aortic valve prosthesis obstruction. However, no significant relation was found between the peak-to-mean pressure ratio and aortic valve prosthesis obstruction (p value = 0.09). Conclusion: Although the peak-to-mean pressure gradient (PG/MG) ratio is a simple, quick, and load-independent method which may be useful for the grading of aortic valve stenosis, it is poorly associated with aortic valve prosthesis obstruction. The TVI index is a useful measure for the detection of aortic prosthesis obstruction. J Teh Univ Heart Ctr 2 (2010) 69-73

Keywords: Aortic valve • Diagnosis • Echocardiography, Doppler

Introduction The incidence of prosthetic valve obstruction has been estimated at 0.1% to 0.4% per year, depending on the The evaluation of prosthetic valves via two-dimensional valve size, type, and location as well as the adequacy (2D) transthoracic echocardiography (TTE) alone is of anticoagulation.1 Whereas the obstruction of a mitral very difficult. Doppler and color flow imaging as well as mechanical prosthesis is caused more frequently by transesophageal echocardiography (TEE) are more reliable thrombus, the obstruction of an aortic mechanical prosthesis to detect prosthetic valve dysfunction. is created more frequently by pannus formation.2 When a

*Corresponding Author: Maryam Esmaeilzadeh, Associate Professor of Cardiology, Echocardiography Research Center of Shaheed Rajaei Hospital, Tehran, Iran. 199691115. Tel: +98 21 23921. Fax: +98 21 22055594. E-mail: [email protected].

The Journal of Tehran University Heart Center 69 The Journal of Tehran University Heart Center Maryam Esmaeilzadeh et al prosthetic valve becomes obstructed, the motion of the disk, 2D, M-mode, pulsed Doppler, continuous, and color ball, or leaflets decreases. Be that as it may, it is difficult to studies were performed in all the patients in accordance visualize and yet more difficult to quantify the restriction of with the recommendations of the American society of the excursion with TTE.3 echocardiography. TEE may be essential in the evaluation of mitral and Pulsed wave signal of the left ventricular outflow tract tricuspid valves, but it is relatively low sensitive for detecting (LVOT) and continuous wave signal of the aortic valve (AV) the dysfunction of aortic prostheses.3 Gross abnormalities prosthesis were obtained using the apical 5-chamber view, such as large thrombi or vegetations can be identified with the the sample volume placed 5 mm below the aortic using 2D echocardiography, but assessing the functional annulus. significance of such changes is difficult.4 Thus, most of the The following echocardiographic variables were measured diagnostic information related to aortic prostheses depends and calculated from the average of 3-5 consecutive beats: 4 on a thorough and quantitative Doppler study. 1. Peak velocity (Vmax) 2 The range of normal Doppler values depends primarily on 2. Peak gradient (PG) was calculated as 4 × (Vmax) and the size of the prosthesis.4 mean gradient (MG) with the algorithm incorporated to the It is important to remember that increased flow velocity ultrasound equipment (Figure 1) itself does not always indicate prosthetic obstruction. The 3. Time velocity integral (TVI) velocity can be increased without stenosis in a high output 4. TVI index (LVOTTVI / AV TVI) state or presence of severe prosthetic regurgitation. TEE: aortic valve prosthesis was evaluated on 0, 45, and The ratio of the left ventricular outflow tract (LVOT) to 120 degrees in the mid esophageal and in deep transgastric aortic valve prosthesis (AVP) velocity or time velocity integral view for the detection of the thrombus or pannus formation. (TVI) is helpful in differentiating increased flow velocity across an aortic prosthesis due to prosthetic obstruction (the ratio < 0.2) from increased velocity due to other causes (the ratio remains normal > 0.3).3 Recently, Chambers et al. reported that the relation of trans aortic peak (PG) and mean gradients (MG), i.e. the PG/MG ratio, is a useful parameter to evaluate the severity of aortic stenosis.5 The purpose of this study was to evaluate the statistical efficacy (sensitivity, specificity, positive and negative predictive values, and accuracy and probability rates in case of a positive or negative result) of the PG/MG ratio to predict aortic valve prosthesis obstruction and to compare it with the TVI ratio.

Methods

From February 2007 to January 2008, we retrospectively Figure 1. Deep transgastric view of an obstructed aortic prosthesis. analyzed the Doppler echocardiograms of 154 consecutive Continuous Doppler echocardiography showed significant increase in peak patients (mean age: 49 years, range: 18-79 years, 52% male) and mean pressure gradient through the aortic prosthesis with aortic valve prosthesis evaluated for several clinical AV peak V, Aortic valve peak velocity; Peak PG, Peak pressure gradient; indications. Mean PG, Mean pressure gradient; AV VTI, Aortic valve velocity time The exclusion criteria were inadequate echocardiographic integral images, rhythm other than sinus rhythm, paravalvular regurgitation, aortic bioprosthesis, and significant mitral Cinefluoroscopy was done in all the patients to assess valve disease. the valve leaflet (s) motion. Cinefluoroscopy is superior Echocardiographic examinations were performed with the to echocardiography in identifying disc motion, whilst subject in the left lateral decubitus position. Commercially Doppler study allowed the measurement of gradients and available ultrasonography instruments equipped with 2.0 to areas. A significant increase in trans-prosthesis pressure 3.5-MHZ transthoracic probes and 2.0 MHz “non-imaging” gradient along with a decreased TVI index through Doppler (Pedoff) transducers were utilized from the left and right echocardiography and decreased leaflet (s) motion (more parasternal, apical, suprasternal, and sub-xyphoid windows than 25 ± 5 degrees)6 using cinefluoroscopy was defined as (GE Medical Systems, Vivid 3). TEE was performed using prosthetic valve obstruction. a commercial 5.0-/3.5-MHz multi-plane probe. Complete All the data are expressed as mean ± SD. Crude associations

70 Is the Peak-to-Mean Pressure Gradient Ratio Useful for Assessment ... TEHRAN HEART CENTER between the PG/MG ratio and the other variables were years). determined via the independent sample t-test and Mann- TEE showed thrombus, pannus, and mixed thrombus with Whitney U test for the categorical data and bivariate pannus in 26.7%, 31%, and 12% of the patients, respectively. linear regression models for the interval data. Multivariate Nonetheless, cinefluoroscopy revealed decreased leaflet analysis was performed using a multiple linear regression motion only in 7.8% of the patients. model to determine adjusted associations. A p value < 0.05 There was an inverse correlation between the PG/MG ratio was considered statistically significant. SPSS 15 (SPSS and MG (β = − 0.010, r = − 0.54, p value < 0.001), but there Corporation, Chicago, Illinois, USA) was used for statistical was no correlation between the PG/MG ratio and the TVI analysis. index (β = 0.09, r = 0.053; p value = 0.52). Additionally, there was a significant negative correlation between the PG/

MG ratio and the Vmax. (β = − 0.03, r = − 0.165, p value = Results 0.04). The logistic regression analysis showed no significant The clinical and echocardiographic characteristics of the relation between the peak-to-mean pressure ratio and aortic patients are summarized in Tables 1 and 2. Time to valve valve prosthesis obstruction (B = 1.25, p value = 0.09, OR replacement surgery was 10±8 years (range from 1 to 36 = 0.29, 95% CI: 0.07-1.23, but a significant relation was

Table 1. Patients’ characteristics and their comparisons in two groups of patients (n=154) AVP Obstruction Total p value (n=154) Yes No (n=71) (n=83) Age (y) (mean±SD) 49±13.0 48±13.9 50±13.6 0.364 Female/Male 75/79 42/29 33/50 0.020 Time from operation (y) (mean±SD) 10±8.0 13.3±7.2 7±6.8 <0.001 Type of mechanical valve (%) 0.011 Mono-leaflet 41 (26.6) 21 (29.6) 12 (14.5) Bi-leaflets 113 (73.4) 37 (70.4) 60 (85.5) Referral reason (%) 0.019 AVR 63 (40.9) 22 (31) 41 (49.4) AVP malfunction 52 (33.8) 29 (40.8) 23 (27.7) Infective endocarditis 13 (8.4) 3 (4.2) 10 (12.1) Cardiac source of systemic emboli 22 (14.2) 15 (21.2) 7 (8.4) Syncope 4 (2.7) 2 (2.8) 2 (2.4) LVEF (%) (mean±SD) 45±10.0 48±9.8 43±12.5 0.072 AVR, Aortic valve replacement; AVP, Aortic valve prosthesis; LVEF, Left ventricular ejection fraction

Table 2. Patients' Doppler echocardiographic findings* AVP Obstruction Total p value (n=154) Yes No (n=71) (n=83) AV peak velocity (m/s) 2.90±1.5 3.40±2 2.50±0.60 <0.01 AV peak PG (mmHg) 35±20 44.5±22.8 27±12.70 <0.01 AV mean PG (mmHg) 20±14 25.2±14.2 16±13 <0.01 AV TVI (cm) 50.70±18 58.3±19.9 43.90±13.70 <0.01 LVOT TVI (cm) 20±7 20±7 20.20±7.10 0.79

LVOT TVI / AV TVI 0.43±0.15 0.37±0.14 0.48±0.15 <0.01 Normally functioning AV 0.44±0.15 0.38±0.14 0.48±0.15 <0.01 Abnormal motion of AV 0.33±0.13 0.30±0.10 0.51±0.15 0.18 PG/MG ratio 1.80±0.27 1.80±0.19 1.90±0.32 0.26 Normally functioning AV 1.80±0.33 1.80±0.17 1.90±0.32 0.85 Abnormal motion of AV 1.80±0.18 1.80±0.26 1.80±0.35 0.50 *Data are presented as mean±SD AV, Aortic valve; PG, Pressure gradient; TVI, Time velocity integral; LVOT, Left ventricular outflow tract; PG/MG ratio, The ratio of peak gradient to mean gradient; AVP, Aortic valve prosthesis

The Journal of Tehran University Heart Center 71 The Journal of Tehran University Heart Center Maryam Esmaeilzadeh et al

Table 3. Logistic regression analysis between PG/MG ratio and multiple variables Coefficient SE PV Odds Ratio 95% CI for OR Sex -1.004 0.496 0.430 0.366 0.139 0.969 Age 0.001 0.017 0.938 1.001 0.969 1.034 Time to surgery 0.125 0.043 0.400 1.113 1.041 1.233 Valve Type 0.570 0.709 0.422 1.768 0.440 7.096 Valve Size -0.072 0.099 0.468 0.930 0.766 1.131 PG/MG ratio -0.276 0.802 0.731 0.759 0.157 3.655 TVI index -5.318 1.830 0.004 0.005 0.000 0.177 Constant 2.357 3.016 0.435 10.560 - - PG, Peak pressure gradient; MG, Mean pressure gradient; TVI, Time velocity integral; SE, Standard error; PV, Probability value; CI, Confidence interval; OR, Odds ratio found between the TVI index and aortic valve prosthesis Discussion obstruction (B = 5.69, p value < 0.001, OR = 0.003, 95% CI: 0.0002-0.0490. Obstruction of the AV prosthesis is an important clinical The receiver operating characteristic (ROC) curve showed entity. It can occur by thrombus formation, pannus ingrowths, that the TVI index was an accurate (AUC = 0.73 ± 0.041, 95% or infective endocarditis. CI: 0.65-0.81) method for the evaluation of AVP obstruction TTE has limited value for the evaluation of AVP (Figure 2). The VTI index<0.2 had a sensitivity of 71%, obstruction3 and has a low sensitivity for the detection of specificity of 100%, positive likelihood ratio of 100%, and its dysfunction.4 Whereas the detection of obstruction and negative likelihood ratio of 54.5% for the prediction of AVP assessment of the functional significance of obstruction is obstruction. difficult by 2D echocardiography, Doppler study can help to evaluate AVP abnormality.4 Doppler study can help to diagnose AVP obstruction by measuring peak velocity, peak and mean pressure gradients, and TVI index, but load dependency can sometimes misguide physicians. The peak-to-mean pressure ratio was previously used to evaluate aortic valve stenosis. This parameter is flow independent.7 Opinions about this variable is controversial. For example, Volbery et al. reported a weak correlation between the PG/MG ratio and aortic valve area.5 They found marked overlap in the PG/MG ratio values in patients with aortic stenosis of variable severity. The sensitivity, specificity, and accuracy of the PG/MG ratio for the diagnosis of severe stenosis in their study were fair. In a study by Chambers et al., this variable was shown to be related to the aortic valve area (1.75 in mild stenosis, 1.66 in moderate stenosis, 1.56 in severe stenosis and 1.57 in severe aortic stenosis with left ventricular ejection fraction less than 40%).5 In the present study, we assessed the usefulness of the PG/ MG ratio as a parameter proposed for the diagnosis of AVP obstruction. This parameter has the advantage, compared Figure 2. ROC curve of the TVI index for the diagnosis of aortic valve to the other available ones, of being independent of flows prosthesis obstruction according to fluoroscopy such as Vmax, and MG, which represents and advantage over the indices that require flow correction. We compared The probability of obstruction was twice higher in the the PG/MG ratio with Vmax MG and TVI index, which are monoleaflet prosthesis in comparison with the bileaflet the three criteria most often used for the diagnosis of AVP prosthesis (OR: 2.8, 95% CI: 0.15-0.79). Furthermore, aortic obstruction. valve prosthesis obstruction was more frequent in the female Using multiple statistical analysis methods, we did not gender (OR: 2.1, 95% CI: 0.24-0.89); it was not, however, find a significant relation between the PG/MG ratio and affected by the patient’s age and time duration from valve AVP obstruction; although the logistic regression method surgery (table 3). did not rule out this association strongly (p value = 0.09).

72 Is the Peak-to-Mean Pressure Gradient Ratio Useful for Assessment ... TEHRAN HEART CENTER

We presumed that it might be secondary to the triangular Acknowledgments shape of the CW Doppler flow profile in the aortic valve prosthesis, which would cause the prosthetic valve mean This study was supported by Iran University of Medical pressure gradient to not follow the classic formula (mean Sciences. We wish to thank all the nursing staff involved in the PG = 2.4 × V2). We, therefore, calculated the mean gradient echocardiography and angiography departments at Shaheed mathematically by applying this formula and compared Rajaei Cardiovascular, Medical and Research Center. them with the previous automatically measured mean gradients. There was an insignificant difference between the automatically and mathematically derived measurements References (16.5 versus 17.49 mmHg, respectively); nevertheless, the linear regression analysis showed a significant correlation 1. Cannegieter SC, Torn M, Rosendual FR. Oral anticoagulant between the two methods (correlation coefficient = 0.96, treatment in patients with mechanical heart valves: how to reduce the risk of thromboembolic and bleeding complications. J Inter regression coefficient of mean pressure gradient = 0.918, p Med 1999;245:369-374. value < 0.001). 2. Girad SE, Miller FA Jr, Orszulak TA, Mullany CJ, Montgomery S, This study showed that the TVI index had a strong relation Edwards WD, Tazelaar HD, Malouf JF, Tajik AJ. Reoperation for with AVP obstruction. Using several analysis methods, we prosthetic aortic valve obstruction in the era of echocardiography: trends in diagnostic testing and comparison with surgical findings. found that the TVI index < 0.2 had a specificity of 100% J Am Coll Cardiol 2001;37:579-584. for the prediction of significant obstruction. The PG/MG 3. OH Jk, Seward JB, Tajik AJ. Prosthetic valve evaluation. In: OH Jk, ratio had a low clinical impact for the diagnosis of AVP Seward JB, Tajik AJ, eds. The Echo Manual. 3rd ed. Philadelphia, Baltimore, New york, London, Buenos Aires, Hong Kong, Sydney, obstruction; be that as it may, further studies are required to Tokyo: Lippincott Williams & Wilkins; 2007. p. 226-242. evaluate the PG/MG ratio as a parameter for the diagnosis of 4. Feigenbaum H, Armstrong W, Ryan T. Prosthetic valves. In: AVP obstruction. Feigenbaum H, Armstrong W, Ryan T, eds. Feigenbaum’s The greatest limitation of this study is that the criteria for Echocardiography. 6th ed. Philadelphia, Baltimore, New york, London, Buenos Aires, Hong Kong, Sydney, Tokyo: Lippincott AVP obstruction, considered to be “standard”, Vmax, MG, and Williams & Wilkins; 2005. p. 399-436. TVI index, are all parts of the PG/MG ratio; consequently, 5. Chambers J, Rajani R, Hankins M, Cook R. The peak to mean there is contamination between the parameters. This limitation pressure decrease ratio: a new method of assessing aortic stenosis. is also shared by Chambers and Volberg et al. Another J Am Soc Echocardiogr 2005;18:674-678. 6. Cianciulli TE, Lax JA, Beck MA, Cerruti FE, Gigena GE, Saccheri limitation is the lack of direct anatomic confirmation at MC, Fernández E, Dorelle AN, Leguizamón JH, Prezioso HA. surgery or post-mortem examinations of abnormalities such Cinefluoroscopic assessment of mechanical disc prostheses: its as thrombus or pannus. Furthermore, we did not follow the value as a complementary method to echocardiography. J Heart Valve Dis 2005;14:664-673. patients during a long-term period, so the clinical relevance 7. Volberg VI, Berensztein CS, Ber MG, Lanosa G, Lerman J, of the non-invasive abnormalities needs to be established. Pineiro DJ. Efficacy of the peak to mean pressure decrease ratio for the assessment of aortic stenosis severity. Rev Argent Cardiol 2006;74:123-128. Conclusion

The PG/MG ratio is a simple, quick, and load-independent method, but the present study showed that the PG/MG ratio correlated weakly with the AVP obstruction. Although this correlation was insignificant, it was not ruled out strongly. There was also a marked overlap between the PG/MG ratio values among patients with AVP obstruction of variable severities. The sensitivity, specificity, and accuracy of the PG/MG ratio for the diagnosis of AVP obstruction were fair. In the population studied, the predictive values of the PG/ MG ratio for the diagnosis of AVP obstruction were modest (0.09). Moreover, the analysis of the probability rates in the case of a positive or negative result showed that the PG/ MG ratio had a low clinical impact for the diagnosis of AVP obstruction. Finally, we found the TVI index a useful measure for detecting aortic prosthesis obstruction.

The Journal of Tehran University Heart Center 73 The Journal of Tehran University Heart Center

Original Article Measurement of Atrial Septal Defect Size: A Comparative Study between Transesophageal Echocardiography and Balloon Occlusive Diameter Method

Hakimeh Sadeghian, MD, Alimohammad Hajizeinali, MD, Bahareh Eslami, MD, Masoumeh Lotfi-Tokaldany, MD, Mahmood Sheikhfathollahi, MD, Mohammad Sahebjam, MD, Elham Hakki, MD, Arezou Zoroufian, MD*, Seyed Ebrahim Kassaian, MD, Mohammad Alidoosti, MD

Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran.

Received 15 December 2009; Accepted 25 February 2010

Abstract

Background: Transcatheter closure of atrial septal defect secundum (ASD-II) has become an alternative method for surgery. We sought to compare the two-dimensional transesophageal echocardiography (TEE) method for measuring atrial septal defect with balloon occlusive diameter (BOD) in transcatheter ASD-II closure. Methods: A total of 39 patients (71.1% female, mean age: 35.31 ± 15.37 years) who underwent successful transcatheter closure of ASD-II between November 2005 and July 2008 were enrolled in this study. Transthoracic echocardiography (TTE) and TEE were performed to select suitable cases for device closure and measure the defect size before the procedure, and BOD measurement was performed during catheterization via TEE. The final size of the selected device was usually either equal to or 1 – 2 mm larger than the BOD of the defect. Results: The mean defect size obtained by TEE and BOD was 18.50 ± 5.08 mm and 22.86 ± 4.76 mm, respectively. The mean difference between the values of ASD size obtained by TEE and BOD was 4.36 ± 2.93 mm. In comparison with BOD, TEE underestimated the defect size in 94.9%, but TEE value being equal to BOD was observed in 5.1%. There was a good linear correlation between the two measurements: BOD = 0.773 × ASD size by TEE+8.562; r2 = 67.9.1%. A negative correlation was found between TEE sizing and the difference between BOD and TEE values (r = -0.394, p value = 0.013). Conclusion: In this study, BOD was larger than ASD size obtained by two-dimensional TEE. However, TEE maximal defect sizing correlates with BOD and may provide credible information in device size selection for transcatheter ASD closure. J Teh Univ Heart Ctr 2 (2010) 74-77

Keywords: Heart septal defect, atrial • Echocardiography, transesophageal • Diagnosis

Introduction of ASD-II has become an effective alternative method for surgery after the first attempt in 1976 by King and Mills.2, 3 The secundum type atrial septal defect (ASD-II) is a An accurate measurement of ASD size and the common form of congenital heart disease with an incidence determination of its spatial relationship with the neighboring of 3.78 per 10,000 live births.1 The transcatheter closure structures are crucial for successful transcatheter closure.

*Corresponding Author: Arezou Zoroufian, Assistant Professor of Cardiology, Department of Cardiology, Tehran Heart Center, Jalal Al Ahmad & North Kargar Crossroads, Tehran, Iran. 1411713138. Tel: +98 21 88029256. Fax: +98 21 88029256. Email: arezou.zoroufi[email protected].

74 Measurement of Atrial Septal Defect Size: A Comparative Study between ... TEHRAN HEART CENTER

The stretch balloon diameter (SBD) measurement of ASD (AGA Medical). A cylindrical sizing balloon was inflated in during catheterization is widely considered the gold standard the left atrium and then pulled back against the ASD. It was for selecting the size of the device.4 Two-dimensional thereafter deflated to reach a size sufficient to enable it to transesophageal echocardiography (2D-TEE) can provide be pulled into the right atrium through the defect. BOD was valuable information about the size, position, and number defined as the balloon size that completely occluded the ASD of defects and the surrounding structures. It can also guide and prevented any shunt across the defect without deforming intracardiac device deployment procedures effectively.5-7 the balloon. The balloon diameter was measured directly on Balloon diameter measured at the point where the maximal the screen connected to the fluoroscopy. diameter of the balloon prevents any residual shunt is TEE was used to ensure that the balloon was perpendicular recently evaluated as balloon occlusive diameter (BOD) to the septum during the balloon sizing of the ASD. After sizing. Measurements by 2D-TEE have been shown to have releasing the device from the cable by unscrewing it, a final better correlation with BOD than SBD. Balloon occlusive TEE examination was performed to demonstrate the position sizing is a commonly used method of ASD measurement in of the device and any residual shunting. our institution. The numerical variables were presented as mean ± SD Therefore, the aim of this study was to compare ASD sizing (range), while the categorical variables were summarized by by two methods: 2D-TEE and BOD, in our catheterization percentages. The continuous variables were compared using laboratory. Student’s t-test across the two age groups (age < 18 vs. age ≥ 18 years) and compared via the paired t-test between the two defect sizing methods. The association between the maximal Methods defect size of ASD obtained by two-dimensional TEE and BOD was assessed through the Pearson correlation and linear Between November 2005 and July 2008, 46 patients with regression analysis. The graphical method of the Bland and the secundum type atrial septal defect (ASD-II) that were Altman plot was also performed so as to assess the agreement appropriate in size, morphology, and rims to the neighboring between the two methods of clinical measurement. For the structures according to transthoracic echocardiography (TTE) statistical analysis, the statistical software SPSS version and TEE were referred to the catheterization laboratory in 13.0 for Windows (SPSS Inc., Chicago, IL) was used. All Tehran Heart Center for ASD closure. the P-values were 2-tailed, with statistical significance being The defect size was obtained via two methods: 1) pre- defined by P ≤ 0.05. procedure TEE and 2) BOD under TEE guidance during catheterization. Due to the growing nature of ASD-II, we hypothesized that Results the relation between the measurements by the two methods might vary with aging. We, therefore, divided the patients Forty-five patients fulfilled the initial inclusion criteria. into two groups according to the age of ASD closure (age < Five patients were excluded because of the failure of the 18 and age ≥ 18 years) to examine this hypothesis. procedures, and complete data of two patients were not Under local anesthesia, two-dimensional TEE was available. The remaining 39 patients (71.1% female) were performed with a multi-plane 5.0 MHz TEE probe (Vivid included for further analysis. The mean age was 35.31 ± 3, GE). The diameter of the defect was measured in various 15.37 years (range: 9-71 years). The mean maximal diameter planes to obtain the maximal defect size. The sizes obtained measured by 2D-TEE was 18.50 ±5.08 mm (range 10–31 in the most useful views consisted of mid-esophageal four- mm), while the mean BOD was 22.86 ± 4.76 mm (range chamber view at 0°, short-axis view at 45-60°, and bicaval 12–31 mm). This difference was statistically significant (p long-axis view at 90-110°. The maximal diameter of the value < 0.001). The mean difference between the values of defect was acquired during the cardiac cycle. the ASD size obtained by TEE and BOD was 4.36 ± 2.93 The rims of the defect were measured from the margin of mm. the defect to the inferior vena cava, superior vena cava, right There was a good correlation between the TEE maximal upper pulmonary vein, tricuspid and mitral valves, aorta, defect sizing and BOD measurements (r = 0.824, p value and coronary sinus wherever possible. Exclusion criteria < 0.001). By the linear regression analysis, BOD = 0.773 × for the device closure in this study were multiple ASDs and ASD size by TEE + 8.562; r2 = 67.9%. A negative correlation maximum ASD diameter > 30 mm, both assessed by TEE; was found between TEE sizing and the difference between and ASD rims ≤ 5 mm, except for the anterior superior rim. BOD and TEE values: the larger the TEE sizing, the smaller TEE was also performed for the second time during balloon the difference between the TEE and BOD sizing (r = -0.394, sizing and device implantation. p value = 0.013). In 94.9% of the cases, BOD values were During catheterization, an appropriate occluder device larger and only in 5.1% were they similar to 2D-TEE. size was estimated by Amplatzer stretched balloon sizing Furthermore, the Bland and Altman plot showed agreement

The Journal of Tehran University Heart Center 75 The Journal of Tehran University Heart Center Hakimeh Sadeghian et al

Table1. Measurement of ASD by TEE and BOD according to age age <18 y age ≥18 y P** (n=6) (n=37) * TEE maximal diameter (mm) 14.67±3.89 19.20±5.00 0.043 (10–19) (10–31) Balloon occlusive diameter* (mm) 18.83±4.31 23.60±4.52 0.022 (12–23) (15-31)

*Data are presented as mean ± SD (range) P**, referred for the comparison by Student’s t-test between the two groups ASD, Atrial septal defect; TEE, Transesophageal echocardiography; BOD, Balloon occlusive diameter between the two measurements because the number of points was larger than two-dimensional TEE measurements with a laid out of the 95% range of agreement (± 1.96 SD) was less mean difference of 2.41 mm. Zhu et al. also found a good than 5% of all the observations (Figure 1). linear correlation between 2-dimentional TEE measurements As depicted in Table 1, in patients ≥ 18 years old, TEE and BOD. and BOD measurements were significantly larger than those In our study, the defect size measured via BOD was larger obtained in younger patients (p value = 0.022 and 0.042, than that via two-dimensional TEE in 94.9% of the patients respectively). The linear regression analysis of the two and there was a good agreement between the two (Figure groups highlighted a higher correlation in the younger age 1). Also, in a study by El-Said and colleagues,8 in 81% of group between the parameters obtained by TEE maximal patients whose TEE results were available, the measurement defect sizing and BOD: BOD = 1.031 × ASD by TEE + obtained via stretch balloon diameter was larger than the pre- 3.712 for age < 18 y (r2 = 86.3%, p value = 0.007); and BOD catheterization measurement by 2-dimensional TEE. = 0.712 × ASD size by TEE + 9.914 for age ≥ 18 years (r2 = In our study, a negative correlation was found between 62.3%, p value < 0.001) TEE sizing and the difference between BOD and TEE values. McMahon et al.9 showed that up to two thirds of isolated secundum ASDs grew over an intermediate-term follow-up. In the present study, ASD size measured by either TEE or BOD was also significantly larger in patients over 18 years old. In patients >18 years of age compared to younger patients, the difference between BOD and TEE was smaller. This finding shows that in larger defects, TEE measurement is closer to BOD.

Conclusion

In this study BOD was larger than the ASD size obtained by 2-dimensional TEE. TEE maximal defect sizing corre- lates with BOD and is a good adjunct in selecting an ap- propriate device size in patients scheduled for transcatheter Figure 1. Bland & Altman plot for assessing agreement between the two ASD closure. methods of ASD measurement TEE, Transesophageal echocardiography; BOD, Balloon occlusive diam- eter; SD, Standard deviation Acknowledgment

We wish to thank all the staff of the echocardiography de- Discussion partment at Tehran Heart Center for their kind assistance in data gathering. This study was supported by Tehran Univer- In our study, there was a good positive linear correlation sity of Medical Science. between TEE and BOD measurements of ASD, while a negative correlation was found between TEE sizing and the difference between BOD and TEE values. The defect size References obtained via BOD was greater than that via TEE. The results of the present study were similar to the findings 1. Chessa M, Carminati M, Butera G, Bini RM, Drago M, Rosti of the Zhu et al. study,4 which showed that balloon sizing L, Giamberti A, Pome` G, Bossone E, Frigiola A. Early and late

76 Measurement of Atrial Septal Defect Size: A Comparative Study between ... TEHRAN HEART CENTER

complications associated with transcatheter occlusion of secundum atrial septal defect. J Am Coll Cardiol 2002;39:1061-1065. 2. Du ZD, Hijazi Z, Kleinman CS, Silverman NH, Larntz K. Comparison between transcatheter and surgical closure of secundum atrial septal defect in children and adults: results of a multicenter nonrandomized trial. J Am Coll Cardiol 2002;39:1836- 1844. 3. King TD, Mills NL. Secundum atrial septal defects: nonoperative closure during cardiac catheterization. JAMA 1976;235:2506- 2509. 4. Zhu W, Cao QL, Rhodes J, Hijazi ZM. Measurement of atrial septal defect size: a comparative study between three-dimensional transesophageal echocardiography and the standard balloon sizing methods. Pediatr Cardiol 2000;21:465-469. 5. Hellenbrand WE, Fahey JT, McGowan FX, Weltin GG, Kleinman CS. Transesophageal echocardiographic guidance of transcatheter closure of atrial septal defect. Am J Cardiol 1990;66:207-213. 6. Carcagni A, Presbitero P. New echocardiographic diameter for amplatzer sizing in adult patients with secundum atrial septal defect: preliminary results. Catheter Cardiovasc Interv 2004;62:409-414. 7. King TD, Thompson SL, Millis NL. Measurement of atrial septal defect during cardiac catheterization. Experimental and clinical results. Am J Cardiol 1978;41:537-542. 8. El Said HG, Benzolid LI, Grifka RG, Pignatelli RH, McMahan CJ, Schutte DA, Smith EO, Mullins CE. Sizing of atrial septal defects to predict successful closure with transcatheter Cardioseal device. Tex Heart Inst 2001;28:177-182. 9. McMohan CJ, Feltes TF, Fraley JK, Bricker JT, Grifka RG, Tortoriel TA, Blake R, Bezold LI. Natural history of growth of secundum atrial septal defects and implications for transcatheter closure. Heart 2002;87:256-259.

The Journal of Tehran University Heart Center 77 The Journal of Tehran University Heart Center

Original Article Relationship between Calcium-Phosphorus Product and Severity of Valvular Heart Insufficiency in Patients Undergoing Chronic Hemodialysis

Masoumeh Kahnooj, MD1*, Mohammad Masoomi, MD1, Ali Naderinasab, MD1, Akram Zaeem, BSc1, Mehrdad Sheikhvatan, MD2

1Shafa Hospital, Kerman University of Medical Sciences, Kerman, Iran. 2Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran.

Received 12 August 2009; Accepted 04 February 2010

Abstract

Background: Recent interests have mainly focused on the roles of serum calcium and phosphorus and their product (Ca-P product) in the development of valvular heart disease. The present study assessed the relationship between the Ca-P product and the severity of valvular heart disease in end-stage renal disease (ESRD) patients undergoing chronic hemodialysis. Methods: This cross-sectional study reviewed the clinical course of 72 consecutive patients with the final diagnosis of ESRD candidated for chronic hemodialysis. The severity of valvular heart disease was determined using M-mode two- dimensional echocardiography. The serum calcium and phosphate values adopted were those values measured on the day between the two consecutive dialyses, and the Ca-P product was calculated. Results: The most common causes of ESRD were diabetic nephropathy, malignant hypertension, and chronic glomerulonephritis. The mean Ca-P product level in the dialysis patients was 50.44 ± 17.78 mg2/dL2. The receiver-operator characteristic (ROC) curve illustrated that a Ca-P product level > 42 mg2/dL2 was the optimal value in terms of sensitivity and specificity for predicting the presence of valvular insufficiency. Aortic insufficiency was directly associated with a high Ca-P product value after adjustment for age, gender, serum albumin, diabetes, hypertension, hyperlipidemia, coronary artery disease, and serum creatinine (β = 0.412, SE = 158, p value= 0.011). Conclusion: A positive relationship between the Ca-P product value and the severity of aortic insufficiency is expected. Achieving an appropriate control of the Ca-P product level may decrease aortic valve calcification and improve the survival of patients on chronic hemodialysis. J Teh Univ Heart Ctr 2 (2010) 78-82

Keywords: Heart valve disease • Renal dialysis • Kidney failure • Calcium • Phosphorus

Introduction patients undergoing chronic dialysis has been described.1 Association between change in some serum chemical Recently, interest has mainly focused on the roles of serum biomarkers such as serum phosphorous, calcium, and calcium and phosphorus and their abnormalities in the their product (Ca-P product) and increased cardiovascular development of valvular heart disease.2 Meanwhile, valvular morbidity and mortality in end-stage renal disease (ESRD) dysfunction related to abnormal calcium and phosphate

* Corresponding Author: Masoumeh Kahnooj, Assistant Professor of Cardiology, Kerman University of Medical Sciences, Shafa Hospital, Jomhouri Eslami Boulevard, Shafa Street, Kerman, Iran. Tel: + 98 913 3424868. Fax: +98 311 2115803. Email: [email protected].

78 Relationship between Calcium-Phosphorus Product and Severity of Valvular Heart ... TEHRAN HEART CENTER metabolism, especially following chronic dialysis, is regarded General demographic variables such as gender, age, cause as a strong and independent predictor of an adverse clinical of renal failure, time on hemodialysis, and serum creatinine outcome, including an increased risk of death and a need for level were used as confounders in subsequent analyses for the valve replacement.3 Calcium deposits in the cardiovascular determination of the relationship between the Ca-P product system have been also suggested as a serious problem in and the severity of valvular disease. The results were expressed patients on chronic dialysis in that they can lead to a high as mean ± SD for the quantitative variables and percentages prevalence of aortic valve calcification.4-6 Additionally, it for the categorical variables. The categorical variables were has been indicated that phosphate elevation may aggravate compared between the groups using the chi-square test. A the effects of coronary atherosclerosis through increased cumulative logit model for determining the relationship vascular calcification.7, 8 However, usefulness of the Ca-P between the severity of valvular heart disease and the Ca-P product index as a determinant of the valvular heart product and the presence of confounders was also employed. disease severity has been questioned. Some studies The optimal Ca-P product cut-off point, associated with the have managed to find higher levels of this product in absence of valvular disease, was assessed using the receiver- patients with mitral annular calcium,9 while some others operator characteristic (ROC) curve. The best discrimination have failed to obtain such findings.10 limit for the Ca x P level was determined at the maximum of The present study assessed the relationship between the the Youden index: J = sensitivity + specificity – 1 (Rufino Ca-P product and the severity of valvular heart disease in 2003). A multivariable linear regression analysis was utilized ESRD patients undergoing chronic dialysis. to evaluate the relationship between the Ca × P measurement and the aortic insufficiency severity. p values of 0.05 or less were considered statistically significant. All the statistical Methods analyses were performed using SPSS version 13.0 (SPSS Inc., Chicago, IL, USA). This cross-sectional study reviewed the clinical course of 72 consecutive patients with the final diagnosis of ESRD who underwent chronic hemodialysis in Shafa Hospital Results between June 1996 and June 2003. Chronic dialysis was defined as the receipt of dialysis for at least 90 days.11 The The mean age of the studied patients was 52.17 ± 15.12 study was reviewed and approved by the Review Board of years (range: 22 to 90 years), and 58.3% of them were male. Kerman University of Medical Sciences. All the studied The most common causes of ESRD were diabetic nephropa- patients were on maintenance hemodialysis for a mean time thy, malignant hypertension, and chronic glomerulonephritis of 29.11 months (range: 1 to 120 months) on thrice-weekly (Figure 1). 3 to 4 hours of standard bicarbonate hemodialysis, with a prescribed urea reduction > 65% in accordance with the standard protocol.12 The severity of valvular heart disease was determined using M-mode two-dimensional echocardiography. Valvular insufficiency was classified as normal (grade 0), trivial (grade 1), mild (grade 2), moderate (grade 3), and severe (grade 4).13 Echocardiography was performed in keeping with the recommendations of the American Society of Echocardiography14 and was analyzed by a single experienced cardiologist. Serum biomarkers were measured < 3 months after echocardiography using standard assays. Serum total calcium was measured with ortho-cresolphthalein complexone (o-CPC) and inorganic phosphate via the molybdenum blue method (Zist-Shimi Inc., Tehran, Iran) using an LKB spectrophotometer (Biochrom, Cambridge, UK). The serum calcium and phosphate values adopted Figure1. Causes of end-stage renal disease in the studied patients were those values measured on the day between the two consecutive dialyses, and the Ca-P product was calculated. Etiology in 15.3% of the patients was also unknown. The other measured laboratory parameters were serum Regarding medical history, 58.3% of the patients were triglyceride and total cholesterol levels, serum creatinine, hypertensive and 40.3% of them had diabetes mellitus. fasting blood sugar, and serum hemoglobin. The daily oral Also, hyperlipidemia was observed in 13.9% of the intakes of the drugs were also noted. subjects, and 23.6% of the studied cases suffered from

The Journal of Tehran University Heart Center 79 The Journal of Tehran University Heart Center Masoumeh Kahnooj et al coronary artery disease, which was assessed on the basis of valvular insufficiency in our population. electrocardiography changes as well as the echocardiography report of wall motion abnormality. The biochemical data are Table 3. Echocardiographic findings in patients undergoing chronic dialysis (n = 72) presented in Table 1. More than two thirds of the patients had Pericardial effusion 23 (31.9) a serum calcium value lower than 9.5 mg/dl, and the serum Left ventricular hypertrophy 52 (72.2) PO level in 52 patients was higher than 4.5 mg/dl, resulting 4 Left atrial hypertrophy 6 (8.3) in a calcium-phosphate product higher than 42 in 72.2% of Wall motion abnormality 20 (27.8) the patients. With regard to oral medications within chronic Valvular diseases hemodialysis (Table 2), common drugs administered were Single valve 33 (45.8) folic acid, calcium carbonate, beta-blockers, and angiotensin- Two valves 16 (22.2) converting enzyme (ACE) inhibitors. The echocardiographic Three valves 5 (6.9) data are summarized in Table 3. The mean left ventricular Mitral insufficiency ejection fraction (LVEF) was 48.39 ± 11.43%, and the Mild 22 (30.6) majority of the patients had an EF between 40 and 55%. Moderate 17 (23.6) Pericardial effusion was reported in 31.9% of the patients. Severe 5 (6.9) Mild insufficiency was the most common finding among Aortic insufficiency three types of valves. None of the patients had severe aortic Mild 14 (19.4) insufficiency. Multiple valvular diseases were observed in Moderate 5 (6.9) 29.1% of the patients, and 6.9% of them suffered from triple Severe 0 (0.0) valvular disease. Tricuspid insufficiency Table 1. Biochemical data of patients undergoing chronic dialysis (n = 72)* Mild 8 (11.1) Calcium (mg/dl) 9.16±1.31 Moderate 8 (11.1) Calcium > 9.5 (mg/dl) 22 (30.6) Severe 1 (1.4) Phosphorus (mg/dl) 5.47±1.74 Numbers in the parentheses are the related percentages Phosphorus > 4.5 (mg/dl) 52 (72.2) Calcium-Phosphorus product (mg2/dL2) 50.44±17.78 Table 4. Relationship between calcium-phosphorus product and the severity Urea (mg/dl) 138.82±50.15 of valvular defects in patients undergoing chronic dialysis (n = 72) Creatinine (mg/dl) 8.59±2.68 Insufficiency severity Normal Mild Moderate Severe p value Triglyceride (mg/dl) 140.70±78.73 Aorta Cholesterol (mg/dl) 143.42±43.46 Ca × P ≤ 42 mg2/dl2 40 (76.9) 11 (21.2) 1 (1.9) 0 0.025 2 2 Hemoglobin (mg/dl) 10.05±2.08 Ca × P > 42 mg /dl 13 (65.0) 3 (15.0) 4 (20.0) 0 Fasting blood sugar (mg/dl) 140.00±72.37 *Data are presented as mean ± SD Mitral Numbers in the parentheses are the related percentages Ca × P ≤ 42 mg2/dl2 8 (40.0) 5 (25.0) 6 (30.0) 1 (5.0) 0.821 Ca × P > 42 mg2/dl2 20 (38.5) 17 (32.7) 11 (21.2) 4 (7.7) Table 2. Oral medications in patients undergoing chronic dialysis (n = 72) Folic acid 57 (79.2) Tricuspid Ca × P ≤ 42 mg2/dl2 14 (70.0) 4 (20.0) 2 (10.0) 0 0.469 Calcium carbonate 46 (63.9) Ca × P > 42 mg2/dl2 41 (78.8) 4 (7.7) 6 (11.5) 1 (1.9) Beta-blockers 36 (50.0) Numbers in the parentheses are the related percentages ACE-inhibitors 33 (45.8) Ca, Calcium; P, Phosphorus Diuretics 19 (26.4)

Calcium-blockers 14 (19.4) Table 5. Relationship between measurement of Calcium-Phosphorus Glibenclamide 14 (19.4) (Ca-P) product and severity of aortic insufficiency with the presence of Insulin 10 (13.9) cofounders Nitrates 10 (13.9) Variable β Standard Error p value Ca-P product 0.412 0.158 0.011 Digoxin 4 (5.6) Male gender -0.177 0.147 0.232 Numbers in the parentheses are the related percentages Age 0.001 0.005 0.977 ACE, Angiotensin-converting enzyme Serum albumin -0.014 0.035 0.699 Diabetes 0.079 0.162 0.626 The mean Ca-P product level in the dialysis patients was Hypertension 0.150 0.156 0.341 2 2 Hyperlipidemia 0.127 0.227 0.578 50.44 ± 17.78 mg /dL . The ROC curves illustrated that a Coronary artery disease 0.146 0.188 0.440 Ca-P product > 42 mg2/dL2 was the optimal value in terms Serum creatinine 0.031 0.028 0.279 of sensitivity and specificity for predicting the presence of R square: 0.179

80 Relationship between Calcium-Phosphorus Product and Severity of Valvular Heart ... TEHRAN HEART CENTER

Aortic insufficiency was directly associated with the has also been shown in animal studies.22 Given that most of severity of the Ca-P product value, so that insufficiency was our studied patients suffered from primary hypertension or more severe in Ca-P products > 42 mg2/dL2 than in those diabetes-related hypertension, aortic insufficiency following with lower values. Aortic insufficiency was also directly aortic valve calcification may be due to the progression of associated with a high Ca-P product value after adjustment the complications of hypertension. for age, gender, diabetes, hypertension, hyperlipidemia, Our findings also showed that the optimal cut-off point for coronary artery disease, and serum creatinine (β = 0.412, SE the Ca-P product measurement for predicting the severity = 0.158, p value = 0.011) (Tables 4 and 5). However, this of aortic insufficiency was 42 mg2/dL2. This discrimination product was not significantly associated with the severity of level was different in other studies. Movilli et al. obtained other valves insufficiency. a break point of 55 mg2/dL2 for an optimal Ca-P product discrimination value.23 Rufino et al. illustrated that a Ca-P product level > 43 mg2/dL2 was the optimal value in terms Discussion of sensitivity and specificity for predicting the presence of valvular calcification in their patient population. 12 Obtaining This study shows that the dialysis patients with a Ca-P a lower cut-off point highlights the importance of this product measurement > 42 mg2/dL2 had more severe aortic product for discriminating valvular disease, and our study insufficiency than did the other patients. Most of the similar is a case in point for this significance. Be that as it may, this studies hitherto published have underscored the value of the lower threshold may be related to the exclusion of those with Ca-P product in predicting cardiac events and even sudden severe aortic insufficiency in the current study. cardiac death. One study found that the relative risk of sudden In our study, the mean Ca-P product level in the dialysis death was strongly associated with an elevated level of the patients was 50.44 ± 17.78 mg2/dL2. Other related studies Ca-P product.15 It was also shown that the ESRD patients have found different means of Ca-P product levels such as 57 with Ca-P products > 72 mg2/dL2 had a relative mortality risk ± 19 in one study15 and 34.7 ± 6.3 mg2/dL2 in another one.24 In of 1.34 relative to those with products of 42 to 52 mg2/dL2 the Qunibi et al. study, this parameter was 59 ± 6 mg2/dL2.25 and, therefore, higher levels of the Ca-P product could beget Our findings, in comparison with those reported by other substantial morbidity and mortality seen in ESRD patients.16 studies, showed a better control of serum calcium and Elsewhere, it was demonstrated that for every 10 higher phosphorus levels and, therefore, Ca-P product measurements units of the Ca-P product, the relative risk of sudden death in our patients. Therefore, this marker can facilitate the increased by 7%.15 prediction of appropriate outcome and low cardiac events, Calcification of the aortic valve has been clearly described especially aortic insufficiency-related morbidity, in patients and is regarded as the potential mechanism through which on maintenance hemodialysis. elevated serum PO4 may contribute to these causes of death.17 It seems that high morbidity due to the severity of aortic insufficiency can be related to Ca-P product elevation Conclusion and valvular calcification. Previous findings were mainly focused on the association between aortic stenosis and this Based on the present study, we found a positive relationship product, whereas our study obtained this positive relationship between the Ca-P product value and the severity of aortic between the aortic valve insufficiency and the Ca-P product insufficiency. Consequently, to prevent aortic insufficiency measurement. As is shown in the Mills et al. study, the Ca-P progression and its co-morbidities, a measurement of the product is associated with the severity of aortic stenosis in serum Ca-P product level in ESRD patients undergoing dialysis patients as measured by the aortic valve area and chronic dialysis can be valuable. Thus, achieving an transvalvular gradients.18 Potential effects of elevated Ca-P appropriate control level of the Ca-P product may decrease products on the aortic valve insufficiency can be explained aortic valve calcification and improve the survival of patients by two mechanisms. Firstly, accelerated calcium deposition on chronic hemodialysis. on the aortic valve, which is commonly observed following chronic dialysis, can be the responsible factor for the induction of aortic valve insufficiency.19 Secondly, the role Acknowledgment of protruding calcium deposits in the augmentation of the rest flow velocity across the aortic valve is thought to give This study was supported by the Kerman University of rise to aortic valve calcification, especially in hypertensive Medical Sciences. We thank the University authorities, patients.20 Huting et al. observed that valve calcification was who offered critical administrative support and managerial simultaneously associated with the severity of predialysis services in carrying out the study and also all researchers for hypertension and high levels of the Ca-P product.21 A their help and support. causal link between hypertension and aortic valve disease

The Journal of Tehran University Heart Center 81 The Journal of Tehran University Heart Center Masoumeh Kahnooj et al

References patients: prevalence, risk factors and association with transvalvular flow velocity. Int J Cardiol 2004;94:7-13. 21. Hüting J. Mitral valve calcification as an index of left ventricular 1. Egbuna OI, Taylor JG, Bushinsky DA, Zand MS. Elevated calcium dysfunction in patients with end-stage renal disease on peritoneal phosphate product after renal transplantation is a risk factor for dialysis. Chest 1994;105:383-388. graft failure. Clin Transplant 2007;21:558-566. 22. Cuniberti LA, Stutzbach PG, Guevara E, Yannarelli GG, Laguens RP, 2. Rasouli M, Kiasari AM. Serum calcium and phosphorus associate Favaloro RR. Development of mild aortic valve stenosis in a rabbit with the occurrence and severity of angiographically documented model of hypertension. J Am Coll Cardiol 2006;47:2303-2309. coronary heart disease, possibly through correlation with 23. Movilli E, Feliciani A, Camerini C, Brunori G, Zubani R, Scolari atherogenic (apo)lipoproteins. Clin Chem Lab Med 2006;44:43-50. F, Parrinello G, Cancarini GC. A high calcium-phosphate product 3. Rosenhek R, Binder T, Porenta G. Predictors of outcome in severe, is associated with high C-reactive protein concentrations in asymptomatic aortic stenosis. N Engl J Med 2000;343:611-617. hemodialysis patients. Nephron Clin Pract 2005;10:161-167. 4. Ohara T, Hashimoto Y, Matsumura A, Suzuki M, Isobe M. 24. Menon V, Greene T, Pereira AA, Wang X, Beck GJ, Kusek JW, Accelerated progression and morbidity in patients with aortic Collins AJ, Levey AS, Sarnak MJ. Relationship of phosphorus and stenosis on chronic dialysis. Circ J 2005;69:1535-1539. calcium-phosphorus product with mortality in CKD. Am J Kidney 5. Mills WR, Einstadter D, Finkelhor RS. Relation of calcium- Dis 2005;46:455-463. phosphorus product to the severity of aortic stenosis in patients 25. Qunibi WY, Nolan CA, Ayus JC. Cardiovascular calcification in with normal renal function. Am J Cardiol 2004;94:1196-1198. patients with end-stage renal disease: a century-old phenomenon. 6. McFalls EO, Archer SL. Rapid progression of aortic stenosis and Kidney Int Suppl 2002;82:73-80. secondary hyperparathyroidism. Am Heart J 1990;120:206-208. 7. Schwarz U, Buzello M, Ritz E, Stein G, Raabe G, Wiest G, Mall G, Amann K. Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure. Nephrol Dial Transplant 2000;15:218-233. 8. Amann K, Ritz E. Microvascular disease: the Cinderella of uremic heart disease. Nephrol Dial Transplant 2000;15:1493-1503. 9. Nair CK, Sudahkaran C, Aronow WS, Thomson W, Woodruff MP, Sketch MH. Clinical characteristics of patients younger than 60 years with mitral annular calcium: comparison with age- and sex- matched control subjects. Am J Cardiol 1984;54:1286-1287. 10. Aronow WS, Ahn C, Kronzon I. Association of mitral annular calcium with symptomatic peripheral arterial disease in older persons. Am J Cardiol 2001;88:333-334. 11. Wald R, Quinn RR, Luo J, Li P, Scales DC, Mamdani MM, Ray JG; University of Toronto Acute Kidney Injury Research Group. Chronic dialysis and death among survivors of acute kidney injury requiring dialysis. JAMA 2009;302:1179-1185. 12. Rufino M, García S, Jiménez A, Alvarez A, Miquel R, Delgado P, Marrero D, Torres A, Hernández D, Lorenzo V. Heart valve calcification and calcium x phosphorus product in hemodialysis patients: analysis of optimum values for its prevention. Kidney Int Suppl 2003;85:115-118. 13. Lange R, Cleuziou J, Hörer J, Holper K, Vogt M, Tassani-Prell P, Schreiber C. Risk factors for aortic insufficiency and aortic valve replacement after the arterial switch operation. Eur J Cardiothorac Surg 2008;34:711-717. 14. Tarrass F, Benjelloun M, Zamd M, Medkouri G, Hachim K, Benghanem MG, Ramdani B. Heart valve calcifications in patients with end-stage renal disease: analysis for risk factors. Nephrology (Carlton) 2006;11:494-496. 15. Ganesh SK, Stack AG, Levin NW, Hulbert-Shearon T, Port FK. Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 2001;12:2131-2138. 16. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998;31:607-617. 17. London GM, Pannier P, Marchais SJ, Guerin AP. Calcification of the aortic valve in the dialyzed patient. J Am Soc Nephrol 2000;11:778-783. 18. Mills WR, Einstadter D, Finkelhor RS. Relation of calcium- phosphorus product to the severity of aortic stenosis in patients with normal renal function. Am J Cardiol 2004;94:1196-1198. 19. Fujise K, Amerling R, Sherman W. Rapid progression of mitral and aortic stenosis in a patient with secondary hyperparathyroidism. Br Heart J 1993;70:282-284. 20. Tenenbaum A, Fisman EZ, Schwammenthal E, Adler Y, Shemesh J, Sherer Y, Motro M. Aortic valve calcification in hypertensive

82 TEHRAN HEART CENTER

Original Article Sonographic Prediction of Body Fat Volume (Subcutane- ous and Visceral Fat) in Cardiovascular Patients

Mir Hatef Shojaei, MD1*, Shapour Shirani, MD1, Mohammad Reza Eshraghian, PhD2, Maryam Soleymanzadeh, MD1

1Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran. 2School of Public Health, Tehran University of Medical Science, Tehran, Iran.

Received 01 November 2009; Accepted 10 February 2010

Abstract

Background: Inappropriate body composition represents impaired energy and nutrient intake and can be a risk factor for many diseases, especially for cardiovascular disease. Different methods have been suggested for the estimation of body fat volume and its distribution. However, they may be either expensive or hazardous for some groups of patients. Sonography is a very accessible technique, which may be used for the evaluation of visceral and subcutaneous fat volume. The purpose of this study was to evaluate the sonographic prediction of body fat and its distribution in subcutaneous and visceral compart- ments. Methods: During a three-month period, we conducted sonographic evaluations for visceral and subcutaneous fat in 106 patients who were admitted to our hospital. The subcutaneous fat was measured at the para-umbilical region and visceral fat was measured in the right para-renal space. The results were compared with the data obtained from the body mass index (BMI) and bioelectric impedance analysis. Results: The mean age of the patients was 58.8 years, and the mean BMI was26.48 ± 0.33. The mean values of fat percent and fat mass obtained by the electric-method were 31.07 ± 0.81% and 22.12 ± 0.68 kg, respectively. The respective mean values of subcutaneous and visceral fat obtained by sonography were 20.50±0.56 mm and 24.14 ± 0.58 mm. The correlation between BMI and subcutaneous fat was 0.85 (p value < 0.0001) and the correlation between BMI and visceral fat was0.46 (p value < 0.0001). Conclusion: Sonography is a reliable and available method for the estimation of body fat and its distribution in cardiovas- cular patients, in subcutaneous and visceral compartments. J Teh Univ Heart Ctr 2 (2010) 83-86

Keywords: Body mass index • Body fat distribution • Subcutaneous fat • Intra-abdominal fat • Ultrasonography

Introduction to be the best method for evaluating visceral fat, but it is not used routinely for the diagnostic procedures of patients. Body fat distribution assessment, especially visceral Magnetic resonance imaging is another alternative method; fat accumulation, is an important method to evaluate the however, factors such as high cost, morbid obesity, and association between obesity, cardiovascular diseases, and claustrophobia in patients, or history of metal prostheses and metabolic disorders.1 There have been various methods for pacemaker limit its utilization.2 body composition analysis. Computed tomography is known Bioelectric impedance analysis (BIA)is not so appropriate

* Corresponding Author: Mir Hatef Shojaei, Assistant Professor of Nutrition, Department of Nutrition, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. Tel: +98 21 88029645. Fax: +98 21 88029731. Email: [email protected].

The Journal of Tehran University Heart Center 83 The Journal of Tehran University Heart Center Mir Hatef Shojaei et al for a wide range of patients with cardiovascular diseases, patients and those with severe edema (more than 3+ edema) including patients suffering from congestive heart failure due to invalid information recorded by BIA method as well (CHF), patients having extra body fluid, patients receiving as those with kidney abnormalities such as polycystic kidney, serum therapy, and patients in post-operation condition.3, 4 renal atrophy, or hydronephrosis were also excluded from Formerly, the waist-hip ratio was used to as a simple the study. indicator of visceral fat volume, but it has been demonstrated Sonographic measurements were performed in all the that this ratio is unable to distinguish between subcutaneous patients with Siemens Sonoline G20 with a 3-5 MHz by a and visceral fat volumes and is, therefore, a poor predictor of single operator (MD) with 8 years of experience in abdominal change in visceral fat volume.5 sonography. The transducer was transversely positioned 1 cm Thus, there is a great need for a simple and appropriate above the umbilical scar on the abdominal midline, without method to estimate the amount of visceral fat in a clinical exerting any pressure over the abdomen. The peri-renal fat setting. The development of sonography has offered reliable was measured with a transducer longitudinally positioned on distance measurement, especially for the assessment and the axillary midline, with identification of the right kidney distribution of fat tissues.6 In a study, Leite reported that image. The peri-renal fat thickness was considered as the intra-abdominal thickness measured by sonography could distance in millimeters between the lateral border of the predict cardiovascular diseases.7 kidney and the internal border of iliopsoas muscle surface The purpose of this study was to evaluate the distribution adjacent to the middle third of the right kidney. of subcutaneous and visceral fat volumes measured by Measurement errors were avoided by performing three sonography as a determinant risk factor for cardiovascular measurements for each patient and recording the mean value. patients and compare its results with those via body mass The sonologist was blind to the measured BIA and Body index (BMI) and BIA methods. Mass Index (BMI) indices. For BIA, all the patients stood with their feet in contact with the foot electrode and grabbed the hand electrodes, and an eight-polar tactile-electrode Methods (Model Bios pace In body 720, Seoul, Korea) was utilized to carry out the measurements. The fat percent and fat mass, This cross sectional study enrolled 106 patients (63 men which were measured with the device, were recorded, and so and 43 women) with coronary artery disease (CAD) who were height and body weight to the nearest 0.1 cm and to the were admitted to our hospital during a 3-month period. The nearest 0.1 kg of the patients. BMI was calculated as weight patients, who had abdominal sonography for the evaluation divided by height squared (kg/m2) (normal range: 18.5 to of gastrointestinal or genitourinary problems, were given a 24.9 kg/m2). complete description of the study. The study was approved The results were expressed as mean ± SD. All the statistical by the Ethics Committee of the hospital, and informed analyses were performed utilizing SPSS software (version written consent was obtained from all of them. 13.0; SPSS, Inc., Chicago, Ill). The Pearson correlation Patients older than 80 years were excluded from the coefficient and linear regression tests were used to assess the study since their normal anatomy was impaired by old age. simple relation between the variables. The level of statistical Additionally, extra dehydrated (more than 10% loss in total significance was defined as p value < 0.05. body water, documented by clinical and laboratory findings)

Table 1. Bivariate Pearson correlation coefficient between BMI and electrical (BIA) and sonographic results according to gender* Pearson correlation coefficient First variable Second variable Male Female Total BMI (kg/m2) Fat percent (by BIA method) 0.667 0.742 0.643 Fat mass (by BIA method) 0.832 0.857 0.834 Visceral fat (by ultrasonography method) 0.462 0.432 0.462 Subcutaneous fat (by ultrasonography method) 0.809 0.865 0.848

Fat percent Fat mass (by BIA method) 0.889 0.874 0.870 Visceral fat (by ultrasonography method) 0.506 0.537 0.538 Subcutaneous fat (by ultrasonography method) 0.733 0.673 0.681

Fat mass (kg) Visceral fat (by ultrasonography method) 0.567 0.404 0.544 Subcutaneous fat (by ultrasonography method) 0.836 0.737 0.799

Visceral fat Thickness (mm) Subcutaneous fat (by ultrasonography method) 0.554 0.583 0.580 *All coefficients were significant at p < 0.05 BMI, Body mass index; BIA, Bioelectric impedance analysis

84 Sonographic Prediction of Body Fat Volume (Subcutaneous and Visceral Fat) ... TEHRAN HEART CENTER

Results Ultrasonography has been proven to be a practical, effective, and low-cost method to measure body fat and This study recruited 106 patients, comprising 43 (41%) its distribution.6, 7 However, ultrasonography accuracy is women and 63 (59%) men, with a mean age of 58.8 ± 1.1 operator-dependent and needs a thorough knowledge of years. The mean BMI was 26.48 ± 0.33 (25.89 ± 0.36 in men, anatomic landmarks and a proper scanning technique. 27.33 ± 0.61 in women). The mean values of fat percent and fat mass obtained by the electric-method were 31.07 ± 0.81% and 22.12 ± 0.68 kg, respectively. The respective Conclusion mean values of subcutaneous and visceral fat obtained by the sonography method were 20.50 ± 0.56 mm and 24.14 ± Our results suggest that both bioelectrical impedance and 0.58 mm. The Pearson correlation coefficients between BMI ultrasonography are useful for predicting the visceral and and the other variables in terms of age are shown in Table 1. percutaneous fat volume. In conclusion, the accuracy and A comparison of the correlations between the electrical and simplicity are factors that make ultrasonography one of sonographic variables and BMI calculation demonstrated a the safest (albeit not the most perfect) methods in clinical significant relation between subcutaneous fat thickness (mm) practice for the measurement of body fat volume. and BMI and between fat mass volume (kg) and BMI (kg/ m2). It was also shown that a measurement of subcutaneous fat and fat mass to predict BMI for the estimation of body fat Acknowledgements volume resulted in almost similar values. The most significant correlation was between subcutaneous fat (by sonography) This study was approved and supported by Tehran and BMI (r = 0.848, p value < 0.0001), and between fat Heart Center, Tehran University of Medical Sciences. mass (BIA) and BMI (r = 0.834, p value < 0.0001). All the All the personnel of Tehran Heart Center are gratefully other correlations between the other variables and BMI were acknowledged. also significant. Generally, correlations between different variables did not differ significantly in both genders, which means that sonographic prediction was valid in both sexes to References almost the same extent. 1. Larsson B, Svärdsudd K, Welin L, Wilhelmsen L, Björntorp P, Tibblin G. Abdominal adipose tissue distribution, obesity, and Discussion risk of cardiovascular disease and death: 13 year follow up of participants in the study of men born in 1913. Br Med J (Clin Res Ed) 1984;288:1401-1404. Our study compared alternative methods in the assessment 2. Seidell JC, Bakker CJ, van der Kooy K. Imaging techniques for of the distribution of adipose tissue. Utilization of non- measuring adipose-tissue distribution: a comparison between invasive and less expensive methods may facilitate the computed tomography and 1.5-T magnetic resonance. Am J Clin Nutr 1990;51:953-957. detection of high-risk patients and allow earlier interventions. 3. Kushner RF, Schoeller DA. Estimation of total body water by Estimation of body composition and body fat distribution bioelectrical impedance analysis. Am J Clin Nutr 1986;44:417- by a method other than BMI calculation can be a great help 424. 4. Lukaski HC, Bolonchuk WW, Hall CB, Siders WA. Validation of for the detection of cardiovascular diseases. tetrapolar bioelectrical impedance method to assess human body Among techniques for the assessment of fat tissue composition. J Appl Physiol 1986;60:1327-1332. distribution, BIA has been used to quantify the percentage 5. van der Kooy K, Leenen R, Seidell JC, Deurenberg P, Droop A, of lean and fat mass. Our results support the idea that this Bakker CJ. Waist-hip ratio is a poor predictor of changes in visceral fat. Am J Clin Nutr 1993;57:327-333. method is as useful as ultrasonography for identifying 6. Abe T, Kawakami Y, Sugita M, Yoshikawa K, Fukunaga T. Use of visceral fat. Such findings are in agreement with those of B-mode ultrasound for visceral fat mass evaluation: comparisons some previous studies.8-10 with magnetic resonance imaging. Appl Human Sci 1995;14:133- Similar to any other method, BIA has some advantages 139. 7. Leite CC, Wajchenberg BL, Radominski R, Matsuda D, Cerri and limitations: Being inexpensive and non-invasive are G , Halpern A. Intra-abdominal thickness by ultrasonography to some of its strong points, this method is highly sensitive and predict risk factors for cardiovascular disease and its correlation can easily be affected by changes in total body water and with anthropometric measurements. Metabolism 2002;51:1034- 1040. altered body temperature. Moreover, its sensitivity for the 8. Miyatani M, Kanehisa H, Fukunaga T. Validity of bioelectrical placement of electrodes (e.g., tall patients) limits its accuracy impedance and ultrasonographic methods for estimating the muscle and utilization.3, 4 Some other simple methods, like waist- volume of the upper arm. Eur J Appl Physiol 2000;82:391-396. hip ratio were not accurate enough to differ subcutaneous 9. Miyatani M, Kanehisa H, Masuo Y, Ito M, Fukunaga T. Validity of estimating limb muscle volume by bioelectrical impedance. J Appl from visceral fat and therefore, a poor predictor of change in Physiol 2001;91:386-394. visceral fat volume.5 10. Kuriyan R, Thomas T, Kurpad AV. Total body muscle mass

The Journal of Tehran University Heart Center 85 The Journal of Tehran University Heart Center Mir Hatef Shojaei et al

estimation from bioelectrical impedance analysis & simple anthropometric measurements in Indian men. Indian J Med Res 2008;127:441-446.

86 TEHRAN HEART CENTER

Original Article Radiofrequency Catheter Ablation of Atrioventricular Nodal Reentrant Tachycardia: Success Rates and Complications During 14 Years of Experience

Ahmad Yaminisharif, MD*, Gholamreza Davoodi, MD, Ali Kazemisaeid, MD, Ali Vasheghani Farahani, MD, Fatemeh Ghazanchai, Mansour Moghaddam, MD

Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran.

Received 25 January 2010; Accepted 25 February 2010

Abstract

Background: Radiofrequency catheter ablation (RFCA) has been introduced as the treatment of choice for supraventricular tachycardia. The aim of this study was to evaluate the success rate as well as procedural and in-hospital complications of RFCA for the treatment of atrioventricular nodal reentrant tachycardia (AVNRT). Methods: Between March 1995 and February 2009, 544 patients (75.9% female, age: 48.89 ± 13.19 years) underwent 548 RFCAs for AVNRT in two large university hospitals. Echocardiography was performed for all the patients before and after the procedure. Electrocardiograms were recorded on digital multichannel systems (EP-Med) or Bard EP system. Anticoagulation was initiated during the procedure. Results: From the 548 patients, 36 had associated arrhythmias, atrial flutter (4%), atrial fibrillation (0.7%), concurrent atrial fibrillation and atrial flutter (0.7%), and concealed atrioventricular pathway (0.4%). The overall success rate was 99.6%. There were 21 (3.9%) transient III-degree AV blocks (up to a few seconds) and 4 (0.7%) prolonged II- or III-degree AV blocks, 2 (0.25%) of which required permanent pacemaker insertion, 3(0.5%) deep vein thrombosis, and one (0.2%) arteriovenous fistula following the procedure. No difference was observed in the echocardiography parameters before and after the ablation. Conclusion: RFCA had a high success rate. The complication rate was generally low and in the above-mentioned centers it was similar to those in other large centers worldwide. Echocardiography showed no difference before and after the ablation. The results from this study showed that the risk of permanent II or III-degree AV block in patients undergoing RFCA was low and deep vein thrombosis was the second important complication. There was no risk of life-threatening complications. J Teh Univ Heart Ctr 2 (2010) 87-91

Keywords: Tachycardia, Atrioventricular nodal reentry • Catheter ablation • Electrophysiological techniques, Cardiac

Introduction used for a variety of arrhythmias. The application and success rate of this treatment have been reported in many centers. During the last decade, radiofrequency catheter ablation One of the most frequent applications is for the treatment of (RFCA) has proved to be a successful method and the atrioventricular nodal reentrant tachycardia (AVNRT), which treatment of choice for supraventricular tachycardia. Since is one of the most frequent causes of regular, paroxysmal the introduction of this method, it has been modified and supraventricular tachycardia. The RFCA of AVNRT has a

*Corresponding Author: Ahmad Yaminisharif, Associate Professor of Cardiology, Tehran University of Medical Sciences, Tehran Heart Center, North Kargar Street, Tehran, Iran.1411713138. Tel: +98 21 88029257. Fax: +98 21 88029256. Email: [email protected].

The Journal of Tehran University Heart Center 87 The Journal of Tehran University Heart Center Ahmad Yaminisharif et al long-term success rate ≥ 95% and a low recurrence rate.1-6 initially and gradually increased to 40 watts in a step-wise In Iran, this method was initiated in 1994 with an increasing fashion. If an accelerated junctional rhythm was recognized frequency in the following years. During a period of 14 years, within 30 seconds, the energy delivery was continued for we have experienced the RFCA of AVNRT in more than 500 a total of 1 minute. The administration of RF energy was patients. This study sought to evaluate the results of RFCA discontinued upon the occurrence of AV block, very rapid on AVNRT in two large hospitals, namely Shariati Hospital junctional rhythm, retrograde block during junctional rhythm, and Tehran Heart Center in Tehran, Iran and to evaluate the impedance rise, catheter displacement, or severe chest pain. success rate during the fourteen years of experience. The procedure was terminated if there was a significant PR prolongation of more than 50% of the baseline value during sinus rhythm. A successful ablation was defined as: Methods if arrhythmia was no longer inducible with an intravenous infusion of isoproterenol and if no more than one The study patients comprised 544 consecutive patients who atrioventricular reentrant beat occurred. underwent the RFCA for AVNRT between March 1995 and Dual AV node physiology was defined as ≥ 50 msec February 2009. All the patients had a history of paroxysmal increment in atrium-to-His (AH) following a 10-msec palpitation lasting between 1 and 25 years, and most of them decrement in coupling interval during single atrial had experienced unsuccessful treatment with different types extrastimulation or ≥ 50 msec increment in AH in of antiarrhythmic drugs. consecutive beats after a 10-msec decrement in pacing cycle Antiarrhythmic drugs were withheld for five half-lives length during incremental atrial pacing. The ablation of the prior to the ablation procedure. For the treatment of AVNRT, slow pathway was diagnosed when, after RF application, the electrophysiological study and ablation were conducted dual AV node physiology could no longer be demonstrated under local anesthesia. Intravenous heparin was administered and neither AV nodal echoes nor AVNRT could be induced with a bolus of 5000 units. with and without isoproterenol infusion. All the patients were ablated via the right-sided approach. All the patients were observed in the hospital for at least In the early years, the five-catheter approach was used, 24 hours after successful ablation, with a daily 12-lead ECG including the placement of four diagnostic catheters (in the recording. Echocardiography was performed for the patients right ventricular apex, the His bundle area, the coronary sinus, before they were discharged. and the high right atrium) plus one ablation catheter. Later, The numerical variables were presented as mean ± standard the three-catheter approach, including the placement of two deviation. The categorical variables were summarized diagnostic catheters and one ablation catheter, was applied. in percentages. The probability values of P < 0.05 were Meanwhile, a two-catheter approach using a single diagnostic considered statistically significant. electrode catheter placed in the high right atrium and one ablation catheter was utilized. Two-catheter approaches were not employed for a period of time and radiofrequency (RF) Results ablation was not continued with this method after 2 cases of atrioventricular (AV) block. Our first 7 years of practice in The study population was comprised of 544 patients one hospital was without temperature-guided RFCA, and all including 131 (24.1%) males and 413 (75.9%) females. The the procedures in the second hospital were performed using mean age of the patients was 48.89 ± 13.19 years (ranging temperature-guided catheters. Our electrophysiology study from 9 to 85). Among them, 2.7% were ≤ 18 years old and included atrial stimulation. Ventricular stimulation was 2.6% were ≥ 75. Underlying heart disease was present in 123 preceded if AVNRT was not induced by atrial stimulation; (23.2%) patients. The frequencies of the underlying heart and if sustained AVNRT (lasting ≥ 30 sec) was not induced diseases are listed in Table 1. It should be noted that 86.7% by this protocol, isoproterenol (1μg/min) was administered of the patients had no history of systemic disease. until the basic sinus rhythm was increased by ≥ 20%, and the More than 91.2% of the patients experienced treatment stimulation protocol was repeated. with different antiarrhythmic drugs, including 15.0% After the confirmation of AVNRT, a standard 7F ablation calcium channel blockers, 15.5% beta blockers, 4.2% catheter was introduced via the right femoral vein to the Sotalol, and 1.1% digoxin. The rest of the patients had tricuspid annulus for RFCA. We used both anatomical used a combination of different drugs during the period and electrical approaches for ablation. The radiofrequency of their palpitation. The frequency of associated cardiac energy used in each approach was 25-40 W. RF energy was diseases in the study population prior to AVNRT ablation delivered with a temperature setting of 70°C using an initial is shown in Table 1. Among these patients, the men had a power of 25 watts, which was gradually increased up to greater incidence of associated valvular and ischemic heart 40 watts if necessary. In patients who were treated without diseases; except for mitral valve prolapse, which presented temperature-guided RF generator, the energy was 25 watts more frequently in the women. Almost all the approaches

88 Radiofrequency Catheter Ablation of Atrioventricular Nodal Reentrant ... TEHRAN HEART CENTER were via the femoral vein; subclavian or internal jugular vein for all the patients before they were discharged. No change approaches were, however, used in some cases for coronary was observed in the echocardiography parameters after the sinus (CS) mapping. ablation compared to the echo findings before the procedure, including grade of tricuspid regurgitation and presence of Table 1. Frequency of associated cardiac diseases in patients prior to pericardial effusion. AVNRT ablation Number Frequency Mitral valve prolapse 35 6.4% Discussion Congenital heart disease 5 0.9% Valvular heart disease 44 8% This study confirms that it is safe and feasible to perform Ischemic heart disease 34 6.1% RFCA for the treatment of AVNRT with a high success rate Hypertension 39 7.1% and a low complication rate. We observed a high success rate (99.6%) as well as low incidence of complications (2.9%) Diabetes mellitus 23 4.2% and need for permanent cardiac pacing (0.4%). None of the Congestive heart failure 1 0.2% patients under 31 years of age was complicated. The risk Hypertension & diabetes mellitus 10 1.8% of permanent AV block in patients who underwent slow AVNRT, Atrioventricular nodal reentrant tachycardia pathway ablation in this study was low. RFCA has been an available option for the management All the patients had sustained AVNRT induced with or of supraventricular tachycardia since 1990 and is now the without the administration of isoproterenol. All AVNRT procedure of choice for the treatment of AVNRT. Several arrhythmias were common type (slow-fast) except one pure studies have reported the results of the RFCA of AVNRT. uncommon AVNRT (fast-slow). A total of 36 patients had The results of the present study were similar to those from associated arrhythmias: atrial flutter in 22 (4%) patients, these reports including multicenter studies.2-9 atrial fibrillation in 4 (0.7%), and concurrent atrial fibrillation The initial approach to the RFCA of AVNRT was the and atrial flutter in 4 (0.7%). With the exception of atrial modification of the fast pathway of AV conduction by fibrillation, the other associated arrhythmias were also lesions placed near the anterosuperior aspect of the triangle subjected to RFCA. A concomitant concealed atrioventricular of Koch.10, 11 The results of this approach demonstrated pathway was identified in two (0.4%) patients; one of the longer PR intervals with longer AH intervals and longer pathways was located in the left lateral free wall and one antegrade Wenckebach cycle lengths and also significant risk located in the right posteroseptal wall. of producing complete AV block necessitating permanent A concomitant Wolff-Parkinson-White syndrome (WPW) pacemaker implementation in as many as 15-20% of was also found in four (0.7%) patients; three pathways were cases.12 located in the right posteroseptal and one in left posterolateral Radiofrequency modification or ablation of the slow wall. pathway, as an alternative technique, was developed to The rate of successful ablation was 99.6%. The two- diminish these risks. This method has become the procedure catheter approach was used in 80 (14.6%) procedures, while of choice in AVNRT. After presenting the theory that the the multi-catheter approach was applied in the remaining reentrant circuit in AVNRT may not be confined to the 468 (85.4%). In 2 (0.4%) patients, the procedure failed in AV node but rather may incorporate the perinodal atrial spite of a long procedural time. myocardium,10, 13 further studies localized the slow pathways There was no in-hospital complication in 519 (94.9%) of fibers inferior toward the coronary sinus ostium.14 The the procedures. Transient second- or third-degree AV block results of this approach have shown it to be extremely was observed in 21 (3.8%) patients, all of whom recovered effective. In contrast to fast pathway modification, there is no within a few minutes. Two of the patients experienced II- significant change in the PR interval, the AH interval, or the degree AV block, which returned to normal conduction AV Wenckebach cycle length in this technique.13, 15, 16 More within a few days after the ablation; these two patients importantly, there is a lower rate of complications reported were ablated using a two-catheter approach. Permanent with this technique, including a lower risk of complete AV III-degree AV block occurred in 2 patients; both were older block as shown in several studies. than 60 years and required the implantation of permanent Despite anticoagulation, deep vein thrombosis developed pacemakers. Deep vein thrombosis developed in three in three (0.5%) patients early after the procedure in our (0.5%) patients early after the procedure; one of the patients institution (one with a history of oral contraception and the was on oral contraceptive prior to ablation. There was no other two without any risk factor for systemic embolism). bleeding complication. Femoral arterio-venous fistula was We did not observe bleeding complications such as cardiac observed in one (0.2%) patient. All the complicated patients tamponade, pericardial effusion, and significant hematoma. were over 31 years old. Echocardiography was performed Recently published guidelines from the Committee of the

The Journal of Tehran University Heart Center 89 The Journal of Tehran University Heart Center Ahmad Yaminisharif et al

European Heart Rhythm Association17 suggested that right- a friendly working environment and their kind assistance sided procedures (except atrial flutter) are at a low risk of in data gathering. This study was supported by Tehran thromboembolism during and after the procedure and the University of Medical Sciences. risk of bleeding seems to be higher with anticoagulation. This consensus document recommended that anticoagulation therapy is not necessary for right-sided procedures (during, References and after the procedures) unless other risk factors for 1. Wang L, Li J, Yao R, Song S, Guo Z. Long-term follow-up of systemic embolism are present. In our experience, deep vein patients with P-R prolongation after catheter ablation of slow thrombosis was second serious complication after right-sided pathway for atrioventricular node re-entrant tachycardia. Arch ablation even during anticoagulation. Med Res 2004;35:442-445. As AVNRT is a definitive treatment by catheter-based 2. Roman CA, Moulton KP, Twidale N, Hazlitt HA, Prior MI. Treatment of supraventricular tachycardia due to atrioventricular RF energy delivery at the slow pathway area, it results in nodal reentry, by radiofrequency catheter ablation of slow-pathway improved quality of life more than medications do.18 Its conduction. N Engl J Med 1992;327:313-318. advantages include relief of symptoms, improvement in 3. Wu D, Yeh SJ, Wang CC, Wen MS, Chang HJ, Lin FC. Nature of functional capacity and the quality of life, elimination of the dual atrioventricular node pathways and the tachycardia circuit as defined by radiofrequency ablation technique. J Am Coll Cardiol need for lifelong antiarrhythmic-drug therapy, and long-term 1992;20:884-895. cost savings.19 In the present study, more than 91% of the 4. Kay GN, Epstein AE, Dailey SM, Plumb VJ. Selective patients experienced treatment by different antiarrhythmic radiofrequency ablation of the slow pathway for the treatment of atrioventricular nodal reentrant tachycardia. Evidence for drugs with no significant improvement in their condition. involvement of perinodal myocardium within the reentrant circuit. Multiple venous sheath placements in the femoral veins Circulation 1992;85:1675-1688. are always required for multiple intracardiac catheter 5. Jazayeri MR, Hempe SL, Sra JS, Dhala AA, Blanck Z, Deshpande insertion. It has been reported20 that multiple venous sheath SS, Avitall B, Krum DP, Gilbert CJ, Akhtar M. Selective transcatheter ablation of the fast and slow pathways using (up to 3 sheaths) placements in a single femoral vein is radiofrequency energy in patients with atrioventricular nodal acceptably safe in patients who have undergone EPS and RF reentrant tachycardia. Circulation 1992;85:1318-1328. ablation, even though non-occlusive deep vein thrombosis 6. Langberg JJ, Leon A, Borganelli M, Kalbfleisch SJ, el-Atassi R, Calkins H. A randomized, prospective comparison of anterior may develop in some patients. As we inserted more than two and posterior approaches to radiofrequency catheter ablation catheters in one femoral vein, it might have increased the of atrioventricular nodal reentry tachycardia. Circulation tendency for developing deep vein thrombosis. The results 1993;87:1551-1556. of this study are limited to short-term follow-ups as long 7. Wanga L, Wub T. Predictors of long-term success in catheter ablation of atrioventricular nodal reentrant tachycardia: a as 3 months; as a result, the recurrence rate and long-term multivariate regression analysis. Int J Cardiol 2002;86:289-294. results were not evaluated. Furthermore, the fact that this 8. Hu DY, Wang LX. Catheter radiofrequency ablation of slow pathway study was a retrospective one precluded a report on all the in patients with atrioventricular nodal re-entrant tachycardia. Int J Cardiol 1993;39:203-208. electrophysiological data of the patients. 9. Baker JH, Plumb VJ, Epstein AE, Kay GN. Predictors of recurrent atrioventricular nodal reentry after selective slow pathway ablation. Am J Cardiol 1994;73:765-769. Conclusion 10. Ro PS, Rhodes LA. Atrioventricular node reentry tachycardia in pediatric patients. Prog Pediatr Cardiol 2001;13:3-10. 11. Huang SKS. Modification of atrioventricular conduction via the RFCA had a high success rate. The in-hospital complication anterior approach for treatment of atrioventricular nodal reentrant rate was generally low, and in the aforementioned centers it tachycardia. In: Huang SKS, ed. Radiofrequency Catheter Ablation of Cardiac Arrhythmias. Basic Concepts and Clinical Applications. was similar to those in other large centers worldwide. The 2nd ed. New York: Futura Publishing Company; 1995. p. 159- results of our echocardiography evaluations were similar 170. before and after the ablation. The risk of permanent II or III- 12. van Hare GF. Supraventricular tachycardia. In: Gillette PC, Garson degree AV block in the patients undergoing RFCA was low. Jr. AR, eds. Clinical Pediatric Arrhythmias. 2nd ed. Philadelphia: WB Saunders; 1999. p. 97-120. There was no risk of life-threatening complications. Deep 13. Kay GN, Epstein AE, Dailey SM, Plumb VJ. Selective vein thrombosis was the second important complication. radiofrequency ablation of the slow pathway for the treatment Although there is a trend to mange the procedure without of atrioventricular nodal reentrant tachycardia. Circulation anticoagulation, the risk of deep vein thrombosis even after 1992;85:1675-1688. 14. Kay GN, Plumb VJ. Selective slow pathway ablation (posterior anticoagulation is still a challenging issue. approach) for treatment of atrioventricular nodal reentrant tachycardia. In: Huang SKS, ed. Radiofrequency Catheter Ablation of Cardiac Arrhythmias. Basic Concepts and Clinical Applications. 2nd ed. New York: Futura Publishing Company; 1995. p. 171- Acknowledgements 173. 15. Wathen M, Natale A, Wolfe K, Yee R, Newman D, Klein G. An We would like to thank all the staff of the filing department anatomically guided approach to atrioventricular node slow in Tehran Heart Center and Shariati Hospital for providing pathway ablation. Am J Cardiol 1992;70:886-889.

90 Radiofrequency Catheter Ablation of Atrioventricular Nodal Reentrant ... TEHRAN HEART CENTER

16. Jackman WM, Beckman KJ, McClelland JH, Wang X, Friday KJ, Roman CA, Moulton KP, Twidale N, Hazlitt HA, Prior MI. Treatment of supraventricular tachycardia due to atrioventricular nodal reentry by radiofrequency catheter ablation of slow-pathway conduction. N Engl J Med 1992;327:313-318. 17. Blanc JJ, Almendral J, Brignole M, Fatemi M, Gjesdal K, González- Torrecilla E, Kulakowski P, Lip GY, Shah D, Wolpert C; Scientific initiatives committee of the European heart rhythm association. Consensus document on antithrombotic therapy in the setting of electrophysiological procedures. Europace 2008;10:513-527. 18. Bathina MN, Mickelsen S, Brooks C, Jaramillo J, Hepton T, Kusumoto FM. Radiofrequency catheter ablation versus medical therapy for initial treatment of supraventricular tachycardia and its impact on quality of life and healthcare costs. Am J Cardiol 1998;82:589-593. 19. Morady F. Radio-Frequency Ablation as Treatment for Cardiac Arrhythmias. N Engl J Med 1999;340:534-544. 20. Chen JY, Chang KC, Lin YC, Chou HT, Hung JS. Safety and outcomes of short-term multiple femoral venous sheath placement in cardiac electrophysiological study and radiofrequency catheter ablation. Jpn Heart J 2004;45:257-264.

The Journal of Tehran University Heart Center 91 The Journal of Tehran University Heart Center

Case Report

Single Stage Aortic Valve Replacement and Splenectomy in a Patient with Severe Aortic Stenosis

Rezayat Parvizi, MD, Rasoul Ibrahim Abdulrahman, MD*, Rezvaneh Salehi, MD, Ghader Shah Mohamadi, MD

Cardiovascular Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran.

Received 09 September 2008; Accepted 25 May 2009

Abstract

Splenomegaly-induced thrombocytopenia is fully described in hematological and surgical literature, but its association with severe aortic stenosis is rare. We present a case of severe aortic valve stenosis with severe splenomegaly-induced thrombocytopenia in which aortic valve replacement was done with a number 23 homograft and splenectomy was performed after the end of cardiopulmonary bypass. Platelet count turned to normal value post-operatively, and the patient spent an ordinary convalescence period and was discharged from the hospital without any complications. J Teh Univ Heart Ctr 2 (2010) 92-94

Keywords: Thrombocytopenia • Splenomegaly • Aortic valve stenosis

literature, and this condition has profound implications in pa- Introduction tients undergoing cardiac surgery with the aid of cardiopul- monary bypass, where heparin is used for anti-coagulation.3-5 Acquired abnormalities of platelets may be quantitative This dilemma is further complicated in the setting of a young or qualitative, although some patients have both types of de- patient undergoing aortic valve replacement, in which the in- fects. Quantitative defects may be a result of the failure of sertion of a mechanical prosthesis would be the procedure of production, shortened survival, or sequestration. The latter choice. This requires life-long anticoagulation with Warfa- is an important cause of thrombocytopenia and usually in- rin, which can predispose the patient to catastrophic bleed- volves the sequestration of platelets in an enlarged spleen ing; using a tissue valve will subject the patient to multiple from any cause (portal hypertension, sarcoidosis, lympho- redo operations in the patient’s lifetime. ma, or Gaucher’s disease). The total body platelet mass is essentially normal in patients with hypersplenism; however, a much larger fraction of the platelets than normal are in the Case report enlarged spleen, in which case splenectomy is indicated to correct the thrombocytopenia. (Except in thrombocytopenia A 22-year-old woman was referred to our cardiac center for caused by portal hypertension).1, 2 the consideration of aortic valve replacement. She had been The presence of concomitant severe aortic valve stenosis diagnosed with severe aortic valve stenosis seven months with splenomegaly-induced thrombocytopenia, which neces- previously. The aortic valve was bicuspid, and there was no sitates aortic valve replacement, is rare. No clear guideline significant associated left ventricular hypertrophy. She had exists for the pre-and post-operative management of patients peptic ulcer disease, iron deficiency anemia, and regular undergoing cardiac surgery in the hematological and surgical menstruation history. The patient’s complaint was fatigue,

*Corresponding Author: Rasoul Ibrahim Abdulrahman, Assistant Professor of Cardiac Surgery, Department of Cardiothoracic Surgery, Cardiovascular Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran. 51665/404. Tel: +98 411 3373919. Fax: +98 411 3344021. E-mail: [email protected].

92 Single Stage Aortic Valve Replacement and Splenectomy in a Patient with Severe Aortic Stenosis TEHRAN HEART CENTER dyspnea, and palpitation, and auscultation revealed systolic a number 23 homograft using the mini root technique. At murmur. There was huge splenomegaly on abdominal the end of cardiopulmonary bypass, the median sternotomy palpation. incision was extended to the above umbilicus; and the layers Biochemical findings were anemia (Hb = 8) were closed anatomically after splenectomy. and thrombocytopenia (platelet count = 50,000). Electrocardiography showed mild ventricular hypertrophy, and chest radiography was normal. Echocardiography revealed Discussion that the aorta was dilated, the aortic valve was calcified, the bicuspid leaflets had moderate aortic stenosis, and there was The presence of concomitant severe aortic valve stenosis moderate to severe aortic regurgitation. The diameters of the and splenomegaly is not common. We believe that open annulus, sino-tubular junction, and the proximal ascending heart surgery valve replacement and splenectomy can aorta were19, 30, and 32mm, respectively, and the dilated be successfully performed simultaneously in a patient part of the aorta was 40mm. In addition, left ventricular with thrombocytopenia and severe aortic valve stenosis. ejection fraction was 60 % ( Figure1). In our patient, splenectomy was performed at the end of cardiopulmonary bypass for aortic valve replacement with good results. There was no post-operative complication, and the patient had ordinary convalescence with a normalized platelet count. The decision to choose a mechanical versus tissue prosthesis in young thrombocytopenia patients with aortic valve stenosis is not an easy one. Laboratory investigations and/or markers can determine whether a patient is more prone to bleeding or to thrombosis, so clinical strategy needs to be tailored on the basis of the clinical presentation of thrombocytopenia and the risks and benefits of the treatment options available.4, 5

Conclusion

It is advisable that splenomegaly be addressed at the time of open heart valve surgery and not during staged operation inasmuch as it can avert secondary operation, eliminate the cause of thrombocytopenia, return normal platelet count immediately after surgery, and confer liberal decision to choose the prosthesis without the fear of thrombocytopenia complications. Meanwhile, it is possible to decrease the disadvantage of bleeding complications of one-stage operation by meticulous dissection, proper hemostasis, reversing heparin at the end of the procedure, and justifying the use of coagulating factors.

Figure 1. Echocardiography showing severe aortic stenosis and moderate to References severe aortic regurgitation AV, Aortic valve; V max, Velocity maximum; V mean, Velocity mean; 1. Seymour I. Schwartz SI. Role of splenectomy in hematologic disorders. World J Surg 1996:20:1156-1159. Max PG, Maximum pressure gradient; Mean PG, Mean pressure gradient; 2. Tefferi A, Murphy s. Current opinion in essential thrombo- VTI, Velocity time integral; Env Ti, Envelope time; HR, Heart rate; AR, cythemia: pathogenesis, diagnosis, and management. Blood Rev Aortic regurgitation; PHT, Pressure half time; Dec Time, Deceleration time; 2001;15:121-131. 3. Sato Y, Yokoyama H, Watanabe M, Hamada O. A surgical case Dec Slope, Deceleration slope of aortic valve replacement in patient with chronic idiopathic thrombocytopenic purpura. Fukushima J Med Sci 2004;50:29-35. After median sternotomy and pericardiectomy, 4. Mori Y, Hadama T, Takasaki H, Oka K, Shigemitsu O, Miyamoto cardiopulmonary bypass was initiated and the severely S, Kimura T, Anai H, Tanaka K, Uchida Y. Aortic valve calcified stenotic bicuspid aortic valve was replaced with replacement and splenectomy in a patient with chronic idiopathic

The Journal of Tehran University Heart Center 93 The Journal of Tehran University Heart Center Rezayat Parvizi et al

thrombocytopenic purpura: preoperative management with high- dose gamma-globulin. Heart Vessels 1991;6:121-124. 5. Ahmed K, Vohra HA, Milne A, Langley SM. Aortic valve replacement in a young patient with essential thrombocytosis. J Cardiothorac Surg 2008;3:5.

94 TEHRAN HEART CENTER

Case Report

Quadricuspid Aortic Valve Diagnosed by Transesophageal Echocardiography: A Case Report

Farahnaz Nikdoust, MD1, Hakimeh Sadeghian, MD1, Bahareh Eslami, MD1, Dariush Javidi, MD2 ,٭Shahla Majidi, MD1

1Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran. 2Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

Received 14 December 2008; Accepted 19 April 2009

AbstractAbstract

Quadricuspid aortic valve (QAV) is an uncommon congenital anomaly which was an incidental finding during surgery or autopsy in the past. We present the case of a 44-year-old woman with moderately severe aortic regurgitation due to unequal cusp size QAV diagnosed via transesophageal echocardiography. Due to echocardiographic imaging improvement, the diagnosis of QAV is now easier and earlier than the past.

J Teh Univ Heart Ctr 2 (2010) 95-97

Keywords: Echocardiography, transesophageal • Aortic valve • Aortic valve insufficiency

Introduction (TTE) examinations, in which only moderate to severe aortic insufficiency was detected. Because of the deterioration of Quadricuspid aortic valve (QAV), a rare congenital heart her dyspnea, she was referred to Tehran Heart Center for defect with an incidence range of 0.008 % to 0.033%,1, 2 was TEE evaluations. first reported by Balington et al.3 In former years, QAV was On physical examination, she had a grade II/VI decrescendo an accidental finding during surgery or necropsy, but recent diastolic murmur in the second intercostal space of the right improvements in echocardiographic imaging techniques sternal border with no radiation and a wide pulse pressure. have conferred an easier and earlier detection of QAV. Here- Blood pressure was 170/70 mmHg with a normal pulse in, we report a case of QAV diagnosed via transesophageal rate, and lung auscultation was normal. Chest radiography echocardiography (TEE). showed a CT ratio at the upper limit of normal; and normal sinus rhythm, normal axis deviation, and left ventricular (LV) hypertrophy were detected on the electrocardiogram. Case report Angiography reported an ejection fraction (EF) of 50%, severe aortic insufficiency, mild aortic root dilatation, LV A 44-year-old woman presented with a history of dyspnea pressure of 150/0-15, aortic pressure of 150/80, and normal on exertion (New York Heart Association functional class II) coronary artery. starting 7 years previously and aggravated in the previous In the treadmill exercise test, she developed fatigue in 2-3 years. Her past medical history revealed hypertension stage III of the Bruce protocol (after 6 minutes). and hypothyroidism, without a positive family history of In TTE, there was mild LV and left atrial dilation with normal heart diseases. She had been under observation for the past LV systolic function (left ventricular end-diastolic diameter 3 years and undergone two transthoracic echocardiography = 57 mm, left ventricular end-systolic diameter = 41 mm, left

*Corresponding Author: Shahla Majidi, Department of Cardiology, Tehran Heart Center, North Kargar Street, Tehran, Iran. 1411713138. Tel & Fax: +98 21 88029256. Email: [email protected].

The Journal of Tehran University Heart Center 95 The Journal of Tehran University Heart Center Farahnaz Nikdoust et al ventricular EF = 55%), moderately severe aortic insufficiency and most dominant abnormalities due to QAV are different with no aortic stenosis, moderate mitral regurgitation, degrees of aortic insufficiency because of malcoaptation of normal right ventricle size and function, mild tricuspid the leaflets.11, 17 Similarly, aortic valve leaflets could not meet regurgitation, and pulmonary artery pressure = 36 mmHg. each other centrally in our patient. TEE was performed for further evaluations of the aortic and mitral valves with regard to the severity and mechanism of the insufficiency of the aortic and mitral valves. After Conclusion precise evaluation, TEE confirmed moderate to severe aortic insufficiency (Figure 1) and moderate mitral regurgitation QAV is an uncommon congenital anomaly which was and also revealed QAV (Figure 2) and the prolapse of both accidentally found in surgery or autopsy in former years. mitral leaflets as the mechanisms of the valvular regurgitation, Aortic insufficiency is the most prevalent abnormalities respectively. Apart from a small patent foramen ovale, no associated with QAV. Nowadays, in tandem with advances dilation of the sinus of Valsalva or ascending aorta was in echocardiographic imaging, TEE helps us to identify QAV visualized. earlier and to manage it more appropriately.

Discussion

A rare congenital heart defect, QAV has an incidence range of 0.008 % to 0.033%.1, 2 It was first reported by Balington et al. in 1826.3 QAV used to be an accidental finding during aortography,4 surgery, or autopsy; currently however, TTE and TEE are the methods of choice in the detection of QAV. It is deserving of note that similar to our case, TTE is reported to only detect aortic regurgitation and not QAV in some patients.5 According to the leaflet morphology, 7 types of QAV are described by Hurwitz and Roberts, named from A to G.2 Because of 1 large cusp, 2 intermediate-sized cusps, and 1 small cusp, our patient was set in type D. In this case, the placement of the left coronary artery was normal. Figure 1. Moderately severe aortic regurgitation by transesophageal Holm et al. reported a case with a large left main coronary echocardiography (arrow) seen in the short-axis view of the aortic valve artery originating unusually low in the aortic root near the LA, Left atrium; RA, Right atrium posterior margin of the left cusp, which produced a “4-leaf clover” appearance.6 And Kaminishi et al. reported a widely patent left coronary ostium in their case.7 QAV is a single malformation which is rarely associated with other congenital defects, including paroxystical supraventricular tachycardia, right double kidney with double renal pelvis and double proximal ureter, hypertrophic obstructive and non-obstructive cardiomyopathy, patent duct, atrial septal defect, ventricular septal defect, pulmonary valve stenosis, bicuspid pulmonary valve, and malformation of the mitral valve.8-12 Associated mitral valve anomalies which are reported include severe mitral regurgitation, prolapsed mitral valve causing a mild regurgitation, mitral regurgitation resulting from annulus dilatation and thickening of the anterior leaflet, severe mitral regurgitation due to infective endocarditis, ruptured mitral valve aneurysm, and hypoplastic anterior mitral leaflet.12-16 Figure 2. Quadricuspid aortic valve (arrow) by transesophageal echocar- In the case presented herein, there was a concomitant patent diography seen in the short-axis view of the aortic valve foramen ovale and eccentric moderate mitral regurgitation LA, Left atrium; PA, Pulmonary artery; QAV, Quadricuspid aortic valve; due to prolapsed mitral valve leaflets. Aortic stenosis is rare, RA, Right atrium; RV, Right ventricle

96 Quadricuspid Aortic Valve Diagnosed by Transesophageal Echocardiography: A Case Report TEHRAN HEART CENTER

References

1. Simonds JP. Congenital malformation of aortic and pulmonary valves. Am J Med Sci 1923;166:584-595. 2. Hurwitz LE, Robert WC. Quadricuspid semilunar valves. Am J Cardiol 1973;31:623-626. 3. Balington, quoted by Robicsek F, Sanger PW, Daugherty HK. Congenital quadricuspid aortic valve with displacement of the left coronary orifice. Am J Cardio 1969;23:288-290. 4. Chang PC, Lin CC, Lee CS, Wang PH, Chen YF. Rare anatomic entity of quadricuspid aortic valve with aortic insufficiency: a case report. Kaoshiung J Med Sci 2007;23:422-425. 5. Formica F, Sangalli F, Ferro O, Paolini G. A rare cause of severe aortic regurgitation: quadricuspid aortic valve. Interact Cardiovasc thorac surg 2004;3:672-674. 6. Holm H, Jacobson S, Reul GJ, Stainback RF. Quadricuspid aortic vavle. Tex Heart Ins J 2004;31:450-451. 7. Kaminishi Y, Terada Y, Nakamura K, Gomi S, Sato F, Mihara W, Enomoto Y, Sakakibara Y, Jikuya T, Atsumi N, Shigeta O, Mitsui T. Aortic valve regurgitation due to quadricuspid valve. A report of complicated case. Kyobu Geka 1997;50:63-66. 8. Vohra RK, Singh H, Failinger CF. A quadricuspid aortic valve with atrial septal defect. Echocardiography 2006;23:865-868. 9. Nucifora G, Badano LP, Iacono MA, Fazio G, Cinello M, Marinigh R, Fioretti PM. Congenital quadricuspid aortic valve associated with obstructive hypertrophic cardiomyopathy. J Cardiovasc Med (Hagerstown) 2008;9:317-318. 10. Turhan S, Tulunay C, Sayin T, Ozdol C, Kilickap M, Dincer I. Two cases of quadricuspid aortic valve. Eur J Echocardiography 2006;7:330-331. 11. Janssens U, Klues HG, Hanrath P. Congenital quadricuspid aortic valve anomaly associated with hypertrophic non-obstructive cardiomyopathy: a case report and review of the literature. Heart 1997;78:83-87. 12. Podesta A, Dottori V, Parodi E, Crivellari R, Regesta T, Passerone GC. Quadricuspid aortic valve, parossistyc supraventricular tachycardia and double right kidney: an uncommon association. Minerva Cardioangiol 2001;49:75-79. 13. Di Pino A, Gitto P, Silvia A, Bianca I. Congenital quadricuspid aortic valve in children. Cardiol Young 2008;14:1-4. 14. Irisawa T, Yoshiya K, Yokosawa T, Iwamatsu T, Arai K, Aoki T. A case of quadricuspid valve associated with mitral regurgitation. Kyobu Geka 1993;46:618-621. 15. Asami H, Asano H, Handa N, Nakamura S, Ogiwara M, Ueda K, Kyo S, Yokote Y, Omoto R. A surgical case of quadricuspid aortic valve associated aortic regurgitation and severe mitral regurgitation due to infective endocarditis. Kyobu Geka 1998;51:216-219. 16. Goh K, Yamamoto H, Inaba M, Kakuchi H, Sasajima T. Ruptured mitral valve aneurysm in patient with quadricuspid aortic valve. J Cardiovasc Surg (Torino) 2000;41:393-394. 17. Feldman BJ, Khanderia BK, Wames CA, Seward JB, Taylor CL, Tajik AJ. Incidence, description and functional assessment of isolated quadricuspid aortic valves. Am J Cardiol 1990;65:937-938.

The Journal of Tehran University Heart Center 97 The Journal of Tehran University Heart Center

Case Report

Perivalvular Abscess of Tricuspid Valve: A Rare Complication of Infective Endocarditis

Ali Reza Moaref, MD, Yadallah Mahmoody, MD*, Khallil Zarrabie, MD

Faghihi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.

Received 24 February 2009; Accepted 26 July 2009

Abstract

Infective endocarditis is a serious complication of intravenous (IV) drug abuse, with a reported mortality of 5 to 10%. A 21-year-old man, who was an intravenous drug abuser, presented with fever and dyspnea. Transthoracic echocardiography showed a highly mobile, large vegetation on the anterior leaflet of the tricuspid valve. Despite antibiotic therapy for ten days, the patient remained febrile. Transesophageal echocardiography revealed severe aortic regurgitation and an echo- lucent space between the tricuspid and aortic valves. Color Doppler demonstrated a flow within the echo-lucent space and a connection between that and the left ventricle, suggesting a perivalvular abscess of the tricuspid valve opening in the left ventricle. The patient was transferred to the operating room, where he unfortunately expired. J Teh Univ Heart Ctr 2 (2010) 98-100

Keywords: Endocarditis • Tricuspid valve • Abscess

Introduction (TTE) for the detection of vegetations in patients with native valve endocarditis (NVE) is approximately 65%, whereas that The incidence of infective endocarditis (IE) remained of transesophageal echocardiography (TEE) in these patients relatively stable from 1950 through 2000 at about 3.6 to is 85 to 95%.2 TEE is the preferred approach in patients in 7.0 cases per 100,000 patient-years.1 In selected areas, whom TTE is technically suboptimal and is the procedure of the incidence may rise because of the concentration of choice for imaging the pulmonic valve.3 When initial TEE is populations at uniquely high risk of infection, specifically negative and the clinical suspicion of IE remains, repeating intravenous (IV) drug abusers. The risk of IE among IV drug TEE within 7 to 10 days is advocated.4 abusers, 2 to 5% per patient-years, is several-fold greater than Perivalvular abscess or intracardiac fistula formation occurs that for patients with rheumatic heart disease or prosthetic in 10 to 14% of patients with NVE.6 Persistent, otherwise valves. IE is located on the tricuspid valve in 46 to 58% of unexplained, fever despite appropriate antimicrobial therapy patients with IV drug abuse. IV drug abuse is a risk factor for in patients with IE suggests infection extending beyond recurrent native valve endocarditis. Staphylococcus aureus the valve leaflet. Perivalvular abscess of the tricuspid causes more than 50% of IE occurring in IV drug abusers valve is very rare. TEE is superior to TTE for detecting overall and 60 to 70% of infection involving the tricuspid invasive infection in patients with NVE and prosthetic valve valve. endocarditis (PVE). Cardiac surgery should be considered to The clinical manifestation of IE in IV drug abusers depends debride abscesses, allowing the eradication of uncontrolled on the valve involved and, to a lesser degree, on the infecting infection, and to reconstruct cardiac structures, restoring organism. The sensitivity of transthoracic echocardiography homodynamic and alleviating congestive heart failure.

*Corresponding Author: Yadallah Mahmoody, Cardiovascular Research Center, Faghihi Hospital, Zand Street, Shiraz, Iran. Tel: +98 917 7203241. Fax: +98 711 2343529. E-mail: [email protected].

98 Perivalvular Abscess of Tricuspid Valve: A Rare Complication of Infective Endocarditis TEHRAN HEART CENTER

Case report Color Doppler demonstrated a flow within the echo-lucent space and a connection between that and the left ventricle, A 21-year-old man, who was an IV drug abuser, presented suggesting a perivalvular abscess of the tricuspid valve with fever and dyspnea. TTE showed highly mobile, large opening in the left ventricle (Figure 2). After consultation vegetation on the anterior leaflet of the tricuspid valve and with a cardiac surgeon, the patient was transferred to the no vegetation on the aortic valve, mitral valve, and pulmonic operating room, where he unfortunately expired due to severe valve. The patient was admitted to the cardiology ward for bleeding and disseminated intravascular coagulation. antibiotic therapy and received vancomycin and gentamycin. The blood culture of the patient became positive for staphylococcus areus 3 times in 24-hour intervals. Despite Discussion the antibiotic therapy for 10 days, the patient remained febrile and developed severe dyspnea. TEE revealed severe IE is a serious complication of IV drug abuse, with a reported aortic insufficiency, moderate tricuspid regurgitation, and an mortality of 5 to 10%.1 Endocarditis in IV drug abusers echo-lucent space between the tricuspid and aortic valves commonly involves the tricuspid valve, and Staphylococcus (Figures 1). aureus is the most common causative organism. Fever and chills are the most common symptoms. Dyspnea, cough, and chest pain are the common complaints of IV drug users. This is likely related to the predominance of tricuspid valve endocarditis in this group and secondary embolic showering of the pulmonary vasculature. Within a week after the initiation of effective antimicrobial therapy, almost 70% of patients with NVE or PVE are afebrile and 90% have defervesced by the end of the second week of treatment.5 Persistence or recurrence of fever more than 10 days after the initiation of antibiotic therapy identifies patients with increased mortality rates and with complications of infection or therapy.5 Patients with a prolonged or recurrent fever should be evaluated for intracardiac complications. Perivalvular infection beyond the valve leaflet results in abscesses in the annulus or adjacent structures, intracardiac Figure 1. Short axis view shows the echo lucent space (abscess) between the fistulas, and purulent pericarditis. Periannular extension is tricuspid and aortic valve (arrow) common, occurring in 10 to 40% of all native valve IE and LA, Left atrium; RA, Right atrium; AV, Aortic valve; TV, Tricuspid valve complicates aortic valve endocarditis more commonly than mitral or tricuspid valve endocarditis.3 Intra-cardiac fistulas are rarely seen and they are estimated to account for < 1% of all cases of IE.6 Fistulization of the paravalvular abscess has been found in 6 to 9% of all cases.7 Perivalvular abscess and intracardiac fistula of the tricuspid valve is very rare. TEE is the method of choice for abscess detection. IE is a lethal disease if not treated aggressively with parental antibiotics, often in combination with surgery. Cardiac surgery should be considered in patients with perivalvular abscess and intracardiac fistula to debride abscesses and to reconstruct cardiac structures, restoring homodynamic and alleviating congestive heart failure.

Conclusion Figure 2. Color Doppler imaging demonstrating the flow within the echo lucent space and connection between that and left ventricle (LV) Perivalvular abscess of the tricuspid valve is a rare LA, Left atrium; RV, Right ventricle complication of infective endocarditis. TEE is the method of choice for abscess detection.

The Journal of Tehran University Heart Center 99 The Journal of Tehran University Heart Center Ali Reza Moaref et al

References

1. Moreillon P, Que YA. Infective endocarditis. Lancet 2004;363:139- 149. 2. Baddour LM, Wilson WR, Bayer AS, Fowler VG Jr, Bolger AF, Levison ME, Ferrieri P, Gerber MA, Tani LY, Gewitz MH, Tong DC, Steckelberg JM, Baltimore RS, Shulman ST, Burns JC, Falace DA, Newburger JW, Pallasch TJ, Takahashi M, Taubert KA; Committee on rheumatic fever, endocarditis, and Kawasaki disease; Council on cardiovascular disease in the young; Councils on clinical cardiology, stroke, and cardiovascular surgery and anesthesia; American heart association; Infectious diseases society of America. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on rheumatic fever, endocarditis, and Kawasaki disease, Council on cardiovascular disease in the young, and the Councils on clinical cardiology, stroke, and cardiovascular surgery and anesthesia, American heart association: endorsed by the Infectious diseases society of America. Circulation 2005;111:e394-434. 3. Bayer AS, Bolger AF, Taubert KA, Wilson W, Dajani AS, Gage TW, Ferrieri P. Diagnosis and management of infective endocarditis and its complications. Circulation 1998;98:2936-2948. 4. Baddour LM, Wilson WR, Bayer AS, Fowler VG, Bolger AF. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications. Circulation 2005;111:3167-3184. 5. Karchmer AW. Infections of prosthetic heart valves. In: Waldvogel F, Bisno AL, eds. Infections Associated with Indwelling Medical Devices. 3rd ed. Washington, DC: American Society for Microbiology; 2000. p. 145-172. 6. Sexton DJ, Bashore TM. Infective endocarditis. In: Topol EJ, ed. Comprehensive Cardiovascular Medicine. Philadelphia: Lippincott-Raven; 1998. p. 637-667. 7. Choussat R, Thomas D, Isnard R, Michel PL, Lung B, Hanania G, Mathieu P, David M. Perivalvular abscesses associated with endocarditis: clinical features and prognostic factors of overall survival in a series of 233 cases. Eur Heart J 1999;20:232-241.

100 TEHRAN HEART CENTER

INTERNATIONAL CARDIOVASCULAR SURGERY MEETINGS CALENDER (2010-2011)

Congress Time-Location Address

7-9 January 2010 Aswan heart center science & practice series: valvu- Aswan, Website: http://www.aswanheartvalve. lar heart disease update Egypt com 14-15 January 2010 Website: http://www.rcseng.ac.uk/educa- Intermediate Cardiac Surgery London, tion/courses/intermediate-cardiac-surgery United Kingdom

13th Society for Cardiovascular Magnetic Resonance 21-24 January 2010 Website: www.scmr.org (SCMR) Annual Scientific Sessions Phoenix, AZ, United States

22-24 January 2010 Website: http://apacvs.org/documents/ APACVS 29th Annual Winter Educational Meeting Ft. Lauderdale, FL PDF/APACVS_2010Program_OctoberFlor. United States pdf

25-27 January 2010 Website: http://www.sts.org/sections/an- 46thAnnual Meeting of The Society of Thoracic Surgeons Fort Lauderdale, nualmeeting/ FL United 27-30 January 2010 MIRA (Minimally Invasive Robotic Association) 5th Website: http://www.mirasurgery. San Diego, CA International Congress - "Latest Trends in Robotics" org/2010congress/index.php United States

Tenth Annual International Symposium on Congeni- 6-9 February 2010 Website: http://www.allkids.org/confer- tal Heart Disease - Special Focus: Rare and Challenging St. Petersburg, FL ences Lesions United States 14-17 February 2010 The 39th Annual Meeting of the German Society for Stuttgart, Email: [email protected] Thoracic and Cardiovascular Surgery Germany

3rd international symposium mechanical circulatory 25-26 February 2010 Website: http://www.ctsnet.org/ support for the treatment of acute and chronic advanced L'Hospitalet Llobregat – Barce- file/3rdIntSymp.pdf heart failure lona, Spain

The Journal of Tehran University Heart Center101 The Journal of Tehran University Heart Center

Congress Time-Location Address

Ct comcon 2010 - Combined Annual Meeting of The 26 February - 1 March 2010 Asian Society for Cardiovascular & Thoracic Surgery New Delhi, (18th) & Indian Association of Cardiovascular Thoracic Website: http://ctcomcon2010.com/ Surgeons (56th) India

The 2nd Joint Meeting - Topic 2010: Aortic Surgery 27 February - 6 March 2010 and Endovascular Interventions Zürs, Website: http://www.surgery-zurs.at Austria

4-7 March 2010 Website: http://www.amainc.com/cref_ The 30th Annual Cardiothoracic Surgery Symposium San Diego, CA cardiothoracic.html United States 04-07 March 2010 30th Annual CREF: Cardiothoracic Surgery Newport Beach, CA, http://www.amainc.com/cref_cardiotho- Symposium United States racic.html

7-9 March 2010 SCTS Annual Meeting and Cardiothoracic Forum Liverpool, Website: http://www.scts.org United Kingdom 11-13 March 2010 Florida Valve 2010 - "Emerging Valvular & Endovas- Orlando, FL Website: http://www.floridavalvesympo- cular Therapies for the Surgeon and Cardiologist" United States sium.com 12-14 March 2010 Sport and Congenital Heart Disease Munich, Email: [email protected] Germany 21-26 March 2010 Website: http://www.scahq.org/sca3/ 15th Annual Update on Cardiopulmonary Bypass Whistler, BC events/2010/cpb Canada 23-26 March 2010 17th Egyptian society of cardiothoracic surgery Cairo, Website: http://escts2010.com/ Egypt

The houston aortic symposium: frontiers in cardiovas- 25-27 March 2010 cular diseases, the third in the series Houston, TX Website: http://www.promedicacme.com United States

ICR 2010: Integrated Cardiovascular Repair - Work- 25-27 March 2010 shop / 5th Interdisciplinary Workshop for Interventional Cardiologists, Cardiac Surgeons and Cardiac Interven- Baltimore, MD Website: http://www.icrworkshop.com/ tion Teams United States

59th European society for cardiovascular surgery 15-18 April 2010 (ESCVS) international congress Izmir, Turkey http://www.escvs2010.org

The 59th international congress of the european 15-18 April 2010 society for cardiovascular in conjunciton with the 6th http://www.escvsannualcongress.org Izmir, Congress of Update in Cardiology and Cardiovascular Website: http://escvs.org/ Surgery - Heart and Health Foundation of Turkey Turkey 29-30 April 2010 Aortic symposium 2010 New York, NY Website: http://www.aats.org United States

6th International Conference on Pediatric Mechanical 6-8 May 2010 Website: http://www.hmc.psu.edu/chil- Circulatory Support Systems and Pediatric Cardiopul- Boston, MA drens/pedscpb/ monary Perfusion United States 13-14 May 2010 Innovations and Practical Applications in Vascular New York City, NY Website: http://www.nypvascularcare.org Surgery United States

102 TEHRAN HEART CENTER

Congress Time-Location Address

18th Annual Conference of the Association of 27-28 May 2010 Cardiovascular Surgeons of Ukraine With International Zaporizhzhya-city Website: http://www.amosovinstitute. Participation Ukraine org.ua 7 June 2010 Bypass, Balloon Pumps and Circulatory Support London, Website: [email protected] United Kingdom 9-12 June 2010 45th Annual Meeting of the European Society for Geneva, Website: http://www.essr2010.ch Surgical Research Switzerland

2010 International Society for Minimally Invasive 16-19 June 2010 Cardiothoracic Surgery (ISMICS) 12th Annual Scien- Berlin, Website: http://www.ismics.org tific Meeting Germany

3rd Scientific Meeting Of The World Society For 23-26 June 2010 Pediatric And Congenital Heart Surgery Istabul, Website: http://www.wspchs2011.org/ Turkey

25-26 June 2010 Website: http://www.valvesympo- 10th Symposium on Aortic Valve Reconstructive Brussels, sium.org/ Surgery Belgium

ISHAC - International Symposium on the Hybrid Ap- 1-3 September 2010 Website: http://www.hybridsympo- proach to Congenital Heart Disease Columbus, OH sium.com United States 11-15 September 2010 24th EACTS Annual Meeting Geneva, Website: http://www.eacts.org Switzerland

6-9 October 2010 Website: http://www.amsect.org/sec- Perfusion Safety & Best Practices Toronto, ON tions/education/index.html Canada

"Congenital Heart Disease"(1st Day: Sequential 14-15 October 2010 Segmental Analysis of Malformed Hearts, 2nd Day: Leiden, Website: http://www.boerhaavenet.nl/ Borderline Hypoplastic Left Ventricle) Netherlands

20th World Congress of The World Society of Car- 20-23 October 2010 dioThoracic Surgeons combined with 6th Global Forum Website: http://www.wscts2010.com on Humanitarian Medicine in Cardiology & Cardiac Chennai, Surgery India

Turkish Cardiovascular Surgery Society 11th Annual 27-31 October 2010 Website: http://www.tkdcd2010.org/ Meeting Antalya, Turkey

The Journal of Tehran University Heart Center103 The Journal of Tehran University Heart Center

INTERNATIONAL CARDIOVASCULAR MEETING AND CONGRESSES CALENDER (2010-2011)

Title City Start Date End Date

Preceptorship in Intraoperative Transesophageal Durham, NC, Echocardiography United States 11 January 2010 13 January 2010

Riyadh, 1st International Cardiovascular Pharmacotherapy Conference Saudi Arabia 12 January 2010 13 January 2010

XXes Journées Européennes de la Société Française de Paris, 13 January 2010 Cardiologie France 16 January 2010

The International Symposium on Endovascular Therapy Hollywood, Florida, 17 January 2010 United States 21 January 2010

World Cardiology, Metabolism and Thrombosis Congress Sao Paulo, 20 January 2010 (WCMTC) Brazil 23 January 2010

13th Society for Cardiovascular Magnetic Resonance (SCMR) Phoenix, AZ 21 January 2010 Annual Scientific Sessions United States 24 January 2010

29th Belgian Society of Cardiology Annual Scientific Meeting Brussels, 28 January 2010 Belgium 30 January 2010

31st Annual Meeting of The American Academy of Nashville, TN, 28 January 2010 Cardiovascular Perfusion (AACP) United States 31 January 2010

35th Annual Cardiovascular Conference at Snowbird Snowbird, UT, 3 February 2010 United States 6 February 2010

Leuven Symposium on Myocardial Velocity and Deformation Leuven, 4 February 2010 5 February 2010 Imaging Belgium

10th Annual International Symposium on Congenital Heart St. Petersburg, FL, 6 February 2010 9 February 2010 Disease United States

London, England, 2nd National Chronic Heart Failure and Hypertension 11 February 2010 United Kingdom 12 February 2010

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Title City Start Date End Date

Cape Canaveral, Heart to Heart 3 Florida 13 February 2010 21 February 2010 United States

The 2nd World Congress on Controversies in Cardiovascular Istanbul, 18 February 2010 21 February 2010 Disease (C-Care) Turkey Baltimore, MD, Cardiovascular Topics at Johns Hopkins 18 February 2010 20 February 2010 United States London, Diagnostic and Interventional Radiology 18 February 2010 19 February 2010 United Kingdom Coral Gables, Cardiovascular Disease Prevention 2010: Eighth Annual Florida, 18 February 2010 20 February 2010 Comprehensive Symposium United States Washington, DC, Cardiovascular Research Technologies (CRT 2010) 21 February 2010 23 February 2010 United States

Preceptorship in Intraoperative Transesophageal Durham, NC, 22 February 2010 24 February 2010 Echocardiography United States Maui, HI, Arrhythmias & the Heart Symposium 22 February 2010 25 February 2010 United States

15th Annual Cardiology at Cancun - Advances in Clinical Cancun, 22 February 2010 26 February 2010 Cardiology and Multi-Modality Imaging Mexico San Antonio, TX, International Stroke Conference 2010 23 February 2010 26 February 2010 United States

International Conference on Early Disease Detection and Munich, 25 February 2010 28 February 2010 Prevention (EDDP 2010) Germany

9th Genoa Meeting on Hypertension, Diabetes and Renal Genoa, 25 February 2010 27 February 2010 Diseases Italy Valencia, First International Meeting on Cardiac Problems in Pregnancy 25 February 2010 28 February 2010 Spain Hong Kong, International Congress of Cardiology (ICC) 26 February 2010 28 February 2010 Hong Kong

Keystone Symposia: Cardiovascular Development and Repair Keystone, CO, 28 February 2010 05 March 2010 (X2) United States

Vascular Care 2010: Current Management of Peripheral Truckee, CA, 28 February 2010 03 March 2010 Vascular Disease: Consensus and Controversies United States Scottsdale, AZ, International Congress XXIII on Endovascular Interventions 28 February 2010 04 March 2010 United States

Kish Island, 4th Middle East Cardiovascular Congress 03 March 2010 05 March 2010 Iran

3rd International Conference on Hypertension, Lipids, Diabetes Berlin, 04 March 2010 06 March 2010 & Stroke Prevention Germany

San Diego, CA, The Future of Genomic Medicine III 05 March 2010 06 March 2010 United States

Interventional Cardiology 2010: 25th Annual International Snowmass Village, 07 March 2010 12 March 2010 Symposium United States

Geneva, 12 March 2010 13 March 2010 10th Annual Spring Meeting on Cardiovascular Nursing Switzerland

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Title City Start Date End Date

American College of Cardiology (ACC) 59th Annual Scientific Atlanta, GA, Session United States 14 March 2010 16 March 2010

Preceptorship in Intraoperative Transesophageal Durham, NC, 15 March 2010 17 March 2010 Echocardiography United States

VIII Congress of the Italian Society of Cardiovascular Rome, Prevention (SIPREC) Italy 18 March 2010 20 March 2010

XI International Forum for the Evaluation of Cardiovascular Prague, Care Czech Republic 18 March 2010 20 March 2010

12th KFAFH Cardiovascular Conference: A balanced approach Jeddah, 24 March 2010 25 March 2010 to treatment of cardiovascular diseases Saudi Arabia

The Houston Aortic Symposium: Frontiers in Cardiovsacular Houston, TX, 25 March 2010 27 March 2010 Diseases, The Third in the Series United States Athens, Athens Cardiology Update 2010 Greece 25 March 2010 27 March 2010 Nicosia, 22nd International Meeting 'Cardiology Today' Cyprus 27 March 2010 28 March 2010

Jeddah, Saudi Hypertension Conference 2010 29 March 2010 31 March 2010 Saudi Arabia

Radboud Symposium: Hypotensive Syndromes - at the Locht, 29 March 2010 29 March 2010 Crossroads of Cardiovascular Medicine and Nephrology Netherlands

The 14th Annual Scientific Meeting of the Egyptian Cairo, Hypertension Society Egypt 07 April 2010 09 April 2010

Vascular Laboratory 2010: Advanced Topics for Vascular Sacramento, CA, 10 April 2010 11 April 2010 Specialists and Other Health-Care Professionals United States

32nd Charing Cross International Symposium: Vascular & London, Endovascular Challenges Update (CX32-2010) United Kingdom 10 April 2010 13 April 2010

Preceptorship in Intraoperative Transesophageal Durham, NC, 12 April 2010 14 April 2010 Echocardiography United States 7th Mediterranean Meeting on Hypertension and Nevsehir, 14 April 2010 18 April 2010 Atherosclerosis Turkey Valves in the Heart of the Big Apple VI: Evaluation & New York, NY, 15 April 2010 17 April 2010 Management of Valvular Heart Diseases 2010 United States

The Tenth International Conference of the Jordan Cardiac Amman, 20 April 2010 22 April 2010 Society Jordan

Cannes, 5th Cardiac MRI & CT Clinical Update 2010 23 April 2010 25 April 2010 France

Auckland, New Zealand Resuscitation Council Conference 2010 30 April 2010 01 May 2010 New Zealand

EuroPRevent 2010 - Cardiovascular Prevention: a Lifelong Prague, 05 May 2010 07 May 2010 Challenge Czech Republic

Dubrovnik, 5th European Cardiology Conference for General Practitioners 07 May 2010 09 May 2010 Croatia

Controversies in Cardiovascular Disease: Practical Approaches St. Paul, MN, 08 May 2010 09 May 2010 to Complex Problems: Medical and Surgical United States

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Title City Start Date End Date

7th Metabolic Syndrome, Type II Diabetes and Atherosclerosis Marrakesh, 12 May 2010 16 May 2010 Congress (MSDA) Morocco

Preceptorship in Intraoperative Transesophageal Durham, NC, 17 May 2010 Echocardiography United States 19 May 2010 Sydney, 3rd Cardiovascular CT, Concord Conference 2010 21 May 2010 Australia 22 May 2010 Paris, EuroPCR 25 May 2010 France 28 May 2010 Berlin, 29 May 2010 Heart Failure Congress 2010 Germany 01 June 2010

9th Asian-Pacific Congress of Cardiovascular & Interventional Seoul, 01 June 2010 04 June 2010 Radiology (APCCVIR 2010 South Korea Prague, International Conference on Pulmonary Circulation 2010 02 June 2010 Czech Republic 05 June 2010

Preceptorship in Intraoperative Transesophageal Nice, NC, 07 June 2010 09 June 2010 Echocardiography United States Beijing, World Congress of Cardiology 16 June 2010 China 19 June 2010

International Workshop on Complications during Cardiac Düsseldorf, 16 June 2010 18 June 2010 Interventions: Management and Prevention Germany

Cardiostim 2010-17th World Congress in Cardiac Nice, 16 June 2010 19 June 2010 Electrophysiology and Cardiac Techniques France Port El Kantaoui, The 7th Tunisian and Europeans Days of Cardiology Practice 17 June 2010 Tunisia 19 June 2010 Marseille, Multidisciplinary European Endovascular Therapy 17 June 2010 19 June 2010 (MEET 2010) France Oslo, 18 June 2010 20th European Meeting on Hypertension Norway 22 June 2010 Hamburg, 20 June 2010 78th European Atherosclerosis Society Congress Germany 23 June 2010 Madrid, 26 Jun 2011 Ehra Europace Spain 29 Jun 2011 Singapore, 01 July 2010 6th Asian Interventional Cardiovascular Therapeutics Congress Singapore 03 July 2010

Milan, 06 July 2010 21st International Congress on Thrombosis 2010 Italy 09 July 2010

Frankfurt, iCi - Imaging in Cardiovascular Interventions 07 July 2010 Germany 08 July 2010

Frankfurt, 08 July 2010 CSI - Congenital & Structural Interventions Germany 10 July 2010

Berlin, Frontiers in CardioVascular Biology 2010 - 1st Meeting of the 16 July 2010 19 July 2010 CBCS of the ESC Germany Johannesburg, The 26th International Pediatric Association Congress of 04 August 2010 09 August 2010 Pediatrics (IPA 2010) South Africa

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Title City Start Date End Date

Stockholm, ESC Congress 2010 Sweden 28 August 2010 01 September 2010

19th EUROCHAP 2010 European Chapter Congress of the Paris, 24 September 2010 26 September 2010 International Union of Angiology France Belo Horizonte, 65th Brazilian Congress of Cardiology 25 September 2010 26 September 2010 Brazil

Cardiovascular and Interventional Radiological Society of Valencia, 02 October 2010 06 October 2010 Europe (CIRSE 2010) Annual Congress Spain

17th Congress of Iranian Heart Association In Collaboration Tehran, 05 October 2010 08 October 2010 with Canadian Cardiovascular Society Iran

26th Annual Echocardiography in Pediatric and Adult Rochester, MN, 10 October 2010 13 October 2010 Congenital Heart Disease Symposium United States Copenhagen, Acute Cardiac Care 2010 16 October 2010 19 October 2010 Denmark Boston, MA, 2010 Cardiometabolic Health Congress 20 October 2010 23 October 2010 United States

8th Annual World Congress on Insulin Resistance, Diabetes, Los Angeles, CA, 04 November 2010 06 November 2010 and Cardiovascular Disease United States

The 3rd International Conference on Fixed Combination in the Brisbane, 18 November 2010 20 November 2010 Treatment of Hypertension, Dyslipidemia and Diabetes Mellitus Australia London, 13th British Society for Heart Failure Annual Meeting 25 November 2010 26 November 2010 United Kingdom Rome, 30 November 2010 03 December 2010 International Symposium on Progress in Clinical Pacing Italy Copenhagen, Euro echo 2010 08 December 2010 11 December 2010 Denmark Lisbon, 09 December 2010 11 December 2010 Heart, Vessels & Diabetes - The European Conference Portugal

108 TEHRAN HEART CENTER

Information for Authors

The first three consecutive issues of "The Journal of Tehran University Heart Center" were published under the title of "The Journal of Tehran Heart Center" with ISSN: 1735-5370. From the fourth issue onward, however, the journal has been entitled ‘’The Journal of Tehran University Heart Center" with ISSN:1735-8620.

Scope of the journal "The Journal of Tehran University Heart Center" aims to publish the highest quality material, both clinical and scientific, on all aspects of Cardiovascular Medicine. It includes articles related to research findings, technical evaluations, and reviews. In addition, it provides a forum for the exchange of information on all aspects of Cardiovascular Medicine, including educational issues. "The journal of Tehran University Heart Center" is an international, English language, peer reviewed journal concerned with Cardiovascular Medicine. It is an official journal of the Cardiovascular Research Center of the Tehran University of Medical Sciences (in collaboration with the Iranian Society of Cardiac Surgeons) and is published quarterly. Papers submitted to this journal which do not adhere to the Instructions for Authors will be returned for appropriate revision to be in line with the Instructions for Authors. They may then be resubmitted. Submission of an article implies that the work described has not been published previously (except in the form of an abstract or as part of a published lecture or academic thesis), that it is not under consideration for publication elsewhere, that its publication is approved by all Authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, without the written consent of the publisher.

Article Categories The Journal of Tehran University Heart Center” accepts the following categories of articles:” Guest Editorial Original Article Clinical and pre-clinical papers based on either normal subjects or patients and the result of cardiovascular pre-clinical research will be Considered for publication provided they have an obvious clinical relevance. Brief communication Case report Review Article "The Journal of Tehran University Heart Center" publishes a limited number of scholarly, comprehensive reviews whose aims are to summarize and critically evaluate research in the field addressed and identify future implications. Reviews should not exceed 5000 words. Letter to editor Letters to the editor must not exceed 500 words and should focus on a specific article published in "The Journal of Tehran University Heart Center" within the preceding 12 weeks. No original data may be included. Authors will receive pre-publication proofs, and the authors of the article cited invited to reply.

Submission of manuscripts Four double spaced copies on 8 1/2 × 11 in. paper should be sent to: Dr. A. Karimi, Editor in Chief, "The Journal of Tehran University Heart Center" , Tehran Heart Center, North Kargar Street, Tehran, Iran 1411713138 Photocopies or good reproductions of illustrations are acceptable only on the spare copies. Included also should be a set of the electronic files of the manuscript on floppy – disk or CD-ROM. For preparation of electronic files, see the instructions herein below. Also, manuscripts can be submitted electronically via the journal’s website: http://jthc.tums.ac.ir. On-line submission allows the manuscript to be handled in electronic forms throughout the review process.

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Review of manuscripts All manuscripts correctly submitted to will first be reviewed by the Editors. Some manuscripts will be returned to authors at this stage if the paper is deemed inappropriate for publication in “The Journal of Tehran University Heart Center”, if the paper does not meet submission requirements, or if the paper is not deemed to have a sufficiently high priority. All papers considered suitable by the Editors to progress further in the review process will undergo appropriate peer review and all papers provisionally accepted for publication will undergo a detailed statistical review.

Preparation of manuscripts All submitted manuscripts must not exceed 5000 words, including References, Figure Legends and Tables. The number of Tables, Figures and References should be appropriate to the manuscript content and should not be excessive. Authors should comply with the manuscript formatting and the ethical conventions of the “Uniform Requirements for Manuscripts Submitted to Biomedical Journals” issued by the International Committee of Medical Journal Editors ( http://www.icmje.org ).

Style and spelling Authors whose first language is not English are requested to have their manuscripts checked carefully before submission. This will help expedite the review process and avoid confusion. Abbreviations of standard SI units of measurement only should be used.

Declaration of Helsinki The Authors should state that their study complies with the Declaration of Helsinki that the locally appointed ethics committee has approved the re- search protocol and that informed consent has been obtained from the subjects (or their guardians).

Clinical trials

Authors should comply with the clinical trial registration statement from the ICMJE. More information can be found at www.icmje.org. Clinical trial reports should also comply with the Consolidated Standards of Reporting Trials (CONSORT) and include a flow diagram presenting the enrollment, intervention allocation, follow-up, and data analysis with number of subjects for each (www.consort-statement.org). Please also refer specifically to the CONSORT Checklist of items to include when reporting a randomized clinical trial.

Section of the manuscripts Original articles should be divided into the following sections: (1) Title page, (2) Abstract and Keywords, (3) Introduction, (4) Methods, (5) Results, (6) Discussion, (7) Conclusion, (8) Acknowledgements, (9) References, (10) Figure legends, (11) Tables, (12) Figures.

General format Prepare your manuscript text using a word processing package. Submissions of text in the form of PDF files are not permitted. Manuscripts should be double-spaced, including text, tables, legends and references. Number each page. Please avoid footnotes; use instead, and as sparingly as possible, parenthesis within brackets. Enter text in the style and order of the Journal. Type references in the correct order and style of the journal. Type unjustified, without hyphenation, except for compound words. Type headings in the style of the journal. Use the TAB key once for paragraph indents. Where possible use Times New Roman for the text font and Symbol for the Greek and special characters. Use the word processing formatting features to indicate Bold, Italic, Greek, Maths, Superscript and subscript characters. Clearly identify unusual symbols and Greek letters. Differentiate between the letter o and zero, and the letters I and i and the number 1. Mark the approximate position of each figure and table. Check the final copy of your paper carefully, as any spelling mistakes and errors may be translated into the typeset version.

Title page The title page should include the following: (1) the title, (2) the name (s) of authors and their highest degree ( no more than 12 authors are acceptable), (3) the institution (s) where work was performed, (4) institution, and location of all authors, (5) the address, telephone number, fax number and e-mail ad- dress of the corresponding author.

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Abstract All abstracts may not contain more than 250 words and should also be submitted as a separate file. The abstract should be formatted with the following heading: (1) Background, (2) Methods, (3) Results, (4) Conclusion. A maximum of six Keywords may be submitted.

Figures

The review process will not begin until all figures are received. Figures should be limited to the number necessary for clarity and must not duplicate data given in tables or in the text. They must be suitable for high quality reproduction and should be submitted in the desired final printed size so that reduc- tion can be avoided. Figures should be no larger than 125 (height)×180 (width) mm (5×7 inches) and should be submitted in a separate file from that of the manuscript.

Electronic submission of figures Figures should be saved in TIFF format at a resolution of at least 300 pixels per inch at the final printed size for colour figures and photographs, and 1200 pixels per inch for black and white line drawings. Although some other formats can be translated into TIFF format by the publisher, the conversion may alter the tones, resolution and contrast of the image. Digital colour art should be submitted in CMYK rather than RGB format, as the printing process requires colours to be separated into CMYK and this conversion can alter the intensity and brightness of colours. Therefore authors should be satisfied with the colours in CMYK (both on screen and when printed) before submission. Please also keep in mind that colours can appear differently on different screens and printers. Failure to follow these guides could result in complications and delays. Photographs: Photographs should be of sufficiently high quality with respect to detail, contrast and fineness of grain to withstand the inevitable loss of contrast and detail inherent in the printing process. Please indicate the magnification by a rule on the photograph. Colour figures: There is a special charge for the inclusion of colour figures. Figure legends: These should be on a separate, numbered manuscript sheet grouped under the heading “Legends” on a separate sheet of the manuscript after the References. Define all symbols and abbreviations used in the figure. All abbreviations and should be redefined in the legend.

Tables Tables should be typed with double spacing, but minimizing redundant space and each should be placed on a separate sheet. Tables should be submitted, wherever possible, in portraits, as opposed to landscape, layout. Each Table should be numbered in sequence using Arabic numerals. Tables should also have a title above and an explanatory footnote below. All abbreviations and should be redefined in the Footnote.

Acknowledgements All sources of funding and support, and substantive contributions of individuals, should be noted in the Acknowledgements, positioned before the list of references.

Reference format Number references sequentially and use Arabic number in superscript to cite the reference in the text. All references should be compiled at the end of the article in the Vancouver style. Complete information should be given for each reference including the title of the article, abbreviated journal title and page numbers. All authors should be listed. Personal communications; manuscripts in preparation and other unpublished data should not be cited in the reference list but may be mentioned in parentheses in the text. Authors should get permission from the source to cite unpublished data. Titles of journals should be abbreviated in accordance with Index Medicus (see list printed annually in the January issue of Index Medicus). If a journal is not listed in Index Medicus then its name should be written out in full. Article citation example: Journal citation example: 1. Schroeder S, Baumbach A, Mahrholdt H. The impact of untreated coronary dissections on the acute and long-term outcome after intravascular ultrasound guided PTCA. Eur Heart J 2000;21:137-145. Chapter citation example: 2. Nichols WW, O’Rourke MF. Aging, high blood pressure and disease in humans. In: Arnold E, ed. McDonald’s Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles. 3rd ed. London/Melbourne/Auckland: Lea and Febiger; 1990. p. 398-420. Webpage citation example: 3. Panteghini M. Recommendations on use of biochemical markers in acute coronary syndrome: IFCC proposals. eJIFCC 14. http://www.ifcc.org/ejifcc/vol14no2/1402062003014n.htm (28 May 2004). Where the date in parenthesis refers to the access date.

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Statistics All manuscripts selected for publication will be reviewed for the appropriateness and accuracy of the statistical methods used and the interpretation of statistical results. All papers submitted should provide in their Methods section a subsection detailing the statistical methods, including the specific method used to summarize the data, the methods used to test their hypothesis testing and (if any) the level of significance used for hypothesis testing.

Conflict of interest

At submission, the editors require authors to disclose any financial association that might pose a conflict of interest in connection with the submitted article. All sources of funding for the work should be acknowledged in a footnote on the title page and in the Acknowledgements within the manuscript, as should all the institutional affiliations of the authors (including corporate appointments). Other kinds of associations, such as consultancies, stock ownership or other equity interest or patent-licensing arrangements should be disclosed to the editors in the cover letter at the time of the of submission. If no conflict of interest exists, please state this in the cover letter.

Proofs Page proofs will be sent to the corresponding author. Please provide an e-mail address to enable page proofs to be sent as PDF files via e-mail. These should be checked thoroughly for any possible changes or typographic errors. Significant alterations instigated at this stage by the author will be charged to the author. It is the intention of the Editor to review, correct and publish your article as quickly as possible. To achieve this it is important that all of your corrections are returned to us in one all- inclusive mail or fax. Subsequent additional corrections will not be possible, so please ensure that your first com- munication is complete.

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Subscription Form The Journal of Tehran University Heart Center

New Subscription: Continuation of Subscription: TEHRAN HEART CENTER

Surname: First Name: Hospital or Organization: Date of subscription: Full mail address:

P.O.BOX: Tell: Fax: E-mail:

The annual Subscription and postage rate: 100/000 Rials for Iran and US $ 100 including postage for other countries.

Please liquidate the total amount of Subscription and postal charges into: Bank: Refah Branch Code: 1232 Account: Tehran Heart Center Account Number: 200001.28 and send the original Bank slip along with Duly completed form of Subscription to the following address:

Tehran Heart Center, North Karegar Street, Tehran, Iran : 1411713138 88029702 21 +98 : FAX: +98 21 88029702 E-mail: [email protected]

Subscription Form The Journal of Tehran University Heart Center

New Subscription: Continuation of Subscription: TEHRAN HEART CENTER

Surname: First Name: Hospital or Organization: Date of subscription: Full mail address:

P.O.BOX: Tell: Fax: E-mail:

The annual Subscription and postage rate: 100/000 Rials for Iran and US $ 100 including postage for other countries.

Please liquidate the total amount of Subscription and postal charges into: Bank: Refah Branch Code: 1232 Account: Tehran Heart Center Account Number: 200001.28 and send the original Bank slip along with Duly completed form of Subscription to the following address:

Tehran Heart Center, North Karegar Street, Tehran, Iran : 1411713138 88029702 21 +98 : FAX: +98 21 88029702 E-mail: [email protected]