Systolic and Diastolic Function in Middle Aged Patients with Sickle B Thalassaemia

711 Postgrad Med J: first published as 10.1136/pgmj.2004.031096 on 4 November 2005. Downloaded from ORIGINAL ARTICLE Systolic and diastolic function in middle aged patients with sickle b thalassaemia. An echocardiographic study I Moyssakis, R Tzanetea, P Tsaftaridis, I Rombos, D P Papadopoulos, V Kalotychou, A Aessopos ......

Postgrad Med J 2005;81:711–714. doi: 10.1136/pgmj.2004.031096

Objective: To evaluate the right and left ventricular systolic and diastolic function in middle aged patients with sickle b thalassaemia. Methods: Forty three patients with sickle b thalassaemia were recruited for echocardiographic study while 55 controls, matched for age and sex, served as the control group. Parameters measured included: See end of article for dimensions and wall thickness of left (LV) and right (RV) ventricle and left atrium, LV mass, and cardiac authors’ affiliations ...... index. LV and RV contractility variables—ejection fraction, circumferential fibre shortening velocity, end systolic stress, end systolic stress/volume index ratio, mitral and tricuspid annulus systolic excursion, and Correspondence to: Tei index—were also calculated. The study also evaluated parameters of RV and LV diastolic function Dr D P Papadopoulos, Laiko General Hospital of including early and late atrioventricular flow velocities (E and A wave respectively), E/A ratio, Athens, Department of deceleration time (DT), isovolumic relaxation time (IVRT) as well as pulmonary and hepatic veins systolic to Cardiology, 6–8 Glykonos diastolic (S/D) ratio. Street St-10675, Athens, Greece; jimpapdoc@ Results: Chamber enlargement, greater LV mass index, cardiac index, and RV wall thickness were found in yahoo.com the anaemic group compared with controls. The LV and RV contractility variables of the patients were similar to controls. Conversely the LV and RV Tei index was significantly greater in the patient group. Submitted Diastolic dysfunction was present in the anaemic patients resulting from the increased LV and RV A-wave, 29 November 2004 Accepted the longer LVIVRT, RVIVRT, and RVDT, as well as the higher hepatic and pulmonary veins S/D ratio. 23 February 2005 Conclusions: The results show that in middle aged patients with sickle b thalassaemia the diastolic function ...... is abnormal in both ventricles but still more in RV, whereas the systolic function remains unchanged.

ickle cell disease is a hereditary haemolytic anaemia and a/b chain synthesis to confirm the thalassaemic characterised by the synthesis of the haemoglobin S genotype. All patients were Sb+ type, with haemoglobin S(HbS, sickle cell haemoglobin). Homozygous sickle cell concentrations higher than 70 g/l; they had painful crises and disease (SS) results from the inheritance of two sickle cell red cell transfusions rarely (less than five per year) while genes (bs). Coinheritance of a bs gene and a b thalassaemia none was receiving drugs such as digoxin, diuretics, or gene (bthal) results in different types of sickle b thalassaemia vasodilators. The study protocol was approved by the (Sb) depending on the mutation, which is carried by the b institutional committee on human research and all subjects http://pmj.bmj.com/ thalassaemia gene, and the amount of HbA synthesised. If gave informed consent. the bs gene is inherited with a b+ thalassaemia gene, in which some b chains are present, the genotype is Sb+ and if the b Echocardiographic evaluation thalassaemia gene is b0, in which b chains are absent, the Comprehensive echocardiographic examination with pulsed, genotype is Sb0. It is well known that whether the interacting continuous, and colour Doppler was performed with a Hewlet b thalassaemia gene is bo the clinical picture is similar to Packard Sonos 1000 ultrasound System, using a 2.5 MHz sickle cell anaemia whereas, when the interacting b transducer by the same cardiologist and was recorded on on September 28, 2021 by guest. Protected copyright. thalassaemia gene is of b+ type it has milder clinical signs tape. The measurements were performed, independently, by and symptoms.1 Cardiac abnormalities in sickle cell disease two cardiologists unaware of the subject’s status. From the have been well described but mainly in sickle cell anaemia.2 two dimensional guided M-mode echocardiogram, LV end However, little is known about heart involvement in sickle b systolic and end diastolic diameters as well as interventri- thalassaemia. cular septum and posterior wall thickness at end diastole The purpose of this study was to investigate the changes in were measured for the calculation of fractional shortening systolic and diastolic function of the left and right ventricle (FS) and LV mass with the Penn convention formula.34 (LV and RV respectively) in middle aged patients with sickle Measurements of LV mass were divided by body surface area b thalassaemia. to obtain LV mass index. The LV ejection fraction (EF) was determined by the biplane Simpson’s method. The LV stroke METHODS volume was also calculated as the product of the cross Study population sectional area of the LV outflow tract and velocity time Forty three consecutive patients between 45 and 66 years (15 integral of the LV outflow velocity.5 The LV cardiac output men, 28 women, aged mean (SD) 54 (10) years) with sickle b was derived as the product of the stroke volume and thalassaemia and no underlying heart disease and 55 (18 heart rate and, divided by body surface area; the LV cardiac men, 37 women, aged 53 (11) years) healthy volunteers were index was calculated. Furthermore, we measured several recruited in our study. Patients with sickle b thalassaemia were recruited from the haemoglobinopathies unit of Laiko Abbreviations: RV, right ventricle; LV, left ventricle; DT, deceleration General Hospital, Athens, Greece. Inclusion criteria were, time; FS, fractional shortening; EF, ejection fraction; TAPSE, tricuspid diagnosis of sickle b thalassaemia, made by solubility annular plane systolic excursion; IVRT, isovolumic relaxation time; ESS, screening test for sickling, haemoglobin electrophoresis, end systolic stress; MAPSE, mitral annular plane systolic excursion

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Table 1 Clinical characteristics of the study population

Characteristics SbT Controls p Value

Age (y) 54 (10) 53 (11) NS Men/women 15/28 18/37 NS Heart rate (b/min) 81 (13) 76 (11) NS SAP (mm/Hg) 121 (13) 126 (17) NS DAP (mm Hg) 69 (9) 78 (7) ,0.05 Packed cell volume (%) 28.70 (4.30) 43.40 (5.20) ,0.01 Haemoglobin (g/l) 95.8 (8.6) 146.0 (15.0) ,0.01 Serum ferritin (mg/l) 782 (346) 81 (29) ,0.01

SAP, systolic arterial pressure; DAP, diastolic arterial pressure; SbT, sickle b thalassaemia. parmaeters of LV systolic function such as the circumferential RESULTS fibre shortening velocity (Vcf) as the ratio FS to ejection As table 1 shows, the patients with sickle b thalassaemia had period, the meridional end systolic stress (ESS), the ratio end lower levels of diastolic blood pressure, packed cell volume, systolic stress/end systolic volume index (ESS/ESVI), and the and haemoglobin and increased concentrations of serum mitral annular plane systolic excursion (MAPSE).6–9 RV end ferritin compared with controls. diastolic diameter and thickness of the free wall was Chamber enlargement (left atrium, LV, and RV), greater LV measured and the RV systolic function was evaluated from mass index (109 (8) compared with 86 (19) g/m2,p,0.01), the tricuspid annular plane systolic excursion (TAPSE).10 11 cardiac index (4.80 (1.80) compared with 3.70 (1.20) l/min/ We also evaluated the myocardial performance index (Tei m2,p,0.01) and RV wall thickness (0.32 (0.07) compared index) of LV and RV.12 13 Using pulsed Doppler from the with 0.29 (0.06) cm, p,0.05) were noted in the anaemic mitral and tricuspid inflow velocity curves the following group (table 2). parameters were calculated: peak early velocity (E-wave), There was no difference in the LV systolic function peak velocity at the time of atrial contraction (A-wave), E/A variables such as the EF, ESS, ESS/ESVI, Vcf, and MAPSE ratio, deceleration time (DT) of the peak early velocity, and between patients and controls. Similarly, the RV systolic the isovolumic relaxation time (IVRT). For the calculation of function was not impaired assessed by the TAPSE. Conversely the RV diastolic variables at least three beats from the end the Tei index expressing combined systolic and diastolic inspiration and three beats from the end expiration were performance was increased for both ventricles in the anaemic recorded and their values were averaged.14–16 Flow velocities group (0.39 (0.07) compared with 0.36 (0.06), p,0.05 for LV of the hepatic veins and upper pulmonary veins were also and 0.37 (0.11) compared with 0.32 (0.09), p,0.05 for RV) recorded for systolic to diastolic forward flow velocity ratio distinguishing global LV and RV dysfunction (table 3). (S/D) calculation. The intraobserver and interobserver mean The diastolic function was also impaired in anaemic percentage error (absolute difference between two measure- patients compared with controls. Specifically, the LV and ments divided by the mean and expressed in percentage) of RV A-wave was increased (53 (12) v 44 (15) cm, p,0.01 and Doppler measurements were respectively (for the LV: 3.1% 47 (9) v 40 (8), p,0.01 respectively), the LV and RV IVRT was and 3.3% for E-wave, 3.3% and 3.6% for A-wave, 3.5% and longer (83 (17) v 76 (11) ms, p,0.05 and 52 (13) v 46 4.2% for DT, 3.5% and 4.3% for IVRT whereas for the RV: (11) ms, p,0.05 respectively) and the RV DT was also longer

6.3% and 6.9% for E-wave, 6.5% and 7% for A-wave, 5.6% and (198 (39) v175 (34) ms, p,0.01) in the group of patients. http://pmj.bmj.com/ 5.9% for DT, 5.2% and 5.5% for IVRT). Continuous wave Furthermore, the ratio S/D in pulmonary and hepatic veins Doppler echocardiogram recorded in the apical four chambers was increased (1.43 (0.50) v 1.22 (0.30), p,0.05 and 2.20 or parasternal short axis view was used to estimate the peak (1.08) v1.64 (0.90), p,0.01 respectively) in the anaemic systolic pressure gradient across the tricuspid valve. A group (table 4). Additionally pulmonary hypertension was tricuspid gradient greater than 30 mm Hg was considered also present in nine (21%) patients and was mild. indicative of pulmonary hypertension.17 18 Serum ferritin concentrations, for the whole group of 43 patients, were correlated significantly with RV Tei index (r = 0.55, p,0.01). Correlation with LV mass index and RV on September 28, 2021 by guest. Protected copyright. Statistical analysis Data are expressed as mean (SD). Differences between IVRT was also less exact but still significant (r = 0.43, p,0.05 groups were compared using the unpaired Student’s t test and r = 0.39, p,0.05 respectively). as appropriate. Linear correlation and regression were used to test the correlations between serum ferritin concentrations DISCUSSION with the echocardiographic findings. A probability (p) value It is well known that the clinical course for patients with of less than 0.05 was considered significant. sickle b thalassaemia is similar to that seen in patients with

Table 2 Echocardiographic variables of the study population

Parameters SbT Controls p Value

LA (cm) 42 (16) 35 (12) ,0.05 EDD (cm) 52.30 (7.50) 49.10 (6.30) ,0.05 ESD (cm) 34.50 (5.10) 31.20 (3.80) NS LV mass index (g/m2) 109 (28) 86 (19) ,0.01 RV diameter (cm) 29.50 (6.20) 26.60 (7.10) ,0.05 RV thickness (cm) 0.32 (0.07) 0.29 (0.06) ,0.05 CI (l/min/m2) 4.80 (1.80) 3.70 (1.20) ,0.01

LA, left atrium; EDD, end diastolic diameter; ESD, end systolic diameter; CI, cardiac index; SbT, sickle b thalassaemia.

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Table 3 Left and right ventricular systolic parameters of the study population

Parameters SbT Controls p Value

EF% 58.50 (8.30) 61 (7.50) NS MAPSE (mm) 13.90 (2.10) 14.60 (1.70) NS ESS (kdyn/cm2) 93 (19) 86 (23) NS ESS/ESVI (kdyn/cm3) 2.29 (0.48/104) 2.52 (0.71/104)NS Vcf (sec) 1.19 (0.50) 1.26 (0.30) NS LV Tei index 0.39 (0.07) 0.36 (0.06) ,0.05 RV Tei index 0.37 (0.11) 0.32 (0.09) ,0.05 TAPSE (mm) 12.80 (1.90) 13.40 (1.50) NS

EF, ejection fraction; MAPSE, mitral annulus plane systolic excursion; TAPSE, tricuspid annulus plane systolic excursion; ESS, meridional end systolic stress; ESVI, end systolic volume index; Vcf, circumferential fibre shortening velocity. homozygous sickle cell disease.19 Thus it is therefore logical to preload and low afterload in anaemic patients would be state that there is a good number of studies on sickle cell expected to cause physiologically an increase of transtricus- anaemia and heart involvement but only a few concerning pid and transmitral inflow velocities and shortened IVRT and sickle b thalassaemia.2 20–22 DT, which was not the case.28 29 Thus the RV and LV filling Acquired chronic anaemia, in young or older patients, was pattern show impaired relaxation. Additionally the pulmon- found causing systolic hyperfunction attributable to the ary and hepatic vein flow characteristics are also compatible hyperdynamic state and no impairment of diastolic func- with abnormal relaxation as the increased preload decreases tion.23 24 Similarly cardiac abnormalities in sickle b thalassae- the S/D ratio and our findings are opposite.28 30 mia are thought to be secondary to anaemia related volume Our findings are in accordance with the findings of Braden overload. However, more factors such as transfusion therapy et al who found abnormal diastolic filling pattern in patients with iron overload and toxicity, renal, pulmonary and heart with sickle cell anaemia and coexisting a thalassaemia-2.31 As injury attributable to vaso-oclusive effect of sickle haemoglo- in our study, they found significantly greater wall thickness bin on the circulation are involved in the sickle syndrome.25 but not chamber enlargement. It is possible that this happens In our study the patients with sickle b thalassaemia had because their population was younger but mainly because of increased dimensions of the left atrium, and left and right the sickle cell anaemia and coexisting a thalassaemia-2 is less ventricle than the controls. Moreover they had a greater LV severe than sickle b thalassaemia.32 Previous studies have also mass index, a thicker RV wall, and a higher cardiac index. established left sided chamber enlargement and biventricular We found that the LV EF and the other traditional dysfunction in patients with sickle cell anaemia. However, contractility parameters—Vcf, ESS, and MAPSE—were not there is controversy about the frequency of the influenced different between patients and controls. It is possible that the ventricle.2 31 33–35 Other investigators have found the LV above variables are insensitive because they are load ventricular performance to be normal in these patients, dependent and in sickle b thalassaemic patients high preload studied by the ejection phase parameters, and only the index and low afterload are present. However, the ratio ESS/ESVI, ESS/ESVI ratio discriminated the above population from which is comparatively load independent, was similar in controls.36–39 In our study the preserved LV and RV systolic patients and controls. Likewise the RV systolic function was function may be associated with the Sb+ type of sickle cell not impaired as assessed by the TAPSE. Conversely the LV thalassaemia, which is less severe.1 http://pmj.bmj.com/ and RV Tei index expressing global myocardial performance In this study, impairment of diastolic parameters of RV significantly differs between patients and controls, distin- function was more pronounced than impairment of the guishing global dysfunction. The fact that the Tei index respective LV function. The explanation for this may be decreases in increased preload and/or decreased afterload and multifactorial. This dissociation possibly reflects a preferen- we found opposite results supports the notion of an tial involvement or a higher susceptibility of the RV. The fact abnormality mainly in diastolic function in such patients.26 27 that the RV diastolic variables are correlated positively with Significant differences as far as the parameters of the serum ferritin concentrations, support the hypothesis ventricular filling and pulmonary and hepatic vein flow were that lung and heart haemochromatosis affects predominantly on September 28, 2021 by guest. Protected copyright. found between patients and controls. These diastolic vari- the RV function. Hyperkinetic circulation and vaso-oclusive ables however are load dependent. Specifically the high effects may have also more effect on the RV, which has

Table 4 Left and right ventricular diastolic parameters of the study population

Parameters SbT Controls p Value

LV E cm/sec 61 (19) 56 (22) NS LV A cm/sec 53 (12) 44 (15) ,0.01 LV E/A 1.17 (0.37) 1.28 (0.26) NS LV DT (ms) 185 (34) 178 (29) NS LV IVRT (ms) 83 (17) 76 (11) ,0.05 RV E cm/sec 53 (10) 49 (13) NS RV A cm/sec 47 (9) 40 (8) ,0.01 RV E/A 1.19 (0.22) 1.23 (0.25) NS RV DT(ms) 198 (39) 175 (34) ,0.01 RV IVRT (ms) 52 (13) 46 (11) ,0.05 Hepatic vein S/D 2.20 (1.08) 1.64 (0.90) ,0.01 Pulmonic vein S/D 1.43 (0.50) 1.22 (0.30) ,0.05

E, peak velocity of early mitral or tricuspid flow; A, peak velocity of late mitral or tricuspid flow; E/A, ratio of early to late peak velocity; DT, deceleration time of early inflow; IVRT, isovolumic relaxation time; S/D, systolic to diastolic forward flow velocity ratio.

www.postgradmedj.com 714 Moyssakis, Tzanetea, Tsaftaridis, et al Postgrad Med J: first published as 10.1136/pgmj.2004.031096 on 4 November 2005. Downloaded from substantially a smaller mass than the LV, resulting in faster 15 Yu CM, Sanderson JE, Skiva Chan, et al. Right ventricular diastolic dysfunction functional derangement. in heart failure. Circulation 1996;93:1509–14. 16 Isobe M, Yazaki Y, Takaku F, et al. Right ventricular filling detected by pulsed In conclusion, our findings show that in middle aged Doppler echocardiography during the convalescent stage of inferior wall patients with sickle b thalassaemia, Sb+ type, the diastolic acute myocardial infarction. Am J Cardiol 1986;59:1245–50. function is abnormal in both ventricles but more noticeable 17 Aessopos A, Farmakis D, Taktikou H, et al. Doppler-determined peak systolic tricuspid pressure gradient in persons with normal pulmonary function and in the RV. The systolic function remains unchanged. tricuspid regurgitation. 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