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Budts Devroe, Hilde Gillijns, Jan Bogaert, Piet Claus, Hein

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Budts Devroe, Hilde Gillijns, Jan Bogaert, Piet Claus, Hein Sildenafil Improves Exercise Hemodynamics in Fontan Patients Alexander Van De Bruaene, Andre La Gerche, Guido Claessen, Pieter De Meester, Sarah Devroe, Hilde Gillijns, Jan Bogaert, Piet Claus, Hein Heidbuchel, Marc Gewillig and Werner Budts Circ Cardiovasc Imaging. 2014;7:265-273; originally published online January 29, 2014; doi: 10.1161/CIRCIMAGING.113.001243 Circulation: Cardiovascular Imaging is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 1941-9651. Online ISSN: 1942-0080 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circimaging.ahajournals.org/content/7/2/265 Data Supplement (unedited) at: http://circimaging.ahajournals.org/content/suppl/2014/01/29/CIRCIMAGING.113.001243.DC1.html Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation: Cardiovascular Imaging can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation: Cardiovascular Imaging is online at: http://circimaging.ahajournals.org//subscriptions/ Downloaded from http://circimaging.ahajournals.org/ at KU Leuven University Library on July 31, 2014 Congenital Heart Disease Sildenafil Improves Exercise Hemodynamics in Fontan Patients Alexander Van De Bruaene, MD, PhD*; Andre La Gerche, MD, PhD*; Guido Claessen, MD; Pieter De Meester, MD; Sarah Devroe, MD; Hilde Gillijns, BSc; Jan Bogaert, MD, PhD; Piet Claus, PhD; Hein Heidbuchel, MD, PhD; Marc Gewillig, MD, PhD*; Werner Budts, MD, PhD* Background—Patients with Fontan circulation have reduced exercise capacity. The absence of a presystemic pump may limit flow through the pulmonary circulation, restricting ventricular filling and cardiac output. We evaluated exercise hemodynamics and the effect of sildenafil on exercise hemodynamics in Fontan patients. Methods and Results—Ten Fontan patients (6 men, 20±4 years) underwent cardiac magnetic resonance imaging at rest and during supine bicycle exercise before and after sildenafil. Systemic ventricular volumes were obtained at rest and during low- (34±15 W), moderate- (69±29 W), and high-intensity (97±36 W) exercise using an ungated, free-breathing cardiac magnetic resonance sequence and analyzed correcting for cardiac phase and respiratory translation. Radial and pulmonary artery pressures and cGMP were measured. Before sildenafil, cardiac index increased throughout exercise (4.0±0.9, 5.9±1.1, 7.0±1.6, 7.4±1.7 L/(min·m2); P<0.0001) with 106±49% increase in heart rate. Stroke volume index (P=0.015) and end-diastolic volume index (P=0.001) decreased during exercise. End-systolic volume index remained unchanged (P=0.8). Total pulmonary resistance index (P=0.005) increased, whereas systemic vascular resistance index decreased during exercise (P<0.0001). Sildenafil increased cardiac index (P<0.0001) and stroke volume index (P=0.003), especially at high-intensity exercise (interaction P=0.004 and P=0.003, respectively). Systemic vascular resistance index was reduced (P<0.0001–interaction P=0.1), whereas total pulmonary resistance index was reduced at rest and reduced further during exercise (P=0.008–interaction P=0.029). cGMP remained unchanged before sildenafil (P=0.9), whereas it increased significantly after sildenafil (P=0.019). Conclusions—In Fontan patients, sildenafil improved cardiac index during exercise with a decrease in total pulmonary resistance index and an increase in stroke volume index. This implies that pulmonary vasculature represents a physiological limitation, which can be attenuated by sildenafil, the clinical significance of which warrants further study. (Circ Cardiovasc Imaging. 2014;7:265-273.) Key Words: cyclic GMP ◼ exercise ◼ Fontan procedure ◼ pulmonary circulation ◼ sildenafil he Fontan circulation provides definite palliation for systemic ventricle and systemic circulation.4 A reduced ven- Tpatients born with a single anatomic or functional ven- tricular preload has been demonstrated during dobutamine tricular chamber. However, exercise tolerance is significantly stress echocardiography in Fontan patients, showing that car- reduced in Fontan patients, even in those with apparently ideal diac index (CI) was dependent on presystemic determinants anastomoses and ventricular function.1,2 In these patients, the of preload rather than on ventricular contractility.5,6 However, absence of a subpulmonary ventricle may limit pulmonary vas- dobutamine may not be a perfect surrogate of the ventricu- cular flow and thus systemic ventricular filling. Furthermore, lar changes that occur with exercise because systemic venous few data exist on the long-term consequences of a Fontan cir- preload is limited. culation on the pulmonary vascular bed because laminar flow (instead of pulsatile flow) may decrease the release of NO Clinical Perspective on p 273 from the endothelium and increase pulmonary vascular resis- Sildenafil targets the endothelial NO pathway by inhibiting tance.3 Thus, limitations in exercise-induced augmentation of phosphodiesterase-5, increasing cGMP, and inducing pulmo- pulmonary vascular flow could explain the cardiac limitation nary vasodilation.7 Giardini et al8 demonstrated an improve- observed during exercise rather than the performance of the ment in peak oxygen consumption and CI after a single oral Received July 9, 2013; accepted January 16, 2014. From the Departments of Adult Congenital Cardiology (A.V.D.B., P.D.M., W.B.), Cardiovascular Medicine (A.L.G., G.C., H.H. H.G.), Anesthesiology (S.D.), Radiology (J.B.), and Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium (M.G.); St. Vincent’s Hospital, Department of Medicine, University of Melbourne, Fitzroy, Australia (A.L.G.); and Medical Imaging Research Center, University of Leuven, Leuven, Belgium (P.C.). *Drs Van De Bruaene and La Gerche contributed equally as first author. Drs Gewillig and Budts contributed equally as senior author. The Data Supplement is available at http://circimaging.ahajournals.org/lookup/suppl/doi:10.1161/CIRCIMAGING.113.001243/-/DC1. Correspondence to Alexander Van De Bruaene, MD, PhD, Congenital and Structural Cardiology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail [email protected] © 2014 American Heart Association, Inc. Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org DOI: 10.1161/CIRCIMAGING.113.001243 Downloaded from http://circimaging.ahajournals.org/265 at KU Leuven University Library on July 31, 2014 266 Circ Cardiovasc Imaging March 2014 dose of sildenafil in Fontan patients, although the underlying exercise level so that the patient would manage to continue exercising. mechanism was not investigated. Extending this experience, Each stage was maintained for ≈3 to 4 minutes—1 minute to obtain an exercise steady state, after which image acquisition was commenced. Goldberg et al9,10 demonstrated an improvement in ventilatory Patients then took a single oral dose of sildenafil 50 mg and were efficiency and ventricular performance after a 6-week period allowed to rest for 30 to 60 minutes. Exercise CMR was repeated at of sildenafil treatment. low-, moderate-, and high-intensity workload using the same wattage We have recently validated a real-time, ungated cardiac as used during the baseline exercise CMR. magnetic resonance (CMR) imaging method, which enables accurate measurements of ventricular volumes obtained dur- Exercise CMR ing intense exercise.11 Ventricular volumes were measured during supine exercise using a Using this novel CMR methodology with simultaneous real-time CMR methodology that we have previously described in invasive vascular pressure recordings during exercise, we detail and validated against invasive standards.11 Subjects performed supine exercise within the CMR bore using a programmable ergom- evaluated exercise hemodynamics and the effect of sildenafil eter. Images were acquired during free breathing at rest and low-, on exercise hemodynamics in Fontan patients. We hypoth- moderate-, and high-intensity exercise using a Philips Achieva 1.5T esized that (1) the exercise capacity in patients with a Fontan CMR with a 5-element phased-array coil (Philips Medical Systems, circulation and seemingly normal anastomotic and ventricu- Best, The Netherlands). Images were acquired during free breathing lar function is limited attributable to an impaired augmen- using steady-state free precession cine imaging obtained in the short axis and horizontal long axis plane as described before.11 A plethys- tation in pulmonary vascular flow, and (2) sildenafil would mograph was placed on the upper abdomen providing data on the improve pulmonary vascular flow and ventricular preload timing or respiration, and ECG data were obtained using a hemody- during exercise.4,12 namic monitor (Maglife Serenity, Schiller, Baar, Switzerland). These physiological data were synchronized with the image acquisition using an in-house developed
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