Normalization of Right Ventricular Performance and Remodeling Evaluated by Magnetic Resonance Imaging at Late Follow-up of Heart Transplantation: Relationship

Between Function, Exercise Capacity and Pulmonary Vascular Resistance

Fernando Bacal, MD, PhD, Philippe Vieira Pires, MD, Luiz Felipe Moreira, MD, PhD, Christiano Pereira Silva, MD, Jose R. Parga Filho, MD, PhD, Ursula M. Costa, MD, Miguel A. Rosrio-Neto, MD, Veridiana M. vila, MD, Ftima D. Cruz, RN, Guilherme V. Guimares, PhD, Victor Sarli Issa, MD, Sylvia Ayub Ferreira, MD, PhD, Noedir Stolf, MD, PhD, Jos Antonio F. Ramires, MD, PhD, and Edimar Bocchi, MD, PhD Background: Right ventricular (RV) dysfunction remains one of the most prominent complications during the period immediately after heart transplantation (HT); however, late adaptation of the RV has not been well described. The aim of our study was to evaluate RV function and remodeling using magnetic resonance imaging (MRI) and to correlate it with exercise capacity and also with hemodynamic data obtained before HT. Methods: We prospectively evaluated RV function of 25 heart-transplanted patients, without cardiac allograft vasculopathy, who were documented by negative dobutamine stress echocardiography during late follow-up (Group 1, 6 4.3 years) using MRI. We then compared Group 1 with a control group consisting of 10 patients, who were 1 year post-HT (Group 2), hemodynamically stable, and with the same pre-operative hemodynamic features as Group 1. Their pulmonary arterial systolic blood pressure (PSBP) varied from 17 to 67 mm Hg (43.2 15.3) and pulmonary vascular resistance (PVR) from 1.0 to 5.4 Wood units (2.5 1.12). The following parameters were studied: RV end-diastolic volume (EDV) and systolic volume (ESV); stroke volume (SV); ejection fraction (EF); and mass (M). We also evaluated the VO2 peak and slope VE/VCO2 values during a treadmill test. Data were analyzed and correlated with the hemodynamic values of PVR and PSBP obtained pre-HT. Results: In Group 1, treadmill evaluation data showed exercise VO2 peak (19.9 3.19 ml/kg/min) and slope VE/VCO2 (36.9 4.5) values comparable to those of sedentary individuals; RV variables according to MRI were within normal ranges, with the following mean values for Groups 1 and 2, respectively: RVEDV, 99.6 4.0 ml vs 127 16 ml (p 0.03); RVESV, 42 2 ml vs 58.5 9 ml (p 0.01); RVSV, 57 3 ml vs 71 10 ml (p 0.1); RVEF, 58 1.4% vs 54 3.8% (p 0.29); and RVM, 43.4 1.9 g vs 74 8.8 g (p 0.001). There was no correlation between hemodynamic pulmonary values before HT or any other index of late RV performance, including RV remodeling and hypertrophy, in our study population (p not signicant). Conclusions: In contrast to what we would expect for heart transplant patients at late follow-up, the RV may adapt to pulmonary pressure and resistance, with reverse remodeling characterized by volume and mass reduction, leading to normalization of RV function despite abnormal hemodynamic pulmonary values being measured before HT. There was no inuence on the low exercise capacity observed in these patients, in the absence of cardiac allograft vasculopathy. J Heart Lung Transplant 2005;24: 2031 6. Copyright 2005 by the International Society for Heart and Lung Transplantation.

Pulmonary hypertension remains the Achilles heel of clinical heart transplantation. Right ventricular failure is
From the Heart Institute (InCor), University of So Paulo Medical School, So Paulo, Brazil. Submitted February 15, 2005; revised May 20, 2005; accepted June 7, 2005. Reprint requests: Fernando Bacal, MD, Heart Failure Unit, Instituto Do Coracao, Rua Joao Castaldi 217, Ap. 42, MoemaSo Paulo CEP 04517-050, Brazil. Telephone: 55-11-30695307. Fax: 55-11-30695502. E-mail: fbacal@uol.com.br Copyright 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$see front matter. doi:10.1016/ j.healun.2005.06.002

a prominent life-threatening problem after adult orthotopic cardiac transplantation and accounts for nearly 50% of all cardiac complications and 19% of all early deaths after implantation of the donor heart and the discontinuation of cardiopulmonary bypass. This failure is most commonly related to pre-existent chronic pulmonary hypertension in the recipient, which occurs as a result of long-standing left ventricular dysfunction, although other possible inuences such as brain death, hypothermic cardioplegic arrest and organ storage may play a role.1 An elevated pulmonary vascular resistance is a widely recognized risk factor for right ventricular dysfunction as well as early death after cardiac transplan2031

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tation,2 4 and it is attributed to the inability of the donor right ventricular myocardium to acutely compensate for the recipients elevated pulmonary vascular resistance. A loss of contractility in the donor heart may be related to the myocardial changes occurring after brain death in the organ donor, as brain death is known to be associated with donor organ dysfunction, cardiovascular deterioration as well as metabolic and hormonal changes.5 The left ventricle of the donor, of course, is much stronger than the recipient left ventriclewhich is the reason for needing the transplantation procedure. Regarding the right ventricle, however, a paradox exists. The recipient right ventricle has, over time, acclimated itself to the increased afterload of high pulmonary artery pressures resulting from the failing left ventricle. The donor right ventricle, on the other hand, is accustomed only to normal pulmonary artery pressures and can easily fail after transplantation. With regard to the ability to cope with elevated recipient pulmonary artery pressures, the discarded recipient right ventricle is often much stronger than the transplanted donor right ventricle. Even with -agonist or phosphodiesterase inhibitor support of the transplanted donor right ventricle, and with vasodilation of the pulmonary arteries with nitrates, nitroprusside, prostaglandins and inhaled nitric oxide, right heart failure after heart transplantation can still be irremediable and often lethal. When mechanical support of the right ventricle needs to be implemented, mortality may approach 50%. However, late adaptation of this chamber is not well described. Patients with pulmonary resistance in the range of 1 to 3 Woods units are optimal candidates for heart transplantation. With pulmonary vascular resistance between 3 and 6 Woods units, patients become high risk. Several studies have shown that patients in this high-risk group have an early mortality of 17% to 60% after transplantation. At 6 Woods units, most authorities believe that heart transplantation is contraindicated.6 Some studies have suggested that heart and lung recipients with primary pulmonary hypertension can provide useful donor hearts to patients with increased pulmonary vascular resistance, and that these hearts function well in the intermediate and long term.7 Thus, we conclude that it is relevant to assess the right ventricular function after orthotopic heart transplantation. Tricuspid regurgitation is the most common valvular abnormality after cardiac transplantation and the interaction with right ventricular function is complex, with the effects on afterload making an accurate assessment difcult when using echocardiographic evaluation.8 Cardiovascular magnetic resonance has become the gold standard in the assessment of left ventricular volumes, function and mass. Excellent results for both

accuracy and reproducibility of measurements have been demonstrated, without exposure to ionizing radiation. It is also well suited for the determination of right ventricular parameters, because of the 3-dimensional volume acquisition of this chamber, which has a variable conguration that is difcult to dene geometrically. Cardiovascular magnetic resonance of right ventricle volumes and muscle mass has shown good correlation with in vitro casts and with in vivo standards such as indicator techniques, radionuclide ventriculography, cine angiography and absolute weight. Magnetic resonance has gained an important position in the assessment of volumes and function of the heart.9,10 The aim of this study was to evaluate right ventricular function and remodeling of patients at both early and late follow-up after heart transplantation, using magnetic resonance imaging, and also to investigate its possible correlation with post-operative exercise capacity and with pre-operative pulmonary hypertension. METHODS We prospectively evaluated the right ventricular function of 25 heart-transplanted patients, without cardiac allograft vasculopathy, in the late follow-up (6 4.3 years) period (Group 1). These patients were compared with a control group (Group 2) comprised of 10 patients, who were 1 year after heart transplantation, hemodynamically stable, and with the same pre-operative hemodynamic features of Group 1. Right ventricular function data were correlated with exercise capacity for Group 1 patients and with hemodynamic data obtained before heart transplantation in both groups. As exclusion criteria, we considered the presence of moderate or severe tricuspid regurgitation on the basis of echocardiogram, hemodynamic instability and pacemaker use. We did not evaluate patients who had clinically severe right ventricular dysfunction during the immediate post-operative period. To evaluate right ventricular function, we used magnetic resonance with a 1.5-T magnet (GE Healthcare, USA) and a dedicated 4-element cardiac coil to signal reception. A fast gradient echo-pulse sequence (Fiesta) was employed with an electrocardiographic gating control and repetition time/echo time of 3.7/1.5 milliseconds, ip angle of 50, eld-of-view 32 to 36 mm, matrix 160 160, 1 excitation, 14 to 18 views per segment, 8-mm slice thickness, 2-mm spacing and 20 phases/ cycle. Cines with 8 to 10 short-axis slices were obtained beginning at 1 cm below the mitral valve plane until the apex to cover the entire left ventricle, using 1-cm intervals. The following right ventricle variables were analyzed: (1) end-diastolic and -systolic volumes; (2) ejection fraction; and (3) mass.

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Hemodynamic data (pulmonary arterial systolic blood pressure [PSBP] and pulmonary vascular resistance [PVR]) were generally obtained using a SwanGanz catheter, before patients were added to the waiting list. We also evaluated the peak VO2 (maximal oxygen consumption) and slope VE/VCO2 values during a maximal treadmill test in Group 1 patients. Pulmonary ventilation and gas-exchange data were determined on a breath-by-breath basis with a computerized system (Model Vmax 229, Sensormedics). The peak oxygen consumption was considered to be the maximum VO2 value obtained. Table 1 shows the characteristics of the study population. We excluded patients with a pacemaker and those with hemodynamic instability, acute allograft rejection or cardiac allograft vasculopathy, which was documented by negative dobutamine stress echocardiography or angio-coronariography. Data obtained in the 2 groups are presented as mean and standard deviation and were compared using the unpaired Students t-test. Correlation between variables was investigated using Pearsons coefcient. p 0.05 indicated statistical signicance. RESULTS There were no pre-operatively signicant differences between the 2 groups. PSBP varied from 17 to 67 mm Hg (43.2 15.3) and PVR from 1.0 to 5.4 Wood units (2.5 1.12). Seven patients in Group 1 and 3 patients in Group 2 had mild tricuspid regurgitation (p not signicant). In Group 1, treadmill evaluation data showed exercise VO2 peak of 19.9 3.19 ml/kg/min and slope

Figure 1. (A) Magnetic resonance imaging analysis of right ventricular end-diastolic volume (RVEDV), comparing the early (Group 2) and late (Group 1) post-operative periods after heart transplantation. (B) Magnetic resonance imaging analysis of right ventricular end-systolic volume (RVESV), comparing the early (Group 2) and late (Group 1) post-operative periods after heart transplantation.

Table 1. Characteristics of the Study Population Number of patients Gender Age (years) Donor age (years) Follow-up (years) Etiology Dilated Chagasic Ischemic Restrictive Valvular ARVD PSBP (mm Hg) PMBP (mm Hg) PVR (Wood units) Group 1 (late) 25 20 M 45 6 31 3 6 4.3 11 5 4 2 2 1 43.2 30.5 2.5 15.3 3.4 1.1 43.3 32.3 2.1 Group 2 (early) 10 8M 43 4 33 4 0.5 0.3 3 4 2 1

11.2 2.6 0.8

ARVD, arrhythmogenic right ventricular dysplasia; PSBP, pulmonary systolic blood pressure; PMBP, pulmonary mean blood pressure; PVR, pulmonary vascular resistance.

VE/VCO2 of 36.9 4.5, values comparable to sedentary individuals. Magnetic resonance imaging data of right ventricular function documented signicant differences between the early and late post-operative periods. Figure 1 shows that right ventricular end-systolic and -diastolic volumes were signicantly elevated early after heart transplantation, when compared with late follow-up (58.5 9.0 ml vs 42.0 2.0 ml, p 0.01; 127 16 ml vs 99.6 4.0 ml, p 0.03, respectively). There were no signicant differences with regard to right ventricular stroke volume (71.0 10.0 ml vs 57.0 3.0 ml, p 0.1) and ejection fraction (54.0 3.8% vs 58.0 1.4%, p 0.29) between the 2 periods. On the other hand, Figure 2 shows an important difference in right ventricular mass between the early and late post-operative periods (74.0 8.8 g vs 43.4 1.9 g, p 0.001). We did not observe any correlation between hemodynamic pulmonary values before heart transplantation

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Figure 2. Magnetic resonance imaging analysis of right ventricular mass, comparing the early (Group 2) and late (Group 1) post-operative periods after heart transplantation.

and any index of post-operative right ventricular performance, including right ventricle remodeling and hypertrophy, in our study population (p not signicant). There was no correlation between right ventricular function data and the exercise capacity indexes in the late heart transplantation follow-up. DISCUSSION One of the most prominent early complications after heart transplantation is right ventricular dysfunction due to the high pulmonary pressure and resistance presented by patients with end-stage heart failure.4,11 This complication may lead to hemodynamic disturbances such as low cardiac output, low urine output and cardiogenic shock. There is a well-known role for inotropes and pulmonary vasodilators as therapeutic agents to promote chamber adaptation, mainly in the rst post-operative week.3,11,12 Diagnosis of right ventricular dysfunction during this period requires echocardiographic evaluation and, frequently, SwanGanz catheter measurements for evolution and therapeutic monitoring. However, echocardiographic analysis is sometimes impaired because of technical considerations and the difculty of analysis in the early postoperative period. After hospital discharge, little is known about the status of the right ventricle, including chamber remodeling during late follow-up. To our knowledge, this is the rst study documenting late right ventricular adaptation and making the comparison to data from patients in early follow-up after heart transplantation. We have chosen magnetic resonance imaging because this method can closely detail volumes and mass, which are important in remodeling analysis.8,9 Our results clearly show that right ventricular adaptation occurs, characterized by volumes and mass reduction

when compared with a group of patients in the early post-operative period (up to 1 year) and with the same pre-operative hemodynamic features. Clinically, the patients had no symptoms, which probably reects pulmonary pressure reduction, because the patients now have normal left ventricular function, which will lead to neurohormonal, sympathetic and inammatory activation normalization.13 With regard to the low exercise capacity observed in these patients, we found no correlation with right or left ventricular function. Other mechanisms, such as physical inactivity, long-term use of corticosteroids and physiologic aspects related to heart denervation, and co-morbidities, such as obesity and systemic arterial hypertension, may have inuenced our results.14 17 The current literature examining the right ventricle and its inuence on the pathophysiologic processes in heart failure has been limited and controversial. Some studies have postulated that right ventricular dysfunction is a powerful predictor of reduced exercise capacity and survival in patients with chronic dilated cardiomyopathy and heart failure.18 Others did not nd an association between peak VO2 at maximum exercise and right ventricular ejection fraction at rest with different radionuclide ventriculography techniques, in patients with congestive heart failure.19 Thus, we tested the hypothesis that right ventricular performance plays a role in the exercise capacity of heart-transplanted patients, but we found no correlation. Patients who undergo supervised physical conditioning can have signicant physical capacity improvement. Nonetheless, it is not available routinely to all patients at our institution. Tricuspid regurgitation is the most common valvular abnormality after orthotopic heart transplantation. A variety of causes have been implicated, including asynchronous contraction of the donor and recipient atrial compartments, disturbed geometry of the right atrial anatomosis with subsequent impairment of the functional integrity of the valvular apparatus, and damage to the sub-valvular apparatus during endomyocardial biopsy. Clinical tricuspid regurgitation may be of functional signicance for the cardiac allograft and may play a role in determining clinical progress.20 Another prominent cause of late right ventricular dysfunction is cardiac allograft vasculopathy; these patients sometimes have right coronary artery disease, which can lead to right ventricular myocardial infarction. This condition may be present even in the absence of chest pain, as the heart has been denervated.21,22 We excluded patients with cardiac allograft vasculopathy from our study population in order to analyze specically the inuence of pulmonary hypertension on right ventricular performance. Reverse remodeling, as indicated by decreased ventricular end-diastolic dimensions and ventricular

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end-diastolic volumes,23 has important prognostic meaning in patients with heart failure that show improved or normalized function and ventricular diameter after therapy is instituted. The present ndings, related specically to right ventricular function, are not well established, but the possibility of normalization of right ventricular performance in heart-transplanted patients is valuable for understanding right ventricular reverse remodeling and the inuence of pulmonary hypertension on this specic population. Concerns regarding right ventricular dysfunction should still be restricted to the early postoperative period, because, as this rst phase passes, this chamber shows an ability to adapt. Study Limitations The ideal study design would be to evaluate right ventricular function of the same patient(s) at both early and late follow-up. Because we did not do this, we included patients with the same pre-operative features, including the presence of pulmonary hypertension and tricuspid regurgitation. We did not include patients who had clinical severe right ventricular dysfunction during the immediate post-operative period, especially patients requiring inotropes or intravenous vasodilators, due to the difculty of providing MRI assessment for these patients. Nevertheless, we did demonstrate right ventricular adaptation, even in the sub-population that did not have severe pulmonary hypertension. In conclusion, in contrast to what we expected, in late follow-up of heart-transplanted patients the right ventricle may adapt to pulmonary pressure and resistance. Reverse remodeling occurs, characterized by volumes and mass reduction, leading to normalization of function despite hemodynamic pulmonary values having been observed before transplantation. The low exercise capacity observed in these patients, which could have been due to impaired right ventricular performance, in the absence of cardiac allograft vasculopathy, had no inuence of its function. REFERENCES
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4. Chen EP, Bittner HB, Davis RD, et al. Right ventricular adaptation to increased afterload after orthotopic cardiac transplantation in the setting of recipient chronic pulmonary hypertension. Circulation 1997;96(suppl II): II-1417. 5. Bittner HB, Chen EP, Biswas SS, et al. Right ventricular dysfunction after cardiac transplantation: primarily related to status of donor heart. Ann Thorac Surg 1999;68: 160511. 6. Elefteriades JA, Lovoulos CJ, Tellides G, et al. Right ventricle-sparing heart transplant: promising new technique for recipients with pulmonary hypertension. Ann Thorac Surg 2000;69:1858 64. 7. Birks EJ, Yacoub MH, Anyanwu A, et al. Transplantation using hearts from primary hypertensive donors for recipients with a high pulmonary vascular resistance. J Heart Lung Transplant 2004;23:1339 44. 8. Burgess MI, Bright-Thomas RJ, Ray SG. Echocardiographic evaluation of right ventricular function. Eur J Echocardiogr 2002;3:252 62. 9. Grothues F, Moon JC, Bellenger NG, et al. Interstudy reproducibility of right ventricular volumes, function, and mass with cardiovascular magnetic resonance. Am Heart J 2004;147:218 23. 10. Jauhiainen T, Jrvinen VM, Hekali PE. Evaluation of methods for MR imaging of human right ventricular heart volumes and mass. Acta Radiol 2002;43:58792. 11. Gavazzi A, Ghio S, Scelsi, L, et al. Response of the right ventricle to acute pulmonary vasodilation predicts the outcome in patients with advanced heart failure and pulmonary hypertension. Am Heart J 2003;145:310 6. 12. Carrier M, Blaise G, Bslile S, et al. Nitic oxide inhalation in the treatment of primary graft failure following heart transplantation. J Heart Lung Transplant 1999;18: 664 7. 13. Perez-Villa F, Roig E, Ferrer E, et al. neurohormonal activation in congestive heart failure: does it normalize after heart transplantation? Rev Esp Cardiol 2004;57:72531. 14. Doutreleau S, Piquard F, Lonsdorfer E, et al. Improving exercise capacity, 6 wk training tends to reduce circulating endothelin after heart transplantation. Clin Transplant 2004;18:6725. 15. Nanas SN, Terrovitis JV, Charitos C, et al. Ventilatory response to exercise and kinetics of oxygen recovery are similar in cardiac transplant recipients and patients with mild chronic heart failure. J Heart Lung Transplant 2004; 23:1154 9. 16. Borrelli E, Pogliaghi S, Molinello A, et al. Serial assessment of peak VO2 kinetics early after heart transplantation. Med Sci Sports Exerc 2003;35:1798 804. 17. Marconi C, Marzorati M. Exercise after heart transplantation. Eur J Appl Physiol 2003;90:250 9. 18. Brieke A, DeNofrio D. Right ventricular dysfunction in chronic dilated cardiomyopathy and heart failure. Coron Artery Dis 2005;16:511. 19. Hacker M, Stork S, Stratakis D, et al. Relationship between right ventricular ejection fraction and maximum exercise oxygen consumption: a methodological study in chronic heart failure patients. J Nucl Cardiol 2003;10:644 9.

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20. Aziz TM, Saad RA, Burgess, MI, et al. Clinical signicance of tricuspid valve dysfunction after orthotopic heart transplantation. J Heart Lung Transplant 2002;21:1101 8. 21. Lietz K, Miller LW. Current understanding and management of allograft vasculopathy. Semin Thorac Cardiovasc Surg 2004;16:386 94. 22. Valantine H. Cardiac allograft vasculopathy after heart

transplantation: risk factors and management. J Heart Lung Transplant 2004;23:18793. 23. Woo GW, Petersen-Stejskal S, Johnson JW, et al. Ventricular reverse remodeling and 6-month outcomes in patients receiving cardiac resynchronization therapy: analysis of MIRACLE study. J Interv Card Electrophysiol 2005;12:10713.