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Cardiac transplantation for hypertrophic cardiomyopathy: a valid therapeutic option
Cardiac Transplantation for Hypertrophic Cardiomyopathy: A Valid Therapeutic Option Marianne Coutu, MD, MSc,a Louis P. Perrault, MD, PhD,a Michel White, MD,a Guy B. Pelletier, MD,a Normand Racine, MD,a Nancy C. Poirier, MD,a,b and Michel Carrier, MDa,b Background: Hypertrophic cardiomyopathy is a rare indication for cardiac transplantation, with only anecdotal reports in the literature. Transplantation has been proposed to patients with hypertrophic cardiomyopathy who remained symptomatic despite optimal medical treatment or who progressed to congestive heart failure, and when conventional surgical correction was not or was no longer possible. In this report, we analyze the clinical results of cardiac transplantation in these patients. Methods: We retrospectively reviewed complete clinical data and prospectively gathered complete follow-up data for 14 patients who underwent orthotopic cardiac transplantation for hypertrophic cardiomyopathy at the Montreal Heart Institute and Ste-Justine Hospital between 1984 and 2001. Results: Ten male (71.4%, 5 adults and 5 children) and 4 female (28.6%, 2 adults and 2 children) patients underwent heart transplantation for hypertrophic cardiomyopathy. The median age of the recipients in the pediatric group was 13 years (range, 6 –16) and was 40 years (range, 22– 46) in the adult group. Median duration of follow-up was 9.5 years (mean, 8.8 ⫾ 4.8 years; range, 1–18) and was 100% complete. We found no operative mortality and found 2 late deaths related to coronary graft atherosclerosis. Long-term survival at 5, 10, and 15 years was 100%, 85%, and 64%, respectively. Freedom from acute rejection at 1, 5, and 10 years was 73%, 32%, and 9%, respectively. The remaining 11 survivors exhibit few symptoms and are currently in New York Heart Association Class I or II. Conclusions: Cardiac transplantation is a valid therapeutic option for patients with symptomatic hypertrophic cardiomyopathy who do not respond to optimal medical management and who are not candidates for conventional surgical treatment. The long-term outcome is excellent in these patients. J Heart Lung Transplant 2004;23:413– 417.
Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric or symmetric myocardial hypertrophy, occurring in the absence of an obvious cause for hypertrophy, such as aortic stenosis and systemic hypertension. Hypertrophic cardiomyopathy predominantly involves the interventricular septum of a nondilated left ventricle and creates a dynamic pressure gradient in the left ventricular outflow tract. The majority of patients are managed medically with adequate relief of symptoms. Septal myotomy–myomectomy is indicated in symptomatic patients with left ventricular pressure gradients ⬎50 mm Hg who have not reFrom the aMontreal Heart Institute, Research Center and Cardiovascular Division, and bSte-Justine Hospital, Cardiovascular Division, University of Montreal, Montreal, Quebec, Canada. Submitted December 2, 2002; revised March 11, 2003; accepted May 3, 2003. Reprint requests: Michel Carrier, MD, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8. Telephone: 514-376-3330. Fax: 514-376-4766. E-mail: carrier@icm. umontreal.ca. Copyright © 2004 by the International Society for Heart and Lung Transplantation. 1053-2498/04/$–see front matter. doi:10.1016/ S1053-2498(03)00225-0
sponded well to medical management.1 However, conventional surgery is not always feasible, especially in patients with the diffuse form of the disease and when progression to congestive heart failure has occurred. In this study, we reviewed the clinical results of heart transplantation in the treatment of HCM at our institution to determine whether this is a valid therapeutic option in these patients. METHODS Patient Population We retrospectively reviewed clinical data of 14 patients with HCM who underwent heart transplantation at the Montreal Heart Institute and Ste-Justine Hospital between 1984 and 2001. All patients were followed prospectively at the transplantation clinics of both institutions. There were 7 adults (5 men and 2 women) and 7 children (5 boys and 2 girls). During the study period, 258 adult patients underwent heart transplantation (7/258, 3% with HCM) and 46 children underwent transplantation (7/46, 15% with HCM). After discharge from the hospital and for the first year after transplantation, follow-up visits were scheduled monthly. 413
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Coutu et al.
The diagnosis of acute rejection (ⱖ3A) was established by endomyocardial biopsy specimen according to the classification of the International Society for Heart and Lung Transplantation (ISHLT). At Ste-Justine’s Hospital, the pediatric patients are observed echocardiographically for rejection. Biopsy is performed 2 weeks after transplantation and then annually. Additional biopsies are performed if echocardiographic or clinical evidence suggests rejection. Rejection was treated with modified immunosuppression according to defined protocols.2 Coronary angiograms were performed before discharge and annually thereafter.3 Surgical Techniques and Immunosuppressive Regimen Donor hearts were procured and implanted using standard techniques.4 At the Montreal Heart Institute, induction of immunosuppression consisted of intravenous thymoglobulin (rabbit anti-human thymocyte immunoglobulin; Pasteur Me´rieux, Lyon, France; 125 mg per day) the day of transplantation and the first 2 post-operative days. Oral prednisone (1 mg/kg tapered to 0.1 mg/kg per day) and azathioprine (3 mg/kg) or mycophenolate mofetil (1 g twice a day) were started after patient extubation. Oral cyclosporine (2– 6 mg/kg) was initiated only after hemodynamic stabilization and normalization of the renal function at post-operative Day 2 to Day 5 after transplantation. At Ste-Justine Hospital, immunosuppressive regimen encompassed intravenous methylprednisolone (2 mg/kg each 3 hours for 3 doses, 1 mg/kg each 3 hours for 3 doses, and 0.5 mg/kg each 3 hours for 3 doses). Oral prednisone (1 mg/kg in 2 doses) was started when intestinal transit resumed. Azathioprine (2 mg/kg) and cyclosporine (1.4 mg/kg IV or 7 mg/kg orally) were begun on post-operative Day 1. Patients received triple-drug treatment based on cyclosporine until 6 to 12 months after transplantation, at which time treatment was individualized to wean oral prednisone in patients who tolerated decreased immunosuppression. Statistical Analysis We retrieved clinical and follow-up data from medical records. We performed statistical analysis with Statistica 4.0 Software (StatSoft; Tulsa, OK). Early post-operative death was defined as occurring within 30 days of transplantation. We report data as median, range, or mean ⫾ SD. We analyzed death, acute rejection, infection, and coronary graft atherosclerosis using KaplanMeier curves. RESULTS Between 1984 and 2001, 10 male (71%, 5 adults and 5 children) and 4 female (29%, 2 adults and 2 children) patients underwent heart transplantation for HCM. The
The Journal of Heart and Lung Transplantation April 2004
median age of the recipients in the pediatric group was 13 years (range, 6 –16) and was 40 years (range, 22– 46) for the adult group. Median duration of follow-up was 9.5 years (mean, 8.8 ⫾ 4.8 years; range, 1–18) and was 100% complete. Diagnosis of HCM was confirmed by myocardial biopsy specimens in all explanted hearts. Family history of HCM or sudden death was present in 10 patients (71%). Two patients were father and son. The most frequent clinical presentations were dyspnea (100%), palpitations (57%), angina (50%), orthopnea (43%), syncope (21%), and sudden death in 1 patient. Prior procedures consisting of myotomy–myomectomy and DDD-pacemaker implantation were performed in 5 (36%) and 2 (14%) patients, respectively. Surgical indications for transplantation were terminal heart failure in 13 patients (93%) and malignant ventricular arrhythmias in 1 patient (7%). Median duration on the waiting list was 9 months (mean ⫾ SD, 10.8 ⫾ 11.5 months). Median donor age was 23 years (mean ⫾ SD, 25.6 ⫾ 16.4 years). Median cardiopulmonary and ischemic times were 109 (mean ⫾ SD, 136 ⫾ 62) and 142 (mean ⫾ SD, 139 ⫾ 44) minutes, respectively. Median hospital stay was 28 days (mean ⫾ SD, 32 ⫾ 22 days). Patient Survival Short-term survival (30-day) was 100%. Five-, 10-, and 15-year survival was 100%, 85%, and 64%, respectively (Figure 1). There were 2 late deaths. One patient who received a donor heart at aged 12 had a massive anterolateral myocardial infarction that rapidly progressed to cardiogenic shock 11 years after cardiac transplantation. The other patient was a 57-year-old man who had significant coronary graft atherosclerosis and ischemic cardiomyopathy. He died of heart failure 11 years after cardiac transplantation. Of the 12 longterm survivors, 11 (92%) have New York Heart Association (NYHA) Class I symptoms. Early and Late Complications Early cardiovascular morbidity was related largely to immunosuppressive drugs. Calcineurin-inhibitor–induced systemic hypertension occurred in 50% of the patients. Acute respiratory distress syndrome secondary to bacterial pneumonia occurred in 1 patient. Seizures developed in 29% of patients (4 children). No patient with renal failure in the post-operative period required hemodialysis. The most frequent late complications were chronic renal failure and infections. One patient required a permanent pacemaker for sick sinus syndrome. One patient experienced concentric left ventricular hypertrophy (indexed ventricular mass ⫽ 151 g/m2) 10 years after transplantation. He remained totally asymptomatic
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Figure 1. Actuarial patient survival.
in NYHA Class I until he died of a massive myocardial infarction. Four patients (29%) who experienced renal toxicity or severe gingival hyperplasia were switched from cyclosporine to tacrolimus. Azathioprine was the most frequent purine anti-metabolite used (10 patients). Three patients (21%) had leukopenia and were switched to mycophenolate mofetil. Steroids were continued in 66% of patients. Acute rejection was detected in 12 patients (86%), with a median of 2 episodes per patient. Freedom from acute rejection at 1, 5, and 10-years was 73%, 32%, and 9%, respectively. Eight patients (57.1%) had at least 1 episode of infection. Eight bacterial (2 dental abcesses, 2 sepses, 2 pneumoniae, 1 scabies, and 1 cystitis) and 5 viral episodes (2 warts, 1 meningitis, 1 mononucleosis, and 1 gastroenteritis). Freedom from infection at 1 and 10 years was 71% and 38%, respectively. We found no cytomegalovirus infection in this cohort of patients. Coronary Graft Atherosclerosis Freedom from coronary graft atherosclerosis as shown with routine angiograms at 5 and 10 years was 91% and
66%, respectively. Three patients (21.4%) had graft coronary atherosclerosis. Two of them had myocardial infarction and died of cardiac failure, as mentioned previously. The third patient is in NYHA Class I and is being treated medically. DISCUSSION Hypertrophic cardiomyopathy is a rare entity occurring in 0.02% of the population.5 Fifty percent of the cases are familial. Genetic defects have been found in more than 1 locus, implicating among them beta cardiac myosin heavy chain, troponin T, and tropomyosin.6 The majority of sporadic forms are caused by spontaneous mutations.7 The natural history of HCM varies. Some patients remain asymptomatic or mildly symptomatic and stable for 5 to 10 years.8 However, progression to left ventricular dilatation and dysfunction occurs in 10% to 15% of patients.1 Shirani et al 9 have studied clinicopathologic features of these dilated hearts; dilated left ventricular cavities and left ventricular scars without significant narrowing of the epicardial coronary arteries. The disease has an annual mortality of approximately 3%, related to both progressive heart failure and sudden cardiac death.10 The annual mortality risk is
416
Coutu et al.
even greater in children, approximating 6% with most related to sudden death.7 This complication often occurs during exercise but also demonstrates a circadian distribution, with clustering of deaths in the morning and early evening.11 Managing patients with HCM involves alleviating symptoms, preventing complications, and decreasing the risk of death. Beta-adrenoreceptor blockers improve the patient’s symptoms by decreasing myocardial oxygen consumption12 and resting or provocable gradients. Inserting dual-chamber DDD pacemakers may be useful in some patients who have outflow gradiens and severe symptoms.1,13 Percutaneous transluminal septal ablation significantly decreases the left ventricular outflow tract gradient, and mid-term follow-up has shown improvement.14,15 Septal myotomy–myomectomy is indicated in patients with gradients ⬎50 mm Hg who remain symptomatic despite medical therapy.16,17 Heart transplantation is the last option for those who remain severely symptomatic despite maximal therapy and for those who progress to congestive heart failure. The major finding of the current study is that heart transplantation is an excellent treatment for patients with HCM who do not respond to optimal medical or surgical management. In the current study, pediatric and adult patients were represented equally. Men were affected twice as often as women. Seventy percent of patients had family history of sudden death or HCM. This result is greater than that of previous data in the literature, probably because of a clustering of families in the province of Quebec. The principal indication for transplantation was congestive heart failure with dyspnea, the most prevalent symptom observed. Dyspnea results principally from systolic dysfunction and impaired ventricular filling because of diastolic dysfunction and ongoing myocardial ischemia. Early and long-term survival in this studied group was superior to survival rates in the Registry of the ISHLT. One-year and 10-year survival was 100% and 85%, compared with 80% and 50% in the Registry. These results also were superior to our overall experience between 1986 and 1999 (n ⫽ 177) at the Montreal Heart Institute, with 5- and 10-year survival of 81% and 74%, respectively. The small population studied, encompassing younger patients with fewer comorbidities compared with patients in the Registry, explains this late mortality related to coronary graft atheroclerosis and accounted for 2 late deaths, 1 of acute myocardial infarction and the other of terminal heart failure. The current study reported the results of a small group of highly selected patients. No patient received left ventricular assistance and all were in stable hemodynamic condition before transplantation. Analysis of the results of heart transplantation requires comparison with a matched group, such as those treated with
The Journal of Heart and Lung Transplantation April 2004
conventional therapy. This is an important limitation that should be addressed in future studies. CONCLUSION Heart transplantation is a valid therapeutic option for patients with HCM who remain symptomatic despite optimal medical treatment and who are not candidates for or are refractory to surgical therapy. Early and late survival rates have been excellent in this selected group of patients. The authors thank Sylvie Levesque, Section of Biostatistics, for her invaluable help with the statistical analysis. REFERENCES 1. Maron BJ. Hypertrophic cardiomyopathy. Curr Probl Cardiol 1993;18:639 –704. 2. Ferraro P, Carrier M, White M, Pelletier GB, Pelletier LC. Antithymocyte globulin and methotrexate therapy of severe or persistent cardiac allograft rejection. Ann Thorac Surg 1995;60:372–6. 3. Ross H, Hendry P, Dipchand A, et al. Transplant coronary artery disease. In: Cardiac Transplantation. Canadian Cardiovascular Society Consensus Conference, Can J Cardiol 2003;19:620 –54. 4. Lower RR, Shumway NE. Studies of orthotopic cardiac homotransplantations of the canine heart. Surg Forum 1960;11:18 –9. 5. Codd MB, Suegrue DD, Gersh BJ, Melton LJ, III. Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted Country, 1975–1984. Circulation 1989;80:564 –72. 6. Davies MJ, Krikler DM. Genetic investigation and counseling of families with hypertrophic cardiomyopathy. Br Heart J 1994;72:99 –101. 7. Clark AL, Coats AJ. Screening for hypertrophic cardiomyopathy. Br Med J 1993;306:409 –10. 8. Spirito P, Chiarella F, Carratino L, Berisso MZ, Bellotti P, Vecchio C. Clinical course and prognosis of hypertrophic cardiomyopathy in an outpatient population. N Engl J Med 1989;320:749 –55. 9. Shirani J, Maron BJ, Cannon RO, et al. Clinicopathological features of hypertrophic cardiomyopathy managed by cardiac transplantation. Am J Cardiol 1993;73:434 –40. 10. Vassali G, Seiler C, Hess OM. Risk stratification in hypertrophic cardiomyopathy. Curr Opin Cardiol 1994;9:330 –6. 11. Maron BJ, Kogan J, Proschan MA, Hecht GM, Robertsd WC. Circadian variability in the occurrence of sudden cardiac death in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1994;23:1405–9. 12. DeRose JJ, Banas JS, Winters SL. Current perspectives on sudden cardiac death in hypertrophic cardiomyopathy. Prog Cardiovasc Dis 1994;36:475–84. 13. McAreavey D, Fananapazir L. Altered cardiac hemodynamic and electrical state in normal sinus rhythm after chronic dual-chamber pacing for relief of left ventricular outflow obstruction in hypertrophic cardiomyopathy. Am J Cardiol 1992;70:651–6.
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14. Knight C, Kurbaan AS, Seggewiss H, et al. Nonsurgical septal reduction for obtructive cardiomyopathy: outcome of the first series of patients. Circulation 1997;95:2075–81. 15. Seggewiss H, Faber L, Gleichmann U. Percutaneous transluminal septal ablation in hypertrophic obstructive cardiomyopathy. Thorac Cardiovasc Surg 1999;47:94 –100. 16. Delahaye F, Jegadan O, Gevigney G, et al. Postoperative
Coutu et al.
417
and long-term prognosis of myotomy-myomectomy for obstructive hypertrophic cardiomyopathy: influence of associated mitral valve replacement. Eur Heart J 1993;14: 1229 –37. 17. Brown PS, Roberts CS, McIntosh CL, et al. Aortic regurgitation after left ventricular myotomy and myectomy. Ann Thorac Surg 1991;51:585–92.
Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric or symmetric myocardial hypertrophy, occurring in the absence of an obvious cause for hypertrophy, such as aortic stenosis and systemic hypertension. Hypertrophic cardiomyopathy predominantly involves the interventricular septum of a nondilated left ventricle and creates a dynamic pressure gradient in the left ventricular outflow tract. The majority of patients are managed medically with adequate relief of symptoms. Septal myotomy–myomectomy is indicated in symptomatic patients with left ventricular pressure gradients ⬎50 mm Hg who have not reFrom the aMontreal Heart Institute, Research Center and Cardiovascular Division, and bSte-Justine Hospital, Cardiovascular Division, University of Montreal, Montreal, Quebec, Canada. Submitted December 2, 2002; revised March 11, 2003; accepted May 3, 2003. Reprint requests: Michel Carrier, MD, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8. Telephone: 514-376-3330. Fax: 514-376-4766. E-mail: carrier@icm. umontreal.ca. Copyright © 2004 by the International Society for Heart and Lung Transplantation. 1053-2498/04/$–see front matter. doi:10.1016/ S1053-2498(03)00225-0
sponded well to medical management.1 However, conventional surgery is not always feasible, especially in patients with the diffuse form of the disease and when progression to congestive heart failure has occurred. In this study, we reviewed the clinical results of heart transplantation in the treatment of HCM at our institution to determine whether this is a valid therapeutic option in these patients. METHODS Patient Population We retrospectively reviewed clinical data of 14 patients with HCM who underwent heart transplantation at the Montreal Heart Institute and Ste-Justine Hospital between 1984 and 2001. All patients were followed prospectively at the transplantation clinics of both institutions. There were 7 adults (5 men and 2 women) and 7 children (5 boys and 2 girls). During the study period, 258 adult patients underwent heart transplantation (7/258, 3% with HCM) and 46 children underwent transplantation (7/46, 15% with HCM). After discharge from the hospital and for the first year after transplantation, follow-up visits were scheduled monthly. 413
414
Coutu et al.
The diagnosis of acute rejection (ⱖ3A) was established by endomyocardial biopsy specimen according to the classification of the International Society for Heart and Lung Transplantation (ISHLT). At Ste-Justine’s Hospital, the pediatric patients are observed echocardiographically for rejection. Biopsy is performed 2 weeks after transplantation and then annually. Additional biopsies are performed if echocardiographic or clinical evidence suggests rejection. Rejection was treated with modified immunosuppression according to defined protocols.2 Coronary angiograms were performed before discharge and annually thereafter.3 Surgical Techniques and Immunosuppressive Regimen Donor hearts were procured and implanted using standard techniques.4 At the Montreal Heart Institute, induction of immunosuppression consisted of intravenous thymoglobulin (rabbit anti-human thymocyte immunoglobulin; Pasteur Me´rieux, Lyon, France; 125 mg per day) the day of transplantation and the first 2 post-operative days. Oral prednisone (1 mg/kg tapered to 0.1 mg/kg per day) and azathioprine (3 mg/kg) or mycophenolate mofetil (1 g twice a day) were started after patient extubation. Oral cyclosporine (2– 6 mg/kg) was initiated only after hemodynamic stabilization and normalization of the renal function at post-operative Day 2 to Day 5 after transplantation. At Ste-Justine Hospital, immunosuppressive regimen encompassed intravenous methylprednisolone (2 mg/kg each 3 hours for 3 doses, 1 mg/kg each 3 hours for 3 doses, and 0.5 mg/kg each 3 hours for 3 doses). Oral prednisone (1 mg/kg in 2 doses) was started when intestinal transit resumed. Azathioprine (2 mg/kg) and cyclosporine (1.4 mg/kg IV or 7 mg/kg orally) were begun on post-operative Day 1. Patients received triple-drug treatment based on cyclosporine until 6 to 12 months after transplantation, at which time treatment was individualized to wean oral prednisone in patients who tolerated decreased immunosuppression. Statistical Analysis We retrieved clinical and follow-up data from medical records. We performed statistical analysis with Statistica 4.0 Software (StatSoft; Tulsa, OK). Early post-operative death was defined as occurring within 30 days of transplantation. We report data as median, range, or mean ⫾ SD. We analyzed death, acute rejection, infection, and coronary graft atherosclerosis using KaplanMeier curves. RESULTS Between 1984 and 2001, 10 male (71%, 5 adults and 5 children) and 4 female (29%, 2 adults and 2 children) patients underwent heart transplantation for HCM. The
The Journal of Heart and Lung Transplantation April 2004
median age of the recipients in the pediatric group was 13 years (range, 6 –16) and was 40 years (range, 22– 46) for the adult group. Median duration of follow-up was 9.5 years (mean, 8.8 ⫾ 4.8 years; range, 1–18) and was 100% complete. Diagnosis of HCM was confirmed by myocardial biopsy specimens in all explanted hearts. Family history of HCM or sudden death was present in 10 patients (71%). Two patients were father and son. The most frequent clinical presentations were dyspnea (100%), palpitations (57%), angina (50%), orthopnea (43%), syncope (21%), and sudden death in 1 patient. Prior procedures consisting of myotomy–myomectomy and DDD-pacemaker implantation were performed in 5 (36%) and 2 (14%) patients, respectively. Surgical indications for transplantation were terminal heart failure in 13 patients (93%) and malignant ventricular arrhythmias in 1 patient (7%). Median duration on the waiting list was 9 months (mean ⫾ SD, 10.8 ⫾ 11.5 months). Median donor age was 23 years (mean ⫾ SD, 25.6 ⫾ 16.4 years). Median cardiopulmonary and ischemic times were 109 (mean ⫾ SD, 136 ⫾ 62) and 142 (mean ⫾ SD, 139 ⫾ 44) minutes, respectively. Median hospital stay was 28 days (mean ⫾ SD, 32 ⫾ 22 days). Patient Survival Short-term survival (30-day) was 100%. Five-, 10-, and 15-year survival was 100%, 85%, and 64%, respectively (Figure 1). There were 2 late deaths. One patient who received a donor heart at aged 12 had a massive anterolateral myocardial infarction that rapidly progressed to cardiogenic shock 11 years after cardiac transplantation. The other patient was a 57-year-old man who had significant coronary graft atherosclerosis and ischemic cardiomyopathy. He died of heart failure 11 years after cardiac transplantation. Of the 12 longterm survivors, 11 (92%) have New York Heart Association (NYHA) Class I symptoms. Early and Late Complications Early cardiovascular morbidity was related largely to immunosuppressive drugs. Calcineurin-inhibitor–induced systemic hypertension occurred in 50% of the patients. Acute respiratory distress syndrome secondary to bacterial pneumonia occurred in 1 patient. Seizures developed in 29% of patients (4 children). No patient with renal failure in the post-operative period required hemodialysis. The most frequent late complications were chronic renal failure and infections. One patient required a permanent pacemaker for sick sinus syndrome. One patient experienced concentric left ventricular hypertrophy (indexed ventricular mass ⫽ 151 g/m2) 10 years after transplantation. He remained totally asymptomatic
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Coutu et al.
415
Figure 1. Actuarial patient survival.
in NYHA Class I until he died of a massive myocardial infarction. Four patients (29%) who experienced renal toxicity or severe gingival hyperplasia were switched from cyclosporine to tacrolimus. Azathioprine was the most frequent purine anti-metabolite used (10 patients). Three patients (21%) had leukopenia and were switched to mycophenolate mofetil. Steroids were continued in 66% of patients. Acute rejection was detected in 12 patients (86%), with a median of 2 episodes per patient. Freedom from acute rejection at 1, 5, and 10-years was 73%, 32%, and 9%, respectively. Eight patients (57.1%) had at least 1 episode of infection. Eight bacterial (2 dental abcesses, 2 sepses, 2 pneumoniae, 1 scabies, and 1 cystitis) and 5 viral episodes (2 warts, 1 meningitis, 1 mononucleosis, and 1 gastroenteritis). Freedom from infection at 1 and 10 years was 71% and 38%, respectively. We found no cytomegalovirus infection in this cohort of patients. Coronary Graft Atherosclerosis Freedom from coronary graft atherosclerosis as shown with routine angiograms at 5 and 10 years was 91% and
66%, respectively. Three patients (21.4%) had graft coronary atherosclerosis. Two of them had myocardial infarction and died of cardiac failure, as mentioned previously. The third patient is in NYHA Class I and is being treated medically. DISCUSSION Hypertrophic cardiomyopathy is a rare entity occurring in 0.02% of the population.5 Fifty percent of the cases are familial. Genetic defects have been found in more than 1 locus, implicating among them beta cardiac myosin heavy chain, troponin T, and tropomyosin.6 The majority of sporadic forms are caused by spontaneous mutations.7 The natural history of HCM varies. Some patients remain asymptomatic or mildly symptomatic and stable for 5 to 10 years.8 However, progression to left ventricular dilatation and dysfunction occurs in 10% to 15% of patients.1 Shirani et al 9 have studied clinicopathologic features of these dilated hearts; dilated left ventricular cavities and left ventricular scars without significant narrowing of the epicardial coronary arteries. The disease has an annual mortality of approximately 3%, related to both progressive heart failure and sudden cardiac death.10 The annual mortality risk is
416
Coutu et al.
even greater in children, approximating 6% with most related to sudden death.7 This complication often occurs during exercise but also demonstrates a circadian distribution, with clustering of deaths in the morning and early evening.11 Managing patients with HCM involves alleviating symptoms, preventing complications, and decreasing the risk of death. Beta-adrenoreceptor blockers improve the patient’s symptoms by decreasing myocardial oxygen consumption12 and resting or provocable gradients. Inserting dual-chamber DDD pacemakers may be useful in some patients who have outflow gradiens and severe symptoms.1,13 Percutaneous transluminal septal ablation significantly decreases the left ventricular outflow tract gradient, and mid-term follow-up has shown improvement.14,15 Septal myotomy–myomectomy is indicated in patients with gradients ⬎50 mm Hg who remain symptomatic despite medical therapy.16,17 Heart transplantation is the last option for those who remain severely symptomatic despite maximal therapy and for those who progress to congestive heart failure. The major finding of the current study is that heart transplantation is an excellent treatment for patients with HCM who do not respond to optimal medical or surgical management. In the current study, pediatric and adult patients were represented equally. Men were affected twice as often as women. Seventy percent of patients had family history of sudden death or HCM. This result is greater than that of previous data in the literature, probably because of a clustering of families in the province of Quebec. The principal indication for transplantation was congestive heart failure with dyspnea, the most prevalent symptom observed. Dyspnea results principally from systolic dysfunction and impaired ventricular filling because of diastolic dysfunction and ongoing myocardial ischemia. Early and long-term survival in this studied group was superior to survival rates in the Registry of the ISHLT. One-year and 10-year survival was 100% and 85%, compared with 80% and 50% in the Registry. These results also were superior to our overall experience between 1986 and 1999 (n ⫽ 177) at the Montreal Heart Institute, with 5- and 10-year survival of 81% and 74%, respectively. The small population studied, encompassing younger patients with fewer comorbidities compared with patients in the Registry, explains this late mortality related to coronary graft atheroclerosis and accounted for 2 late deaths, 1 of acute myocardial infarction and the other of terminal heart failure. The current study reported the results of a small group of highly selected patients. No patient received left ventricular assistance and all were in stable hemodynamic condition before transplantation. Analysis of the results of heart transplantation requires comparison with a matched group, such as those treated with
The Journal of Heart and Lung Transplantation April 2004
conventional therapy. This is an important limitation that should be addressed in future studies. CONCLUSION Heart transplantation is a valid therapeutic option for patients with HCM who remain symptomatic despite optimal medical treatment and who are not candidates for or are refractory to surgical therapy. Early and late survival rates have been excellent in this selected group of patients. The authors thank Sylvie Levesque, Section of Biostatistics, for her invaluable help with the statistical analysis. REFERENCES 1. Maron BJ. Hypertrophic cardiomyopathy. Curr Probl Cardiol 1993;18:639 –704. 2. Ferraro P, Carrier M, White M, Pelletier GB, Pelletier LC. Antithymocyte globulin and methotrexate therapy of severe or persistent cardiac allograft rejection. Ann Thorac Surg 1995;60:372–6. 3. Ross H, Hendry P, Dipchand A, et al. Transplant coronary artery disease. In: Cardiac Transplantation. Canadian Cardiovascular Society Consensus Conference, Can J Cardiol 2003;19:620 –54. 4. Lower RR, Shumway NE. Studies of orthotopic cardiac homotransplantations of the canine heart. Surg Forum 1960;11:18 –9. 5. Codd MB, Suegrue DD, Gersh BJ, Melton LJ, III. Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted Country, 1975–1984. Circulation 1989;80:564 –72. 6. Davies MJ, Krikler DM. Genetic investigation and counseling of families with hypertrophic cardiomyopathy. Br Heart J 1994;72:99 –101. 7. Clark AL, Coats AJ. Screening for hypertrophic cardiomyopathy. Br Med J 1993;306:409 –10. 8. Spirito P, Chiarella F, Carratino L, Berisso MZ, Bellotti P, Vecchio C. Clinical course and prognosis of hypertrophic cardiomyopathy in an outpatient population. N Engl J Med 1989;320:749 –55. 9. Shirani J, Maron BJ, Cannon RO, et al. Clinicopathological features of hypertrophic cardiomyopathy managed by cardiac transplantation. Am J Cardiol 1993;73:434 –40. 10. Vassali G, Seiler C, Hess OM. Risk stratification in hypertrophic cardiomyopathy. Curr Opin Cardiol 1994;9:330 –6. 11. Maron BJ, Kogan J, Proschan MA, Hecht GM, Robertsd WC. Circadian variability in the occurrence of sudden cardiac death in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1994;23:1405–9. 12. DeRose JJ, Banas JS, Winters SL. Current perspectives on sudden cardiac death in hypertrophic cardiomyopathy. Prog Cardiovasc Dis 1994;36:475–84. 13. McAreavey D, Fananapazir L. Altered cardiac hemodynamic and electrical state in normal sinus rhythm after chronic dual-chamber pacing for relief of left ventricular outflow obstruction in hypertrophic cardiomyopathy. Am J Cardiol 1992;70:651–6.
The Journal of Heart and Lung Transplantation Volume 23, Number 4
14. Knight C, Kurbaan AS, Seggewiss H, et al. Nonsurgical septal reduction for obtructive cardiomyopathy: outcome of the first series of patients. Circulation 1997;95:2075–81. 15. Seggewiss H, Faber L, Gleichmann U. Percutaneous transluminal septal ablation in hypertrophic obstructive cardiomyopathy. Thorac Cardiovasc Surg 1999;47:94 –100. 16. Delahaye F, Jegadan O, Gevigney G, et al. Postoperative
Coutu et al.
417
and long-term prognosis of myotomy-myomectomy for obstructive hypertrophic cardiomyopathy: influence of associated mitral valve replacement. Eur Heart J 1993;14: 1229 –37. 17. Brown PS, Roberts CS, McIntosh CL, et al. Aortic regurgitation after left ventricular myotomy and myectomy. Ann Thorac Surg 1991;51:585–92.