Abstract
We present 3 heart transplant recipients who developed hypertrophic cardiomyopathy years after transplantation. In all 3 cases, the diagnosis was initially made based on echocardiography and confirmed using cardiac magnetic resonance imaging. (Level of Difficulty: Advanced.)
Key Words: heart transplantation, hypertrophic cardiomyopathy
Graphical abstract
Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) not explained by myocardial loading conditions such as hypertension. It is associated with variants in genes encoding structural components of the sarcomere. We report 3 heart transplant/transplantation (HT) recipients with normal left ventricular (LV) wall thickness at the time of HT who later developed increased LV wall thickness and associated findings consistent with HCM based on magnetic resonance imaging (MRI).
Learning Objectives
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To understand the possible mechanisms that may lead to development of HCM in transplant recipients.
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To understand potential therapies that may be of clinical use once HCM has been identified.
Case 1
A 34-year-old man underwent redo HT for cardiac allograft vasculopathy 11 years after his initial HT for nonischemic cardiomyopathy. The donor echocardiogram demonstrated normal LV wall thickness.
The patient had no rejection. He had well-controlled hypertension on amlodipine 10 mg daily and enalapril 20 mg daily. Initial immunosuppression regimen included tacrolimus, mycophenolate mofetil, and prednisone. Five years post-transplantation, he was switched to sirolimus for allograft vasculopathy prevention. Ten years post-transplantation, sirolimus was switched back to mycophenolate mofetil due to nephrotic syndrome.
Routine echocardiogram 7 years post-transplantation demonstrated new moderate concentric LV hypertrophy, with an intraventricular septal thickness in diastole (IVSd) of 1.5 cm, left ventricular posterior wall thickness in diastole (LVPWd) of 1.4 cm, and no left ventricular outflow tract (LVOT) obstruction. An echocardiogram 2 years later demonstrated interval development of LVOT obstruction, with a resting gradient of 18 mm Hg, increasing to 30 mm Hg with Valsalva. By year 10 post-transplantation, the patient reported dyspnea on exertion and stress echocardiogram revealed a resting LVOT gradient 33 mm Hg, 92 mm Hg postexercise.
Metoprolol and verapamil both caused fatigue. Fifteen years post-HT, he was hospitalized with decompensated heart failure. Echocardiogram showed ejection fraction of 80%, IVSd and LVPWd of 2.3 and 2.1 cm, respectively, and a LVOT gradient of 78 mm Hg, which increased to 84 mm Hg with Valsalva. Pulmonary artery (PA) catheterization demonstrated right atrial (RA) pressure of 15 mm Hg, PA pressure of 50/29 mm Hg, and pulmonary capillary wedge pressure (PCWP) of 33 mm Hg, with cardiac index (CI) of 2.77 L/min/m2. Cardiac MRI demonstrated normal biventricular size with preserved systolic function, LVH with septal predominance, and diffuse fibrosis characteristic of hypertrophic obstructive cardiomyopathy. Alcohol septal ablation and septal myectomy were not pursued because the patient demonstrated an intracavitary gradient in addition to an increased LVOT gradient. Due to progressive symptoms and cardiogenic shock requiring inotropic support, the patient underwent a third HT with kidney transplantation 16 years after the second HT. Pathology of the cardiac explant revealed hypertrophy of the left and right ventricles (Figure 1) and architectural disarray and nuclear hypertrophy consistent with HCM and coronary arteries with minimal coronary allograft vasculopathy.
Figure 1.
Case 1 Explant Pathology and Imaging
(A) Cardiac explant gross pathology. (B) Cardiac MRI 4-chamber view. (C) Transthoracic echo parasternal long view. (D) Transthoracic echo apical 4-chamber view with LVOT gradient. LVOT = left ventricular outflow tract; MRI = magnetic resonance imaging.
Case 2
A 37-year-old woman with viral myocarditis underwent HT, with a donor heart demonstrating normal LV wall thickness. She had antibody-mediated rejection (with no donor-specific antibodies) 15 days after transplantation based on histology and immunohistochemistry. She underwent plasmapheresis and intravenous immunoglobulin infusion, and was discharged on prednisone, tacrolimus, and mycophenolate mofetil, as well as lisinopril 10 mg daily for hypertension.
Echocardiogram 3 years post-HT revealed new apical hypertrophy. Left-sided heart catheterization 8 years post-HT showed mid- to apical LV pressure gradient, with midcavitary left ventricular pressure gradient of 126 mm Hg (apical LV 241/ 20 mm Hg and basal LV 125/22 mm Hg). Coronary angiography demonstrated coronary artery ectasias of unclear etiology and a PA catheterization showed RA pressure of 9 mm Hg, PA of 32/18 mm Hg, PCWP of 17 mm Hg, and CI of 3.31 L/min/m2. Due to progressive shortness of breath felt either due to HCM or cardiac allograft vasculopathy, she was offered redo HT evaluation but declined. Initiation of sirolimus was not started due to prohibitive cost. Her average outpatient blood pressure was 126/88 mm Hg over 19 years post-transplantation.
Cardiac MRI showed right- and left-sided coronary ectasia, as well as significant concentric LVH in the mid- and apical segments consistent with apical hypertrophic cardiomyopathy.
She experienced progressive symptoms, eventually presenting 19 years post-HT with cardiogenic shock. She again declined consideration for redo HT and died.
Case 3
A 25-year-old nonbinary person (male sex at birth) underwent redo HT for progressive cardiac allograft vasculopathy 9 years after their initial HT for nonischemic cardiomyopathy. The donor heart had normal LV wall thickness.
Immunosuppression consisted of prednisone, tacrolimus, and mycophenolate mofetil. Hypertension was managed with amlodipine 10 mg daily and benazepril 40 mg 2 times a day, with an average outpatient blood pressure of 129/79 mm Hg. Echocardiogram 1 year post-transplantation demonstrated new LVH with an IVSd of 1.9 cm and LVPWd of 1.5 cm. Echocardiogram 9 years post-HT revealed IVSd and LVPWd of 2.1 cm and 2.0 cm, respectively, with a LVOT gradient of 18 mm Hg at rest and 33 mm Hg after Valsalva. PA catheterization showed RA of 2 mm Hg, PA of 18/6 mm Hg, PCWP of 6 mm Hg, and CI of 2.6 L/min/m2. Cardiac MRI 15 years post-HT showed severe eccentric increased septal thickness (thickest: 3.4 cm), outflow tract turbulence, systolic anterior motion of the mitral valve, and diffuse fibrosis consistent with hypertrophic cardiomyopathy. The patient reported no symptoms and is not receiving treatment for the asymptomatic LVOT gradient.
Discussion
Multiple mechanisms are likely responsible for myocardial hypertrophy of the cardiac allograft: increased afterload from systemic hypertension, chronic inflammation, and direct myocyte proliferation from immunosuppression. Systemic hypertension occurs in 75% of recipients in the first year post-transplantation,1 and is common especially from calcineurin inhibitors.2 Chronic inflammatory states, in particular, the persistent expression of intracardiac tumor necrosis factor-alpha, is also associated with the development of allograft hypertrophy independent of hypertension.3 Last, calcineurin inhibitors may directly provoke hypertrophy by up-regulation of profibrotic signaling pathways.4
The development of the HCM phenotype with LVOT obstruction and characteristic changes on MRI and pathology suggests these allografts might have had a genetic predisposition to HCM, although genetic testing of the donor hearts was not possible. In a large population-based genetic study, likely pathogenic/pathogenic HCM variants were noted in 0.25% of participants, but LVH ≥13 mm was only present in 18% of those patients, suggesting low penetrance/expressivity.5 Taken together, we hypothesize a "multi-hit" model whereby allografts genetically susceptible to HCM via the presence of sarcomeric variants manifest HCM due to environmental factors such as hypertension, chronic inflammation, and immunosuppression.
Phenotypic HCM causing LVOT obstruction has been reported in HT recipients.6 A strength of our case series was the ability to confirm HCM in all cases using cardiac MRI and in 1 case by explant pathology (Table 1, Figure 2).
Table 1.
Additional Echocardiographic Data
| Months Since HT | LVEF (%) | IVSd (mm) | LVPWd (mm) | LVIDd (mm) | Peak LVOT or Midcavitary LV Gradient (mm Hg) | Peak LVOT or Midcavitary LV Gradient After Valsalva or Exercise (mm Hg) | |
|---|---|---|---|---|---|---|---|
| Case 1 | |||||||
| 80 | 82 | 15 | 14 | 41 | 7 | ||
| 101 | 72.5 | 24 | 13 | 44 | 11 | ||
| 107 | 21 | 13 | 45 | 18 | 30 | ||
| 119 | 86 | 23 | 14 | 48 | 13 | 92 | |
| 132 | 73 | 21 | 11 | 36 | 49 | 60 | |
| 138 | 72 | 18.5 | 16 | 36 | 53 | ||
| 149 | 72 | 25.8 | 16.3 | 38 | 57 | ||
| 155 | 67 | 30 | 55 | 107 | |||
| 167 | 66 | 25 | 10 | 52 | 44 | 60 | |
| 179 | 73 | 21 | 11 | 49 | 72 | 94 | |
| 183 | 80 | 23.3 | 21.1 | 45 | 78 | 84 | |
| 184 | 65 | 23 | 15 | 38 | 80 | 86 | |
| Case 2 | |||||||
| 9 | 55-60 | 15 | 13 | 35 | |||
| 38 | 65 | 15 | 12 | 42 | |||
| 73 | 65 | 9 | 10 | 44 | |||
| 80 | 65 | 15 | 17 | 35 | 12.35 | ||
| 103 | 55-60 | 14 | 14 | 45 | 4 | ||
| 116 | 55-60 | 14 | 14 | 49 | 2 | ||
| 133 | 61 | 15 | 15 | 46 | 5 | ||
| 150 | 68 | 12 | 14 | 37 | 3 | ||
| 154 | 65 | 17.4 | 13.1 | 46 | 3 | ||
| 168 | 60 | 16 | 12 | 44 | 5 | ||
| 179 | 55-60 | 21 | 13 | 40 | 3 | ||
| 190 | 65 | 14.7 | 11.1 | 49 | |||
| 209 | 55 | 12 | 11 | 38 | |||
| 215 | 72 | 11.3 | 10 | 28 | 3 | ||
| 223 | 40-45 | 12.6 | 13.7 | 40 | 17 | ||
| 223 | 17.6 | 17.8 | >25 | ||||
| Case 3 | |||||||
| 1 | 60-65 | 15 | 15 | 48 | |||
| 5 | 55-60 | 19 | 15 | 45 | |||
| 24 | 55-60 | 14 | 14 | 45 | |||
| 48 | 65-70 | 16 | 14 | 45 | 6.82 | ||
| 59 | 65 | 18 | 15 | 45 | 6.42 | ||
| 71 | 65-70 | 16 | 12 | 50 | |||
| 84 | 85 | 21 | 11 | 45 | 19 | ||
| 89 | 76 | 19 | 18 | 47 | 10 | ||
| 110 | 80 | 21 | 20 | 38 | 18 | 33 | |
| 117 | 70-75 | 21 | 11 | 47 | 9 | ||
| 131 | 75-80 | 21 | 22 | 39 | 24 | 51 | |
| 155 | 80 | 24.7 | 19.5 | 42 | 17 | 85 | |
| 159 | 80 | 23.8 | 18.6 | 44 | 21 | 46 | |
| 179 | 80 | 25 | 26 | 32 | 17 | 73 | |
| 184 | 79 | 24.5 | 19.3 | 45 | 30 | ||
| 185 | 75-80 | 23 | 25 | 36 | 16 | 41 |
HT = heart transplantation; IVSd = intraventricular septal thickness in diastole; LV = left ventricle; LVEF = left ventricular ejection fraction; LVIDd = left ventricular internal diameter end diastole; LVOT = left ventricular outflow tract; LVPWd = left ventricular posterior wall thickness in diastole
Figure 2.
Interventricular Septal Thickness in Diastole Over Time
The development of HCM post-HT should be considered when HT patients present with shortness of breath and LVH, even years after transplantation. Cardiac MRI may confirm the diagnosis, quantify fibrosis burden for risk stratification, and characterize LVOT anatomy during planning for septal reduction therapies.7 Adjusting immunosuppression may attenuate the development of LVH; the combination of low-dose everolimus and tacrolimus attenuates LVH after transplantation and reduces fibrosis as measured using cardiac MRI.8 However, therapeutic options once HCM has developed remain less clear. Beta-blockers and calcium channel inhibitors provide symptomatic benefit in other case reports.9 The benefit of mavacamten, a cardiac myosin inhibitor, in HT patients is not established,9,10 nor are there reports of septal reduction therapies in HT recipients. However, for the HT patient with HCM who has not been able to tolerate first-line medical therapy, these options warrant further study.
The development of LV hypertrophy at 1 year post-transplantation is not uncommon and has been associated with increased mortality,11 but progression to HCM remains rarely described. Further investigation is needed into its mechanisms, disease course, and treatments, including the efficacy of cardiac myosin inhibitors.
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
References
- 1.Stehlik J., Edwards L.B., Kucheryavaya A.Y., et al. The Registry of the International Society for Heart and Lung Transplantation: Twenty-Eighth Adult Heart Transplant Report—2011. J Heart Lung Transplant. 2011;30:1078–1094. doi: 10.1016/j.healun.2011.08.003. [DOI] [PubMed] [Google Scholar]
- 2.Hoorn E.J., Walsh S.B., McCormick J.A., Zietse R., Unwin R.J., Ellison D.H. Pathogenesis of calcineurin inhibitor–induced hypertension. J Nephrol. 2012;25:269–275. doi: 10.5301/jn.5000174. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Stetson S.J., Perez-Verdia A., Mazur W., et al. Cardiac hypertrophy after transplantation is associated with persistent expression of tumor necrosis factor. Circulation. 2001;104:676–681. doi: 10.1161/hc3101.093765. [DOI] [PubMed] [Google Scholar]
- 4.Kushwaha S.S., Raichlin E., Sheinin Y., et al. Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients. Eur Heart J. 2008;29:2742–2750. doi: 10.1093/eurheartj/ehn407. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.de Marvao A., McGurk K.A., Zheng S.L., et al. Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2021;78:1097–1110. doi: 10.1016/j.jacc.2021.07.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Golovina G.A., Stavenchuk T.V., Kizhvatova N.V., Kosmacheva E.D. Hypertrophic obstructive cardiomyopathy in a heart transplant recipient: a case report. Russ J Cardiol. 2021;26:4625. [Google Scholar]
- 7.Maron B.J., Desai M.Y., Nishimura R.A., et al. Diagnosis and evaluation of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2022;79:372–389. doi: 10.1016/j.jacc.2021.12.002. [DOI] [PubMed] [Google Scholar]
- 8.Anthony C., Imran M., Pouliopoulos J., et al. Everolimus for the prevention of calcineurin-inhibitor-induced left ventricular hypertrophy after heart transplantation (RADTAC Study) J Am Coll Cardiol HF. 2021;9:301–313. doi: 10.1016/j.jchf.2021.01.007. [DOI] [PubMed] [Google Scholar]
- 9.Olivotto I., Oreziak A., Barriales-Villa R., et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;396:759–769. doi: 10.1016/S0140-6736(20)31792-X. [DOI] [PubMed] [Google Scholar]
- 10.Desai M.Y., Owens A., Geske J.B., et al. Myosin inhibition in patients with obstructive hypertrophic cardiomyopathy referred for septal reduction therapy. J Am Coll Cardiol. 2022;80:95–108. doi: 10.1016/j.jacc.2022.04.048. [DOI] [PubMed] [Google Scholar]
- 11.Goodroe R., Bonnema D.D., Lunsford S., et al. Severe left ventricular hypertrophy 1 year after transplant predicts mortality in cardiac transplant recipients. J Heart Lung Transplant. 2007;26:145–151. doi: 10.1016/j.healun.2006.11.003. [DOI] [PubMed] [Google Scholar]