
==== Front
JACC Case Rep
JACC Case Rep
JACC Case Reports
2666-0849
Elsevier

S2666-0849(24)00247-X
10.1016/j.jaccas.2024.102454
102454
Heart Failure and Cardiomyopathies
Case Report: Clinical Case: ACC.24
Mavacamten Safety and Efficacy in a Heart Transplant Patient Exhibiting Obstructive Hypertrophic Cardiomyopathy Phenotype
Abood Zaid MD a
Ghafoor Asad MD ab
Ashraf Muddasir MD a
Peters Matthew MD a
Galazka Patrycja MD ab
Misicka Amanda RN a
Jan M. Fuad MBBS (Hons), MD ab
Jahangir Arshad MD ab
Tajik A. Jamil MD a.jamil.tajik@aah.org
@AJamilTajik
ab∗
a Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke’s Medical Centers, Aurora Health Care, Milwaukee, Wisconsin, USA
b Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health, Milwaukee Clinical Campus, Milwaukee, Wisconsin, USA
∗ Address for correspondence: Dr A. Jamil Tajik, Aurora Cardiovascular and Thoracic Services, Aurora St. Luke’s Medical Center, 2801 West Kinnickinnic River Parkway, Suite 530, Milwaukee, Wisconsin 53215, USA. a.jamil.tajik@aah.org@AJamilTajik
21 8 2024
21 8 2024
21 8 2024
29 16 10245425 4 2024
21 5 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Hypertrophic cardiomyopathy is the most common inherited cardiac disease, exhibiting diverse phenotypes. Obstructive hypertrophic cardiomyopathy occurs in about two-thirds of cases and carries a worse prognosis. Mavacamten use in heart transplant recipients is limited. This paper reports a recipient who developed severe symptomatic obstructive hypertrophic cardiomyopathy phenotype/phenocopy and was initiated on mavacamten.

Graphical Abstract

Key Words

heart transplant
hypertrophic cardiomyopathy
left ventricular outflow tract obstruction
mavacamten
Abbreviations and Acronyms

HCM hypertrophic cardiomyopathy

HTN hypertension

LV left ventricular

LVH left ventricular hypertrophy

LVOT left ventricular outflow tract

LVOTO left ventricular outflow tract obstruction

oHCM obstructive hypertrophic cardiomyopathy
==== Body
pmcHistory of Presentation

A 49-year-old Asian man with a history of orthotopic heart transplantation and kidney transplantation, maintained on mycophenolate mofetil, tacrolimus, and prednisone, presented to our clinic with progressive fatigue and shortness of breath 5 years post-transplant. The patient’s vital signs were unremarkable; the physical examination revealed a grade 1 of 6 systolic ejection murmur at rest that increased to 2 of 6 with the Valsalva maneuver. Transthoracic echocardiograms showed an increased left ventricular (LV) wall thickness of 18 mm with the development of new left ventricular outflow tract obstruction (LVOTO) with the Valsalva maneuver. Computed tomography was negative for pulmonary embolism. A left coronary angiogram showed nonobstructive coronary artery disease; hemodynamics revealed a left ventricular outflow tract gradient of 28 mm Hg at rest and 88 mm Hg with the Valsalva maneuver. Pulmonary artery catheterization demonstrated a right atrial pressure of 8 mm Hg, a pulmonary artery pressure of 49/26 mm Hg, and a pulmonary capillary wedge pressure of 17 mm Hg, with a cardiac index of 3.2 L/min/m2.Learning Objectives

• To increase understanding of HCM as a potential complication in heart transplant recipients.

• To explore therapeutic options for obstructive HCM management post-transplantation.

• To evaluate the effectiveness and safety of mavacamten in individuals with obstructive HCM phenotypes/phenocopies who have undergone heart transplantation.

Past Medical History

The patient’s past medical history included hypertension (HTN), ischemic cardiomyopathy, coronary artery disease, end-stage renal disease requiring peritoneal dialysis beginning 2 years prior to simultaneous orthotopic heart transplantation and kidney transplantation, and biopsy-proven acute cellular rejection 1-year post-transplant that was successfully treated with Thymoglobulin (Sanofi, Bridgewater, NJ), plasmapheresis, intravenous immunoglobulin, and rituximab.

Differential Diagnosis

Left ventricular hypertrophy (LVH) in a transplanted heart could be caused by uncontrolled systemic HTN, HTN-induced calcineurin inhibitors, direct proliferation of cardiac myocytes resulting from calcineurin inhibitors, chronic inflammation/rejection, or other causes of increased afterload (eg, aortic stenosis). Hypertrophic cardiomyopathy (HCM) also has been reported in heart transplantation.

Investigations

The patient maintained controlled blood pressure on amlodipine and lisinopril. He was switched to sirolimus for the prevention of allograft vasculopathy about 1.5 years after the transplant procedure and continued without rejection or complaints until his presentation to our HCM clinic about 5 years post-transplantation. A 30-day event monitor was unremarkable for any arrhythmia. Follow-up echocardiograms showed increasing LV wall thickness and worsening LVOTO, defined as a left ventricular outflow tract (LVOT) gradient ≥30 mm Hg (Table 1). Based on these findings, the diagnosis of obstructive hypertrophic cardiomyopathy (oHCM) phenotype/phenocopy was made. About 7 years later, the patient’s echocardiogram was notable for a septal wall thickness of 19 mm, mitral systolic anterior motion, moderate mitral regurgitation, and severe LVOTO of 83 mm Hg at rest and 119 mm Hg with the Valsalva maneuver (Figure 1, Videos 1 and 2).Table 1 Echocardiography Findings and Symptoms Trends

Year	EF, %	IVSd, mm	Diastolic Dysfunction
Grade	GLS, %	SAM	MR	LVOT-G at Rest,
mm Hg	LVOT-G
Valsalva Maneuver,
mm Hg	NYHA
Functional Class	
1	75	12	II	NA	−	Mild	0	NA	I	
2	75	11	II	NA	−	Mild	0	NA	I	
3	75	11	II	−16	+	Mild	0	NA	II	
4	70	12	II	−16	+	Mild	0	25	II	
5	72	18	II	−17	+	Mild	25	60	III	
6	73	18	II	−15	+	Mild	23	45	III	
7	64	18	III	−12	+	Mild	20	52	III	
8	63	20	III	−17	+	Mild	42	150	III	
9	70	19	III	−17	+	Mild	44	105	III	
10	65	19	III	−13	+	Mild	30	80	III	
11	65	19	III	−13	+	Mod	0	72	III	
12	60	19	III	−12	+	Mod	83	119	III	
4 weeksa	60	19	II	−12	+	Mild	18	30	II	
8 weeksa	59	17	II	−13	−	Mild	14	40	I	
12 weeksa	66	17	II	−13	−	Trivial	12	17	I	
16 weeksa	58	17	II	−13	+	Trivial	9	18	I	
24 weeksa	59	17	II	−12	+	Trivial	10	16	I	
EF = ejection fraction; GLS = global longitudinal strain; IVSd = interventricular septum thickness; LVOT-G = left ventricular outflow tract gradient; MR = mitral regurgitation; NA = not performed/not available; SAM = systolic anterior motion.

a Weeks of mavacamten treatment.

Figure 1 2-Dimensional Echocardiography Before Mavacamten Treatment

(A) Parasternal long-axis view demonstrates concentric, severely increased left ventricular wall thickness measuring 1.9 cm (double-headed arrows). (B) Short-axis view at midlevel shows hypertrophied papillary muscles (arrow). (C) Apical long-axis view shows severe resting left ventricular outflow tract (LVOT) obstruction with systolic anterior motion of the mitral valve (arrowhead) and doming of the bicuspid aortic valve (arrow). (D) Turbulent flow in the LVOT caused by systolic anterior motion (arrowhead) and moderate eccentric posterior mitral regurgitation (arrow) are seen. Continuous-wave Doppler through the LVOT demonstrates a gradient of 83 mm Hg at rest (E) and 119 mm Hg with Valsalva (F).

Management

On evidence of LVOTO, the patient was started on a beta blocker and calcium channel blocker. Subsequently, disopyramide was also introduced. The patient continued to be in NYHA functional class III with persistent, severe LVOTO despite being on the maximum tolerated triple-drug treatment with metoprolol 200 mg, verapamil 360 mg, and disopyramide 480 mg. The patient had no interest in any septal reduction, including septal myectomy or alcohol septal ablation. Given the patient’s deteriorating quality of life, and after a thorough discussion with the patient, we decided to introduce mavacamten into the medical regimen. The patient was initiated on 5 mg.

Discussion

The development of LVH after heart transplantation is well known and multifactorial. Although the precise etiology remains elusive, various mechanisms have been proposed, encompassing systemic HTN, chronic inflammation, and direct myocyte proliferation driven by immunosuppressive therapies. HTN is highly prevalent in heart transplant recipients, especially in the first year.1,2 It remains unclear whether LVH in heart transplant recipients is primarily a consequence of calcineurin inhibitor-induced HTN or arises from a direct myocardial impact via the upregulation of intracellular signaling pathways.3,4 Additionally, the sustained expression of intracardiac tumor necrosis factor-alpha observed in heart transplant recipients suggests the potential role of chronic inflammation as an independent driver of LVH.5

Whether due to one or a combination of the aforementioned mechanisms vs a genetic predisposition to HCM, oHCM phenotype has been reported in heart transplant recipients and should be considered in cases with unexplained progressive shortness of breath and LVH with LVOTO.6,7

Until recently, the only therapeutic option for patients with oHCM refractory to maximally tolerated medical therapy was septal reduction therapy, either myectomy or septal alcohol ablation. Recently, however, mavacamten has become a noninvasive option for such cases (medical myectomy). By inhibiting myosin adenosine triphosphatase activity, mavacamten increases the percentage of myosin heads in the super-relaxed or “off” state and renders them less accessible to interaction with actin filaments. Therefore, it decreases hypercontractility and LV filling pressure, ameliorating the LVOT gradient associated with oHCM.8 It also has been shown to decrease Ca2+ sensitivity, energy consumption, and diastolic dysfunction.9 Conducted clinical trials have demonstrated the safety and efficacy of mavacamten, and the U.S. Food and Drug Administration approved its use in the treatment of oHCM in April 2022. Although its use in heart transplant recipients is not established, it may be the only available option and should be considered. In the presented case, mavacamten demonstrated high effectiveness and was well tolerated despite the patient being on multiple immunotherapies and having stage 3 chronic kidney disease. No drug–drug interactions were noted, no specific adjustments to immunotherapy were made based on the initiation and maintenance of mavacamten, and no major side effects were observed. It is worth mentioning that this case highlights the safety and efficacy of mavacamten in the late post-transplantation (12 years) period. Safety and efficacy of mavacamten in the early post-transplantation period are not well described. Close monitoring is advised in the transplant cohort on mavacamten, particularly in the early phase.

Follow-Up

The patient reported marked symptom improvement without side effects. By week 12 of mavacamten treatment, the LVOTO was totally resolved, both at rest and with the Valsalva maneuver (Figure 2, Video 3). Verapamil was discontinued to avoid hypotension. The ejection fraction continued to be relatively stable and remained above 55% while the patient was on metoprolol and disopyramide for 12 weeks. Subsequently, disopyramide was discontinued at week 16, and the patient continued with only metoprolol and mavacamten with a stable ejection fraction.Figure 2 2-Dimensional Echocardiogram 12 Weeks Post-Mavacamten Treatment

(A) Parasternal long-axis view reveals concentric, severely increased left ventricular wall thickness. (B) Apical long-axis view shows no systolic anterior motion. (C) Trivial posterior mitral regurgitation (arrow) is demonstrated. Continuous-wave Doppler through the left ventricular outflow tract (LVOT) demonstrates significantly decreased LVOT gradients with no obstruction at rest (D) or with Valsalva (E).

Conclusions

HCM is a rare yet possible diagnosis in heart transplant recipients and requires expert-level approach and management. For cases of refractory, symptomatic oHCM phenotypes/phenocopies despite maximally tolerated medical therapy, mavacamten should be considered. This patient’s positive response, as evidenced by improved NYHA functional class and echocardiographic parameters along with good tolerability despite immunotherapy, suggests the potential of mavacamten as a therapeutic option for LVOTO in heart transplant recipients. Future research should focus on long-term safety and efficacy in larger cohorts, which will be crucial for establishing the role of mavacamten in HCM therapy for heart transplant recipients.

Addendum

The most recent echocardiogram, performed after 48 weeks of treatment, continued to show no evidence of LVOTO at rest or during Valsalva maneuvers. The patient remained asymptomatic, and the ejection fraction was stable.

Funding Support and Author Disclosures

Dr Abood’s time was supported by the Colton Scholarship, which played no role in this case or this manuscript, including the decision to submit it for publication. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Appendix

Video 1

Transthoracic Echocardiography

Transthoracic echocardiography in the parasternal long-axis view performed prior to mavacamten initiation shows severely increased left ventricular wall thickness with systolic anterior motion of mitral leaflet.

Video 2

Transthoracic Echocardiography

Transthoracic echocardiography in the apical long-axis view with color Doppler demonstrates turbulent flow in the left ventricular outflow tract as a result of mitral systolic anterior motion and subsequent moderate eccentric posterior mitral regurgitation.

Video 3

Apical Long-Axis Echocardiographic View

The apical long-axis echocardiographic view performed at 12 weeks of treatment with mavacamten shows a decrease in mitral regurgitation.

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.

Appendix

For supplemental videos, please see the online version of this paper.
==== Refs
References

1 Lumish H.S. Kennel P.J. Concha D. Incidence and treatment of arterial hypertension after heart transplantation J Heart Lung Transplant 41 2022 S322 S323
2 Stehlik J. Edwards L.B. Kucheryavaya A.Y. The Registry of the International Society for Heart and Lung Transplantation: twenty-eighth adult heart transplant report--2011 J Heart Lung Transplant 30 2011 1078 1094 21962016
3 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 25 2012 269 275 22573529
4 Kushwaha S.S. Raichlin E. Sheinin Y. Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients Eur Heart J 29 2008 2742 2750 18790727
5 Stetson S.J. Perez-Verdia A. Mazur W. Cardiac hypertrophy after transplantation is associated with persistent expression of tumor necrosis factor-alpha Circulation 104 2001 676 681 11489774
6 Golovina G.A. Stavenchuk T.V. Kozhvatova N.V. Kosmacheva E.D. Hypertrophic obstructive cardiomyopathy in a heart transplant recipient: a case report Russ J Cardiol 26 2021 4625
7 Gao H. Kransdorf E. Ebinger J. Kittleson M.M. Hypertrophic cardiomyopathy after heart transplantation: a single-center case series JACC Case Rep 14 2023 101825
8 Green E.M. Wakimoto H. Anderson R.L. A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice Science 351 2016 617 621 26912705
9 Awinda P.O. Watanabe M. Bishaw Y. Mavacamten decreases maximal force and Ca(2+) sensitivity in the N47K-myosin regulatory light chain mouse model of hypertrophic cardiomyopathy Am J Physiol Heart Circ Physiol 320 2021 H881 H890 33337957
