Abstract 4363064: Late-Onset Donor-Derived Hypertrophic Cardiomyopathy Following Orthotopic Heart Transplant

Abstract

Background: Heart transplantation (HT) complications include rejection and infection. Rarely, monogenic donor cardiomyopathies—especially hypertrophic cardiomyopathy (HCM)—can manifest years later. Large biobanks suggest pathogenic or likely pathogenic (P/LP) variants in sarcomeric genes in up to ~1% of the population. While aggregate penetrance is low (~23%), carriers have increased risk of heart failure (HR4.2), arrhythmia (HR2.1), and major adverse events (HR1.7). Case: A 29-year-old woman with chemotherapy-induced cardiomyopathy underwent HT at age 17. Eleven years later, she developed progressive dyspnea and syncope with unremarkable physical exam. She was on tacrolimus 1.5 mg BID and mycophenolic acid 720 mg BID. One year prior, echocardiography revealed apical hypertrophy (~1.6 cm). On presentation, there was progression without LV outflow tract obstruction. A loop recorder showed no arrhythmia. Cardiac MRI (cMRI) demonstrated preserved LVEF and apical LVH without aneurysm. She was started on bisoprolol 2.5 mg, with improvement in 5 months. Follow-up echo revealed a peak Valsalva gradient of 23mmHg and apical wall thickness ~2.0 cm. Bisoprolol was uptitrated and repeat cMRI is pending. Tacrolimus was tapered in favor of sirolimus. Reasoning: Imaging is consistent with the apical variant of HCM. While LVH is common after HT (~75% at 1 year) secondary to calcineurin-inhibitor (CNI)-induced hypertension, the apical LVH, fibrosis, dynamic obstruction and timing more strongly suggest development of sarcomeric HCM in a genetically predisposed donor heart. While penetrance is generally low, many modifying factors (e.g., genetic, biologic, environmental) can drive greater penetrance and expressivity. The commonest inciting factor in those with HCM is hypertension. In addition, CNIs activate hypertrophic and profibrotic (e.g., TGF-β) pathways, and CNI use in mice harboring pathogenic sarcomere variants causes a marked increase in LVH. The RADTAC trial showed mTOR-based regimens can attenuate LVH and fibrosis. In this case, beta-blockade and switching to a CNI-free regimen were performed. Genetic testing was not performed with no relevance to her germline or family. Conclusion: This case illustrates a rare but likely underrecognized form of late-onset allograft dysfunction. Though uncommon, donor-derived genetic cardiomyopathies should be considered in HT patients with unexplained LVH, as this may warrant a significant change to the post-HT immunosuppressive regimen.