The Emerging Phenotype of HFpEF in Cardiac Allografts: A Review of Pathophysiology, Diagnosis, and Management

Advances in donor selection, organ preservation technologies, donation after circulatory death, and broader geographic sharing have expanded access to heart transplantation but have also introduced new challenges that affect allograft function. The transplanted heart is exposed to multiple insults, including donor brain death, ischemia–reperfusion injury, acute and chronic rejection, and cardiac allograft vasculopathy. Increasingly, heart failure with preserved ejection fraction (HFpEF) is being recognized as a distinct manifestation of cardiac allograft dysfunction that may contribute to late graft failure. Diastolic dysfunction occurs frequently after heart transplantation and may develop early as a consequence of ischemia–reperfusion injury, primary graft dysfunction, and/or rejection. Cardiac allograft vasculopathy, chronic immune-mediated injury, metabolic comorbidities, and aging of the donor heart further contribute to the HFpEF phenotype. Although the process is multifactorial and can be variable, progressive abnormalities in myocardial relaxation, compliance, microvascular function, and extracellular matrix remodeling may lead to restrictive physiology and then the clinical syndrome of heart failure with low cardiac output and end-organ dysfunction despite preserved left ventricular ejection fraction. However, the epidemiology, diagnostic criteria, and natural history of HFpEF in transplant recipients remain incompletely characterized. As a result, the goal of this paper is to consolidate the current understanding of the pathophysiology, epidemiology, diagnostic evaluation, and management of HFpEF in cardiac allografts, while identifying current gaps in understanding to guide future research.