What are HFpEF mimics and what are they mimicking? Insights into our conceptualization of heart failure with preserved ejection fraction as a disease

During the initial workup of a patient with chronic heart failure, increased left ventricular (LV) filling pressures at rest or during exercise, and a LV ejection fraction ≥50%, physicians are expected to exclude the presence of established diseases that masquerade as heart failure with preserved ejection fraction (HFpEF), referred to as “HFpEF mimics”. These diseases include (1) cardiac amyloidosis; (2) hypertrophic cardiomyopathy; (3) infiltrative, restrictive and inflammatory cardiomyopathies (sarcoidosis, hemochromatosis, Fabry’s disease, and radiation- and chemotherapy induced restrictive disorders); (4) hemodynamically significant valvular heart disease; (5) pericardial diseases (particularly constrictive pericarditis); (6) high-output heart failure; and (7) end-stage kidney disease. These diseases were recognized long before HFpEF was defined as a disorder, have specific targeted treatments, and have generally been excluded from randomized controlled trials of new drugs for HFpEF. Interestingly, following the exclusion of HFpEF mimics, patients demonstrate the typical clinical and pathophysiological features of cardiometabolic HFpEF, with an exceptionally high prevalence of central adiposity, dysglycemia, hypertension and systemic inflammation — even though large-scale trials did not require participants to have any feature of a cardiometabolic disorder. The homogeneity of the phenotypic presentations of these patients is consistent with the lack of observed heterogeneity in the responses to broad-based treatments (i.e., sodium-glucose cotransporter 2 inhibitors, finerenone and incretins). Importantly, many patients with adiposity-related HFpEF were not permitted to participate in large-scale trials, which excluded patients with severe obesity, lower natriuretic peptides and without manifest echocardiographic diastolic filling abnormalities. In conclusion, the exclusion of HFpEF mimics from the broad population of patients with left-sided heart failure and an ejection fraction ≥50% yields a relatively homogeneous patient population with the features of adiposity-related HFpEF.