HFpEF in Japan: When an Epidemiological Transition Becomes an Epidemiological Opportunity

Approximately 10 years ago, projections from the Get with the Guidelines-Heart Failure registry predicted that by 2020, 65% of patients hospitalized for heart failure (HF) would be composed of patients with ejection fractions > 40%. In the intervening years, 4 large international multicenter randomized clinical trials have been conducted to address the need to mitigate cardiovascular death and urgent visits due to HF and/or hospitalizations by those afflicted with HF with preserved ejection fraction (HFpEF). Although the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) and the Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trials did not meet their primary endpoints, the HF community breathed a sigh of relief when the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-PRESERVED) trial and, most recently, the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial showed that sodium-glucose cotransporter 2 inhibition (SGLT2i) finally emerged as the first proven therapy to improve outcomes compared to placebo in this commonly older, comorbid group of patients. ^{,  ,}  During the past decade, it has also become apparent, as we have delved further into the reasons underlying the overall neutral results of TOPCAT and PARAGON-HF, that not all HFpEF is the same. It is a heterogeneous syndrome that makes conducting large-scale clinical trials based simply on broad criteria (eg, ejection fraction > 40–45% and elevated natriuretic peptides) risky. What if the wrong patients are chosen? What if we were treating different underlying disease processes? Much has been written about the heterogeneity of HFpEF in the United States and Europe and the development of risk scores specific to American and European HFpEF populations, but HFpEF trials have demonstrated that there are multifaceted layers of heterogeneity lurking beneath the surface. For example, in addition to heterogeneity due to comorbidities (risk factors) and predominant pathophysiology, we now understand that sex/gender and geographic differences are also important pieces of the puzzle of HFpEF heterogeneity. Yet somehow, as we grapple with neutral trial results in most HFpEF trials and only modest benefits in the positive EMPEROR-PRESERVED and DELIVER SGLT2i trials (in which absolute risk reduction was only ∼3%, and benefit was due almost entirely to HF events and not to cardiovascular death), the messaging on heterogeneity from the trials is often still myopic and tends to focus primarily on the heart. Is left ventricular ejection fraction mildly reduced, improved (recovered) or truly preserved? Is left ventricular hypertrophy or infiltrative cardiomyopathy present? Has the disease process progressed so far that the pulmonary vasculature and right ventricle are now affected?