General Principles, Clinical Definition, Epidemiology, and Pathophysiology

HFpEF Versus HFrEF

Heart failure is a clinical spectrum with a similar presentation regardless of ejection fraction. To add historical perspective, the recognition of diastolic dysfunction as a distinct clinical entity is roughly 50 years old. Over the years, it has become apparent that both HFpEF and HFrEF are equally prevalent and carry similar risks of morbidity and mortality. Knowledge of the fundamental pathophysiologic differences and overlaps between the two syndromes has progressed greatly in the recent past. Nomenclature has changed dramatically over the last 20 years, thus highlighting the evolving understanding of the syndrome. Originally called diastolic heart failure, it was soon appreciated that the mechanism of impaired relaxation was much more than the single descriptive term. In fact, it encompasses a syndrome of maladaptive changes that are more accurately encapsulated with the broad descriptor of heart failure with preserved ejection fraction, hence HFpEF.

Nonetheless, practical questions remain with this current terminology. It is still unclear what the exact EF partition value should be when categorizing between the two syndromes. It is gathered from available data that there is an ejection fraction cutoff in which traditional neurohormonal blockade is much more effective in treatment. This observation underscores the vastly different mechanisms of HFrEF and HFpEF. The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial data perfectly summarize this point. This was a large trial of spironolactone in HFpEF that failed to show an improvement in the primary end point of cardiovascular death, HF hospitalization, or aborted cardiac arrest in people with HF and an EF greater than or equal to 45%. However, Solomon et al. elegantly analyzed this data and found that the efficacy of spironolactone was apparent in reducing the primary end point in patients with a lower EF range, and essentially of no benefit in those with a higher EF range (>55%). This supports the proposition that neurohormonal blockade may still be effective in the so-called mildly depressed EF with the range of 45% to 55%. It is hypothesized that perhaps this group should be treated as HFrEF patients. Thus the EF can be an important tool to distinguish separate biologic mechanisms of disease that would warrant separate therapies. It is important to note that although ejection fraction is used as one of the distinguishing features between HFrEF and HFpEF, there have been recent data demonstrating an impairment in systolic function in the HFpEF population. It is quite apparent that there is a complex interaction among several pathways, which fall under the umbrella of HFpEF. Recent insights in microvascular inflammation, pulmonary vascular dysfunction, cellular and structural changes, and the involvement of left atrial hypertension only add to the complexity of the syndrome; thus nomenclature will also likely evolve to reflect the growing sophistication in the pathophysiology of the disease.