Novel Mechanisms in Heart Failure With Preserved, Midrange, and Reduced Ejection Fraction

Heart failure (HF) represents a major epidemic with high morbidity and mortality rates, imposing a significant burden on healthcare systems worldwide (Savarese and Lund, 2017). HF has long been distinguished by ejection fraction (EF) into two types—HF with reduced ejection fraction (HFrEF), for which EF is below 40%, and HF with preserved ejection fraction (HFpEF), for which EF is above 50% and, according to the 2016 European Society of Cardiology (ESC) Guidelines (Ponikowski et al., 2016), accompanies (1) an elevated level of natriuretic peptides (BNP > 35 pg/ml and/or NT-proBNP > 125 pg/mL) and (2) the presence of either structural heart disease (left ventricular hypertrophy and/or left atrial enlargement) or diastolic dysfunction. HFrEF and HFpEF were initially considered to be binary opposing entities at two ends of the same spectrum. However, whilst several studies have demonstrated the efficacy of drug therapies in improving quality-of-life and long-term clinical outcomes in HFrEF patients, such pharmacological approaches have often failed to yield similar observable benefits in HFpEF cohorts. As such, the current paradigm follows that the pathogenesis underscoring the development and progression of HFrEF and HFpEF are distinct. In more recent developments, the 2016 ESC Guidelines (Ponikowski et al., 2016) also proposed a third class of HF–HF with mid-range ejection fraction (HFmrEF), for which EF is between 40 and 49%, and accompanies the same two aforementioned components of HFpEF. Investigations into this newly defined group of HF patients have yielded contradicting results: whilst some findings have demonstrated an overlap between HFmrEF and the other two classes, others have shown no such association. As a result, a greater understanding of the underlying mechanistic differences between the HF groups, particularly pertaining to HFpEF and HFmrEF, is still needed in order to ensure successful diagnoses and holistic treatment provision. The proposed mechanism for HFrEF is generally well-understood, in which adverse myocardial remodeling, resulting from cardiomyocyte death (Gonzalez et al., 2011) secondary to an inciting stimulus, such as viral myocarditis, myocardial infarction, or drug-induced cardiomyopathy (Bloom et al., 2017), leads to systolic dysfunction (Figure 1A). The same however cannot be said for HFpEF, which is instead associated with a more heterogeneous pathophysiology (Kao et al., 2015). Epidemiological studies have illustrated a comparatively stronger relationship between HFpEF (as opposed to HFrEF) with multiple cardiac and non-cardiac co-morbidities, including but not limited to type 2 diabetes mellitus (T2DM), arterial hypertension, renal failure, obesity, and atrial fibrillation (Elguindy and Yacoub, 2012). This evidently diverse clinical phenotype has elicited much debate regarding the precise mechanisms involved in the development of HFpEF.