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A new paradigm has emerged in our understanding of the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF) versus HF with reduced ejection fraction (HFrEF). Comorbidity-driven cardiac endothelial dysfunction plays a primary role in HFpEF, leading to cardiomyocyte dysfunction, left ventricular (LV) concentric remodelling and predominantly diastolic dysfunction1 (figure 1). Conversely in HFrEF, direct cardiomyocyte injury is the key trigger for systemic neuroendocrine activation, LV eccentric remodelling and predominantly systolic dysfunction.1 Whereas neuroendocrine activation exists as a common defining domain of the HF syndrome in both HFrEF and HFpEF, in HFrEF it plays a dominant role in adverse remodelling and outcomes; thus antagonists of the renin-angiotensin-aldosterone and adrenergic systems have been effective in improving survival in HFrEF. Similarly, whereas cardiovascular endothelial dysfunction exists in both HFpEF and HFrEF, by the new paradigm, it is postulated to play a dominant role in the pathophysiology and outcomes of HFpEF. This distinction is critical since targeting endothelial dysfunction may be a winning strategy in HFpEF—a condition now recognised as one of the largest unmet needs in cardiovascular medicine, responsible for half the HF epidemic and without proven therapies to improve survival.2
Contributors Both authors made substantial contributions to the drafting of this manuscript.
Competing interests CSPL is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Boston Scientific, Medtronic, and Vifor Pharma; and has consulted for Bayer, Novartis, Takeda, Merck, AstraZeneca, Janssen Research & Development, LLC and Menarini. LHL is supported by a Clinical Research Award from the Swedish Research Council; has received research support from Boston Scientific, AstraZeneca, Medtronic and Thoratec and lecture and/or consulting honoraria from AstraZeneca, Novartis, Vifor Pharma, Servier, St Jude and Medtronic.
Provenance and peer review Commissioned; internally peer reviewed.