For the past decade, the prevailing paradigm to explain heart failure with preserved ejection fraction (HFpEF) has assumed that multiple comorbidities act in concert to trigger a systemic inflammatory state that causes coronary microvascular dysfunction, nitric oxide/cyclic guanosine monophosphate (cGMP) deficiency-dependent titin abnormalities, and load-dependent cellular inflammation and fibrosis of the myocardium. By contrast, the recently proposed adipokine hypothesis elevates one comorbidity-visceral adiposity-to explain the coexistence of systemic inflammation, multiple comorbidities, and HFpEF and identifies a specific proximal causal mechanism (ie, the secretion of a proinflammatory suite of signaling molecules from dysfunctional fat). Excess visceral adiposity and adipokine imbalances have been shown not only to produce HFpEF experimentally but also to directly cause hypertension, insulin resistance and type 2 diabetes, and chronic kidney disease. Visceral adiposity and proinflammatory adipokines can also explain features of HFpEF that are not addressed by the coronary microvascular inflammation hypothesis (eg, atrial fibrillation, skeletal muscle and pulmonary abnormalities, and renal sodium retention and plasma volume expansion). Adipokine imbalances can also cause microvascular dysfunction and defects in cGMP signaling and in titin phosphorylation, and they can directly cause cardiac hypertrophy and fibrosis independently of an effect on the microvasculature. The comorbidity-driven microvascular inflammation hypothesis did not identify a blood-borne molecular mediator that selectively targets the heart, and phenomapping based on the clustering of comorbidities has not yielded reproducible groupings. By contrast, selective silencing of specific proinflammatory adipokines only in adipose tissue causes distant effects on the heart to modulate cardiac structure and the evolution of HFpEF. Clinical trials of drugs that enhance nitric oxide/cGMP signaling or have nonspecific anti-inflammatory effects have not produced favorable effects in clinical HFpEF whereas drugs that produce benefits in HFpEF (eg, glucagon-like peptide 1 receptor agonists, sodium-glucose cotransporter 2 inhibitors) act to normalize the adipokine secretory profile. Finally, whereas coronary microvascular dysfunction is present in 60% to 70% of patients with HFpEF (with endothelium-dependent dysfunction being seen in only 30%), central obesity (assessed by an increased waist-to-height ratio) or visceral adiposity (as by mesenteric, or epicardial fat) is present in >85% to 95% of patients with the disorder. Therefore, when compared with the comorbidity-driven coronary microvascular endothelial inflammation hypothesis, the adipokine hypothesis provides an explanatory framework with a stronger evidentiary support and applicable to a broader range of patients with HFpEF. Further work is needed to support these observations.
