Perhaps the biggest cardiology story of the year, an entire issue of JACC now hypothesizes that heart failure with preserved ejection fraction (HFpEF) might actually be caused by visceral fat tissue that triggers cardiac weakening through adipokine signaling.
- HFpEF has traditionally been seen as a heterogeneous disorder related to comorbidities like obesity, hypertension, and diabetes, with an unclear cause of pathophysiology.
- Obesity is present in over 95% of HFpEF patients and tracks with disease severity, yet it has been viewed as a contributing factor rather than the cause.
- Adipokines are substances that are released by fat tissue and act as hormones to regulate body functions like appetite, metabolism, and inflammation.
The new unifying adiposity framework now proposes that visceral fat expansion causes secretion of an altered adipokine profile that leads to systemic inflammation alongside cardiac hypertrophy and fibrosis. The hypothesis organizes adipokines into three functional domains…
- Domain I adipokines are cardioprotective molecules suppressed by excess body fat, representing a critical protective pathway that becomes disabled.
- Domain II adipokines are also cardioprotective molecules but they are increased by the body as a compensatory response to body fat level.
- Domain III adipokines, which are heightened during high body fat and drive the inflammation, hypertrophy, and fibrosis effects directly causing HFpEF
Taking the hypothesis a step further, this means that HFpEF is the result of high body fat imbalances that promote the Domain III adipokines while suppressing Domain I adipokines with Domain II.
Although we have yet to see a definitive adipokine study, the authors put together several converging lines of evidence supporting adipose tissue as the primary pathogenic driver of HFpEF. Some examples include…
- Obesity and calorie excess are the drivers of experimental HFpEF models, with visceral fat changes visible years before HF diagnosis specifically predicting HFpEF (but not HFrEF).
- Striking parallels exist between obesity and HFpEF in molecular, pathophysiological, and clinical features, with adipokine levels correlating with disease severity in both.
- Experimental interventions targeting only adipose tissue to modify specific adipokine secretion cause distant cardiac effects, changing cardiomyopathy progression.
The Takeaway
This unifying hypothesis fundamentally reframes HFpEF from a multi-cause cardiac disorder with obesity as one comorbidity to an adipose-driven endocrine disease. If future studies validate this hypothesis, it could transform HFpEF treatment and the conversation around how to prevent our hearts from failing.
