Heart failure with a preserved ejection fraction (HFpEF) and
heart failure with a reduced ejection fraction (HFrEF) have distinctive pathophysiologies, and thus, therapeutic approaches to the 2 disorders should differ. Neurohormonal activation drives the progression of HFrEF, and neurohormonal antagonists are highly effective in HFrEF, but not in HFpEF. Conversely, a broad range of chronic systemic inflammatory or metabolic disorders cause an expansion and
inflammation of epicardial adipose tissue; the secretion of
adipocytokines may lead to microvascular dysfunction and
fibrosis of the underlying myocardium, which (if the left atrium is affected) may lead to
atrial fibrillation (AF) and (if the left ventricle is affected) may lead to HFpEF. Anti-inflammatory drugs (such as
statins and anticytokine agents) can ameliorate epicardial adipose tissue dysfunction.
Statins appear to ameliorate the development of atrial
myopathy (both experimentally and clinically), and in randomized controlled trials, they reduce the incidence of new-onset and recurrent AF and decrease the risk of
heart failure with the features of HFpEF; yet, they have no benefits in HFrEF. Similarly, anticytokine agents appear to prevent
heart failure in patients with or prone to HFpEF, but adversely affect HFrEF. Several
antihyperglycemic agents also reduce epicardial fat mass and
inflammation, but this benefit may be offset by additional actions to cause
sodium retention and neurohormonal activation.
Thiazolidinediones have favorable effects on experimental AF and HFpEF, but their antinatriuretic actions negate these benefits, and they worsen the
clinical course of HFrEF.
Glucagon-like peptide-1 receptor agonists also ameliorate AF and HFpEF in laboratory models, but their positive inotropic and chronotropic effects may be deleterious in HFrEF. By contrast,
metformin and
sodium-glucose cotransporter 2 inhibitors alleviate epicardial adipose tissue dysfunction and may reduce the risk of AF and HFpEF; yet, they may have additional actions to promote cardiomyocyte survival that are useful in HFrEF. The concordance of the benefits of anti-inflammatory and
antihyperglycemic drugs on AF and HFpEF (but not on HFrEF) supports the paradigm that epicardial adipose tissue is a central pathogenetic mechanism and therapeutic target for both AF and HFpEF in patients with chronic systemic inflammatory or
metabolic diseases.