Differential Pathophysiological Mechanisms in Heart Failure With a Reduced or Preserved Ejection Fraction in Diabetes

State-of-the-art Review

Milton Packer, MD


JACC Heart Fail. 2021;9(7):535-549. 

In This Article

Pathophysiological Distinctions Between HFrEF and HFpEF

HFrEF is commonly regarded as a disorder of impaired systolic function, whereas HFpEF has long been perceived as a disorder where contractile function is intact and myocardial relaxation is impaired. However, this conceptual framework is inconsistent with the available evidence. Myocardial shortening can be markedly impaired in heart failure whether the ejection fraction is in the normal range or severely reduced; similarly, LV filling dynamics are abnormal in heart failure, regardless of the ejection fraction.[14,15]

The primary distinction between HFrEF and HFpEF lies in the fact that a loss of contractile function is accompanied by proportional LV enlargement in HFrEF, but by only modest LV dilatation in HFpEF.[14] Because stroke volume is typically maintained, the marked increase in LV volume in HFrEF causes the calculated LV ejection fraction to fall, whereas when infiltrative or inflammatory disorders limit LV distensibility and dilatation, ejection fraction is typically maintained at >40%-50%. Importantly, in most patients with HFpEF, the LV end-diastolic pressure–volume relationship is unchanged,[16] and increases in LV filling pressure are caused by LV overfilling, either because of plasma volume expansion or a reduction in systemic venous capacitance.[17,18] In contrast with hypertrophic or amyloid cardiomyopathy, the LV walls in patients with HFpEF caused by a metabolic disorder (such as diabetes) show no or minimal thickening, and they often have an elevated blood pressure caused by the expansion of central blood volume.[19]

Type 2 diabetes is associated with a more than 2-fold increase in the development of both HFrEF and HFpEF.[20] Thus, the term "diabetic cardiomyopathy" does not refer to a clinical entity, but instead, encompasses any abnormality in cardiac structure and function that is related to or accelerated by diabetes. It seems likely that diabetes promotes the development of heart failure in all patients with hyperinsulinemia, whether or not they have other identified reasons for LV dysfunction (eg, myocardial infarction).

Diabetes can lead to the development of HFrEF and HFpEF through diverse mechanisms. This paper reviews the available evidence that diabetes can promote the development of HFrEF in 2 ways: 1) by suppressing nutrient deprivation signaling and autophagy and thereby promoting cardiomyocyte stress and dysfunction; and 2) by activating the sodium-hydrogen exchanger and undermining cardiomyocyte survival. In parallel, diabetes can promote the development of HFpEF by enhancing the expansion of visceral (and especially epicardial) adipose tissue depots, which can promote cardiac inflammation, microcirculatory dysfunction, and fibrosis. Finally, in both HFrEF and HFpEF, an action of insulin on the renal tubules to stimulate sodium hyperabsorption can lead to plasma volume expansion and increased LV filling pressures. Other potential mechanisms for the development of HFrEF and HFpEF are not included in this review.