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

Epicardial Adipose Tissue Expansion, Proinflammatory Adipocytokine Secretion, Microcirculatory Dysfunction, and Myocardial Inflammation

Many systemic metabolic or inflammatory disorders (including diabetes) lead to the development of HFpEF, potentially through their common action to cause endothelial dysfunction of the coronary microvasculature,[62] which is often accompanied by myocardial inflammation and fibrosis.[63] These changes in the LV impair its distensibility, predisposing to disproportionate increases in LV filling pressure if central blood volume increases caused by plasma volume expansion or regional changes in systemic venous capacitance.[17,18] The mechanisms by which a systemic disorder (such as diabetes) can lead to coronary microcirculatory changes and myocardial inflammation/fibrosis are complex. However, it is noteworthy that the systemic disorders that cause HFpEF also lead to the expansion of epicardial adipose tissue, suggesting that the biological activity and physical proximity of epicardial fat allow it to act as a transducer that amplifies and focuses the derangements of the systemic disorder onto the myocardium.[64]

Embryonically, the epicardium is a major source of mesenchymal stem cells for cardiac regeneration, and healthy epicardial fat has the biological properties of brown adipose tissue, which combusts proinflammatory fatty acids and secretes adaptive adipokines (eg, adiponectin) that nourish the myocardium. However, when influenced by systemic inflammatory or metabolic disorders, epicardial adipose tissue expands and develops features of white adipose tissue.[64] When overfilled with lipids, these adipocytes are prone to lipolysis, and the release of fatty acids triggers macrophage infiltration[65] and the secretion of proinflammatory cytokines (leptin, tumor necrosis factor-α, interleukin-6, interleukin-1β and resistin).[66,67] The epicardium shares an unobstructed microcirculation with the underlying muscle, thus allowing these biological derangements to be transmitted to the adjoining muscle. Proinflammatory cytokines synthesized in epicardial fat depots can adversely influence the structure and function of the underlying tissues. These relationships explain why the volume of epicardial adipose tissue is closely associated with the severity of coronary microvascular dysfunction, myocardial fibrosis, and LV hypertrophy.[67–70] Lipids may also accumulate within the myocardium itself and be the source of adipocytokines that cause adverse structural and functional changes.[70,71]

Epicardial fat volume is increased in patients with established HFpEF—a feature that may distinguish HFpEF from HFrEF.[17,72–76] Importantly, diabetes is accompanied by epicardial adipose expansion and inflammation;[77] when diabetes and obesity coexist, each contributes to the expanded volume of epicardial fat.[78] Epicardial adiposity is associated with insulin resistance[79] and changes in ventricular structure and function in patients with glucose intolerance or type 2 diabetes.[80] Epicardial fat volume in patients with insulin resistance is associated with markers of systemic inflammation,[81,82] myocardial fibrosis and coronary microcirculatory abnormalities,[70,83] vascular stiffness,[84] and an increased risk of cardiovascular and renal disease and mortality (Figure 3).[85,86]

Figure 3.

Type 2 Diabetes Causes Expansion and Inflammation of Systemic and Epicardial Adipose Tissue Depots Leading to Proinflammatory Adipocytokine-Mediated Coronary Microvascular Dysfunction and Myocardial Inflammation and Fibrosis
Type 2 diabetes leads to the expansion and proinflammatory transformation of adipose tissue depots, particularly those surrounding the heart and kidney. Coronary microcirculatory dysfunction results from the following: 1) the effects of systemic adipose tissue inflammation on the coronary endothelium; or 2) the release of proinflammatory adipocytokines from biologically active epicardial adipose tissue, which causes inflammation, microcirculatory dysfunction, and fibrosis of the adjoining myocardium, thereby impairing left ventricular (LV) distensibility. Similar effects occurring in perirenal fat may contribute to inflammation of the renal parenchyma and progressive renal dysfunction.

The expansion and biological transformation of epicardial adipose tissue promotes its synthesis of proinflammatory adipocytokines, including leptin, tumor necrosis factor-α, interleukin-1β and interleukin-6.[64] These mediators are released locally (promoting cardiac inflammation and microcirculatory dysfunction) and systemically (potentially contributing to renal tubular sodium hyper-reabsorption and renal dysfunction). Among the candidate adipocytokines, leptin is most likely to cause sodium retention and be linked to systemic inflammatory and adipogenic metabolic disorders.[66] Circulating leptin levels are correlated with epicardial fat mass[87] and are increased in patients with HFpEF[88,89] and with diabetes.[81] Leptin can adversely affect calcium handling in cardiomyocytes so as to impair myocardial relaxation.[90] Leptin may also promote adverse changes in ventricular geometry and can stimulate the synthesis of collagen, thus causing cardiac and vascular fibrosis.[91] Finally, leptin has been shown to stimulate sodium tubular hyper-reabsorption through an action to enhance the secretion of aldosterone, augment the activity of renal sympathetic nerves, and stimulate Na+/K+-ATPases.[66]

These observations, taken together, suggest that diabetes may promote the development of HFpEF by causing epicardial adipose tissue expansion and the secretion of proinflammatory adipocytokines onto the adjoining myocardium, leading to coronary microcirculatory dysfunction and myocardial inflammation and fibrosis.