The Diabetic Cardiomyopathy: The Contributing Pathophysiological Mechanisms

Abstract

Individuals with diabetes mellitus (DM) disclose a higher incidence and a poorer prognosis of heart failure (HF) than non-diabetic people, even in the absence of other HF risk factors. The adverse impact of diabetes on HF likely reflects an underlying “diabetic cardiomyopathy” (DM–CMP), which may by exacerbated by left ventricular hypertrophy and coronary artery disease (CAD). The pathogenesis of DM-CMP has been a hot topic of research since its first description and is still under active investigation, as a complex interplay among multiple mechanisms may play a role at systemic, myocardial, and cellular/molecular levels. Among these, metabolic abnormalities such as lipotoxicity and glucotoxicity, mitochondrial damage and dysfunction, oxidative stress, abnormal calcium signaling, inflammation, epigenetic factors, and others. These disturbances predispose the diabetic heart to extracellular remodeling and hypertrophy, thus leading to left ventricular diastolic and systolic dysfunction. This Review aims to outline the major pathophysiological changes and the underlying mechanisms leading to myocardial remodeling and cardiac functional derangement in DM-CMP.

Disturbed Glucose Metabolism and Left Ventricular Geometry in the General Population

“…Individuals with T2DM are at a higher risk for developing coronary heart disease [1], heart failure [2], peripheral artery disease [3], and acute cardiovascular events such as myocardial infarction and stroke [4]. Besides the well-known cardiac affection due to the development of coronary artery disease and cardiac autonomic neuropathy, T2DM also represents a risk factor for cardiac hypertrophy, which is highly prevalent even in asymptomatic diabetic patients and strongly associated with an increased risk for heart failure, stroke, and sudden death [5].…”

“…A body of evidence suggests that the activation of the renin-angiotensin system and alterations in calcium homeostasis as well as glycosylation of proteins and lipids are main contributors to myocardial fibrosis and promote myocardial hypertrophy [6,7]. Cardiac hypertrophy and fibrosis represent two main structural impairments of the diabetic heart, which are triggered by cardiomyocyte loss with compensatory hypertrophy of resident cardiomyocytes and inflammatory pathways generating fibrosis [5]. Additionally, microvascular endothelial dysfunction and the formation of nitrogen species as well as reactive oxygen seem to play key roles in this myocardial pathology [5,8].…”

“…Cardiac hypertrophy and fibrosis represent two main structural impairments of the diabetic heart, which are triggered by cardiomyocyte loss with compensatory hypertrophy of resident cardiomyocytes and inflammatory pathways generating fibrosis [5]. Additionally, microvascular endothelial dysfunction and the formation of nitrogen species as well as reactive oxygen seem to play key roles in this myocardial pathology [5,8]. Myocardial alterations lead to abnormal contractile function and can later on result in heart failure [8].…”

“…In the prediabetic state, functional myocardial changes without structural modification were described [10], but also an increase of left ventricular hypertrophy (LVH) and left ventricular mass index (LVMI) was detected [9,11]. Raising evidence suggests insulin resistance as a key factor in diabetic cardiomyopathy development, leading to an impairment of myocardial glucose utilization and several further pathways resulting in cardiac stiffness and diastolic dysfunction [5]. Aggravated glucose intolerance was associated with increased left ventricular mass and cardiac wall thickness in the Framingham Heart Study [12] and an association between insulin resistance and the presence of cardiac remodeling and hypertrophy was shown in cardiac magnetic-resonance imaging studies [5,13,14].…”

Cardiovascular Benefits from Gliflozins: Effects on Endothelial Function

“…Type 2 diabetes mellitus (T2DM) is a well-known independent risk factor for atherosclerotic cardiovascular disease (CVD), including coronary, cerebral, and peripheral vasculopathy, a clinical condition that globally represents the worldwide primary cause of complications and death in diabetic patients [1][2][3][4][5][6][7]. Moreover, robust epidemiological evidence indicates heart failure (HF) among the most common CVDs of diabetes, since 1974 when the Framingham study reported a risk of HF in T2DM greater than that of coronary heart disease (CHD) [8,9]. Based on these data, it is imperative to consider the prevention of CV outcomes as an effective goal for the management of diabetic patients, as important as lowering blood glucose.…”