Myocardial Contractile Dysfunction Is Associated With Impaired Mitochondrial Function and Dynamics in Type 2 Diabetic but Not in Obese Patients

Abstract

O besity and type 2 diabetes mellitus (DM) have reached epidemic levels worldwide. These 2 metabolic disorders are independent risk factors for the development of heart failure. [1][2][3] Epidemiological and clinical studies strongly support the existence of obesity and diabetic cardiomyopathies unrelated to coronary artery disease, hypertension, and other comorbidities. 4,5 Clinical Perspective on p 564Studies in rodent models of obesity and DM have identified intrinsic cardiomyocyte dysfunctions secondary to alterations in energy substrate utilization, mitochondrial dysfunction, increased oxidative stress, and intracellular accumulation of lipotoxic byproducts. Similarly, human studies have shown that dysregulation of the energy conversion process is one of the major characteristics of the failing heart of subjects with cardiomyopathy related to DM or obesity. 6,7Background-Obesity and diabetes mellitus are independently associated with the development of heart failure. In this study, we determined the respective effects of obesity, insulin resistance, and diabetes mellitus on the intrinsic contraction and mitochondrial function of the human myocardium before the onset of cardiomyopathy. Methods and Results-Right atrial myocardium was obtained from 141 consecutive patients presenting no sign of cardiomyopathy. We investigated ex vivo isometric contraction, mitochondrial respiration and calcium retention capacity, and respiratory chain complex activities and oxidative stress status. Diabetes mellitus was associated with a pronounced impairment of intrinsic contraction, mitochondrial dysfunction, and increased myocardial oxidative stress, regardless of weight status. In contrast, obesity was associated with less pronounced contractile dysfunction without any significant perturbation of mitochondrial function or oxidative stress status. Tested as continuous variables, glycated hemoglobin A 1C , but neither body mass index nor the insulin resistance index (homeostasis model assessment-insulin resistance), was independently associated with cardiac mitochondrial function. Furthermore, diabetes mellitus was associated with cardiac mitochondrial network fragmentation and significantly decreased expression of the mitochondrial fusion related protein MFN1. Myocardial MFN1 content was inversely proportional to hemoglobin A 1C . Conclusion-Worsening

Chronic Heart Failure and Inflammation

“…68,[126][127][128][129][130] It has been hypothesized that the mechanism of inflammasome activation in diabetic cardiomyopathy is dependent on the combination of oxidative stress and reactive oxygen species production, as a result of mitochondrial dysfunction. 131,132 Damaged mitochondria are removed from the cell in a process known as mitophagy, and if this system is overwhelmed or ineffective, increased reactive oxygen species ensues.…”

“…135 In addition, impaired autophagy has been reported in a variety of clinical risk factors for HF, such as hypertension, ischemia, diabetes mellitus, aging, and genetic predisposition. 132,[136][137][138] During chronic ICM (4 weeks post MI), mice treated with resveratrol, which possess proautophagic functions, exhibited partially reversed LV dilation and improved LV function in the chronic state, whereas the inhibition of autophagy worsened LV function. 139 Mitochondria are responsible for supplying the beating myocardium with ATP and are intimately involved in regulating apoptosis in stressed or damaged cells.…”

Myocardial autophagic energy stress responses—macroautophagy, mitophagy, and glycophagy

“…Since our first report of increased cardiac autophagy in the type 2 diabetic fructose-fed mouse (59), the experimental literature in this field has expanded considerably, but it is not yet possible to synthesize a comprehensive understanding. Relying on a variable selection of molecular tools, states of increased (4,12,49,50,59,61,78,93,102), unchanged (47,48,57,62), and decreased (6,23,28,29,73,82,101,103,104,110) basal cardiac autophagy activity have all been reported in diabetic/ insulin resistant contexts (see Table 1). These discrepancies are not necessarily attributable to the different models of diabetes, since contrasting findings have been observed within the same diabetic model [e.g., STZ-mouse: increased LC3BII (12) vs. decreased LC3BII (103)].…”

Metabolic abnormalities of the heart in type II diabetes

“…Indeed, in the hearts of animals and humans with T2DM, a consistent reduction in the amount and catalytic activity of ETC complexes have been shown, and ETC dysfunction has been linked to oxidative stress. [69][70][71][72][73] Reductions in OxPhos also result from FA-mediated upregulation of UCPs which uncouple mitochondria, and to attenuations in mitochondrial density (only in animal models), size and internal complexity. 14,[74][75][76][77] In patients with T2DM, reductions in mitochondrial size relate to impaired mitochondrial fusion with decreased mitofusin-2 expression.…”

“…16,79,80 Moreover, in atrial trabeculae excised from surgical patients with T2DM, reductions in OxPhos were associated with impaired contractility. 71 While mitochondrial dysfunction could be deleterious solely via its ability to limit ATP supply to myofibrils (leading to systolic impairment) and SERCA (leading to diastolic impairment), it also augments ROS production which is implicated in cardiac remodelling. 72,73 Increased ROS production results from the abundance of electrons delivered to the ETC (due to increased FA oxidation) which, because the ETC is defective, increasing leak to form ROS.…”