Impact of type 2 diabetes and the metabolic syndrome on myocardial structure and microvasculature of men with coronary artery disease

Abstract

BackgroundType 2 diabetes and the metabolic syndrome are associated with impaired diastolic function and increased heart failure risk. Animal models and autopsy studies of diabetic patients implicate myocardial fibrosis, cardiomyocyte hypertrophy, altered myocardial microvascular structure and advanced glycation end-products (AGEs) in the pathogenesis of diabetic cardiomyopathy. We investigated whether type 2 diabetes and the metabolic syndrome are associated with altered myocardial structure, microvasculature, and expression of AGEs and receptor for AGEs (RAGE) in men with coronary artery disease.MethodsWe performed histological analysis of left ventricular biopsies from 13 control, 10 diabetic and 23 metabolic syndrome men undergoing coronary artery bypass graft surgery who did not have heart failure or atrial fibrillation, had not received loop diuretic therapy, and did not have evidence of previous myocardial infarction.ResultsAll three patient groups had similar extent of coronary artery disease and clinical characteristics, apart from differences in metabolic parameters. Diabetic and metabolic syndrome patients had higher pulmonary capillary wedge pressure than controls, and diabetic patients had reduced mitral diastolic peak velocity of the septal mitral annulus (E'), consistent with impaired diastolic function. Neither diabetic nor metabolic syndrome patients had increased myocardial interstitial fibrosis (picrosirius red), or increased immunostaining for collagen I and III, the AGE Nε-(carboxymethyl)lysine, or RAGE. Cardiomyocyte width, capillary length density, diffusion radius, and arteriolar dimensions did not differ between the three patient groups, whereas diabetic and metabolic syndrome patients had reduced perivascular fibrosis.ConclusionsImpaired diastolic function of type 2 diabetic and metabolic syndrome patients was not dependent on increased myocardial fibrosis, cardiomyocyte hypertrophy, alteration of the myocardial microvascular structure, or increased myocardial expression of Nε-(carboxymethyl)lysine or RAGE. These findings suggest that the increased myocardial fibrosis and AGE expression, cardiomyocyte hypertrophy, and altered microvasculature structure described in diabetic heart disease were a consequence, rather than an initiating cause, of cardiac dysfunction.

Role of advanced glycation end products in cardiovascular disease

“…The study demonstrated no significant differences in either myocardial AGE or RAGE expression between patient groups or the control group suggesting that myocardial AGE/RAGE expression was not an important factor in diastolic dysfunction development in diabetes. In a similar study in which endomyocardial biopsies of failing hearts of diabetic patients were studied, no increase in myocardial fibrosis or myocardial CML expression was observed in cases with preserved left ventricular ejection fraction although both myocardial fibrosis and CML expression were elevated in cases with significant systolic dysfunction [60] .…”

“…For instance, in another study, the authors demonstrated that increased serum sRAGE levels are associated with increased severity of HF particularly in patients with an ischemic cause of heart failure although this correlation was shown to be independent of AGE serum levels [59] . Similarly, in the study of Campbell et al [60] , left ventricular biopsies were taken from pre-diabetic, type 2 diabetic and control subjects undergoing coronary heart bypass surgery to assess myocardial fibrosis and myocardial expression of the AGE N-CML and the RAGE. All the patients had similar degrees of coronary disease with no previous history of myocardial infarction or heart failure although diabetic patients exhibited diastolic dysfunction on echocardiography.…”

Serum advanced glycation endproducts are associated with left ventricular dysfunction in normal glucose metabolism but not in type 2 diabetes: The Hoorn Study

“…8 The above suggests that the associations between circulating AGEs and LV function and structure are not straightforward. Studies conducted on human 7,[26][27][28][29][30][31][32] or animal [33][34][35][36][37][38] cardiac tissue have shown that AGEs accumulate within the myocardium, 7,26-34 even more so in T2DM [26][27][28][29][30][31]34 or IGM. 33 In addition, these studies showed that the myocardial accumulation of AGEs was associated with impaired diastolic function 30,[33][34][35][36] and/or impaired systolic function.…”

Assessment of Pulmonary Function in Patients with Type 2 Diabetes Mellitus: A Case-Control Study.

“…33 Such microvasculature changes in the form of tissue fibrosis not only observed in lung parenchyma but also in heart myocardium as well, evidence mentioned that such myocardial fibrosis, cardiomyocyte hypertrophy and altered microvasculature was resulted due to DM. 36 For such fibrotic process Angiotensin II plays an important factor for diabetic lung fibrosis resulted due to NOX activation-mediated nitrosative damage. 35 Thus, our study has demonstrated clear cut negative effect on mechanical lung function in diabetic subjects suggesting lung as a target organ, but could not establish its relationship to the glycaemic control and the other microvascular complications.…”