Diabetes Mellitus–Induced Microvascular Destabilization in the Myocardium

Hinkel, Rabea; Howe, Andrea; Renner, Simone; Ng, Judy King Man; Lee, Seungmin; Klett, Katharina; Kaczmarek, Veronika; Moretti, Alessandra; Laugwitz, Karl‐Ludwig; Skroblin, Philipp; Mayr, Manuel; Milting, Hendrik; Dendorfer, Andreas; Reichart, Bruno; Wolf, Eckhard; Kupatt, Christian

doi:10.1016/j.jacc.2016.10.058

Cited by 136 publications

(135 citation statements)

References 34 publications

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“…Mechanisms of this type that have been implicated in the development of retinopathy include inflammation, oxidative stress and persistent activation of the renin–angiotensin system . In addition, microvascular disease may particularly affect the myocardium in patients with diabetes which is clearly of greatest danger in patients with already dysfunctional myocardium . Due to the suggestion of less benefit of drug therapy and higher rates of diabetic complications in African‐Americans, we repeated analyses without these patients with similar results .…”

Section: Discussionmentioning

confidence: 99%

“…11 In addition, microvascular disease may particularly affect the myocardium in patients with diabetes which is clearly of greatest danger in patients with already dysfunctional myocardium. 19 Due to the suggestion of less benefit of drug therapy and higher rates of diabetic complications in African-Americans, we repeated analyses without these patients with similar results. 20,21 Another potential risk factor for developing heart failure in diabetes patients with microvascular complications is their presumed more severe diabetes and for this reason intensified glucose-lowering therapy, where some drug classes including pioglitazones have been linked to an increased risk of heart failure.…”

Section: Risk According To Type Of Microvascular Complicationmentioning

confidence: 99%

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Microvascular complications in diabetes patients with heart failure and reduced ejection fraction—insights from the Beta‐blocker Evaluation of Survival Trial

Kristensen

Rørth

Jhund

et al. 2018

European J of Heart Fail

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Section: Discussionmentioning

confidence: 99%

Section: Risk According To Type Of Microvascular Complicationmentioning

confidence: 99%

Microvascular complications in diabetes patients with heart failure and reduced ejection fraction—insights from the Beta‐blocker Evaluation of Survival Trial

Kristensen

Rørth

Jhund

et al. 2018

European J of Heart Fail

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“…For several tissues, there is already evidence for morphological or functional alterations. A recent study of myocardium showed capillary rarefaction and reduced pericyte investment in 5-month-old MIDY pigs compared to age-matched WT littermates [27]. Additionally, the retina of MIDY pigs (age: 24 or 40 months) exhibited several diabetes associated morphologic alterations [28].…”

Section: Discussionmentioning

confidence: 99%

The Munich MIDY Pig Biobank – A unique resource for studying organ crosstalk in diabetes

Blutke¹,

Renner

Flenkenthaler³

et al. 2017

Molecular Metabolism

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ObjectiveThe prevalence of diabetes mellitus and associated complications is steadily increasing. As a resource for studying systemic consequences of chronic insulin insufficiency and hyperglycemia, we established a comprehensive biobank of long-term diabetic INSC94Y transgenic pigs, a model of mutant INS gene-induced diabetes of youth (MIDY), and of wild-type (WT) littermates.MethodsFemale MIDY pigs (n = 4) were maintained with suboptimal insulin treatment for 2 years, together with female WT littermates (n = 5). Plasma insulin, C-peptide and glucagon levels were regularly determined using specific immunoassays. In addition, clinical chemical, targeted metabolomics, and lipidomics analyses were performed. At age 2 years, all pigs were euthanized, necropsied, and a broad spectrum of tissues was taken by systematic uniform random sampling procedures. Total beta cell volume was determined by stereological methods. A pilot proteome analysis of pancreas, liver, and kidney cortex was performed by label free proteomics.ResultsMIDY pigs had elevated fasting plasma glucose and fructosamine concentrations, C-peptide levels that decreased with age and were undetectable at 2 years, and an 82% reduced total beta cell volume compared to WT. Plasma glucagon and beta hydroxybutyrate levels of MIDY pigs were chronically elevated, reflecting hallmarks of poorly controlled diabetes in humans. In total, ∼1900 samples of different body fluids (blood, serum, plasma, urine, cerebrospinal fluid, and synovial fluid) as well as ∼17,000 samples from ∼50 different tissues and organs were preserved to facilitate a plethora of morphological and molecular analyses. Principal component analyses of plasma targeted metabolomics and lipidomics data and of proteome profiles from pancreas, liver, and kidney cortex clearly separated MIDY and WT samples.ConclusionsThe broad spectrum of well-defined biosamples in the Munich MIDY Pig Biobank that will be available to the scientific community provides a unique resource for systematic studies of organ crosstalk in diabetes in a multi-organ, multi-omics dimension.

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“…Microvascular insufficiency takes a critical role in the development of DCM. Accumulating evidences have demonstrated a progressive reduction of the microvasculature and an impaired angiogenic response to chronic ischemia with the development of diabetes [2, 3]. These microvascular changes may lead to reduced perfusion of myocardium and contribute to adverse cardiovascular events [4].…”

Section: Introductionmentioning

confidence: 99%

Neuregulin-1 Promotes Myocardial Angiogenesis in the Rat Model of Diabetic Cardiomyopathy

Gui

Zeng

Chen³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Microvascular insufficiency takes a critical role in the development of diabetic cardiomyopathy (DCM). So this study was designed to investigate the effects of Neuregulin-1 (NRG-1) treatment on myocardial angiogenesis and the changes of VEGF/Flk1 and Ang-1/Tie-2 signaling in the rat model of DCM. Methods: Diabetic rats were induced by a single intraperitoneal injection of Streptozotocin. 12 weeks after the diabetes induction, the rats with NRG-1 treatment were treated with tail vein injection of NRG-1 at the dose of 10µg/kg/d for consecutive 10 days. Cardiac function was assessed using catheter MPA cardiac function analysis system. Myocardial blood flow (MBF) was assessed with stable-isotope labeled microspheres. Capillary density was measured by CD31 immunohistochemistry. The protein expression and receptors phosphorylation were assessed using western blot. Results: Left ventricular function, capillary density and MBF were significantly reduced in DCM group when compared with those in the control group (P< 0.01, P< 0.01 and P< 0.05 respectively). Left ventricular function and capillary density were significantly increased in NRG-1 treatment group when compared with those in the DCM group (P< 0.05 and P< 0.05 respectively). The expression of VEGF and Ang-1 and the phosphorylation of Flk1 and Tie-1 were significantly decreased in DCM group as compared with those in the control group. However, those in the NRG-1 treatment group were significantly increased as compared with those in the DCM group. In vitro, NRG-1 treatment increased significantly the expression of VEGF and Ang-1 in human coronary artery smooth muscle cells. Conclusions: NRG-1 can increase the myocardial angiogenesis of DCM, probably via the direct effects of NRG-1 and via the increasing expression of VEGF and Ang-1. These findings may contribute to developing a novel approach to reverse the impaired angiogenic responses in diabetes or coronary artery disease.

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Diabetes Mellitus–Induced Microvascular Destabilization in the Myocardium

Abstract: Diabetes mellitus destabilized microvascular vessels of the heart, affecting the amplitude of therapeutic neovascularization via rAAV.Tβ4 in a translational large animal model of hibernating myocardium.

Cited by 136 publications

References 34 publications

Microvascular complications in diabetes patients with heart failure and reduced ejection fraction—insights from the Beta‐blocker Evaluation of Survival Trial

Microvascular complications in diabetes patients with heart failure and reduced ejection fraction—insights from the Beta‐blocker Evaluation of Survival Trial

The Munich MIDY Pig Biobank – A unique resource for studying organ crosstalk in diabetes

Neuregulin-1 Promotes Myocardial Angiogenesis in the Rat Model of Diabetic Cardiomyopathy

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