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Activin A is associated with impaired myocardial glucose metabolism and left ventricular remodeling in patients with uncomplicated type 2 diabetes.

ABSTRACT: BACKGROUND: Activin A released from epicardial adipose tissue has been linked to contractile dysfunction and insulin resistance in cardiomyocytes. This study investigated the role of activin A in clinical diabetic cardiomyopathy by assessing whether circulating activin A levels associate with cardiometabolic parameters in men with uncomplicated type 2 diabetes (T2D), and the effects of treatment with pioglitazone versus metformin on these associations. METHODS: Seventy-eight men with uncomplicated T2D and fourteen healthy men with comparable age were included, in this randomized, double-blind, active comparator intervention study. All T2D men were on glimipiride monotherapy, and randomized to a 24-week intervention with either pioglitazone or metformin. Cardiac dimensions and -function were measured using magnetic resonance imaging, whilst myocardial glucose metabolism (MMRglu) was determined using [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography during a hyperinsulinemic-euglycemic clamp. RESULTS: Circulating activin A levels were comparable in T2D men and controls. Activin A levels were independently inversely associated with MMRglu, and positively with left ventricular mass/volume (LVMV)-ratio in T2D men. Intervention with metformin decreased activin A levels, whereas pioglitazone did not alter activin A levels. The changes in plasma activin A levels were not correlated with the changes in MMRglu following either pioglitazone or metformin treatment. A borderline significant correlation (p?=?0.051) of changes in plasma activin A levels and changes in LVMV-ratio was observed after pioglitazone treatment. CONCLUSIONS: Circulating activin A levels are associated with impaired myocardial glucose metabolism and high LVMV-ratio in patients with uncomplicated T2D, reflecting a potential detrimental role in early human diabetic cardiomyopathy. TRIAL REGISTRATION NUMBER: Current Controlled Trials SRCTN53177482.

SUBMITTER: Chen WJ

PROVIDER: S-EPMC4015886 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Activin A is associated with impaired myocardial glucose metabolism and left ventricular remodeling in patients with uncomplicated type 2 diabetes.

Chen Weena J Y WJ Greulich Sabrina S van der Meer Rutger W RW Rijzewijk Luuk J LJ Lamb Hildo J HJ de Roos Albert A Smit Johannes W A JW Romijn Johannes A JA Ruige Johannes B JB Lammertsma Adriaan A AA Lubberink Mark M Diamant Michaela M Ouwens D Margriet DM

Cardiovascular diabetology 20131017

<h4>Background</h4>Activin A released from epicardial adipose tissue has been linked to contractile dysfunction and insulin resistance in cardiomyocytes. This study investigated the role of activin A in clinical diabetic cardiomyopathy by assessing whether circulating activin A levels associate with cardiometabolic parameters in men with uncomplicated type 2 diabetes (T2D), and the effects of treatment with pioglitazone versus metformin on these associations.<h4>Methods</h4>Seventy-eight men wit ...[more]

PMID: 24134550

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Project description:BACKGROUND:Early detection of subclinical myocardial dysfunction in patients with diabetes mellitus (DM) is essential for recommending therapeutic interventions that can prevent or reverse heart failure, thereby improving the prognosis in such patients. This study aims to quantitatively evaluate left ventricular (LV) myocardial deformation and perfusion using cardiovascular magnetic resonance (CMR) imaging in patients with type 2 diabetes mellitus (T2DM), and to investigate the association between LV subclinical myocardial dysfunction and coronary microvascular perfusion. METHODS:We recruited 71 T2DM patients and 30 healthy individuals as controls who underwent CMR examination. The T2DM patients were subdivided into two groups, namely the newly diagnosed DM group (n?=?31, patients with diabetes for???5 years) and longer-term DM group (n?=?40, patients with diabetes?>?5 years). LV deformation parameters, including global peak strain (PS), peak systolic strain rate, and peak diastolic strain rate (PSDR), and myocardial perfusion parameters such as upslope, time to maximum signal intensity (TTM), and max signal intensity (Max SI, were measured and compared among the three groups. Pearson's correlation was used to evaluate the correlation between LV deformation and perfusion parameters. RESULTS:Pooled data from T2DM patients showed a decrease in global longitudinal, circumferential, and radial PDSR compared to healthy individuals, apart from lower upslope. In addition, increased TTM and reduced Max SI were found in the longer-term diabetics compared to the normal subjects (p?<?0.017 for all). Multivariable linear regression analysis showed that T2DM was independently associated with statistically significant CMR parameters, except for TTM (??=?0.137, p?=?0.195). Further, longitudinal PDSR was significantly associated with upslope (r?=?-?0.346, p?=?0.003) and TTM (r?=?0.515, p?<?0.001). CONCLUSIONS:Our results imply that a contrast-enhanced 3.0T CMR can detect subclinical myocardial dysfunction and impaired myocardial microvascular perfusion in the early stages of T2DM, and that the myocardial dysfunction is associated with impaired coronary microvascular perfusion.

Project description:PurposeNitric oxide (NO) is constitutively produced and released from the endothelium and several blood cell types by the isoform 3 of the NO synthase (NOS3). We have shown that NO protects against myocardial ischemia/reperfusion (I/R) injury and that depletion of circulating NOS3 increases within 24 h of ischemia/reperfusion the size of myocardial infarction (MI) in chimeric mice devoid of circulating NOS3. In the current study we hypothesized that circulating NOS3 also affects remodeling of the left ventricle following reperfused MI.MethodsTo analyze the role of circulating NOS3 we transplanted bone marrow of NOS3-/- and wild type (WT) mice into WT mice, producing chimerae expressing NOS3 only in vascular endothelium (BC-/EC+) or in both, blood cells and vascular endothelium (BC+/EC+). Both groups underwent 60 min of coronary occlusion in a closed-chest model of reperfused MI. During the 3 weeks post MI, structural and functional LV remodeling was serially assessed (24 h, 4 d, 1 w, 2 w and 3 w) by echocardiography. At 72 hours post MI, gene expression of several extracellular matrix (ECM) modifying molecules was determined by quantitative RT-PCR analysis. At 3 weeks post MI, hemodynamics were obtained by pressure catheter, scar size and collagen content were quantified post mortem by Gomori's One-step trichrome staining.ResultsThree weeks post MI, LV end-systolic (53.2±5.9 μl; ***p≤0.001; n = 5) and end-diastolic volumes (82.7±5.6 μl; *p<0.05; n = 5) were significantly increased in BC-/EC+, along with decreased LV developed pressure (67.5±1.8 mm Hg; n = 18; ***p≤0.001) and increased scar size/left ventricle (19.5±1.5%; n = 13; **p≤0.01) compared to BC+/EC+ (ESV: 35.6±2.2 μl; EDV: 69.1±2.6 μl n = 8; LVDP: 83.2±3.2 mm Hg; n = 24; scar size/LV13.8±0.7%; n = 16). Myocardial scar of BC-/EC+ was characterized by increased total collagen content (20.2±0.8%; n = 13; ***p≤0.001) compared to BC+/EC+ (15.9±0.5; n = 16), and increased collagen type I and III subtypes.ConclusionCirculating NOS3 ameliorates maladaptive left ventricular remodeling following reperfused myocardial infarction.

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Activin A is associated with impaired myocardial glucose metabolism and left ventricular remodeling in patients with uncomplicated type 2 diabetes.

Publications

Activin A is associated with impaired myocardial glucose metabolism and left ventricular remodeling in patients with uncomplicated type 2 diabetes.

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