The epicardium makes essential cellular and paracrine contributions to the growth of the fetal myocardium and the formation of the coronary vasculature. However, whether the epicardium has similar roles postnatally in the normal and injured heart remains enigmatic. Here, we have investigated this question using genetic fate-mapping approaches in mice. In uninjured postnatal heart, epicardial cells were quiescent. Myocardial infarction increased epicardial cell proliferation and stimulated formation of epicardium-derived cells (EPDCs), which remained in a thickened layer on the surface of the heart. EPDCs did not adopt cardiomyocyte or coronary EC fates, but rather differentiated into mesenchymal cells expressing fibroblast and smooth muscle cell markers. In vitro and in vivo assays demonstrated that EPDCs secreted paracrine factors that strongly promoted angiogenesis. In a myocardial infarction model, EPDC-conditioned medium reduced infarct size and improved heart function. Our findings indicate that epicardium modulates the cardiac injury response by conditioning the subepicardial environment, potentially offering a new therapeutic strategy for cardiac protection.
Background No studies have yet assessed the ability of statin treatment to reduce arterial inflammation and achieve regression of coronary atherosclerosis in HIV-infected patients, a population with elevated risk of myocardial infarction. Methods In a randomized, double-blind, placebo-controlled trial, 40 HIV-infected participants with subclinical coronary atherosclerosis, evidence of arterial inflammation in the aorta by fluorodeoxyglucose positron emission tomography (FDG-PET) and low density lipoprotein(LDL)-cholesterol <3·37mmol/L(130mg/dL) were randomized to one year of treatment with atorvastatin (n=19) or placebo (n=21). Randomization was carried out by the MGH Clinical Research Pharmacy using a permuted-block algorithm, stratified by gender with a fixed block size of four, with 1:1 allocation to atorvastatin or identical matching placebo. Study codes were available only to the MGH Research Pharmacy and not to study investigators or participants. The prespecified primary endpoint was arterial inflammation, as assessed by FDG-PET of the aorta. Additional prespecified endpoints included coronary atherosclerotic plaque as assessed by coronary computed tomography angiography. We quantitatively assessed non-calcified and calcified plaque and high risk plaque features. Analysis was performed using intention-to-treat principle, using all available data, without imputation for missing data. Findings Thirty seven out of forty (92·5%) subjects completed the study, with equivalent discontinuation rates in both groups. Baseline parameters were similar between groups. After 12 months, change in FDG-PET uptake of the most diseased segment of the aorta was not different between atorvastatin and placebo, but technically adequate results comparing longitudinal changes in identical regions could only be assessed in a subset of patients (atorvastatin Δ −0·03 [95% CI: −0·17, 0·12] vs. placebo Δ −0·06 [−0·25, 0·13], p=0·77, n=21). Change in plaque could be assessed in all subjects completing the study. Atorvastatin reduced noncalcified coronary plaque volume compared to placebo (−19·4%(IQR: −39·2%, 9·3%) vs. +20·4%(−7·1%, 94·4%), p=0·009, n=37). In addition, the number of high risk plaques was significantly reduced by atorvastatin compared to placebo (change in number of low attenuation plaques −0·2[95% CI: −0·6, 0·2] vs. 0·4[0·0, 0·7], p=0·03, n=37 and change in number of positively remodeled plaques −0·2[95% CI −0·4, 0·1] vs. 0·4[−0·1, 0·8], p=0·04, n=37). Direct LDL-cholesterol (−1·00[95% CI −1·38, 0·61] vs. 0·30[0·04, 0·55] mmol/L, p<0·0001) and lipoprotein-associated phospholipase A2 (−52·2[95% CI −70·4, −34·0] vs. −13·3[−32·8, 6·2] ng/mL, p=0·005, n=37) significantly decreased with atorvastatin compared to placebo. Statin therapy was well-tolerated, with low incidence of clinical adverse events. Interpretation Compared to placebo, statin therapy reduces noncalcified plaque volume and high risk plaque features in HIV-infected patients with subclinical coronary atherosclerosis. Significant effects of statin therapy...
Myocardial infarction (MI) is one of the leading causes of morbidity and mortality world-wide. Whether endogenous repair and regenerative ability could be augmented by drug administration is an important issue for generation of novel therapeutic approach. Recently it was reported that in mice pretreated with thymosin beta 4 (TB4) and subsequently subjected to experimental MI, a subset of epicardial cells differentiated into cardiomyocytes. In clinical settings, epicardial priming with TB4 prior to MI is impractical. Here we tested if TB4 treatment after MI could reprogram epicardium into cardiomyocytes and augment the epicardium’s injury response. Using epicardium genetic lineage trace line Wt1CreERT2/+ and double reporter line Rosa26mTmG/+, we found post-MI TB4 treatment significantly increased the thickness of epicardium and coronary capillary density. However, epicardium-derived cells did not adopt cardiomyocyte fate, nor did they migrate into myocardium to become coronary endothelial cells. Our result thus indicates that TB4 treatment after MI does not alter epicardial cell fate to include the cardiomyocyte lineage, providing both cautions and insights for the full exploration of the potential benefits of TB4 in the clinical settings. This article is part of a Special Issue entitled ‘Possible Editorial’.
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