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Endoglin (CD105) is a type III auxiliary receptor for the transforming growth factor beta (TGFβ) superfamily. Several lines of evidence suggest that endoglin plays a critical role in maintaining cardiovascular homeostasis. Seemingly disparate disease conditions, including hereditary hemorrhagic telangiectasia, pre-eclampsia, and cardiac fibrosis, have now been associated with endoglin. Given the central role of the TGFβ superfamily in multiple disease conditions, this review provides a detailed update on endoglin as an evolving therapeutic target in the management of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Increased utrophin expression is known to reduce pathology in dystrophin-deficient skeletal muscles. Transgenic overexpression of PGC-1α has been shown to increase levels of utrophin mRNA and improve the histology of mdx muscles. Other reports have shown that PGC-1α signaling can lead to increased oxidative capacity and a fast to slow fiber type shift. Given that it has been shown that slow fibers produce and maintain more utrophin than fast skeletal muscle fibers, we hypothesized that over-expression of PGC-1α in post-natal mdx mice would increase utrophin levels via a fiber type shift, resulting in more slow, oxidative fibers that are also more resistant to contraction-induced damage. To test this hypothesis, neonatal mdx mice were injected with recombinant adeno-associated virus (AAV) driving expression of PGC-1α. PGC-1α over-expression resulted in increased utrophin and type I myosin heavy chain expression as well as elevated mitochondrial protein expression. Muscles were shown to be more resistant to contraction-induced damage and more fatigue resistant. Sirt-1 was increased while p38 activation and NRF-1 were reduced in PGC-1α over-expressing muscle when compared to control. We also evaluated if the use a pharmacological PGC-1α pathway activator, resveratrol, could drive the same physiological changes. Resveratrol administration (100 mg/kg/day) resulted in improved fatigue resistance, but did not achieve significant increases in utrophin expression. These data suggest that the PGC-1α pathway is a potential target for therapeutic intervention in dystrophic skeletal muscle. [ABSTRACT FROM AUTHOR]

Background: Cardiogenic shock (CS) is associated with high mortality despite advances in early revascularization and acute mechanical circulatory support (AMCS) devices. Optimal risk stratification and management strategies for CS are not known. Methods: We retrospectively analyzed 946 consecutive patients with CS defined as clinical signs of hypoperfusion and a systolic BP<90 mmHg across 4 medical centers between 2012-2017. Results: Among 946 patients, CS was managed with medical therapy alone (19%), IABP alone (32%) or AMCS (49%). AMCS device configurations included Impella (41%), VA-ECMO (35%), VA-ECMO plus Impella (18%), and other (6%). Pulmonary artery catheter data was available in 545 patients. Biventricular congestion, defined as RAP≥14 mmHg and PCWP≥18 mmHg, was the most common hemodynamic presentation. Compared to either non-congested (RAP<14 and PCWP<18 mmHg) or LV-dominant congestion (PCWP>18), RV-dominant (RAP>14 and PCWP<18) and biventricular congestion were associated with higher mortality (13% and 18%, 42% and 44% respectively, p<0.01). Renal insufficiency (sCr≥1.48 mg/dl) or mixed hepatopathy (elevated AST>42 IU/L, ALT>54 IU/L, total bilirubin>1.1 mg/dl or direct bilirubin>0.3 mg/dl) was associated with higher mortality compared to sCr<1.41 mg/dl (55% vs. 38%, p<0.01) and normal liver profile (33% vs. 18%, p<0.01). Irrespective of CS management strategy, venous congestion was associated with increased mortality and renal insufficiency (Figure A-B). Among patients with CS requiring AMCS, venous congestion correlated with increased risk of mortality (54% vs. 30%), renal insufficiency (60% vs. 43%), and hepatopathy (87% vs. 77%). Irrespective of AMCS strategy, concomitant venous congestion and renal insufficiency was associated with higher mortality. In the presence of venous congestion alone, mortality for Impella was lower compared to VA-ECMO (Figure C). Conclusions: We report findings from the largest registry of CS comparing AMCS strategies. Elevated right atrial pressure is a major determinant of morbidity and mortality in CS. The combination of venous congestion and renal insufficiency is associated with the highest mortality irrespective of AMCS strategy. [ABSTRACT FROM AUTHOR]

Apelin interacts with the APJ receptor to enhance inotropy. In heart failure, apelin-APJ coupling may provide a means of enhancing myocardial function. The alterations in apelin and APJ receptor concentrations with ischemic cardiomyopathy are poorly understood. We investigated the compensatory changes in endogenous apelin and APJ levels in the setting of ischemic cardiomyopathy.Male, Lewis rats underwent LAD ligation and progressed into heart failure over 6 weeks. Corresponding animals underwent sham thoracotomy as control. Six weeks after initial surgery, the animals underwent hemodynamic functional analysis in the presence of exogenous apelin-13 infusion and the hearts were explanted for western blot and enzyme immunoassay analysis. Western blot analysis of myocardial APJ concentration demonstrated increased APJ receptor protein levels with heart failure (1890750+/-133500 vs. 901600+/-143120 intensity units, n=8, p=0.00001). Total apelin protein levels increased with ischemic heart failure as demonstrated by enzyme immunoassay (12.0+/-4.6 vs. 1.0+/-1.2 ng/ml, n=5, p=0.006) and western blot (1579400+/-477733 vs. 943000+/-157600 intensity units, n=10, p=0.008). Infusion of apelin-13 significantly enhanced myocardial function in sham and failing hearts. We conclude that total myocardial apelin and APJ receptor levels increase in compensation for ischemic cardiomyopathy.

Cellular therapy for myocardial injury has improved ventricular function in both animal and clinical studies, though the mechanism of benefit is unclear. This study was undertaken to examine the effects of cellular injection after infarction on myocardial elasticity. Coronary artery ligation of Lewis rats was followed by direct injection of human mesenchymal stem cells (MSCs) into the acutely ischemic myocardium. Two weeks postinfarct, myocardial elasticity was mapped by atomic force microscopy. MSC-injected hearts near the infarct region were twofold stiffer than myocardium from noninfarcted animals but softer than myocardium from vehicle-treated infarcted animals. After 8 wk, the following variables were evaluated: MSC engraftment and left ventricular geometry by histological methods, cardiac function with a pressure-volume conductance catheter, myocardial fibrosis by Masson Trichrome staining, vascularity by immunohistochemistry, and apoptosis by TdT-mediated dUTP nick-end labeling assay. The human cells engrafted and expressed a cardiomyocyte protein but stopped short of full differentiation and did not stimulate significant angiogenesis. MSC-injected hearts showed significantly less fibrosis than controls, as well as less left ventricular dilation, reduced apoptosis, increased myocardial thickness, and preservation of systolic and diastolic cardiac function. In summary, MSC injection after myocardial infarction did not regenerate contracting cardiomyocytes but reduced the stiffness of the subsequent scar and attenuated postinfarction remodeling, preserving some cardiac function. Improving scarred heart muscle compliance could be a functional benefit of cellular cardiomyoplasty.