Rationale Multiple biological mechanisms contribute to the efficacy of cardiac cell therapy. Most prominent among these are direct heart muscle and blood vessel regeneration from transplanted cells, as opposed to paracrine enhancement of tissue preservation and/or recruitment of endogenous repair. Objective Human cardiac progenitor cells, cultured as cardiospheres (CSps) or as CSp-derived cells (CDCs), have been shown to be capable of direct cardiac regeneration in vivo. Here we characterized paracrine effects in CDC transplantation and investigated their relative importance versus direct differentiation of surviving transplanted cells. Methods and Results In vitro, many growth factors were found in media conditioned by human adult CSps and CDCs; CDC-conditioned media exerted antiapoptotic effects on neonatal rat ventricular myocytes, and proangiogenic effects on human umbilical vein endothelial cells. In vivo, human CDCs secreted vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor 1 when transplanted into the same SCID mouse model of acute myocardial infarction where they were previously shown to improve function and to produce tissue regeneration. Injection of CDCs in the peri-infarct zone increased the expression of Akt, decreased apoptotic rate and caspase 3 level, and increased capillary density, indicating overall higher tissue resilience. Based on the number of human-specific cells relative to overall increases in capillary density and myocardial viability, direct differentiation quantitatively accounted for 20% to 50% of the observed effects. Conclusions Together with their spontaneous commitment to cardiac and angiogenic differentiation, transplanted CDCs serve as “role models,” recruiting endogenous regeneration and improving tissue resistance to ischemic stress. The contribution of the role model effect rivals or exceeds that of direct regeneration.

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Pathological molecular mechanisms involved in myocardial remodeling contribute to alter the existing structure of the heart, leading to cardiac dysfunction. Among the complex signaling network that characterizes myocardial remodeling, the distinct processes are myocyte loss, cardiac hypertrophy, alteration of extracellular matrix homeostasis, fibrosis, defective autophagy, metabolic abnormalities, and mitochondrial dysfunction. Several pathophysiological stimuli, such as pressure and volume overload, trigger the remodeling cascade, a process that initially confers protection to the heart as a compensatory mechanism. Yet chronic inflammation after myocardial infarction also leads to cardiac remodeling that, when prolonged, leads to heart failure progression. Here, we review the molecular pathways involved in cardiac remodeling, with particular emphasis on those associated with myocardial infarction. A better understanding of cell signaling involved in cardiac remodeling may support the development of new therapeutic strategies towards the treatment of heart failure and reduction of cardiac complications. We will also discuss data derived from gene therapy approaches for modulating key mediators of cardiac remodeling.

Heart failure is a highly morbid and mortal clinical condition that represents the last stage of most cardiovascular disorders. Diabetes is strongly associated with an increased incidence of heart failure and directly promotes cardiac hypertrophy, fibrosis, and apoptosis. These changes, in turn, contribute to the development of ventricular dysfunction. The clinical condition associated with the spectrum of cardiac abnormalities induced by diabetes is termed diabetic cardiomyopathy. Myocardial inflammation has recently emerged as a pathophysiological process contributing to cardiac hypertrophy, fibrosis, and dysfunction in cardiac diseases. Myocardial inflammation is also implicated in the development of diabetic cardiomyopathy. Several molecular mechanisms link diabetes to myocardial inflammation. The NF-κB signalling pathway and the renin-angiotensin-aldosterone system are strongly activated in the diabetic heart, thereby promoting myocardial inflammation. Advanced glycation end-products and damage-associated molecular pattern molecules also represent strong triggers for inflammation. The mediators resulting from this inflammatory process modulate specific intracellular signalling mechanisms in cardiac cells that promote the development of diabetic cardiomyopathy. This review article will provide an overview of the signalling molecular mechanisms linking diabetic cardiomyopathy to myocardial inflammation.

Background Little clinical research on new‐generation heat‐not‐burn cigarettes ( HNBC ) in comparison with electronic vaping cigarettes ( EVC ) and traditional tobacco combustion cigarettes ( TC ) has been reported. We aimed to appraise the acute effects of single use of HNBC , EVC, and TC in healthy smokers. Methods and Results This was an independent, cross‐over, randomized trial in 20 TC smokers, with allocation to different cycles of HNBC , EVC , and TC . All participants used all types of products, with an intercycle washout of 1 week. End points were oxidative stress, antioxidant reserve, platelet activation, flow‐mediated dilation, blood pressure, and satisfaction scores. Single use of any product led to an adverse impact on oxidative stress, antioxidant reserve, platelet function, flow‐mediated dilation, and blood pressure. HNBC had less impact than EVC and TC on soluble Nox2‐derived peptide (respectively, P =0.004 and 0.001), 8‐iso‐prostaglandin F2α‐ III ( P =0.004 and <0.001), and vitamin E ( P =0.018 and 0.044). HNBC and EVC were equally less impactful than TCs on flow‐mediated dilation ( P =0.872 for HNBC versus EVC ), H 2 O 2 ( P =0.522), H 2 O 2 breakdown activity ( P =0.091), soluble CD 40 ligand ( P =0.849), and soluble P‐selectin ( P =0.821). The effect of HNBC and, to a lesser extent EVC , on blood pressure was less evident than that of TC , whereas HNBC appeared more satisfying than EVC (all P <0.05). Conclusions Acute effects of HNBC , EVC, and TC are different on several oxidative stress, antioxidant reserve, platelet function, cardiovascular, and satisfaction dimensions, with TCs showing the most detrimental changes in clinically relevant features. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: ...