Effects of tamoxifen inducible MerCreMer on gene expression in cardiac myocytes in mice

The Cre-LoxP technology, including the tamoxifen (TAM) inducible MerCreMer (MCM), is increasingly used to delineate gene function, understand the disease mechanisms, and test therapeutic interventions. We set to determine the effects of TAM-MCM on cardiac myocyte transcriptome. Expression of the MCM was induced specifically in cardiac myocytes upon injection of TAM to myosin heavy chain 6-MCM (Myh6-Mcm) mice for 5 consecutive days. Cardiac function, myocardial histology, and gene expression (RNA-sequencing) were analyzed 2 weeks after TAM injection. A total of 346 protein coding genes (168 up- and 178 down-regulated) were differentially expressed. Transcript levels of 85 genes, analyzed by a reverse transcription-polymerase chain reaction in independent samples, correlated with changes in the RNA-sequencing data. The differentially expressed genes were modestly enriched for genes involved in the interferon response and the tumor protein 53 (TP53) pathways. The changes in gene expression were relatively small and mostly transient and had no discernible effects on cardiac function, myocardial fibrosis, and apoptosis or induction of double-stranded DNA breaks. Thus, TAM-inducible activation of MCM alters cardiac myocytes gene expression, provoking modest and transient interferon and DNA damage responses without exerting other discernible phenotypic effects. Thus, the effects of TAM-MCM on gene expression should be considered in discerning the bona fide changes that result from the targeting of the gene of interest.

Cardiac myocyte intrinsic contractility and calcium handling deficits underlie heart organ dysfunction in murine cancer cachexia

Cachexia is a muscle wasting syndrome occurring in many advanced cancer patients. Cachexia significantly increases cancer morbidity and mortality. Cardiac atrophy and contractility deficits have been observed in patients and in animal models with cancer cachexia, which may contribute to cachexia pathophysiology. However, underlying contributors to decreased in vivo cardiac contractility are not well understood. In this study, we sought to distinguish heart-intrinsic changes from systemic factors contributing to cachexia-associated cardiac dysfunction. We hypothesized that isolated heart and cardiac myocyte functional deficits underlie in vivo contractile dysfunction. To test this hypothesis, isolated heart and cardiac myocyte function was measured in the colon-26 adenocarcinoma murine model of cachexia. Ex vivo perfused hearts from cachectic animals exhibited marked contraction and relaxation deficits during basal and pacing conditions. Isolated myocytes displayed significantly decreased peak contraction and relaxation rates, which was accompanied by decreased peak calcium and decay rates. This study uncovers significant organ and cellular-level functional deficits in cachectic hearts outside of the catabolic in vivo environment, which is explained in part by impaired calcium cycling. These data provide insight into physiological mechanisms of cardiomyopathy in cachexia, which is critical for the ultimate development of effective treatments for patients.

Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review

Arrhythmogenic cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance. ACM also has wide phenotype variability, ranging from premature ventricular contractions to sudden cardiac death and heart failure. Among other drivers and modulators of phenotype, inflammation in response to viral infection and immune triggers have been postulated to be an aggravator of cardiac myocyte damage and necrosis. This theory is supported by multiple pieces of evidence, including the presence of inflammatory infiltrates in more than two-thirds of ACM hearts, detection of different cardiotropic viruses in sporadic cases of ACM, the fact that patients with ACM often fulfill the histological criteria of active myocarditis, and the abundance of anti–desmoglein-2, antiheart, and anti-intercalated disk autoantibodies in patients with arrhythmogenic right ventricular cardiomyopathy. In keeping with the frequent familial occurrence of ACM, it has been proposed that, in addition to genetic predisposition to progressive myocardial damage, a heritable susceptibility to viral infections and immune reactions may explain familial clustering of ACM. Moreover, considerable in vitro and in vivo evidence implicates activated inflammatory signaling in ACM. Although the role of inflammation/immune response in ACM is not entirely clear, inflammation as a driver of phenotype and a potential target for mechanism-based therapy warrants further research. This review discusses the present evidence supporting the role of inflammatory and immune responses in ACM pathogenesis and proposes opportunities for translational and clinical investigation.

Regenerating Damaged Myocardium: A Review of Stem-Cell Therapies for Heart Failure

Cardiovascular disease (CVD) is one of the contributing factors to more than one-third of human mortality and the leading cause of death worldwide. The death of cardiac myocyte is a fundamental pathological process in cardiac pathologies caused by various heart diseases, including myocardial infarction. Thus, strategies for replacing fibrotic tissue in the infarcted region with functional myocardium have long been a goal of cardiovascular research. This review begins by briefly discussing a variety of somatic stem- and progenitor-cell populations that were frequently studied in early investigations of regenerative myocardial therapy and then focuses primarily on pluripotent stem cells (PSCs), especially induced-pluripotent stem cells (iPSCs), which have emerged as perhaps the most promising source of cardiomyocytes for both therapeutic applications and drug testing. We also describe attempts to generate cardiomyocytes directly from cardiac fibroblasts (i.e., transdifferentiation), which, if successful, may enable the pool of endogenous cardiac fibroblasts to be used as an in-situ source of cardiomyocytes for myocardial repair.

Analysis of Corticosteroids in Immune Checkpoint Inhibitor(ICE)Induced Myocarditis-A Systematic Review of 352 Screened Articles

Introduction:Immune Checkpoint Inhibitors(ICI)is used as a single agent or as a combination therapies for early or late-stage malignancies.The common malignancies that ICI targets include the following:melanoma, lung cancer, renal cell carcinoma, and hematological malignancies such as Hodgkin lymphoma.ICI use is associated with many immune-related adverse events, and ICI-induced myocarditis is one of the rare and most severe AE with a high mortality rate. There is no consensus evidence-based treatment guideline; the expert recommendation is to use high-dose steroids. We aim in this review to assess the effectiveness of steroids in treating ICI-induced myocarditis. Methods: We searched the following database Pubmed, Scopus, Cinhale, and Google Scholar, using the following keywords: ICI-induced myocarditis, treatment, steroid. We included articles in the English language, case reports, case series, and published in the last five years. Results: 352 articles were screened using PRISMA guidelines. After excluding the articles that were duplicate, irrelevant, and did not meet inclusion criteria, 35 articles with a total number of 50 patients were included. All patients treated with ICI either as a single or combination regimen. The onset of symptoms post-initiation varied from one day to a year. 46 out of the 50 cases received high doses of Intravenous steroids as a loading dose followed by an oral or intravenous maintenance dose. Out of 50 patients 14 patients (28 %) died but 34 (68 %) patients survived, and 2 (4 %) patients data were not available. The mean age of the patients was 66.31+/-14.071 (range 23-88 years), 29 were male (58%), 21 were female (42%). Most of the cases were from the USA (42%), followed by Australia (20 %), Japan (14%), Germany, France, and China (4%), Switzerland, Canada, and Spain (2%), and for (6%) cases. A total of 23 patients had cardiovascular comorbidities (46%), which were HTN (14 patients, 60.87%), hyperlipidemia (5 patients, 21.73%), and less than 1 % of patients had myocardial ischemia, congestive heart failure, atrial fibrillation, and peripheral vascular disease. While 26 patients (52%) had normal basal cardiac status. Conclusion: Our results showed that high doses of steroids were effective in controlling cardiac myocyte inflammation and mortality by 28%. The race was not included in the analysis as it was not reported. More in depth studies are needed to provide a broader representation of steroids in myocarditis.