108 research outputs found
Transdifferentiation of blood-derived human adult endothelial progenitor cells into functionally active cardiomyocytes
Background - Further to promoting angiogenesis, cell therapy may be an approach for cardiac regeneration. Recent studies suggest that progenitor cells can transdifferentiate into other lineages. However, the transdifferentiation potential of endothelial progenitor cells (EPCs) is unknown
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Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling
Background— Transplantation of endothelial progenitor cells (EPCs) improves vascularization and left ventricular function after experimental myocardial ischemia. However, tissue distribution of transplanted EPCs has not yet been monitored in living animals. Therefore, we tested whether radioactive labeling allows us to detect injected EPCs
Genetic predisposition for sudden cardiac death in myocardial ischaemia: the Arrhythmia Genetics in the NEtherlandS study
Sudden cardiac death from ventricular fibrillation during myocardial infarction is a leading cause of total and cardiovascular mortality. This multifactorial, complex condition clusters in families, suggesting a substantial genetic cause. We carried out a genomewide association study (GWAS) for sudden cardiac death, in the AGNES (Arrhythmia Genetics in the Netherlands) population, consisting of patients with (cases) and without (controls) ventricular fibrillation during a first ST-elevation myocardial infarction. The most significant association was found at chromosome 21q21 (rs2824292; odds ratio = 1.78, 95% CI 1.47–2.13, P = 3.3 × 10−10), 98 kb proximal of the CXADR gene, encoding the Coxsackie and adenovirus receptor. This locus has not previously been implicated in arrhythmia susceptibility. Further research on the mechanism of this locus will ultimately provide novel insight into arrhythmia mechanisms in this condition
Mesenchymal stromal cells inhibit NLRP3 inflammasome activation in a model of Coxsackievirus B3-induced inflammatory cardiomyopathy
Inflammation in myocarditis induces cardiac injury and triggers disease
progression to heart failure. NLRP3 inflammasome activation is a newly
identified amplifying step in the pathogenesis of myocarditis. We previously
have demonstrated that mesenchymal stromal cells (MSC) are cardioprotective in
Coxsackievirus B3 (CVB3)-induced myocarditis. In this study, MSC markedly
inhibited left ventricular (LV) NOD2, NLRP3, ASC, caspase-1, IL-1β, and IL-18
mRNA expression in CVB3-infected mice. ASC protein expression, essential for
NLRP3 inflammasome assembly, increased upon CVB3 infection and was abrogated
in MSC-treated mice. Concomitantly, CVB3 infection in vitro induced NOD2
expression, NLRP3 inflammasome activation and IL-1β secretion in HL-1 cells,
which was abolished after MSC supplementation. The inhibitory effect of MSC on
NLRP3 inflammasome activity in HL-1 cells was partly mediated via secretion of
the anti-oxidative protein stanniocalcin-1. Furthermore, MSC application in
CVB3-infected mice reduced the percentage of NOD2-, ASC-, p10- and/or IL-1β-
positive splenic macrophages, natural killer cells, and dendritic cells. The
suppressive effect of MSC on inflammasome activation was associated with
normalized expression of prominent regulators of myocardial contractility and
fibrosis to levels comparable to control mice. In conclusion, MSC treatment in
myocarditis could be a promising strategy limiting the adverse consequences of
cardiac and systemic NLRP3 inflammasome activation
Functional Substitution by TAT-Utrophin in Dystrophin-Deficient Mice
James Ervasti and colleagues show that injection of a truncated form of utrophin transduced all tissues examined, integrated with members of the dystrophin complex, and reduced serum levels of creatine kinase in a mouse model of muscular dystrophy
The Heart Is an Early Target of Anthrax Lethal Toxin in Mice: A Protective Role for Neuronal Nitric Oxide Synthase (nNOS)
Anthrax lethal toxin (LT) induces vascular insufficiency in experimental animals through unknown mechanisms. In this study, we show that neuronal nitric oxide synthase (nNOS) deficiency in mice causes strikingly increased sensitivity to LT, while deficiencies in the two other NOS enzymes (iNOS and eNOS) have no effect on LT-mediated mortality. The increased sensitivity of nNOS−/− mice was independent of macrophage sensitivity to toxin, or cytokine responses, and could be replicated in nNOS-sufficient wild-type (WT) mice through pharmacological inhibition of the enzyme with 7-nitroindazole. Histopathological analyses showed that LT induced architectural changes in heart morphology of nNOS−/− mice, with rapid appearance of novel inter-fiber spaces but no associated apoptosis of cardiomyocytes. LT-treated WT mice had no histopathology observed at the light microscopy level. Electron microscopic analyses of LT-treated mice, however, revealed striking pathological changes in the hearts of both nNOS−/− and WT mice, varying only in severity and timing. Endothelial/capillary necrosis and degeneration, inter-myocyte edema, myofilament and mitochondrial degeneration, and altered sarcoplasmic reticulum cisternae were observed in both LT-treated WT and nNOS−/− mice. Furthermore, multiple biomarkers of cardiac injury (myoglobin, cardiac troponin-I, and heart fatty acid binding protein) were elevated in LT-treated mice very rapidly (by 6 h after LT injection) and reached concentrations rarely reported in mice. Cardiac protective nitrite therapy and allopurinol therapy did not have beneficial effects in LT-treated mice. Surprisingly, the potent nitric oxide scavenger, carboxy-PTIO, showed some protective effect against LT. Echocardiography on LT-treated mice indicated an average reduction in ejection fraction following LT treatment in both nNOS−/− and WT mice, indicative of decreased contractile function in the heart. We report the heart as an early target of LT in mice and discuss a protective role for nNOS against LT-mediated cardiac damage
Cardiac Tissue Engineering: Implications for Pediatric Heart Surgery
Children with severe congenital malformations, such as single-ventricle anomalies, have a daunting prognosis. Heart transplantation would be a therapeutic option but is restricted due to a lack of suitable donor organs and, even in case of successful heart transplantation, lifelong immune suppression would frequently be associated with a number of serious side effects. As an alternative to heart transplantation and classical cardiac reconstructive surgery, tissue-engineered myocardium might become available to augment hypomorphic hearts and/or provide new muscle material for complex myocardial reconstruction. These potential applications of tissue engineered myocardium will, however, impose major challenges to cardiac tissue engineers as well as heart surgeons. This review will provide an overview of available cardiac tissue-engineering technologies, discuss limitations, and speculate on a potential application of tissue-engineered heart muscle in pediatric heart surgery
Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited
The chemotherapeutic agent doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10% of pediatric cancer survivors will 10–20 years later develop severe dilated cardiomyopathy (DCM), whereby the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation. Based on recent literature evidence, we first argue why a dilated phenotype can occur when little apoptosis is detected. We then review findings suggesting that mature cardiomyocytes are protected against DOX-induced apoptosis downstream, but not upstream of mitochondrial outer membrane permeabilisation (MOMP). This lack of MOMP induction is proposed to alter the metabolic phenotype, induce hypertrophic remodeling, and lead to functional cardiac impairment even in the absence of cardiomyocyte apoptosis. We discuss findings that DOX exposure can lead to increased sensitivity to further cardiomyocyte apoptosis, which may cause a gradual loss in cardiomyocytes over time and a compensatory hypertrophic remodeling after treatment, potentially explaining the long lag time in disease onset. We finally note similarities between DOX-exposed cardiomyocytes and apoptosis-primed cancer cells and propose computational system biology as a tool to predict patient individual DOX doses. In conclusion, combining recent findings in rodent hearts and cardiomyocytes exposed to DOX with insights from apoptosis signal transduction allowed us to obtain a molecularly deeper insight in this delayed and still enigmatic pathology of DC
Stem Cell Therapy: Pieces of the Puzzle
Acute ischemic injury and chronic cardiomyopathies can cause irreversible loss of cardiac tissue leading to heart failure. Cellular therapy offers a new paradigm for treatment of heart disease. Stem cell therapies in animal models show that transplantation of various cell preparations improves ventricular function after injury. The first clinical trials in patients produced some encouraging results, despite limited evidence for the long-term survival of transplanted cells. Ongoing research at the bench and the bedside aims to compare sources of donor cells, test methods of cell delivery, improve myocardial homing, bolster cell survival, and promote cardiomyocyte differentiation. This article reviews progress toward these goals
Use of anticoagulants and antiplatelet agents in stable outpatients with coronary artery disease and atrial fibrillation. International CLARIFY registry
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