Kartik Mani

Death begets failure in the heart

Recently, low--but abnormal--rates of cardiomyocyte apoptosis have been observed in failing human hearts. Genetic and pharmacological studies suggest that this cell death is causally linked to heart failure in rodent models. Herein, we review these data and discuss potential therapeutic implications.

ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR 2013 appropriate use criteria for implantable cardioverter-defibrillators and cardiac resynchronization therapy

Steven R. Bailey, MD, FACC, FSCAI, FAHA, Moderator Andrea M. Russo, MD, FACC, FHRS, Writing Group Liaison [⁎][1] Suraj Kapa, MD, Writing Group Liaison Michael B. Alexander, MD, FACC[§][2] Steven R. Bailey, MD, FACC, FSCAI, FAHA[∥][3] Ulrika Birgersdotter-Green, MD, FHRS[∥][3] Alan S.

Regulation of p53 tetramerization and nuclear export by ARC

Inactivation of the transcription factor p53 is central to carcinogenesis. Yet only approximately one-half of cancers have p53 loss-of-function mutations. Here, we demonstrate a mechanism for p53 inactivation by apoptosis repressor with caspase recruitment domain (ARC), a protein induced in multiple cancer cells. The direct binding in the nucleus of ARC to the p53 tetramerization domain inhibits p53 tetramerization. This exposes a nuclear export signal in p53, triggering Crm1-dependent relocation of p53 to the cytoplasm. Knockdown of endogenous ARC in breast cancer cells results in spontaneous tetramerization of endogenous p53, accumulation of p53 in the nucleus, and activation of endogenous p53 target genes. In primary human breast cancers with nuclear ARC, p53 is almost always WT. Conversely, nearly all breast cancers with mutant p53 lack nuclear ARC. We conclude that nuclear ARC is induced in cancer cells and negatively regulates p53.

Myocyte apoptosis: Programming ventricular remodeling

Of the more than 1 million Americans who suffer recognized myocardial infarctions (MIs) annually, about 300,000 die in the first year, and a similar number fall victim to crippling heart failure (HF) [(1)][1]. Although advances in revascularization and HF therapies have somewhat blunted its

Opposing Effects Mediated by the Chemokine Receptor CXCR2 on Myocardial Ischemia-Reperfusion Injury Recruitment of Potentially Damaging Neutrophils and Direct Myocardial Protection

Background—The timely reperfusion of ischemic myocardium limits infarction, but components of reperfusion, such as inflammation, may be injurious. The chemokine receptor CXCR2 mediates neutrophil chemotaxis. CXCR2 activation also inhibits hypoxia-induced death of isolated cardiac myocytes. This study assesses whether CXCR2 mediates protection in the intact heart and, if so, the magnitude of this protection relative to CXCR2-mediated chemotaxis of potentially damaging inflammatory cells. Methods and Results—After ischemia-reperfusion in vivo, CXCR2−/− mice exhibited infarcts that were 50.5% smaller (P <0.05) with 44.3% fewer inflammatory cells (P <0.05) than wild type mice. These data suggest that in this model, CXCR2-mediated chemotaxis may be important in myocardial cell death. To isolate the role of CXCR2 specifically on blood cells, adoptive transfer experiments were performed. After ischemia-reperfusion, infarcts were 53.4% smaller (P <0.05) and contained 65.0% fewer inflammatory cells (P <0.05) in lethally irradiated wild type mice reconstituted with CXCR2−/− compared with wild type bone marrow. Thus, CXCR2 on blood cells is important in myocardial damage, most likely because of CXCR2-mediated chemotaxis. To unmask whether CXCR2 mediates direct myocardial protection in the intact heart, wild type and CXCR2−/− hearts were studied in the absence of blood using Langendorff preparations. In this case, infarcts were 19.7% larger in CXCR2−/− than wild type hearts (P <0.05), revealing a novel CXCR2-mediated cardioprotective effect. Conclusions—CXCR2 exerts opposing effects on myocardial viability during ischemia-reperfusion with recruitment of damaging inflammatory cells predominant over direct tissue protection.

Programmed cell death in cardiac myocytes: strategies to maximize post-ischemic salvage

The most common cause of systolic dysfunction in the United States is prior ischemic injury. As the basic functional unit of the myocardium, the cardiac myocyte is the ultimate target of both the pathogenesis and possible therapies in this paradigm. Maintaining adequate numbers of these terminally differentiated units in the myocardium has been the focus of all therapies in ischemic syndromes, including reperfusion strategies. Programmed cell death, in the forms of apoptosis, necrosis and possibly, autophagic cell death are the final arbiters of myocyte numbers following myocardial infarction. This review will focus on the evidence for cell death in the development of heart failure following myocardial infarction, a brief review of the relevant pathways and the targets for development of future therapies

The apoptosis inhibitor ARC undergoes ubiquitin-proteasomal-mediated degradation in response to death stimuli: identification of a degradation-resistant mutant.

Efficient induction of apoptosis requires not only the activation of death-promoting proteins but also the inactivation of inhibitors of cell death. ARC (apoptosis repressor with caspase recruitment domain) is an endogenous inhibitor of apoptosis that antagonizes both central apoptosis pathways. Despite its potent inhibition of cell death, cells that express abundant ARC eventually succumb. A possible explanation is that ARC protein levels decrease dramatically in response to death stimuli. The mechanisms that mediate decreases in ARC protein levels during apoptosis and whether these decreases initiate the subsequent cell death are not known. Here we show that endogenous ARC protein levels decrease in response to death stimuli in a variety of cell contexts as well as in a model of myocardial ischemia-reperfusion in intact mice. Decreases in ARC protein levels are not explained by alterations in the abundance of ARC transcripts. Rather, pulse-chase experiments show that decreases in steady state ARC protein levels during apoptosis result from marked destabilization of ARC protein. ARC protein destabilization, in turn, is mediated by the ubiquitin-proteasomal pathway, as mutation of ARC ubiquitin acceptor residues stabilizes ARC protein and preserves its steady state levels during apoptosis. In addition, this degradation-resistant ARC mutant exhibits improved cytoprotection. We conclude that decreases in ARC protein levels in response to death stimuli are mediated by increased ARC protein degradation via the ubiquitin-proteasomal pathway. Moreover, these data demonstrate that decreases in ARC protein levels are a trigger, and not merely a consequence, of the ensuing cell death.

Nipping at cardiac remodeling.

Much of the mortality following myocardial infarction results from remodeling of the heart after the acute ischemic event. Cardiomyocyte apoptosis has been thought to play a key role in this remodeling process. In this issue of the JCI, Diwan and colleagues present evidence that Bnip3, a proapoptotic Bcl2 family protein, mediates cardiac enlargement, reshaping, and dysfunction in mice without influencing infarct size.

Aortic Arch Vessel Disease and Rationale for Echocardiographic Screening

Atherosclerosis of the proximal branches of the aortic arch has compelling clinical implications that warrant the application of direct noninvasive detection of the disease. The prevalence of aortic arch vessel disease in an aging and at-risk community and clinical population has been underreported and undertreated despite an associated increase of all-cause and cardiovascular mortality. Intrathoracic duplex imaging has been validated as an accurate noninvasive tool to detect, characterize, and follow native aortic arch vessel disease and its sequelae and correction. Such duplex techniques are easily integrated into routine echocardiography with focused training and minimal time investment in the examination. A paucity of available resources exists across disciplines regarding ultrasonographic investigation of these supra-aortic trunk vessels, including textbooks, journal articles, seminars, and manuals. This review has been compiled to familiarize physicians and sonographers with the relevant anatomy, pathophysiology, treatment, and diagnostic duplex surveillance of aortic arch vessel disease. Illustrative cases along with clinical rationale are discussed with the intent to facilitate the integration of arch vessel duplex imaging into the scope and practice of echocardiography.