Background-IGF-1 has been shown to protect myocardium against death in animal models of infarct and ischemia-reperfusion injury. In the present study, we investigated the role of the IGF-1-regulated protein kinase Akt in cardiac myocyte survival in vitro and in vivo.

Heart failure is a common, lethal condition whose pathogenesis is poorly understood. Recent studies have identified low levels of myocyte apoptosis (80–250 myocytes per 105 nuclei) in failing human hearts. It remains unclear, however, whether this cell death is a coincidental finding, a protective process, or a causal component in pathogenesis. Using transgenic mice that express a conditionally active caspase exclusively in the myocardium, we demonstrate that very low levels of myocyte apoptosis (23 myocytes per 105 nuclei, compared with 1.5 myocytes per 105 nuclei in controls) are sufficient to cause a lethal, dilated cardiomyopathy. Interestingly, these levels are four- to tenfold lower than those observed in failing human hearts. Conversely, inhibition of cardiac myocyte death in this murine model largely prevents the development of cardiac dilation and contractile dysfunction, the hallmarks of heart failure. To our knowledge, these data provide the first direct evidence that myocyte apoptosis may be a causal mechanism of heart failure, and they suggest that inhibition of this cell death process may constitute the basis for novel therapies

Heart failure is a common, lethal condition whose pathogenesis is poorly understood. Recent studies have identified low levels of myocyte apoptosis (80-250 myocytes per 10(5) nuclei) in failing human hearts. It remains unclear, however, whether this cell death is a coincidental finding, a protective process, or a causal component in pathogenesis. Using transgenic mice that express a conditionally active caspase exclusively in the myocardium, we demonstrate that very low levels of myocyte apoptosis (23 myocytes per 10(5) nuclei, compared with 1.5 myocytes per 10(5) nuclei in controls) are sufficient to cause a lethal, dilated cardiomyopathy. Interestingly, these levels are four- to tenfold lower than those observed in failing human hearts. Conversely, inhibition of cardiac myocyte death in this murine model largely prevents the development of cardiac dilation and contractile dysfunction, the hallmarks of heart failure. To our knowledge, these data provide the first direct evidence that myocyte apoptosis may be a causal mechanism of heart failure, and they suggest that inhibition of this cell death process may constitute the basis for novel therapies.

Background: Risk stratifying patients with cardiogenic shock (CS) is a major unmet need. The recently proposed Society for Cardiovascular Angiography and Interventions (SCAI) stages as an approach to identify patients at risk for in-hospital mortality remains under investigation. We studied the utility of the SCAI stages and further explored the impact of hemodynamic congestion on clinical outcomes. Methods: The CS Working Group registry includes patients with CS from 8 medical centers enrolled between 2016 and 2019. Patients were classified by the maximum SCAI stage (B–E) reached during their hospital stay according to drug and device utilization. In-hospital mortality was evaluated for association with SCAI stages and hemodynamic congestion. Results: Of the 1414 patients with CS, the majority were due to decompensated heart failure (50%) or myocardial infarction (MI; 35%). In-hospital mortality was 31% for the total cohort, but higher among patients with MI (41% versus 26%, MI versus heart failure, P <0.0001). Risk for in-hospital mortality was associated with increasing SCAI stage (odds ratio [95% CI], 3.25 [2.63–4.02]) in both MI and heart failure cohorts. Hemodynamic data was available in 1116 (79%) patients. Elevated biventricular filling pressures were common among patients with CS, and right atrial pressure was associated with increased mortality and higher SCAI Stage. Conclusions: Our findings support an association between the proposed SCAI staging system and in-hospital mortality among patient with heart failure and MI. We further identify that venous congestion is common and identifies patients with CS at high risk for in-hospital mortality. These findings provide may inform future management protocols and clinical studies.

Abstract-We have previously shown that the calcium-calmodulin-regulated phosphatase calcineurin (PP2B) is sufficient to induce cardiac hypertrophy that transitions to heart failure in transgenic mice. Given the rapid onset of heart failure in these mice, we hypothesized that calcineurin signaling would stimulate myocardial cell apoptosis. However, utilizing multiple approaches, we determined that calcineurin-mediated hypertrophy protected cardiac myocytes from apoptosis, suggesting a model of heart failure that is independent of apoptosis. Adenovirally mediated gene transfer of a constitutively active calcineurin cDNA (AdCnA) was performed in cultured neonatal rat cardiomyocytes to elucidate the mechanism whereby calcineurin affected myocardial cell viability. AdCnA infection, which induced myocyte hypertrophy and atrial natriuretic factor expression, protected against apoptosis induced by 2-deoxyglucose or staurosporine, as assessed by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) labeling, caspase-3 activation, DNA laddering, and cellular morphology. The level of protection conferred by AdCnA was similar to that of adenoviral Bcl-x L gene transfer or hypertrophy induced by phenylephrine. In vivo, failing hearts from calcineurin-transgenic mice did not demonstrate increased TUNEL labeling and, in fact, demonstrated a resistance to ischemia/reperfusion-induced apoptosis. We determined that the mechanism whereby calcineurin afforded protection from apoptosis was partially mediated by nuclear factor of activated T cells (NFAT3) signaling and partially by Akt/protein kinase B (PKB) signaling. Although calcineurin activation protected myocytes from apoptosis, inhibition of calcineurin with cyclosporine was not sufficient to induce TUNEL labeling in Gq␣-transgenic mice or in cultured cardiomyocytes. Collectively, these data identify a calcineurin-dependent mouse model of dilated heart failure that is independent of apoptosis. (Circ Res. 2000;86:255-263.)

Currently accepted symptom and LV performance indications for valve replacement, as well as sudden cardiac death, can be predicted in asymptomatic/minimally symptomatic patients with AR by load-adjusted deltaLVEF-deltaESS index, which includes data obtained during exercise.

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