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A defining cellular event in the transition from compensated hypertrophy to dilated cardiomyopathy is cardiomyocyte drop-out due to apoptosis, programmed necrosis, and autophagy. The importance of apoptosis in heart failure has been recognized for over a decade, while other forms of programmed cell death have more recently been appreciated, and their pathophysiological roles continue to be defined in experimental and clinical heart failure. The major focus of this review is on apoptosis in heart failure, with a discussion of molecular cross-talk between apoptosis, autophagy, and programmed necrosis.

Programmed cardiac myocyte death via the intrinsic, or mitochondrial, pathway is a mechanism of pathological ventricular remodeling after myocardial infarction and during chronic pressure overload hypertrophy. Transcriptional upregulation of the closely related proapoptotic Bcl2 family members BNip3 in ischemic myocardium and Nix in hypertrophied myocardium suggested a molecular mechanism by which programmed cell death can be initiated by cardiac stress and lead to dilated cardiomyopathy. Studies using transgenic and gene knockout mice subsequently demonstrated that expression of BNip3 and Nix is both sufficient for cardiomyopathy development and necessary for cardiac remodeling after reversible coronary occlusion and transverse aortic banding, respectively. Here, these data are reviewed in the context of recent findings showing that Nix not only stimulates cardiomyocyte apoptosis but also induces mitochondrial autophagy (mitophagy) and indirectly activates the mitochondrial permeability transition pore, causing cell necrosis. New findings are presented suggesting that Nix and BNip3 have an essential function, "mitochondrial pruning," that restrains mitochondrial proliferation in cardiomyocytes and without which an age-dependent mitochondrial cardiomyopathy develops. KeywordsApoptosis; Heart Failure; Mitochondria; Autophagy BNip3 and Nix are Inducible Cardiomyocyte Death FactorsThe cellular hallmark of acquired dilated cardiomyopathy is loss of functioning cardiomyocytes, frequently with their replacement by fibrotic tissue [1]. In the case of myocardial infarction, this "cardiomyocyte drop-out" is early and localized and constitutes the primary injury. In chronically ischemic hearts and nonischemic cardiomyopathies, cardiomyocyte drop-out (typically characterized in the literature as apoptosis) is widespread and induced as a programmed secondary response to the primary injury [2][3][4][5]. Because adult cardiac myocytes are incapable of meaningful cellular regeneration [6], chronic persistent apoptosis at a rate of 0.1-1% of total cardiomyocytes is sufficient to produce cardiac dilation and heart failure [7]. The workload placed on the heart by programmed cardiac myocyte loss initiates a feed-forward cycle of unfavorable geometrical remodeling that further induces cardiomyocyte death genes, resulting in a downward functional spiral progressing to dilated cardiomyopathy and end-stage heart failure [8,9].Cardiomyocyte apoptosis can be mediated either through the extrinsic cytokine death receptor pathway, or the intrinsic mitochondrial pathway. The focus here is on mitochondrial apoptosis, regulated by the Bcl2 family of mitochondrial-targeted pro-and anti-"apoptotic" proteins. These factors unambiguously regulate caspase-dependent apoptosis and so the moniker of "pro-" or "anti-apoptotic" is at least partially correct. As explained in more detail below, however, evidence is accumulating that Bcl2 family proteins also regulate nonapoptotic forms of programmed cell death that occur concomitantly and can be ...

Mitochondrial fission and fusion have been observed, and their importance revealed, in almost every tissue and cell type except adult cardiac myocytes. As each human heart is uniquely dependent upon mitochondria to generate massive amounts of ATP that fuel its approximately 38 million contractions per year, it seems odd that cardiac myocytes are the sole exception to the general rule that mitochondrial dynamism is important to function. Here, I briefly review the mechanisms for mitochondrial fusion and fission and examine current data that dispel the previous notion that mitochondrial fusion is dispensable in the heart. Rare and generally overlooked examples of cardiomyopathies linked either to naturally-occurring mutations or to experimentally-induced mutagenesis of mitochondrial fusion/fission genes are described. New findings from genetically targeted Drosophila and mouse models wherein mitochondrial fusion deficiency has specifically been induced in cardiac myocytes are discussed.

This review examines the impact of recent discoveries defining personal genetics of adrenergic signaling polymorphisms on scientific discovery and medical practice related to cardiovascular diseases. The adrenergic system is the major regulator of minute-by-minute cardiovascular function. Inhibition of adrenergic signaling with pharmacological beta-adrenergic receptor antagonists (beta-blockers) is first-line therapy for heart failure and hypertension. Advances in pharmacology, molecular biology, and genetics of adrenergic signaling pathways have brought us to the point where personal genetic differences in adrenergic signaling factors are being assessed as determinants of risk or progression of cardiovascular disease. For a few polymorphisms, functional data generated in cell-based systems, genetic mouse models, and pharmacological provocation of human subjects are concordant with population studies that suggest altered risk of cardiovascular disease or therapeutic response to beta-blockers. For the majority of adrenergic pathway polymorphisms however, published data conflict, and the clinical relevance of individual genotyping remains uncertain. Here, the current state of laboratory and clinical evidence that adrenergic pathway polymorphisms can affect cardiovascular pathophysiology is comprehensively reviewed and compared, with a goal of placing these data in the broad context of potential clinical applicability.