Autophagy, an evolutionarily conserved process for the bulk degradation of cytoplasmic components, serves as a cell survival mechanism in starving cells. Although altered autophagy has been observed in various heart diseases, including cardiac hypertrophy and heart failure, it remains unclear whether autophagy plays a beneficial or detrimental role in the heart. Here, we report that the cardiac-specific loss of autophagy causes cardiomyopathy in mice. In adult mice, temporally controlled cardiac-specific deficiency of Atg5 (autophagy-related 5), a protein required for autophagy, led to cardiac hypertrophy, left ventricular dilatation and contractile dysfunction, accompanied by increased levels of ubiquitination. Furthermore, Atg5-deficient hearts showed disorganized sarcomere structure and mitochondrial misalignment and aggregation. On the other hand, cardiac-specific deficiency of Atg5 early in cardiogenesis showed no such cardiac phenotypes under baseline conditions, but developed cardiac dysfunction and left ventricular dilatation one week after treatment with pressure overload. These results indicate that constitutive autophagy in the heart under baseline conditions is a homeostatic mechanism for maintaining cardiomyocyte size and global cardiac structure and function, and that upregulation of autophagy in failing hearts is an adaptive response for protecting cells from hemodynamic stress.

Heart failure is a leading cause of morbidity and mortality in industrialized countries. Although infection with microorganisms is not involved in the development of heart failure in most cases, inflammation has been implicated in the pathogenesis of heart failure1. However, the mechanisms responsible for initiating and integrating inflammatory responses within the heart remain poorly defined. Mitochondria are evolutionary endosymbionts derived from bacteria and contain DNA similar to bacterial DNA2,3,4. Mitochondria damaged by external hemodynamic stress are degraded by the autophagy/lysosome system in cardiomyocytes5. Here, we show that mitochondrial DNA that escapes from autophagy cell-autonomously leads to Toll-like receptor (TLR) 9-mediated inflammatory responses in cardiomyocytes and is capable of inducing myocarditis, and dilated cardiomyopathy. Cardiac-specific deletion of lysosomal deoxyribonuclease (DNase) II showed no cardiac phenotypes under baseline conditions, but increased mortality and caused severe myocarditis and dilated cardiomyopathy 10 days after treatment with pressure overload. Early in the pathogenesis, DNase II-deficient hearts exhibited infiltration of inflammatory cells and increased mRNA expression of inflammatory cytokines, with accumulation of mitochondrial DNA deposits in autolysosomes in the myocardium. Administration of the inhibitory oligodeoxynucleotides against TLR9, which is known to be activated by bacterial DNA6, or ablation of Tlr9 attenuated the development of cardiomyopathy in DNase II-deficient mice. Furthermore, Tlr9-ablation improved pressure overload-induced cardiac dysfunction and inflammation even in mice with wild-type Dnase2a alleles. These data provide new perspectives on the mechanism of genesis of chronic inflammation in failing hearts.

Abstract-Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is an important contributor to population morbidity and mortality. An arrhythmia that is particularly common in the elderly, AF is growing in prevalence with the aging of the population. Our understanding of the basic mechanisms that govern AF occurrence and persistence has been increasing rapidly. This article reviews the basic pathophysiology of AF over a broad range of levels, touching on the tissue mechanisms that maintain the arrhythmia, the relationship between clinical presentation and basic mechanisms, ion channel and transporter abnormalities that lead to ectopic impulse formation, basic models and tissue determinants of reentry, ion channel determinants of reentry, the nature and roles of electric and structural remodeling, autonomic neural components, anatomic factors, interactions between atrial and ventricular functional consequences of AF, and the basic determinants of atrial thromboembolism. We then review the potential implications of the basic pathophysiology of the arrhythmia for its management. We first discuss consequences for improved rhythm control pharmacotherapy: targeting underlying conditions, new atrium-selective drug targets, new targets for focal ectopic source suppression, and upstream therapy aiming to prevent remodeling. We then review the implications of basic mechanistic considerations for rate control therapy, AF ablation, and the prevention of thromboembolic events. We conclude with some thoughts about the future of translational research related to AF mechanisms. (Circulation. 2011; 124:2264-2274.)Key Words: antiarrhythmia agents Ⅲ arrhythmia Ⅲ calcium Ⅲ electrophysiology Ⅲ reentry A trial fibrillation (AF), the most common sustained cardiac arrhythmia, is becoming progressively more prevalent with population aging. 1 Enormous advances in the understanding of AF pathophysiology have occurred over the past 20 years. 2,3 The present article, part of a thematic series in Circulation on AF, provides a broad overview of AF pathophysiology and the potential implications for AF management. In addition, it furnishes background information on basic mechanisms relevant to other articles in the series dealing with AF epidemiology and genetics, stroke prevention, rate control therapy, sinus rhythm maintenance pharmacotherapy, management in structural heart disease, and catheter ablation. For more comprehensive treatment of specific mechanisms, the reader is referred to detailed review articles. [2][3][4][5]

In acute myocardial infarction (MI), reactive oxygen species (ROS) are generated in the ischaemic myocardium especially after reperfusion. ROS directly injure the cell membrane and cause cell death. However, ROS also stimulate signal transduction to elaborate inflammatory cytokines, e.g. tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and -6, in the ischaemic region and surrounding myocardium as a host reaction. Inflammatory cytokines also regulate cell survival and cell death in the chain reaction with ROS. Both ROS and inflammatory cytokines are cardiodepressant mainly due to impairment of intracellular Ca(2+) homeostasis. Inflammatory cytokines stimulate apoptosis through a TNF-alpha receptor/caspase pathway, whereas Ca(2+) overload induced by extensive ROS generation causes necrosis through enhanced permeability of the mitochondrial membrane (mitochondrial permeability transition). Apoptosis signal-regulating kinase-1 (ASK1) is an ROS-sensitive, mitogen-activated protein kinase kinase kinase that is activated by many stress signals and can activate nuclear factor kappaB and other transcription factors. ASK1-deficient mice demonstrate that the ROS/ASK1 pathway is involved in necrotic as well as apoptotic cell death, indicating that ASK1 may be a therapeutic target to reduce left ventricular (LV) remodelling after MI. ROS and inflammatory cytokines activate matrix metalloproteinases which degrade extracellular matrix, causing a slippage of myofibrils and hence LV dilatation. Consequently, collagen deposition is increased and tissue repair is enhanced with myocardial fibrosis and angiogenesis. Since the extent of LV remodelling is a major predictor of prognosis of the patients with MI, the therapeutic approach to attenuating LV remodelling is critically important.

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Damaged mitochondria are removed by mitophagy. Although Atg32 is essential for mitophagy in yeast, no Atg32 homologue has been identified in mammalian cells. Here, we show that Bcl-2-like protein 13 (Bcl2-L-13) induces mitochondrial fragmentation and mitophagy in mammalian cells. First, we hypothesized that unidentified mammalian mitophagy receptors would share molecular features of Atg32. By screening the public protein database for Atg32 homologues, we identify Bcl2-L-13. Bcl2-L-13 binds to LC3 through the WXXI motif and induces mitochondrial fragmentation and mitophagy in HEK293 cells. In Bcl2-L-13, the BH domains are important for the fragmentation, while the WXXI motif facilitates mitophagy. Bcl2-L-13 induces mitochondrial fragmentation in the absence of Drp1, while it induces mitophagy in Parkin-deficient cells. Knockdown of Bcl2-L-13 attenuates mitochondrial damage-induced fragmentation and mitophagy. Bcl2-L-13 induces mitophagy in Atg32-deficient yeast cells. Induction and/or phosphorylation of Bcl2-L-13 may regulate its activity. Our findings offer insights into mitochondrial quality control in mammalian cells.

Autophagy has evolved as a conserving process that uses bulk degradation and recycling of cytoplasmic components, such as long-lived proteins and organelles. In the heart, autophagy is important for the turnover of organelles at low basal levels under normal conditions and it is upregulated in response to stresses such as ischemia/reperfusion and in cardiovascular diseases such as heart failure. Cardiac remodeling involves increased rates of cardiomyocyte cell death and precedes heart failure. The simultaneously occurring multiple features of failing hearts include not only apoptosis and necrosis but also autophagy as well. However, it has been unclear as to whether autophagy is a sign of failed cardiomyocyte repair or is a suicide pathway for failing cardiomyocytes. The functional role of autophagy during ischemia/reperfusion in the heart is complex. It has also been unclear whether autophagy is protective or detrimental in response to ischemia/reperfusion in the heart. In this review, we will summarize the role of autophagy in the heart under both normal conditions and in response to stress.

These data indicate that GPCR agonist-induced cardiac hypertrophy is mediated through NF-kappaB activation via the generation of ROS. ASK1 is involved in GPCR agonist-induced NF-kappaB activation and resulting hypertrophy.