Background-Cardiac hypertrophy involves growth responses to a variety of stimuli triggered by increased workload. It is an independent risk factor for heart failure and sudden death. Mammalian target of rapamycin (mTOR) plays a key role in cellular growth responses by integrating growth factor and energy status signals. It is found in 2 structurally and functionally distinct multiprotein complexes called mTOR complex (mTORC) 1 and mTORC2. The role of each of these branches of mTOR signaling in the adult heart is currently unknown. Methods and Results-We generated mice with deficient myocardial mTORC1 activity by targeted ablation of raptor, which encodes an essential component of mTORC1, during adulthood. At 3 weeks after the deletion, atrial and brain natriuretic peptides and ␤-myosin heavy chain were strongly induced, multiple genes involved in the regulation of energy metabolism were altered, but cardiac function was normal. Function deteriorated rapidly afterward, resulting in dilated cardiomyopathy and high mortality within 6 weeks. Aortic banding-induced pathological overload resulted in severe dilated cardiomyopathy already at 1 week without a prior phase of adaptive hypertrophy. The mechanism involved a lack of adaptive cardiomyocyte growth via blunted protein synthesis capacity, as supported by reduced phosphorylation of ribosomal S6 kinase 1 and 4E-binding protein 1. In addition, reduced mitochondrial content, a shift in metabolic substrate use, and increased apoptosis and autophagy were observed. Conclusions-Our results demonstrate an essential function for mTORC1 in the heart under physiological and pathological conditions and are relevant for the understanding of disease states in which the insulin/insulin-like growth factor signaling axis is affected such as diabetes mellitus and heart failure or after cancer therapy. (Circulation. 2011;123:1073-1082.)Key Words: heart failure Ⅲ hypertrophy Ⅲ myocardial metabolism Ⅲ signal transduction A lthough cardiac hypertrophy is a growth response that initially normalizes wall tension, it is associated with an unfavorable outcome: Affected patients are threatened with sudden death or progression to heart failure. 1 Much research is therefore aimed at understanding myocardial growth regulation, and in this setting, the insulin-like growth factor/PI3-kinase/Akt signaling cascade has been studied extensively. 2,3 Experiments with cultured cardiomyocytes have suggested that downstream of Akt, mammalian target of rapamycin (mTOR) mediates responses to pathological stimuli. 4,5 mTOR is an evolutionary conserved Ser/Thr kinase known to control cell growth. 6 Nutrient, energy, and growth factor shortage will impair mTOR activity, resulting in diverse effects, including the slowdown of macromolecule synthesis, enhanced autophagy, and activation of nutrient-or stressresponsive transcription factors. mTOR is found in 2 structurally and functionally distinct multiprotein complexes called mTOR complex 1 (mTORC1) and mTORC2. The 2 best-characterized substrates of mTORC1 ...

We report on 4 new cases of valvular heart disease in Parkinson's disease patients treated with the ergot derivative dopamine agonists pergolide and cabergoline. Noninflammatory fibrotic degeneration of cardiac valves has been reported to occur in patients with carcinoid syndrome and to occasionally complicate therapies with the anti-migraine ergot alkaloid ergotamine and methysergide and with the appetite suppressants fenfluramine and dexfenfluramine. In these cases, the pathogenesis is suspected to involve serotonin-mediated abnormal fibrogenesis by means of the 5-HT2B receptors, which are expressed in the fibroblasts of heart valves. Based on strikingly similar echocardiographic and histopathological features, we strongly suspect that ergot-derived dopamine agonists may cause a valvular heart disease nearly identical to that seen in those conditions. These cases add to a rapidly growing and worrying list of similar published reports, suggesting that we may well be facing a novel, yet unrecognized, complication of this class of agents, which are widely used not only in Parkinson's disease but also in restless legs syndrome and various common endocrine dysfunctions. Therefore, until more is known about the true prevalence of this side effect, we propose that an assessment of cardiac function be performed before and in the course of a long-term therapy with ergot derivative dopamine agonists.

Nampt inhibition appears as a new strategy to dampen CXCL2-induced neutrophil recruitment and thereby reduce neutrophil-mediated tissue injury in mice.