Background-Recent work has demonstrated the importance of chromatin remodeling, especially histone acetylation, in the control of gene expression in the heart. In cell culture models of cardiac hypertrophy, pharmacological suppression of histone deacetylases (HDACs) can either blunt or amplify cell growth. Thus, HDAC inhibitors hold promise as potential therapeutic agents in hypertrophic heart disease. Methods and Results-In the present investigation, we studied 2 broad-spectrum HDAC inhibitors in a physiologically relevant banding model of hypertrophy, observing dose-responsive suppression of ventricular growth that was well tolerated in terms of both clinical outcome and cardiac performance measures. In both short-term (3-week) and long-term (9-week) trials, cardiomyocyte growth was blocked by HDAC inhibition, with no evidence of cell death or apoptosis. Fibrotic change was diminished in hearts treated with HDAC inhibitors, and collagen synthesis in isolated cardiac fibroblasts was blocked. Preservation of systolic function in the setting of blunted hypertrophic growth was documented by echocardiography and by invasive pressure measurements. The hypertrophy-associated switch of adult and fetal isoforms of myosin heavy chain expression was attenuated, which likely contributed to the observed preservation of systolic function in HDAC inhibitor-treated hearts. Conclusions-Together, these data suggest that HDAC inhibition is a viable therapeutic strategy that holds promise in the treatment of load-induced heart disease.

Background-Cellular hypertrophy requires coordinated regulation of progrowth and antigrowth mechanisms. In cultured neonatal cardiomyocytes, Foxo transcription factors trigger an atrophy-related gene program that counters hypertrophic growth. However, downstream molecular events are not yet well defined. Methods and Results-Here, we report that expression of either Foxo1 or Foxo3 in cardiomyocytes attenuates calcineurin phosphatase activity and inhibits agonist-induced hypertrophic growth. Consistent with these results, Foxo proteins decrease calcineurin phosphatase activity and repress both basal and hypertrophic agonist-induced expression of MCIP1.4, a direct downstream target of the calcineurin/NFAT pathway. Furthermore, hearts from Foxo3-null mice exhibit increased MCIP1.4 abundance and a hypertrophic phenotype with normal systolic function at baseline. Together, these results suggest that Foxo proteins repress cardiac growth at least in part through inhibition of the calcineurin/NFAT pathway. Given that hypertrophic growth of the heart occurs in multiple contexts, our findings also suggest that certain hypertrophic signals are capable of overriding the antigrowth program induced by Foxo. Consistent with this, multiple hypertrophic agonists triggered inactivation of Foxo proteins in cardiomyocytes through a mechanism requiring the PI3K/Akt pathway. In addition, both Foxo1 and Foxo3 are phosphorylated and consequently inactivated in hearts undergoing hypertrophic growth induced by hemodynamic stress. Key Words: angiotensin Ⅲ calcineurin Ⅲ hypertrophy I n response to stress from neurohumoral activation, hypertension, or other myocardial injury, the heart initially compensates with an adaptive hypertrophic increase in mass. The resulting growth and remodeling response alters the balance between protein synthesis and protein degradation. In skeletal muscle, activation of progrowth signaling pathways is accompanied by deactivation of pathways that promote proteolysis. Prominent among the atrophy-inducing pathways are those governed by Forkhead box transcription factors, O subfamily (Foxo). Conclusions-This Clinical Perspective p 1168Foxo transcription factors regulate key physiological functions, including responses to stress, cell-cycle progression, protein degradation, and apoptosis. 1,2 There are 4 mammalian Foxo genes: Foxo1 (FKHR), Foxo3 (FKHRL1), Foxo4 (AFX), and Foxo6. The transcriptional activities of Foxo proteins are governed by posttranslational modifications such as phosphorylation and acetylation. With respect to myocyte growth and remodeling, Foxo proteins induce ubiquitin ligases and promote proteolysis in skeletal muscle. 3,4 In heart, a number of signaling cascades involving transcription factors, kinases, and G-protein-coupled receptors are implicated in the regulation of muscle growth (see reviews 5-7 ). Among these, the calcineurin/nuclear factor of activated T cells (NFAT) pathway has been shown to be a key signaling cascade that promotes cardiac hypertrophy. 8 It has been reported recently...

Ventricular hypertrophy develops in response to numerous forms of cardiac stress, including pressure or volume overload, loss of contractile mass from prior infarction, neuroendocrine activation, and mutations in genes encoding sarcomeric proteins. Hypertrophic growth is believed to have a compensatory role that diminishes wall stress and oxygen consumption, but Framingham and other studies established ventricular hypertrophy as a marker for increased risk of developing chronic heart failure, suggesting that hypertrophy may have maladaptive features. However, the relative contribution of comorbid disease to hypertrophy-associated systolic failure is unknown. For instance, coronary artery disease is induced by many of the same risk factors that cause hypertrophy and can itself lead to systolic dysfunction. It is uncertain, therefore, whether ventricular hypertrophy commonly progresses to systolic dysfunction without the contribution of intervening ischemia or infarction. In this review, we summarize findings from epidemiologic studies, preclinical experiments in animals, and clinical trials to lay out what is known-and not known-about this important question.

Hypertrophic growth of the myocardium occurs in most forms of heart failure and may contribute to the pathogenesis of the failure state. Little is known about the regulatory mechanisms governing the often-coexisting phenotypes of hypertrophy, systolic failure, and diastolic stiffness that characterize clinical disease. We hypothesized that intracellular signaling pathways are differentially activated by graded degrees of hemodynamic stress. To test this, we developed models of graded pressure stress in mice and used them to directly compare compensated hypertrophy and pressure-overload heart failure. Surgical interventions were designed to be similar, on either side of a threshold separating compensated from decompensated responses. Our findings revealed two dramatically different hypertrophic phenotypes with only modest differences in the activation of relevant intracellular signaling pathways. Furthermore, we uncovered a functional requirement of calcineurin signaling in each model such that calcineurin suppression blunted hypertrophic growth. Remarkably, in each case, suppression of calcineurin signaling was not associated with clinical deterioration or increased mortality. Profiles of stress-response signaling and Ca2+ handling differ between the steady-state, maintenance phases of load-induced cardiac hypertrophy and failure. This information may be useful in identifying novel targets of therapy in chronic disease.

The rising incidence of the human immunodeficiency virus (HIV) infection in women and the prolonged survival increases the risk of development of breast cancer in this population. Through December 2001, 38 cases of breast cancer, two occurring in men, have been reported in persons infected with HIV. Between 1995 and 2001, five HIV infected premenopausal women presented with breast cancer to the Karmanos Cancer Institute. Three patients presented 3-5 years after the diagnosis of HIV infection. One patient presented with stage IV breast cancer, three with stage III, and one with stage II disease. Chemotherapy-induced myelosuppression was pronounced in all patients. Two patients had progression of HIV on treatment manifested by a rise in HIV-1 RNA or development of opportunistic infections. In general, the outcome of breast cancer in our small series of patients was worse than in a non-HIV population. HIV infection may influence the natural history and treatment of breast cancer.