A latent cardiomyocyte regeneration potential in human heart disease.

Cardiomyocytes in the adult human heart show a regenerative capacity, with an annual renewal rate around 0.5%. Whether this regenerative capacity of human cardiomyocytes is employed in heart failure has been controversial. Using retrospective 14C birth dating we analyzed cardiomyocyte renewal in patients with end-stage heart failure. We show that cardiomyocyte generation is minimal in end-stage heart failure patients at rates 18-50 times lower compared to the healthy heart. However, patients receiving left ventricle support device therapy, who showed significant functional and structural cardiac improvement, had a >6-fold increase in cardiomyocyte renewal relative to the healthy heart. Our findings reveal a substantial cardiomyocyte regeneration potential in human heart disease, which could be exploited therapeutically.

Challenges to aging in place for African American older adults living with dementia and their families.

A culturally informed community health assessment was conducted to explore the community context of care for older adults in African American urban neighborhoods. The purpose of this study is to explore the challenges to aging in place for African American older adults living with dementia and their family members. Data collection and analysis were conducted as concurrent iterative procedures between photographs, media clippings, semi-structured interviews (N = 24), observation notes, and journaling. Content analysis revealed shame, improper housing, financial constraints, resource inadequacy, transportation concerns, and knowledge deficit as common challenges faced by the older adults and their families to receiving health services to support aging in place within urban neighborhoods. Data from this report are to inform clinicians, community partners, families, and service organizations, to promote uptake of future research and programing to improve outcomes for African American older adults living with dementia and their family members.

Development of dilated cardiomyopathy and impaired calcium homeostasis with cardiac-specific deletion of ESRRß.

Mechanisms underlying the development of idiopathic dilated cardiomyopathy (DCM) remain poorly understood. Using transcription factor expression profiling, we identified estrogen-related receptor-ß (ESRRß), a member of the nuclear receptor family of transcription factors, as highly expressed in murine hearts and other highly oxidative striated muscle beds. Mice bearing cardiac-specific deletion of ESRRß (MHC-ERRB KO) develop DCM and sudden death at ~10 mo of age. Isolated adult cardiomyocytes from the MHC-ERRB KO mice showed an increase in calcium sensitivity and impaired cardiomyocyte contractility, which preceded echocardiographic cardiac remodeling and dysfunction by several months. Histological analyses of myocardial biopsies from patients with various cardiomyopathies revealed that ESRRß protein is absent from the nucleus of cardiomyocytes from patients with DCM but not other forms of cardiomyopathy (ischemic, hypertrophic, and arrhythmogenic right ventricular cardiomyopathy). Taken together these observations suggest that ESRRß is a critical component in the onset of DCM by affecting contractility and calcium balance.NEW & NOTEWORTHY Estrogen-related receptor-ß (ESRRß) is highly expressed in the heart and cardiac-specific deletion results in the development of a dilated cardiomyopathy (DCM). ESRRß is mislocalized in human myocardium samples with DCM, suggesting a possible role for ESRRß in the pathogenesis of DCM in humans.

Dating the Heart: Exploring Cardiomyocyte Renewal in Humans.

Regenerative mechanisms reported in the hearts of lower vertebrates have been recapitulated in the mammalian milieu, and recent studies have provided strong evidence for cardiomyocyte turnover in humans. These findings speak to an emerging consensus that adult mammalian cardiomyocytes do have the ability to divide, and it stands to reason that enrichment of this innate proliferative capacity should prove essential for complete cardiac regeneration.

FNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice.

FNDC4 is a secreted factor sharing high homology with the exercise-associated myokine irisin (FNDC5). Here we report that Fndc4 is robustly upregulated in several mouse models of inflammation as well as in human inflammatory conditions. Specifically, FNDC4 levels are increased locally at inflamed sites of the intestine of inflammatory bowel disease patients. Interestingly, administration of recombinant FNDC4 in the mouse model of induced colitis markedly reduces disease severity compared with mice injected with a control protein. Conversely, mice lacking Fndc4 develop more severe colitis. Analysis of binding of FNDC4 to different immune cell types reveals strong and specific binding to macrophages and monocytes. FNDC4 treatment of bone marrow-derived macrophages in vitro results in reduced phagocytosis, increased cell survival and reduced proinflammatory chemokine expression. Hence, treatment with FNDC4 results in a state of dampened macrophage activity, while enhancing their survival. Thus, we have characterized FNDC4 as a factor with direct therapeutic potential in inflammatory bowel disease and possibly other inflammatory diseases.

Impact of exercise on muscle and nonmuscle organs.

Exercise is known to prevent and treat metabolic diseases such as diabetes. However, the underlying mechanisms are not fully understood, and there is currently much focus on detailing such pathways. Traditionally, much emphasis has been placed on skeletal muscle; however, recently, nonmuscle organs such as adipose tissue have been highlighted in mediating protective actions after training. Moreover, novel paracrine- and endocrine-signaling molecules have been shown to trigger important responses in nonmuscle organs after exercise. This is exciting because, when administered exogenously, such signals have obvious therapeutic potential. In this review, the authors have described some general and historical aspects of training and disease protection. The authors have also highlighted some of the current knowledge on how exercise impacts nonmuscle organs.

Isolation, culture, and functional characterization of adult mouse cardiomyoctyes.

The use of primary cardiomyocytes (CMs) in culture has provided a powerful complement to murine models of heart disease in advancing our understanding of heart disease. In particular, the ability to study ion homeostasis, ion channel function, cellular excitability and excitation-contraction coupling and their alterations in diseased conditions and by disease-causing mutations have led to significant insights into cardiac diseases. Furthermore, the lack of an adequate immortalized cell line to mimic adult CMs, and the limitations of neonatal CMs (which lack many of the structural and functional biomechanics characteristic of adult CMs) in culture have hampered our understanding of the complex interplay between signaling pathways, ion channels and contractile properties in the adult heart strengthening the importance of studying adult isolated cardiomyocytes. Here, we present methods for the isolation, culture, manipulation of gene expression by adenoviral-expressed proteins, and subsequent functional analysis of cardiomyocytes from the adult mouse. The use of these techniques will help to develop mechanistic insight into signaling pathways that regulate cellular excitability, Ca(2+) dynamics and contractility and provide a much more physiologically relevant characterization of cardiovascular disease.

Pathological role of serum- and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling.

BACKGROUND: Heart failure is a growing cause of morbidity and mortality. Cardiac phosphatidylinositol 3-kinase signaling promotes cardiomyocyte survival and function, but it is paradoxically activated in heart failure, suggesting that chronic activation of this pathway may become maladaptive. Here, we investigated the downstream phosphatidylinositol 3-kinase effector, serum- and glucocorticoid-regulated kinase-1 (SGK1), in heart failure and its complications. METHODS AND RESULTS: We found that cardiac SGK1 is activated in human and murine heart failure. We investigated the role of SGK1 in the heart by using cardiac-specific expression of constitutively active or dominant-negative SGK1. Cardiac-specific activation of SGK1 in mice increased mortality, cardiac dysfunction, and ventricular arrhythmias. The proarrhythmic effects of SGK1 were linked to biochemical and functional changes in the cardiac sodium channel and could be reversed by treatment with ranolazine, a blocker of the late sodium current. Conversely, cardiac-specific inhibition of SGK1 protected mice after hemodynamic stress from fibrosis, heart failure, and sodium channel alterations. CONCLUSIONS: SGK1 appears both necessary and sufficient for key features of adverse ventricular remodeling and may provide a novel therapeutic target in cardiac disease.