Michael A. Rosenberg

Myostatin inhibits IGF-I-induced myotube hypertrophy through Akt

Myostatin is a highly conserved negative regulator of skeletal muscle growth. Loss of functional myostatin in cattle, mice, sheep, dogs, and humans results in increased muscle mass. The molecular mechanisms responsible for this increase in muscle growth are not fully understood. Previously, we have reported that phenylephrine-induced cardiac muscle growth and Akt activation are enhanced in myostatin knockout mice compared with controls. Here we report that skeletal muscle from myostatin knockout mice show increased Akt protein expression and overall activity at baseline secondary to an increase in Akt mRNA. We examined the functional role of myostatin modulation of Akt in C2C12 myotubes, a well-established in vitro model of skeletal muscle hypertrophy. Adenoviral overexpression of myostatin attenuated the insulin-like growth factor-I (IGF-I)-mediated increase in myotube diameter, as well as IGF-I-stimulated Akt phosphorylation. Inhibition of myostatin by overexpression of the NH(2)-terminal portion of myostatin was sufficient to increase myotube diameter and Akt phosphorylation. Coexpression of myostatin and constitutively active Akt (myr-Akt) restored the increase in myotube diameter. Conversely, expression of dominant negative Akt (dn-Akt) with the inhibitory myostatin propeptide blocked the increase in myotube diameter. Of note, ribosomal protein S6 phosphorylation and atrogin-1/muscle atrophy F box mRNA were increased in skeletal muscle from myostain knockout mice. Together, these data suggest myostatin regulates muscle growth at least in part through regulation of Akt.

SIRT2 induces the checkpoint kinase BubR1 to increase lifespan

Mice overexpressing the mitotic checkpoint kinase gene BubR1 live longer, whereas mice hypomorphic for BubR1 (BubR1H/H) live shorter and show signs of accelerated aging. As wild‐type mice age, BubR1 levels decline in many tissues, a process that is proposed to underlie normal aging and age‐related diseases. Understanding why BubR1 declines with age and how to slow this process is therefore of considerable interest. The sirtuins (SIRT1‐7) are a family of NAD+‐dependent deacetylases that can delay age‐related diseases. Here, we show that the loss of BubR1 levels with age is due to a decline in NAD+ and the ability of SIRT2 to maintain lysine‐668 of BubR1 in a deacetylated state, which is counteracted by the acetyltransferase CBP. Overexpression of SIRT2 or treatment of mice with the NAD+ precursor nicotinamide mononucleotide (NMN) increases BubR1 abundance in vivo. Overexpression of SIRT2 in BubR1H/H animals increases median lifespan, with a greater effect in male mice. Together, these data indicate that further exploration of the potential of SIRT2 and NAD+ to delay diseases of aging in mammals is warranted.

mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy

Previous studies have suggested that inhibition of the mammalian target of rapamycin (mTOR) by rapamycin suppresses myocardial hypertrophy. However, the role of mTOR in the progression of cardiac dysfunction in pathological hypertrophy has not been fully defined. Interestingly, recent reports indicate that the inflammatory response, which plays an important role in the development of heart failure, is enhanced by rapamycin under certain conditions. Our aim in this study was to determine the influence of mTOR on pathological hypertrophy and to assess whether cardiac mTOR regulates the inflammatory response. We generated transgenic mice with cardiac-specific overexpression of wild-type mTOR (mTOR-Tg). mTOR-Tg mice were protected against cardiac dysfunction following left ventricular pressure overload induced by transverse aortic constriction (TAC) (P < 0.01) and had significantly less interstitial fibrosis compared with littermate controls (WT) at 4 wk post-TAC (P < 0.01). In contrast, TAC caused cardiac dysfunction in WT. At 1 wk post-TAC, the proinflammatory cytokines interleukin (IL)-1β and IL-6 were significantly increased in WT mice but not in mTOR-Tg mice. To further characterize the effects of mTOR activation, we exposed HL-1 cardiomyocytes transfected with mTOR to lipopolysaccharide (LPS). mTOR overexpression suppressed LPS-induced secretion of IL-6 (P < 0.001), and the mTOR inhibitors rapamycin and PP242 abolished this inhibitory effect of mTOR. In addition, mTOR overexpression reduced NF-κB-regulated transcription in HL-1 cells. These data suggest that mTOR mitigates adverse outcomes of pressure overload and that this cardioprotective effect of mTOR is mediated by regulation of the inflammatory reaction.

Echocardiographic diastolic parameters and risk of atrial fibrillation: the Cardiovascular Health Study

AIMS Atrial fibrillation (AF) is the most common sustained arrhythmia in the elderly, and shares several risk factors with diastolic dysfunction, including hypertension and advanced age. The purpose of this study is to examine diastolic dysfunction as a risk for incident AF. METHODS AND RESULTS We examined the association of echocardiographic parameters of diastolic function with the incidence of AF in 4480 participants enrolled in the Cardiovascular Health Study, an ongoing cohort of community-dwelling older adults from four US communities. Participants underwent baseline echocardiography in 1989-1990 and were followed for incident AF on routine follow-up and hospitalizations. After 50 941 person-years of follow-up (median follow-up time 12.1 years), 1219 participants developed AF. In multivariable-adjusted age-stratified Cox models, diastolic echocardiographic parameters were significantly associated with the risk of incident AF. The most significant parameters were the Doppler peak E-wave velocity and left atrial diameter, which demonstrated a positive nonlinear association [HR 1.5 (CI 1.3-1.9) and HR 1.7 (CI 1.4-2.1) for highest vs. lowest quintile, respectively], and Doppler A-wave velocity time integral, which displayed a U-shaped relationship with the risk of AF [HR 0.7 (CI 0.6-0.9) for middle vs. lowest quintile]. Each diastolic parameter displayed a significant association with adjusted NT-proBNP levels, although the nature of the association did not entirely parallel the risk of AF. Further cluster analysis revealed unique patterns of diastolic function that may identify patients at risk for AF. CONCLUSION In a community-based population of older adults, echocardiographic measures of diastolic function are significantly associated with an increased risk of AF.

Ventricular Arrhythmia Following Alcohol Septal Ablation for Obstructive Hypertrophic Cardiomyopathy

We sought to assess the risk of sudden cardiac death (SCD) and ventricular arrhythmia after alcohol septal ablation (ASA) for obstructive hypertrophic cardiomyopathy. ASA is a nonsurgical alternative to septal myectomy for treatment of symptomatic, drug-refractory, obstructive hypertrophic cardiomyopathy. The effect of ASA on ventricular arrhythmia risk is not well established. We examined the rates of SCD among 89 patients treated with ASA. The secondary end point was ventricular tachycardia/ventricular fibrillation (VT/VF), appropriate implantable cardioverter defibrillator (ICD) therapy, or cardiac arrest after ASA among those with implanted ICDs or permanent pacemakers (n = 42). Patients were classified as either high-risk or low-risk on the basis of established clinical indications for ICD implantation. No mortality was attributable to SCD at a mean follow-up of 5.0 +/- 2.3 years in the entire cohort. Among the 42 patients with an ICD or permanent pacemaker, 9 had documented VT/VF, cardiac arrest, or appropriate ICD therapy, resulting in an annual event rate of 4.9%/year. The annual event rate for VT/VF, cardiac arrest, or appropriate ICD therapy was 2.8%/year (4 of 29 patients) in low-risk patients and 13.4% in high-risk patients (5 of 13 patients). A 10-mm Hg increase in the immediate post-ASA gradient was associated with a hazard ratio of 2.66 for arrhythmic events (95% confidence interval 1.55 to 4.56, p <0.001). In conclusion, ASA was performed in patients with highly symptomatic, drug-refractory hypertrophic cardiomyopathy with no mortality attributable to SCD and an annual rate of VT/VF, cardiac arrest, or appropriate ICD therapy of 4.9%/year.

Effects of myostatin deletion in aging mice

Inhibitors of myostatin, a negative regulator of skeletal muscle mass, are being developed to mitigate aging‐related muscle loss. Knock‐out (KO) mouse studies suggest myostatin also affects adiposity, glucose handling and cardiac growth. However, the cardiac consequences of inhibiting myostatin remain unclear. Myostatin inhibition can potentiate cardiac growth in specific settings ( Morissette et al., 2006) , a concern because of cardiac hypertrophy is associated with adverse clinical outcomes. Therefore, we examined the systemic and cardiac effects of myostatin deletion in aged mice (27–30 months old). Heart mass increased comparably in both wild‐type (WT) and KO mice. Aged KO mice maintained twice as much quadriceps mass as aged WT; however, both groups lost the same percentage (36%) of adult muscle mass. Dual‐energy X‐ray absorptiometry revealed increased bone density, mineral content, and area in aged KO vs. aged WT mice. Serum insulin and glucose levels were lower in KO mice. Echocardiography showed preserved cardiac function with better fractional shortening (58.1% vs. 49.4%, P = 0.002) and smaller left ventricular diastolic diameters (3.41 vs. 2.71, P = 0.012) in KO vs. WT mice. Phospholamban phosphorylation was increased 3.3‐fold in KO hearts (P < 0.05), without changes in total phospholamban, sarco(endo)plasmic reticulum calcium ATPase 2a or calsequestrin. Aged KO hearts showed less fibrosis by Masson’s Trichrome staining. Thus, myostatin deletion does not affect aging‐related increases in cardiac mass and appears beneficial for bone density, insulin sensitivity and heart function in senescent mice. These results suggest that clinical interventions designed to inhibit skeletal muscle mass loss with aging could have beneficial effects on other organ systems as well.

Diastolic Dysfunction and Risk of Atrial Fibrillation A Mechanistic Appraisal

Atrial fibrillation (AF) is the most common sustained arrhythmia, and its prevalence in the population is increasing.1 Diastolic dysfunction shares many common risk factors with AF, including age, hypertension,2–5 obesity,6,7 and diabetes.8,9 Like AF, diastolic dysfunction increases with age,10 and patients given the diagnosis of diastolic dysfunction are more likely to have AF at the time.11 Diastolic dysfunction has significant pathological effects on atrial structure and function, many of which are proarrhythmic. However, much remains to be learned about the specific mechanisms through which diastolic dysfunction ultimately promotes AF. Previous reviews have examined the broad association of diastolic dysfunction and AF.12 In this review, we attempt to examine this association on a mechanistic level. We begin with a basic review of the physiology of diastolic function, with particular attention to the complex interaction between the atrium and the ventricle during diastole. We then provide an overview of some of the most common clinical methods to quantify diastolic function and highlight the strengths and weaknesses of these methods with regard to providing an accurate picture of this physiology. We describe how these methods are applied to diagnose diastolic dysfunction, including the development of a widely adopted classification scheme of diastolic dysfunction. We then review the limited clinical data available connecting diastolic dysfunction with the risk of incident, nonvalvular AF, with a focus on studies examining diastolic dysfunction in populations without structural heart disease—ie, with preserved systolic function in the absence of hypertrophic cardiomyopathic disease or congenital heart disease. Finally, we attempt to reconcile the results of these clinical studies with experimental data in both human, animal, and cellular models, to create a mechanistic link between diastolic dysfunction and pathological changes that increase the likelihood of AF. A number …

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.

The impact of height on the risk of atrial fibrillation: the Cardiovascular Health Study.

AIMS Atrial fibrillation (AF) is the most common sustained arrhythmia. Increased body size has been associated with AF, but the relationship is not well understood. In this study, we examined the effect of increased height on the risk of AF and explore potential mediators and implications for clinical practice. METHODS AND RESULTS We examined data from 5860 individuals taking part in the Cardiovascular Health Study, a cohort study of older US adults followed for a median of 13.6 (women) and 10.3 years (men). Multivariate linear models and age-stratified Cox proportional hazards and risk models were used, with focus on the effect of height on both prevalent and incident AF. Among 684 (22.6%) and 568 (27.1%) incident cases in women and men, respectively, greater height was significantly associated with AF risk [hazard ratio (HR)(women) per 10 cm 1.32, confidence interval (CI) 1.16-1.50, P < 0.0001; HR(men) per 10 cm 1.26, CI 1.11-1.44, P < 0.0001]. The association was such that the incremental risk from sex was completely attenuated by the inclusion of height (for men, HR 1.48, CI 1.32-1.65, without height, and HR 0.94, CI 0.85-1.20, with height included). Inclusion of height in the Framingham model for incident AF improved discrimination. In sequential models, however, we found minimal attenuation of the risk estimates for AF with adjustment for left ventricular (LV) mass and left atrial (LA) dimension. The associations of LA and LV size measurements with AF risk were weakened when indexed to height. CONCLUSION Independent from sex, increased height is significantly associated with the risk of AF.

B-type natriuretic peptide is a major predictor of ventricular tachyarrhythmias

BACKGROUND The cost-effective use of implantable cardioverter-defibrillators (ICDs) for the prevention of sudden cardiac death requires identification of patients at risk for ventricular tachyarrhythmias, not just for total mortality. OBJECTIVE To determine whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) or B-type natriuretic peptide (BNP) are independent predictors of ventricular arrhythmias in patients receiving primary prevention ICDs. METHODS One hundred sixty-one patients with NT-proBNP levels and 403 patients with BNP levels at the time of ICD implantation were retrospectively assessed for the occurrence of first appropriate ICD therapy and mortality. RESULTS In multivariable Cox proportional hazards regression analysis, NT-proBNP or BNP levels in the upper 50th percentile were the strongest predictor of ICD therapy after adjustment for sex, age, left ventricular ejection fraction, New York Heart Association class, history of coronary artery disease, blood urea nitrogen, creatinine clearance, and history of atrial fibrillation (hazard ratio [HR] 5.75, P < .001 for NT-proBNP; HR 3.40, P = .01 for BNP). Patients were divided into quartiles on the basis of NT-proBNP or BNP levels. The adjusted HR for ICD therapy in the highest and second highest quartiles of NT-proBNP levels (HR 12.9, P < .001, and HR 4.6, P = .03, respectively) were higher than the adjusted HR for total mortality in these 2 quartiles (HR 3.4, P = .021 and HR 2.3, P = .13, respectively). Similarly, the adjusted HR for ICD therapy in the highest and second highest quartiles of BNP levels (HR 4.74, P = .01 and HR 2.17, P = .04, respectively) were higher than the adjusted HR for total mortality in these 2 quartiles (HR 3.05, P = .01 and HR 1.07, P = .3, respectively). CONCLUSION In this study, elevated baseline NT-proBNP and BNP levels are independently associated with the risk for ventricular tachyarrhythmias, which significantly exceeds the risk for total mortality, in multivariable analysis.