Estibaliz Castillero

Cardiac Myostatin Upregulation Occurs Immediately After Myocardial Ischemia and is Involved in Skeletal Muscle Activation of Atrophy

UNLABELLEDnMyostatin (MSTN), a negative regulator of muscle growth and size, is increased after acute myocardial infarction (AMI) but timing of upregulation after injury is not known. In this study, we investigated the timing of the MSTN/AKT/p38 pathway activation in heart and skeletal muscle after AMI, as well as the potential effect of cardiac injury-related MSTN endocrine signaling on skeletal muscle and other circulating growth factors.nnnMETHODSnCoronary artery ligation was performed in C57BL/6 mice at age 8 weeks to induce AMI. Mice were sacrificed at different time points (10 m, 1 h, 2 h, 6 h, 12 h, 24 h, 1 week, 2 weeks, 1 months and 2 months) after surgery (n=3 per time point, n=18 total).nnnRESULTSnCardiac and circulating MSTN upregulation occurred as early as 10 min after AMI. Two months after AMI, increased cardiac MSTN/SMAD2,3 and p38 together with decreased IGF-1/AKT signaling suggest an anti-hypertrophic profile. In skeletal muscle, an absence of local MSTN increase was accompanied by increased MSTN-dependent SMAD2,3 signaling, suggestive of paracrine effects due to cardiac-derived MSTN. Protein degradation by the ubiquitin-proteasome system in the skeletal muscle was also evident. Serum from 24h post-MI mice effectively induced a MSTN-dependent increase in atrogin1 and MuRF1.nnnCONCLUSIONnOur study shows that cardiac MTSN activation occurs rapidly after cardiac ischemia and may be involved in peripheral protein degradation in the skeletal muscle by activating atrogin1 and MuRF1.

Cardiac Donor Risk Factors Predictive of Short-Term Heart Transplant Recipient Mortality: An Analysis of the United Network for Organ Sharing Database.

INTRODUCTIONnTo address the shortage of donor hearts for transplantation, there is significant interest in liberalizing donor acceptance criteria. Therefore, the aim of this study was to evaluate cardiac donor characteristics from the United Network for Organ Sharing (UNOS) database to determine their impact on posttransplantation recipient outcomes.nnnMETHODSnAdult (≥18 years) patients undergoing heart transplantation from July 1, 2004, to December 31, 2012, in the UNOS Standard Transplant Analysis and Research (STAR) database were reviewed. Patients were stratified by 1-year posttransplantation status; survivors (group S, n = 13,643) and patients who died or underwent cardiac retransplantation at 1-year follow-up (group NS/R = 1785). Thirty-three specific donor variables were collected for each recipient, and independent donor predictors of recipient death or retransplantation at 1 year were determined using multivariable logistic regression analysis.nnnRESULTSnOverall 1-year survival for the entire cohort was 88.4%. Mean donor age was 31.5 ± 11.9 years, and 72% were male. On multivariable logistic regression analysis, donor age >40 years (odds ratio [OR] 1.44, 95% confidence interval [CI] 1.27 to 1.64), graft ischemic time >3 hours (OR 1.32, 1.16 to 1.51), and the use of cardioplegia (OR 1.17, 1.01 to 1.35) or Celsior (OR 1.21, 1.06 to 1.38) preservative solution were significant predictors of recipient death or retransplantation at 1 year posttransplantation. Male donor sex (OR 0.83, 0.74 to 0.93) and the use of antihypertensive agents (OR 0.88, 0.77 to 1.00) or insulin (OR 0.84, 0.76 to 0.94) were protective from adverse outcomes at 1 year.nnnCONCLUSIONSnThese data suggest that donors who are older, female, or have a long projected ischemic time pose greater risk to heart transplant recipients in the short term. Additionally, certain components of donor management protocols, including antihypertensive and insulin administration, may be protective to recipients.

Bridging Anticoagulation After Mechanical Aortic Heart Valve Replacement: A Questionable Routine

BACKGROUNDnThis retrospective single-center study evaluates differences in bleeding and thrombotic events between a homogenous group of patients undergoing mechanical aortic valve replacement who either received or did not receive intravenous unfractionated heparin or subcutaneous low-molecular weight heparin as bridging strategy to warfarin therapy.nnnMETHODSnClinical data on a total of 158 patients undergoing mechanical aortic valve replacement at our center between 2001 and 2014 were collected. Patients were grouped according to postoperative anticoagulation strategy: warfarin only (nxa0= 53) and warfarin plus heparin bridge (nxa0= 105). The outcomes of interest were bleeding event and thromboembolic event recorded during hospital stay.nnnRESULTSnPatients baseline characteristics were comparable between the two groups except for preoperative atrial fibrillation, which was more common in the warfarin plus heparin group than the warfarin group (pxa0= 0.04). There were significantly more bleeding complications in the warfarin plus heparin group versus warfarin group as evidenced by higher rates of pericardial effusions (24% versus 8%, pxa0= 0.02) and reoperation for bleeding (8% versus 0%, pxa0= 0.05). All observed thromboembolic events (nxa0= 4) occurred in the warfarin plus heparin group (pxa0= 0.55). Logistic regression analysis identified group assignment (warfarin plus heparin versus warfarin only) to be significantly associated with the odds of bleeding (odds ratio 4.46, 95% confidence interval:1.42 to 14.02, pxa0= 0.01).nnnCONCLUSIONSnBridging anticoagulation therapy increases the chances of bleeding in the postoperative phase for mechanical aortic valve replacement patients. Owing to low incidence, no statistically significant difference was detected for thromboembolic event rates.

Structural and Functional Cardiac Profile after Prolonged Duration of Mechanical Unloading: Potential Implications for Myocardial Recovery

Clinical and experimental studies have suggested that the duration of left ventricular assist device (LVAD) support may affect remodeling of the failing heart. We aimed to 1) characterize the changes in Ca2+/calmodulin-dependent protein kinase type-IIδ (CaMKIIδ), growth signaling, structural proteins, fibrosis, apoptosis, and gene expression before and after LVAD support and 2) assess whether the duration of support correlated with improvement or worsening of reverse remodeling. Left ventricular apex tissue and serum pairs were collected in patients with dilated cardiomyopathy ( nu2009= 25, 23 men and 2 women) at LVAD implantation and after LVAD support at cardiac transplantation/LVAD explantation. Normal cardiac tissue was obtained from healthy hearts ( n = 4) and normal serum from age-matched control hearts ( n = 4). The duration of LVAD support ranged from 48 to 1,170 days (median duration: 270 days). LVAD support was associated with CaMKIIδ activation, increased nuclear myocyte enhancer factor 2, sustained histone deacetylase-4 phosphorylation, increased circulating and cardiac myostatin (MSTN) and MSTN signaling mediated by SMAD2, ongoing structural protein dysregulation and sustained fibrosis and apoptosis (all Pu2009< 0.05). Increased CaMKIIδ phosphorylation, nuclear myocyte enhancer factor 2, and cardiac MSTN significantly correlated with the duration of support. Phosphorylation of SMAD2 and apoptosis decreased with a shorter duration of LVAD support but increased with a longer duration of LVAD support. Further study is needed to define the optimal duration of LVAD support in patients with dilated cardiomyopathy. NEW & NOTEWORTHY A long duration of left ventricular assist device support may be detrimental for myocardial recovery, based on myocardial tissue experiments in patients with prolonged support showing significantly worsened activation of Ca2+/calmodulin-dependent protein kinase-IIδ, increased nuclear myocyte enhancer factor 2, increased myostatin and its signaling by SMAD2, and apoptosis as well as sustained histone deacetylase-4 phosphorylation, structural protein dysregulation, and fibrosis.

MYOSTATIN INHIBITION IMPROVES CARDIAC GLUCOSE METABOLISM IN A MURINE MODEL OF HEART FAILURE

Myostatin (MSTN) is a negative regulator of muscle growth that may improve insulin sensitivity. We hypothesized that systemic MSTN inhibition would improve cardiomyocyte glucose metabolism in experimental heart failure (HF).nnC57BL/6J mice were subjected to left anterior descending coronary artery

DIFFERING PATTERNS OF MYOSTATIN SIGNALING REGULATE HYPERTROPHY IN SEVERE AORTIC STENOSIS AND HYPERTROPHIC CARDIOMYOPATHY

Myostatin (MSTN), a negative regulator of muscle growth, is induced by cardiac overload and may regulate the transition from physiologic hypertrophy to ventricular dilatation. We hypothesized that patients with severe aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) have distinctive anti-