Effect of eplerenone on extracellular cardiac matrix biomarkers in patients with acute ST-elevation myocardial infarction without heart failure: insights from the randomized double-blind REMINDER Study

Objective: Aldosterone stimulates cardiac collagen synthesis. Circulating biomarkers of collagen turnover provide a useful tool for the assessment of cardiac remodeling in patients with an acute myocardial infarction (MI).  Methods: The REMINDER trial assessed the effect of eplerenone in patients with an acute ST-elevation Myocardial Infarction (STEMI) without known heart failure (HF), when initiated within 24 h of symptom onset. The primary outcome was almost totally (>90%) driven by natriuretic peptide (NP) thresholds after 1-month post-MI (it also included a composite of cardiovascular death or re-hospitalization or new onset HF or sustained ventricular tachycardia or fibrillation or LVEF ≤40% after 1-month post-MI). This secondary analysis aims to assess the extracellular matrix marker (ECMM) levels with regards to: (1) patients` characteristics; (2) determinants; (3) and eplerenone effect.  Results: Serum levels of ECMM were measured in 526 (52%) of the 1012 patients enrolled in the REMINDER trial. Patients with procollagen type III N-terminal propeptide (PIIINP) above the median were older and had worse renal function (p < 0.05). Worse renal function was associated with increased levels of PIIINP (standardized β ≈ 0.20, p < 0.05). Eplerenone reduced PIIINP when the levels of this biomarker were above the median of 3.9 ng/mL (0.13 ± 1.48 vs. -0.37 ± 1.56 ng/mL, p = 0.008). Higher levels of PIIINP were independently associated with higher proportion of NP above the prespecified thresholds (HR = 1.95, 95% CI 1.16-3.29, p = 0.012).  Conclusions: Eplerenone effectively reduces PIIINP levels when baseline values were above the median. Eplerenone may limit ECMM formation in post-MI without HF

SCA15 due to large ITPR1 deletions in a cohort of 333 white families with dominant ataxia

BACKGROUND: Deletions in ITPR1, coding for the inositol-triphosphate receptor type 1, have been recently identified in spinocerebellar ataxia type 15 (SCA15). OBJECTIVE: To determine the frequency and the phenotypical spectrum of SCA15. DESIGN: Taqman polymerase chain reaction (258 index cases) or single-nucleotide polymorphism genome-wide genotyping (75 index cases). SETTING: A collaboration between the Centre de Recherche de l'Institut de Cerveau et de la Moelle Epiniere of the Salpetriere Hospital (Paris, France) and the Molecular Genetics Unit of the National Institute of Aging (Bethesda, Maryland). Patients Index cases of 333 families with autosomal dominant cerebellar ataxia negative for CAG repeat expansions in coding exons. MAIN OUTCOME MEASURES: Detection of ITPR1 copy number alterations. RESULTS: A deletion of ITPR1 was found in 6 of 333 families (1.8%), corresponding to 13 patients with SCA15. Age at onset ranged from 18 to 66 years (mean [SD] age, 35 [16] years). The symptom at onset was cerebellar gait ataxia, except in 1 patient with isolated upper limb tremor. Although families were tested irrespective of their phenotype, patients with SCA15 had a homogeneous phenotype and were characterized by a slowly progressive cerebellar ataxia. However, pyramidal signs (2 patients) and mild cognitive problems (2 patients) were occasionally present. Radiologic findings showed global or predominant vermian cerebellar atrophy in all patients. CONCLUSIONS: In this series, ITPR1 deletions were rare and accounted for approximately 1% of all autosomal dominant cerebellar ataxias. The SCA15 phenotype mostly consists of a slowly progressive isolated cerebellar ataxia with variable age at onset; an additional pyramidal syndrome and problems in executive functions may be present

Simple scoring system to predict in-hospital mortality after surgery for infective endocarditis

BACKGROUND: Aspecific scoring systems are used to predict the risk of death postsurgery in patients with infective endocarditis (IE). The purpose of the present study was both to analyze the risk factors for in-hospital death, which complicates surgery for IE, and to create a mortality risk score based on the results of this analysis. METHODS AND RESULTS: Outcomes of 361 consecutive patients (mean age, 59.1\ub115.4 years) who had undergone surgery for IE in 8 European centers of cardiac surgery were recorded prospectively, and a risk factor analysis (multivariable logistic regression) for in-hospital death was performed. The discriminatory power of a new predictive scoring system was assessed with the receiver operating characteristic curve analysis. Score validation procedures were carried out. Fifty-six (15.5%) patients died postsurgery. BMI >27 kg/m2 (odds ratio [OR], 1.79; P=0.049), estimated glomerular filtration rate 55 mm Hg (OR, 1.78; P=0.032), and critical state (OR, 2.37; P=0.017) were independent predictors of in-hospital death. A scoring system was devised to predict in-hospital death postsurgery for IE (area under the receiver operating characteristic curve, 0.780; 95% CI, 0.734-0.822). The score performed better than 5 of 6 scoring systems for in-hospital death after cardiac surgery that were considered. CONCLUSIONS: A simple scoring system based on risk factors for in-hospital death was specifically created to predict mortality risk postsurgery in patients with IE

E008 Study on the mechanism of human telomerase assembly

Telomerase, a ribonucleoprotein enzyme, catalyses the synthesis of repeated telomeric sequences. Telomeres are required for chromosome stability and cell viability and a decrease of their length was found to be associated with several cardiovascular diseases. Telomerase contains the hTR RNA, and several proteins, including the reverse transcriptase hTERT. The hTR 5’ domain contains the template sequence for DNA synthesis and binds hTERT. The H/ACA 3’ domain is required for stability and associates with 4 proteins (Dyskerin, GAR1, NOP10 and NHP2 proteins). Limited information is available on telomerase assembly. A pre-complex containing Dyskerine, NOP10, NHP2 and an assembly factor, called NAF1, is likely formed in the cytoplasm and transported to the nucleus, where it associates with the H/ACA domain of nascent RNA. Exchange of NAF1 for GAR1 allows the production of the functional H/ACA RNP domain. We showed that several factors are implicated in H/ACA RNP assembly : NUFIP, the R2TP complex, and HSP90. The SMN complex, containing the SMN, Gemin2 to Gemin8 and Unrip proteins may also be involved, since protein SMN interacts with GAR1.For further analysis on the role of the SMN complex in telomerase assembly, we tested by yeast two hybrid assays whether other proteins of this complex can interact with H/ACA RNP proteins and their assembly factors. We discovered a possible interaction between NAF1, Gemin 3 and Gemin8. Hence, the SMN complex may be involved in the replacement of NAF1 by GAR1: it may associate with GAR1 through an interaction with SMN, and with the pre-H/ACA RNP complex through interaction of NAF1 with Gemin3 and 8, allowing the replacement of NAF1 by GAR1. We are testing this hypothesis. The SMN complex may also be involved in hTERT binding to the 5’ domain of hTR and we will also explore this possibility.Through these studies we should bring insight into telomerase assembly that may be useful to understand telomere attrition in cardiovascular diseases

Relationship between the morphology of myocardial infarction scar border assessed by cardiacmagnetic resonance and the inducibility of ventricular tachycardia

International audienceP5887 Relationship between the morphology of myocardial infarction scar border assessed by cardiac magnetic resonance and the inducibility of ventricular tachycardi