Yoshiaki Ohyama

Mitochondrial transcription factors TFAM and TFB2M regulate Serca2 gene transcription.

AIMS Sarco(endo)plasmic reticulum Ca²(+)-ATPase 2a (SERCA2a) transports Ca²(+) by consuming ATP produced by mitochondrial respiratory chain enzymes. Messenger RNA (mRNA) for these enzymes is transcribed by mitochondrial transcription factors A (TFAM) and B2 (TFB2M). This study examined whether TFAM and TFB2M coordinately regulate the transcription of the Serca2 gene and mitochondrial genes. METHODS AND RESULTS Nuclear localization of TFAM and TFB2M was demonstrated by immunostaining in rat neonatal cardiac myocytes. Chromatin immunoprecipitation assay and fluorescence correlation spectroscopy revealed that TFAM and TFB2M bind to the -122 to -114 nt and -122 to -117 nt regions of the rat Serca2 gene promoter, respectively. Mutation of these sites resulted in decreased Serca2 gene transcription. In a rat myocardial infarction model, Serca2a mRNA levels significantly correlated with those of Tfam (r = 0.54, P < 0.001) and Tfb2m (r = 0.73, P < 0.001). Overexpression of TFAM and TFB2M blocked hydrogen peroxide- and norepinephrine-induced decreases in Serca2a mRNA levels. In addition, overexpression of TFAM and TFB2M increased the mitochondrial DNA (mtDNA) copy number and mRNA levels of mitochondrial enzymes. CONCLUSION Although TFAM and TFB2M are recognized as mtDNA-specific transcription factors, they also regulate transcription of nuclear DNA, i.e. the Serca2 gene. Our findings suggest a novel paradigm in which the transcription of genes for mitochondrial enzymes that produce ATP and the gene for SERCA2a that consumes ATP is coordinately regulated by the same transcription factors. This mechanism may contribute to maintaining proper cardiac function.

Estimated Glomerular Filtration Rate and Proteinuria Are Separately and Independently Associated with the Prevalence of Atrial Fibrillation in General Population

Background Both, proteinuria and a decline in glomerular filtration rate (GFR) are associated with greater cardiovascular mortality. However, few studies have explored that proteinuria and lower GFR are related with prevalent atrial fibrillation (AF). Methods This cross-sectional study was based on annual health check-up program of community-based population in Gunma, Japan from April 2011 to March 2012. A total of 20,019 adult participants were included. AF was ascertained by a standard 12-lead electrocardiogram. Cross-sectional association and correlates with prevalent AF were examined using multivariable logistic regression analysis. Results The overall prevalence of AF was 0.6% (2.2 % in participants with eGFR < 60 mL▪min-1･1.73m-2, 0.4% and 0.2% in those with eGFR 60 to 89 and ≧90 mL▪min-1･1.73m-2, p for trend <0.001). The multivariable odds ratio (OR) for AF was 2.86 (95 % CI 1.16 - 7.08, p<0.001) for eGFR< 60 mL▪min-1▪1.73m-2 versus eGFR≧ 90 mL▪min-1▪1.73m-2. This association remained significant with further adjustment for proteinuria. In addition, proteinuria was also strongly associated with increased prevalence of AF (OR 2.96, 95 % CI 1.55-5.68, p<0.001), an association that remained significant after adjustment for eGFR. Conclusions Proteinuria and lower eGFR are separately and significantly associated with prevalence of AF independent of well-established risk factors for AF in general population.

A Risk Score with Additional Four Independent Factors to Predict the Incidence and Recovery from Metabolic Syndrome: Development and Validation in Large Japanese Cohorts

Background Although many risk factors for Metabolic syndrome (MetS) have been reported, there is no clinical score that predicts its incidence. The purposes of this study were to create and validate a risk score for predicting both incidence and recovery from MetS in a large cohort. Methods Subjects without MetS at enrollment (n = 13,634) were randomly divided into 2 groups and followed to record incidence of MetS. We also examined recovery from it in rest 2,743 individuals with prevalent MetS. Results During median follow-up of 3.0 years, 878 subjects in the derivation and 757 in validation cohorts developed MetS. Multiple logistic regression analysis identified 12 independent variables from the derivation cohort and initial score for subsequent MetS was created, which showed good discrimination both in the derivation (c-statistics 0.82) and validation cohorts (0.83). The predictability of the initial score for recovery from MetS was tested in the 2,743 MetS population (906 subjects recovered from MetS), where nine variables (including age, sex, γ-glutamyl transpeptidase, uric acid and five MetS diagnostic criteria constituents.) remained significant. Then, the final score was created using the nine variables. This score significantly predicted both the recovery from MetS (c-statistics 0.70, p<0.001, 78% sensitivity and 54% specificity) and incident MetS (c-statistics 0.80) with an incremental discriminative ability over the model derived from five factors used in the diagnosis of MetS (continuous net reclassification improvement: 0.35, p < 0.001 and integrated discrimination improvement: 0.01, p<0.001). Conclusions We identified four additional independent risk factors associated with subsequent MetS, developed and validated a risk score to predict both incident and recovery from MetS.

Early increase in serum fatty acid binding protein 4 levels in patients with acute myocardial infarction

Background: Acute myocardial infarction (AMI) induces marked activation of the sympathetic nervous system. Fatty acid binding protein 4 (FABP4) is not only an intracellular protein, but also a secreted adipokine that contributes to obesity-related metabolic complications. Here, we examined the role of serum FABP4 as a pathophysiological marker in patients with AMI. Methods and results: We studied 106 patients presenting to the emergency unit with a final diagnosis of AMI, including 12 patients resuscitated from out-of-hospital cardiac arrest (OHCA) caused by ventricular fibrillation. FABP4 levels peaked on admission or just after percutaneous coronary intervention and declined thereafter. Regression analysis revealed no significant correlation between peak FABP4 and peak cardiac troponin T determined by Roche high-sensitive assays (hs-TnT). Notably, FABP4 levels were particularly elevated in AMI patients who were resuscitated from OHCA (median 130.2 ng/mL, interquartile range (IQR) 51.8–243.9 ng/mL) compared with those without OHCA (median 26.1 ng/ml, IQR 17.1–43.4 ng/mL), while hs-TnT levels on admission were not associated with OHCA. Immunohistochemistry of the human heart revealed that FABP4 is abundantly present in adipocytes within myocardial tissue and epicardial adipose tissue. An in vitro study using cultured adipocytes showed that FABP4 is released through a β3-adrenergic receptor (AR)-mediated mechanism. Conclusions: FABP4 levels were significantly elevated during the early hours after the onset of AMI and were robustly increased in OHCA survivors. Together with the finding that FABP4 is released from adipocytes via β3-AR-mediated lipolysis, our data provide a novel hypothesis that serum FABP4 may represent the adrenergic overdrive that accompanies acute cardiovascular disease, including AMI.

Reversible Cardiomyopathy After Epirubicin Administration

Anthracycline-containing chemotherapy can cause irreversible and progressive left ventricular dysfunction. Epirubicin, which is widely used for breast cancer chemotherapy, is an anthracycline that has less cardiac toxicity than doxorubicin. The present report describes the case of a 70-year-old woman with breast cancer who developed severe congestive heart failure and severe cardiac dysfunction at 6 weeks from epirubicin final administration. Left ventricular function gradually improved after intensive treatment for heart failure and recovered completely within 2 months. To the best of our knowledge, this is the first report to describe epirubicin-induced subacute reversible cardiotoxicity.

Pulmonary hypertension with extensive calcification in small pulmonary vessels and alveolar capillary wall in a chronic hemodialysis patient

We report a case of a 41-year-old male with end-stage renal disease receiving chronic hemodialysis who was referred to this hospital because of dyspnea. He had been on a regular dialysis for 20 years due to chronic glomerulonephritis. His transthoracic echocardiography revealed severe pulmonary hypertension (PH), and cardiac catheterization confirmed this diagnosis. From clinical examination and review of the chest X-ray and computed tomography images, we thought PH was due to multifactorial mechanisms typical of hemodialysis patients. However, microscopic examination of lung tissue from autopsy specimen revealed extensive calcium deposits not only in alveolar septal wall but also in alveolar capillaries and small vessels, which had diffuse intimal thickening causing the narrowing of the lumens. These pathological findings suggest that pulmonary vascular calcification contributed to the PH in this patient. <Learning objective: Pulmonary hypertension (PH) is prevalent and associated with mortality in patients with end-stage renal disease (ESRD). However, the pathogenesis of PH with ESRD remains uncertain. Here we report a PH case receiving long-term hemodialysis, and whose pathological findings revealed extensive calcification in small pulmonary vessels and alveolar capillaries. This case will provide evidence indicating the causative role of pulmonary calcification for the development of PH in dialysis patients.>.

Multiple spontaneous coronary artery ruptures and cardiac tamponade in vascular Ehlers-Danlos syndrome

We report a case of a 45-year-old woman with Ehlers-Danlos syndrome (EDS) type IV, the vascular type, who presented with multiple coronary artery ruptures causing cardiac tamponade. She had sudden onset of chest pain soon after transarterial embolization for right carotid-cavernous fistula. Transthoracic echocardiography confirmed cardiac tamponade and hypokinetic inferolateral wall. Enhanced CT and transesophageal echocardiography ruled out aortic dissection. Coronary angiography showed contrast extravasation from multiple sites of the right coronary artery and left circumflex coronary artery. We suspected EDS type IV, and a skin biopsy for DNA and RNA analysis was done after taking written informed consent. Polymerase chain reaction (PCR) and sequencing of the PCR product showed a heterozygous missense mutation of codon 85 in the COL3A1 gene, which converted glycine to aspartic acid, and thus a diagnosis of EDS type IV was established. To our best knowledge, this is the first case of EDS type IV causing multiple coronary artery ruptures.

Proximal Aortic Distensibility is an Independent Predictor of All-cause Mortality and Incident Cardiovascular Events in the Multi-Ethnic Study of Atherosclerosis

BACKGROUND The predictive value of ascending aortic distensibility (AAD) for mortality and hard cardiovascular disease (CVD) events has not been fully established. OBJECTIVES This study sought to assess the utility of AAD to predict mortality and incident CVD events beyond conventional risk factors in MESA (Multi-Ethnic Study of Atherosclerosis). METHODS AAD was measured with magnetic resonance imaging at baseline in 3,675 MESA participants free of overt CVD. Cox proportional hazards regression was used to evaluate risk of death, heart failure (HF), and incident CVD in relation to AAD, CVD risk factors, indexes of subclinical atherosclerosis, and Framingham risk score. RESULTS There were 246 deaths, 171 hard CVD events (myocardial infarction, resuscitated cardiac arrest, stroke and CV death), and 88 HF events over a median 8.5-year follow-up. Decreased AAD was associated with increased all-cause mortality with a hazard ratio (HR) for the first versus fifth quintile of AAD of 2.7 (p = 0.008) independent of age, sex, ethnicity, other CVD risk factors, and indexes of subclinical atherosclerosis. Overall, patients with the lowest AAD had an independent 2-fold higher risk of hard CVD events. Decreased AAD was associated with CV events in low to intermediate- CVD risk individuals with an HR for the first quintile of AAD of 5.3 (p = 0.03) as well as with incident HF but not after full adjustment. CONCLUSIONS Decreased proximal aorta distensibility significantly predicted all-cause mortality and hard CV events among individuals without overt CVD. AAD may help refine risk stratification, especially among asymptomatic, low- to intermediate-risk individuals.

SERUM FATTY ACID BINDING PROTEIN 4 IS AN EARLY MARKER FOR ACUTE MYOCARDIAL INFARCTION

Fatty acid binding protein 4 (FABP4, also designated as adipocyte-FABP or aP2) has been described to be most exclusively expressed in adipocytes and macrophages. Circulating FABP4 levels have been linked to metabolic alternations that are associated adiposity. We have recently reported that FABP4 is

INTEGRATED AREA DESATURATION INDEX IS MAJOR PREDICTOR OF FATAL CARDIOVASCULAR EVENTS IN PATIENTS WITH HEART FAILURE AFTER ADAPTIVESERVO VENTILATION THERAPY

Adaptive servo ventilation (ASV) has been successfully used for treating heart failure (HF) in patients with central sleep apnea. However, it remains what factors are the most important predictors of fatal cardiovascular events after ASV therapy. The Integrated Area of Desaturation (IAD) index is