BACKGROUND-Brugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype.
Background-Coronary spasm plays an important role in the pathogenesis of ischemic heart diseases in general. However, the precise mechanism(s) responsible for coronary spasm remains to be elucidated, and we examined the molecular genetics of coronary spasm. Methods and Results-We searched for the possible mutations in the endothelial nitric oxide synthase (eNOS) gene in patients with coronary spasm. In this study, we demonstrate the existence of 3 linked mutations in the 5Ј-flanking region of the eNOS gene (T
Abstract-Essential hypertension has a genetic basis. Accumulating evidence, including findings of elevation of arterial blood pressure in mice lacking the endothelial nitric oxide synthase (eNOS) gene, strongly suggests that alteration in NO metabolism is implicated in hypertension. There are, however, no reports indicating that polymorphism in the eNOS gene is associated with essential hypertension. We have identified a missense variant, Glu298Asp, in exon 7 of the eNOS gene and demonstrated that it is associated with both coronary spastic angina and myocardial infarction. To explore the genetic involvement of the eNOS gene in essential hypertension, we examined the possible association between essential hypertension and several polymorphisms including the Glu298Asp variant, variable number tandem repeats in intron 4 (eNOS4b/4a), and two polymorphisms in introns 18 and 23. We performed a large-scale study of genetic association using two independent populations from Kyoto (nϭ458; 240 normotensive versus 218 hypertensive subjects) and Kumamoto (nϭ421; 223 normotensive versus 187 hypertensive subjects), Japan. In both groups, a new coding variant, Glu298Asp, showed a strong association with essential hypertension (Kyoto: odds ratio, 2.3 [95% confidence interval, 1.4 to 3.9]; Kumamoto: odds ratio, 2.4 [95% confidence interval, 1.4 to 4.0]). The allele frequencies of 298Asp in hypertensive subjects were significantly higher than those in normotensive subjects in both groups (Kyoto: 0.103 versus 0.050, PϽ0.0017; Kumamoto: 0.120 versus 0.058, PϽ0.0013, respectively). No such disequilibrium between genotypes was significantly associated with any other polymorphisms we examined; the Glu298Asp variant was also not linked to any other polymorphisms. In conclusion, the Glu298Asp missense variant was significantly associated with essential hypertension, which suggests that it is a genetic susceptibility factor for essential hypertension.(Hypertension. 1998;32:3-8.)Key Words: genes Ⅲ nitric oxide synthase Ⅲ hypertension, essential Ⅲ polymorphism Ⅲ genetics W ith a genetic contribution of from 25% to 60%, human essential hypertension has a genetic basis. Among persons younger than age 50 years, essential hypertension occurs 3.8 times more often in those having two or more first-degree relatives who developed high blood pressure before age 55.1 NO synthesis by the vascular endothelium is important for the regulation of vasodilator tone and the control of blood pressure in humans.2 A recent study using mice with disrupted eNOS gene revealed that eNOS function is required for vascular and hemodynamic responses to acetylcholine and that the disruption of the eNOS gene leads to hypertension. 3 Moreover, recent reports demonstrate that whole-body NO production in patients with essential hypertension is diminished under basal conditions, as established by measurement of urinary and plasma nitrate. 4 In addition, the offspring of hypertensive patients exhibit a reduced response to acetylcholine linked to a defect in the NO pathway.5...
Background-Type-1 long-QT syndrome (LQTS) is caused by loss-of-function mutations in the KCNQ1-encoded I Ks cardiac potassium channel. We evaluated the effect of location, coding type, and biophysical function of KCNQ1 mutations on the clinical phenotype of this disorder. Methods and Results-We investigated the clinical course in 600 patients with 77 different KCNQ1 mutations in 101 proband-identified families derived from the US portion of the International LQTS Registry (nϭ425), the Netherlands' LQTS Registry (nϭ93), and the Japanese LQTS Registry (nϭ82). The Cox proportional hazards survivorship model was used to evaluate the independent contribution of clinical and genetic factors to the first occurrence of time-dependent cardiac events from birth through age 40 years. The clinical characteristics, distribution of mutations, and overall outcome event rates were similar in patients enrolled from the 3 geographic regions. Biophysical function of the mutations was categorized according to dominant-negative (Ͼ50%) or haploinsufficiency (Յ50%) reduction in cardiac repolarizing I Ks potassium channel current.Patients with transmembrane versus C-terminus mutations (hazard ratio, 2.06; PϽ0.001) and those with mutations having dominant-negative versus haploinsufficiency ion channel effects (hazard ratio, 2.26; PϽ0.001) were at increased risk for cardiac events, and these genetic risks were independent of traditional clinical risk factors. Conclusions-This genotype-phenotype study indicates that in type-1 LQTS, mutations located in the transmembrane portion of the ion channel protein and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder.
Atrial fibrillation (AF) is associated with a high risk of thromboembolic events, and its prevalence is projected to increase because of population aging. 17 Indeed, the thromboembolic complications of AF are an important cause of morbidity and mortality. The CHADS 2 and CHA 2 DS 2 -VASc scores are useful for thromboembolic risk stratification. 18,19 Background-Coronary artery embolism (CE) is recognized as an important nonatherosclerotic cause of acute myocardial infarction. Its prevalence, clinical features, and prognosis remain insufficiently characterized. Methods and Results-We screened 1776 consecutive patients who presented with de novo acute myocardial infarction between 2001 and 2013. CE was diagnosed based on criteria encompassing histological, angiographic, and other diagnostic imaging findings. The prevalence, clinical characteristics, treatment strategies, in-hospital outcomes, and long-term risk of CE recurrence or major adverse cardiac and cerebrovascular events (cardiac death, fatal arrhythmia, or recurrent thromboembolism) were evaluated. The prevalence of CE was 2.9% (n=52), including 8 (15%) patients with multivessel CE. Atrial fibrillation was the most common cause (n=38, 73%). Only 39% of patients with CE were treated with vitamin K antagonists, and the median international normalized ratio was 1.42 (range, 0.95-1.80). Eighteen of the 30 CE patients with nonvalvular atrial fibrillation had a CHADS 2 score of 0 or 1. When those patients were reevaluated using CHA 2 DS 2 -VASc, 61% were reassigned to a higher risk category. During a median follow-up of 49 months, CE and thromboembolism recurred in 5 atrial fibrillation patients. The 5-year rate of major adverse cardiac and cerebrovascular events was 27.1%. In the propensity score-matched cohorts (n=45 each), Kaplan-Meier analysis showed a significantly higher incidence of cardiac death in the CE group than in the non-CE group (hazard ratio, 9.29; 95% confidence interval, 1.13-76.5; P<0.001). Correspondence to Teruo Noguchi, MD, PhD, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, 565-8565, Japan. E-mail tnoguchi@hsp. The present study was designed to evaluate the prevalence, clinical characteristics, and initial management of CE, and early and late outcomes, as well, in a large consecutive series of patients. We also propose new diagnostic criteria for CE based on histological, angiographic, and other diagnostic imaging findings. Conclusions-Atrial Methods Study Population and PCI ProcedureWe retrospectively analyzed a total of 2135 consecutive patients with AMI from January 2001 to December 2013 in the National Cerebral and Cardiovascular Center AMI database. We excluded 359 patients with a history of previous myocardial infarction (n=241), PCI (n=90), coronary artery bypass grafting (n=18), or both PCI and coronary artery bypass grafting (n=10), resulting in a total of 1776 patients with de novo AMI that were ultimately analyzed in this study (Figure 1). All study patients under...
Reactivation of the fetal cardiac gene program is a characteristic feature of hypertrophied and failing hearts that correlates with impaired cardiac function and poor prognosis. However, the mechanism governing the reversible expression of fetal cardiac genes remains unresolved. Here we show that neuronrestrictive silencer factor (NRSF), a transcriptional repressor, selectively regulates expression of multiple fetal cardiac genes, including those for atrial natriuretic peptide, brain natriuretic peptide and a-skeletal actin, and plays a role in molecular pathways leading to the re-expression of those genes in ventricular myocytes. Moreover, transgenic mice expressing a dominant-negative mutant of NRSF in their hearts exhibit dilated cardiomyopathy, high susceptibility to arrhythmias and sudden death. We demonstrate that genes encoding two ion channels that carry the fetal cardiac currents I f and I Ca,T , which are induced in these mice and are potentially responsible for both the cardiac dysfunction and the arrhythmogenesis, are regulated by NRSF. Our results indicate NRSF to be a key transcriptional regulator of the fetal cardiac gene program and suggest an important role for NRSF in maintaining normal cardiac structure and function.
IMPORTANCE Previous studies have suggested an association between vegetarian diets and lower blood pressure (BP), but the relationship is not well established. OBJECTIVE To conduct a systematic review and meta-analysis of controlled clinical trials and observational studies that have examined the association between vegetarian diets and BP.
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