The role of GPD1L, a sodium channel interacting gene, in the pathogenesis of Brugada Syndrome.

Background: Brugada Syndrome (BrS) is an inherited arrhythmia syndrome in which mutations in the cardiac sodium channel (Na1.5) account for approximately 20% of cases. Mutations in sodium channel-modifying genes may account for additional BrS cases, though BrS may be polygenic given common SNPs associated with BrS have been identified.

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls.

IDENTIFYING NEW SUDDEN DEATH GENES.

Inherited conditions that lead to cardiac arrhythmias and sudden cardiac death remain an important cause of morbidity and mortality. Identifying the genes responsible for these rare conditions can provide insights into the more common and heritable forms of sudden cardiac death seen in patients with structural heart disease. We and others have used candidate gene approaches and positional cloning in large families to show that mutations in ion channels and ion channel related proteins cause familial arrhythmia syndromes including long QT and Brugada syndromes.

Multi-ethnic genome-wide association study for atrial fibrillation.

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis.

A common variant alters SCN5A-miR-24 interaction and associates with heart failure mortality.

SCN5A encodes the voltage-gated Na+ channel NaV1.5 that is responsible for depolarization of the cardiac action potential and rapid intercellular conduction. Mutations disrupting the SCN5A coding sequence cause inherited arrhythmias and cardiomyopathy, and single-nucleotide polymorphisms (SNPs) linked to SCN5A splicing, localization, and function associate with heart failure-related sudden cardiac death.

Serum amine-based metabolites and their association with outcomes in primary prevention implantable cardioverter-defibrillator patients.

Aims: Heart failure patients are at increased risk of ventricular arrhythmias and all-cause mortality. However, existing clinical and serum markers only modestly predict these adverse events. We sought to use metabolic profiling to identify novel biomarkers in two independent prospective cohorts of patients with implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden cardiac death (SCD).

Anesthetic Considerations for a Patient With Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome) Undergoing a Five-Box Thoracoscopic Maze Procedure for Atrial Fibrillation.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder involving the abnormal communication of vascular structures. HHT typically presents with recurrent epistaxis and telangiectasis of the nasal and buccal mucosa, tongue, and lips. More serious manifestations of this disease include cerebral, pulmonary, gastrointestinal, and hepatic arteriovenous malformations.

Left Ventricular Dilatation Increases the Risk of Ventricular Arrhythmias in Patients With Reduced Systolic Function.

Background: Reduced left ventricular (LV) ejection fraction increases the risk of ventricular arrhythmias; however, LV ejection fraction has a low sensitivity to predict ventricular arrhythmias. LV dilatation and mass may be useful to further risk-stratify for ventricular arrhythmias.

Methods And Results: Patients from the Genetic Risk of Assessment of Defibrillator Events (GRADE) study (N=930), a study of heart failure subjects with defibrillators, were assessed for appropriate implantable cardioverter-defibrillator shock and death, heart transplant, or ventricular assist device placement by LV diameter and mass.

Effect of angiotensin-converting enzyme inhibitors and receptor blockers on appropriate implantable cardiac defibrillator shock in patients with severe systolic heart failure (from the GRADE Multicenter Study).

Sudden cardiac death (SCD) is a leading cause of mortality in patients with cardiomyopathy. Although angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) decrease cardiac mortality in these cohorts, their role in preventing SCD has not been well established. We sought to determine whether the use of ACEi or ARB in patients with cardiomyopathy is associated with a lower incidence of appropriate implantable cardiac defibrillator (ICD) shocks in the Genetic Risk Assessment of Defibrillator Events study that included subjects with an ejection fraction of ≤30% and ICDs.

Preoperative Prevalence of Staphylococcus aureus in Cardiothoracic and Neurological Surgical Patients.

Methicillin-resistant Staphylococcus aureus (MRSA) is a global cause of both hospital and community-acquired infection. This retrospective, observational study determined the prevalence of MRSA carriers in cardiothoracic and neurological surgical patients presenting to an outpatient preoperative assessment center in Columbus, OH. Aggressive skin and soft-tissue infection may be caused by MRSA with potentially fatal complications.

Genetic variation in the alternative splicing regulator RBM20 is associated with dilated cardiomyopathy.

Background: Dilated cardiomyopathy (DCM) is a leading cause of heart failure and death. The etiology of DCM is genetically heterogeneous.

Objectives: We sought to define the prevalence of mutations in the RNA splicing protein RBM20 in a large cohort with DCM and to determine whether genetic variation in RBM20 is associated with clinical outcomes.

Array-based comparative genomic hybridization identifies CDK4 and FOXM1 alterations as independent predictors of survival in malignant peripheral nerve sheath tumor.

Purpose: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCGH) on a large set of MPNSTs.

Experimental Design: Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens.

Statins Decrease Oxidative Stress and ICD Therapies.

Recent studies demonstrate that statins decrease ventricular arrhythmias in internal cardioverter defibrillator (ICD) patients. The mechanism is unknown, but evidence links increased inflammatory and oxidative states with increased arrhythmias. We hypothesized that statin use decreases oxidation.

Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias.

Background: Brugada syndrome is a rare, autosomal-dominant, male-predominant form of idiopathic ventricular fibrillation characterized by a right bundle-branch block and ST elevation in the right precordial leads of the surface ECG. Mutations in the cardiac Na+ channel SCN5A on chromosome 3p21 cause approximately 20% of the cases of Brugada syndrome; most mutations decrease inward Na+ current, some by preventing trafficking of the channels to the surface membrane. We previously used positional cloning to identify a new locus on chromosome 3p24 in a large family with Brugada syndrome and excluded SCN5A as a candidate gene.