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Biomedical subjects

Michael Gollob

Publications and source records attributed to Michael Gollob.

8 recordsLinked to original sources
PubMed2026

RBM20 Truncating Variants and Human Cardiomyopathy.

IMPORTANCE: Genetic diagnosis has become increasingly important to guide clinical decision-making for patients with dilated cardiomyopathy (DCM). Pathogenic or likely pathogenic (P/LP) missense variants in the gene RBM20 cause a highly penetrant arrhythmogenic DCM, but the role of RBM20 truncating variants (RBM20tvs) is unclear. OBJECTIVE: To assess the contribution of RBM20 variants to arrhythmogenic DCM. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, participants in the genome-first UK Biobank (UKB) and All of Us populations were evaluated to assess the etiologic fraction, natural history and penetrance of RBM20 variants. Retrospective data were collected from an international cohort of patients with DCM and RBM20 variants identified at centers of excellence for genetic heart disease and compared based on time to event. Study dates are not disclosed because the institutional review board did not authorize the sharing of this information. EXPOSURES: RBM20 variants were compared to known P/LP variants and variants of uncertain significance in RBM20 as well as titin truncating variants (TTNtvs). MAIN OUTCOMES AND MEASURES: Major ventricular arrhythmias, end-stage heart failure, and heart failure hospitalization as measured by medical record review (retrospective cohort) and diagnostic codes (UKB). RESULTS: Two main cohorts were studied for this project. In UK Biobank, a cohort of participants with RBM20tvs, RBM20 synonymous variants, and TTNtvs was studied. Of these 4249 participants, 1869 (44%) were male. The mean (SD) age at enrollment was 56 (8.2) years. In the RBM20 registry, of 179 patients, 105 (58.6%) were male, and the mean (SD) age at enrollment was 43.8 (19.1) years. A validation cohort from the All of Us biobank was also used. This consisted of 7002 participants, 4342 of whom (62.0%) were male, and the mean (SD) age was 52.7 (16.7) years. The etiologic fraction of RBM20 variants in arrhythmogenic DCM was 0.53 (95% CI, 0.32-0.67; P&#x2009;<&#x2009;.001). In genome-first biobanks, lifetime incidence of cardiomyopathy, heart failure, or major ventricular arrhythmia diagnosis was lower in participants with RBM20 variants than in those with TTNtvs (hazard ratio, 0.55; 95% CI, 0.36-0.84; P&#x2009;<&#x2009;.001). Patients with RBM20tvs and DCM presented to referral centers later in life than those with P/LP RBM20 and DCM (mean [SD], 53 [10] vs 34 [18] years; P&#x2009;<&#x2009;.001) and were less likely to have a family history of sudden cardiac arrest (2 of 10 [20%] vs 11 of 17 [65%]; P&#x2009;=&#x2009;.046) or cardiomyopathy (2 of 10 [20%] vs 14 of 18 [78%]; P&#x2009;<&#x2009;.001). There was no significant difference in age- and sex-adjusted incident major heart failure or arrhythmia events between patients with RBM20tv and DCM or those with P/LP RBM20 and DCM, though sex-adjusted lifetime hazard was reduced in those with RBM20tv and DCM (hazard ratio, 0.13; 95% CI, 0.03-0.56; P&#x2009;=&#x2009;.01). CONCLUSIONS AND RELEVANCE: This study found that RBM20 variants contributed to arrhythmogenic DCM phenotypes but conferred reduced lifetime disease penetrance compared to TTNtvs and milder disease severity alone than P/LP RBM20 variants. Their potential for additive interactions with other damaging variants should be considered in patients with DCM and their families.

Humans↗
PubMed2006

Reasons for escalating pacemaker implants.

Surveys of pacing practice have shown a steady increase in pacemaker implantation rates in the past 15 years, despite no major changes in United States guidelines for permanent pacing. There are no data to explain why this is occurring. In this study, records were extracted from the National Hospital Discharge Survey to investigate this. There were 3 major findings. First, age-adjusted implantation rates increased progressively over the study period from 370 per million in 1990 to 612 per million in 2002. Second, it was found that the escalating implantation rate is attributable to increasing implantation for isolated sinus node dysfunction (SND). Implantation for SND increased significantly over the study period (by 102%), whereas implantation for all other indications did not. The increasing implantation for SND is due primarily to the increasing prevalence of SND, with a lesser increase in implantation rate relative to prevalence rate. The third major finding of this study is that there has been a progressive relative and absolute increase in the dual-chamber implantation rate. In 2002, 82.8% of all initial pacemaker implantations were dual-chamber devices. Furthermore, the National Hospital Discharge Survey data indicate that the major randomized pacing trials seem to have had no impact on pacing practice in the United States. In conclusion, age-adjusted implantation rates increased progressively over the study period. This escalating implantation rate is primarily attributable to increasing implantation for SND.

Age Factors↗
PubMed2006

Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation.

BACKGROUND: Numerous reports have demonstrated an association between autonomic tone and atrial fibrillation (AF). Pulmonary vein (PV) denervation during catheter ablation of AF has been shown to significantly reduce recurrence of AF. OBJECTIVES: The purpose of this study was to assess the safety and efficacy of high-frequency stimulation at mapping cardiac ganglionated plexuses in patients undergoing catheter ablation of AF. METHODS: Fourteen patients with a history of symptomatic AF underwent a single transseptal approach and electroanatomic mapping of the left atrium, right atrium, and coronary sinus. Using high-frequency stimulation with patients under general anesthesia (20-50 Hz, 5-15 V, pulse width 10 ms), mapping of ganglionated plexuses was performed. Radiofrequency (RF) ablation was performed during AF guided by complex fractionated atrial electrograms. Lesions were mostly delivered circumferentially in the antral area of the PVs, predominantly over and adjacent to regions of ganglionated plexuses. RESULTS: There was a mean of 4 +/- 1 (range 2-6) ganglionated plexuses per patient, and a mean total of 3 +/- 1 RF applications were delivered over positive vagal sites. Although a vagal response occurred infrequently during ablation (0.9%), postablation high-frequency stimulation failed to provoke a vagal response in 30 (88%) of 34 previously positive vagal sites that underwent ablation. CONCLUSION: Ganglionated plexuses can be precisely mapped using high-frequency stimulation and are located predominantly in the path of lesions delivered during ablation of AF. Objective documentation of modification of autonomic tone can be documented in the majority of patients. Future studies are required to determine the specific role of mapping and targeting of ganglionated plexuses in patients undergoing catheter ablation of AF.

Adult↗
PubMed2006

Molecular cardiology and genetics in the 21st century--a primer.

The terminology and technology of molecular genetics and recombinant DNA have become an essential part of academic cardiology and will soon be applied at the bedside. The treatise includes a brief summary of the essentials of the DNA molecule, the more common techniques, and their application to genetics and molecular cardiology. It is written to be understood by physicians, scientists, and paramedical personnel who would not necessarily have a background in molecular biology. Inherent in the DNA molecule are three properties fundamental to all of the diagnostic and therapeutic applications, namely, the ability of DNA to separate into single strands, recombine (annealment or hybridization), and the presence of the negative charge enables DNA fragments to be separated easily by electrophoresis. Genetic linkage analysis of a family with an inherited disease enables one to identify the gene without knowing its protein product. Over 50 diseases in cardiology due to single-gene disorders have been identified and multiple mutations have been detected. The new therapeutic frontier will be stem cells and nuclear transfer. Identification of genes responsible for coronary artery disease made possible by genome-wide single nucleotide polymorphism (SNP) mapping techniques paves the way for personalized medicine.

Animals↗
PubMed2006

Clinical trials, the renin angiotensin system and atrial fibrillation.

PURPOSE OF REVIEW: Atrial fibrillation is the most common clinical arrhythmia. Current treatment strategies are far from optimal. One new research direction is to target the atrial fibrillation substrate and to examine whether drugs can produce atrial structural and/or electrophysiological remodeling and whether this results in a reduction in atrial fibrillation burden. RECENT FINDINGS: Two prospective randomized studies have shown that the addition of an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker to amiodarone reduces the recurrence rate of atrial fibrillation after electrical cardioversion. There are ten completed prospective clinical trials with atrial fibrillation as a secondary endpoint or assessed in post-hoc analysis. Five of these studies have reported a positive impact of angiotensin converting enzyme inhibitors or angiotensin receptor blockers on atrial fibrillation burden. A meta-analysis showed that active drugs reduced the overall risk of development of atrial fibrillation by 28%. Patients in the heart failure trials obtained most benefit from these drugs (relative risk reduction 44%, P = 0.07). SUMMARY: The initial basic science and clinical trial data suggest that modulation of the renin angiotensin system may be an effective treatment for atrial fibrillation. The following, however, remain to be clarified: do these drugs have a clinically meaningful impact on atrial fibrillation burden; if there is an impact, is it similar in all atrial fibrillation patients or just in certain subsets; do angiotensin converting enzyme inhibitors and angiotensin receptor blockers have similar benefits; and is there a role for aldosterone antagonists?

Angiotensin Receptor Antagonists↗
PubMed2005

Diagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusion.

BACKGROUND: Cardiac arrest with preserved left ventricular function may be caused by uncommon genetic conditions. Although these may be evident on the ECG, long-term monitoring or provocative testing is often necessary to unmask latent primary electrical disease. METHODS AND RESULTS: Patients with unexplained cardiac arrest and no evident cardiac disease (normal left ventricular function, coronary arteries, and resting corrected QT) underwent pharmacological challenge with adrenaline and procainamide infusions to unmask subclinical primary electrical disease. Family members underwent noninvasive screening and directed provocative testing on the basis of findings in the proband. Eighteen patients (mean+/-SD age, 41+/-17 years; 11 female) with unexplained cardiac arrest were assessed. The final diagnosis was catecholaminergic ventricular tachycardia (CPVT) in 10 patients (56%), Brugada syndrome in 2 patients (11%), and unexplained (idiopathic ventricular fibrillation) in 6 patients (33%). Of 55 family members (mean+/-SD age, 27+/-17 years; 33 female), 9 additional affected family members were detected from 2 families, with a single Brugada syndrome patient and 8 CPVT patients. CONCLUSIONS: Provocative testing with adrenaline and procainamide infusions is useful in unmasking the etiology of apparent unexplained cardiac arrest. This approach helps to diagnose primary electrical disease, such as CPVT and Brugada syndrome, and provides the opportunity for therapeutic intervention in identified, asymptomatic family members who harbor the same disease.

Anti-Arrhythmia Agents↗
PubMed2005

Long-term outcome of cardiac resynchronization therapy in patients with severe congestive heart failure.

BACKGROUND: Cardiac resynchronization therapy (CRT) has recently been shown to be an effective short-term therapy for patients with drug-refractory heart failure and intraventricular conduction delay. Little is known about the long-term effects of this therapy. OBJECTIVES: To determine the long-term outcome of all consecutive patients who underwent CRT at two Canadian centres, and to determine what baseline variables predict a response to CRT. RESULTS AND CONCLUSIONS: The present study comprised a total of 85 patients (mean age 66+/-9 years; 88% male) with New York Heart Association class II (4%), class III (84%) or class IV (12%) heart failure. All patients fulfilled the standard CRT indications with a QRS duration of 168+/-22 ms and a nuclear gated ejection fraction (EF) of 21+/-6%. Eighteen of the 85 patients were implanted with a combination automatic implantable cardioverter-defibrillator and CRT device. Within a mean clinical follow-up of 3.0+/-1.0 years, 26 of the 85 patients died, and eight patients underwent cardiac transplantation, with four transplant-related deaths (mean survival 3.53+/-0.26 years). Ten patients died of sudden cardiac death, eight patients died of progressive heart failure and eight patients died of noncardiac causes. None of the baseline factors (age, sex, EF, etiology, New York Heart Association class, QRS duration or implantable cardioverter-defibrillator) or indexes of CRT (change in EF or QRS duration) were predictive of a poor outcome. There was a clear trend for patients with a greater left ventricular EF gain to have a better outcome (P=0.1). The present observational data represent one of the longest follow-up databases of patients undergoing CRT. The significant morbidity and mortality found after CRT highlight the severity of the underlying cardiac pathology and concurrent illnesses.

Aged↗