Faisal M. Merchant

The early repolarization pattern in the general population: clinical correlates and heritability

OBJECTIVES This study sought to describe the clinical correlates and heritability of the early repolarization pattern (ERP) in 2 large, population-based cohorts. BACKGROUND There is growing recognition that ERP is associated with adverse outcomes. METHODS Participants of the Framingham Heart Study (FHS) (N = 3,995) and the Health 2000 Survey (H2K) (N = 5,489) were included. ERP was defined as a J-point elevation ≥0.1 mV in ≥2 leads in either the inferior (II, III, aVF) or lateral (I, aVL, V(4-6)) territory or both. We tested the association between clinical characteristics and ERP, and estimated sibling recurrence risk. RESULTS ERP was present in 243 of 3,955 (6.1%) of FHS and 180 of 5,489 (3.3%) of H2K subjects. Male sex, younger age, lower systolic blood pressure, higher Sokolow-Lyon index, and lower Cornell voltage were independently associated with the presence of ERP. In the FHS sample, siblings of individuals with ERP had an ERP prevalence of 11.6% (recurrence risk ratio of 1.89). Siblings of individuals with ERP had an increased unadjusted odds of ERP (odds ratio: 2.22, 95% confidence interval: 1.01 to 4.85, p = 0.047). CONCLUSIONS ERP has strong association with clinical factors and has evidence for a heritable basis in the general population. Further assessment of the genetic determinants of ERP is warranted.

Expedited PublicationThe Early Repolarization Pattern in the General Population: Clinical Correlates and Heritability

OBJECTIVES This study sought to describe the clinical correlates and heritability of the early repolarization pattern (ERP) in 2 large, population-based cohorts. BACKGROUND There is growing recognition that ERP is associated with adverse outcomes. METHODS Participants of the Framingham Heart Study (FHS) (N = 3,995) and the Health 2000 Survey (H2K) (N = 5,489) were included. ERP was defined as a J-point elevation ≥0.1 mV in ≥2 leads in either the inferior (II, III, aVF) or lateral (I, aVL, V(4-6)) territory or both. We tested the association between clinical characteristics and ERP, and estimated sibling recurrence risk. RESULTS ERP was present in 243 of 3,955 (6.1%) of FHS and 180 of 5,489 (3.3%) of H2K subjects. Male sex, younger age, lower systolic blood pressure, higher Sokolow-Lyon index, and lower Cornell voltage were independently associated with the presence of ERP. In the FHS sample, siblings of individuals with ERP had an ERP prevalence of 11.6% (recurrence risk ratio of 1.89). Siblings of individuals with ERP had an increased unadjusted odds of ERP (odds ratio: 2.22, 95% confidence interval: 1.01 to 4.85, p = 0.047). CONCLUSIONS ERP has strong association with clinical factors and has evidence for a heritable basis in the general population. Further assessment of the genetic determinants of ERP is warranted.

In vivo association between positive coronary artery remodelling and coronary plaque characteristics assessed by intravascular optical coherence tomography

AIMS Positive coronary arterial remodelling has been shown to be associated with unstable coronary syndromes and ex vivo histological characteristics of plaque vulnerability such as a large lipid core and high macrophage content. The aim of this study is to evaluate the in vivo association between coronary artery remodelling and underlying plaque characteristics identified by optical coherence tomography (OCT). OCT is a unique imaging modality capable of characterizing these important morphological features of vulnerable plaque. METHODS AND RESULTS OCT and intravascular ultrasound imaging was performed at corresponding sites in patients undergoing catheterization. OCT plaque characteristics for lipid content, fibrous cap thickness, and macrophage density were derived using previously validated criteria. Thin-cap fibroatheroma (TCFA) was defined as lipid-rich plaque (two or more quadrants) with fibrous cap thickness <65 microm. Remodelling index (RI) was calculated as the ratio of the lesion to the reference external elastic membrane area. A total of 54 lesions from 48 patients were imaged. Positive remodelling compared with absent or negative remodelling was more commonly associated with lipid-rich plaque (100 vs. 60 vs. 47.4%, P = 0.01), a thin fibrous cap (median 40.2 vs. 51.6 vs. 87 microm, P = 0.003) and the presence of TCFA (80 vs. 38.5 vs. 5.6%, P < 0.001). Fibrous cap macrophage density was also higher in plaques with positive remodelling showing a positive linear correlation with the RI (r = 0.60, P < 0.001). CONCLUSION Coronary plaques with positive remodelling exhibit characteristic features of vulnerable plaque. This may explain the link between positive remodelling and unstable clinical presentations.

Impact of segmental left ventricle lead position on cardiac resynchronization therapy outcomes

BACKGROUND The optimal pacing site for cardiac resynchronization therapy (CRT) is along the left ventricle (LV) lateral or posterolateral wall. However, little is known about the impact of segmental pacing site on outcomes. OBJECTIVE We assessed the impact of segmental LV lead position on CRT outcomes. METHODS Patients (n = 115) undergoing CRT were followed prospectively. Segmental LV lead position along the longitudinal axis (apical, midventricle, or basal) was determined retrospectively by examining coronary sinus (CS) venograms and chest X-rays. The primary outcome was a combined endpoint of heart failure hospitalization, cardiac transplantation, or all-cause mortality. Secondary outcomes included change in New York Heart Association (NYHA) functional class and degree of LV reverse remodeling. RESULTS Patients were divided into two groups based on LV lead position: apical (n = 25) and basal/midventricle (n = 90). The apical group was older (72.9 +/- 8.9 vs. 66.5 +/- 13.3 years; P = .010) and more likely to have ischemic cardiomyopathy (77% vs. 52%, P <.001). During a mean follow-up of 15.1 +/- 9.0 months, event-free survival was significantly lower in the apical group: 52% vs. 79%, hazard ratio [HR] 2.7 (95% confidence interval [CI] 1.5-5.5, P = .006). The adverse impact of apical lead placement remained significant after adjusting for clinical covariates: HR 2.3 (95% CI 1.1-4.8, P = .03). The apical group also experienced less improvement in NYHA functional class and less LV reverse remodeling. CONCLUSIONS Apical LV lead placement is associated with worse CRT outcomes. Preferential positioning of LV leads in the basal/midventricle segments may improve outcomes.

A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern

BACKGROUND The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable, and mutations have been described in syndromatic cases. OBJECTIVE To conduct a meta-analysis of genome-wide association studies to identify common genetic variants influencing ERP. METHODS We ascertained ERP on the basis of electrocardiograms in 3 large community-based cohorts from Europe and the United States: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed genome-wide association studies in participants with and without ERP by logistic regression assuming an additive genetic model and meta-analyzed individual cohort results. We then sought to strengthen support for findings that reached P ≤ 1 × 10(-5) in independent individuals by direct genotyping or in-silico analysis of genome-wide data. We meta-analyzed the results from both stages. RESULTS Of 7482 individuals in the discovery stage, 452 showed ERP (ERP positive: mean age 46.9 ± 8.9 years, 30.3% women; ERP negative: 47.5 ± 9.4 years, 54.2% women). After meta-analysis, 8 single nucleotide polymorphisms reached P ≤ 1 × 10(-5): The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36-0.61; P = 6.9 × 10(-9)). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95% confidence interval 1.25-1.69; P = 8.5 × 10(-7)). In the replication step (7151 individuals), none of the 8 variants replicated, and combined meta-analysis results failed to reach genome-wide significance. CONCLUSIONS In a genome-wide association study, we were not able to reliably identify genetic variants predisposing to ERP, presumably due to insufficient statistical power and phenotype heterogeneity. The reported heritability of ERP warrants continued investigation in larger well-phenotyped populations.

Implantable sensors for heart failure.

Heart failure (HF) affects more than 5 million Americans, and acute decompensated heart failure (ADHF) has emerged as the leading cause of hospitalization among people over the age of 65 years.1 Importantly, HF is a leading public health concern, and hospitalization expenses related to management of ADHF impose a substantial financial burden on the health care system. Additionally, readmission rates after hospitalization for ADHF may be as high as 50% at 6 months,2 and insights from the ADHERE registry suggest that a majority of patients admitted with ADHF have a history of heart failure.1 These data demonstrate that the majority of patients admitted with ADHF are known to the medical system and to medical providers, thereby creating an opportunity for upstream strategies that may be capable of detecting early HF destabilization and implementing therapies to restabilize the patient and avert hospitalization. The anticipated changes in the health care system—with a focus on bundled payments for disease management—will necessitate robust disease management programs to optimize therapy and minimize recurrent admissions once patients have been diagnosed with HF. Perhaps even more importantly, averting repeat episodes of ADHF is likely to have a stabilizing effect on the progression of HF and may improve long-term morbidity and mortality. The transition from chronic HF to ADHF involves perturbations in multiple intersecting processes including neurohormonal circuits, inflammatory mediators, cardiorenal interactions, and myocardial performance. Concurrently, derangements in comorbid illnesses such as coronary disease, atrial and ventricular arrhythmias, and hypertension also contribute to the pathophysiology of ADHF.3 Ultimately, these multiple pathways lead to an elevation in ventricular filling pressures and signs of vascular congestion, which, in concert with symptoms from impaired cardiac output, lead to the clinical constellation of ADHF. This pathophysiologic paradigm highlights multiple opportunities for detecting early changes in the processes that …

Interlead Distance and Left Ventricular Lead Electrical Delay Predict Reverse Remodeling During Cardiac Resynchronization Therapy

Background: Both anatomic interlead separation and left ventricle lead electrical delay (LVLED) have been associated with outcomes following cardiac resynchronization therapy (CRT). However, the relationship between interlead distance and electrical delay in predicting CRT outcomes has not been defined.

Catheter ablation of atrial fibrillation the search for substrate-driven end points.

Indications for catheter ablation of atrial fibrillation (AF) have expanded to include increasingly complex cases, such as long-standing persistent AF and structural heart disease. Although pulmonary vein isolation remains essential for most ablation procedures, the role of substrate modification has taken on increasing importance. Despite the various ablation strategies available, single-procedure efficacy remains suboptimal among patients with structural heart disease or long-standing persistent AF, where recurrence rates may exceed 50% after a single procedure. These high rates of AF recurrence support the notion that currently available procedural end points are ineffective in identifying which patients are most likely to benefit from substrate modification and defining when that substrate has been sufficiently modified such that additional ablation is unnecessary. In order to improve outcomes, the next generation of procedural end points should seek to define specific properties of the underlying atrial electrical substrate and characterize the impact of catheter ablation on those electrophysiologic properties. The use of substrate-driven end points would be a major step in the process of moving from empiric ablation lesions to a customized ablation strategy based on atrial physiology. In this article, we review current approaches to catheter ablation of AF and discuss specific procedural end points as they pertain to each ablation strategy. We also provide a paradigm for the future development of novel substrate-driven procedural end points.

Outcome of Subcutaneous Implantable Cardioverter Defibrillator Implantation in Patients with End‐Stage Renal Disease on Dialysis

Although the subcutaneous ICD (S‐ICD®) is an attractive alternative in patients with end‐stage renal disease (ESRD), data on S‐ICD outcomes in dialysis patients are lacking.

Incidence of defibrillator shocks after elective generator exchange following uneventful first battery life.

Background A significant number of implantable cardioverter‐defibrillator (ICD) patients do not experience shocks after ICD implant. Elective generator exchange (GE) has been associated with increased risk of infection and ICD lead failure. There is a paucity of contemporary data reporting on shock incidence with replacement devices. Methods and Results Patients undergoing elective GE (n=24 203) who transmit data remotely via a remote monitoring system were analyzed to determine the incidence of ICD shocks after GE. A total of 16 230 patients (67%) did not experience a shock with the first ICD (group A), and 7973 (33%) received at least 1 shock (group B). Patients in group A were older (71.3 versus 68.8 years, P<0.001) and more often female (71% versus 77% male, P<0.001). Over an average follow‐up of 1.9±1.2 years after GE, the proportion of patients with shocks and risk of ICD shocks was lower for those who did not receive a shock during the first battery life (group A: 9.9% versus 27.7%, hazard ratio 0.36, 95% CI 0.34 to 0.38, P<0.001). The cumulative rate of ICD shocks at 5 years after GE was 25.7% in group A and 51.1% in group B. Conclusions In this large cohort of ICD patients implanted across the United States, two thirds did not receive ICD shock therapy prior to GE. The occurrence of ICD shocks prior to GE is an important predictor of shocks after GE; however, even among those without shocks during first battery life, the incidence of shocks at 5 years following GE is >25%. These data should support informed decision making for patients and physicians at the time of ICD generator end of service.