A genome-wide scan suggests a locus on chromosome 1q21-q23 contributes to normal variation in plasma cholesterol concentration

To identify genes that influence plasma cholesterol, triglyceride, and high-density and low-density lipoproteins concentrations we conducted a genome-wide scan using 354 polymorphic markers spaced at 10-cM intervals in 75 obese but otherwise normal human families. The results of the genome scan using sibling pair analysis of quantitative phenotypes suggested that 1q21-q23 contains a locus that influences plasma cholesterol concentration. Chromosome 12 gave evidence of linkage to plasma triglyceride concentration (D12SPAH) and chromosomes 3, 6, 7, 10, 11, 17, and 20 yielded additional evidence of linkage for lipid phenotypes at lower levels of statistical significance. Allele sharing for markers near prominent candidate genes was either very weakly related or unrelated to sibling similarity for lipid concentrations. Together these results suggest that genes with important roles in regulating normal cholesterol and triglyceride concentrations do not coincide with the location of previously known candidate genes.     

Inappropriate therapy from atrial fibrillation and sinus tachycardia in automated implantable cardioverter defibrillators

BACKGROUND: Inappropriate therapy from supraventricular tachyarrhythmias (atrial fibrillation [AF] and sinus tachycardia [ST]) in patients with implanted cardioverter defibrillators is a major challenge. We tested the performance of stability algorithms from 3 manufacturers for episodes of inappropriate therapy delivered because of AF and an onset algorithm for all episodes of inappropriate therapy caused by ST. METHODS: Therapy was classified as caused by ventricular tachycardia (VT), ST, or AF from review of stored intracardiac electrograms, history, clinical information, and R-R data before study inception. By using 30 to 60 R-R intervals before therapy, sensitivity and specificity for a family of stability values and percentage of onset values were calculated for each manufacturer and receiver operating characteristic curves generated. RESULTS: Of the 217 patients monitored, 62 (29%) received inappropriate therapy, and 40 had complete R-R information available. Of the 40 patients, 21 patients received therapy for AF, 19 for ST, and 1 patient for noise; 15 (38%) also received appropriate therapy for VT. We analyzed 83 episodes of VT from 18 patients, 94 episodes of AF from 21 patients, and 56 episodes of ST from 19 patients. Specificity, in the clinically relevant sensitivity range of >/=95%, was comparable across manufacturers at about 40%. An onset value of 80% was associated with 91% sensitivity and 95% specificity for the specific algorithm tested. CONCLUSIONS: Inappropriate therapy is a common problem in implantable cardiac defibrillators. The performance of the stability algorithms used to differentiate AF from VT was less than ideal, though comparable across manufacturers. The onset algorithm accurately differentiates ST from VT.     

Prophylactic implantable cardioverter-defibrillator therapy in patients with left ventricular systolic dysfunction: a pooled analysis of 10 primary prevention trials

Strategies to decrease sudden cardiac death in patients with left ventricular systolic dysfunction are evolving. Recent clinical trials have evaluated the role of prophylactic implantable cardioverter-defibrillators (ICDs) in patients with and without additional risk stratifiers. We pooled studies comparing treatment with and without ICDs from published data and presented abstracts, irrespective of QRS duration and etiology of systolic dysfunction. On the basis of the available clinical trials, implantation of an ICD for primary prevention of death provides a 7.9% absolute mortality reduction (p = 0.003) in patients with left ventricular (LV) systolic dysfunction who were receiving optimized medical therapy. This finding was not sensitive to the exclusion of any individual trial. The ICD is an effective primary preventative measure in patients who are at risk for death; however, the application of this therapy needs to be individualized for the patient, similar to drug therapies in LV systolic dysfunction. In health care settings without unlimited resources, optimal use of this therapy will require better risk stratification methods or lowering of the initial device cost.     

Evolving electroanatomic substrate and intra-atrial reentrant tachycardia late after Fontan surgery

Atrial Remodeling After the Fontan Operation. Introduction: The prevalence of intra‐atrial reentrant tachycardia (IART) increases with age in Fontan patients. This study aimed to characterize the atrial electroanatomic substrate for IART late after Fontan surgery. Methods and Results: Detailed electroanatomic mapping of the right atrium (RA) was performed in 11 consecutive patients (33 ± 9 years) with older style Fontan circulation (atriopulmonary and atrioventricular connection) who underwent their first radiofrequency catheter ablation (RFCA) for IART. A comparative group of 30 non‐Fontan congenital heart disease (CHD) patients were also studied. Fontan patients had larger RA (P = 0.004), larger low‐voltage area ≤0.5 mV (P = 0.01), and more fractionated potentials (P < 0.001) than non‐Fontan CHD patients. RA enlargement correlated significantly with both low‐voltage zones (Spearman ρ= 0.68, P < 0.001) and fractionated potentials (Spearman ρ= 0.48, P = 0.001). Among Fontan patients, both age and time since Fontan surgery were significantly correlated to the amount of low‐voltage areas (Spearman ρ= 0.87, P < 0.001; Spearman ρ= 0.63, P = 0.04, respectively). Successful RFCA was accomplished in 30 (73%) patients and was less likely in Fontan patients (54% vs 83%, P = 0.04). Larger RA was significantly associated with a lower success rate (P = 0.04). During a follow‐up duration of 2.3 ± 1.6 years, IART recurred in 47% of patients. Larger RA size and larger low‐voltage areas predicted IART recurrence after RFCA. Conclusion: Fontan patients demonstrate progressive adverse atrial electrical remodeling with increasing age and time since surgery. Newer strategies beyond surgical incisions, such as pharmacotherapies that retard the progression of atrial fibrosis, may be required to reduce the long‐term risk of atrial arrhythmias.     

Is Inappropriate Implantable Defibrillator Shock Therapy Predictable?

Objective: To identify implantable cardioverter defibrillator (ICD) patients who are at risk of receiving inappropriate shock. Background: Inappropriate ICD shock, usually from atrial fibrillation (AF) or sinus tachycardia (ST), is a common problem. We hypothesized that clinical variables would predict which patients with single chamber ICDs would be more likely to receive inappropriate therapy and be candidates for more accurate discriminators such as those available in dual chamber ICDs. Methods: The ICD registry at St. Michael's Hospital has it's clinical information and demographic data updated after each clinic visit. Inappropriate shock was considered as the outcome variable. Possible predictors considered were age, gender, ejection fraction, NYHA class, prior CABG and prior history of AF. Univariate predictors were identified using t-test for continuous variables and Chi-square test for categorical variables. Multivariate predictors were identified using stepwise logistic regression analyses. Results: Of 299 patients, 261 had complete data for analysis. In this population 78% were male, mean age was 60 ± 13 years, mean ejection fraction was 37 ± 15% and mean follow up was 53 ± 36 months. One hundred and sixteen of the 261 patients (44%) received one or more inappropriate therapies (73% within 2 years of receiving their device), and 140 (51%) received one or more appropriate therapies. Significant predictors of inappropriate therapy by multivariate model were prior AF (OR 2.6, 95% CI 1.5–4.5) and NYHA class 1 vs. classes 2–4 (OR 2.2, 95% CI 1.2–3.7). Conclusion: Clinical characteristics of ICD patients can predict those at risk for inappropriate shock and should be considered for interventions to decrease such shocks.     

A genome-wide scan for linkage to chromosomal regions in 382 sibling pairs with schizophrenia or schizoaffective disorder

OBJECTIVE: Some genome-wide scans and association studies for schizophrenia susceptibility genes have yielded significant positive findings, but there is disagreement between studies on their locations, and no mutation has yet been found in any gene. Since schizophrenia is a complex disorder, a study with sufficient power to detect a locus with a small or moderate gene effect is necessary. METHOD: In a genome-wide scan of 382 sibling pairs with a diagnosis of schizophrenia or schizoaffective disorder, 396 highly polymorphic markers spaced approximately 10 centimorgans apart throughout the genome were genotyped in all individuals. Multipoint nonparametric linkage analysis was performed to evaluate regions of the genome demonstrating increased allele sharing, as measured by a lod score. RESULTS: Two regions with multipoint maximum lod scores suggesting linkage were found. The highest lod scores occurred on chromosome 10p15-p13 (peak lod score of 3.60 at marker D10S189) and the centromeric region of chromosome 2 (peak lod score of 2.99 at marker D2S139). In addition, a maximum lod score of 2.00 was observed with marker D22S283 on chromosome 22q12, which showed evidence of an imprinting effect, whereby an excess sharing of maternal, but not paternal, alleles was present. No evidence of linkage was obtained at several locations identified in previous studies, including chromosomes 1q, 4p, 5p-q, 6p, 8p, 13q, 15p, and 18p. CONCLUSIONS: The findings of this large genome-wide scan emphasize the weakness and fragility of linkage reports on schizophrenia. No linkage appears to be consistently replicable across large studies. Thus, it has to be questioned whether the genetic contribution to this disorder is detectable by these strategies and the possibility raised that it may be epigenetic, i.e., related to gene expression rather than sequence variation. Nevertheless, the positive findings on chromosome 2, 10, and 22 should be pursued further.     

Endocardial and epicardial repolarization alternans in human cardiomyopathy: evidence for spatiotemporal heterogeneity and correlation with body surface T-wave alternans.

OBJECTIVES: The aim of this study was to define the spatiotemporal distribution of intracardiac alternans and its relationship to body surface alternans in humans. BACKGROUND: Spatial heterogeneity of alternans exists in the animal heart owing to nonuniform calcium cycling and restitution kinetics. Patients with cardiomyopathy manifest similar myocardial substrate, which might influence the distribution of intracardiac alternans and its projection onto the body surface. METHODS: Repolarization alternans was simultaneously measured from unipolar electrograms in the right ventricular endocardium, left ventricular (LV) epicardium, and the surface electrocardiogram in patients with cardiomyopathy (n = 14, LV ejection fraction 29 +/- 2%) during atrial pacing at cycle length (CL) 800, 600, and 500 ms. Alternans was determined from the entire JT interval as well as the early, mid, and late JT interval with spectral analysis. RESULTS: Alternans was not uniformly distributed within the heart, with alternating and nonalternating myocardial segments lying adjacent to one another. A greater number of epicardial sites exhibited alternans than endocardial sites at CL 600 ms. Temporal heterogeneity in alternans was present along the JT interval, and apical segments had proportionately less alternans in the late JT interval than mid or basal segments, resulting in apicobasal alternans heterogeneity in late JT interval. Discordant alternans was seen in 5 patients confined to the epicardium. Patients with surface alternans had a greater proportion of intracardiac sites with alternans when compared with those patients without surface alternans. CONCLUSIONS: Spatiotemporal heterogeneity and discordant alternans are evident in patients with cardiomyopathy. Greater spatial distribution of intracardiac alternans is associated with measurable body surface alternans.