Long QT Syndrome

The hereditary long QT syndrome (LQTS) is a genetic channelopathy with variable penetrance that is associated with increased propensity to syncope, polymorphous ventricular tachycardia (torsades de pointes), and sudden arrhythmic death. This inherited cardiac disorder constitutes an important cause of malignant ventricular arrhythmias and sudden cardiac death in young individuals with normal cardiac morphology. Risk assessment in affected LQTS patients relies upon a constellation of electrocardiographic, clinical, and genetic factors. Administration of beta-blockers is the mainstay therapy in affected patients, and primary prevention with an implantable cardioverter defibrillator or left cervicothoracic sympathetic denervation are therapeutic options in patients who remain symptomatic despite beta-blocker therapy. Accumulating data from the International LQTS Registry have recently facilitated a comprehensive analysis of risk factors for aborted cardiac arrest or sudden cardiac death in pre-specified age groups, including the childhood, adolescence, adulthood, and post-40 periods. These analyses have consistently indicated that the phenotypic expression of LQTS is time dependent and age specific, warranting continuous risk assessment in affected patients. Furthermore, the biophysical function, type, and location of the ion-channel mutation are currently emerging as important determinants of outcome in genotyped patients. These new data may be used to improve risk stratification and for the development of gene-specific therapies that may reduce the risk of life-threatening cardiac events in patients with this inherited cardiac disorder

T wave alternans in idiopathic long QT syndrome

AbstractObjectives. The study evaluates the association between T wave alternans and the risk of cardiac events (syncope, aborted cardiac arrest or cardiac death) in a large population of patients with idiopathic long QT syndrome.Background. T wave alternans is an infrequently recorded electrocardiographic (ECG) finding in patients with delayed repolarization, and its clinical significance is not clear.Methods. A total of 4,656 ECG recordings in 2,442 patients enrolled in the International Long QT Syndrome Registry were reviewed for episodes of T wave alternans. To determine the risk associated with T wave alternans, independent of corrected QT interval (QTc) duration, patients with T wave alternans were matched for QTc value (every 0.025 s1/2) to patients with long QT syndrome without T wave alternans.Results. T wave alternans was identified in 39 patients (25 of whom had a QTc interval >0.50 s1/2). A strong association between QTc prolongation and T wave alternans was observed (odds ratio 1.23 per 0.01-s1/2unit increase in QTc, p < 0.0001). Conditional logistic regression analyses with adjustment for age, gender, status and QTc value revealed that T wave alternans did not make a significant independent contribution to the risk of cardiac events. The risk of experiencing a major cardiac event was primarily related to length of QTc.Conclusions. T wave alternans, a marker of electrical instability and regional heterogeneity of repolarization, identifies a high risk subset of patients with prolonged repolarization. Patients with T wave alternans have an increased risk of cardiac events, but this risk is primarily related to the magnitude of repolarization delay (QTc prolongation). T wave alternans does not make an independent contribution to the risk of cardiac events after adjustment for QTc length

Efficacy of Different Beta-Blockers in the Treatment of Long QT Syndrome

AbstractBackgroundIn LQTS, β-blocker therapy is effective in reducing the risk of cardiac events (syncope, aborted cardiac arrest, sudden cardiac death). Limited studies have compared the efficacy of different β-blockers.ObjectivesThe goal of this study was to compare the efficacy of different β-blockers in long QT syndrome (LQTS) and in genotype-positive patients with LQT1 and LQT2.MethodsThe study included 1,530 patients from the Rochester, New York–based LQTS Registry who were prescribed common β-blockers (atenolol, metoprolol, propranolol, or nadolol). Time-dependent Cox regression analyses were used to compare the efficacy of different β-blockers with the risk of cardiac events in LQTS.ResultsRelative to being off β-blockers, the hazard ratios and 95% confidence intervals (CIs) for first cardiac events for atenolol, metoprolol, propranolol, and nadolol were 0.71 (0.50 to 1.01), 0.70 (0.43 to 1.15) 0.65 (0.46 to 0.90), and 0.51 (0.35 to 0.74), respectively. In LQT1, the risk reduction for first cardiac events was similar among the 4 β-blockers, but in LQT2, nadolol provided the only significant risk reduction (hazard ratio: 0.40 [0.16 to 0.98]). Among patients who had a prior cardiac event while taking β-blockers, efficacy for recurrent events differed by drug (p = 0.004), and propranolol was the least effective compared with the other β-blockers.ConclusionsAlthough the 4 β-blockers are equally effective in reducing the risk of a first cardiac event in LQTS, their efficacy differed by genotype; nadolol was the only β-blocker associated with a significant risk reduction in patients with LQT2. Patients experiencing cardiac events during β-blocker therapy are at high risk for subsequent cardiac events, and propranolol is the least effective drug in this high-risk group

Data in support of a central role of plasminogen activator inhibitor-2 polymorphism in recurrent cardiovascular disease risk in the setting of high HDL cholesterol and C-reactive protein using Bayesian network modeling

AbstractData is presented that was utilized as the basis for Bayesian network modeling of influence pathways focusing on the central role of a polymorphism of plasminogen activator inhibitor-2 (PAI-2) on recurrent cardiovascular disease risk in patients with high levels of HDL cholesterol and C-reactive protein (CRP) as a marker of inflammation, “Influences on Plasminogen Activator Inhibitor-2 Polymorphism-Associated Recurrent Cardiovascular Disease Risk in Patients with High HDL Cholesterol and Inflammation” (Corsetti et al., 2016; [1]). The data consist of occurrence of recurrent coronary events in 166 post myocardial infarction patients along with 1. clinical data on gender, race, age, and body mass index; 2. blood level data on 17 biomarkers; and 3. genotype data on 53 presumptive CVD-related single nucleotide polymorphisms. Additionally, a flow diagram of the Bayesian modeling procedure is presented along with Bayesian network subgraphs (root nodes to outcome events) utilized as the data from which PAI-2 associated influence pathways were derived (Corsetti et al., 2016; [1])

The common apolipoprotein A-1 polymorphism −75A>G is associated with ethnic differences in recurrent coronary events after recovery from an acute myocardial infarction

Since data regarding the relationship between a common polymorphism (SNP) of the apoA1 gene with apoA1 levels and risk of coronary artery disease are inconsistent, we hypothesized that its association with recurrent coronary events differs for White and Black individuals with diagnosed coronary heart disease. The apoA1 −75G>A SNP was genotyped in a cohort of 834 Black (n=129) and White (n=705) post-myocardial infarction patients. Recurrent coronary events (coronary-related death, non-fatal myocardial infarction, or unstable angina) were documented during an average follow-up of 28 months. Thirty percent of White and 21% of Black patients carried the SNP. Cox proportional-hazards regression analysis, adjusting for clinical and laboratory covariates, demonstrated that the SNP was not associated with recurrent events in the total cohort (HR=1.37, 95% CI 0.95–1.97; p= 0.09) but was the only variable associated with an increased risk of recurrent cardiac events in Blacks (HR=2.40, 95% CI 1.07–5.40; p= 0.034). Conversely in Whites, the SNP was not associated with recurrent events (HR=1.12, 95% CI 0.75–1.67; p= 0.59) whereas apoB (HR=1.78, 95% CI 1.20 −2.65; p= 0.0042) and calcium channel blocker use (HR=2.53, 95% CI 1.72–3.72; p<0.001) were associated; p= 0.0024 for interaction between ethnicity and the SNP. A common apoA1 SNP is associated with a significantly increased risk of recurrent cardiac events among Black, but not White, postmyocardial infarction patients. Relationships with lipoproteins may help explain this finding

Insulin resistance predicts the risk for recurrent coronary events in post-infarction patients

Background: We investigated the risk for recurrent coronary events associated with insulin resistance in post-infarction patients from the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) study. Methods: The association between insulin resistance expressed by Homeostatic Model As­sessment 2 for Insulin Resistance (HOMA2-IR) and the risk for recurrent coronary events was investigated in a cohort of 1,032 patients evaluated 2 months after myocardial infarction (MI) with a follow-up of 26 months. The endpoint for the study was recurrent coronary event defined as cardiac death, nonfatal MI, or unstable angina, whichever occurred first. We used time dependent survival analysis and Cox proportional hazards regression method to determine the association between HOMA2 categorized as high &gt; 75th percentile and endpoints after adjustment for relevant clinical covariates and series of thrombogenic and dyslipogenic factors. Results: High HOMA2-IR defined as in fourth quartile (≥ 2.4) was associated with increased risk for recurrent coronary events (HR 1.44; CI 1.03–2.01; p = 0.03) after adjustment for the clinical covariates: age, gender, diabetes, prior MI, pulmonary congestion, coronary artery bypass grafting and percutaneous transluminal coronary angioplasty. The highest risk of cardiac events was observed in non-obese patients (body mass index [BMI] ≤ 30 kg/m2) with high HOMA2-IR (HR 1.5; CI 1.02–2.22; p = 0.038). The plasma level of plasminogen activa­tor inhibitor-1 was associated with higher risk for recurrent coronary events in patients with insulin resistance (HR 1.79; CI 1.05–3.03; p = 0.03, interaction p = 0.018). Conclusions: In conclusion, insulin resistance predicts recurrence of coronary events in post-infarction population. HOMA2-IR is better than BMI in stratifying risk of recurrent coronary events

The influence of left ventricular ejection fraction on the effectiveness of cardiac resynchronization therapy: MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy).

OBJECTIVES: The goal of this study was to evaluate the influence of left ventricular (LV) lead position on the risk of ventricular tachyarrhythmia in patients undergoing cardiac resynchronization therapy (CRT). BACKGROUND: Left ventricular ejection fraction (LVEF) is a surrogate marker of heart failure (HF) status and associated risk. Data on the effectiveness of cardiac resynchronization therapy with defibrillator (CRT-D) in patients with mild HF and better LVEF are limited. METHODS: In the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) study, the echocardiography core laboratory assessed baseline LVEF independent of the enrolling centers and identified a range of LVEFs, including those >30% (i.e., beyond the eligibility criteria). Echocardiographic response with CRT, defined as percent change in left ventricular end-diastolic volume (LVEDV), was analyzed in 3 prespecified LVEF groups: >30%, 26% to 30%, and 30% (in the range of 30.1% to 45.3%); 914 patients (50.5%) with LVEF 26% to 30%; and 199 patients with LVEF 30%: 22.3%; LVEF 26% to 30%: 20.1%; and LVEF 30% (hazard ratio [HR]: = 0.56 [95% confidence interval (CI): 0.39 to 0.82], p = 0.003), LVEF 26% to 30% (HR: 0.67: [95% CI: 0.50 to 0.90], p = 0.007), and LVEF 0.1). CONCLUSIONS: In MADIT-CRT, the clinical benefit of CRT was evident regardless of baseline LVEF, including those with LVEF >30%, whereas the echocardiographic response was increased with increasing LVEF, indicating that CRT might benefit patients with better LVEF. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271)