JT interval: What does this interval mean?

The JTp interval gained interest as a marker differentiating effects of drugs on cardiac ion channels. For JTp interval, both the beginning - identification of J point and identification of T wave end remains the subject of substantial variability. We aimed to analyze diagnostic and prognostic performance of JTp interval in the International LQTS Registry data. ECGs from 804 gene carriers and 1139 non-carriers from LQT1 families, 735 carriers and 1145 non-carriers from LQT2 families, and 238 carriers and 554 non-carriers from LQT3 families were evaluated. The diagnostic performance of JTpc was similar to QTc in LQT1 and LQT3 patients but inferior in LQT2 patients, whereas repolarization duration in general had limited diagnostic performance in LQT3 patients. The prognostic significance for predicting cardiac events in LQT1 and LQT2 patients was similar for JTpc and QTc. In LQT3 patients, JTpc fails to be associated with arrhythmic events.

Early procedure-related adverse events by gender in MADIT-CRT.

BACKGROUND: Whether gender differences exist in procedure-related adverse events following cardiac resynchronization therapy (CRT-D) implantation is unknown. We investigated the type and frequency of procedure-related adverse events among those enrolled in MADIT-CRT and identified clinical predictors for gender-specific events. METHODS: We compared differences in the rate of procedure-related adverse events by gender (444 females and 1,346 males) that occurred ≤30 days after the index procedure in the implantable cardioverter defibrillator (ICD) and CRT-D groups. Eight types of major adverse events were identified, defined as procedure-related complications deemed potentially life-threatening. Best subset regression analysis (P < 0.10) was performed to identify baseline clinical factors associated with procedure-related adverse events that differed by gender. RESULTS: Women randomized to CRT-D received a greater reduction in the risk of heart failure or death versus men (P < 0.001). Women were twice as likely as men to experience a major procedure-related adverse event (6.3% vs. 2.7%; P < 0.001), including pneumothorax/hemothorax (3% vs. 1%; P < 0.001). Women were more likely to experience a major adverse event related to CRT-D than ICD implantation (7.7% vs. 2.9%; P = 0.018). Clinical predictors of major adverse events in females were smaller body mass index (BMI), elevated blood urea nitrogen, and elevated creatinine. The main predictor for pneumothorax/hemothorax was reduced BMI for women and men. CONCLUSION: Women demonstrate greater clinical benefit from CRT than men but are more likely to experience adverse procedure-related events within the first 30 days after device implantation. A smaller BMI seems to be a major factor associated with pneumothorax/hemothorax in both females and males.

A metric for evaluating the cardiac response to resynchronization therapy.

We hypothesized that the response to cardiac resynchronization therapy with a defibrillator (CRT-D) in patients with mildly symptomatic heart failure (HF) is more favorable than the commonly referenced figure of 70%. This study involves the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study population in which paired echocardiograms from baseline and 1-year follow-up were available in 621 implantable cardioverter-defibrillator-treated patients and 749 patients treated with CRT-D. We prespecified CRT-D responders as the patients who at 1-year follow-up had a reduction in left ventricular end-systolic volume (LVESV) that corresponded to the top (best) quintile of LVESV reduction in the implantable cardioverter-defibrillator-treated patients, that is, a ≥17% reduction in LVESV. Using this metric, 88% of patients treated with CRT-D and 91% of the patients treated with CRT-D with left bundle branch block (LBBB) were identified as cardiac resynchronization therapy responders. Landmark multivariate Cox model analyses revealed a significant interaction (p=0.038) involving LVESV (responders vs nonresponders) and LBBB (present vs not present) in risk reduction for HF or death. The interaction finding indicates that cardiac resynchronization therapy responders with LBBB have a significantly lower risk for HF or death (hazard ratio [HR] 0.24) than patients without LBBB (HR 0.62). In the patients treated with CRT-D, LVESV response was associated with reduction in the risk of death (HR 0.20, p<0.001). An increasing percent reduction in LVESV was associated with progressively lower rates of HF or death, a finding consistent with a dose-response relation. In conclusion, approximately 90% of CRT-D-treated patients in MADIT-CRT had a significant and meaningful reduction in LVESV, and these LVESV responders had reduced rates of cardiac events during long-term follow-up.

The effect of weight loss on clinical outcomes in patients implanted with a cardiac resynchronization therapy device-A MADIT-CRT substudy.

BACKGROUND: There are no data regarding the effect of weight loss on clinical outcomes in patients undergoing cardiac resynchronization therapy. This study was designed to evaluate the effect of weight loss on clinical outcomes in patients implanted with a cardiac resynchronization therapy with defibrillator (CRT-D). METHODS AND RESULTS: The risk of heart failure (HF) or death, and of death alone, was compared between patients with and without weight loss of ≥2 kg or more at 1 year in the CRT-D arm of the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT). Weight loss was observed in 170 of 994 patients (17%) implanted with a CRT-D. Multivariate analysis showed a significant increase in the risk of HF or death among patients with weight loss compared with those without weight loss (hazard ratio [HR] 1.82, 95% confidence interval [CI] 1.26-2.63; P = .001). Weight loss was associated with a 79% increase in the risk of all-cause mortality (HR 1.79, 95% CI 1.16-3.34; P = .01). When analyzed in a continuous fashion, each kg of weight loss was associated with a 4% increase in the risk of HF or death (P = .03). In left bundle branch block (LBBB) patients with a CRT-D, weight loss was associated with an especially high risk of HF or death (HR 2.23, 95% CI 1.36-3.65; P = .002) and of death alone (HR 2.33, 95% CI 1.07-5.06; P = .03; interaction P = .26). CONCLUSIONS: In patients with mild symptoms of HF receiving CRT-D, weight loss observed at 1 year is associated with adverse clinical outcomes, especially in those with a LBBB electrocardiographic pattern.

Prognostic value of average T-wave alternans and QT variability for cardiac events in MADIT-II patients.

BACKGROUND: Identifying which patients might benefit the most from ICD therapy remains challenging. We hypothesize that increased T-wave alternans (TWA) and QT variability (QTV) provide complementary information for predicting appropriate ICD therapy in patients with previous myocardial infarction and reduced ejection fraction. METHODS: We analyzed 10-min resting ECGs from MADIT-II patients with baseline heart rate >80 beats/min. TWA indices IAA and IAA90 were computed with the multilead Laplacian Likelihood ratio method. QTV indices QTVN and QTVI were measured using a standard approach. Cox proportional hazard models were adjusted considering appropriate ICD therapy and sudden cardiac death (SCD) as endpoints. RESULTS: TWA and QTV were measured in 175 patients. Neither QTV nor TWA predicted SCD. Appropriate ICD therapy was predicted by combining IAA90 and QTVN after adjusting for relevant correlates. CONCLUSION: Increased TWA and QTV are independent predictors of appropriate ICD therapy in MADIT-II patients with elevated heart rate at baseline.

Response of right ventricular size to treatment with cardiac resynchronization therapy and the risk of ventricular tachyarrhythmias in MADIT-CRT.

BACKGROUND: Cardiac resynchronization therapy (CRT) is increasingly recognized for its ability to reduce ventricular tachyarrhythmias, possibly associated with left ventricular reverse remodeling, but the role of the right ventricle (RV) in this process has not been examined. OBJECTIVE: The purpose of this study was to investigate the relationship between ventricular tachyarrhythmias and change in RV dimensions in patients receiving CRT with a defibrillator (CRT-D). METHODS: Multivariate Cox proportional hazards regression modeling was used to assess the risk for fast (≥180 bpm) ventricular tachycardia/ventricular fibrillation (VT/VF) or death by baseline and follow-up RV size (defined as right ventricular end-diastolic area [RVEDA]) among 1495 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT). RESULTS: Multivariate analysis showed that treatment with CRT-D was independently associated with a 27% (P = .003) reduction in the risk of VT/VF or death among patients with larger RVs (>first quartile RVEDA ≥13 mm(2)/m(2)) compared with implantable cardioverter-defibrillator (ICD)-only therapy, whereas in patients with smaller RVs there was no significant difference in the risk of VT/VF between the 2 treatment arms (hazard ratio = 1.00, P = .99). At 1-year follow-up, CRT-D patients displayed significantly greater reductions in RVEDA compared to ICD-only patients (P <.001), associated with a corresponding reduction in the risk of subsequent VT/VF or death (>first quartile reduction in RVEDA with CRT-D vs ICD-only: hazard ratio = 0.55, P <.001) independent of changes in left ventricular dimensions. CONCLUSION: Our findings suggest that the RV may have an important role in determining the antiarrhythmic effect of CRT independent of the effect of the device on the left ventricle.

Effectiveness of cardiac resynchronization therapy with defibrillator in at-risk black and white cardiac patients.

BACKGROUND: There are limited data regarding racial differences in response to cardiac resynchronization therapy with defibrillator (CRT-D). METHODS: We assessed the effectiveness of CRT-D, as compared to implantable cardioverter defibrillator (ICD) therapy alone, in reducing the risk of heart failure (HF) or death and changes in cardiac volumes among 1638 (90%) white patients and 143 (8%) black patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT). RESULTS: Enrolled black patients displayed a higher frequency of diabetes mellitus, treated hypertension, higher creatinine levels, and a lower distance walked in the baseline 6-minute walk test. Kaplan-Meier survival analysis showed that at 3 years of follow-up the cumulative probability of HF or death was higher among blacks (29%) as compared with whites (22%; P = 0.05). Both black and white patients experienced similar and pronounced reductions in cardiac volumes with CRT-D therapy (all P values for comparison between the two groups >0.10). Risk reduction conferred by CRT-D therapy as not significantly different between blacks and whites (hazard ratio = 0.78 and 0.60, respectively; P for the difference = 0.44). However, possibly due to sample size limitations the CRT-D versus ICD only adjusted risk for HF/death in blacks was not statistically significant. CONCLUSIONS: Black patients in MADIT-CRT experienced increased risk of HF or death as compared with whites, but displayed a similar magnitude echocardiographic response to CRT-D. These findings suggest that cardiac resynchronization therapy may be an effective therapeutic modality in black patients. However, further studies are needed to assess the clinical response to CRT-D in this high-risk population.

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 aim of this study was to evaluate the relationship between left ventricular (LV) ejection fraction and clinical outcome to cardiac resynchronization therapy (CRT) in mild heart failure patients enrolled in MADIT-CRT [corrected]. 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 ≤25%. The primary endpoint was HF or death. Secondary endpoint included all-cause mortality. RESULTS: LVEF was evaluated in 1,809 study patients. There were 696 (38%) patients with LVEF >30% (in the range of 30.1% to 45.3%); 914 patients (50.5%) with LVEF 26% to 30%; and 199 patients with LVEF ≤25% (11%). The mean reduction in LVEDV with CRT-D therapy at the 1-year follow-up was directly related to increasing LVEF (LVEF >30%: 22.3%; LVEF 26% to 30%: 20.1%; and LVEF ≤25%: 18.7% reduction, respectively [p = 0.001]). CRT-D treatment similarly reduced the risk of HF/death in patients with 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 ≤25% (HR: 0.57 [95% CI: 0.35 to 0.95], p = 0.03; all p values for LVEF-by-treatment interactions >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).

Left ventricular lead location and the risk of ventricular arrhythmias in the MADIT-CRT trial.

AIMS: We aimed to evaluate the influence of left ventricular (LV) lead position on the risk of ventricular tachyarrhythmias in cardiac resynchronization therapy (CRT) patients. METHODS AND RESULTS: Left ventricular (LV) lead position was evaluated by biplane coronary venograms and anterior/posterior, lateral chest X-rays in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy (MADIT-CRT). The LV lead location could be defined in 797 of 1089 patients (73%). The LV lead was placed at the LV apex in 110 (14%) patients, in the anterior position in 146 (18%), in the lateral position in 448 (56%), and in the posterior position in 93 (12%) patients. After adjustment for clinical covariates, lateral or posterior lead location was associated with significantly lower risk of ventricular tachycardia (VT)/ventricular fibrillation (VF) [hazard ratio (HR) = 0.57, 95% confidence interval (CI): 0.38-0.85; P = 0.006] when compared with an anterior lead location. Patients with anterior lead position had similar risk of VT/VF as patients with implantable cardioverter defibrillator (ICD)-only (HR = 1.04, 95% CI: 0.72-1.81; P = 0.837). There was no difference in the risk of mortality between posterior or lateral and anterior LV lead locations. CONCLUSION: Cardiac resynchronization therapy with posterior or lateral LV lead position is associated with decreased risk of arrhythmic events in comparison with anterior lead location and ICD-only patients. There is no evidence for increased risk of VT/VF episodes associated with CRT.

Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome.

BACKGROUND: Men and women with type 1 long QT syndrome (LQT1) exhibit time-dependent differences in the risk for cardiac events. OBJECTIVE: We hypothesized that sex-specific risk for LQT1 is related to the location and function of the disease-causing mutation in the KCNQ1 gene. METHODS: The risk for life-threatening cardiac events (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years was assessed among 1051 individuals with LQT1 (450 men and 601 women) by the location and function of the LQT1-causing mutation (prespecified as mutations in the intracellular domains linking the membrane-spanning segments [ie, S2-S3 and S4-S5 cytoplasmic loops] involved in adrenergic channel regulation vs other mutations). RESULTS: Multivariate analysis showed that during childhood (age group: 0-13 years) men had >2-fold (P < .003) increased risk for ACA/SCD than did women, whereas after the onset of adolescence the risk for ACA/SCD was similar between men and women (hazard ratio = 0.89 [P = .64]). The presence of cytoplasmic-loop mutations was associated with a 2.7-fold (P < .001) increased risk for ACA/SCD among women, but it did not affect the risk among men (hazard ratio 1.37; P = .26). Time-dependent syncope was associated with a more pronounced risk-increase among men than among women (hazard ratio 4.73 [P < .001] and 2.43 [P = .02], respectively), whereas a prolonged corrected QT interval (≥ 500 ms) was associated with a higher risk among women than among men. CONCLUSION: Our findings suggest that the combined assessment of clinical and mutation location/functional data can be used to identify sex-specific risk factors for life-threatening events for patients with LQT1.

Risk of syncope in family members who are genotype-negative for a family-associated long-QT syndrome mutation.

BACKGROUND: Current clinical diagnosis of long-QT syndrome (LQTS) includes genetic testing of family members of mutation-positive patients. The present study was designed to assess the clinical course of individuals who are found negative for the LQTS-causing mutation in their families. METHODS AND RESULTS: Multivariate Cox proportional hazards model was used to assess the risk for cardiac events (comprising syncope, aborted cardiac arrest [ACA], or sudden cardiac death [SCD]) from birth through age 40 years among 1828 subjects from the LQTS Registry who were found negative for their family LQTS-causing mutation. The median QTc of study subjects was 423 ms (interquartile range, 402-442 ms). The cumulative probability of a first syncope through age 40 years was 15%. However, only 2 patients (0.1%) had ACA, and none died suddenly during follow-up. Independent risk factors for syncope in genotype-negative subjects included female sex (hazard ratio [HR], 1.60; P=0.002), prolonged QTc (HR=1.63 per 100 ms increment, P=0.02), family history of ACA or SCD (HR=1.89, P=0.002), and LQT2 versus LQT1 family mutation (HR=1.41, P=0.03). Subgroup analysis showed that the presence of the K897T polymorphism in the LQT2 gene in an affected family was associated with an 11-fold (P=0.001) increase in the risk of recurrent syncope in genotype-negative subjects. CONCLUSIONS: Our findings suggest that cardiac events among genotype-negative family members of LQTS patients are dominated by nonfatal syncopal episodes without occurrence of sudden cardiac death. The risk for nonfatal events in this population may be mediated by the presence of common polymorphisms in LQTS genes.

Reduction of the risk of recurring heart failure events with cardiac resynchronization therapy: MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy).

OBJECTIVES: The evaluation of the risk of recurring heart failure events (HFEs) was a pre-specified substudy of MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy). BACKGROUND: There are limited data regarding the effect of cardiac resynchronization therapy with a defibrillator (CRT-D) on the occurrence of recurring heart failure episodes after a first post-implantation HFE. METHODS: Data with regard to recurring HFEs were prospectively collected for all 1,820 MADIT-CRT participants. The CRT-D versus defibrillator-only risk for nonfatal first- and subsequent-HFEs was assessed by Cox proportional hazards and Andersen-Gill proportional intensity regression modeling, respectively, in efficacy analyses recognizing active device-type during follow-up. RESULTS: Multivariate analysis showed that CRT-D was associated with a significant reduction in the risk of a first HFE (hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.44 to 0.67, p < 0.001) and with a similar magnitude of reduction in the risk of HFEs subsequent to a first post-enrollment event (HR: 0.62, 95% CI: 0.45 to 0.85, p = 0.003). The benefit of CRT-D for the prevention of first and subsequent HFEs was pronounced among patients with left bundle branch block (HR: 0.38, 95% CI: 0.29 to 0.49, p < 0.001; and HR: 0.50, 95% CI: 0.33 to 0.76, p = 0.001, respectively) and nonsignificant in non-left bundle branch block patients (HR: 1.12, 95% CI: 0.77 to 1.64, p = 0.55; and HR: 0.99, 95% CI: 0.58 to 1.69, p = 0.96, respectively; p values for interaction: p < 0.001 and p = 0.06, respectively). The occurrences of first and second HFEs were associated with 7- and nearly 19-fold respective increases in the risk of subsequent mortality. CONCLUSIONS: In the MADIT-CRT trial, the benefit of cardiac resynchronization therapy for the reduction in recurring HFEs was maintained after the occurrence of a first post-enrollment event. The occurrence of HFEs greatly increased the risk of death. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy; NCT00180271).

Genotype-specific QT correction for heart rate and the risk of life-threatening cardiac events in adolescents with congenital long-QT syndrome.

BACKGROUND: A prolonged QT interval corrected for heart rate (QTc) is a major risk factor in patients with long QT syndrome (LQTS). However, heart rate-related risk in this genetic disorder differs among genotypes. OBJECTIVE: This study hypothesized that risk assessment in LQTS patients should incorporate genotype-specific QT correction for heart rate. METHODS: The independent contribution of 4 repolarization measures (the absolute QT interval, and Bazett's, Fridericia's, and Framingham's correction formulas) to the risk of aborted cardiac arrest or sudden cardiac death during adolescence, before and after further adjustment for the RR interval, was assessed in 727 LQTS type 1 and 582 LQTS type 2 patients. Improved QT/RR correction was calculated using a Cox model, dividing the coefficient on log(RR) by that on log(QT). RESULTS: Multivariate analysis demonstrated that in LQTS type 1 patients 100-ms increments in the absolute QT interval were associated with a 3.3-fold increase in the risk of life-threatening cardiac events (P = .020), and 100-ms decrements in the RR interval were associated with a further 1.9-fold increase in the risk (P = .007), whereas in LQTS type 2 patients, resting heart rate was not a significant risk factor (hazard ratio 1.11; P = .51; P value for heart rate × genotype interaction = .036). Accordingly, analysis of an improved QT correction formula showed that patients with the LQTS type 1 genotype required a greater degree of QT correction for heart rate (improved QTc = QT/RR°·8) than LQTS type 2 patients (improved QTc = QT/RR°·²). CONCLUSION: Our findings suggest that risk stratification for life-threatening cardiac events in LQTS patients can be improved by incorporating genotype-specific QT correction for heart rate.

Mutation and gender-specific risk in type 2 long QT syndrome: implications for risk stratification for life-threatening cardiac events in patients with long QT syndrome.

BACKGROUND: Men and women with type 2 long QT syndrome (LQT2) exhibit time-dependent differences in the risk for cardiac events. We hypothesized that data regarding the location of the disease-causing mutation in the KCNH2 channel may affect gender-specific risk in LQT2. OBJECTIVE: This study sought to risk-stratify LQT2 patients for life-threatening cardiac events based on clinical and genetic information. METHODS: The risk for life-threatening cardiac events from birth through age 40 years (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) was assessed among 1,166 LQT2 male (n = 490) and female (n = 676) patients by the location of the LQTS-causing mutation in the KCNH2 channel (prespecified in the primary analysis as pore-loop vs. non-pore-loop). RESULTS: During follow-up, the cumulative probability of life-threatening cardiac events years was significantly higher among LQT2 women (26%) as compared with men (14%; P <.001). Multivariate analysis showed that the risk for life-threatening cardiac events was not significantly different between women with and without pore-loop mutations (hazard ratio 1.20; P =.33). In contrast, men with pore-loop mutations displayed a significant >2-fold higher risk of a first ACA or SCD as compared with those with non-pore-loop mutations (hazard ratio 2.18; P = .01). Consistently, women experienced a high rate of life-threatening events regardless of mutation location (pore-loop: 35%, non-pore-loop: 23%), whereas in men the rate of ACA or SCD was high among those with pore-loop mutations (28%) and relatively low among those with non-pore-loop mutations (8%). CONCLUSION: Combined assessment of clinical and mutation-specific data can be used for improved risk stratification for life-threatening cardiac events in LQT2.

T-wave morphology abnormalities in benign, potent, and arrhythmogenic I(kr) inhibition.

BACKGROUND: There is a consensus on the limited value of the QTc interval prolongation as a surrogate marker of drug cardiotoxicity and as a risk stratifier in inherited long QT syndrome (LQTS) patients. OBJECTIVE: We investigated the interest of repolarization morphology in the acquired and the inherited LQTS. METHODS: We analyzed 2 retrospective electrocardiographic (ECG) datasets from healthy on/off moxifloxacin and from genotyped KCNH2 patients. We measured QT, RR, and T-peak to T-end intervals, early repolarization duration (ERD) and late repolarization duration, T-roundness, T-amplitude, left (αL) and right slopes of T-waves. We designed multivariate logistic models to predict the presence of the KCNH2 mutation or moxifloxacin while adjusting for the level of QTc prolongation and the level of heart rate in LQT2 patients. Independent learning and validation sets were used. A list of 4,874 ECGs from 411 healthy individuals, 293 from 143 LQT2 carriers and 150 noncarrier family members were analyzed. RESULTS: In the moxifloxacin model, ERD was associated with the presence of the drug (odds ratio = 1.15 per ms increase, confidence interval 1.04 to 1.26, P = .0001) after adjustment for QTc. The model for the LQT2 revealed that left slope was associated with the presence of the KCNH2 mutation (odds ratio = 0.38 per 1.5 µV/ms decrease, confidence interval 0.23 to 0.64, P = .0002). Only T-roundness complemented QTc in the model investigating cardiac events in LQT2. CONCLUSIONS: These observations demonstrate that the phenotypic expression of KCNH2 mutations and the effect of IKr-inhibitory drug on the surface electrocardiogram are specific. Future research should investigate whether this phenomenon is linked to different level/form of loss functions of Ikr channels, and whether they could result in different arrhythmogenic mechanisms.

Highly automated QT measurement techniques in 7 thorough QT studies implemented under ICH E14 guidelines.

Thorough QT (TQT) studies are designed to evaluate potential effect of a novel drug on the ventricular repolarization process of the heart using QTc prolongation as a surrogate marker for torsades de pointes. The current process to measure the QT intervals from the thousands of electrocardiograms is lengthy and expensive. In this study, we propose a validation of a highly automatic-QT interval measurement (HA-QT) method. We applied a HA-QT method to the data from 7 TQT studies. We investigated both the placebo and baseline-adjusted QTc interval prolongation induced by moxifloxacin (positive control drug) at the time of expected peak concentration. The comparative analysis evaluated the time course of moxifloxacin-induced QTc prolongation in one study as well. The absolute HA-QT data were longer than the FDA-approved QTc data. This trend was not different between ECGs from the moxifloxacin and placebo arms: 9.6 ± 24 ms on drug and 9.8 ± 25 ms on placebo. The difference between methods vanished when comparing the placebo-baseline-adjusted QTc prolongation (1.4 ± 2.8 ms, P = 0.4). The differences in precision between the HA-QT and the FDA-approved measurements were not statistically different from zero: 0.1 ± 0.1 ms (P = 0.7). Also, the time course of the moxifloxacin-induced QTc prolongation adjusted for placebo was not statistically different between measurements methods.

Value of the signal-averaged electrocardiogram in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited disease that causes structural and functional abnormalities of the right ventricle (RV). The presence of late potentials as assessed by the signal-averaged electrocardiogram (SAECG) is a minor task force criterion. OBJECTIVE: The purpose of this study was to examine the diagnostic and clinical value of the SAECG in a large population of genotyped ARVC/D probands. METHODS: We compared the SAECGs of 87 ARVC/D probands (age 37 ± 13 years, 47 males) diagnosed as affected or borderline by task force criteria without using the SAECG criterion with 103 control subjects. The association of SAECG abnormalities was also correlated with clinical presentation, surface ECG, ventricular tachycardia (VT) inducibility at electrophysiologic testing, implantable cardioverter-defibrillator therapy for VT, and RV abnormalities as assessed by cardiac magnetic resonance imaging (cMRI). RESULTS: Compared with controls, all three components of the SAECG were highly associated with the diagnosis of ARVC/D (P <.001). They include the filtered QRS duration (97.8 ± 8.7 ms vs 119.6 ± 23.8 ms), low-amplitude signal (24.4 ± 9.2 ms vs 46.2 ± 23.7 ms), and root mean square amplitude of the last 40 ms of the QRS (50.4 ± 26.9 µV vs 27.9 ± 36.3 µV). The sensitivity of using SAECG for diagnosis of ARVC/D was increased from 47% using the established 2 of 3 criteria (i.e., late potentials) to 69% by using a modified criterion of any 1 of 3 criteria, while maintaining a high specificity of 95%. Abnormal SAECG as defined by this modified criterion was associated with a dilated RV volume and decreased RV ejection fraction detected by cMRI (P <.05). SAECG abnormalities did not vary with clinical presentation or reliably predict spontaneous or inducible VT and had limited correlation with ECG findings. CONCLUSION: Using 1 of 3 SAECG criteria contributed to increased sensitivity and specificity for the diagnosis of ARVC/D. This finding is incorporated in the recent modification of the task force criteria.

Beta-blocker efficacy in high-risk patients with the congenital long-QT syndrome types 1 and 2: implications for patient management.

BACKGROUND: Beta-blockers are the mainstay therapy in patients with the congenital long-QT syndrome (LQTS) types 1 and 2. However, limited data exist regarding the efficacy and limitations of this form of medical management within high-risk subsets of these populations. METHODS AND RESULTS: Multivariate analysis was carried out to identify age-related gender- and genotype-specific risk factors for cardiac events (comprising syncope, aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years among 971 LQT1 (n = 549) and LQT2 (n = 422) patients from the International LQTS Registry. Risk factors for cardiac events included the LQT1 genotype (HR = 1.49, P = 0.003) and male gender (HR = 1.31, P = 0.04) in the 0-14 years age group; and the LQT2 genotype (HR = 1.67, P < 0.001) and female gender (HR = 2.58, P < 0.001) in the 15-40 years age group. Gender-genotype subset analysis showed enhanced risk among LQT1 males (HR = 1.93, P < 0.001) and LQT2 females (HR = 3.28, P < 0.001) in the 2 respective age groups. Beta-blocker therapy was associated with a significant risk-reduction in high-risk patients, including a 67% reduction (P = 0.02) in LQT1 males and a 71% reduction (P < 0.001) in LQT2 females. Life-threatening events (ACA/SCD) rarely occurred as a presenting symptom among beta-blocker-treated patients. However, high-risk patients who experienced syncope during beta-blocker therapy had a relatively high rate of subsequent ACA/SCD (>1 event per 100 patient-years). CONCLUSIONS: The present findings suggest that beta-blocker therapy should be routinely administered to all high-risk LQT1 and LQT2 patients without contraindications as a first line measure, whereas primary defibrillator therapy should be recommended for those who experience syncope during medical therapy.

Abnormal P-wave morphology is a predictor of atrial fibrillation development and cardiac death in MADIT II patients.

BACKGROUND: Several ECG-based approaches have been shown to add value when risk-stratifying patients with congestive heart failure, but little attention has been paid to the prognostic value of abnormal atrial depolarization in this context. The aim of this study was to noninvasively analyze the atrial depolarization phase to identify markers associated with increased risk of mortality, deterioration of heart failure, and development of atrial fibrillation (AF) in a high-risk population with advanced congestive heart failure and a history of acute myocardial infarction. METHODS: Patients included in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) with sinus rhythm at baseline were studied (n = 802). Unfiltered and band-pass filtered signal-averaged P waves were analyzed to determine orthogonal P-wave morphology (prespecified types 1, 2, and 3/atypical), P-wave duration, and RMS20. The association between P-wave parameters and data on the clinical course and cardiac events during a mean follow-up of 20 months was analyzed. RESULTS: P-wave duration was 139 + or - 23 ms and the RMS20 was 1.9 + or - 1.1 microV. None of these parameters was significantly associated with poor cardiac outcome or AF development. After adjustment for clinical covariates, abnormal P-wave morphology was found to be independently predictive of nonsudden cardiac death (HR 2.66; 95% CI 1.41-5.04, P = 0.0027) and AF development (HR 1.75; 95% CI 1.10-2.79, P = 0.019). CONCLUSION: Abnormalities in P-wave morphology recorded from orthogonal leads in surface ECG are independently predictive of increased risk of nonsudden cardiac death and AF development in MADIT II patients.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia clinical presentation and diagnostic evaluation: results from the North American Multidisciplinary Study.

BACKGROUND: Prior reports on patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) focused on individuals with advanced forms of the disease. Data on the diagnostic performance of various testing modalities in newly identified individuals suspected of having ARVC/D are limited. OBJECTIVE: The purpose of the Multidisciplinary Study of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia was to study the clinical characteristics and diagnostic evaluation of a large group of patients newly identified with ARVC/D. METHODS: A total of 108 newly diagnosed patients with suspected ARVC/D were prospectively enrolled in the United States and Canada. The patients underwent noninvasive and invasive tests using standardized protocols that initially were interpreted by the enrolling center and adjudicated by blind analysis in six core laboratories. Patients were followed for a mean of 27 +/- 16 months (range 0.2-63 months). RESULTS: The clinical profile of these newly diagnosed patients differs from the profile of reported patients with more advanced disease. There was considerable difference in the initial and final classification of the presence of ARVC/D after the diagnostic tests were evaluated by the core laboratories. Final clinical diagnosis was 73 affected, 28 borderline, and 7 unaffected. Individual tests agreed with the final diagnosis in 50% to 70% of the 73 patients with a final classification of affected. CONCLUSION: The clinical profile of 108 newly diagnosed probands with suspected ARVC/D indicates that a combination of diagnostic tests is needed to evaluate the presence of right ventricular structural, functional, and electrical abnormalities. Echocardiography, right ventricular angiography, signal-averaged ECG, and Holter monitoring provide optimal clinical evaluation of patients suspected of ARVC/D.