Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study.

BACKGROUND: Risk stratification in patients with type 3 long-QT syndrome (LQT3) by clinical and genetic characteristics and effectiveness of ß-blocker therapy has not been studied previously in a large LQT3 population. METHODS: The study population included 406 LQT3 patients with 51 sodium channel mutations; 391 patients were known to be event free during the first year of life and were the focus of our study. Clinical, electrocardiographic, and genetic parameters were acquired for patients from 7 participating LQT3 registries. Cox regression analysis was used to evaluate the independent contribution of clinical, genetic, and therapeutic factors to the first occurrence of time-dependent cardiac events (CEs) from age 1 to 41 years. RESULTS: Of the 391 patients, 118 (41 males, 77 females) patients (30%) experienced at least 1 CE (syncope, aborted cardiac arrest, or long-QT syndrome-related sudden death), and 24 (20%) suffered from LQT3-related aborted cardiac arrest/sudden death. The risk of a first CE was directly related to the degree of QTc prolongation. Cox regression analysis revealed that time-dependent ß-blocker therapy was associated with an 83% reduction in CEs in females (P=0.015) but not in males (who had many fewer events), with a significant sex × ß-blocker interaction (P=0.04). Each 10-ms increase in QTc duration up to 500 ms was associated with a 19% increase in CEs. Prior syncope doubled the risk for life-threatening events (P<0.02). CONCLUSIONS: Prolonged QTc and syncope predispose patients with LQT3 to life-threatening CEs. However, ß-blocker therapy reduces this risk in females; efficacy in males could not be determined conclusively because of the low number of events.

Risk factors for recurrent heart failure events in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II).

UNLABELLED: Risk Factors for Recurrent Heart Failure. BACKGROUND: This study was designed to identify risk factors for recurrent heart failure (HF) events in patients with ischemic left ventricular dysfunction enrolled in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II). METHODS AND RESULTS: The Prentice, Williams, and Peterson (PWP) statistical model was utilized to identify and compare risk factors for 1 or ≥ 2 HF hospitalizations among 1,218 patients with ischemic left ventricular dysfunction enrolled in the MADIT-II trial. Risk factors for a first HF hospitalization included treatment with an ICD (HR = 1.31; P = 0.05), New York Heart Association class > II (HR = 1.95; P < 0.001), female gender (HR = 1.38; P = 0.05), atrial fibrillation (HR = 1.90; P = 0.001), QRS >120 ms (HR = 1.41; P = 0.01), diabetes mellitus (HR = 1.51; P = 0.003), heart rate ≥ 80 (HR = 1.35; P = 0.04), diuretic therapy (HR = 1.82; P < 0.001), and the presence of prerenal azotemia (defined as blood urea nitrogen:creatinine > 20; HR = 1.45; P = 0.01). In contrast, prerenal azotemia was the only risk factor that was independently associated with a significant increase in the risk of ≥ 2 HF hospitalizations (HR = 1.52; P = 0.027). The occurrence of 1 HF event after enrollment was associated with a 2.8-fold (P < 0.001) increase in the risk of death, whereas after the occurrence of a second event there was a 6.7-fold (P < 0.001) increase in the risk of subsequent mortality. CONCLUSIONS: In MADIT-II, prerenal azotemia was the only significant and independent risk factor for HF progression after a first event, and recurrent HF was the most powerful predictor of mortality. These findings stress the importance of identifying risk factors for HF progression among patients who receive an ICD for primary prevention.

Long-QT syndrome after age 40.

BACKGROUND: Previous studies that assessed the risk of life-threatening cardiac events in patients with congenital long-QT syndrome (LQTS) have focused mainly on the first 4 decades of life, whereas the clinical course of this inherited cardiac disorder in the older population has not been studied. METHODS AND RESULTS: The risk of aborted cardiac arrest or death from age 41 though 75 years was assessed in 2759 subjects from the International LQTS Registry, categorized into electrocardiographically affected (corrected QT interval [QTc] > or = 470 ms), borderline (QTc 440 to 469 ms), and unaffected (QTc < 440 ms) subgroups. The affected versus unaffected adjusted hazard ratio for aborted cardiac arrest or death was 2.65 (P<0.001) in the age range of 41 to 60 years and 1.23 (P=0.31) in the age range of 61 to 75 years. The clinical course of study subjects displayed gender differences: Affected LQTS women experienced a significantly higher cumulative event rate (26%) than borderline (16%) and unaffected (12%) women (P=0.001), whereas event rates were similar among the 3 respective subgroups of men (29%, 26%, and 27%; P=0.16). Recent syncope (< 2 years in the past) was the predominant risk factor in affected subjects (hazard ratio 9.92, P<0.001), and the LQT3 genotype was identified as the most powerful predictor of outcome in a subset of 871 study subjects who were genetically tested for a known LQTS mutation (hazard ratio 4.76, P=0.02). CONCLUSIONS: LQTS subjects maintain a high risk for life-threatening cardiac events after age 40 years. The phenotypic expression of affected subjects is influenced by age-specific factors related to gender, clinical history, and the LQTS genotype.

Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome.

BACKGROUND: The congenital long-QT syndrome (LQTS) is an important cause of sudden cardiac death in children without structural heart disease. However, specific risk factors for life-threatening cardiac events in children with this genetic disorder have not been identified. METHODS AND RESULTS: Cox proportional-hazards regression modeling was used to identify risk factors for aborted cardiac arrest or sudden cardiac death in 3015 LQTS children from the International LQTS Registry who were followed up from 1 through 12 years of age. The cumulative probability of the combined end point was significantly higher in boys (5%) than in girls (1%; P<0.001). Risk factors for cardiac arrest or sudden cardiac death during childhood included corrected QT interval [QTc] duration > 500 ms (hazard ratio [HR]; 2.72; 95% confidence interval [CI], 1.50 to 4.92; P=0.001) and prior syncope (recent syncope [< 2 years]: HR, 6.16; 95% CI 3.41 to 11.15; P<0.001; remote syncope [> or = 2 years]: HR, 2.67; 95% CI, 1.22 to 5.85; P=0.01) in boys, whereas prior syncope was the only significant risk factor among girls (recent syncope: HR, 27.82; 95% CI, 9.72 to 79.60; P<0.001; remote syncope: HR, 12.04; 95% CI, 3.79 to 38.26; P<0.001). Beta-blocker therapy was associated with a significant 53% reduction in the risk of cardiac arrest or sudden cardiac death (P=0.01). CONCLUSIONS: LQTS boys experience a significantly higher rate of fatal or near-fatal cardiac events than girls during childhood. A QTc duration > 500 ms and a history of prior syncope identify risk in boys, whereas prior syncope is the only significant risk factor among girls. Beta-blocker therapy is associated with a significant reduction in the risk of life-threatening cardiac events during childhood.

Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene.

BACKGROUND: Type-1 long-QT syndrome (LQTS) is caused by loss-of-function mutations in the KCNQ1-encoded I(Ks) cardiac potassium channel. We evaluated the effect of location, coding type, and biophysical function of KCNQ1 mutations on the clinical phenotype of this disorder. METHODS AND RESULTS: We investigated the clinical course in 600 patients with 77 different KCNQ1 mutations in 101 proband-identified families derived from the US portion of the International LQTS Registry (n=425), the Netherlands' LQTS Registry (n=93), and the Japanese LQTS Registry (n=82). The Cox proportional hazards survivorship model was used to evaluate the independent contribution of clinical and genetic factors to the first occurrence of time-dependent cardiac events from birth through age 40 years. The clinical characteristics, distribution of mutations, and overall outcome event rates were similar in patients enrolled from the 3 geographic regions. Biophysical function of the mutations was categorized according to dominant-negative (> 50%) or haploinsufficiency (< or = 50%) reduction in cardiac repolarizing I(Ks) potassium channel current. Patients with transmembrane versus C-terminus mutations (hazard ratio, 2.06; P<0.001) and those with mutations having dominant-negative versus haploinsufficiency ion channel effects (hazard ratio, 2.26; P<0.001) were at increased risk for cardiac events, and these genetic risks were independent of traditional clinical risk factors. CONCLUSIONS: This genotype-phenotype study indicates that in type-1 LQTS, mutations located in the transmembrane portion of the ion channel protein and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder.

Mechanisms of ventricular fibrillation initiation in MADIT II patients with implantable cardioverter defibrillators.

BACKGROUND: The availability of stored intracardiac electrograms from implantable defibrillators (ICDs) has facilitated the study of the mechanisms of ventricular tachyarrhythmia onset. This study aimed to determine the patterns of initiation of ventricular fibrillation (VF) in Multicenter Automatic Defibrillator Implantation Trial (MADIT) II patients along with associated electrocardiogram (ECG) parameters and clinical characteristics. METHODS: Examination of stored electrograms enabled us to evaluate the rhythm preceding each episode of VF and to calculate (intracardiac) ECG parameters including QT, QT peak (QTp), coupling interval, and prematurity index. RESULTS: Sixty episodes of VF among 29 patients (mean age 64.4 +/- 2.5 years) were identified. A single ventricular premature complex (VPC) initiated 46 (77%) episodes whereas a short-long-short (SLS) sequence accounted for 14 (23%) episodes. Of the 29 patients studied, 23 patients had VF episodes preceded by a VPC only, two patients with SLS only, and four patients with both VPC and SLS-initiated episodes. There were no significant differences between initiation patterns in regards to the measured ECG parameters; a faster heart rate with SLS initiation (mean RR prior to VF of 655 +/- 104 ms for SLS and 744 +/- 222 ms for VPC) approached significance (P = 0.06). The two patients with SLS only were not on beta-blockers compared to 83% of the VPC patients. CONCLUSION: Ventricular fibrillation is more commonly initiated by a VPC than by a SLS sequence among the MADIT II population. Current pacing modes designed to prevent bradycardia and pause-dependent arrhythmias are unlikely to decrease the incidence of VPC-initiated episodes of VF.

Phenotypic variability in Caucasian and Japanese patients with matched LQT1 mutations.

BACKGROUND: Ethnic differences may affect the phenotypic expression of genetic disorders. However, data regarding the effect of ethnicity on outcome in patients with genetic cardiac disorders are limited. We compared the clinical course of Caucasian and Japanese long QT type-1 (LQT1) patients who were matched for mutations in the KCNQ1 gene. METHODS: The study population comprised 62 Caucasian and 38 Japanese LQT1 patients from the International LQTS Registry who were identified as having six identical KCNQ1 mutations. The biophysical function of the mutations was categorized into dominant-negative (> 50%) or haploinsufficiency (< or =50%) reduction in cardiac repolarizing IKs potassium channel current. The primary end point of the study was the occurrence of a first cardiac event from birth through age 40 years. RESULTS: Japanese patients had a significantly higher cumulative rate of cardiac events (67%) than Caucasian patients (39%; P = 0.01). The respective frequencies of dominant negative mutations in the two ethnic groups were 63% and 28% (P < 0.001). In multivariate analysis, Japanese patients had an 81% increase in the risk of cardiac events (P = 0.06) as compared with Caucasians. However, when the biophysical function of the mutations was included in the multivariate model, the risk associated with Japanese ethnicity was no longer evident (HR = 1.05; P = 0.89). Harboring a dominant negative mutation was shown to be the most powerful and significant predictor of outcome (HR = 3.78; P < 0.001). CONCLUSIONS: Our data indicate that ethnic differences in the clinical expression of LQTS can be attributed to the differences in frequencies of the specific mutations within the two populations.

Causes and consequences of heart failure after prophylactic implantation of a defibrillator in the multicenter automatic defibrillator implantation trial II.

BACKGROUND: Implantable cardioverter-defibrillator (ICD) therapy may be associated with an increased risk for heart failure (HF). The present study evaluated the frequency, causes, and consequences of HF after ICD implantation. METHODS AND RESULTS: We performed a retrospective analysis of the clinical factors and outcomes associated with postenrollment HF events in 1218 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial II. The adjusted hazard ratios (HRs) of ICD:conventional therapy for first and recurrent HF events were 1.39 (P=0.02) and 1.58 (P<0.001), respectively. The risk was increased among patients who received single-chamber or dual-chamber ICDs. Development of HF was associated with an increased mortality risk (HR, 3.80; P<0.001). Among patients who received a single-chamber ICD, there was a similar survival benefit before and after the development of HF (HR, 0.59 and 0.61, respectively; P=0.92 for difference), whereas among patients with dual-chamber devices, there was a significant reduction in survival benefit after HF (HR, 0.26 and 0.83, respectively; P=0.01 for difference). Within the defibrillator arm of the trial, patients who received life-prolonging therapy from the ICD had an increased risk for first and recurrent HF events (HR, 1.90; P=0.01 and 1.74; P<0.001, respectively). CONCLUSIONS: Patients with chronic ischemic heart disease who are treated with either single-chamber or dual-chamber ICDs have improved survival but an increased risk of HF. The present data suggest that ICD therapy transforms sudden death risk to a subsequent HF risk. These findings should direct more attention to the prevention of HF in patients who receive an ICD.

Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.

BACKGROUND: Patients with reduced left ventricular function after myocardial infarction are at risk for life-threatening ventricular arrhythmias. This randomized trial was designed to evaluate the effect of an implantable defibrillator on survival in such patients. METHODS: Over the course of four years, we enrolled 1232 patients with a prior myocardial infarction and a left ventricular ejection fraction of 0.30 or less. Patients were randomly assigned in a 3:2 ratio to receive an implantable defibrillator (742 patients) or conventional medical therapy (490 patients). Invasive electrophysiological testing for risk stratification was not required. Death from any cause was the end point. RESULTS: The clinical characteristics at base line and the prevalence of medication use at the time of the last follow-up visit were similar in the two treatment groups. During an average follow-up of 20 months, the mortality rates were 19.8 percent in the conventional-therapy group and 14.2 percent in the defibrillator group. The hazard ratio for the risk of death from any cause in the defibrillator group as compared with the conventional-therapy group was 0.69 (95 percent confidence interval, 0.51 to 0.93; P=0.016). The effect of defibrillator therapy on survival was similar in subgroup analyses stratified according to age, sex, ejection fraction, New York Heart Association class, and the QRS interval. CONCLUSIONS: In patients with a prior myocardial infarction and advanced left ventricular dysfunction, prophylactic implantation of a defibrillator improves survival and should be considered as a recommended therapy.

Improved survival associated with prophylactic implantable defibrillators in elderly patients with prior myocardial infarction and depressed ventricular function: a MADIT-II substudy.

INTRODUCTION: We aim to evaluate the mortality benefit from defibrillator therapy in eligible elderly patients. Effective primary prevention of sudden cardiac death with implantable cardioverter defibrillators is well demonstrated in patients with coronary disease and depressed ventricular function. METHODS AND RESULTS: Among 1,232 patients enrolled with prior infarct and left ventricular ejection fraction < or = 0.30, 204 were > or = 75 years old. Of these 204 patients, 121 underwent defibrillator implant. Relative to the younger patients, those > or = 75 years had a higher incidence of atrial fibrillation, elevated blood urea nitrogen (BUN), widened QRS, and lower use of beta-blockers and HMG-CoA reductase inhibitors. Relevant clinical covariates were similar in elderly patients randomized to conventional and defibrillator therapy. The hazard ratio for the mortality risk in patients > or = 75 years assigned to defibrillator implant compared with those in conventional therapy was 0.56 (95 confidence interval 0.29-1.08; P = 0.08) after a mean follow-up of 17.2 months. Comparatively, the hazard ratio in patients < 75 years assigned to defibrillator implant was 0.63 (0.45-0.88; P = 0.01) after 20.8 months. Elderly patients had similar reductions in quality of life (QoL) regardless of treatment randomization. Scores through Health Utilities Index Mark III (HUI) Questionnaire changes from baseline to 1 year were -0.22 for patients with conventional therapy versus -0.20 for patients with ICD, and -0.36 versus -0.27 at 2 years, respectively (P = NS). CONCLUSION: The implantable defibrillator is associated with an equivalent reduction of mortality in elderly and younger patients, with no compromise in the QoL in the older age subjects.

Ventricular arrhythmia storms in postinfarction patients with implantable defibrillators for primary prevention indications: a MADIT-II substudy.

BACKGROUND: Much of prognostic implications of ventricular arrhythmia storms remain unclear. OBJECTIVE: We evaluated the risk associated with electrical storm in patients with defibrillators in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) study. METHODS: Electrical storm was defined as > or =3 episodes of ventricular tachycardia (VT) or ventricular fibrillation (VF) in 24 hours. RESULTS: Of the 719 patients who received internal cardiac defibrillator (ICD) implants and had follow-up in the MADIT-II, 27 patients (4%) had electrical storm, 142 (20%) had isolated episodes of VT/VF, and the remaining 550 patients had no ICD-recorded VT events. Baseline clinical characteristics among the groups were similar. Patients who experienced electrical storm had a significantly higher risk of death. After adjustments for relevant clinical covariates, the hazard ratio (HR) for death in the first 3 months after the storm event was 17.8 (95% confidence interval [CI] 8.0 to 39.5, P <.01) in comparison with those with no VT/VF. This risk continued even after 3 months for those with electrical storm (HR of 3.5, 95% CI 1.2 to 9.8, P = .02). Study patients with isolated VT/VF episodes also were at an increased risk of dying (HR = 2.5, 95% CI 1.5 to 4.0, P <.01) when compared with patients without VT/VF episodes. Statistically significant predictors of electrical storm were interim postenrollment coronary events (myocardial infarction or angina) HR 3.1 (95% CI 1.2 to 8.1, P = .02) and isolated VT or VF HR 9.2 (95% CI 4.0 to 20.9, P <.01). CONCLUSION: Postinfarction patients with severe left ventricular dysfunction in whom electrical storm developed have significantly higher mortality than patients with only isolated VT/VF as well as those without any episodes of VT/VF. Patients who experienced postenrollment ventricular arrhythmias and/or interim coronary events during follow-up were at higher risk for VT/VF storms.

Relations among renal function, risk of sudden cardiac death, and benefit of the implanted cardiac defibrillator in patients with ischemic left ventricular dysfunction.

Implanted cardioverter defibrillator therapy has been shown to be associated with a significant reduction in the risk of sudden cardiac death (SCD) in patients with ischemic left ventricular dysfunction. However, data on the relation between renal function and SCD in this population are limited, and the effect of renal dysfunction on the implanted cardioverter defibrillator benefit has not been determined. We performed a retrospective analysis of the outcome associated with renal dysfunction, as determined by the estimated glomerular filtration rate (eGFR), in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-II. Multivariate analysis in conventionally treated patients showed that for each 10-U reduction in eGFR, the risk of all-cause mortality and SCD increased by 16% (p = 0.005) and 17% (p = 0.03), respectively. Defibrillator therapy was associated with a survival benefit in each eGFR category of > or = 35 ml/min/1.73 m2 (overall risk reduction for all-cause mortality 32%, p = 0.01 and for SCD 66%, p < 0.001). However, no implanted cardioverter defibrillator benefit was shown among patients with an eGFR < 35 ml/min/1.73 m2 (all-cause mortality hazard ratio 1.09, p = 0.84; SCD hazard ratio 0.95, p = 0.95). In conclusion, in patients with high-risk cardiac disease enrolled in the Multicenter Automatic Defibrillator Implantation Trial-II, a significant increase was found in the risk of SCD with declining renal function. Defibrillator therapy was associated with a significant survival benefit among the study patients with mild to moderate or no renal disease, but no benefit was shown among patients with more advanced renal dysfunction.

Cigarette smoking and the risk of supraventricular and ventricular tachyarrhythmias in high-risk cardiac patients with implantable cardioverter defibrillators.

INTRODUCTION: Nicotine elevates serum catecholamine concentration and is therefore potentially arrhythmogenic. However, the effect of cigarette smoking on arrhythmic risk in coronary heart disease patients is not well established. METHODS AND RESULTS: The risk of appropriate and inappropriate defibrillator therapy by smoking status was analyzed in 717 patients who received an implantable cardioverter defibrillator (ICD) in the Multicenter Automatic Defibrillator Implantation Trial-II. Compared with patients who had quit smoking before study entry (past smokers) and patients who had never smoked (never smokers), patients who continued smoking (current smokers) were significantly younger and generally had more favorable baseline clinical characteristics. Despite this, the adjusted hazard ratio (HR) for appropriate ICD therapy for fast ventricular tachycardia (at heart rates >or=180 b.p.m) or ventricular fibrillation was highest among current smokers (HR = 2.11 [95% CI 1.11-3.99]) and intermediate among past smokers (HR = 1.57 [95% CI 0.95-2.58]), as compared with never smokers (P for trend = 0.02). Current smokers also exhibited a higher risk of inappropriate ICD shocks (HR = 2.93 [95% CI 1.30-6.63]) than past (HR = 1.91 [95% CI 0.97-3.77]) and never smokers (P for trend = 0.008). CONCLUSIONS: In patients with ischemic left ventricular dysfunction, continued cigarette smoking is associated with a significant increase in the risk of life-threatening ventricular tachyarrhythmias and inappropriate ICD shocks induced by rapid supraventricular arrhythmias. Our findings stress the importance of complete smoking cessation in this high-risk population.

Time dependence of mortality risk and defibrillator benefit after myocardial infarction.

BACKGROUND: Prophylactic implantable defibrillators (ICDs) improve survival in patients with impaired ventricular function after myocardial infarction (MI), but it is uncertain whether mortality risk and survival benefit depend on the elapsed time from MI. METHODS AND RESULTS: The Multicenter Automatic Defibrillator Implantation Trial II examined the impact of ICDs on survival in post-MI patients with ejection fractions < or =30%. In 1159 patients, mean time from most recent MI to enrollment was 81+/-78 months. Patients were randomized to an ICD (n=699) or conventional care (n=460) in a 3:2 ratio. Mortality rates (deaths per 100 person-years of follow-up) in both treatment groups were analyzed by time from MI divided into quartiles (<18, 18 to 59, 60 to 119, and > or =120 months). In conventional care patients, these rates increased as time from MI increased (7.8%, 8.4%, 11.6%, 14.0%; P=0.03). Mortality rates in ICD patients were consistently lower in each quartile and showed minimal increase over time (7.2%, 4.9%, 8.2%, 9.0%; P=0.19). Covariate-adjusted hazard ratios for risk of death associated with ICD therapy were 0.97 (95% CI, 0.51 to 1.81; P=0.92) for recent MI (<18 months) and 0.55 (95% CI, 0.39 to 0.78; P=0.001) for remote MI (> or =18 months). CONCLUSIONS: Mortality risk in patients with ejection fractions < or =30% increases as a function of time from MI. The survival benefit associated with ICDs appears to be greater for remote MI and remains substantial for up to > or =15 years after MI.

Long-term clinical course of patients after termination of ventricular tachyarrhythmia by an implanted defibrillator.

BACKGROUND: The implanted cardioverter defibrillator (ICD) improves survival in high-risk cardiac patients. This analysis from the MADIT-II trial database examines the long-term clinical course and subsequent mortality risk of patients after termination of life-threatening ventricular tachyarrhythmias by an ICD. METHODS AND RESULTS: Life-table survival analysis was performed, and proportional hazards regression analysis was used to evaluate the contribution of baseline clinical factors and time-dependent defibrillator therapy to mortality during long-term follow-up. Of 720 patients with an ICD (average follow-up 21 months), 169 patients received 701 antiarrhythmic device therapies for ventricular tachyarrhythmias. Few baseline characteristics distinguished patients who received appropriate ICD therapy for their first ventricular tachyarrhythmic episode. The probability of survival for at least 1 year after first therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF) was 80%. The hazard ratios for the risk of death due to any cause in those who survived appropriate therapy for termination of VT and VF were 3.4 (P<0.001) and 3.3 (P=0.01), respectively, compared with those who survived without receiving ICD therapy, with a high frequency of heart failure and late nonsudden cardiac death after first successful ICD therapy for VF. CONCLUSIONS: Successful appropriate therapy by an ICD for VT or VF is associated with 80% survival at 1 year after arrhythmia termination. These patients are at increased risk for heart failure and nonsudden cardiac death after device termination of VT or VF and should receive special attention for the prevention and management of progressive left ventricular dysfunction during long-term follow-up.

Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel.

BACKGROUND: The hereditary long-QT syndrome is characterized by prolonged ventricular repolarization and a variable clinical course with arrhythmia-related syncope and sudden death. Mutations involving the human ether-a-go-go-related gene (HERG) channel are responsible for the LQT2 form of long-QT syndrome, and in cellular expression studies these mutations are associated with reduction in the rapid component of the delayed rectifier repolarizing current (I(Kr)). We investigated the clinical features and prognostic implications of mutations involving pore and nonpore regions of the HERG channel in the LQT2 form of this disorder. METHODS AND RESULTS: A total of 44 different HERG mutations were identified in 201 subjects, with 14 mutations located in the pore region (amino acid residues 550 through 650). Thirty-five subjects had mutations in the pore region and 166 in nonpore regions. Follow-up extended through age 40 years. Subjects with pore mutations had more severe clinical manifestations of the genetic disorder and experienced a higher frequency (74% versus 35%; P<0.001) of arrhythmia-related cardiac events occurring at earlier age than did subjects with nonpore mutations. Multivariate Cox proportional hazard regression analysis revealed that pore mutations dominated the risk, with hazard ratios in the range of 11 (P<0.0001) for QTc at 500 ms, with a 16% increase in the pore hazard ratio for each 10-ms increase in QTc. CONCLUSION: Patients with mutations in the pore region of the HERG gene are at markedly increased risk for arrhythmia-related cardiac events compared with patients with nonpore mutations.

Analysis of mortality events in the Multicenter Automatic Defibrillator Implantation Trial (MADIT-II).

OBJECTIVES: The purpose of this study was to determine the efficacy of implantable cardiac defibrillator (ICD) therapy in preventing sudden cardiac death (SCD) in post-infarction patients with advanced left ventricular (LV) dysfunction. BACKGROUND: The Multicenter Automatic Defibrillator Implantation Trial (MADIT-II) randomized 1,232 post-infarction patients with an ejection fraction of < or =30% to ICD or conventional therapy. In the ICD group, there was a 31% decrease in the risk of total mortality. However, a better understanding of the mode of death is desirable in order to refine therapeutic interventions in high-risk populations. METHODS: We evaluated the 202 deaths, using a variation of the Hinkle-Thaler classification system as well as a clinical classification system to determine the incidence of SCD and the incidence of cardiac death due to progressive LV failure. RESULTS: The SCD rates were 10.0% in the conventional group and 3.8% in the ICD group (p < 0.01). The hazard ratio for the risk of SCD in the ICD group compared with the conventional therapy group was 0.33 (95% confidence interval 0.20 to 0.53, p < 0.0001). The ICD had no meaningful effect on non-sudden death (p = 0.32). The effect of defibrillator therapy in reducing SCD was similar in subgroup analyses stratified according to relevant baseline characteristics. CONCLUSIONS: The decrease in mortality with ICD therapy in MADIT-II is entirely due to a reduction in SCD, with similar reductions in SCD in a spectrum of subgroups stratified according to relevant baseline characteristics.

QT interval variability and spontaneous ventricular tachycardia or fibrillation in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II patients.

OBJECTIVES: This study aimed to determine whether increased QT interval variability is associated with an increased risk for ventricular tachycardia (VT) or ventricular fibrillation (VF), documented by interrogation of the implantable cardioverter-defibrillator (ICD), in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II. BACKGROUND: Unstable repolarization has been proposed as a risk factor for re-entrant arrhythmias, but confirmatory data from clinical trials are lacking. METHODS: The QT variability was assessed in 10-min, resting high-resolution electrocardiogram recordings at study entry using a semiautomated algorithm that measured beat-to-beat QT duration in 817 MADIT II patients. The incidence of VT/VF requiring device therapy was determined by ICD interrogation. RESULTS: Median normalized QT variability (QTVN) was 0.179 and 0.125, respectively, in patients with VT/VF versus those without VT/VF (p = 0.001); QTVI (QTVN adjusted for heart rate variance) also was significantly (p < 0.05) higher in VT/VF patients than in those without VT/VF. Either QTVN or QTVI was linked with a significantly higher probability of VT/VF: two-year risk of VT/VF from Kaplan-Meier curves was 40% in highest quartile versus 21% in lower quartiles for QTVN, and 37% versus 22% for QTVI (p < 0.05 for each). In multivariate Cox regression models adjusting for clinical covariates (race, New York Heart Association functional class, time after myocardial infarction), top-quartile QTVI and QTVN were independently associated with VT/VF (hazard ratio for QTVN 2.18, 95%confidence interval [CI] 1.34 to 3.55, p = 0.002; hazard ratio for QTVI 1.80, 95% CI 1.09 to 2.95, p = 0.021). CONCLUSIONS: In postinfarction patients with severe left ventricular dysfunction, increased QT variability, a marker of repolarization lability, is associated with an increased risk for VT/VF.

Modulating effects of age and gender on the clinical course of long QT syndrome by genotype.

OBJECTIVES: We aimed to determine whether long QT syndrome (LQTS) genotype has a differential effect on clinical course of disease in male and female children and adults after adjustment for QTc duration. BACKGROUND: Genotype influences clinical course of the LQTS; however, data on the effect of age and gender on this association are limited. METHODS: The LQTS genotype, QTc duration, and follow-up were determined in 243 cases of LQTS caused by the KCNQ1 potassium channel gene mutations (LQT1), 209 cases of LQTS caused by the HERG potassium channel gene mutations (LQT2), and 81 cases of LQTS caused by the SCN5A sodium channel gene mutation (LQT3) gene carriers. The probability of cardiac events (syncope, aborted cardiac arrest, or sudden death) was analyzed by genotype, gender, and age (children < or = 15 years and adults 16 to 40 years). In addition, the risk of sudden death and lethality of cardiac events were evaluated in 1,075 LQT1, 976 LQT2, and 324 LQT3 family members from families with known genotype. RESULTS: During childhood, the risk of cardiac events was significantly higher in LQT1 males than in LQT1 females (hazard ratio [HR] = 1.72), whereas there was no significant gender-related difference in the risk of cardiac events among LQT2 and LQT3 carriers. During adulthood, LQT2 females (HR = 3.71) and LQT1 females (HR = 3.35) had a significantly higher risk of cardiac events than respective males. The lethality of cardiac events was highest in LQT3 males and females (19% and 18%), and higher in LQT1 and LQT2 males (5% and 6%) than in LQT1 and LQT2 females (2% for both). CONCLUSIONS; Age and gender have different, genotype-specific modulating effects on the probability of cardiac events and electrocardiographic presentation in LQT1 and LQT2 patients.

New Mexico Community Health Councils: Documenting Contributions to Systems Changes.

CONTEXT: Coalition research has shifted from delineating structures and processes to identifying intermediate, systems changes (e.g., changes in policies) that contribute to longterm community health improvement. OBJECTIVE: The University of New Mexico, the New Mexico Department of Health, and community health councils entered a multiyear participatory evaluation process to answer: What actions did health councils take that led to improving health through intermediate, systems changes? DESIGN: The evaluation system was created over several phases through an iterative, participatory process. Data were collected for councils' health priority areas (e.g., substance abuse) from 2009 to 2011. PARTICIPANTS: Twenty-three community health councils participated. MAIN OUTCOME MEASURES: Intermediate systems changes were measured: 1) networking and partnering, 2) joint planning of strategies, programs, and services, 3) leveraging resources, and 4) policy initiatives. RESULTS: Health councils reported data for each intermediate outcome by health priority area. Data showed councils identified local public health priorities and addressed those priorities through strengthening networks and partnerships, which lead to the creation and enhancement of strategies, services, and programs. Data also showed councils influenced policies in several ways (e.g., developing policy, identifying new policy, or sponsoring informational forums). Additionally, data showed councils leveraged $1.10 for every dollar invested by the state. When funding was suspended in July 2010, data showed dramatic decreases in activity levels from 2010 to 2011. CONCLUSIONS: The data demonstrate the feasibility and utility of an Internet-based system designed to gather intermediate systems changes evaluation data. This process is a model for similar efforts to capture common outcomes across diverse coalitions and partnerships.