W. Jackson Hall

IMPROVED SURVIVAL WITH AN IMPLANTED DEFIBRILLATOR IN PATIENTS WITH CORONARY DISEASE AT HIGH RISK FOR VENTRICULAR ARRHYTHMIA

BACKGROUND Unsustained ventricular tachycardia in patients with previous myocardial infarction and left ventricular dysfunction is associated with a two-year mortality rate of about 30 percent. We studied whether prophylactic therapy with an implanted cardioverter-defibrillator, as compared with conventional medical therapy, would improve survival in this high-risk group of patients. METHODS Over the course of five years, 196 patients in New York Heart Association functional class I, II, or III with prior myocardial infarction; a left ventricular ejection fraction < or = 0.35; a documented episode of asymptomatic unsustained ventricular tachycardia; and inducible, nonsuppressible ventricular tachyarrhythmia on electrophysiologic study were randomly assigned to receive an implanted defibrillator (n = 95) or conventional medical therapy (n=101). We used a two-sided sequential design with death from any cause as the end point. RESULTS The base-line characteristics of the two treatment groups were similar. During an average follow-up of 27 months, there were 15 deaths in the defibrillator group (11 from cardiac causes) and 39 deaths in the conventional-therapy group (27 from cardiac causes) (hazard ratio for overall mortality, 0.46; 95 percent confidence interval, 0.26 to 0.82; P=0.009). There was no evidence that amiodarone, beta-blockers, or any other antiarrhythmic therapy had a significant influence on the observed hazard ratio. CONCLUSIONS In patients with a prior myocardial infarction who are at high risk for ventricular tachyarrhythmia, prophylactic therapy with an implanted defibrillator leads to improved survival as compared with conventional medical therapy.

Effectiveness and limitations of β-blocker therapy in congenital long-QT syndrome

BACKGROUND beta-blockers are routinely prescribed in congenital long-QT syndrome (LQTS), but the effectiveness and limitations of beta-blockers in this disorder have not been evaluated. METHODS AND RESULTS The study population comprised 869 LQTS patients treated with beta-blockers. Effectiveness of beta-blockers was analyzed during matched periods before and after starting beta-blocker therapy, and by survivorship methods to determine factors associated with cardiac events while on prescribed beta-blockers. After initiation of beta-blockers, there was a significant (P<0.001) reduction in the rate of cardiac events in probands (0.97+/-1.42 to 0.31+/-0.86 events per year) and in affected family members (0. 26+/-0.84 to 0.15+/-0.69 events per year) during 5-year matched periods. On-therapy survivorship analyses revealed that patients with cardiac symptoms before beta-blockers (n=598) had a hazard ratio of 5.8 (95% CI, 3.7 to 9.1) for recurrent cardiac events (syncope, aborted cardiac arrest, or death) during beta-blocker therapy compared with asymptomatic patients; 32% of these symptomatic patients will have another cardiac event within 5 years while on prescribed beta-blockers. Patients with a history of aborted cardiac arrest before starting beta-blockers (n=113) had a hazard ratio of 12.9 (95% CI, 4.7 to 35.5) for aborted cardiac arrest or death while on prescribed beta-blockers compared with asymptomatic patients; 14% of these patients will have another arrest (aborted or fatal) within 5 years on beta-blockers. CONCLUSIONS beta-blockers are associated with a significant reduction in cardiac events in LQTS patients. However, syncope, aborted cardiac arrest, and LQTS-related death continue to occur while patients are on prescribed beta-blockers, particularly in those who were symptomatic before starting this therapy.

Influence of the Genotype on the Clinical Course of the Long-QT Syndrome

BACKGROUND The congenital long-QT syndrome, caused by mutations in cardiac potassium-channel genes (KVLQT1 at the LQT1 locus and HERG at the LQT2 locus) and the sodium-channel gene (SCN5A at the LQT3 locus), has distinct repolarization patterns on electrocardiography, but it is not known whether the genotype influences the clinical course of the disease. METHODS We determined the genotypes of 541 of 1378 members of 38 families enrolled in the International Long-QT Syndrome Registry: 112 had mutations at the LQT1 locus, 72 had mutations at the LQT2 locus, and 62 had mutations at the LQT3 locus. We determined the cumulative probability and lethality of cardiac events (syncope, aborted cardiac arrest, or sudden death) occurring from birth through the age of 40 years according to genotype in the 246 gene carriers and in all 1378 members of the families studied. RESULTS The frequency of cardiac events was higher among subjects with mutations at the LQT1 locus (63 percent) or the LQT2 locus (46 percent) than among subjects with mutations at the LQT3 locus (18 percent) (P<0.001 for the comparison of all three groups). In a multivariate Cox analysis, the genotype and the QT interval corrected for heart rate were significant independent predictors of a first cardiac event. The cumulative mortality through the age of 40 among members of the three groups of families studied was similar; however, the likelihood of dying during a cardiac event was significantly higher (P<0.001) among families with mutations at the LQT3 locus (20 percent) than among those with mutations at the LQT1 locus (4 percent) or the LQT2 locus (4 percent). CONCLUSIONS The genotype of the long-QT syndrome influences the clinical course. The risk of cardiac events is significantly higher among subjects with mutations at the LQT1 or LQT2 locus than among those with mutations at the LQT3 locus. Although cumulative mortality is similar regardless of the genotype, the percentage of cardiac events that are lethal is significantly higher in families with mutations at the LQT3 locus.

Inappropriate Implantable Cardioverter-Defibrillator Shocks in MADIT II : Frequency, Mechanisms, Predictors, and Survival Impact

OBJECTIVES This study sought to identify the incidence and outcome related to inappropriate implantable cardioverter-defibrillator (ICD) shocks, that is, those for nonventricular arrhythmias. BACKGROUND The MADIT (Multicenter Automatic Defibrillator Implantation Trial) II showed that prophylactic ICD implantation improves survival in post-myocardial infarction patients with reduced ejection fraction. Inappropriate ICD shocks are common adverse consequences that may impair quality of life. METHODS Stored ICD electrograms from all shock episodes were adjudicated centrally. An inappropriate shock episode was defined as an episode during which 1 or more inappropriate shocks occurred; another inappropriate ICD episode occurring within 5 min was not counted. Programmed parameters for patients with and without inappropriate shocks were compared. RESULTS One or more inappropriate shocks occurred in 83 (11.5%) of the 719 MADIT II ICD patients. Inappropriate shock episodes constituted 184 of the 590 total shock episodes (31.2%). Smoking, prior atrial fibrillation, diastolic hypertension, and antecedent appropriate shock predicted inappropriate shock occurrence. Atrial fibrillation was the most common trigger for inappropriate shock (44%), followed by supraventricular tachycardia (36%), and then abnormal sensing (20%). The stability detection algorithm was programmed less frequently in patients receiving inappropriate shocks (17% vs. 36%, p = 0.030), whereas other programming parameters did not differ significantly from those without inappropriate shocks. Importantly, patients with inappropriate shocks had a greater likelihood of all-cause mortality in follow-up (hazard ratio 2.29, p = 0.025). CONCLUSIONS Inappropriate ICD shocks occurred commonly in the MADIT II study, and were associated with increased risk of all-cause mortality.

ECG T-Wave Patterns in Genetically Distinct Forms of the Hereditary Long QT Syndrome

BACKGROUND The long QT syndrome is an inherited disorder with prolonged ventricular repolarization and a propensity to ventricular tachyarrhythmias and sudden arrhythmic death. Recent linkage studies have demonstrated three separate loci for this disorder on chromosomes 3, 7, and 11, and specific mutated genes for long QT syndrome have been identified on two of these chromosomes. We investigated ECG T-wave patterns (phenotypes) in members of families linked to three genetically distinct forms of the long QT syndrome. METHODS AND RESULTS Five quantitative ECG repolarization parameters, ie, four Bazett-corrected time intervals (QTonset-c, QTpeak-c, QTc, and Tduration-c, in milliseconds) and the absolute height of the T wave (Tamplitude, in millivolts), were measured in 153 members of six families with long QT syndrome linked to markers on chromosomes 3 (n = 47), 7 (n = 30), and 11 (n = 76). Genotypic data were used to define each family member as being affected or unaffected with long QT syndrome. Affected members of all six families had longer QT intervals (QTonset-c, QTpeak-c, or QTc) than unaffected family members (P < .01). Each of the three long QT syndrome genotypes was associated with somewhat distinctive ECG repolarization features. Among affected individuals, the QTonset-c was unusually prolonged in those individuals with mutations involving the cardiac sodium channel gene SCN5A on chromosome 3 (lead II QTonset-c [mean +/- SD]: chromosome 3, 341 +/- 42 ms; chromosome 7, 290 +/- 56 ms; chromosome 11, 243 +/- 73 ms; P < .001); Tamplitude was generally quite small in the chromosome 7 genotype (lead II Tamplitude, mV: chromosome 3, 0.36 +/- 0.14; chromosome 7, 0.13 +/- 0.07; chromosome 11, 0.37 +/- 0.17; P < .001); and Tduration was particularly long in the chromosome 11 genotype (lead II Tduration-c: chromosome 3, 187 +/- 33 ms; chromosome 7, 191 +/- 51 ms; chromosome 11, 262 +/- 65 ms; P < .001). Similar ECG findings were observed in leads aVF and V5. A considerable variability exists in the quantitative repolarization parameters associated with each genotype, with overlap in the T-wave patterns among the three genotypes. CONCLUSIONS Three separate genetic loci for the long QT syndrome including mutations in two cardiac ionic channel genes were associated with different phenotypic T-wave patterns on the ECG. This study provides insight into the influence of genetic factors on ECG manifestations of ventricular repolarization.

Effectiveness of Cardiac Resynchronization Therapy by QRS Morphology in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT)

Background— This study aimed to determine whether QRS morphology identifies patients who benefit from cardiac resynchronization therapy with a defibrillator (CRT-D) and whether it influences the risk of primary and secondary end points in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT) trial. Methods and Results— Baseline 12-lead ECGs were evaluated with regard to QRS morphology. Heart failure event or death was the primary end point of the trial. Death, heart failure event, ventricular tachycardia, and ventricular fibrillation were secondary end points. Among 1817 patients with available sinus rhythm ECGs at baseline, there were 1281 (70%) with left bundle-branch block (LBBB), 228 (13%) with right bundle-branch block, and 308 (17%) with nonspecific intraventricular conduction disturbances. The latter 2 groups were defined as non-LBBB groups. Hazard ratios for the primary end point for comparisons of CRT-D patients versus patients who only received an implantable cardioverter defibrillator (ICD) were significantly (P<0.001) lower in LBBB patients (0.47; P<0.001) than in non-LBBB patients (1.24; P=0.257). The risk of ventricular tachycardia, ventricular fibrillation, or death was decreased significantly in CRT-D patients with LBBB but not in non-LBBB patients. Echocardiographic parameters showed significantly (P<0.001) greater reduction in left ventricular volumes and increase in ejection fraction with CRT-D in LBBB than in non-LBBB patients. Conclusions— Heart failure patients with New York Heart Association class I or II and ejection fraction ⩽30% and LBBB derive substantial clinical benefit from CRT-D: a reduction in heart failure progression and a reduction in the risk of ventricular tachyarrhythmias. No clinical benefit was observed in patients with a non-LBBB QRS pattern (right bundle-branch block or intraventricular conduction disturbances). Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

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.

Left Cardiac Sympathetic Denervation in the Management of High-Risk Patients Affected by the Long-QT Syndrome

Background—The management of long-QT syndrome (LQTS) patients who continue to have cardiac events (CEs) despite β-blockers is complex. We assessed the long-term efficacy of left cardiac sympathetic denervation (LCSD) in a group of high-risk patients. Methods and Results—We identified 147 LQTS patients who underwent LCSD. Their QT interval was very prolonged (QTc, 543±65 ms); 99% were symptomatic; 48% had a cardiac arrest; and 75% of those treated with β-blockers remained symptomatic. The average follow-up periods between first CE and LCSD and post-LCSD were 4.6 and 7.8 years, respectively. After LCSD, 46% remained asymptomatic. Syncope occurred in 31%, aborted cardiac arrest in 16%, and sudden death in 7%. The mean yearly number of CEs per patient dropped by 91% (P <0.001). Among 74 patients with only syncope before LCSD, all types of CEs decreased significantly as in the entire group, and a post-LCSD QTc <500 ms predicted very low risk. The percentage of patients with >5 CEs declined from 55% to 8% (P <0.001). In 5 patients with preoperative implantable defibrillator and multiple discharges, the post-LCSD count of shocks decreased by 95% (P =0.02) from a median number of 25 to 0 per patient. Among 51 genotyped patients, LCSD appeared more effective in LQT1 and LQT3 patients. Conclusions—LCSD is associated with a significant reduction in the incidence of aborted cardiac arrest and syncope in high-risk LQTS patients when compared with pre-LCSD events. However, LCSD is not entirely effective in preventing cardiac events including sudden cardiac death during long-term follow-up. LCSD should be considered in patients with recurrent syncope despite β-blockade and in patients who experience arrhythmia storms with an implanted defibrillator.

Risk stratification for primary implantation of a cardioverter-defibrillator in patients with ischemic left ventricular dysfunction.

OBJECTIVES The study was designed to develop a simple risk stratification score for primary therapy with an implantable cardioverter-defibrillator (ICD). BACKGROUND Current guidelines recommend primary ICD therapy in patients with a low ejection fraction (EF). However, the benefit of the ICD in the low EF population may not be uniform. METHODS Best-subset proportional-hazards regression analysis was used to develop a simple clinical risk score for the end point of all-cause mortality in patients allocated to the conventional therapy arm of MADIT (Multicenter Automatic Defibrillator Implantation Trial)-II after excluding a pre-specified subgroup of very high-risk (VHR) patients (defined by blood urea nitrogen [BUN] >or=50 mg/dl and/or serum creatinine >or=2.5 mg/dl). The benefit of the ICD was then assessed within risk score categories and separately in VHR patients. RESULTS The selected risk score model comprised 5 clinical factors (New York Heart Association functional class >II, age >70 years, BUN >26 mg/dl, QRS duration >0.12 s, and atrial fibrillation). Crude mortality rates in the conventional group were 8% and 28% in patients with 0 and >or=1 risk factors, respectively, and 43% in VHR patients. Defibrillator therapy was associated with a 49% reduction in the risk of death (p < 0.001) among patients with >or=1 risk factors (n = 786), whereas no ICD benefit was identified in patients with 0 risk factors (n = 345; hazard ratio 0.96; p = 0.91) and in VHR patients (n = 60; hazard ratio 1.00; p > 0.99). CONCLUSIONS Our data suggest a U-shaped pattern for ICD efficacy in the low-EF population, with pronounced benefit in intermediate-risk patients and attenuated efficacy in lower- and higher-risk subsets.

Age- and Sex-Related Differences in Clinical Manifestations in Patients With Congenital Long-QT Syndrome Findings From the International LQTS Registry

BACKGROUND Unexplained female predominance is observed in long-QT syndrome (LQTS), a congenital autosomal disorder with prolonged repolarization and syncope or sudden death due to ventricular tachyarrhythmias. Our objectives were to evaluate age- and sex-related differences in events among LQTS patients referred to the LQTS International Registry. METHODS AND RESULTS Age- and sex-related occurrence of events was analyzed in 479 probands (70% females) and 1041 affected family members (QTc >440 ms, 58% females). LQTS-gene mutations were identified in 162 patients: 69 LQT1 carriers (KVLQT1 on 11p15.5), 62 LQT2 carriers (HERG on 7q35-36), and 31 LQT3 carriers (SCN5A on 3p21-24). Females predominated among 366 probands (71% females) and 230 symptomatic family members (62% females). Male probands were younger than females at first event (8+/-7 versus 14+/-10 years, P<0.0001) and had higher event rates by age 15 years than females (74% versus 51%, P<0.0001). Affected family members had similar findings. By Cox analysis adjusting for QTc duration, the hazard ratio for female probands of experiencing events by age 15 years was 0.48 (P<0.001), and it was 1.87 (P=0.09) by age 15 to 40 years. In female family members, the hazard ratio was 0.58 (P<0.001) by age 15 years, and it was 3.25 (P<0.001) by age 15 to 40 years. The event rate was higher in male than female LQT1 carriers (69% versus 32%, P=0.001). No age-sex difference in event rate was detected in LQT2 and LQT3 carriers. CONCLUSIONS Among LQTS patients, the risk of cardiac events was higher in males until puberty and higher in females during adulthood. The same pattern was evident among LQT1 gene carriers. Unknown sex factors modulate QT duration and arrhythmic events, with preliminary evidence of gene-specific differences in age-sex modulation.