Cardiac resynchronization and death from progressive heart failure. a meta-analysis of randomized controlled trials

Results: The mean QTC in Group 1 (507 ms) was significantly longer than in Groups 2– 4 (417–27 ms). Epinephrine prolonged several electrocardiographic parameters of repolarization in Groups 1 and 2 but not Groups 3 or 4. In the baseline state, the sensitivity and specificity of electrocardiographic criteria for identifying mutation carriers among family members and controls were 59% and 100%. During epinephrine, the sensitivity of the electorcardiographic criteria for identifying mutation carriers rose to 91%, and the specificity remained at 100%. Conclusions: Epinephrine is highly effective in unmasking LQT1 mutation carriers who do not have QT prolongation in the baseline state. Perspective: Although the sample sizes were fairly small, the results suggest that an epinephrine challenge may be an excellent screening tool for family members of a patient identified to have the LQT1 form of LQTS. If these results are confirmed in larger studies, the decision to institute prophylactic therapy for family members of probands could be based simply on the response to epinephrine, rather than on the more expensive and lengthy process of gene analysis. FM

apply only to the LQT1 and LQT2 genotypes. Because the causative mutation cannot be identified in a majority of patients with LQTS, the sensitivity and specificity of exercise-induced repolarization abnormalities in unselected patients with LQTS in unknown. FM

Haploinsufficiency in Combination With Aging Causes SCN5A-Linked Hereditary Lenegre Disease Probst V, Kyndt F, Potet F, et al. J Am Coll Cardiol 2003;41: 643–52. Study Question: What is the correlation between genotype and phenotype among patients with progressive conduction system (Lenegre) disease who have a SCN5A gene mutation? Methods: Genotyping was performed in 65 members of a family affected by SCN5A-linked conduction system disease to identify carriers of a splicing mutation. Conduction intervals were measured by analysis of the 12-lead or signalaveraged electrocardiogram. In an in vitro patch-clamp preparation, inward currents were measured in SCN5Atransfected cells. Results: Twenty-five family members were found to be carriers of the splice mutation of SCN5A. Only four of these 25 patients had a normal electrocardiogram, and the rest had a bundle branch block, hemiblock and/or 1° atrioventricular block, along with P wave prolongation. Six of these patients had syncope and underwent pacemaker implantation. Unaffected family members had normal electrocardiograms. In five patients with serial electrocardiograms over 11–16 years, the QRS duration and/or PR interval lengthened with age. Crosssectional analysis demonstrated a correlation between age and QRS duration. In vitro studies demonstrated complete loss of function of the affected allele. Conclusions: Lenegre disease is caused by haploinsufficiency of the SCN5A gene, which in combination with age, results in progressive slowing of conduction in the atrium, conduction system and ventricle. Perspective: Mutations of the SCN5A gene disrupt the function of the sodium channel, explaining why patients with Lenegre disease develop conduction slowing throughout the heart. Mutations of the same gene also have been implicated in the LQT3 form of the long-QT syndrome and in the Brugada syndrome, demonstrating that sodium channelopathies may be associated with very different phenotypes. FM

Exercise Stress Test Amplifies Genotype-Phenotype Correlation in the LQT1 and LQT2 Forms of the Long-QT Syndrome Takenaka K, Tomohiko A, Shimizu W, et al. Circulation 2003; 107:838 – 44. Study Question: How does exercise affect the QT interval and T-wave morphology in the LQT1 and LQT2 subtypes of the long-QT syndrome (LQTS)? Methods: Gene analysis in 183 patients with LQTS identified in 30 patients with a KCNQ1 mutation (LQT1), and 19 patients with a KCNH2 mutation (LQT2). An exercise test was performed in these patients and in 22 healthy control subjects. The corrected QT interval (QTc) and T-wave morphology were analyzed in blinded fashion at rest and during exercise. Results: The baseline QTcs in the LQT1 and LQT2 groups (511 and 513 ms, respectively) were longer than in control subjects (402 ms). During exercise, the QTc lengthened to 599 ms in the LQT1 patients and remained unchanged in the others. During exercise, the percentage of LQT1 patients with a broad-based T-wave increased from 43% to 77%, while the percentage of LQT2 patients with a bifid T-wave increased from 58% to 89%. Conclusions: Exercise exaggerates the phenotypic differences in QTc and T-wave morphology between patients with the LQT1 and LQT2 forms of LQTS. Perspective: The finding that QTc prolongation is accentuated by exercise only in LQT1 is interesting because it is consistent with the clinical observation that cardiac events are more likely to occur during states of adrenergic activation in LQT1 than in LQT2. However, the diagnostic value of the exercise-induced changes in QTc and T-wave morphology are of limited value, since the results of the study

Cardiac Resynchronization and Death From Progressive Heart Failure. A Meta-Analysis of Randomized Controlled Trials Bradley DJ, Bradley EA, Baughman KL, et al. JAMA 2003;289: 730 – 40. Study Question: Does biventricular pacing for the purpose of cardiac resynchronization (CR) reduce the risk of death from heart failure (HF)?

ACC CURRENT JOURNAL REVIEW May/Jun 2003

81

Methods: This was a meta-analysis of randomized trials of CR in which the duration of follow-up was ⱖ3 months. Four trials qualified for inclusion in the meta-analysis, with a total sample size of 1634 patients. All patients underwent implantation of a pacemaker (n⫽590) or implantable cardioverter/defibrillator (ICD, n⫽1044) capable of biventricular pacing, then were randomized to CR on or CR off groups. The duration of follow-up after randomization was 3– 6 months. Results: The mean age in the four trials was 63– 66 years, and the majority were men with functional class III–IV HF. The mean ejection fraction was 21–23% and the mean QRS duration was 158 –176 ms. The use of angiotensin-converting enzyme inhibitors ranged from 87–96%, while the use of beta-blockers ranged from 28 – 60%. CR reduced mortality from HF by 51%, from 3.5% to 1.7% during 3– 6 months of follow-up, and was associated with a 29% reduction in hospitalizations for HF. CR did not significantly reduce non-HF mortality or all-cause mortality. Conclusions: CR reduces HF-related mortality and hospitalizations in patients with left ventricular dysfunction and a wide QRS complex. Perspective: Unfortunately, the reduction in mortality from HF did not translate to a significant reduction in all-cause mortality. This suggests that CR sometimes may change the mode of death from HF to some other cause, such as malignant ventricular arrhythmias. Because ICDs offer protection from arrhythmia-induced death and pacemakers do not and because approximately one third of subjects in this study did not receive an ICD, at present one can only speculate on whether CR will improve all-cause mortality when used in conjunction with an ICD. FM

than during EndoRVP (197 vs. 163 ms). In two patients, polymorphic ventricular tachycardia (PVT) was reproducibly caused by BiVP or EpiLVP. In the ventricular wedge preparation, epicardial pacing significantly prolonged the QT interval and TDR compared to endocardial pacing. Conclusions: EpiLVP and BiVP cause repolarization abnormalities that may result in ventricular proarrhythmia. Perspective: The study provides convincing evidence that QT prolongation and PVT may be precipitated by BiVP. However, the prevalence of this complication is unclear, and almost certainly is less than the 7% prevalence found in this study. Nevertheless, an important implication is that BiVP may increase the susceptibility to PVT when a patient is exposed to aggravating factors such as hypokalemia, erythromycin or amitriptyline. This may provide an argument in favor of an implantable cardioverter/defibrillator in patients who undergo BiVP. FM

Frequent Ventricular Ectopy after Exercise as a Predictor of Death Frolkis JP, Pothier CE, Blackstone EH, et al. N Engl J Med 2003; 348:781–90. Study Question: Is ventricular ectopy (VE) during recovery from exercise a stronger predictor of death than VE during exercise? Methods: After a structured interview and chart review, a symptom-limited exercise test was performed in 29,244 patients ⱖ30 years of age who did not have heart failure or frequent VE at rest. Frequent VE was defined as ⱖ7 ventricular premature beats per minute, ventricular bigeminy or trigeminy, ventricular couplets or triplets or ventricular tachycardia/fibrillation. The primary end point was death, as determined by the Social Security Death Index. The mean duration of follow-up was 5.3 years. Results: Frequent VE occurred only during exercise in 3% of patients, only during recovery in 2%, and during both exercise and recovery in 2%. The 5-year death rates were 9% in patients with frequent VE during exercise and 11% in patients with frequent VE during recovery. After adjustment for other variables that may be associated with death, frequent VE during recovery was an independent predictor of death (hazard ratio 1.6), while frequent VE during exercise was not. Conclusions: Frequent VE during the recovery phase of an exercise test is a better predictor of death than VE that occurs only during exercise. Perspective: Benign VE often occurs more frequently during recovery than during exercise and yet is not predictive of death. Therefore the results of this study should not be extrapolated to all patients who undergo exercise testing. The findings may be most applicable to patients with coronary artery disease, but this is unclear because outcomes were not analyzed according to the type of structural heart disease. Also unclear is whether treatment aimed at the

Effect of Epicardial or Biventricular Pacing to Prolong QT Interval and Increase Transmural Dispersion of Repolarization Medina-Ravell VA, Lankipalli RS, Yan GX, et al. Circulation 2003;107:740 – 6. Study Question: Do epicardial left ventricular pacing (EpiLVP) and endocardial right ventricular pacing (EndoRVP) predispose to ventricular proarrhythmia? Methods: Biventricular pacing (BiVP) was instituted in 29 patients with congestive heart failure and a mean ejection fraction of 23%. Leads were positioned in the right ventricular apex and in an epicardial vein via the coronary sinus. The QT and JT intervals were measured during pacing, as was the interval from the peak to the end of the T wave, an index of transmural dispersion of repolarization (TDR). In addition, in a rabbit left ventricular wedge preparation, microelectrodes were used to record epicardial and endocardial transmembrane potentials during pacing. Results: The JT interval was significantly longer during EpiLVP (359 ms) and biventricular pacing (350 ms) than during EndoRVP (302 ms). TDR was longer during EpiLVP

ACC CURRENT JOURNAL REVIEW May/Jun 2003

82