Showing papers by "Arthur J. Moss published in 2008"

Long-QT Syndrome After Age 40

Abstract: 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] ≥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 265 (P<0001) in the age range of 41 to 60 years and 123 (P=031) 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

Gender Related Differences in Electrocardiographic Parameters and Their Association with Cardiac Events in Patients After Myocardial Infarction

Abstract: There are limited data regarding gender-related differences in electrocardiographic (ECG) presentation in patients after myocardial infarction (MI) and the prognostic value of ECG variables in women. A series of ECG parameters were analyzed in 838 patients (216 women, 622 men) using standard electrocardiography performed 5 to 7 days after first MI, and their associations with gender and risk for cardiac events, defined as cardiac death, nonfatal MI, or unstable angina, were evaluated. Heart rate was faster and QTc duration was longer, whereas QRS duration was shorter in women compared with men. Women had more lateral ST depressions and more T-wave inversions in the anterior and lateral regions. During mean 2-year follow-up, there were 138 events in men and 65 in women; women had a 38% greater risk for recurrent events (adjusted hazard ratio [HR] 1.38, p = 0.031). In multivariate Cox regression analysis, ST-segment elevation in leads V 1 to V 4 on the fifth to seventh day after MI was associated with increased risk for recurrent events in women (adjusted HR 2.16, p = 0.003) but not in men (adjusted HR = 0.81, p = 0.32). ST depressions in leads V 5 , V 6 , I, or aVL (adjusted HR 1.70, p = 0.006) in men but not in women (adjusted HR 0.98, p = 0.93) were identified as a risk factor for recurrent events. In conclusion, there are gender-related differences in ECG presentation and the prognostic significance of ECG findings after MI. ST-segment elevation in anterior leads is a significant predictor of events in women, whereas ST depression in lateral leads is a significant predictor in men.

Congenital long QT syndrome: considerations for primary care physicians.

Abstract: Congenital long QT syndrome is an inherited disorder of cardiac repolarization that predisposes to syncope and to sudden death from polymorphic ventricular tachycardia. The disorder should be suspected when the electrocardiogram shows characteristic QT abnormalities, or when there is a family history of long QT syndrome or of an event that raises suspicion of long QT syndrome, such as sudden death, syncope, or ill-defined "seizure" disorder. We can now classify some types of congenital long QT syndrome according to their genetic mutations and their triggers, such as exercise, rest, or startle.

Importance of Knowing the Genotype and the Specific Mutation When Managing Patients With Long-QT Syndrome

Abstract: Long-QT syndrome (LQTS) is an inherited disorder with prolonged ventricular repolarization and an increased propensity to ventricular tachyarrhythmias of the torsade de pointes type that are responsible for arrhythmogenic syncope and sudden cardiac death.1 During the past 13 years, 10 different genotype forms of LQTS have been identified (LQT1–LQT10), with the most frequent clinical types (LQT1–LQT3) categorized as ion channelopathies.2 The remaining 7 infrequently occurring forms of LQTS (LQT4–LQT10) also affect myocellular ion channel currents either directly or indirectly, but LQT4–LQT10 make up less than 5% of the genotype-identified LQTS. To date, approximately 500 different LQTS mutations have been identified in the 10 LQTS genes, and cellular expression studies of these mutations have elucidated basic electrophysiological mechanisms responsible for the delayed repolarization and the manifest QT prolongation. Different LQTS genes affect different ion current mechanisms, and the clinical course of patients with LQT1–LQT3 genotypes have been shown to be quite different.3 In addition, different mutations on the same LQTS gene may produce different electrophysiological effects. For example, mutations involving the LQT1 gene are all associated with reduction in the repolarizing I Ks current, but the magnitude of the reduction in this current can vary considerably among the different LQT1 mutations.4 This variability in the electrophysiological effects of different mutations contributes to the variability in the risk of life-threatening cardiac events that are independent of the manifest QTc interval on the ECG. Thus, knowledge of the LQTS genotype and the associated specific mutations are useful in risk-stratifying individual patients for the selection of appropriate therapy for patient-specific risk-reduction. Response by Vincent see p 219 Because of the extensive literature that currently exists in LQTS, we will focus on the 3 common forms of LQTS (LQT1–LQT3) and related mutations to make our point that this information is useful …

Risk of Cardiac Events in Patients With Asthma and Long-QT Syndrome Treated With Beta2 Agonists

Abstract: The clinical course and risk factors associated with beta(2)-agonist therapy for asthma have not been investigated previously in patients with the long-QT syndrome (LQTS). The risk of a first LQTS-related cardiac event due to beta(2)-agonist therapy was examined in 3,287 patients enrolled in the International LQTS Registry with QTc > or = 450 ms. The Cox proportional hazards model was used to assess the independent contribution of clinical factors for first cardiac events (syncope, aborted cardiac arrest, or sudden death) from birth through age 40. Time-dependent beta(2)-agonist therapy for asthma was associated with an increased risk for cardiac events (hazard ratio [HR] = 2.00, 95% confidence interval 1.26 to 3.15, p = 0.003) after adjustment for relevant covariates including time-dependent beta-blocker use, gender, QTc, and history of asthma. This risk was augmented within the first year after the initiation of beta(2)-agonist therapy (HR = 3.53, p = 0.006). The combined use of beta(2)-agonist therapy and anti-inflammatory steroids was associated with an elevated risk for cardiac events (HR = 3.66, p <0.01); beta-blocker therapy was associated with a reduction in cardiac events in those using beta(2) agonists (HR = 0.14, p = 0.05). In conclusion, beta(2)-agonist therapy was associated with an increased risk for cardiac events in patients with asthma with LQTS, and this risk was diminished in patients receiving beta blockers.

Improving the Detection of Subtle IKr-Inhibition : Assessing Electrocardiographic Abnormalities of Repolarization Induced by Moxifloxacin

Abstract: Background: QT prolongation is an incomplete measure of drug-induced changes in repolarization. In this study, we investigated a novel, automatic ECG technique for describing ventricular repolarization morphology and we compared these results to corrected QT (QTc) prolongation for identifying ECGs of healthy individuals on moxifloxacin.

Plasminogen Activator Inhibitor-1 Polymorphism (4G/5G) Predicts Recurrence in Nonhyperlipidemic Postinfarction Patients

Abstract: Objective— Nonhyperlipidemic postinfarction patients are at high risk for recurrent coronary events by virtue of incident myocardial infarction (MI); however, few studies assess risk beyond incident MI. The aim of this study was to assess such risk as a function of 37 atherosclerosis-associated genetic polymorphisms and 17 blood marker variables. Methods and Results— Screening of polymorphisms in nonhyperlipidemic postinfarction patients revealed significant risk only for the 4G/5G insertion/deletion polymorphism in the promoter of the plasminogen-activator inhibitor-1 (PAI-1) gene. Outcome event mapping, an exploratory data analysis tool, was then applied to define a subgroup (182 patients from total study population of 846 nondiabetic patients) exhibiting maximal functional dependence of risk on the PAI-1 polymorphism. Cox multivariable regression analyses within the subgroup adjusted for significant clinical covariates and medication use as a function of the PAI-1 polymorphism and 17 atherosclerosis-associated blood markers revealed significant risk for patients homozygous for the 4G allele (hazard ratio 4.30, 95% CI 1.98 to 9.33, P =0.00023), and lack of significant risk-association with any blood marker. Conclusions— In a subgroup of normolipidemic postinfarction patients, only the PAI-1 4G/5G polymorphism was associated with recurrent risk from a set of atherosclerosis-associated genetic polymorphisms and blood markers.

Phenotypic Variability in Caucasian and Japanese Patients with Matched LQT1 Mutations

Abstract: 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 (≤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.

A covariance-based algorithm: A novel technique for rhythm discrimination in ICDs

Abstract: Inappropriate shocks due to misclassification of supraventricular and ventricular arrhythmias remain a major problem in the care of patients with Implantable Cardioverter defibrillators (ICDs). In this study we have investigated the ability of a new covariance-based algorithm, to distinguish Ventricular Tachycardia from other rhythms such as Supraventricular Tachycardia. The proposed algorithm has a low computational demand and with a small adjustment is applicable on both single-chamber and dual-chamber ICDs. The results are promising and suggest that the new covariance-based algorithm may be an effective method for ICD rhythm classification and may decrease inappropriate shocks.

A statement on ethics from the HEART Group.

Abstract: Over the past several years, the editors of leading international cardiovascular journals have met to form the HEART group and to discuss areas of growing, common interest. Recently, the HEART group has developed a document that addresses general ethical principles in the conduct of the scientific process with which all of the editors concur. Published essentially simultaneously in all of the participating journals, including this journal, this document presents the ethical tenets accepted by all of the undersigned editors that will (continue to) guide their decisions in the editorial process. These are the general principles on which the HEART Group is based and by which we, as a group, abide; however, please note that individual journal members and their respective societies may have their own rules and regulations that supersede the guidelines of the HEART Group.

Lp(a) and risk of recurrent cardiac events in obese postinfarction patients

Abstract: Studies of recurrent coronary events in obese postinfarction patients show mixed results despite potential importance of obesity-related pathophysiologic processes and associated markers in establishing and predicting risk. The study aim was to determine specific markers of recurrent risk in obese postinfarction patients. Nondiabetic patients of the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) postinfarction study were classified according to BMI as normal weight ( A polymorphism of the apolipoprotein A-I gene and the −250G>A polymorphism of the hepatic lipase gene in establishing risk. We conclude that interactions of elevated Lp(a) with polymorphisms of the apolipoprotein A-I and hepatic lipase genes, primarily reflective of altered lipoprotein metabolism, play an important role in the establishment of recurrent coronary event risk in obese, nondiabetic postinfarction patients. These findings suggest close monitoring and consideration of weight reduction for obese postinfarction patients with elevated Lp(a) levels.

The long and short of a constipation-reducing medication.

Abstract: In this issue of the Journal, Camilleri et al.1 report on their 12-week randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of prucalopride in the treatment of chronic constipation (ClinicalTrials.gov number, NCT00483886). The authors clearly document the efficacy of prucalopride in improving bowel function and quality of life in the 411 patients who received the drug, as compared with 209 patients who received placebo. However, there is concern about a potential cardiac risk associated with this constipation-reducing drug. Prucalopride is a prokinetic 5-hydroxytryptamine4 (5-HT4) receptor agonist similar in function to cisapride and tegaserod, two constipation-reducing . . .

Life Versus Death

Abstract: Randomized clinical trials have clearly shown that the implanted cardiac defibrillator (ICD) saves lives1–3 and that cardiac resynchronization therapy (CRT) and combined ICD and CRT devices reduce both heart failure and mortality.4–6 However, during long-term follow-up of patients with these implanted devices, only a minority will use appropriate ICD therapy for life-threatening ventricular tachyarrhythmic events. For example, in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II), only 35% of the patients in the ICD arm received appropriate ICD therapy (shock or antitachycardia pacing) during 3-year follow-up.7 The challenge facing the medical profession is how to better identify and select patients who will benefit from implanted ICD or combined ICD and CRT devices so as to achieve greater therapeutic efficacy without losing patients. During recent years, several noninvasive and invasive electrophysiological tests have been evaluated, including signal-averaged ECG, heart rate variability, heart rate turbulence, T-wave alternans, and programmed electrophysiological testing, but the risk-stratification results from these tests have not been very encouraging. Recently, Goldenberg et al demonstrated that the ICD:conventional therapy hazard ratio in patients with advanced renal disease (blood urea nitrogen >50 mg/dL) and in good-risk patients without adverse clinical factors such as heart failure, atrial fibrillation, older age, and wide QRS complex, renal dysfunction was close to 1.0 in 35% of the …

History of Electrocardiology: “The Nature of Fibrillary Contraction of the Heart-Its Relation to Tissue Mass and Form”

Abstract: Most cardiologists are familiar with the contributions of Sir James Mackenzie and Sir Thomas Lewis to the clinical disorder auricular fibrillation as it was called at the turn of the century. In a classic chapter on this arrhythmia in the first edition of the book, Diseases of the Heart published in 1908, Mackenzie describes in detail the clinical aspects of auricular fibrillation. Mackenzie made clever use of synchronous polygraphic records of venous and arterial pulses to highlight the absence of auricular waves during the heart‘s irregular action in auricular fibrillation. Sir Thomas Lewis, a disciple of Mackenzie, focused on the electrical aspects of auricular fibrillation. Although Lewis made many important contributions to the field, he wrongly concluded that auricular fibrillation was the result of extra-systole formation. One of the true pioneers who elucidated the fundamental mechanism of fibrillation was the physiologist, Walter Garrey. We reprint his classic article on the nature of fibrillation that was published in the American]ournal of Physiology in 1914.’ In animal experiments, he showed that the size of the myocardial tissue was critical, with small loci unable to maintain the fibrillatory activity while large tissue mass sustained the fibrillation. In addition, he showed that narrow pathways of atrial or ventricular myocardium prevent the transmission of the fibrillatory process from one region to another, whether this is an artificially constructed band of tissue or the atrioventricular conduction pathway. Garrey concluded from these observations that fibrillatory activity was dependent on the presence of transient conduction block that varied in location. Such conditions do not exist in small pieces of myocardial tissue or in narrow tissue pathways the former inhibiting the persistence of fibrillation and the latter preventing its extension. This article by Garrey provided the basic electrophysiologic foundation for both atrial and ventricular fibrillation, and as such, it significantly advanced the science of cardiac arrhythmias.