Aharon Medina

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.

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.

Comparison of clinical and genetic variables of cardiac events associated with loud noise versus swimming among subjects with the long QT syndrome

Acute auditory stimuli and swimming activities are frequently associated with syncope, aborted cardiac arrest, and death in the long QT syndrome (LQTS). We investigated the clinical and genetic findings associated with cardiac events precipitated by these arousal factors. The study population involved 195 patients with an index cardiac event associated with a loud noise (n = 77) or swimming activity (n = 118). Patients with events associated with loud auditory stimuli were older at their index event and were more likely to be women than patients who experienced events during swimming-related activities. Patients with an index event associated with loud noise were likely to have subsequent events related to auditory stimuli; patients with an index event associated with swimming were likely to have recurrent events related to swimming or physical activities. Family patterning of auditory and swimming and/or physical activity-related events was evident. Genotype analyses in 25 patients revealed a significant difference in the distribution of index cardiac events by genotype (p <0.001), with all 19 patients with swimming-related episodes associated with LQT1 genotype and 5 of 6 patients with auditory-related events associated with LQT2 genotype. The clinical profile and genotype findings of patients with LQTS who experience cardiac events related to acute auditory stimuli are quite different from those who experience events accompanying swimming activities.

Natural history of left ventricular thrombi: Their appearance and resolution in the posthospitalization period of acute myocardial infarction

A series of 198 consecutive patients with acute myocardial infarction were prospectively studied before hospital discharge and during 24.0 +/- 8.6 months of follow-up. A predischarge thrombus was found in 38 (31%) of 124 patients with anterior infarction but in none of 74 patients with inferior infarction (p less than 0.001). Early thrombolytic therapy in 34 patients did not decrease the rate of thrombus occurrence. Acute anterior infarction, ejection fraction less than or equal to 35% and apical dyskinesia or aneurysm (but not akinesia) were significantly related to the appearance of thrombus during hospitalization by stepwise logistic regression analysis. Echocardiographic follow-up of 159 patients for at least 6 months (mean 26.6 +/- 8.4) revealed that thrombus disappeared in 14 (48%) of 29. Disappearance of thrombus was related to predischarge apical akinesia (but not dyskinesia) and to warfarin therapy during the follow-up period. A new thrombus first appeared after hospital discharge in 13 of 130 patients, and in 7 of the 13 it resolved during further follow-up. Thus, 30% (13 of 42) of thrombi in these patients appeared after discharge from the hospital. Three factors were related to occurrence of new thrombi during the follow-up period: deterioration in left ventricular ejection fraction, predischarge ejection fraction less than or equal to 35% and ventricular aneurysm or dyskinesia. Systemic embolism occurred in six patients, all with a predischarge thrombus (p less than 0.001). Mobility of the thrombus was the only variable significantly related to subsequent embolic events (p = 0.001) by logistic regression analysis. Thus, the predischarge echocardiogram identifies patients with thrombus and those at highest risk of embolic events. It can indicate patients who are likely to have thrombus resolution and those at risk of developing a new thrombus after hospital discharge. Follow-up echocardiograms may help in guiding the length of long-term anticoagulant therapy. Four additional patients with a predischarge apical mobile thrombus (not part of the consecutive series) received thrombolytic therapy. In two of the four, lysis of thrombus was achieved without complications, but systemic embolism occurred in the other two, and proved fatal in one.

Clinical and genetic variables associated with acute arousal and nonarousal-related cardiac events among subjects with the long QT syndrome☆

In patients with the long QT syndrome (LQTS), the occurrence of cardiac events (syncope or cardiac arrest) is frequently associated with acute arousal caused by exercise, swimming, emotion, or noise. However, cardiac events may also occur during sleep or with ordinary daily activities. The purpose of this study was to determine whether there are differential clinical, electrocardiographic, and genetic features among LQTS patients who experienced cardiac events with and without acute arousal. We identified 1,325 patients with cardiac events from the International LQTS Registry. Based on the precipitating conditions of the first event, 427 patients were classified as arousal, 345 as nonarousal, and the remaining 553 were unknown (not classifiable). Gene linkage was known in 78 of the 772 patients with classifiable first events. The age at first cardiac event was significantly younger in the arousal than the nonarousal group (11.7 vs. 15.5 years, respectively; p<0.001). The arousal-type patients had a higher rate of subsequent cardiac events during follow-up after the index event than the nonarousal-type patients (p = 0.02). Arousal-related cardiac events occurred in 85% of LQT1, 67% of LQT2, and 33% of LQT3 patients (p = 0.008). This study provides evidence that the genotype is an important determinant of the LQTS phenotype in terms of arousal and nonarousal-related cardiac events.

Effect of Metoprolol in Reducing Myocardial Ischemic Threshold During Exercise and During Daily Activity 1

In a study of 48 patients with coronary artery disease and evidence of ischemia during exercise and daily life, metoprolol reduced the threshold of myocardial ischemia in a dose-dependent manner. This effect of beta blockers is probably due to increased coronary tone.

Lysis of mobile left ventricular thrombi during acute myocardial infarction with urokinase

Abstract Left ventricular (LV) thrombi occur in about onethird of patients who have had an acute myocardial infarction (AMI). 1,2 Autopsy 3 and echocardiographic studies 1,2 suggest that patients with protruding and mobile LV thrombi are at risk of systemic embolization. Kremer et al 4 reported the successful use of urokinase for lysis of protruding and mobile LV thrombi during AMI but no further reports followed this initial communication. We report the effect of urokinase on mobile LV thrombi in a patient with AMI.

Usefulness of severity of myocardial ischemia on exercise testing in predicting the severity of myocardial ischemia during daily activities.

To determine the relation between myocardial ischemic indexes on exercise testing and on ambulatory Holter recording, 60 patients with stable coronary artery disease who exhibited an ischemic response to both testing procedures were studied. All patients performed a Bruce protocol exercise test and underwent 24-hour Holter recording within 2 weeks without antianginal medications. Mean exercise duration was 7.4 +/- 2.8 minutes, mean heart rate at 1-mm ST depression was 118 +/- 20 beats/min and mean maximal ST depression during exercise was 2.2 +/- 1 mm. During Holter recording the average number of ischemic episodes was 4.7 +/- 2.6 per patient, mean duration of daily ischemia was 62 +/- 54 minutes, mean maximal ST depression was 3.2 +/- 1.3 mm and average heart rate at 1-mm ST depression was 93 +/- 17 beats/min. Overall, the correlations between ischemic indexes on both testing procedures were very weak (mean r2 = 0.054). The only exercise variable that had a significant correlation (p less than 0.05) with all Holter variables was heart rate at 1-mm ST depression, yet it correlated very weakly (0.064 less than or equal to r2 less than or equal to 0.125) with most Holter covariates and had a better correlation (r2 = 0.256) only with average heart rate at 1-mm ST depression during Holter. Thus, ischemic indexes on exercise testing cannot accurately predict ischemic indexes on ambulatory Holter recording in patients with stable coronary artery disease who exhibit ischemic changes on both tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Long QT Syndrome and Complete Situs inversus

The familial long QT syndrome is a rare condition that may occur with or without deafness. Dextrocardia with complete situs inversus is a familial syndrome generally found in normal subjects with a high incidence of consanguinity among the parents. In this report we describe a Jerbian family with both disorders and with several cases of sudden death. Of 27 members of this family (3 generations) in whom ECG was performed, 15 had QT prolongation (QTc greater than 0.45). Four members (2 generations) had complete situs inversus, 3 of them also had ECG evidence of QT prolongation. The combined occurrence of these rare diseases within the same family has not been previously reported. It may be due to the high incidence of consanguinity and may raise the possibility that the loci responsible for the 2 conditions are closely related and located on the same chromosome. A more extensive study of the family is being carried out.