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Biomedical subjects

A J Moss

Publications and source records attributed to A J Moss.

At least 55 records · Page 3Linked to original sources
PubMed1999

Long-term nitrate use may be deleterious in ischemic heart disease: A study using the databases from two large-scale postinfarction studies. Multicenter Myocardial Ischemia Research Group.

BACKGROUND: Secondary coronary prevention studies have generally focused on specific medications, often to the exclusion of commonly used therapies. To date, long-term nitrate use has not been investigated in large-scale clinical trials. METHODS AND RESULTS: We examined the relation between long-acting nitrates given during the chronic phase of the disease and the outcome. We analyzed data prospectively acquired in a large, observational study involving 1042 patients enrolled for the Multicenter Study of Myocardial Ischemia (MSMI) in North America, Israel, and Japan as well as 1779 patients enrolled for the Multicenter Diltiazem Post Infarction Trial (MDPIT). The Cox analyses with all the variables retained revealed that nitrates were associated with a significantly increased mortality risk (MSMI: hazard ratio 3.78, P =.011; MDPIT: hazard ratio 1.61, P =.019) in patients who had recovered from an acute coronary event. The analyses with the propensity score method on the MSMI and the MSMI databases also showed that the risk for cardiac death with use of nitrates was increased in most of the 5 subclasses according to the score. CONCLUSION: These analyses raise concern about the potential adverse effects of long-acting nitrate therapy in chronic coronary disease.

Databases, Factual↗
PubMed1999

A review of the cardiac systemic side-effects of antihistamines: ebastine.

The cardiac safety of ebastine, a long-acting, non-sedating antihistamine, has been thoroughly assessed in phase I-III clinical studies. Ebastine alone at the recommended doses of 10 mg and 20 mg has no clinically relevant effect on QTc interval in adults and in special patient populations (elderly, children or subjects with hepatic or renal impairment). Ebastine administered at 60 and 100 mg/day (3-5 times the maximum recommended dose) for 1 week had statistically significantly smaller effects (3.7 and 10.3 msec, respectively) on the QTc interval than terfenadine (18 msec) at three times the recommended dose (360 mg/day). The mean QTc interval prolongation observed with ebastine 100 mg/day was small and not clinically meaningful, although the results were statistically significant vs. placebo. The effect of ebastine 60 mg/day was not statistically different from placebo. Steady-state drug interaction studies demonstrated that the co-administration of ebastine 20 mg with ketoconazole or erythromycin produced significant increases in systemic exposure for ebastine, which were accompanied by small increases in QTc (approximately 10 msec above ketoconazole or erythromycin alone). Results from individual studies suggest that, when coadministered with ketoconazole, ebastine produces similar changes in QTc interval measurements compared to loratadine and cetirizine. Pooled data from clinical efficacy trials of ebastine 1-30 mg/day administered for 2-3 weeks showed no clinically relevant cardiac effects as assessed by serial electrocardiographs and Holter monitoring. The overall cardiac safety profile based on currently available information suggests that ebastine, like loratadine and cetirizine, has a lower potential for causing adverse cardiovascular effects than terfenadine.

Adult↗
PubMed1999

Beat-to-Beat repolarization variability in LQTS patients with the SCN5A sodium channel gene mutation.

Current techniques evaluating beat-to-beat variability of repolarization rely on accurate determination of T wave endpoints. This study proposes a T wave endpoint-independent method to quantify repolarization variability in a standard 12-lead ECG using a wavelet transformation. Our method was used to identify repolarization variability in long QT syndrome patients (LQTS) with the SCN5A sodium channel gene mutation. Using wavelet transformations based on the second Gaussian derivative, we evaluated repolarization variability in 11 LQTS patients with the mutation, 13 noncarrier family members, and 28 unrelated healthy subjects. Time-domain repolarization variability parameters (SDRTo, SDRTm) and wavelet parameters describing temporal (beat-to-beat) variability of repolarization in time (TVT) and in amplitude (TVA) were analyzed. Reproducibility of wavelet parameters and relationship of wavelet-based variability with heart rate and preceding RR interval were investigated. The wavelet-based method quantified beat-to-beat variability of the entire repolarization segment (regardless of QT interval identification) providing insight into variability in repolarization morphology. Our method showed that SCN5A carriers have significantly increased repolarization variability in amplitude (23% +/14% vs 8 +/- 4%, P < 0.001) and in time (14 +/- 17 ms vs 3 +/-2 ms, P < 0.004) compared to noncarriers. Variability of repolarization amplitude was found to be heart rate dependent with variability decreasing with increasing heart rate. Relative error describing reproducibility of TVA and TVT was < or = 5% and < or =10%, respectively. Our method quantifies repolarization variability in amplitude and in time without the need to identify T or U wave endpoints. Wavelet-detected repolarization variability contributes to phenotypic identification of SCN5A carriers, with more pronounced beat-to-beat variability in repolarization amplitude than in time.

Adolescent↗
PubMed1999

The QT interval and torsade de pointes.

The QT interval on the electrocardiogram is the time from the onset of ventricular depolarisation (the Q wave) to completion of repolarisation (the end of the T wave). It is influenced by heart rate, autonomic factors, electrolyte levels, gender and age. Aprolonged QT interval indicates an increased risk of developing malignant ventricular tachyarrhythmias, particularly torsade de pointes. QT prolongation may be primary (inherited, familial, congenital, idiopathic) or caused by disease, drugs or toxins. Drugs that have been associated with the development of torsade de pointes include antiarrhythmic, antibacterial and psychotropic agents and antihistamines. Several of these drugs depress myocardial ion channels, particularly the rapidly activating delayed rectifier (repolarising) potassium current (I(Kr)). Overdosage of drugs that affect the delayed rectifier (repolarising) potassium currents (I(K)), or coadministration of these drugs with another medication that inhibits their metabolism (e.g. an antihistamine such as terfenadine with an antifungal agent such as ketoconazole, which inhibits the cytochrome P450 3A4 hepatic enzyme), can induce torsade de pointes. Torsade de pointes is a potentially life-threatening ventricular tachyarrhythmia and the risks of administering drugs that can induce this condition must be carefully considered.

Animals↗
PubMed1999

Cardiac effects of ebastine and other antihistamines in humans.

The electrocardiographic effects of ebastine and its active metabolite, carebastine, have been studied alone and in relevant drug-interaction studies in various patient populations. The overall cardiac tolerability of ebastine is excellent. In ebastine dose-ranging studies in adults and children, there were no meaningful dose-related changes in the QTc interval. At high doses of ebastine (5 to 10 times the recommended dose), a modest 10.3 msec increase in QTc was observed. Recommended doses of ebastine had no meaningful effect on QTc in the elderly or in patients with renal or hepatic insufficiency. Interaction studies involving ebastine with ketoconazole revealed a significant increase in the serum ebastine concentration and in the elimination half-life of ebastine, with a modest 18.1 msec increase in QTc (approximately 10 msec above ketoconazole alone) and a plateau QTc-ebastine relationship at higher ebastine levels. Similar, though more minor, QTc findings were observed during coadministration of ebastine with erythromycin. No QTc effects were noted when ebastine was administered with theophylline, and the QTc was similar when ebastine was administered with or without food. These findings indicate that ebastine is well tolerated and, in contrast to terfenadine and astemizole, has no clinically meaningful effect on the QTc interval even at high serum concentrations. As with other 'safe' antihistamines, which have shown similar modest increases in QTc when coadministered with ketoconazole, caution should be exercised when administering ebastine to patients having the long QT syndrome or hypokalaemia, and in patients receiving azole antifungals or macrolide antibacterials.

Aged↗
PubMed1999

Automated latex agglutination and ELISA testing yield equivalent D-dimer results in patients with recent myocardial infarction. THROMBO Research Investigators.

Our previous prospective study of post-infarction patients described a strong and significant association of increased plasma D-dimer concentrations in those who experienced a subsequent coronary death or non-fatal myocardial infarction. In the present study, we compare results on stored plasma obtained two months after the index myocardial infarction from 1,038 patients of this trial, using a simple automated latex agglutination (LA) assay in parallel with the standard ELISA test. Results show a somewhat higher mean value for the LA assay (702+/-1092 vs. 638+/-986 ng/ml, p = 0.0002), a strong linear correlation of the two assays (r = 0.86) and 88% agreement for values below 500 ng/ml by the ELISA test. D-dimer concentrations determined by each assay were highly correlated in patients with subsequent coronary artery events (p = 0.93) and quartile values for both the LA and ELISA were equally predictive of such events (p = 0.003 and p = 0.001, respectively). This is the first demonstration that a latex agglutination assay for D-dimer can be used to assess the prognostic risk of recurrent coronary thrombotic disease after myocardial infarction

Adult↗
PubMed1998

Influence of the genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group.

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.

Adolescent↗
PubMed1998

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.

Adult↗
PubMed1998

The cost-effectiveness of automatic implantable cardiac defibrillators: results from MADIT. Multicenter Automatic Defibrillator Implantation Trial.

BACKGROUND: The recently reported Multicenter Automatic Defibrillator Implantation Trial (MADIT) showed improved survival in selected asymptomatic patients with coronary disease and nonsustained ventricular tachycardia. The economic consequences of defibrillator management in this patient population are unknown. METHODS AND RESULTS: Patients were followed up to quantify their use of healthcare services, including hospitalizations, physician visits, medications, laboratory tests, and procedures, during the trial. The costs of these services, including the costs of the defibrillator, were determined in patients randomized to defibrillator and nondefibrillator therapy. Incremental cost-effectiveness ratios were calculated by relating these costs to the increased survival associated with the use of the defibrillator. The average survival for the defibrillator group over a 4-year period was 3.66 years compared with 2.80 years for conventionally treated patients. Accumulated net costs were $97,560 for the defibrillator group compared with $75,980 for individuals treated with medications alone. The resulting incremental cost-effectiveness ratio of $27,000 per life-year saved compares favorably with other cardiac interventions. Sensitivity analyses showed that the incremental cost-effectiveness ratio would be reduced to approximately $23,000 per life-year saved if transvenous defibrillators were used instead of the older devices, which required thoracic surgery for implantation. CONCLUSIONS: An implanted cardiac defibrillator is cost-effective in selected individuals at high risk for ventricular arrhythmias.

Cost-Benefit Analysis↗
PubMed1998

New mutations in the KVLQT1 potassium channel that cause long-QT syndrome.

BACKGROUND: Long-QT syndrome (LQTS) is an inherited cardiac arrhythmia that causes sudden death in young, otherwise healthy people. Four genes for LQTS have been mapped to chromosome 11p15.5 (LQT1), 7q35-36 (LQT2), 3p21-24 (LQT3), and 4q25-27 (LQT4). Genes responsible for LQT1, LQT2, and LQT3 have been identified as cardiac potassium channel genes (KVLQT1, HERG) and the cardiac sodium channel gene (SCN5A). METHODS AND RESULTS: After studying 115 families with LQTS, we used single-strand conformation polymorphism (SSCP) and DNA sequence analysis to identify mutations in the cardiac potassium channel gene, KVLQT1. Affected members of seven LQTS families were found to have new, previously unidentified mutations, including two identical missense mutations, four identical splicing mutations, and one 3-bp deletion. An identical splicing mutation was identified in affected members of four unrelated families (one Italian, one Irish, and two American), leading to an alternatively spliced form of KVLQT1. The 3-bp deletion arose de novo and occurs at an exon-intron boundary. This results in a single base deletion in the KVLQT1 cDNA sequence and alters splicing, leading to the truncation of KVLQT1 protein. CONCLUSIONS: We have identified LQTS-causing mutations of KVLQT1 in seven families. Five KVLQT1 mutations cause the truncation of KVLQT1 protein. These data further confirm that KVLQT1 mutations cause LQTS. The location and character of these mutations expand the types of mutation, confirm a mutational hot spot, and suggest that they act through a loss-of-function mechanism or a dominant-negative mechanism.

Case-Control Studies↗
PubMed1998

Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome. LQTS Investigators.

BACKGROUND: The effects of pregnancy on women with the hereditary long QT syndrome are currently unknown. The appropriate medical management of pregnant patients with the long QT syndrome has not been established. METHODS AND RESULTS: The study was a retrospective analysis of the 422 women (111 probands affected with the long QT syndrome and 311 first-degree relatives) enrolled in the long QT syndrome registry who had one or more pregnancies. The first-degree relatives were classified as affected (QTc >0.47), borderline (QTc=0.45 to 0.47), and unaffected (QTc <0.45). Cardiac events were defined as the combined incidence of long QT syndrome-related death, aborted cardiac arrest, and syncope. The incidence of cardiac events was compared during equal prepregnancy, pregnancy, and postpartum intervals (40 weeks each). Multivariate logistic regression analysis was performed by use of a mixed-effects model to identify independent predictors of cardiac events among probands. The pregnancy and postpartum intervals were not associated with cardiac events among first-degree relatives. The postpartum interval was independently associated with cardiac events among probands (odds ratio [OR], 40.8; 95% confidence interval [CI], 3.1 to 540; P=.01); the pregnancy interval was not associated with cardiac events. Treatment with beta-adrenergic blockers was independently associated with a decrease in the risk for cardiac events among probands (OR, 0.023; 95% CI, 0.001 to 0.44; P=.01). CONCLUSIONS: The postpartum interval is associated with a significant increase in risk for cardiac events among probands with the long QT syndrome but not among first-degree relatives. Prophylactic treatment with beta-adrenergic blockers should be continued during the pregnancy and postpartum intervals in probands with the long QT syndrome.

Abortion, Induced↗
PubMed1998

TU wave area-derived measures of repolarization dispersion in the long QT syndrome.

The purpose of this study was to evaluate area-derived parameters of repolarization dispersion in LQTS patients and their unaffected family members and to use this analysis to challenge the concept of dispersion of repolarization in surface ECG. The area under the curve between the J point and the next P wave was measured automatically in 12 leads of the digital ECG in 34 LQTS patients and 22 unaffected family members. The area-derived measures of repolarization included total repolarization area, T wave amplitude, time to accumulate the first (tA50) and the median (tA25-75) 50% of the total area, and the time to accumulate 97% of the total repolarization area (tA97). In comparison with unaffected family members, LQTS patients had significantly higher dispersion of tA50 (tA50-SD = 34 +/- 18 ms vs 11 +/- 6 ms, respectively, P < .001) and tA25-75 (t[A25-75]-SD = 44 +/- 19 ms vs 24 +/- 15 ms, respectively, P < .001), whereas no significant difference was observed in the dispersion of total repolarization area, T wave amplitude, and time to accumulate total repolarization area (tA97-SD = 44 +/- 20 ms vs 53 +/- 19 ms, respectively, ns). It is concluded the analysis of area-derived parameters of repolarization showed that LQTS patients have increased interlead variability of the repolarization morphology (tA50-SD and t[A25-75]-SD), whereas they do not have increased dispersion of the total repolarization duration (tA97-SD). This observation indicates that an increase in traditional measures of dispersion (QT dispersion) may represent a heterogeneity of repolarization shape, whereas the true dispersion of the total duration of repolarization, which is related to electrocardiographic lead projection, is similar in patients and healthy subjects.

Electrocardiography↗
PubMed1998

ECG features of microvolt T-wave alternans in coronary artery disease and long QT syndrome patients.

UNLABELLED: T-wave alternans (TWA) is a marker of myocardial electrical instability. We compared ECG features of microvolt TWA in coronary artery disease (CAD) and long QT syndrome (LQTS) patients. METHOD: The study populations consisted of 43 CAD and 39 LQTS patients. TWA was detected in resting Holter recordings using the new correlation method (CM). After preprocessing to adjust for RR variability and respiratory modulation, CM was used to quantify TWA amplitude (A(CM)), duration (N(CM)), and magnitude (MAG(CM); defined as the product of A(CM) and N(CM)). RESULTS: TWA was detected in 19 (44%) CAD and 17 (44%) LQTS patients. TWA was associated with longer RR intervals (P = 0.006) and had larger magnitudes (P = 0.067) in LQTS than CAD patients. The TWA was identified as transient (nonstationary) in 15 of 19 (79%) TWA-positive CAD patients, and in 8 of 17 (47%) TWA-positive LQTS patients (P = 0.047). CONCLUSIONS: The frequency of TWA detected with CM is similar in LQTS and CAD patients. TWA is larger in LQTS than in CAD patients, whereas TWA is more frequently transient (nonstationary) in LAD than LQTS patients. In LQTS patients, but not in CAD patients, a longer RR is associated with TWA, indicating different electrophysiologic mechanisms in the two pathologies.

Adult↗
PubMed1998

Management of patients with the hereditary long QT syndrome.

The hereditary long QT syndrome is an inherited ion channel disorder with QT prolongation, morphologic changes in the T waves, and a relatively high frequency of syncope, T wave alternans, torsades de pointes-type ventricular tachycardia, and sudden death. Monotherapy with beta blockers is the treatment of first choice. In patients with recurrent syncope despite therapy with beta blockers, pacemakers and/or ganglionectomy may be useful in selected cases, with an implantable cardioverter defibrillator used as a fail-safe approach in high-risk patients.

Adult↗
PubMed1997

Electrocardiographic findings in patients with diphenhydramine overdose.

QT interval prolongation and torsades de pointes ventricular tachycardia have been reported after therapeutic doses and overdosage of second generation antihistamines, such terfenadine and astemizol. Diphenhydramine (DPHM), a first generation H1 antagonist, is the most frequently used antihistaminic drug. Despite its widespread use, there are no data about cardiac action and electrocardiographic consequences of DPHM overdose. The 12-lead electrocardiograms of 126 patients (mean age 26 +/- 11 years) who had DPHM overdose were evaluated. The ingestion of large doses of DPHM (in majority of cases the dose was >500 mg) was primarily suicidal. Repolarization duration, dispersion, and morphology were evaluated in DPHM overdose patients and compared with those of healthy subjects. Mean heart rate of DPHM overdose patients was 103 +/- 25 beats/min. The QTc duration was significantly longer (453 +/- 43 vs 416 +/- 35 ms, respectively, p <0.001) and mean T-wave amplitude significantly lower (0.20 +/- 0.10 vs 0.33 +/- 0.15 mV, respectively, p <0.001) in DPHM-overdose patients than in control subjects. Dispersion of repolarization was significantly lower in DPHM-overdose patients than in control subjects (42 +/- 25 vs 52 +/- 21 ms, respectively; p = 0.003). None of the DPHM-overdose patients experienced torsades de pointes. In conclusion, DPHM overdose is associated with a significant increase in heart rate and a significant but moderate QTc prolongation. None of the studied patients, including those who had apparent QTc prolongation, experienced torsades de pointes ventricular tachycardia.

Adult↗