Collaborative meta-analysis of individual participant data from observational studies of Lp-PLA2 and cardiovascular diseases.

BACKGROUND: A large number of observational epidemiological studies have reported generally positive associations between circulating mass and activity levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) and the risk of cardiovascular diseases. Few studies have been large enough to provide reliable estimates in different circumstances, such as in different subgroups (e.g., by age group, sex, or smoking status) or at different Lp-PLA2 levels. Moreover, most published studies have related disease risk only to baseline values of Lp-PLA2 markers (which can lead to substantial underestimation of any risk relationships because of within-person variability over time) and have used different approaches to adjustment for possible confounding factors. OBJECTIVES: By combination of data from individual participants from all relevant observational studies in a systematic 'meta-analysis', with correction for regression dilution (using available data on serial measurements of Lp-PLA2), the Lp-PLA2 Studies Collaboration will aim to characterize more precisely than has previously been possible the strength and shape of the age and sex-specific associations of plasma Lp-PLA2 with coronary heart disease (and, where data are sufficient, with other vascular diseases, such as ischaemic stroke). It will also help to determine to what extent such associations are independent of possible confounding factors and to explore potential sources of heterogeneity among studies, such as those related to assay methods and study design. It is anticipated that the present collaboration will serve as a framework to investigate related questions on Lp-PLA2 and cardiovascular outcomes. METHODS: A central database is being established containing data on circulating Lp-PLA2 values, sex and other potential confounding factors, age at baseline Lp-PLA2 measurement, age at event or at last follow-up, major vascular morbidity and cause-specific mortality. Information about any repeat measurements of Lp-PLA2 and potential confounding factors has been sought to allow adjustment for possible confounding and correction for regression dilution. The analyses will involve age-specific regression models. Synthesis of the available observational studies of Lp-PLA2 will yield information on a total of about 15 000 cardiovascular disease endpoints.

Effect of smoking on lipid and thrombogenic factors two months after acute myocardial infarction.

Cigarette smoking is linked to increased cardiac morbidity and mortality, and has been shown to affect both lipid profiles and thrombotic factors in healthy subjects. However, the influence of smoking on the atherothrombotic environment has not been studied in a large population of patients after acute myocardial infarction (AMI). Blood samples and medical history, including smoking status, were obtained from 1,045 patients at a 2-month visit after AMI. Smokers were asked to refrain 24 hours before the visit, but not all complied. Measurements included total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein-B, apolipoprotein-A, triglycerides, factor VII, factor VIIa, von Willebrand factor, D-dimer, and plasminogen activator inhibitor. There were 247 current, 443 past, and 349 nonsmokers. After adjustment for clinical variables, current smokers had higher levels of total cholesterol and apolipoprotein-B than past and nonsmokers (p <0.01). High-density lipoprotein cholesterol and apolipoprotein-A levels were similar between groups. Fibrinogen was elevated in current (p = 0.001) and past (p = 0.029) smokers, compared with nonsmokers. Smokers who smoked within 24 hours of blood sampling had higher apolipoprotein-B (p = 0.005), total cholesterol (p = 0.001), and fibrinogen (p = 0.015) levels than those who refrained from smoking. In conclusion, postinfarction patients, who historically have higher levels of atherogenic lipids than healthy subjects, have increased levels of these lipids attributed to active smoking. After smoking cessation, lipid profiles approach nonsmoker levels, but fibrinogen remains elevated. Smoking within 24 hours of blood sampling was associated with further adverse prothrombotic and lipogenic effects.

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.

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.

Clinical management of patients with the long QT syndrome: drugs, devices, and gene-specific therapy.

The familial long QT syndrome (LQTS) is now recognized as a genetic channelopathy with a propensity to arrhythmogenic syncope and sudden death. Three genetic mutations have been identified that involve the slow and fast delayed potassium rectifier currents and the sodium current. Distinctive ECG-T wave phenotypes are associated with each of the three genotypes. Current day therapy includes: beta-adrenergic blocking drugs; pacemakers; left cervicothoracic sympathetic ganglionectomy; implanted cardioverter defibrillators; and possibly, drugs that improve mutant ionic channel dysfunction. LQTS has provided unique insight into the complex relationship between ionic channel dysfunction and ventricular tachyarrhythmias.

Comparison between Japan and North America in the post-hospital course after recovery from an acute coronary event.

We compared the post-hospital prognosis after an acute coronary event (acute myocardial infarction and unstable angina) in 106 patients in Japan vs. 789 patients in North America who were prospectively enrolled in the Multicenter Study of Myocardial Ischemia and were followed-up for an average of 26 months per patients. Risk factors more frequent in Japan were older age, males and smoking at enrollment, but the rest of many risk factors were similar. After adjusting for differences in clinical and medication variables, Cox analyses indicated patients in North America had a significantly greater risk of experiencing a primary end-point (cardiac death, non-fatal myocardial infarction or unstable angina) than patients in Japan (hazard ratio [North America:Japan] = 3.1, P = 0.003). There was a non-significant trend in the restricted end-points (cardiac death or non-fatal myocardial infarction) with North America having more frequent events than Japan (hazard ratio = 2.2, P = 0.12). The long-term outcome after recovery from an acute coronary event is more favorable in Japan than in North America, mostly due to a reduction in subsequent hospitalization for unstable angina. The reason for these findings cannot be explained by differences in the measured risk factors or medications.

Long QT syndrome: an indication for cervicothoracic sympathectomy.

Beta-blockade represents the primary treatment modality in patients with long QT syndrome, but left cervicothoracic sympathectomy (LCS) has been employed in refractory cases and in cases with malignant arrhythmias. LCS was performed in ten patients (six male, four female) with long QT syndrome, ranging in age from 1 month to 40 years (median 15 years). Familial long QT syndrome was present in seven patients (70%). The mean(s.e.m.) (range) preoperative corrected QT interval (QTc) was 0.52(0.01) (0.46-0.60)s. The mean(s.e.m.) duration of symptoms was 4.4(1.1) years with a mean(s.e.m.) of 4.1(0.9) syncopal episodes and 1.2(0.2) cardiac arrests per patient. LCS was carried out for refractory symptoms on beta-blockers in nine cases; a single patient was unable to tolerate beta-blockers and LCS represented the primary treatment modality. A left supraclavicular approach was utilized in each patient, resecting a portion of the stellate and all of the T2 and T3 ganglia. The median(range) length of hospitalization following operation was 2(2-6) days. There were no unexpected complications of operation, although nine (90%) of the patients developed Horner's syndrome. The QTc decreased a mean(s.e.m.) of 0.03(0.01)s following operation (P < 0.01). The frequency of symptomatic episodes decreased from a mean(s.e.m.) of 7.1(3.1)/year before LCS to 0.1(0.1) after operation (P < 0.001). Patients have been followed for a mean of 1.3(0.3) years, and all but one patient remains symptom-free; the youngest patient died suddenly 10 months after surgery. These results suggest that LCS is associated with significant clinical benefits in patients with long QT syndrome and the procedure should be considered when symptoms are refractory and malignant, or when contraindications to beta-blockers are present.

Health-risk behaviors among our nation's youth: United States, 1992.

This report presents national estimates of the prevalence of selected health risk behaviors among youth ages 12-21 years, by sex, Hispanic origin, and race for youth of non-Hispanic origin. Topics include: cigarette and other tobacco use, alcohol and other drug use, sexual experience, HIV/AIDS education, runaway and homeless experiences, violence, unintentional injury control, weight control, and participation in physical activities. Data are from the 1992 National Health Interview Survey's Youth Risk Behavior Survey.

Cigarette smoking and the age at onset of a first non-fatal myocardial infarction.

BACKGROUND: Smoking is a major risk factor for coronary heart disease. Discontinuance of smoking is associated with a reduction in the risk of coronary disease; this risk approaches the level among non-smokers after stopping smoking for periods ranging from 6 months to several years. We analyzed pertinent prospectively accumulated data from our multicenter postinfarction studies to gain further insight into the complex relationship between cigarette smoking and the premature occurrence of a first myocardial infarction. METHODS: Retrospective analysis of the relationship between the number of cigarettes smoked and the age at onset of patients experiencing their first non-fatal myocardial infarction was investigated in 2445 patients. The intensity of smoking was quantitated in terms of the average number of packs per day smoked during adult years, subcategorized in increments of a half-pack per day up to more than two packs per day. Ex-smokers were identified if they had stopped smoking 1 month before their index infarction. Analysis of variance was used to adjust for the effects of relevant confounding risk factors. RESULTS: The adjusted age for first non-fatal infarction progressively declined with increasing smoking exposure, with an average age reduction of 8.7 years (95% confidence interval; 7.2, 10.2) in those smoking more than two packs per day compared with non-smokers. The graded effect was somewhat more marked in women than in men. The number of cigarettes smoked before infarction had no effect on the severity of the acute infarction or on mortality from cardiac causes during more than 2-year post-hospital follow-up. Those who stopped smoking 1 month or longer before the infarction were significantly older at the time of first infarction than active smokers in all smoking categories. CONCLUSION: This study provides strong evidence that active smoking is associated with an earlier age at onset of first infarctions, with a striking inverse dose-response effect. Stopping smoking appears to reduce the premature occurrence of coronary events.

Locus heterogeneity of autosomal dominant long QT syndrome.

Autosomal dominant long QT syndrome (LQT) is an inherited disorder that causes syncope and sudden death from cardiac arrhythmias. In genetic linkage studies of seven unrelated families we mapped a gene for LQT to the short arm of chromosome 11 (11p15.5), near the Harvey ras-1 gene (H ras-1). To determine if the same locus was responsible for LQT in additional families, we performed linkage studies with DNA markers from this region (H ras-1 and MUC2). Pairwise linkage analyses resulted in logarithm of odds scores of -2.64 and -5.54 for kindreds 1977 and 1756, respectively. To exclude the possibility that rare recombination events might account for these results, we performed multipoint linkage analyses using additional markers from chromosome 11p15.5 (tyrosine hydroxylase and D11S860). Multipoint analyses excluded approximately 25.5 centiMorgans of chromosome 11p15.5 in K1756 and approximately 13 centiMorgans in K1977. These data demonstrate that the LQT gene in these kindreds is not linked to H ras-1 and suggest that mutations in at least two genes can cause LQT. While the identification of locus heterogeneity of LQT will complicate genetic diagnosis, characterization of additional LQT loci will enhance our understanding of this disorder.

Measurement of the QT interval and the risk associated with QTc interval prolongation: a review.

The accurate measurement of the QT interval and its correction or adjustment for cycle length, age, and gender have been topics of increasing interest over the course of the past 70 years. The availability of digitized electrocardiographic recordings on large normal populations together with statistical adjustment for pertinent covariates has provided useful data for defining QT interval prolongation. Data from the International Long QT Syndrome Registry indicate that the probabilistic risk of developing malignant arrhythmias in patients with QT prolongation is exponentially related to the length of the QTc interval. The risk is further accentuated by the development of T-wave alternans, particularly at very prolonged QTc intervals.

Prevention of sudden cardiac death.

Since the vast majority of these deaths are triggered by arrhythmias, the first step in prevention is to understand the risk factors for malignant rhythms. The second is to identify patients who may benefit from preventive intervention. Finally, who should get drugs, who automatic cardioverter-defibrillator implantation. The determinants of that choice remain to be elucidated.

Hypolipidemic effect of type Ia antiarrhythmic agents in postinfarction patients.

BACKGROUND: Elevated levels of cholesterol and apoprotein B (apo B), the essential carrier protein for low density lipoprotein, are major lipid risk factors for premature coronary disease. Antiarrhythmic agents are frequently prescribed to patients with coronary heart disease and associated cardiac arrhythmias. As part of another study, we retrospectively investigated the effect of antiarrhythmic agents on blood lipids. METHODS AND RESULTS: The study population consisted of 1,567 postinfarction patients on whom we prospectively collected serial blood samples for lipid and apoprotein determinations and recorded the concomitant medications the patients were receiving at three follow-up time periods. The lipids, analyzed at a central core laboratory, included total cholesterol, triglycerides, high density lipoprotein cholesterol (HDL C), and apoproteins A-I (apo A-I), A-II (apo A-II), and apo B. The difference in the group mean lipid values for patients receiving and not receiving type Ia antiarrhythmic agents (quinidine, procainamide, and disopyramide) was evaluated by the two-sample t test, and multiple linear regression analyses were performed to adjust for relevant covariates. Patients using type Ia antiarrhythmic agents at the 30-month postinfarction contact (n = 76) had 8.6% lower cholesterol (p less than 0.003), 22.3% lower triglycerides (p less than 0.0002), 6.2% lower apo A-I (p = 0.02), 10.1% lower apo A-II (p less than 0.001), and 12.7% lower apo B (p less than 0.0001) levels than patients not on these medications (n = 1,491). These lower lipid levels were found after adjustment for age, sex, diabetes, smoking status, concomitant medications, and a variety of clinical factors relating to the severity of the coronary disease process. The HDL C levels were similar in those receiving and not receiving type Ia agents. CONCLUSIONS: Patients on type Ia antiarrhythmic agents had significantly and meaningfully lower cholesterol, triglyceride, apo A-II, and apo B levels than patients not receiving these agents. The mechanism of this hypolipidemic effect is undefined, but the mechanism may be related to an alteration by these agents of ionic membrane currents at the hepatocyte level.

Treatment of aortic coarctation by axillofemoral bypass grafting in the high-risk patient.

Operative correction of coarctation of the aorta has been performed for 45 years. Reoperation for recurrent coarctation is necessary in as many as 5% to 10% of patients. Repair of recurrent coarctation carries an operative mortality of between 5% and 10%. Coarctation repair involves an increased risk in patients with advanced age, recurrent coarctation, congestive heart failure, and pulmonary disease. We report 3 cases where axillofemoral bypass has been used to treat high-risk patients with aortic coarctation. Two patients had had previous coarctation repair in addition to serious medical problems. Another patient had suffered three myocardial infarctions and had disabling congestive heart failure. All patients had an immediate marked decrease in their preoperative peak systolic pressure gradient across the coarctation. Systemic hypertension and symptoms of congestive heart failure were improved in all patients. The length of follow-up was 15 months, 8.5 years, and 10.5 years. Reassessment with noninvasive vascular segmental pressure studies with and without an exercise component showed no recurrence of the pressure gradient. This procedure should be considered when treating coarctation of the aorta in the high-risk adult.