Saskia le Cessie

Dispersion of ventricular repolarization and arrhythmic cardiac death in coronary artery disease

In a recent prospective study of myocardial ischemia, arrhythmic cardiac death occurred in 17 of 936 patients (2%) during a 2-year follow-up after acute myocardial infarction or unstable angina. Dispersion of ventricular repolarization was evaluated on the 12-lead electrocardiogram at enrollment in 17 patients who subsequently died of cardiac arrhythmia and in 51 matched survivors. The aim of this study was to evaluate the relation between various measurements of dispersion of repolarization and subsequent arrhythmic cardiac death, and to determine if dispersion of repolarization makes an independent contribution to the risk of arrhythmic cardiac death. Ventricular depolarization quantitated in terms of mean QRS (QRS-m) duration, and ventricular repolarization quantitated in terms of mean (m), maximal-minimal dispersion (d), standard deviation (s), and coefficient of variation (cv) of QT and JT intervals, were determined. Univariate analyses revealed that 2 standard electrocardiographic parameters, QRS-m and QT-m, and 3 dispersion variables, JT-d, JT-s, and JTc-d, were associated with arrhythmic cardiac death (p < 0.01). Multivariate analyses revealed that the combination of the dispersion parameter (JT-d, JT-s, or JTc-d) and QRS-m made an independent contribution to the risk of arrhythmic cardiac death. The findings highlight the importance of both delayed depolarization and heterogenous repolarization as risk factors for arrhythmic cardiac death. Thus, increased dispersion of repolarization is associated with an elevated likelihood of arrhythmic cardiac death. Prolonged QRS duration and increased dispersion of repolarization make independent contributions to the risk of arrhythmic cardiac death in patients with coronary artery disease.

Use of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study.

Objectives To investigate the performance of classic risk factors, and of some new biomarkers, in predicting cardiovascular mortality in very old people from the general population with no history of cardiovascular disease. Design The Leiden 85-plus Study (1997-2004) is an observational prospective cohort study with 5 years of follow-up. Setting General population of the city of Leiden, the Netherlands. Participants Population based sample of participants aged 85 years (215 women and 87 men) with no history of cardiovascular disease; no other exclusion criteria. Main measurements Cause specific mortality was registered during follow-up. All classic risk factors included in the Framingham risk score (sex, systolic blood pressure, total and high density lipoprotein cholesterol, diabetes mellitus, smoking and electrocardiogram based left ventricular hypertrophy), as well as plasma concentrations of the new biomarkers homocysteine, folic acid, C reactive protein, and interleukin 6, were assessed at baseline. Results During follow-up, 108 of the 302 participants died; 32% (35/108) of deaths were from cardiovascular causes. Classic risk factors did not predict cardiovascular mortality when used in the Framingham risk score (area under receiver operating characteristic curve 0.53, 95% confidence interval 0.42 to 0.63) or in a newly calibrated model (0.53, 0.43 to 0.64). Of the new biomarkers studied, homocysteine had most predictive power (0.65, 0.55 to 0.75). Entering any additional risk factor or combination of factors into the homocysteine prediction model did not increase its discriminative power. Conclusions In very old people from the general population with no history of cardiovascular disease, concentrations of homocysteine alone can accurately identify those at high risk of cardiovascular mortality, whereas classic risk factors included in the Framingham risk score do not. These preliminary findings warrant validation in a separate cohort.

Long-Term Impact of Delay in Assessment of Patients With Early Arthritis

OBJECTIVE During the last decade, rheumatologists have learned to initiate disease-modifying antirheumatic drugs (DMARDs) early to improve the outcome of rheumatoid arthritis (RA). However, the effect of delay in assessment by a rheumatologist on the outcome of RA has scarcely been explored. The purpose of this study was to examine the association between delay in assessment by a rheumatologist, rates of joint destruction, and probability of achieving DMARD-free remission in patients with RA. Patient characteristics associated with components of delay (by the patient, by the general practitioner [GP], and overall) were assessed. METHODS A total of 1,674 early arthritis patients from the Leiden Early Arthritis Clinic cohort were evaluated for patient delay, GP delay, and total delay in assessment by a rheumatologist. Among 598 RA patients, associations between total delay, achievement of sustained DMARD-free remission, and the rate of joint destruction over 6 years followup were determined. RESULTS The median patient, GP, and total delays in seeing a rheumatologist among patients with early arthritis were 2.4 weeks, 8.0 weeks, and 13.7 weeks, respectively. Among all diagnoses, those diagnosed as having RA or spondylarthritis had the longest total delay (18 weeks). Among the RA patients, 69% were assessed in ≥12 weeks; this was associated with a hazard ratio of 1.87 for not achieving DMARD-free remission and a 1.3 times higher rate of joint destruction over 6 years, as compared with assessment in <12 weeks. Older age, female sex, gradual symptom onset, involvement of the small joints, lower levels of C-reactive protein, and the presence of autoantibodies were associated with longer total delay. CONCLUSION Only 31% of the RA patients were assessed in <12 weeks of symptom onset. Assessment in <12 weeks is associated with less joint destruction and a higher chance of achieving DMARD-free remission as compared with a longer delay in assessment. These results imply that attempts to diminish the delay in seeing a rheumatologist will improve disease outcome in patients with RA.

Right Ventricular Diastolic Function in Children With Pulmonary Regurgitation After Repair of Tetralogy of Fallot: Volumetric Evaluation by Magnetic Resonance Velocity Mapping

OBJECTIVES We sought to assess right ventricular diastolic function in young patients with corrected tetralogy of Fallot and pulmonary regurgitation. BACKGROUND Pulmonary regurgitation is an important problem in repair of tetralogy of Fallot. Its effects on right ventricular diastolic function in children are unknown. METHODS Nineteen children with repair of tetralogy of Fallot (mean age [+/- SD] 12 +/- 3 years, mean age at operation 1.5 +/- 1) and 12 healthy children were studied. Summation of magnetic resonance velocity mapping pulmonary and tricuspid volume flow curves provided right ventricular time-volume curves. Ventricular size was assessed with tomographic magnetic resonance imaging (MRI). Graded exercise testing was performed. RESULTS Systematic and random differences (mean +/- SD) of velocity mapping and Doppler tricuspid time to peak velocities (peak E: 1 +/- 26 ms, r = 0.43; peak A: 2 +/- 11 ms, r = 0.76), E/A ratio (0.04 +/- 0.5, r = 0.63) and duration of pulmonary regurgitation (20 +/- 35 ms, r = 0.74) were satisfactory. In 6 patients (group I), late diastolic forward pulmonary artery flow was absent; in 13 patients (group II), this flow contributed 1% to 14% to right ventricular stroke volume. Significant differences were increased deceleration time (315 +/- 91 vs. 168 +/- 28 ms, p < 0.001), decreased filling fraction (44 +/- 11 vs. 55 +/- 16%, p = 0.02) and increased peak early filling rate (378 +/- 124 vs. 286 +/- 112 ml/s, p = 0.018) between control subjects and group I, and increased deceleration time (230 +/- 40, p = 0.03) between control subjects and group II. Pulmonary regurgitation, ventricular size and ejection fraction did not differ significantly between patient groups. Exercise function was diminished with restrictive right ventricular physiology (p < 0.001, group II vs. control subjects). CONCLUSIONS Impaired relaxation and restriction to filling affect right ventricular function in children with repair of tetralogy of Fallot and pulmonary regurgitation. Restrictive right ventricular physiology is associated with decreased exercise function.

Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations

In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), body weight, height and body mass index (BMI) were evaluated as risk factors. Additionally, the joint effect of obesity together with oral contraceptive use and prothrombotic mutations on the risk of venous thrombosis were analysed. Three‐thousand eight‐hundred and thirty‐four patients with a first venous thrombosis and 4683 control subjects were included, all non‐pregnant and without active malignancies. Relative to those with a normal BMI (<25 kg/m2), overweight (BMI ≥ 25 and BMI < 30 kg/m2) increased the risk of venous thrombosis 1·7‐fold [odds ratio (OR)adj(age and sex) 1·70, 95% confidence interval (CI) 1·55–1·87] and obesity (BMI ≥ 30 kg/m2) 2·4‐fold (ORadj 2·44, 95% CI 2·15–2·78). An increase in body weight and body height also individually increased thrombotic risk. Obese women who used oral contraceptives had a 24‐fold higher thrombotic risk (ORadj 23·78, 95% CI 13·35–42·34) than women with a normal BMI who did not use oral contraceptives. Relative to non‐carriers of normal BMI, the joint effect of factor V Leiden and obesity led to a 7·9‐fold increased risk (ORadj 7·86, 95% CI 4·70–13·15); for prothrombin 20210A this was a 6·6‐fold increased risk (ORadj 6·58, 95% CI 2·31–18·69). Body height, weight and obesity increase the risk of venous thrombosis, especially obesity in women using oral contraceptives.

Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1

Elevated plasma clot lysis time (CLT) increases risk of venous and arterial thrombosis. It is unclear which fibrinolytic factors contribute to thrombosis risk. In 743 healthy control subjects we investigated determinants of CLT. By comparison with 770 thrombosis patients, we assessed plasma levels of fibrinolytic proteins as risk factors for a first thrombosis. Plasminogen activator inhibitor-1 (PAI-1) levels were the main determinants of CLT, followed by plasminogen, thrombin-activatable fibrinolysis inhibitor (TAFI), prothrombin, and alpha2-antiplasmin. Fibrinogen, factor VII, X, and XI contributed minimally. These proteins explained 77% of variation in CLT. Levels of the fibrinolytic factors were associated with thrombosis risk (odds ratios, highest quartile vs lowest, adjusted for age, sex, and body mass index: 1.6 for plasminogen, 1.2 for alpha2-antiplasmin, 1.6 for TAFI, 1.6 for PAI-1, and 1.8 for tissue plasminogen activator [t-PA]). Adjusting for acute-phase proteins attenuated the risk associated with elevated plasminogen levels. The risk associated with increased t-PA nearly disappeared after adjusting for acute-phase proteins and endothelial activation. TAFI and PAI-1 remained associated with thrombosis after extensive adjustment. In conclusion, CLT reflects levels of all fibrinolytic factors except t-PA. Plasminogen, TAFI, PAI-1, and t-PA are associated with venous thrombosis. However, plasminogen and t-PA levels may reflect underlying risk factors.

F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis

This systematic review was designed to provide more precise effect estimates of inhibitor development for the various types of F8 gene mutations in patients with severe hemophilia A. The primary outcome was inhibitor development and the secondary outcome was high-titer-inhibitor development. A systematic literature search was performed to include cohort studies published in peer-reviewed journals with data on inhibitor incidences in the various F8 gene mutation types and a mutation detection rate of at least 80%. Pooled odds ratios (ORs) of inhibitor development for different types of F8 gene mutations were calculated with intron 22 inversion as the reference. Data were included from 30 studies on 5383 patients, including 1029 inhibitor patients. The inhibitor risk in large deletions and nonsense mutations was higher than in intron 22 inversions (pooled OR = 3.6, 95% confidence interval [95% CI], 2.3-5.7 and OR = 1.4, 95% CI, 1.1-1.8, respectively), the risk in intron 1 inversions and splice-site mutations was equal (pooled OR = 0.9; 95% CI, 0.6-1.5 and OR = 1.0; 95% CI, 0.6-1.5), and the risk in small deletions/insertions and missense mutations was lower (pooled OR = 0.5; 95% CI, 0.4-0.6 and OR = 0.3; 95% CI, 0.2-0.4, respectively). The relative risks for developing high titer inhibitors were similar.

T wave alternans in idiopathic long QT syndrome

OBJECTIVES The study evaluates the association between T wave alternans and the risk of cardiac events (syncope, aborted cardiac arrest or cardiac death) in a large population of patients with idiopathic long QT syndrome. BACKGROUND T wave alternans is an infrequently recorded electrocardiographic (ECG) finding in patients with delayed repolarization, and its clinical significance is not clear. METHODS A total of 4,656 ECG recordings in 2,442 patients enrolled in the International Long QT Syndrome Registry were reviewed for episodes of T wave alternans. To determine the risk associated with T wave alternans, independent of corrected QT interval (QTc) duration, patients with T wave alternans were matched for QTc value (every 0.025 s1/2) to patients with long QT syndrome without T wave alternans. RESULTS T wave alternans was identified in 30 patients (25 of whom had a QTc interval > 0.50 s1/2). A strong association between QTc prolongation and T wave alternans was observed (odds ratio 1.23 per 0.01-s1/2 unit increase in QTc, p < 0.0001). Conditional logistic regression analyses with adjustment for age, gender, status and QTc value revealed that T wave alternans did not make a significant independent contribution to the risk of cardiac events. The risk of experiencing a major cardiac event was primarily related to length of QTc. CONCLUSIONS T wave alternans, a marker of electrical instability and regional heterogeneity of repolarization, identifies a high risk subset of patients with prolonged repolarization. Patients with T wave alternans have an increased risk of cardiac events, but this risk is primarily related to the magnitude of repolarization delay (QTc prolongation). T wave alternans does not make an independent contribution to the risk of cardiac events after adjustment for QTc length.

A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon.

BACKGROUND Observational evidence suggests that the use of a genotype-guided dosing algorithm may increase the effectiveness and safety of acenocoumarol and phenprocoumon therapy. METHODS We conducted two single-blind, randomized trials comparing a genotype-guided dosing algorithm that included clinical variables and genotyping for CYP2C9 and VKORC1 with a dosing algorithm that included only clinical variables, for the initiation of acenocoumarol or phenprocoumon treatment in patients with atrial fibrillation or venous thromboembolism. The primary outcome was the percentage of time in the target range for the international normalized ratio (INR; target range, 2.0 to 3.0) in the 12-week period after the initiation of therapy. Owing to low enrollment, the two trials were combined for analysis. The primary outcome was assessed in patients who remained in the trial for at least 10 weeks. RESULTS A total of 548 patients were enrolled (273 patients in the genotype-guided group and 275 in the control group). The follow-up was at least 10 weeks for 239 patients in the genotype-guided group and 245 in the control group. The percentage of time in the therapeutic INR range was 61.6% for patients receiving genotype-guided dosing and 60.2% for those receiving clinically guided dosing (P=0.52). There were no significant differences between the two groups for several secondary outcomes. The percentage of time in the therapeutic range during the first 4 weeks after the initiation of treatment in the two groups was 52.8% and 47.5% (P=0.02), respectively. There were no significant differences with respect to the incidence of bleeding or thromboembolic events. CONCLUSIONS Genotype-guided dosing of acenocoumarol or phenprocoumon did not improve the percentage of time in the therapeutic INR range during the 12 weeks after the initiation of therapy. (Funded by the European Commission Seventh Framework Programme and others; EU-PACT ClinicalTrials.gov numbers, NCT01119261 and NCT01119274.).

Psychological functioning and quality of life following bone marrow transplantation : A 3-year follow-up study

OBJECTIVE To assess changes in quality of life and psychological distress following bone marrow transplantation (BMT) and variables related to this change. METHODS One hundred twenty-five consecutive patients who underwent bone marrow transplantation (BMT) at the Leiden University Medical Centre between 1987 and 1992 filled in questionnaires measuring quality of life, functional limitations, psychological distress, anxiety, depression, self-esteem, and health locus of control. Measurements were taken before the BMT; 1 month after discharge; and 6 months, 1 year, and 3 years after the BMT. RESULTS Three years after BMT, a quarter of the patients continued to experience serious functional limitations. Thirteen percent of the patients scored >4 on the General Health Questionnaire (GHQ-12), a percentage comparable to general population prevalence. Quality of life was reported to be good to excellent by almost 90% of the patients at three years. Changes in quality of life could be explained entirely by changes in functional limitations and somatic symptoms. Changes in psychological distress were also related to these measures, and furthermore to baseline psychological functioning. CONCLUSION Although patients were doing well three years after BMT, there was a group of patients needing help. In interventions special attention should be given to patients with ongoing psychological problems. Emphasis should be on coping with physical limitations.