The CAREGENE study: genetic variants of the endothelium and aerobic power in patients with coronary artery disease.

OBJECTIVES: Aerobic phenotypes show a wide variability to similar aerobic training stimuli, which can be partly attributed to heritability. Endothelial function affects aerobic power. Various physiological pathways may influence the endothelial function. Therefore, we aimed to examine whether polymorphisms of the eNos gene, the CAT gene, the VEGF gene, the GPX1 gene, the subunit P22 phox of the NAD(P)H-odixase gene, the PPAR-alpha gene, and the PGC-alpha gene are associated with aerobic power or with its response to physical training in patients with coronary artery disease (CAD). METHODS: 935 biologically unrelated Caucasian patients with CAD who had exercised until exhaustion during graded bicycle testing at baseline and after completion of 3 months of training were included in the CAREGENE study (Cardiac Rehabilitation and GENetics of exercise performance). Polymorphisms were detected using the invader assay and MassARRAY technology. Haplotype analysis was performed on the polymorphisms of the eNos gene, the VEGF gene and the NAD(P)H-oxidase gene. RESULTS: Physical training significantly increased aerobic power by 24.2 +/- 0.6% (P < 0.001). Associations of P < 0.05 were found between aerobic power and the eNOS 273C>T variant and the catalase -262C>T variant and aerobic power response. Haplotypes of the eNOS polymorhisms were predictive of aerobic power and its response to training (P < 0.05). After Bonferroni correction of multiple testing no significant differences remained. CONCLUSION: We believe that genetic factors are very important in the explanation of the great variability of aerobic power and its response. However, after Bonferroni-correction, differences in these polymorphisms remained no longer statistically significant.

The CAREGENE study: polymorphisms of the beta1-adrenoceptor gene and aerobic power in coronary artery disease.

AIMS: The heritability of aerobic power and of the response to physical training has been shown in healthy subjects. beta(1)-Adrenergic receptor (beta(1)AR) function affects exercise performance. This study aims to investigate whether the Ser49Gly and Gly389Arg polymorphisms of the beta(1)AR gene or their haplotypes are associated with aerobic power or its response to physical training in coronary artery disease (CAD). METHODS AND RESULTS: Nine hundred and thirty-five biologically unrelated Caucasian patients with CAD who had exercised until exhaustion during graded bicycle testing at baseline and after completion of 3 months of exercise training from 1990 to 2001 (n = 1095) were eligible for inclusion in the CAREGENE (CArdiac REhabilitation and GENetics of Exercise performance) study. Polymorphisms were detected using the invader assay (Third Wave Technologiestrade mark, Madison, Wisconsin, USA). Patients with the Gly49Gly genotype had significantly higher covariate-adjusted aerobic power at baseline than those with Ser49Ser and Ser49Gly (P < 0.05). Adjusted aerobic power at baseline was highest in the Ser49-Gly389/Gly49-Gly389 and Gly49-Arg389/Gly49-Arg389 haplotype combinations. Aerobic power increased significantly (P < 0.001) with physical training. There was no association with the effect of physical training. CONCLUSION: Ser49Gly and haplotype combinations of Ser49Gly and Gly389Arg of the beta(1)AR gene are associated with aerobic power, but not with the response to physical training in patients with CAD included in the CAREGENE study.

Changes in QRS duration are associated with maximal exercise capacity in adult patients with repaired tetralogy of Fallot.

OBJECTIVE: In adult patients with repaired tetralogy of Fallot (TF) QRS duration at rest seems to be a predictor of maximal exercise. We examined the relationship between QRS duration during exercise and exercise performance. DESIGN: In 57 consecutive TF patients QRS duration in V1 (ms) was measured at rest, at maximal exercise (Wmax, W), and at peak oxygen consumption (peak VO2, ml/min). Stroke volume (SV) was calculated from cardiac output, obtained by CO2 rebreathing. Spearman rank correlation was used to describe the relationship between QRS duration and exercise performance. Statistical significance was defined as P<0.05. RESULTS: Seven patients, who didn't pass the anaerobic threshold, and one outlier (Wmax=340 W) were excluded, resulting in a sample of 49 patients (75.5% male; median age=24 years, range 16-43 years). QRS duration at rest (median=160 ms, range 78-194 ms) and at maximal exercise (median=153 ms, range 80-193 ms) did not differ significantly. The median change of QRS duration during exercise was -5 ms (range -31 to +83 ms). This was negatively correlated with Peak VO2 (2081+/-577 ml/min; rho=-0.33, P=0.02) and Wmax (182+/-53 Watt; rho=-0.33, P=0.02). In patients with QRS shortening peak VO2 and the exercise induced increase in SV were significantly higher than in patients with QRS shortening. CONCLUSIONS: This study indicates that QRS shortening during exercise in TF patients is related with a better exercise performance. Lower increase in stroke volumes may be responsible for this difference. Further research is needed to elaborate these findings.

The caregene study: muscle-specific creatine kinase gene and aerobic power in coronary artery disease.

In 927 biologically unrelated Caucasian patients with coronary artery disease it was investigated whether the NcoI restriction fragment length polymorphism of the muscle-specific creatine kinase (CKMM) gene is associated with aerobic power and with the response to physical training. Physical training significantly (P<0.001) increased peak oxygen consumption in the GG, AG and AA NcoI genotypes. Covariate-adjusted peak oxygen consumption at baseline, after training and the response to training were not different across CKMM NcoI genotypes.

The TUBB1 Q43P functional polymorphism reduces the risk of cardiovascular disease in men by modulating platelet function and structure.

The discoid form of platelets is maintained by a marginal band of tightly coiled microtubules. beta1-tubulin is the major isoform within platelet and megakaryocyte microtubules. In 24.2% of 33 unrelated inherited macrothrombocytopenia patients and in 10.6% of 272 subjects of a healthy population a P for Q substitution in beta1-tubulin was found in the highly conserved residue 43. Heterozygous carriers of the Q43P variant showed a reduced platelet protein beta1-tubulin expression. Transfection of green fluorescent protein (GFP)-tagged Q43P beta1-tubulin in megakaryocytic MEG01 cells resulted in a disturbed tubulin organization. Electron microscopy revealed enlarged spherocytic platelets with a disturbed marginal band and organelle-free zones. In addition, platelets with the Q43P beta1-tubulin variant had reduced adenosine triphosphate (ATP) secretion, thrombin receptor activating peptide (TRAP)-induced aggregation and collagen adhesion. The prevalence of the Q43P beta1-tubulin variant was also 2 times higher (odds ratio, [OR] = 2.1;95% confidence interval [CI], 1.22-3.59) among control subjects than among patients with cardiovascular disease (10.4% versus 5.2%, P < .001). By analyzing this protective factor in men and women separately, this association was only found in men. This study thus presents the functional consequences of the platelet Q43P beta1-tubulin substitution that is frequent in the healthy population and may protect men against arterial thrombosis.

Determinants of the effects of physical training and of the complications requiring resuscitation during exercise in patients with cardiovascular disease.

BACKGROUND: Benefits of cardiac rehabilitation with exercise therapy are well-established, although individual reactions are heterogeneous. The identification of determinants of training effects is useful from a prognostic point of view, but data regarding this are scarce. Furthermore, limited data exist on the determinants of complications during exercise in cardiac patients. This study aimed to investigate the determinants (1) of training effects in cardiac rehabilitation and (2) of complications requiring resuscitation during exercise activities at the hospital and during continued exercise at a sports club for cardiac patients. DESIGN: Clinical association study. METHODS: Determinants of changes in peak oxygen uptake (VO2) after 3 months of cardiac rehabilitation were determined by multiple regression analysis (n=1909). Determinants of events requiring resuscitation (n=21) were assessed by logistic regression analysis. RESULTS: Improvements in peak VO2 and exercise duration averaged 26%. Eighteen per cent of the variance in absolute improvements of peak VO2 was explained, with age and training characteristics as the strongest determinants. Twenty-one per cent of the variation in relative improvements was explained, with baseline exercise performance and training characteristics being the strongest determinants. The intake of anti-arrhythmics (odds ratio=5.5; P<0.001) and the presence of ST-segment depression (> or =1 mm) at baseline exercise testing (odds ratio=1.6; P<0.001) were predictive for serious complications. The occurrence of events requiring resuscitation was higher at the sports club (1/16,533 versus 1/29,214 patient-hours). CONCLUSIONS: Age, baseline exercise performance and training characteristics were predictive for training effects in cardiac rehabilitation. Anti-arrhythmics and ST-segment depression at baseline exercise testing were predictive for complications.

Effect of exercise training in patients with an implantable cardioverter defibrillator.

AIMS: Little research exists on exercise performance and training in patients with an implemented cardioverter defibrillator (ICD) and only in a limited number of patients. This study aims to investigate the effect of exercise training in ICD patients in comparison to the effects in other cardiac patients without an ICD. METHODS AND RESULTS: 92 ICD patients were compared with a control group of 473 patients. A maximal cycle-spiroergometric test was performed until exhaustion before and after an ambulatory exercise training programme. Exercise training was offered 3 times a week for 3 months. The cut-off heart rate was set at (ICD detection rate -20 beats/min). At baseline, the ICD patients had a lower peak oxygen uptake (VO(2)) compared to the control group. Training effects were smaller for peak VO(2) (mL/min/kg) and oxygen pulse in the ICD group (18 vs. 27%, p = 0.006 and 11 vs. 17%, p = 0.016, respectively). Several appropriate shocks were delivered during (n = 5), and in between (n = 7), testing or training and one inappropriate shock during training. CONCLUSIONS: ICD patients can safely participate in an exercise training programme with favorable results. A randomised control study with evaluation of the physical and the psychosocial effects is warranted.

Influence of work rate on the determinants of oxygen deficit during short-term submaximal exercise: implications for clinical research.

OBJECTIVE: The effect of increasing work rate was studied on the determinants of the oxygen deficit. METHODS: Exercise testing was performed on a treadmill and gas exchange was measured on a breath-by-breath basis. Eleven healthy subjects, aged 18-25 years, performed three square wave exercise tests of different intensity. Before exercise, gas exchange was measured at rest in the standing position for 3 min, followed by a 6-min square wave exercise test, randomly assigned at 4, 8 or 12% inclination. Immediately after exercise the recovery gas exchange was determined for 3 min. To calculate oxygen deficit, the oxygen uptake (O2) values at onset of exercise were subtracted from the steady-state value, the differences were cumulated and expressed as a percentage of the total oxygen cost for the 6-min exercise. RESULTS: The oxygen deficit increased significantly (P<0.001) with increasing work rate (6.1 +/- 1.4% for 4%, 8.4 +/- 2.1% for 8% and 9.4 +/- 1.7% at 12% inclination). This resulted from a somewhat slower increase of O2 at the onset of exercise at the highest work rate, reflected by a significantly higher time constant for O2 at 8 and 12% (24.6 +/- 7.3 s at 8% and 24.1 +/- 6.3 s at 12% versus 20.2 +/- 8.1 s at 4%). More importantly a significantly higher steady-state value for O2 was found at the highest exercise level, compared with the other exercise intensities. CONCLUSION: The higher oxygen deficit at the highest level of exercise is determined by a slower time constant and a higher asymptote value for O2.