Geert Frederix

Aerobic interval training and continuous training equally improve aerobic exercise capacity in patients with coronary artery disease: the SAINTEX-CAD study.

BACKGROUND Exercise-based cardiac rehabilitation increases peak oxygen uptake (peak VO₂), which is an important predictor of mortality in cardiac patients. However, it remains unclear which exercise characteristics are most effective for improving peak VO₂ in coronary artery disease (CAD) patients. Proof of concept papers comparing Aerobic Interval Training (AIT) and Moderate Continuous Training (MCT) were conducted in small sample sizes and findings were inconsistent and heterogeneous. Therefore, we aimed to compare the effects of AIT and Aerobic Continuous Training (ACT) on peak VO₂, peripheral endothelial function, cardiovascular risk factors, quality of life and safety, in a large multicentre study. METHODS Two-hundred CAD patients (LVEF >40%, 90% men, mean age 58.4 ± 9.1 years) were randomized to a supervised 12-week cardiac rehabilitation programme of three weekly sessions of either AIT (90-95% of peak heart rate (HR)) or ACT (70-75% of peak HR) on a bicycle. Primary outcome was peak VO₂; secondary outcomes were peripheral endothelial function, cardiovascular risk factors, quality of life and safety. RESULTS Peak VO₂ (ml/kg/min) increased significantly in both groups (AIT 22.7 ± 17.6% versus ACT 20.3 ± 15.3%; p-time<0.001). In addition, flow-mediated dilation (AIT+34.1% (range -69.8 to 646%) versus ACT+7.14% (range -66.7 to 503%); p-time<0.001) quality of life and some other cardiovascular risk factors including resting diastolic blood pressure and HDL-C improved significantly after training. Improvements were equal for both training interventions. CONCLUSIONS Contrary to earlier smaller trials, we observed similar improvements in exercise capacity and peripheral endothelial function following AIT and ACT in a large population of CAD patients.

Exercise acutely reverses dysfunction of circulating angiogenic cells in chronic heart failure.

AIMS Recruitment of endothelial progenitor cells (EPCs) and enhanced activity of circulating angiogenic cells (CACs) might explain the benefits of exercise training in reversing endothelial dysfunction in chronic heart failure (CHF) patients. We studied baseline EPC numbers and CAC function and the effect of a single exercise bout. METHODS AND RESULTS Forty-one CHF patients (mild, n = 22; severe, n = 19) and 13 healthy subjects were included. Migratory activity of CACs was evaluated in vitro and circulating CD34+ and CD34+/KDR+ (EPC) cells were quantified by flow cytometry before and after cardiopulmonary exercise testing (CPET). Circulating stromal cell-derived factor-1alpha (SDF-1alpha) and vascular endothelial growth factor (VEGF) concentrations were measured. Both CAC migration as well as CD34+ cell numbers were significantly reduced in CHF, whereas CD34+/KDR+ cells were not different from controls. Endothelial dysfunction was related to impaired CAC migration (r = 0.318, P = 0.023). Cardiopulmonary exercise testing improved CAC migration in severe (+52%, P < 0.005) and mild CHF (+31%, P < 0.005), restoring it to levels similar to controls. Following CPET, SDF-1alpha increased in healthy controls and mild CHF (P < 0.005). Vascular endothelial growth factor, CD34+, and CD34+/KDR+ cell numbers remained unchanged. CONCLUSION The present findings reveal a potent stimulus of acute exercise to reverse CAC dysfunction in CHF patients with endothelial dysfunction.

Endothelial progenitor cells and endothelial microparticles are independent predictors of endothelial function.

OBJECTIVE To examine the degree of microvascular endothelial dysfunction in relation to classical cardiovascular risk factors, arterial stiffness, and numbers of circulating endothelial progenitor cells (EPCs) and endothelial microparticles (EMPs), in obese and normal-weight children. STUDY DESIGN Cross-sectional study with 57 obese (15.2±1.4 years) and 30 normal-weight children (15.4±1.5 years). The principal outcome was microvascular endothelial function measured with peripheral arterial tonometry. Fasting blood samples were taken for biochemical analysis and EMPs (CD31+/CD42b- particles) and EPCs (CD34+/KDR+/CD45dim/- cells) flow cytometry. Characteristics between groups were compared by use of the appropriate independent samples test; a stepwise multiple regression analysis was used to determine independent predictors of microvascular endothelial function. RESULTS Microvascular endothelial function was significantly impaired in obese children and inversely correlated with body mass index Z scores (r=-0.249; P=.021) and systolic blood pressure (r=-0.307; P=.004). The number of EPCs was significantly lower in obese children and correlated with endothelial function (r=0.250; P=.022), and the number of EMPs was significantly greater in obese children and correlated inversely with endothelial function (r=-0.255; P=.021). Multivariate analysis revealed that systolic blood pressure and numbers of circulating EPCs and EMPs are important determinants of endothelial function. CONCLUSION Obese children demonstrate impaired endothelial microvascular function, increased arterial stiffness, fewer EPCs, and more EMPs. Besides systolic blood pressure, EPC and EMP counts independently predict the presence of microvascular endothelial dysfunction.

Diet, Exercise, and Endothelial Function in Obese Adolescents

BACKGROUND AND OBJECTIVES: Endothelial dysfunction is the first, although reversible, sign of atherosclerosis and is present in obese adolescents. The primary end point of this study was to investigate the influence of a multicomponent treatment on microvascular function. Additional objectives and end points were a reduced BMI SD score, improvements in body composition, exercise capacity, and cardiovascular risk factors, an increase in endothelial progenitor cells (EPCs), and a decrease in endothelial microparticles (EMPs). METHODS: We used a quasi-randomized study with 2 cohorts of obese adolescents: an intervention group (n = 33; 15.4 ± 1.5 years, 24 girls and 9 boys) treated residentially with supervised diet and exercise and a usual care group (n = 28; 15.1 ± 1.2 years, 22 girls and 6 boys), treated ambulantly. Changes in body mass, body composition, cardiorespiratory fitness, microvascular endothelial function, and circulating EPCs and EMPs were evaluated after 5 months and at the end of the 10-month program. RESULTS: Residential intervention decreased BMI and body fat percentage, whereas it increased exercise capacity (P < .001 after 5 and 10 months). Microvascular endothelial function also improved in the intervention group (P = .04 at 10 months; + 0.59 ± 0.20 compared with + 0.01 ± 0.12 arbitrary units). Furthermore, intervention produced a significant reduction in traditional cardiovascular risk factors, including high-sensitivity C-reactive protein (P = .012 at 10 months). EPCs were increased after 5 months (P = .01), and EMPs decreased after 10 months (P = .004). CONCLUSIONS: A treatment regimen consisting of supervised diet and exercise training was effective in improving multiple adolescent obesity-related end points.

Rationale and design of a randomized trial on the effectiveness of aerobic interval training in patients with coronary artery disease: The SAINTEX-CAD study

BACKGROUND Exercise-based cardiac rehabilitation is considered an important adjunct treatment and secondary prevention measure in patients with coronary artery disease (CAD). However, the issues of training modality and exercise intensity for CAD patients remain controversial. OBJECTIVE Main aim of the present study is to test the hypothesis that aerobic interval training (AIT) yields a larger gain in peak aerobic capacity (peakVO2) compared to a similar training programme of moderate continuous training (MCT) in CAD patients. STUDY DESIGN In this multicentre study stable CAD patients with left ventricular ejection fraction>40% will be randomized after recent myocardial infarction or revascularization (PCI or CABG) to a supervised 12-week programme of three weekly sessions of either AIT (85-90% of peak oxygen uptake [peakVO2], 90-95% of peak heart rate) or MCT (60-70% of peakVO2, 65-75% of peak heart rate). The primary endpoint of the study is the change of peakVO2 after 12 weeks training. Secondary endpoints include safety, changes in peripheral endothelial vascular function, the evolution of traditional cardiovascular risk factors, quality of life and the number and function of circulating endothelial progenitor cells as well as endothelial microparticles. Possible differences in terms of long-term adherence to prescribed exercise regimens will be assessed by regular physical activity questionnaires, accelerometry and reassessment of peakVO2 12 months after randomization. A total number of 200 patients will be randomized in a 1:1 manner (significance level of 0.05 and statistical power of 0.90). Enrolment started December 2010; last enrolment is expected for February 2013.

Effects of aerobic interval training and continuous training on cellular markers of endothelial integrity in coronary artery disease: a SAINTEX-CAD substudy

In this large multicenter trial, we aimed to assess the effect of aerobic exercise training in stable coronary artery disease (CAD) patients on cellular markers of endothelial integrity and to examine their relation with improvement of endothelial function. Two-hundred CAD patients (left ventricular ejection fraction > 40%, 90% male, mean age 58.4 ± 9.1 yr) were randomized on a 1:1 base to a supervised 12-wk rehabilitation program of either aerobic interval training or aerobic continuous training on a bicycle. At baseline and after 12 wk, numbers of circulating CD34(+)/KDR(+)/CD45dim endothelial progenitor cells (EPCs), CD31(+)/CD3(+)/CXCR4(+) angiogenic T cells, and CD31(+)/CD42b(-) endothelial microparticles (EMPs) were analyzed by flow cytometry. Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery. After 12 wk of aerobic interval training or aerobic continuous training, numbers of circulating EPCs, angiogenic T cells, and EMPs were comparable with baseline levels. Whereas improvement in peak oxygen consumption was correlated to improvement in FMD (Pearson r = 0.17, P = 0.035), a direct correlation of baseline or posttraining EPCs, angiogenic T cells, and EMP levels with FMD was absent. Baseline EMPs related inversely to the magnitude of the increases in peak oxygen consumption (Spearman rho = -0.245, P = 0.027) and FMD (Spearman rho = -0.374, P = 0.001) following exercise training. In conclusion, endothelial function improvement in response to exercise training in patients with CAD did not relate to altered levels of EPCs and angiogenic T cells and/or a diminished shedding of EMPs into the circulation. EMP flow cytometry may be predictive of the increase in aerobic capacity and endothelial function.

Levels of Circulating CD34+/KDR+ Cells Do Not Predict Coronary In-Stent Restenosis

BACKGROUND Angiographic and clinical parameters are poor predictors of in-stent restenosis. Bone marrow-derived CD34(+) cells that coexpress a receptor for vascular endothelial growth factor (kinase insert domain receptor [KDR]) are committed to endothelial lineage. Mobilization and infusion of CD34(+)/KDR(+) cells accelerates re-endothelialization and reduces neointimal thickness in vascular injury models. Bioengineered stents capturing CD34(+) cells also show expedited re-endothelialization. We examined whether circulating CD34(+)/KDR(+) cell counts can be used to predict restenosis in a bare-metal stent (BMS). METHODS CD34(+)/KDR(+) cells were counted by flow cytometry in 124 nondiabetic patients before BMS implantation and the relation to in-stent late luminal loss (LLL) was examined by angiography at 6 months (primary end point). Neointima was also quantified as the maximum percentage area stenosis (M%AS) and percentage volume intima hyperplasia (%VIH) on intravascular ultrasonography (secondary end points). RESULTS Multiple linear regression analysis, taking into account implanted stent length and diameter, revealed no relation between CD34(+)/KDR(+) cell counts and LLL (partial regression coefficient b = 0.11; 95% confidence interval [CI], -0.19-0.42; P = 0.46). Similarly, no relation between CD34(+)/KDR(+) cell counts and M%AS or %VIH could be demonstrated. Moreover, the increase in CD34(+)/KDR(+) cell counts over 6 months was unrelated to LLL (b = -0.15; 95% CI, -0.42-0.12; P = 0.28), M%AS, and %VIH. CONCLUSIONS Although our study does not exclude a pathophysiologic role for CD34(+)/KDR(+) cells in the formation of neointima, cell counts before percutaneous coronary intervention proved to be unrelated to LLL or intravascular ultrasonographically derived restenosis parameters in coronary BMSs at 6 months.

Long-Term Vascular Responses to Resolute® and Xience V® Polymer-Based Drug-Eluting Stents in a Rabbit Model of Atherosclerosis

OBJECTIVES To assess the late postinterventional response to iliac stenting in atheromatous rabbits using the Xience V everolimus-eluting stent (Xience V EES; Abbott Vascular) and the Resolute zotarolimus-eluting stent (Resolute ZES; Medtronic Vascular) with the MultiLink Vision bare metal stent (BMS; Abbott Vascular) as a reference. BACKGROUND Xience V EES and Resolute ZES were developed to overcome shortcomings of first-generation DES. METHODS Functional and microscopic changes were assessed by organ bath experiments and histopathologic examination. Gene expression was investigated using RT-PCR. RESULTS After 91 days, re-endothelialization was nearly complete (BMS: 93 ± 3%; Resolute ZES: 92 ± 2%; Xience V EES: 94 ± 3%; P = 0.10). Neointima thickness was similar in Resolute ZES (0.17 ± 0.08 mm) and BMS (0.17 ± 0.09 mm), and reduced in Xience V EES (0.03 ± 0.01 mm; P < 0.0001). Xience V EES had less peri-strut inflammation compared with BMS (P = 0.001) and Resolute ZES (P = 0.0001), while arterial segments distal to Xience V EES were more sensitive to acetylcholine than those distal to BMS and Resolute ZES (P = 0.02). Lectin-like oxidized receptor-1 was overexpressed in stented arteries (P < 0.001), whereas thrombomodulin was downregulated in Resolute ZES (P = 0.01) and BMS (P = 0.02) compared to unstented arteries of rabbits on regular chow. No significant changes were seen for vascular cell adhesion molecule-1, nitric oxide synthase 3, or endothelin-1. CONCLUSIONS At 3-month follow-up, nearly complete re-endothelialization was achieved for all stent groups. Xience V EES induced greater suppression of neointimal growth and peri-strut inflammation, higher vasorelaxation to acetylcholine, and expression of thrombomodulin at the level of unstented controls.

The effect of aerobic interval training and continuous training on exercise capacity and its determinants

Objective We aimed to investigate (1) the effects of aerobic interval training (AIT) and aerobic continuous training (ACT) on (sub)maximal exercise measures and its determinants including endothelial function, muscle strength and cardiac autonomic function, and (2) the relationship between exercise capacity and these determinants. Methods Two-hundred coronary artery disease (CAD) patients (58.4 ± 9.1 years) were randomized to AIT or ACT for 12 weeks. All patients performed a cardiopulmonary exercise test and endothelial function measurements before and after the intervention; a subpopulation underwent muscle strength and heart rate variability (HRV) assessments. Results The VO2, heart rate and workload at peak and at first and second ventilatory threshold increased (P-time <0.001); the oxygen uptake efficiency slope (P-time <0.001) and half time of peak VO2 (P-time <0.001) improved. Endothelial function and heart rate recovery (HRR) at 1 and 2 min improved (P-time <0.001), while measures of muscle strength and HRV did not change. Both interventions were equally effective. Significant correlations were found between baseline peak VO2 and (1) quadriceps strength (r = 0.44; P < 0.001); (2) HRR at 2 min (r = 0.46; P < 0.001). Changes in peak VO2 correlated significantly with changes in (1) FMD (ρ = 0.17; P < 0.05); (2) quadriceps strength (r = 0.23; P < 0.05); (3) HRR at 2 min (ρ = 0.18; P < 0.05) and Total power of HRV (ρ = 0.41; P < 0.05). Conclusions This multicentre trial shows equal improvements in maximal and submaximal exercise capacity, endothelial function and HRR after AIT and ACT, while these training methods seem to be insufficient to improve muscle strength and HRV. Changes in peak VO2 were linked to changes in all underlying parameters.