Publications

Background: Although regular physical activity is recommended for prevention of cardiovascular diseases, no data are available on its antiatherosclerotic effects in the general population. Objective: To determine whether progressive aerobic exercise compared with usual activity slows progression of atherosclerosis in men. Design: A 6-year randomized, controlled trial. Setting: Eastern Finland. Participants: 140 middle-aged men randomly selected from the population registry. Intervention: Low- to moderate-intensity aerobic exercise. Measurements: Atherosclerosis was quantitated ultrasonographically as the mean intima–media thickness in the carotid artery at baseline and at years 2 through 6. Results: On the basis of intention-to-treat analyses, a 19.5% net increase (P < 0.001) in ventilatory aerobic threshold was evident in the exercise group after 6 years. High-sensitivity C-reactive protein levels were statistically nonsignificantly lower in the exercise group than in the control group (P > 0.2). The progression of intima–media thickness in the carotid artery did not differ between the study groups (P > 0.2). A subgroup analysis that excluded men taking statins showed that the 6-year progression of intima–media thickness, adjusted for smoking and annual measures of low-density lipoprotein cholesterol level, systolic blood pressure, and waist circumference, was 40% less in the exercise group (0.12 mm [95% CI, −0.010 to 0.26 mm]) than in the control group (0.20 mm [CI, 0.05 to 0.35 mm]). Limitations: Only middle-aged white men were included. The intervention included mainly aerobic exercises. Conclusions: Aerobic physical exercise did not attenuate progression of atherosclerosis, except in a subgroup of men not taking statins.

546 It is unclear how to classify responders or non-responders to exercise training. In subjects with similar body mass and fitness levels, one can use 1) absolute [ABS] change in VO2max (ml/min) or (ml/kg/min) or 2) relative [REL] change (%) in both. Because HERITAGE subjects were heterogeneous (age=16-65 yr, body mass=40-138 kg, VO2max=1172-4434 ml/min and 15-57 ml/kg/min), we looked at 431 subjects in the lowest, middle two and highest quartiles of ABS and REL change in VO2max. For REL change, those with the lowest VO2max had the largest % change in ml/min and in ml/kg/min. For ABS change, those with the highest VO2max (ml/min) weighed most and changed most. There was no difference in initial VO2max (ml/kg/min) among those who had different ABS changes in ml/kg/min. More males were in the high response group for ABS changes (greater body mass) but fewer males were in that group for REL changes, i.e., women had lower values. There were no group differences in number of Blacks or Whites or in body composition. Group differences in response to submaximal exercise were related to body mass or fitness. It is concluded that body mass and fitness influence the classification of response to training by heterogeneous groups. Changes in VO2max (ml/min) should be statistically adjusted for age, sex, body mass and body composition. Supported by NIH-NHLBI grants

There are few reports of the change in sex hormone levels accompanying a weight change in men, although an excessive decline in testosterone (TESTO) has been described as an associate of stress-induced weight loss. Plasma levels of cortisol, TESTO, dihydrotesosterone (DHT), dehydroepiandrosterone sulfate (DHEA-S), androsterone glucuronide (ADT-G), and androstane-3α, 17β-diol glucuronide (3αDIOL-G) were measured in seven pairs of sedentary male monozygotic twins (age, 21.0 ± 0.8 years; body mass index [BMI], 26.2 ± 5.5 kg/m2) before and after 93 days of standardized submaximal (50% to 55% maximum oxygen consumption) cycle-ergometer exercise. A total energy deficit of 244 ± 9.7 MJ induced significant changes (P < .0001) in body weight ([BW] −5.0 ± 2.2 kg) and body fatness measures. Plasma TESTO and DHEA-S increased and 3αDIOL-G decreased. The increase in TESTO was a significant inverse correlate of loss in all measures of body fat, particularly central adiposity (r = −.58 to −.86, P < .001, fat loss-adjusted). Lower postexercise levels of 3αDIOL-G correlated positively with decreased body composition measures (r = .65 to .68, P < .01). The increase in plasma TESTO accompanying the loss of abdominal visceral fat (AVF) was greater in men with lower fasting insulin levels (P < .0001). The baseline within—twin-pair resemblance in TESTO and 3αDIOL-G (intraclass correlation coefficients [ICC] = .83 and .78, respectively, P < .01) was lost with intervention. Cortisol, DHEA-S, and ADT-G developed within—twin-pair similarity (ICC adjusted for fat loss: cortisol, .72; ADT-G, .62, P < .05; DHEA-S, .85, P < .002). We conclude that a steroid profile characterized by high TESTO and low androgen metabolite levels accompanied the changes in body composition and body fat distribution generated by the exercise-induced negative energy balance. Furthermore, these changes were characterized by a significant resemblance within identical-twin pairs.

No abstract is provided for this article.

Introduction: The blood pressure (BP) response during acute exercise (acute exercise blood pressure (AEBP)) is related to future risk of hypertension (HTN) and cardiovascular disease (CVD). Biochemical characterization of AEBP could identify novel biomarkers of CVD risk and inform understanding of its biology. Methods: We applied an aptamer-based proteomics platform to assay ~5000 proteins at rest in 681 healthy individuals of the HERITAGE Family Study (mean age 34y, 54% women) who underwent an acute exercise perturbation. AEBP was measured during submaximal exercise on a cycle ergometer. We then performed a proteomic association study of resting BP and AEBP. Top protein associations with acute exercise SBP and DBP were analyzed for their association with incident HTN and CVD in the Framingham Heart Study (FHS). Putative causal effects of AEBP-related proteins were investigated by Mendelian randomization (MR), using cis-protein quantitative loci genetic instruments. Results: We identified new markers of AEBP, many of which are secreted proteins that span biological processes relevant to vascular function including transforming-growth factor beta-receptor 3 (β = -3.39, p = 2.33e-6), prostaglandin D2-synthase (β = -2.50, p = 1.18e-10-9), and angiopoietin-related protein 4 (β = 2.44, p = 1.05e-4). The addition of 12 AEBP-associated proteins to clinical information informed future risk of HTN and CVD among normotensive community-dwelling individuals (clinical model, clinical proteomic model AUCs: incident HTN 0.69, 0.73; coronary heart disease 0.73, 0.76; heart failure 0.83, 0.87). MR analysis of AEBP-associated proteins supported a potential causal relationship between 5 proteins and BP regulation (TGFBR3, ANGPTL4, CGA FSHB, PTGDS, KLK8). Conclusions: We identified new blood biomarkers of BP regulation that were elicited only by an acute exercise perturbation and highlight novel potential causal pathways.

PÉRUSSE, L., J. GAGNON, M. A. PROVINCE, D. C. RAO, J. H. WILMORE, A. S. LEON, C. BOUCHARD, and J. S. SKINNER. Familial aggregation of submaximal aerobic performance in the HERITAGE Family study. Med. Sci. Sports Exerc., Vol. 33, No. 4, 2001, pp. 597–604. Purpose: This study examines the contribution of genetic factors to submaximal aerobic performance phenotypes measured before and after 20 wk of endurance training. Methods: Submaximal oxygen consumption (V̇O2) at three power outputs, 50 W (V̇O250W), 60% (V̇O260%) and 80% (V̇O280%) of V̇O2max and power outputs at 60% (PO60%) and 80% (PO80%) of V̇O2max were measured during cycle ergometer exercise tests in 483 subjects from 99 white families participating in the HERITAGE Family study. The baseline phenotypes were adjusted for the effects of age, sex, and body mass using stepwise multiple regression procedures. The response phenotypes, computed as the difference (Δ) between the posttraining and baseline measures, were adjusted for age, sex, and the baseline value. Results: All submaximal exercise phenotypes measured at baseline and in response to training were characterized by a significant familial resemblance. Maximal heritabilities of the baseline phenotypes range from 48% to 74% with significant spouse, sibling, and parent-offspring correlations. The hypothesis of maternal inheritance where mother-offspring and sibling correlations were forced to be equal was found to fit the data for V̇O260%, V̇O280% and PO80%. For the response phenotypes, the maximal heritabilities tended to be lower (23–57%) with a significant maternal inheritance for ΔV̇O260%, ΔPO60%, and ΔPO80%. Conclusion: These results suggest that the submaximal working capacities of sedentary subjects and their responses to endurance training are influenced by familial/genetic factors with a significant contribution of maternal inheritance.

No abstract is provided for this article.

Background: Little is known about the genes influencing dietary energy and nutrient intakes, despite evidence that these intakes are influenced by genetic factors. Objective: We aimed to identify, by using a genome-wide linkage analysis, chromosomal regions harboring genes that affect energy and macronutrient intakes. Design: Energy, carbohydrate, lipid, and protein intakes were assessed in 836 subjects from 217 families by using a 3-d dietary record. A total of 443 markers were genotyped and tested for linkage; age- and sex-adjusted energy and macronutrient intakes were expressed in grams and as percentages of total energy intake. Regression-based (Haseman-Elston) and variance-component (MERLIN) methods were applied to test for linkage with dietary data. A maximum of 454 sibpairs from 217 nuclear families were available for analysis. Results: The genome scan provided suggestive evidence (P ≤ 0.0023) for the presence of 6 quantitative trait linkages influencing total caloric and macronutrient intakes in the Québec Family Study. Of these, multiple linkages were found on chromosome 3q27.3, in a region harboring the adiponectin gene, at marker D3S1262 for energy [logarithm of odds (LOD): 2.24], carbohydrate (LOD: 2.00), and lipid (LOD: 1.65) intakes. The peak linkages for carbohydrate, lipid, and protein intakes were found on chromosomes 1p32.2 (LOD: 2.39), 1p35.2 (LOD: 2.41), and 10p15.3 (LOD: 2.72), respectively. The linkage results remained significant after adjustment for body mass index, which suggested that the genes underlying these quantitative trait linkages influence dietary intake independent of body size. Conclusion: The linkage on chromosome 3q27.3 with energy, lipid, and carbohydrate intakes suggests that this region of the genome may harbor genes that influence energy and macronutrient intakes in humans.

The present study investigated the role of heredity in determining changes in the energy cost of submaximal exercise in response to short-term overfeeding. Six pairs of monozygotic twins were subjected to a 1,000 kcal/day surplus for 22 days with careful experimental controls over food intake and physical activities. O2 consumption (VO2) was measured during a submaximal treadmill exercise test 165 min postprandially before and the morning after the overfeeding protocol. As expected, overfeeding induced significant increases in body weight and fat mass. No significant increase in mean exercise VO2 was observed after overfeeding. However, the interindividual variation in overfeeding-induced changes in exercise VO2 was large and not randomly distributed. When comparing intrapair variance for changes in exercise VO2 to interpair variance, a moderate to high within-pair resemblance in response, i.e., a genotype-overfeeding interaction, was observed. Changes in exercise VO2 were positively correlated with those in postexercise levels of blood catecholamines, particularly epinephrine. A negative correlation was found between changes in exercise VO2 and body fat gain. These results are consistent with the concept of a role for the sympathoadrenal system in the regulation of adaptive thermogenesis and the predisposition to store fat. Moreover, these data suggest that the sensitivity to adapt in exercise energy expenditure after overfeeding is inherited to a significant extent.

PURPOSE: We investigated if high- or low-responsiveness to exercise training aggregates in the same individuals or if the response patterns are randomly distributed across seven clinically relevant traits. METHODS: A total of 566 participants from the HERITAGE Family Study completed a 20-week endurance training program (>95% compliance) and had complete response data available for maximal oxygen uptake, percent body fat, resting heart rate, and fasting levels of insulin, HDL-cholesterol, small LDL particles, and inflammatory marker GlycA. For each exercise response trait, race, sex, and generation-specific quintiles were created and high responders were defined as those within the 20th percentile representing the favorable end of the response trait distribution (e.g., top end for VO2max response, bottom end for fasting insulin response), while low responders were defined as the 20th percentile from the least favorable end. Those between the 20th and 80th percentile were labeled as average responders. RESULTS: Only one individual each was classified as a universal high or low responder for all seven traits (Table). Half (51%) of the cohort was both a low and high responder for at least one trait. About 24% had at least one high response but no low responses, 23% had one or more low-response traits but no high responses, and 2% were average responders across all traits. Pearson correlations between response traits were low, ranging from -0.22 to 0.11. CONCLUSIONS: Inter-individual variation in exercise responses applied to all investigated cardiometabolic traits, even with the same exercise intervention and level of compliance. Neither high- nor low-responsiveness aggregated consistently in the same individuals, as a low responder for one trait may be a high responder for another. From a clinical perspective, adherence to an exercise prescription is likely to produce multiple health benefits for an individual even if the targeted risk factor level doesn’t improve.

The I allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism has been associated with endurance performance in some studies, but failure to find evidence of association with maximal oxygen uptake has led to the suggestion that the association could be modulated by the impact of the polymorphism on skeletal muscle metabolic characteristics. PURPOSE To examine the association between the ACE I/D polymorphim and skeletal muscle characteristics in sedentary subjects from the Quebec (QFS) and HERITAGE Family Studies. METHODS Muscle biopsies of the vastus lateralis were obtained in a total of 117 subjects from QFS (n = 39) and HERITAGE (n = 78) cohorts. The ACE I/D polymorphism was genotyped and tested for association with fiber type characteristics, capillary density and activities of glycolytic (PFK, PHOS, CK) and oxydative (COX, CS, HADH, GAPDH, CPT) enzymes after adjustment for age, sex, cohort effects and maximal oxygen uptake using a procedure taking into account the non-independence of subjects within families. RESULTS The genotype frequencies were not significantly different between QFS (II = 0.26; ID = 0.38; DD = 0.36) and HERITAGE (II = 0.31; ID = 0.41; DD = 0.28) cohorts. Muscle CK was found to be higher (p = 0.02) in II (mean ± SEM: 399 ± 10) compared to DD (362 ± 13) subjects. In the HERITAGE cohort, the association was stronger (p = 0.007), with CK activity values of 423 ± 14 and 376 ± 16 in II and DD subjects, respectively. No association was found with the other skeletal muscle phenotypes. CONCLUSION These results suggest that the ACE I/D polymorphism could affect skeletal muscle creatine kinase activity, which could partly explain the association previously reported between the ACE gene and muscular performance. Supported by Canadian Institutes of Health Research and National Heart, Lung and Blood Institute, NIH.