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Oxidant stress and overproduction of reactive oxygen species (ROS) contribute to the development of cardiovascular disease. Oxidative modifications of low-density lipoproteins (LDL) are thought to play an early and critical role in atherogenesis. LDL oxidation can be reproduced in vitro, but results usually show a large interindividual variation not entirely explained by the environment. Free radical-induced hemolysis is also proposed to reveal the overall antioxidant capacity. The roles of genetic factors and exercise on the variability of both measures were investigated. The study was conducted in 146 healthy individuals from 28 families participating in a 20-week exercise-training program. In addition to important biological and environmental influences on variation, significant familial aggregation was detected in all oxidation measures. Exercise did not significantly modify the LDL oxidation parameters, but significantly increased resistance was observed in the free radical-induced hemolysis, especially in women, this effect was not observed in smokers. In total, the findings suggest the presence of familial effects in the response to ex vivo oxidation. Further, smoking negates the beneficial effect of exercise training on erythrocyte resistance to free radical-induced hemolysis. These observations emphasize the importance of context in the evaluation of exercise and oxidant stress.

We investigated whether regular aerobic exercise could affect plasma total homocysteine (tHcy), and whether there were sex-related or racial differences in tHcy changes. Data were available for 816 black and white men and women, aged 17-65 years, 711 of whom completed a 20 week aerobic exercise training program. The tHcy concentration was measured in frozen plasma samples by an HPLC method. In Blacks, tHcy did not change with exercise training [men -0.5 (SD 3.7) micromol/l, women 0.0 (2.2) micromol/l) but increased significantly in Whites (men +0.3 (1.7) micromol/l, women +0.2 (1.6) micromol/l). No sex-related differences were found in either racial group. Changes in tHcy correlated negatively with baseline homocysteine (r = -0.40, P < 0.0001). Homocysteine levels of the "High" (hyperhomocysteinemia) (>or=15 micromol/l) group (n = 30) decreased significantly with regular aerobic exercise from 23.1 (12.1) to 19.6 (7.6) micromol/l. Homocysteine levels of the "Normal" group increased slightly from 8.2 +/- 2.2 to 8.5 +/- 2.4 micromol/l. Men exhibit racial differences for tHcy responses to exercise training. Regular aerobic exercise has favorable effects on individuals with hyperhomocysteinemia, but tHcy slightly increased in individuals within the normal range.

Fasting triglyceride (TG) levels in total plasma and in lipoprotein subfractions were assessed both at baseline and after a 20-week exercise training intervention in 99 White and 101 Black families. A genome-wide multipoint variance component linkage analysis was performed separately by race, using 509 markers. The strongest evidence of linkage was for the TG subfractions of low-density lipoprotein (LDL-TG) and high-density lipoprotein (HDL-TG) rather than for overall levels of TG. For baseline levels, the maximum LOD score was 3.8 on 13q12-q14 with HDL-TG in Whites. Additional linkage evidence was found on 14q31 (LOD=3.2) and 10p14 (LOD=2.9) for baseline LDL-TG in Whites. Suggestive linkage signal at baseline in Whites was detected for HDL-TG (LOD=2.6) on 12q24 and for LDL-TG on 19p13. For training response in Whites, suggestive signal (LOD=2.2) was observed on 13q12-q14 with LDL-TG and for HDL-TG on 10q23. For Blacks, weak signals (LODs<2.0) were found either for baseline and responses to training, perhaps due to small sample sizes that reduced the power of the linkage analysis. These results represent the first report of linkage for the lipoprotein subfractions and for the lipid and lipoprotein responses to exercise training. It is interesting that the strongest signals were found for the LDL-TG and HDL-TG subfractions, given their particular relationships with the atherogenic lipid profile including dense LDL and HDL particles.

Aims: To study the effect of exercise training on plasma C-reactive protein, a marker of inflammation., Methods and Results: We performed a 20 week standardized exercise training programme in 652 sedentary healthy white and black men and women. C-reactive protein was measured with a high sensitivity assay. The study sample was stratified according to baseline C-reactive protein levels using a recommended classification (low <1.0 mg/L, n=265; moderate 1.0-3.0 mg/L, n=225; high >3.0 mg/L, n=162). The median C-reactive protein reduction was 1.34 mg/L in the high baseline C-reactive protein group. C-reactive protein levels did not change in the low or moderate baseline C-reactive protein groups. The difference among the C-reactive protein groups was significant adjusting for all correlates of baseline C-reactive protein (P<0.001) and additionally for changes in body weight, glucose, insulin, LDL cholesterol, HDL cholesterol, triglycerides, systolic and diastolic blood pressure, and maximal oxygen uptake (P<0.001). The C-reactive protein reduction in the high baseline C-reactive protein group was consistent across all population groups (P<0.001 for difference among baseline C-reactive protein groups)., Conclusion: Plasma C-reactive protein levels are reduced in response to exercise training in sedentary healthy adults with high initial C-reactive protein levels. This finding may partly explain the effectiveness of regular physical activity in the prevention and treatment of cardiovascular and metabolic diseases.

Objective: To determine the effect of a 20-week endurance training program in healthy, previously sedentary participants on measures derived from an intravenous glucose tolerance test (i.v.GTT)., Research Design and Methods: An i.v.GTT was performed before and after a standardized training program in 316 women and 280 men (173 blacks and 423 whites). Participants exercised on cycle ergometers 3 days per week for 60 sessions. The exercise intensity was progressively increased from 55% VO2max for 30 min per session to 75% VO2max for 50 min per session., Results: Mean insulin sensitivity increased by 10% (P < 0.001) following the intervention, but the variability in the changes was high. Men had larger improvements than women (P = 0.02). Improvements in fasting insulin were transitory, disappearing 72 h after the last bout of exercise. There were also significant mean increases in the glucose disappearance index (3%, P = 0.02) and in glucose effectiveness (11%, P < 0.001), measures of glucose tolerance and of the capacity of glucose to mediate its own disposal, respectively. The acute insulin response to glucose, a measure of insulin secretion, increased by 7% in the quartile with the lowest baseline glucose tolerance and decreased by 14% in the quartile with the highest baseline glucose tolerance (P < 0.001). The glucose area below fasting levels during the i.v.GTT was reduced by 7% (P = 0.02)., Conclusions: Although the effects of structured regular exercise were highly variable, there were improvements in virtually all i.v.GTT-derived variables. In the absence of substantial weight loss, regular exercise is required for sustained improvements in glucose homeostasis.

Objective: Despite the well known genetic component influencing plasma lipid-lipoprotein levels and the observed correlations among these traits, little is known about pleiotropic heritable determinants among them. Our aim is to investigate pair-wise polygenic and environmental correlations among lipid-lipoprotein levels at baseline and in response to regular exercise in Whites and Blacks., Methods: Common pair-wise genetic and environmental correlations among levels of total cholesterol (TC), LDL-C, ApoB, HDL-C (also HDL2-C and HDL3-C), triglycerides (TG, HDL-TG and LDL-TG) and ApoA-1 were investigated at baseline and again after a 20-week endurance exercise program using a variance-components-decomposition., Results: With a few exceptions, all lipid phenotypes were heritable at baseline and for training responses in Blacks and Whites. Strong to high genetic and environmental correlations (0.4 < rho(g) < 0.7) were observed for the majority of the baseline pair-wise traits. For training responses, many of the same patterns were noted, although fewer genetic correlations were significant as compared to the baseline results., Conclusions: Results suggest that the observed phenotypic correlations among many of these traits may be due to in part to pleiotropic genes, in particular between LDL-C and ApoB and between TG and HDL-C. This shared genetic architecture should be considered in follow-up gene finding studies., (Copyright 2005 S. Karger AG, Basel.)

Purpose: This study explores sex and race differences in the association between changes in fat mass (FM), abdominal visceral fat (AVF), and abdominal subcutaneous fat (ASF) on blood lipid changes consequent to aerobic exercise training., Methods: The sample included 613 participants (428 white and 185 black, 46% men) from the HERITAGE Family Study. Total FM was determined by densitometry, whereas AVF and ASF cross-sectional areas were determined by computed tomography at the L4-L5 level. Blood lipid measurements included total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and the TC/HDL-C ratio, which were obtained before and after 20 wk of supervised aerobic exercise. Canonical correlation was used to determine the multivariate associations between body fatness and blood lipids at baseline and the changes induced by exercise training., Results: Body fat accounted for 26-36% of the variance in baseline blood lipids, and changes in body fat accounted for 7-21% of the variance in changes in blood lipids with exercise training. The pattern of loadings indicated similar relationships between body fatness and blood lipids at baseline, and their respective changes with exercise training among the four sex-by-race groups. Greater fat loss, characterized by loss of FM, AVF, and ASF, was associated with a greater blood lipid response characterized by an increase in HDL-C and decreases in LDL-C, TG, TC, and TC/HDL-C. Although the pattern of loadings was similar in all groups, the strength of the association was stronger in blacks than in whites., Conclusion: The multivariate associations among fat loss and changes in blood lipids consequent to aerobic exercise training are similar in black and white men and women.

We recently reported that a genomic region close to the leptin locus was linked to fasting insulin response to exercise training in nondiabetic white subjects. We tested the hypothesis that common exonic variants in the leptin (LEP) and leptin receptor (LEPR) genes modify the effects of regular physical activity on glucose homeostasis in nondiabetic whites (n = 397) and blacks (n = 143). In whites, exercise increased insulin sensitivity index (P = 0.041) and disposition index (P = 0.046) in the LEPR 109R allele carriers but not in the K109K homozygotes, increased glucose disappearance index more in the R109R homozygotes than in the K109 allele carriers (P = 0.039), and decreased fasting glucose only in the 109R allele carriers (P = 0.018). We also found an interaction between the LEP A19G and LEPR K109R polymorphisms on the change in fasting insulin in whites (P = 0.010). The association between the LEP A19G polymorphism and the change in insulin was evident only in the LEPR 109R carriers (P = 0.019). The decrease in insulin was strongest in the LEP A19A homozygotes who carried the LEPR 109R allele. Similar interaction was observed in blacks (P = 0.046). Variations in the LEP and LEPR genes are associated with the magnitude of the effects of regular exercise on glucose homeostasis in nondiabetic individuals.

The relationship of apolipoprotein E (apo E) genotypes to plasma lipid and maximal oxygen uptake (Vo(2max)) was studied in the sedentary state and after a supervised exercise training program in black and white men and women. At baseline, the apo E 2/3 genotype was associated with the lowest, and apo E 3/4 and E4/4 with the highest low-density liporpotein (LDL) cholesterol and apo B levels in men and women of both races, while female (not male) carriers of apo E3 had higher high-density lipoprotein (HDL) cholesterol levels than carriers of other genotypes. Very-low-density lipoprotein (VLDL) cholesterol and triglyceride levels were significantly higher in carriers of both apo E2 and apo E4 in white men only. Racial and sex differences were noted in lipid responses to exercise training across genotypes with a significantly greater increase in HDL cholesterol observed only in white female carriers of apo E 2/3 and E3/3, as compared to apo E4/4. Apo E polymorphism was not found to be associated with Vo(2max) levels either in the sedentary state nor the Vo(2max) response to exercise training, contrary to previous reports.

Introduction/purpose: We hypothesized that skeletal muscle histological and biochemical phenotypes aggregate within families., Methods: Nineteen families (78 Caucasians) from the HERITAGE Family Study participated in the study. Proportions and areas of Type I, IIA, and IIX muscle fibers, capillary density, and maximal enzyme activities were determined in biopsy samples from the vastus lateralis obtained in the sedentary state and after a 20-wk endurance-training program., Results: In the sedentary state, there was evidence for familial resemblance for Type I fiber area (P = 0.007), number of capillaries around Type I and Type IIA fibers (P = 0.04), and Type I and IIA fiber areas per capillary (P = 0.01 and P = 0.04, respectively). Significant familial aggregation (0.05>P > 0.0001) was observed for maximal activities of enzymes of the energy production pathways. With regard to the training response, significant familial aggregation (0.05 > P < 0.0001) was observed for maximal activities of enzymes of the energy production pathways., Conclusion: These data provide evidence of familial aggregation for enzyme activities of the main energy metabolism pathways of the skeletal muscle in the sedentary state and in response to regular exercise.

Several genome-wide linkage scans have been carried out to identify quantitative trait loci for type 2 diabetes and related metabolic phenotypes. However, no previous linkage scans have focused on the response to exercise training of relevant metabolic traits. We performed a genome-wide linkage scan for baseline fasting glucose, insulin, and C-peptide and their responses to a 20-week exercise training program in nondiabetic white and black men and women from the HERITAGE Family Study. In SIBPAL linkage analyses, the maximum number of sibpairs available was 344 and 93 for baseline phenotypes and 300 and 72 for exercise training response phenotypes in whites and blacks, respectively. A total of 509 markers with an average spacing of 6.0 Mb were used. The strongest linkage was found for the changes in fasting insulin in response to exercise training with a marker in the leptin gene on 7q31 (empirical multipoint P = 0.0004) in whites. In blacks, the strongest linkage was observed for baseline fasting glucose on 12q13-q14 (empirical multipoint P = 0.0006). These regions harbor several potential candidate genes. The present findings may be important in identifying individuals at increased risk of developing type 2 diabetes and who are most likely to benefit from a physically active lifestyle.

The relationship between sex hormone-binding globulin (SHBG) concentrations and body fat accumulation and distribution is governed by complex dynamic factors, which may involve common genetic and/or environmental factors. The current study investigated the genetic and environmental basis for the correlation between SHBG and body fat. Several measures of adiposity were investigated including body mass index (BMI) and a trunk to extremity skinfold thickness ratio (TER) assessed by anthropometry, body composition measured by hydrostatic weighing (total body fat mass [FM], fat-free mass [FFM], and percent body fat [%BF]), and abdominal fat measured by computerized tomography scanning (abdominal visceral fat [AVF]). The study comprised 501 white subjects from 99 families and 277 black subjects from 117 families participating in the HERITAGE Family Study. Familial correlations between traits and their cosegregation were investigated both at baseline and in response to endurance exercise training. Significant inverse phenotypic correlations were detected in both races between SHBG and adiposity measures at baseline and also in response to training. Significant cross-trait familial resemblance was found between SHBG and both BMI and FFM at baseline that accounted for 11% and 4% of maximal heritability, respectively, in white families. However, a joint segregation analysis of the traits failed to implicate shared genetic effects. Specifically, neither a pleiotropic major locus nor pleiotropic polygenic effects were detected between SHBG and BMI or FFM. A maximal cross-trait heritability of 45% was obtained for SHBG and TER at baseline in black families. However, no firm conclusions as to the etiology of this relationship could be drawn because of the limitations of small sample size. For the training response phenotypes, there was no significant cross-trait correlation between SHBG and any adiposity measures studied here, suggesting that their correlation may have an environmental basis. Therefore, this study fails to support the hypothesis of genetic pleiotropy between SHBG concentrations and body fat phenotypes, and suggests an environmental basis for the correlation, ie, SHBG concentrations are genetically independent of body composition and abdominal adiposity phenotypes., (Copyright 2003, Elsevier Science (USA). All rights reserved.)

This study investigates whether there are major gene effects on oxygen uptake at the ventilatory threshold (VO(2VT)) and the VO(2VT) maximal oxygen uptake (VT%VO(2 max)), at baseline and in response to 20 wk of exercise training by using data on 336 whites and 160 blacks. Segregation analysis was performed on the residuals of VO(2VT) and VT%VO(2 max). In whites, there was strong evidence of a major gene, with 3 and 2% of the sample in the upper distribution, that accounted for 52 and 43% of the variance in baseline VO(2VT) and VT%VO(2 max), respectively. There were no genotype-specific covariate effects (sex, age, weight, fat mass, and fat-free mass). The segregation results were inconclusive for the training response in whites, and for the baseline and training response in blacks, probably due to insufficient power because of reduced sample sizes or smaller gene effect or both. The strength of the genetic evidence for VO(2VT) and VT%VO(2 max) suggests that these traits should be further investigated for potential relations with specific candidate genes, if they can be identified, and explored through a genome-wide scan.

A genome-wide linkage scan was performed for genes affecting submaximal exercise cardiac output (Q) and stroke volume (SV) in the sedentary state and their responses to a standardized 20-wk endurance training program. A total of 509 polymorphic markers were used, and 328 pairs of siblings from 99 white nuclear families and 102 sibling pairs from 105 black family units were available. Q and SV were measured in relative steady state during exercise at 50 W (Q50 and SV50, respectively). Baseline phenotypes were adjusted for age, sex, and body surface area (BSA), and the training responses (post-training - baseline, Delta) were adjusted for age, sex, baseline BSA, and baseline value of the phenotype. Three analytical strategies were used: a multipoint variance components linkage analysis using all the family data, and regression-based single- and multipoint linkage analyses using pairs of siblings. In whites, baseline SV50 and DeltaSV50 showed promising linkages (P < 0.0023) with markers on chromosomes 14q31.1 and 10p11.2, respectively. Suggestive evidence of linkage (0.01 > P > 0.0023) for DeltaSV50 and Delta Q50 was detected on chromosome 2q31.1 and for baseline SV50 and Q50 on chromosome 9q32-q33. In blacks, markers on 18q11.2 showed promising linkages with baseline Q50. Suggestive evidence of linkage was found in three regions for baseline SV50 (1p21.3, 3q13.3, 12q13.2) and one for baseline SV50 and Q50 (10p14). All these chromosomal regions include several potential candidate genes and therefore warrant further studies in the HERITAGE cohort and other studies.

The purpose of this study was to search for genomic regions influencing resting systolic (SBP) and diastolic (DBP) blood pressure (BP) in sedentary families (baseline), and for resting BP responses (changes) resulting from a 20-week exercise training intervention (post-training-baseline) in the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study. A genome-wide scan was conducted on 317 black individuals from 114 families and 519 white individuals from 99 families using a multipoint variance-components linkage model and a panel of 509 markers. Promising results were primarily, but not exclusively, found in the black families. Linkage evidence (P<0.0023) with baseline BP replicated other studies within a 1-logarithm of odds (LOD) interval on 2p14, 3p26.3, and 12q21.33, and provided new evidence on 3q28, 11q21, and 19p12. Results for several known hypertension genes were less compelling. For response BP, results were not very strong, although markers on 13q11 were mildly suggestive (P<0.01). In conclusion, these HERITAGE data, in conjunction with results from previous genomewide scans, provide a basis for planning future investigations. The major areas warranting further study involve fine mapping to narrow down 3 regions on 2q, 3p, and 12q that may contain "novel" hypertension genes, additional typing of some biological candidate genes to determine whether they are the sources of these and other signals, multilocus investigations to understand how and to what extent some of these candidates may interact, and multivariate studies to characterize any pleiotropy.

Purpose: The heritability of the response to exercise training in resting blood pressure (BP) and heart rate (HR) was assessed in 482 Caucasian individuals comprising 98 families participating in the HERITAGE Family Study., Methods: All individuals were sedentary at the baseline visit (time 1 measurement). After completing a 20-wk exercise-training program, subjects were measured again (time 2). A familial correlation model was used to assess the heritability (genetic plus familial environmental) of the response in resting systolic BP (SBP), diastolic BP (DBP), and HR, computed as the difference between the two measurement times. This response was adjusted for the effects of baseline levels and age within sex and generation groups. Analyses were conducted separately in a subsample of families in which at least one family member was considered to have elevated BP (95th percentile; SBP > or = 135 or DBP > or = 80)., Results: Several novel findings emerged from this study. First, the SBP and HR response may be influenced by genetic factors. The maximal heritabilities were 20% (SBP) and 36% (HR) in the elevated BP, 18% and 24% in the complete, and not significant in the normotensive samples. For DBP, there were cohort effects (significant sibling and spouse but not parent-offspring correlations) in the complete and normotensive samples that may be due to generation-specific environmental influences., Conclusion: The trainability of SBP and HR in families with elevated BP appears to be determined in part by genetic factors, whereas DBP trainability may be more a function of environmental effects.

Background: Fasting levels of plasma lipids and lipoproteins are reported to improve with regular exercise training. However, little is known on whether the training responses are influenced by heritable factors., Methods and Results: The lipid profile was assessed in 115 black (224 individuals) and 99 white families (469 individuals), who participated in the HERITAGE Family Study, while in a sedentary state (baseline visit) and after exercise training for 20 weeks (post visit). Variables included total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I, and HDL-C subfractions 2 (HDL2-C) and 3 (HDL3-C). Familial correlations for the training responses (Delta=post-baseline) were significant for most variables, and the percent variance accounted for by familial factors (ie, maximal heritabilities) ranged from 25% to 38%. Exceptions were for higher heritabilities near 60% for DeltaApoB in blacks and DeltaHDL2-C in whites and a lower estimate of zero for DeltaLDL-C in blacks., Conclusions: Heritable factors in part determine lipid profile responses to regular exercise. Maximal heritabilities were similar across ethnic groups and variables, except for DeltaLDL-C, DeltaApoB, and DeltaHDL2-C. Molecular studies to identify the markers and genes associated with these influences are currently underway.

Purpose: To investigate the influences of menopause, hormone replacement, and endurance exercise training on cardiovascular hemodynamics and oxygen uptake parameters during exercise in women., Methods: Subjects were 338 premenopausal women, 29 postmenopausal women taking hormone replacement, and 28 postmenopausal women not taking hormone replacement, all enrolled in the HERITAGE Family Study. Hemodynamic and oxygen uptake data were gathered on a cycle ergometer at 50 watts (W), 60% peak oxygen uptake, and at peak exercise, both before and after a 20-wk regimen of endurance exercise training on a cycle ergometer., Results: Systolic blood pressure (SBP) during peak exercise was found to be an average of 14 mm Hg less in postmenopausal women receiving hormones than in those not receiving hormones. Furthermore, menopause was associated with a 26.2 mm Hg higher SBP at 50 W power output, which remained physiologically significant after adjustment for age. At 50 W, postmenopausal women not taking hormones showed a 13.8 mm Hg greater training-induced reduction in SBP than those taking hormones., Conclusion: It was concluded that hormone replacement may be associated with a vasodilatory reserve at high exercise intensities and that endurance exercise training elicits favorable hemodynamic and oxygen uptake adaptations during exercise that are, in most instances, independent of menstrual status or hormone replacement.

This article summarizes the final report of a work group on physical fitness and exercise, which identified national trends in these areas for the 1980 report "Promoting Health/Preventing Disease: Objectives for the Nation," published by the Department of Health and Human Services. (JN)

Presents information on a study which examined the effects of endurance exercise training on the resting metabolic rate (RMR) of the human body. Objective of the study; Discussion on the effects of RMR; Percentage of RMR that is accountable of a normally active person per day; Reference to the HERITAGE Family Study; Method used in the study; Results from the study.

A role for dopamine neurotransmission in the regulation of motor activity and reinforcement of behavior is supported by considerable evidence. We studied the association between a marker in the dopamine D2 receptor gene (DRD2) and physical activity level in two cohorts. A first cohort consisted of 721 participants from 161 families of the Quebec Family Study (QFS). Physical activity phenotypes were obtained from a three-day diary and a questionnaire probing physical activity during the past year. The second cohort was the HERITAGE Family Study (HERITAGE), which included 275 Black and 497 White participants from 228 families, among whom past year leisure time and occupational physical activity were probed. A fragment length polymorphism in exon 6 of the DRD2 gene was detected by the polymerase chain reaction (PCR) and NcoI digestion. Frequencies for the T and C alleles were 28% and 72% in the QFS. In the QFS, TT homozygote women had 25% and 34% lower age and BMI-adjusted physical activity level during the past year, compared to CC homozygotes and CT heterozygotes (F=4.42, P=.016). The DRD2 genotype was not associated with the QFS phenotypes obtained from the three-day diary. In the HERITAGE, the frequency of the T allele was 30% among Whites and 63% among Blacks. Similarly, the TT homozygote White women had 29–38% lower sports index (F=4.09, P=.023) and 27–33% lower work index (F=6.23, P=.004) than the CC homozygotes and CT heterozygotes. The results suggest that DNA sequence variation in the DRD2 gene is associated with physical activity levels among White women. [Copyright &y& Elsevier]