Publications

0710 The K+ voltage-gated channel of the shaw-related subfamily member 1 (KCNC1) gene (11p15), encodes for a voltage-gated K+ channel that serves as an oxygen sensor in*uencing pulmonary artery smooth muscle (PASM) cells excitability in hypoxic conditions, such as high intensity physical activity. PURPOSE: We examined the hypothesis of association between a G\A transition in the KCNC1 gene and OV2max in the sedentary (SS) and trained (TS) states, as well as in response (Δ) to 20-wk endurance-training (ET). METHODS: Pre- and Post-ET VO2 was measured by progressive exercise tests on a cycle ergometer. The polymorphism was detected by PCR and digestion with MspI in 777 DNA samples from the HERITAGE Family Study (Blacks = 275 and Whites = 502). RESULTS: Genotypic distributions were in Hardy- Weinberg equilibrium. χ2 indicated that genotype frequencies were different between races (P <0.0001) but not between genders (p>0.05). ANCOVA revealed statistically significant genotype effects for SS OV2max (P = 0.04) and TS OV2max (P = 0.01) values adjusted for age, gender and body mass. In Blacks only, homozygotes for the rare A allele had significantly higher SS (2329 ± 44 mL/min) and TS OV2max (2729 ± 45 mL/min) than both GG homozygotes (SS = 2314 ± 40 mL/min; TS = 2683 ± 43 mL/min) and GA heterozygotes (SS = 2241 ± 36 mL/min; TS = 2614 ± 36 mL/min). CONCLUSIONS: These findings suggest that DNA sequence variation in the KCNC1 gene is part of the complex genotype associated with OV2max in the sedentary and trained states in Blacks, but not in Whites. Supported by several grants from NHLBI of NIH, CRC-RCMI #1P20RR11126, and RCMI #G12RR03051.

Experimentally, desflurane causes a moderate positive inotropic effect and a transient increase in arterial pressure with rapid increases in concentration compared with isoflurane. We used a continuous oesophageal aortic blood flow echo Doppler device to study the myocardial effects of equi-anaesthetic concentrations of isoflurane and desflurane in 32 healthy patients undergoing superficial surgery. After induction of anaesthesia with midazolam, etomidate and fentanyl general anaesthesia was maintained in 16 patients with 0.6% end-expired concentration of isoflurane and in 16 patients with 3% end expired concentration of desflurane. Isoflurane induced a rapid decrease in aortic blood flow (ABF) which remained almost stable whereas desflurane induced an early, moderate and transient increase in ABF (1 min after introduction of the halogenated agent, mean ABF was 107 (SD 3)% in the desflurane group vs 95 (9)% in isoflurane group compared with control values before introduction of the inhalation agent; P = 0.005), followed by a marked secondary decrease in ABF. The maximal decrease in ABF reached 71 (15)% of its initial value in the desflurane group compared with 80 (14)% in the isoflurane group (ns). Neither agent caused significant changes in other variables except for PE'CO2 which decreased in both groups. Continuous ABF echo-Doppler monitoring demonstrated an early transient positive inotropic effect of desflurane.

Background : In paediatric healthy patients and in real peroperative conditions, the cardiovascular effects of isoflurane have been poorly described. Methods : We have evaluated the myocardial effects of 1% end‐expired concentration (EEC) of isoflurane in 25 healthy infants or small children undergoing superficial surgical therapy for small burns with a continuous aortic blood flow echo‐Doppler device. Aortic blood flow (ABF) was measured with a small oesophageal probe specially designed for infants. The aortic flowmeter was connected with satelitte devices to visualize the haemodynamic profile variations during the isoflurane inhalation period. Results : Isoflurane significantly decreased ABF and increased pre‐ejection period/left ventricular ejection time (PEP/LVET), when compared with control values previously recorded 5 min after induction with halothane‐fentanyl and atracurium (respectively, 80 ± 7%, mean ± SD; P &lt;0.001 and 111 ± 11%; P =0.017, 5 min after EEC of isoflurane reached 1%, then respectively, 75 ± 12%; P &lt;0.001 and 119 ± 16%; P &lt;0.001, at the end of the isoflurane inhalation period). These variations reversed to a great extent when isoflurane was switched off (97 ± 17% for ABF; P =0.08 and 105 ± 12% for PEP/LVET; P =0.75). Among the usual parameters, 1% EEC of isoflurane caused no significant changes in heart rate, moderately decreased mean arterial pressure (successively, 88 ± 12%; P =0.045 and 87 ± 19%; P =0.049), but belatedly decreased end‐tidal CO 2 pressure (87 ± 11% at the end of the inhalation period ( P &lt;0.001) which persisted 5 min after isoflurane was turned off (90 ± 11%; P &lt;0.001)). Conclusions : These findings suggest that isoflurane can transiently depress cardiac function in healthy infants.

The objective of this study was to quantify familial resemblance for coronary heart disease risk in 260 Black and 427 White participants in the HERITAGE Family Study. Coronary heart disease risk was estimated using a coronary heart disease risk index (CHDRI) computed from the revised Framingham Heart Study algorithm, based on age, LDL-cholesterol, HDL-cholesterol, blood pressure, diabetes, and smoking status. Using a familial correlation model to test hypotheses regarding familial aggregation, significant familial resemblance was detected in both Blacks and Whites. There were significant sibling correlations in both Blacks and Whites, while spouse correlations were significant only in the White sample. The maximal heritabilities, which have to be interpreted cautiously in light of negligible parent-offspring correlations, were 34% and 53% in Whites and Blacks, respectively. Thus, the maximal heritability, which includes both genetic and non-genetic sources of variation, is higher in Blacks than Whites, and explains a significant proportion of the total phenotypic variance. The results indicate that risk of coronary heart disease runs along family lines, and common environmental effects are important in explaining the observed familial resemblance.

A genome-wide association study conducted by the Wellcome Trust Case Control Consortium recently associated single nucleotide polymorphisms (SNPs) in the FTO (fatso/fat mass and obesity associated) gene with type 2 diabetes. These associations were shown to be mediated by obesity. Other research groups found similar results in Europeans and Hispanics but not African Americans. The mechanism by which FTO influences obesity and type 2 diabetes is currently unknown. The present study investigated the role of two FTO SNPs (rs17817449 and rs1421085) in adiposity, insulin sensitivity, and body weight regulation, including energy intake and expenditure.We genotyped 908 individuals from the Quebec City metropolitan area that participated in the Quebec Family Study, a long-term study of extensively phenotyped individuals designed to investigate factors involved in adiposity.We found significant associations for both SNPs with several obesity-related phenotypes. In particular, rs17817449 was associated with BMI (P = 0.0014), weight (P = 0.0059), and waist circumference (P = 0.0021) under an additive model. In addition, this FTO SNP influenced fasting insulin (P = 0.011), homeostasis model assessment of insulin resistance (P = 0.038), and an insulin sensitivity index derived from an oral glucose tolerance test (P = 0.0091). Associations were also found with resting metabolic rate (RMR) (P = 0.042) and plasma leptin levels (P = 0.036). Adjustment for BMI abolished the associations with insulin sensitivity, RMR, and plasma leptin levels.These results confirm that genetic variation at the FTO locus contributes to the etiology of obesity, insulin resistance, and increased plasma leptin levels.

No abstract is provided for this article.

Hypertriglyceridemia and apolipoprotein E4 genotype are associated with increased risk of premature atherosclerosis. The aim of the present study was to analyze the relation of cardiorespiratory fitness to serum triglycerides(S-TG) with regard to the carrier status of the ε4 allele in the apolipoprotein E gene in 140 men, aged 53 to 62 years. The data were derived from the 2,5 year run-in period of the DNASCO exercise intervention trial. Maximal oxygen uptake (˙VO2max) was measured using breath by breath respiratory gas analyses during maximal, symptom limited cycle ergometer exercise stress test. Serum triglycerides were assayed enzymatically and ApoE genotype with a PCR based method. During the follow-up, ˙VO2max increased from 2.4 (SD 0.4) to 2.5 (0.5) l/min, BMI from 26.7 (3.6) to 27.1(3.4), and S-TG from 1.28 (0.72) to 1.48 (0.80) mmol/l (p≤0.001 for all). Change (Δ) in ˙VO2max correlated inversely (r=-0.23, p=0.008) and ΔBMI positively (r=0.22, p=0.011) with ΔS-TG. The inverse association between Δ˙VO2max and ΔS-TG was independent(p=0.01 for trend) of ΔBMI and Δenergy intake, baseline S-TG level and Apo E genotype (carrier vs. non-carrier of the ε4 allele). The present results indicate that the relationship between cardiorespiratory fitness and serum triglycerides is not influenced by the presence or absence of the ε4 allele in the apolipoprotein E gene.

PURPOSE: To examine the molecular mechanisms underlying beneficial effects of regular exercise on lipid metabolism. METHODS: Circulating proteins (n = 4979), metabolites (n = 300), and lipids/lipoproteins were measured in 647 Black and White adults from the HERITAGE Family Study at baseline and after 20 weeks of supervised endurance training. The current analysis focused on 7 lipid/lipoprotein traits that significantly changed with training: HDL- cholesterol (HDL-C), triglycerides (TG), large TG-rich lipoprotein particles (LTRLP), large HDL particles (LHDLP), small LDL particles (SLDLP), and mean TRLP (TRLPz) and LDLP size (LDLPz). The relationship between exercise-induced fold changes in circulating molecules and changes in lipid traits was examined using sparse canonical correlation analysis, which tests the joint associations between two sets of variables by creating composite canonical variates. All variables were corrected for age, sex, race, BMI, baseline value, and family membership via linear mixed models. RESULTS: We identified 3 canonical variate pairs of exercise-induced changes in lipid traits and circulating molecules. Molecular variate 1 was positively correlated with changes in TG, LTRLP, SLDLP, and TRLPz (r = 0.29-0.57, p < 0.0001). Conversely, molecular variate 3 was negatively correlated with changes in TG, LTRLP, SLDLP, and TRLPz (r = -0.30 to -0.39, p < 0.0001), and positively correlated with changes in LDLPz (r = 0.38, p < 0.0001). Molecular variate 2 was negatively correlated with HDL-C (r = -0.46, p < 0.0001) and LHDLP (r = -0.22, p < 0.0001) changes with training. Molecular loadings on the respective variates were largely distinct (Table 1). CONCLUSIONS: We identified groups of circulating molecules whose changes in response to exercise training are associated with changes in the plasma lipid and lipoprotein profile and may provide insights into the mechanisms underlying exercise-induced changes in lipid metabolism.

This study determined the effects of endurance exercise training on the resting metabolic rate (RMR). It was hypothesized that the RMR would be increased posttraining, but that this increase would reflect the influence of the last exercise bout, not a chronic adaptation to exercise training. Seventy-four subjects (40 men and 37 women) aged 17–63 y participated in a 20-wk endurance training program. RMR and maximal oxygen uptake (VO2max) were each measured on 2 separate days both pre- and posttraining; the posttraining RMR measurements were taken 24 and 72 h after the last exercise bout. There were small but significant changes posttraining in relative body fat (−1.0%), fat mass (−0.6 kg), and fat-free mass (0.7 kg) and a 17.9% increase in VO2max. The RMR remained unchanged posttraining, both 24 and 72 h after the last exercise bout, even when the data were adjusted to account for the potential confounding effects of age, sex, body composition, and VO2max. In conclusion, 20 wk of endurance exercise training had no effect on the RMR even in the presence of small changes in body composition and a large increase in VO2max. Am J Clin Nutr 1998; 68:66–71

No abstract is provided for this article.

OBJECTIVE—To assess the effect of age on glucose metabolism by examining 1) glucose metabolism in young and middle-aged subjects when total or regional adiposity is taken into account and 2) in vitro glucose transport in adipose tissue explants from young and middle-aged women paired for total and abdominal adiposity. RESEARCH DESIGN AND METHODS—Study 1: body composition, subcutaneous abdominal and visceral adipose tissue areas, and fasting and oral glucose–stimulated glucose and insulin were measured in 84 young and 81 middle-aged men and in 110 young and 91 middle-aged women. Study 2: glucose uptake in subcutaneous abdominal and visceral adipose tissue explants were measured in eight young and eight middle-aged women. RESULTS—Study 1: young and middle-aged men showed similar subcutaneous abdominal tissue area, whereas fat mass and visceral adipose tissue were greater in middle-aged than in young men (P &amp;lt; 0.01). Fat mass and subcutaneous and visceral adipose tissue areas were greater in middle-aged as compared with young women (P &amp;lt; 0.01). Fasting plasma glucose and the glucose response to an oral glucose tolerance test were significantly higher in middle-aged than in young men and women (P &amp;lt; 0.001). Statistical control for visceral adipose tissue area eliminated the difference seen in glucose response in men and women. Study 2: glucose transport in subcutaneous and omental adipose tissue did not differ between young and middle-aged women. CONCLUSIONS—1) Visceral obesity, more than age per se, correlates with glucose intolerance in middle-aged subjects; 2) aging does not influence in vitro adipose tissue glucose uptake.

Several lines of evidence suggest that small dense LDL particles are associated with the risk of coronary heart disease. Heritability and segregation studies suggest that LDL particle size is characterized by a large genetic contribution and the presence of a putative major genetic locus. However, association and linkage analyses have thus far been inconclusive in identifying the underlying gene(s).An autosomal genome-wide scan for LDL peak particle diameter (LDL-PPD) was performed in the Québec Family Study. A total of 442 markers were genotyped, with an average intermarker distance of 7.2 cM. LDL-PPD was measured by gradient gel electrophoresis in 681 subjects from 236 nuclear families. Linkage was tested by both sib-pair-based and variance components-based linkage methods. The strongest evidence of linkage was found on chromosome 17q21.33 at marker D17S1301, with an LOD score of 6.76 by the variance-components method for the phenotype adjusted for age, body mass index, and triglyceride levels. Similar results were obtained with the sib-pair method (P<0.0001). Other chromosomal regions harboring markers with highly suggestive evidence of linkage (P< or =0.0023; LOD > or =1.75) include 1p31, 2q33.2, 4p15.2, 5q12.3, and 14q31. Several candidate genes are localized under the peak linkages, including apolipoprotein H on chromosome 17q, the apolipoprotein E receptor 2, and members of the phospholipase A2 family on chromosome 1p as well as HMG-CoA reductase on chromosome 5q.This genome-wide scan for LDL-PPD indicates the presence of a major quantitative trait locus located on chromosome 17q and others interesting loci influencing the phenotype.