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Biomedical subjects

H E Montgomery

Publications and source records attributed to H E Montgomery.

At least 19 recordsLinked to original sources
PubMed2004

The -344T>C promoter variant of the gene for aldosterone synthase (CYP11B2) is not associated with cardiovascular risk in a prospective study of UK healthy men.

INTRODUCTION: The tissue renin-angiotensin system is implicated in the pathogenesis of coronary artery disease (CAD). As locally synthesised aldosterone is a potential mediator of CAD, we have sought an association of the -344T>C variant of the aldosterone synthase (CYP11B2) gene with CAD events. METHODS: Subjects comprised of the Second Northwick Park Heart Study (NPHSII), a prospective study of unrelated, healthy middle-aged Caucasian males. CAD events were recorded in 2490 subjects, and defined as a sudden cardiac death, myocardial infarction or coronary artery revascularisation procedure. Mean follow-up was 10.8 years. Aldosterone synthase genotype was determined in 2490 subjects. Power calculation suggests that we have 80% power (at a significance level of 0.05) to detect a difference in hazard ratio (HR) between homozygote groups of 0.45. RESULTS: One hundred and eighty-seven CAD events were recorded in 2490 subjects. In the group overall, CAD events were independent of genotype with adjusted hazard ratios being 1.00 versus 1.25 versus 0.80 for TT versus TC versus CC genotypes, respectively, P = 0.07. Genotype interactions with smoking and blood pressure were sought. Whilst CAD events were independent of genotype amongst non-smokers, CC genotype in smokers was associated with a reduced risk HR 2.02 versus 2.28 versus 0.82 for TT versus TC versus CC genotypes, P = 0.05 (HR for TT + TC versus CC were 1.77 versus 0.67, P = 0.02). This apparent interaction remained after adjustment for conventional risk factors. No such interaction was found with blood pressure. CONCLUSIONS: Aldosterone synthase genotype is unrelated to overall CAD events risk. A possible interaction with smoking requires confirmation.

Analysis of Variance↗
PubMed2004

Cardiac effects of anabolic steroids.

Anabolic steroid abuse in athletes has been associated with a wide range of adverse conditions, including hypogonadism, testicular atrophy, impaired spermatogenesis, gynaecomastia, and psychiatric disturbance. But what effect does steroid abuse have on the cardiovascular system?

Anabolic Agents↗
PubMed2003

Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease.

OBJECTIVE: C-reactive protein (CRP) concentrations are predictive of cardiovascular disease, and levels are heritable, in part. We identified novel polymorphisms in the CRP gene and assessed their influence on CRP level. METHODS AND RESULTS: CRP was measured in 250 male army recruits before and after strenuous exercise and perioperatively in 193 coronary artery bypass graft (CABG) patients. Two novel polymorphisms were identified in the CRP gene, -717G>A in the promoter and +1444C>T in the 3'UTR. Among army recruits, CRP was higher in +1444TT homozygotes than +1444 C-allele carriers at baseline (1.04+/-0.38 versus 0.55+/-0.06, P=0.014) and at all time points after exercise (2.35+/-0.68 versus 1.07+/-0.12, 2.11+/-0.53 versus 0.88+/-0.09, and 1.77+/-0.44 versus 0.71+/-0.09, P=0.034, P=0.007, and P=0.013, at 2, 48, and 96 hours after exercise, respectively). In the CABG patients, mean CRP (mg/L) rose from 1.97+/-0.36 at baseline to 167.2+/-5.0 72 hours postoperatively. Genotype did not influence CRP at baseline; however, peak post-CABG CRP levels were higher in +1444TT homozygotes compared with +1444C-allele carriers (198+/-17 versus 164+/-5, P=0.03). CONCLUSIONS: The CRP gene +1444C>T variant influences basal and stimulated CRP level. These findings have implications both for the prediction and pathogenesis of coronary heart disease.

Acute-Phase Reaction↗
PubMed2003

Angiotensin-converting enzyme genotype and the ventilatory response to exertional hypoxia.

The "insertion" (I) rather than "deletion" (D) variant of the human angiotensin-converting enzyme (ACE) gene is associated with both lower tissue ACE activity and elite performance at high altitude. Three genotypes, II, ID and DD, are thus represented in the population. The authors examined whether an improved ventilatory response to hypoxic exercise may contribute to this effect. Subjects (n=60; 37 male, mean+/-SEM age 23.6+/-0.6 yrs, 14 II, 30 ID, 16 DD) underwent incremental cardiopulmonary exercise testing to establish maximal oxygen uptake and ventilatory threshold (VT). Four hours later, subjects exercised for 6 mins at 50% of the workload at VT. The protocol was repeated 15 mins later while breathing 12.5+/-0.5% oxygen in nitrogen. All subject characteristics were independent of genotype, as were data during normoxic exercise. However, the hypoxia-induced rise in minute ventilation was significantly greater among those of II genotype (39.6+/-4.1% versus 27.9+/-2.0% versus 28.4+/-2.2% for II versus ID versus DD, respectively). These data are supported by a significantly greater decrease in end tidal carbon dioxide (consistent with an increase in alveolar ventilation) among those homozygous for the I allele (II -18.7+/-1.3%, ID -15.7+/-0.4%, DD -15.1%+/-1.1). The ventilatory response to hypoxic exercise is influenced by angiotensin-converting enzyme genotype. Potential implications concern high altitude performance and the pathogenesis and management of hypoxic lung disease.

Adult↗
PubMed2002

Endurance enhancement related to the human angiotensin I-converting enzyme I-D polymorphism is not due to differences in the cardiorespiratory response to training.

Human physical performance is strongly influenced by genetic factors. We have previously reported that the I variant of the human angiotensin I-converting enzyme (ACE) gene is associated with greater endurance performance in mountaineers and Olympic runners and improved performance in army recruits. In this study we examined whether this effect is mediated by improvements in cardiovascular fitness with training in 58 army recruits homozygous for the insertion (I, ACE genotype II) or deletion (D, ACE genotype DD) allele. A submaximal and maximal exercise protocol was used to calculate both the heart rate/oxygen uptake (VO2) relationship and changes in maximal oxygen uptake (VO2max), respectively. There was no significant intergroup difference in VO2max at baseline (P=0.19) or after training (P=0.22). There was no difference between genotypes with training in the heart rate/VO2 elevation (P = 0.79 for the mean difference in mean adjusted heart rates). However, VO2 at all exercise intensities in the submaximal test was lower for all subjects after training and at 80 W the reduction in VO2 was greater for the II subjects compared to DD subjects [mean(SEM)] [1.6 (0.27) and 0.68 (0.27) ml kg(-1) min(-1), respectively; P = 0.02 for mean difference]. The I/D polymorphism may play a role in enhanced endurance performance but this is not mediated by differences in VO2max or the heart rate/VO2 relationship in response to training.

Exercise↗
PubMed2002

The effect of the Interleukin-6-174G > C promoter gene polymorphism on endothelial function in healthy volunteers.

AIMS: Atherosclerosis is a chronic inflammatory condition, manifest in its early stages by endothelial dysfunction. Interleukin-6 (IL6) plays a key role in driving this process through stimulation of acute phase protein synthesis. We have examined the effect of the IL6 gene -174G > C promoter polymorphism on endothelial function in a group of healthy subjects. METHODS: 248 adults aged 20-28 years participated. Polymerase chain reaction was performed for the -174G > C polymorphism. Brachial artery diameter was measured at rest and after forearm cuff occlusion by high-resolution ultrasound. Responses were represented as absolute flow mediated dilatation (FMDA). RESULTS: Overall there was a trend towards greater FMDA for genotype CC, P = 0.14. No effect was seen in women; however, in men, following multivariate analysis, there was a significant association between genotype and FMDA, P = 0.04. In addition, a significant detrimental effect of smoking on FMDA was only seen in males of genotype CC (P < 0.05) when compared to nonsmokers of the same genotype. CONCLUSION: IL6-174G > C promoter polymorphism influences endothelial function in healthy male subjects. The detrimental effect of smoking on endothelial function is most clearly seen in men of genotype -174 CC, suggesting a genotype-specific interaction with smoking.

Adult↗
PubMed2002

Impact of angiotensin converting enzyme inhibition on post-coronary artery bypass interleukin 6 release.

BACKGROUND: Angiotensin 1 converting enzyme (ACE) inhibitors reduce morbidity and mortality after coronary artery bypass graft surgery (CABG). This benefit may result from an anti-inflammatory action. OBJECTIVE: To examine the effect of ACE inhibition on interleukin 6 (IL-6) concentrations after CABG. PATIENTS AND METHODS: 161 patients undergoing elective first time CABG were recruited, of whom 41 (25%) were receiving ACE inhibitor treatment; 21 patients with confounding postoperative complications were excluded. After these exclusions there were 33 patients (24%) on ACE inhibitor treatment. Plasma IL-6 was measured preoperatively and again six hours after CABG. RESULTS: Baseline IL-6 concentrations (geometric mean (SEM)) were non-significantly lower among the patients receiving ACE inhibitors (3.7 (0.1) v 4.3 (0.1) pg/ml, p = 0.12). Overall, post-CABG IL-6 concentrations increased significantly (mean rise 177 (12) pg/ml, p < 0.0005). This response was blunted among ACE inhibitor treated patients. Median increases in IL-6 concentrations were 117 v 193 pg/ml, for treated v non-treated patients, respectively (Kruskal-Wallis, p = 0.02), with peak postoperative IL-6 concentrations lower among the subjects receiving ACE inhibitors than in untreated subjects (142 (19) v 196 (13) pg/ml, p = 0.02). The effect of ACE inhibitors remained significant after multivariate analysis (p = 0.018). CONCLUSIONS: ACE inhibitor treatment is associated with a reduction in IL-6 response to CABG. The data suggest that this class of drug may have a direct anti-inflammatory effect, which could explain some of its clinical benefit.

Acute-Phase Reaction↗
PubMed2002

Lipoprotein (a) does not participate in the early acute phase response to training or extreme physical activity and is unlikely to enhance any associated immediate cardiovascular risk.

AIMS: To investigate the proposal that lipoprotein (a) (Lp(a)) contributes to the acute phase response and thus possibly to the acute cardiac risks associated with major physical effort. METHODS/RESULTS: Fit, healthy, British army recruits were reviewed at the beginning and the end of a 10 week programme of basic training concluding with an intense 48 hour military exercise. Final recruit assessment was staggered over the last week of training, giving rise to six recruit groups, with determination of Lp(a), C reactive protein (CRP), fibrinogen, albumin, and total creatine kinase values from 12 hours to five days after the final exercise. A clear acute phase response was seen following the final exercise, marked by a significant increase in circulating concentrations of fibrinogen and a reduction of albumin, and a trend with non-significant increases in CRP. CONCLUSION: Lp(a) did not behave as an early marker of the acute response. Previous reports may have been confounded by concurrent disease in older subjects and by late sampling. Lp(a) determination for cardiovascular risk profiling is not confounded by associated physical effort. It is also unlikely that the acute risks of major physical effort are enhanced by any process involving Lp(a).

Acute-Phase Reaction↗
PubMed2002

The effect of fibrinogen genotype on fibrinogen levels after strenuous physical exercise.

We have examined the effect of two beta-fibrinogen gene promoter polymorphisms (-455G>A and -854G>A) on the fibrinogen response to severe exercise in a group of male army recruits undergoing basic training. Fibrinogen was measured pre-training and again serially after severe 48 h final military exercise (FME). Out of 884 subjects, 762 completed training of whom 250 were selected for post-FME study. Fibrinogen levels (g/l) were significantly elevated over baseline levels 2, 48 and 96 h after FME, representing increases of 15.7%, 3.4% and 7.6% (p <0.005; p = 0.05 and p <0.005 respectively), with higher levels in -455A allele carriers than genotype -455GG: 3.17+/-0.05 vs. 2.94+/-0.05 (p <0.001), 2.86+/-0.05 vs. 2.60+/-0.05 (p <0.0005) and 2.98+/-0.06 vs. 2.69+/-0.06 (p <0.0005) at 2, 48 and 96 h respectively. There was no effect of the -854G>A polymorphism on fibrinogen, even after taking into account beta-fibrinogen -455 genotype. Thus the fibrinogen -455G>A polymorphism influences fibrinogen levels following exercise. The effect of genotype might be clinically relevant at times of hyperfibrinogenaemia such as following an acute inflammatory response.

Acute-Phase Reaction↗
PubMed2001

Left ventricular hypertrophy with exercise and ACE gene insertion/deletion polymorphism: a randomized controlled trial with losartan.

BACKGROUND: Local cardiac renin-angiotensin systems may regulate left ventricular (LV) hypertrophic responses. The absence (deletion [D]) of a 287-bp marker in the ACE gene is associated with greater myocardial ACE levels and exercise-related LV growth than is its presence (insertion [I]), an effect potentially mediated through either increased activity of the cellular growth factor angiotensin II on the angiotensin type 1 (AT(1)) receptor or increased degradation of growth-inhibiting kinins. We sought to confirm ACE genotype-associated exertional LV growth and to clarify the role of the AT(1) receptor in this association. METHODS AND RESULTS: One hundred forty-one British Army recruits homozygous for the ACE gene (79 DD and 62 II) were randomized to receive losartan (25 mg/d, a subhypotensive dose inhibiting tissue AT(1) receptors) or placebo throughout a 10-week physical training program. LV mass, determined by cardiac magnetic resonance, increased with training (8.4 g, P:<0.0001 overall; 12.1 versus 4.8 g for DD versus II genotype in the placebo limb, P:=0.022). LV growth was similar in the losartan arm: 11.0 versus 3.7 g for DD versus II genotypes (P:=0.034). When indexed to lean body mass, LV growth in the II subjects was abolished, whereas it remained in the DD subjects (-0.022 versus 0.131 g/kg, respectively; P:=0.0009). CONCLUSIONS: ACE genotype dependence of exercise-induced LV hypertrophy is confirmed. Additionally, LV growth in DD (unlike II) subjects is in excess of the increase in lean body mass. These effects are not influenced by AT(1) receptor antagonism with the use of losartan (25 mg/d). The 2.4-fold greater LV growth in DD men may be due to the effects of angiotensin II on other receptors (eg, angiotensin type 4) or lower degradation of growth-inhibitory kinins.

Adult↗
PubMed2001

The angiotensin converting enzyme I/D polymorphism in Russian athletes.

The deletion (D) allele of the human ACE gene is associated with higher ACE activity than the insertion (I) allele. There is controversy as to whether the ACE genotype may be associated with elite athletic status; recent studies have identified no significant associations amongst those drawn from mixed sporting disciplines. However, such lack of association may reflect the mixed nature of such cohorts, given that an excess frequency of the I allele has been reported amongst elite endurance athletes, and an excess of the D allele amongst those engaged in more power-orientated sports. We examined this hypothesis by determining ACE I/D allele frequency amongst 217 Russian athletes (swimmers, skiers, triathletes and track-and-field participants) prospectively stratified by performance ('outstanding' or 'average'), and the duration of their event (SDA (<1 min), MDA (1 to 20 min), and LDA (>20 min): short, middle and long distance athletes respectively). ACE genotype and allele frequencies were compared to 449 controls. ACE genotype frequency amongst the whole cohort, or the outstanding athletes alone, was no different to that amongst sedentary controls. However, there was an excess of the D allele (frequency 0.72, P=0.001) amongst the outstanding SDA group, and an excess of the I allele (frequency 0.63, P=0.032) amongst the outstanding MDA group. These findings were replicated in the outstanding swimmers, with track and field SDA similarly demonstrating an excess of the D allele (P=0.01). There was no association found between the outstanding LDA and ACE genotype (P=0.27). These data not only confirm an excess of the D allele in elite SDA, and I allele in elite MDA, but also offer an explanation as to why any such association may be hard to detect amongst a heterogeneous cohort of mixed athletic ability and discipline.

Adult↗
PubMed2001

Angiotensin-converting enzyme and genetics at high altitude.

As part of the renin-angiotensin system (RAS), angiotensin-converting enzyme (ACE) plays a key role in circulatory homeostasis. ACE degrades vasodilator kinins and generates angiotensin II. A polymorphism in intron 16 of the human ACE gene has been identified in which the presence (insertion, I allele) rather than the absence (deletion, D allele) of a 287 bp fragment is associated with lower serum and tissue ACE activity. The I allele has been associated with some aspects of endurance performance, being found with excess frequency in elite distance runners, rowers, and other elite athletes. Mountaineers also demonstrate an allele skew with a significant excess of the I allele and II genotype in elite, male, British mountaineers who have ascended beyond 7000 m without the use of supplemental oxygen. This review evaluates the evidence for and against an association of the I allele with human endurance, and performance at high altitude. We conclude that the I allele does confer an advantage, most likely mediated via improved muscle efficiency with secondary benefits in terms of conservation of non-fat mass.

Alleles↗
PubMed2001

Effect of a COL1A1 Sp1 binding site polymorphism on arterial pulse wave velocity: an index of compliance.

-Reduced arterial compliance precedes changes in blood pressure, which may be mediated through alterations in vessel wall matrix composition. We investigated the effect of the collagen type I-alpha1 gene (COL1A1) +2046G>T polymorphism on arterial compliance in healthy individuals. We recruited 489 subjects (251 men and 238 women; mean age, 22.6+/-1.6 years). COL1A1 genotypes were determined using polymerase chain reaction and digestion by restriction enzyme Bal1. Arterial pulse wave velocities were measured in 3 segments, aortoiliac (PWVA), aortoradial (PWVB), and aorto-dorsalis-pedis (PWVF), as an index of compliance using a noninvasive optical method. Data were available for 455 subjects. The sample was in Hardy-Weinberg equilibrium with genotype distributions and allele frequencies that were not significantly different from those reported previously. The T allele frequency was 0.22 (95% confidence interval, 0.19 to 0.24). Two hundred eighty-three (62.2%) subjects were genotype GG, 148 (35.5%) subjects were genotype GT, and 24 (5.3%) subjects were genotype TT. A comparison of GG homozygotes with GT and TT individuals demonstrated a statistically significant association with arterial compliance: PWVF 4.92+/-0.03 versus 5.06+/-0.05 m/s (ANOVA, P=0.009), PWVB 4.20+/-0.03 versus 4.32+/-0.04 m/s (ANOVA, P=0.036), and PWVA 3.07+/-0.03 versus 3.15+/-0.03 m/s (ANOVA, P=0.045). The effects of genotype were independent of age, gender, smoking, mean arterial pressure, body mass index, family history of hypertension, and activity scores. We report an association between the COL1A1 gene polymorphism and arterial compliance. Alterations in arterial collagen type 1A deposition may play a role in the regulation of arterial compliance.

Adult↗
PubMed2001

Interleukin-6 gene -174g>c and -572g>c promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery.

Interleukin-6 (IL-6) synthesized in response to diverse stimuli may play an important role in bridging the inflammatory and atherosclerotic processes. The acute-phase response after coronary artery bypass graft surgery (CABG) is associated with the induction and release of cytokines, such as IL-6. We have examined the effect of common polymorphisms in the IL-6 gene promoter (-174G>C, -572G>C, and -597G>A) on IL-6 levels after elective CABG. DNA extracted from the peripheral blood of 127 patients was amplified by polymerase chain reaction. IL-6 genotypes were resolved by gel electrophoresis after restriction enzyme digestion. Serum IL-6 was measured before surgery and in serial samples at 6, 24, 48, and 72 hours after CABG. Genotype distribution was as expected for a population in Hardy-Weinberg equilibrium for all polymorphisms. Rare allele frequencies (+/-95% CIs) were similar to those reported previously: -597A 0.36 (0.30 to 0.42), -572C 0.07 (0.04 to 0.10), and -174C 0.37 (0.31 to 0.43). The -174G>C and -597G>A genotypes were in strong allelic association (Delta=0.97, P<0.001). Baseline IL-6 levels did not significantly differ between patients with different genotypes for any polymorphism. However, 6 hours after CABG, peak IL-6 levels were significantly higher (P=0.03) in carriers of the -572C allele than in those of the -572GG genotype (355+/-67 versus 216+/-13 pg/mL, respectively) and in those with genotype -174CC compared with -174G allele carriers (287+/-31 versus 227+/-15 pg/mL, respectively; P=0.04). These effects remained statistically significant after adjusting for possible confounders, including age, sex, smoking, duration of cardiopulmonary bypass, aortic cross-clamp time, and total duration of surgery. These data demonstrate that IL-6 promoter polymorphisms influence peak IL-6 production after CABG, suggesting that these polymorphisms, which are functional in vitro, are also functional in vivo, suggesting a genetic influence on IL-6 levels after acute severe injury.

Coronary Artery Bypass↗