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Biomedical subjects

W S Hillis

Publications and source records attributed to W S Hillis.

At least 19 recordsLinked to original sources
PubMed2005

Increased titres of anti-human heat shock protein 60 predict an adverse one year prognosis in patients with acute cardiac chest pain.

OBJECTIVE: To assess whether antibodies to human heat shock protein 60 (anti-huhsp60) or to mycobacterial heat shock protein 65 (anti-mhsp65) predict an adverse one year prognosis in patients admitted with acute cardiac chest pain. DESIGN: Prospective observational study. SETTING: Teaching hospital. PATIENTS: 588 consecutive emergency admissions of patients with acute chest pain of suspected cardiac origin. MAIN OUTCOME MEASURES: Anti-huhsp60 and anti-mhsp65 titres were assayed on samples drawn on the morning after admission. The end points after discharge were coronary heart disease death, non-fatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, angiogram, or readmission with further cardiac ischaemic chest pain. RESULTS: During follow up after discharge (mean of 304 days, range 1-788 days), 277 patients had at least one of the study outcomes. Patients with increased titres of anti-huhsp60 had an adverse prognosis (hazard ratio 1.56 (95% confidence interval 1.09 to 2.23) comparing highest versus lowest quartiles, p = 0.015). Anti-mhsp65 titres were not predictive. CONCLUSIONS: Patients admitted with acute cardiac chest pain and increased titres of anti-huhsp60 had an adverse one year prognosis.

Acute Disease↗
PubMed2004

Glucocorticoids contribute to the heritability of leptin in Scottish adult female twins.

OBJECTIVE: The precise interactions between glucocorticoids and leptin are complex and poorly understood. The aim of the study was to investigate whether the glucocorticoid/leptin interaction is influenced by shared environmental or genetic factors. DESIGN: We investigated the heritability of body mass index (BMI), circulating leptin and urinary glucocorticoid metabolites [tetrahydrocortisol (THF), alloTHF and tetrahydrocortisone (THE)] in 54 monozygotic (MZ) and 39 dizygotic (DZ) female twins. Analysis was performed using a structural equation modelling package Mx, developed by Neale. RESULTS: Leptin and BMI showed substantial heritability (68.3% and 71.3%, respectively). Bivariate analysis indicated that the genetic determinants of BMI and leptin are partly shared. Total cortisol metabolites (THF + alloTHF + THE), the (THE + alloTHF)/THE ratio [a marker of 11beta-hydroxysteroid dehydrogenase (11HSD) activity] and the alloTHF/THF ratio (marker for 5alpha-reductase activity) followed an environmental pattern. The heritability of leptin was significantly lowered to 63.8% (P = 0.012) when values were corrected for the influence of total cortisol metabolites but unaffected by markers of 11HSD and 5alpha-reductase activity. CONCLUSIONS: We confirm that the genetic influence on both BMI and the circulating leptin concentration is substantial and show that these genetic determinants are highly correlated. These genetic factors, which are more likely to be dominant than additive, can be modestly but significantly modified by urinary total cortisol metabolites implying an adrenal influence.

Adult↗
PubMed2003

The determination of carotid intima medial thickness in adults--a population-based twin study.

INTRODUCTION: Although cardiovascular events are known to cluster in families it is unclear the extent to which atherosclerosis per se is genetically determined. The aim of this study was to assess the heritability of carotid intima media thickness (IMT) measurements, a surrogate marker of early atherosclerosis, using a population-based twin study methodology. METHODS: B-mode carotid artery ultrasound images were acquired on 264 twin subjects (142 monozygotic (MZ); mean age 54.3 years and 122 dizygotic (DZ); mean age 51.7 years). An estimate of genetic determination, heritability, was calculated for the IMT parameters before and after correction for confounding variables. RESULTS: An increased carotid IMT was associated with known cardiovascular risk factors (total cholesterol r=0.24, P<0.001 and systolic blood pressure r=0.42, P<0.001) and with a history of coronary events (0.79+/-0.12 vs. 0.72+/-0.14, P=0.01). Carotid IMT measurements demonstrated a familial influence (intra-class correlation of 0.54 for MZ vs. 0.39 for DZ) but no specific genetic determination (heritability estimate 0.31, P=0.15). CONCLUSION: Within a normal population carotid IMT is under a familial, but not genetic influence. The mechanism of genetic control over cardiovascular events may not be mediated through atherosclerotic load as measured by IMT.

Adult↗
PubMed2003

The genetic determination of left ventricular mass in healthy adults.

AIMS: The extent to which left ventricular (LV) mass, an independent cardiovascular risk factor, is determined by genetic factors is unclear. The aim of this study was to assess the heritability of LV mass and its association with three potential candidate genes. METHODS: A population-based adult twin study model was utilized. Echocardiographic assessment of LV mass was performed in 110 twin pairs (mean age 55.9+/-10.9 years). An estimate of genetic determination, heritability, was calculated for the main echocardiographic parameters. The cohort were genotyped for the G-protein beta-3, aldosterone synthase, and beta-1 adrenoceptor genes. RESULTS: The intra-class correlation coefficients for LV mass were 0.69 for monozygotic (r-MZ) twins and 0.32 for dizygotic (r-DZ) twins, P=0.008 (heritability estimate of 0.69). This pattern persisted following correction for known confounding factors. Within-pair differences in the monozygotic, discordant and concordant dizygotic twins showed no differences for the three genes with respect to left ventricular wall thickness or mass. There was a non-significant trend towards a relationship between LV mass and the beta-1 adrenoceptor genotype. CONCLUSION: Within a normal population left ventricular mass has a significant genetic determination. Further investigation of potential candidate genes is required.

Cohort Studies↗
PubMed2001

An influence of variation in the aldosterone synthase gene (CYP11B2) on corticosteroid responses to ACTH in normal human subjects.

OBJECTIVE: Previous evidence suggests that the efficiency of 11beta-hydroxylase is at least partly heritable and also that it may be mildly impaired in essential hypertension. In both cases, assessment of activity was based on the response of 11-deoxycorticosterone (DOC) and 11-deoxycortisol to ACTH. The gene (CYP11B1) coding for this enzyme is highly homologous with and lies a relatively short distance downstream from the gene coding for aldosterone synthase (CYP11B2) on chromosome 8. Two polymorphisms of CYP11B2 have been described. The first involves a change of -344C to T in a putative steroidogenic factor-1 (SF-1) binding site and the other, the intron conversion, an exchange of intron 2 for that of CYP11B1. These polymorphisms are in linkage dysequilibrium. Their effects on 11beta-hydroxylation were studied. METHODS AND RESULTS: Normal subjects (n = 135) were genotyped and those homozygous for either or both the polymorphisms were given ACTH (250 microg, i.v.). Plasma was sampled before and 30 minutes after administration. Basal concentrations of DOC, corticosterone, 11-deoxycortisol and cortisol and responses of corticosterone and cortisol to ACTH were not affected by genotype. However, the responses of DOC (P = 0.002 and P = 0.001, respectively) and 11-deoxycortisol (P = 0.025 and P = 0.002, respectively) were significantly greater in subjects homozygous for SF-1 T and/or intron conversion than in those homozygous for SF-1 C and/or normal intron. CONCLUSIONS: These results indicate different 11beta-hydroxylase efficiencies. Thus, variation in CYP11B2 appears to affect the product of CYP11B1. The mechanism is unclear. The close proximity of the two genes may lead to competition for transcription factors or specific differences in intron 2 may affect transcription. Alternatively, the polymorphisms may be acting as markers for adjacent functional genetic variations.

Adrenocorticotropic Hormone↗
PubMed2000

Exercise prescription in adults with congenital heart disease: a long way to go.

OBJECTIVE: To determine if appropriate advice had been given to adults with congenital heart disease regarding safe and effective exercise, and to assess pre-existing misconceptions of the potential benefits and dangers of exercise. DESIGN: An anonymous self assessment questionnaire. SETTING: A tertiary referral clinic. PATIENTS: 99 adults (57 men, 42 women) with congenital heart disease, mean age 25.6 years. MAIN OUTCOME MEASURES: The extent and nature of exercise advice given over previous years; a measure of current activity level compared with the American Heart Association recommendations; and an assessment of exercise limiting symptoms and a description of barriers to further exercise. RESULTS: 44% of the cohort assumed all exercise was safe despite their cardiac disease. A health care professional had only raised the issue of specific exercise advice in 28 cases. Of those given instruction it was more common to receive prohibitive advice (30%) than to be encouraged to take more exercise (19%). Despite this 61% were involved in some form of at least light exercise. The most prevalent barriers to exercise were current symptoms (32.3%), lack of interest in exercise (24.2%), and health fears (16.1%). CONCLUSIONS: The education of adults with congenital heart disease regarding exercise and its potential benefits and limitations is suboptimal even in a specialist clinic.

Adolescent↗
PubMed2000

Sumatriptan reduces exercise capacity in healthy males: a peripheral effect of 5-hydroxytryptamine agonism?

5-Hydroxytryptamine (5-HT; serotonin) has been implicated in the perception of exercise-induced fatigue. Sumatriptan is a selective 5-HT(1B/D) receptor agonist which does not cross the blood-brain barrier. The aim of the present study was to determine the effect of sumatriptan on exercise capacity. Ten healthy male subjects (mean age 28.4+/-10.8 years) performed a maximal treadmill exercise test according to the Bruce protocol with expired gas analysis on two occasions. Either 6 mg of sumatriptan or placebo was administered subcutaneously in a randomized, double-blind, placebo-controlled, cross-over design. Exercise time was greater after placebo compared with sumatriptan [914 and 879 s respectively; 95% confidence interval (CI) of difference 12.1 s, 59.1 s; P = 0.008]. There was no significant effect on peak oxygen consumption (placebo, 50.6+/-6.3 ml.min(-1).kg(-1); sumatriptan, 51.7+/-7.6 ml.min(-1).kg(-1)). Sumatriptan administration resulted in decreases in both heart rate (sumatriptan, 188+/-14 beats/min, placebo, 196+/-12 beats/min; 95% CI of difference 12.6, 2.6; P = 0.008) and respiratory exchange ratio (sumatriptan, 1.23+/-0.06; placebo, 1.26+/-0.07; 95% CI of difference 0.05, 0.01; P = 0.01) at peak exercise. There were no significant differences in blood pressure, heart rate or submaximal oxygen consumption between sumatriptan and placebo treatments at any stage of exercise. Thus sumatriptan reduces maximal exercise capacity in normal males. The failure to demonstrate any haemodynamic or cardiorespiratory effect suggests that sumatriptan enhances perception of fatigue by a peripheral mechanism affecting 5-HT modulation.

Adult↗
PubMed1999

The prevalence of left ventricular hypertrophy in elite professional footballers.

BACKGROUND: We evaluated the prevalence of left ventricular hypertrophy in elite footballers compared with sedentary controls. A total of 141 elite male professional footballers and 32 healthy sedentary controls were studied. Echocardiographic and demographic variables were compared between groups by unpaired t-test. RESULTS: The prevalence of left ventricular hypertrophy with maximal wall thickness values out with the normal range (>12 mm) was noted. Footballers were significantly younger than controls (20.9 vs. 24.3 years, P<0.005: 95% CI (-5.2, -1.73)) but there were no significant differences in height, weight or body surface area between the groups. Each of inter-ventricular septum (10.4 vs. 9.1 mm, P<0.0001; 95% CI (0.88, 1.72)), posterior wall (9.2 vs. 8.5 mm, P<0.01; 95% CI (0.22, 1.21)), left ventricular cavity (systolic and diastolic) (34.5 vs. 28.4 mm, P<0.0001; 95% CI (4.31, 7.76) in systole; 50.1 vs. 48.2 mm, P<0.05; 95% CI (0.15, 3.74) in diastole), aortic root size (29.1 vs. 27.8 mm, P<0.05; 95% CI (0.03,2.49)) and left ventricular mass index (112 vs. 89 g/m2, P<0.0001; 95% CI (14.4, 32.1)) were significantly greater in footballers than in controls. Absolute left ventricular wall thickness >12 mm was present in 17 footballers (12%) (range 13-15 mm) and in no controls. CONCLUSIONS: Elite professional footballers have increased cardiac dimensions compared with healthy controls. The prevalence of absolute wall thicknesses out with the normal range is relatively high.

Adult↗
PubMed1999

The ergoreflex in patients with chronic stable heart failure.

BACKGROUND: The main symptoms of chronic heart failure are breathlessness and fatigue on exertion. Abnormalities of skeletal muscle cause early metabolic distress on exercise, with resultant ergoreceptor stimulation causing increased ventilation. The aim of this study is to determine the extent of enhanced ergoreflex activity in chronic heart failure in the leg. METHODS: Ten patients with chronic stable heart failure (New York Heart Association class II-III) and nine healthy age-matched controls performed two bouts of ankle dorsiflexion. On one occasion a cuff was inflated round the thigh to suprasystolic levels for 3 min immediately post-exercise: regional circulatory occlusion. Recovery with regional circulatory occlusion was compared to recovery without it. RESULTS: Systolic and diastolic blood pressure and ventilation were higher after 3 min post-exercise regional circulatory occlusion than after 3 min control recovery in the patient group (184+/-13.3 vs. 165+/-12.5 mm Hg, P<0.01, 94+/-4.7 vs. 86+/-3.5 mm Hg, P<0.05, 9.8+/-0.7 vs. 7.9+/-0.36 l/min, P<0.01). Systolic and diastolic blood pressure were higher after post-exercise regional circulatory occlusion than after control recovery in the control group (149+/-7.8 vs. 138+/-5.7 mm Hg, P<0.01, 86+/-3.3 vs. 82+/-2.5 mm Hg, P<0.05), but this was not the case for ventilation (8.1+/-0.62 vs. 8.1+/-0.62 l/min). Ergoreflex activity was greater in the patient group than in the controls for systolic blood pressure (91 vs. 48%, P<0.001), diastolic blood pressure (86 vs. 49%, P<0.05) and ventilation (39 vs. -1%, P<0.05). CONCLUSIONS: Ergoreceptor stimulation contributes to an increased ventilation and blood pressure response to leg exercise in chronic heart failure patients, perhaps contributing to dyspnoea and exercise limitation. Peripheral factors such as skeletal muscle abnormalities contribute to the pathogenesis of symptoms in chronic heart failure.

Blood Pressure↗
PubMed1999

Management strategies in unstable coronary artery disease--current problems and future directions. The UCAD Council.

Unstable coronary artery disease continues to pose a major challenge to clinicians. The advent of new therapies, such as percutaneous transluminal coronary angioplasty, low-molecular-weight heparins, and glycoprotein IIb/IIIa inhibitors, provides new management options for this indication but also raises new questions with regard to optimal management. Prospective randomized trials with well-defined, long-term outcome measures and a means of identifying which patients will derive most benefit from each treatment, together with a means of rapid and clear dissemination of study results and implications, are required in order to advance the management of unstable coronary artery disease.

Angina, Unstable↗
PubMed1999

Hemodynamic and coronary effects of intravenous eletriptan, a 5HT1B/1D-receptor agonist.

OBJECTIVE: To investigate the systemic, pulmonary, and coronary artery effects of eletriptan, a new 5HT1B/1D-agonist in patients undergoing cardiac catheterization. METHODS: Ten patients (two men and eight women) without significant obstructive coronary artery disease were administered 3.33 microg/kg/min intravenous eletriptan after they were given a placebo infusion of 0.9% saline solution. Serial measurements of right heart and systemic pressures were taken at 5-minute intervals during placebo infusion, eletriptan infusion, and a 30-minute postinfusion period. Cardiac output by the thermodilution technique and coronary angiography were performed every 15 minutes. Quantitative coronary angiography was carried out to measure coronary artery dimensions. RESULTS: A small but statistically significant increase in occluded wedge pressure (7.4 versus 8.8 mm Hg; 95% confidence interval [CI], 0.74, 2.51; P < .01), right atrial pressure (5.3 versus 6.1 mm Hg; 95% CI, 0.0, 1.4; P < .05), and mean pulmonary artery pressure (13.2 versus 14.6 mm Hg; 95% CI, 0.0, 2.7; P = .05) was observed during the eletriptan infusion compared with placebo. A statistically significant increase in systemic vascular resistance (1256 versus 1519 dyne/sec/cm(-5); 95% CI, 126, 398; P < .01) and pulmonary vascular resistance (76.4 versus 100.8 dyne/sec/cm(-5); 95% CI, 1.9, 46.9; P < .05) was observed in the period after drug infusion. No overall effect was observed on the coronary arteries, although a segmental right coronary artery constriction developed in one patient, possibly as a result of catheter-induced spasm. CONCLUSIONS: Eletriptan, a 5HT1B/1D-agonist effective in migraine, causes no significant coronary artery constriction in patients without significant obstructive coronary artery disease. This finding may reflect a relative selectivity for the 5HT1D-receptor subtype.

Adult↗
PubMed1999

Changes in systolic time intervals-a non-invasive marker for the haemodynamic effects of sumatriptan.

AIMS: This study assessed the use of systolic time intervals (STI) as a potential non-invasive marker of the haemodynamic effects of sumatriptan, a 5HT1 receptor agonist. METHODS: Twenty-six patients undergoing diagnostic cardiac catheterization participated. STIs were derived from haemodynamic pressure tracings at baseline, following placebo injection and following either subcutaneous (n=18) or intravenous injection (n=8) of sumatriptan. RESULTS: Sumatriptan (i.v. or s.c.) was associated with significant increases in mean arterial pressure (95% C.I. 9,14mmHg, P=0.0001), total electromechanical systole (95% C.I.8,36ms, P<0.0001), pre-ejection period (95%C.I. 8,21ms, P=0.0001) and left ventricular ejection time (95% C.I. 2,12ms, P=0.004). Conclusion STI responses were consistent with sumatriptan-induced changes in afterload. In summary, the measurement of STIs is a potential non-invasive method of investigating the influence of serotonergic compounds on the cardiovascular system.

Blood Pressure↗
PubMed1999

The haemodynamic effect of the 5HT1 agonist BMS-180048: a class effect of triptans?

AIMS: To investigate the effects of an intravenous infusion of BMS-180048, a novel 5HT1-like agonist, on the systemic, pulmonary and coronary circulations in patients undergoing diagnostic cardiac catheterisation. METHODS: Ten patients (mean age 55 years (range 41-65)) were studied during diagnostic cardiac catheterisation. The haemodynamic response to an intravenous (i.v.) infusion for 30 min of BMS-180048 (0.56 mg kg(-1) h(-1) for 10 min and 0.39 mg kg(-1) h(-1) for 20 min) was assessed via a 7F Swan Ganz catheter and thermodilution cardiac output system. Quantitative coronary angiography was performed at 10 min intervals. RESULTS: BMS-180048 caused a significant increase in systemic arterial systolic blood pressure (rise of 32.5 mmHg, 95% CI 24,44.5) P=0.009), pulmonary artery systolic (12.2 mmHg, 95% CI 6.8,18.5; P=0.009) and diastolic pressures (8.5 mmHg, 95% CI 5.0,13.8; P=0.009), right atrial pressure (4 mmHg, 95% CI 1.5,5.2; P=0.013) and pulmonary capillary wedge pressure (9.5 mmHg 95% CI 5.2,14.0; P=0.09). There was no significant change in cardiac output (0.1 l min(-1), 95% CI -0.17,0.57, P>0.05). Mean coronary artery diameter in the proximal coronary segments decreased by 0.73 mm (95% CI -1.22,-0.15; P=0.03) at 35 min. The corresponding reduction in middle segments was 0.26 mm (95% CI -0.395,-0.08; P=0.02). There was a non-significant trend to constriction in the most distal segments of 0.28 mm (95% CI -0.68,0.015); P=0.06). One patient experienced chest pain with ECG changes suggestive of ischaemia. CONCLUSIONS: BMS-180048 displayed a cardiovascular profile similar to that previously reported for sumatriptan. These changes appear to reflect a class effect of these agents.

Adult↗
PubMed1999

Humoral and cellular immune responses up to 7.5 years after administration of streptokinase for acute myocardial infarction.

AIMS: Administration of streptokinase results in an immunological response which may lead to increased risk of anaphylactic reaction or reduced thrombolytic efficacy on repeat administration. For these reasons current recommendations suggest that streptokinase should not be given up to 1 year after first administration. We sought to define the profile of both the circulating antibody and T-cell response to streptokinase in patients who had received streptokinase up to 7.5 years previously following acute myocardial infarction. METHODS: Neutralizing anti-streptokinase antibody and total anti-streptokinase IgG were measured in 219 patients who had suffered acute myocardial infarction between 12 and 90 months previously and had received streptokinase. T-cell response to streptokinase was assessed by in-vitro proliferation of peripheral blood mononuclear cells (n=234). Data on all parameters were available in 184 patients. Controls (n=22) had suffered acute myocardial infarction between 73 and 84 months previously but had not received thrombolytic therapy. RESULTS: Compared to controls, anti-streptokinase antibodies were elevated at all time periods from 12 to 90 months after streptokinase treatment. Total anti-streptokinase titres showed the expected correlation with neutralizing anti-streptokinase antibodies (P<0.0001). Peripheral blood mononuclear cells showed a vigorous in-vitro proliferative response to streptokinase 6 days after treatment (P=0.05 vs pre-treatment), but this was not detectable at 6 weeks or subsequently. CONCLUSION: There is as yet no evidence of a time limit beyond which administration of streptokinase on a second occasion can be regarded as safe and likely to be effective. Measurement of neutralizing anti-streptokinase or total anti-streptokinase IgG titre appear to provide equivalent information regarding the antibody status of a population. Further studies are required regarding the apparent lack of peripheral blood mononuclear cells responsiveness in patients previously exposed to streptokinase.

Adult↗
PubMed1999

Effects of subcutaneous naratriptan on systemic and pulmonary haemodynamics and coronary artery diameter in humans.

Naratriptan, an effective antimigraine agent, is a selective 5-hydroxytryptamine (5-HT1 )-receptor agonist with a pharmacologic profile similar to that of sumatriptan. The object of this study was to assess the haemodynamic effects of naratriptan in a clinical model previously applied to sumatriptan. Cardiac haemodynamics and coronary artery diameter were measured at baseline and after subcutaneous injections of placebo and naratriptan (1.5 mg, s.c.) in 10 patients undergoing diagnostic cardiac catheterisation. No statistically significant change in mean coronary artery diameter was observed after naratriptan [95% confidence interval (CI), -0.27-0.11 mm: p = 0.37]. Naratriptan injection was associated with statistically significant increases in systolic arterial pressure (95% CI, 7.6-22.0 mm Hg; p = 0.0015), total systemic vascular resistance (95% CI, 74-253 dyn/s/cc; p = 0.003), pulmonary artery systolic pressure (95% CI, 2.0-6.9 mm Hg; p = 0.003), pulmonary vascular resistance (95% CI, 3-34 dyn/s/cc; p = 0.025), and pulmonary artery wedge pressure (95% CI, 1.9-2.4 mm Hg; p = 0.009). Naratriptan, a selective 5-HT1-receptor agonist, caused a vasopressor response in the systemic and pulmonary arterial circulations but was not associated with coronary artery vasoconstriction.

Adult↗