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Biomedical subjects

A D Struthers

Publications and source records attributed to A D Struthers.

At least 37 records · Page 2Linked to original sources
PubMed2004

In vitro generation and stability of the lactokinin beta-lactoglobulin fragment (142-148).

The objectives of this study were to investigate the generation of beta-lactoglobulin fragment (142-148) (beta-LG f(142-148) during the hydrolysis of whey proteins, and the in vitro stability of this fragment upon incubation with gastrointestinal and serum proteinases and peptidases. An enzyme immunoassay (EIA) protocol was developed for the quantification of beta-LG f(142-148) in whey protein hydrolysates and in human blood serum. The minimum detection limit was 3 ng/mL. The level of the peptide in whey protein hydrolysates was influenced by the degree of hydrolysis (DH). As expected, highest levels of this peptide were found in hydrolysates generated with trypsin. Sequential incubation of hydrolysates at different DH values with pepsin and Corolase PP, to simulate gastrointestinal digestion, generally resulted in the degradation of beta-LG f(142-148) as determined by EIA. Reversed-phase HPLC and angiotensin-I-converting enzyme (ACE) activity assays demonstrated that synthetic beta-LG f(142-148) was rapidly degraded upon incubation with human serum. Furthermore, beta-LG f(142-148) could not be detected by EIA in the sera of 2 human volunteers following its oral ingestion or in sera from these volunteers subsequently spiked with beta-LG f(142-148). These in vitro results indicate that beta-LG f(142-148) is probably not sufficiently stable to gastrointestinal and serum proteinases and peptidases to act as an hypotensive agent in humans following oral ingestion. The in vitro methodology described herein has general application in evaluating the hypotensive potential of food protein-derived ACE inhibitory peptides.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Does a prolonged QT peak identify left ventricular hypertrophy in hypertension?

BACKGROUND: Left ventricular hypertrophy is a powerful predictor of death. Hypertensive subjects with left ventricular hypertrophy can have increased QT (end) dispersion, which is associated with cardiac death. Despite its prognostic value, QT (end) dispersion is not widely used. QTp (i.e. start of QRS to peak of T wave) is easier to measure. Therefore, we tested the hypothesis that long QT peak was associated with left ventricular hypertrophy and assessed its cost-effectiveness at diagnosing left ventricular hypertrophy. METHODS: ECGs and echocardiograms were recorded in 47 hypertensive patients. The onset of the QRS complex and peak of T wave of lead I of each subject's ECGs were digitised by one observer blind to results of the echocardiogram. Receiver-operator characteristics curves were plotted to determine the sensitivity and specificity of different cut-off values of QT peak at predicting left ventricular hypertrophy (defined as left ventricular mass index> or =134 g/m2 in male, > or =110 g/m2 in female). RESULTS: The heart-rate corrected QT peak of lead I correlated with left ventricular mass index (r=0.45, P=0.002). If all patients with a prolonged QT peak (> or =300 ms) had an echocardiogram, then no cases of left ventricular hypertrophy would be missed (100% sensitive). This novel ECG criterion not only had better positive and negative predictive values than the Sokolow-Lyon voltage criteria, but also resulted in more cost-effective resource use (< pound 370 vs. pound 1750/case of left ventricular hypertrophy detected). CONCLUSION: If the results of this small pilot study are confirmed in larger studies, then measuring QT peak of lead I may become a cost-effective way of identifying hypertensives who are likely to have echocardiographic left ventricular hypertrophy.

Adult↗
PubMed2003

QTc dispersion as a marker for medical complications after severe subarachnoid haemorrhage.

BACKGROUND AND OBJECTIVE: Morbidity from subarachnoid haemorrhage is common and results from complications including myocardial dysfunction and neurogenic pulmonary oedema causing hypotension and hypoxia--both major causes of secondary brain injury. Predicting patients at risk of developing these complications may facilitate early intervention. METHODS: Using QTc dispersion to assess repolarization inhomogeneity, patients who had suffered severe acute subarachnoid haemorrhage were studied in an intensive care unit. Electrocardiograms were recorded within 24 h of ictus. Subsequent development of myocardial dysfunction was defined as a requirement for inotropes, and neurogenic pulmonary oedema as a PaO2 (kPa)/FiO2 ratio < 40. Together they constituted cardiorespiratory compromise. RESULTS: Twenty-seven patients were recruited. QTc dispersion was greater in patients (74.1 ms, SD +/- 26.1) than in controls (48.3 ms, 12.0) P < 0.0001, 95% CI 14.6, 37.0. Thirteen patients developed cardiorespiratory compromise and had greater QTc dispersion (84.5 ms, 26.2) than patients who did not develop cardiorespiratory compromise (64.5 ms, 22.7) P = 0.046, 95% CI 0.3, 39.6. There was no difference in QTc dispersion between patients who did and those who did not develop myocardial dysfunction alone. Similarly, there was no difference in QTc dispersion between patients who did and those who did not develop neurogenic pulmonary oedema alone. CONCLUSIONS: Increased QTc dispersion is associated with the later development of cardiorespiratory compromise in poor-grade subarachnoid haemorrhage patients. QTc dispersion may be used as a marker to predict impending clinical deterioration, providing an opportunity for early intervention.

Adult↗
PubMed2003

Long QTc predicts future cardiac death in stroke survivors.

OBJECTIVES: To test the hypothesis that the QTc of any lead of the ECG predicts death after stroke, and to determine which lead of the ECG carries the greatest risk of cardiac death when its QTc is measured. DESIGN: Standard 12 lead ECGs were analysed by one observer who was blind to patient outcome. SETTING: A major teaching hospital in Scotland. PATIENTS: 404 stroke survivors were studied at approximately one year after the cerebrovascular event and followed for up to 6.3 years. OUTCOME MEASURES: Death from any cause and cardiac mortality. RESULTS: The QTc measured from any lead of the ECG (except aVR) was associated with death from any cause. A prolonged QTc in limb lead III and chest lead V6 carried the highest relative risk of cardiac death (a 3.1-fold incease). After adjusting for overt ischaemic heart disease, pulse pressure, glucose, and cholesterol, a prolonged QTc in lead V6 was associated with a relative risk of cardiac death of 2.8 (95% confidence interval (CI) 1.1 to 7.3) (p = 0.028) and of death from all causes of 2.9 (95% CI 1.6 to 5.3) (p < 0.001). If the QTc in V6 exceeded 480 ms, then the specificity of predicting cardiac death within five years after the stroke was 94%. CONCLUSIONS: Although treatment of the conventional modifiable risk factors is important, stroke survivors with a prolonged QTc in lead V6 are still at a high risk of cardiac death and may need more intensive investigations and treatments than are currently routine practice.

Adult↗
PubMed2002

Reversible hypertension following coeliac disease treatment: the role of moderate hyperhomocysteinaemia and vascular endothelial dysfunction.

The vascular endothelium maintains a relatively vasodilated state via the release of nitric oxide (NO), a process that could be disrupted by hyperhomocysteinaemia. Since endothelial dysfunction is associated with increased systemic vascular resistance that is the hallmark of sustained arterial hypertension, we hypothesised that in patients with both hypertension and coeliac disease with hyperhomocysteinaemia (via malabsorption of essential cofactors), treatment of the latter disease could improve blood pressure (BP) control. A single patient with proven sustained hypertension and newly-diagnosed coeliac disease had baseline and post-treatment BP and endothelial function assessed by ambulatory BP monitoring (ABPM) and brachial artery forearm occlusion plethysmography respectively. This 49 year-old woman had uncomplicated sustained hypertension proven on repeated ABPM carried out 6 weeks apart (daytime mean 151/92 mm Hg and 155/95 mm Hg), and sub-clinical coeliac disease (gluten-sensitive enteropathy). Initial assessments revealed raised homocysteine levels with low normal vitamin B(12) level. It was likely that she had impaired absorption of essential cofactors for normal homocysteine metabolism. She adhered to a gluten-free diet and was give oral iron, folate and B(6) supplementations as well as B(12) injections for 3 months. Her BP had improved by 6 months and normalised by 15 months (daytime ABPM mean 128/80 mm Hg). There was parallel restoration of normal endothelial function with normalisation of her homocysteine levels. These observations suggest that sub-clinical coeliac disease related hyperhomocysteinaemia might cause endothelial dysfunction, potentially giving rise to a reversible form of hypertension. In addition, this case study supports the notion that irrespective of aetiology, endothelial dysfunction may be the precursor of hypertension. This highlights the need to resolve co-existing vascular risk factors in patients with hypertension.

Blood Pressure↗
PubMed2002

Urate predicts subsequent cardiac death in stroke survivors.

AIMS: To test the hypothesis that urate predicts cardiac death after stroke independent of conventional risk factors of atherosclerosis, creatinine and diuretic use. METHODS AND RESULTS: Serum urate concentration was measured in an unselected cohort of 354 stroke survivors who were followed-up for a median of 2.8 years. Cardiac death was the primary end-point. Urate was associated with a statistically significant threefold increase in relative risk of cardiac death even after adjustment for other conventional risk factors. In the subgroup of patients who were not on diuretics, raised urate was associated with a 12-fold significant increase in relative risk of cardiac death after adjusting for renal function and other conventional risk factors. A urate concentration of greater than 0.31 mmol. l(-1) was 78% sensitive at predicting cardiac death within 5 years after stroke, but was only 54% specific. If urate exceeded 0.38 mmol. l(-1), specificity of predicting cardiac death within 5 years after stroke was 88%. CONCLUSIONS: Elevated serum urate concentration may be used to stratify risk of future cardiac death after stroke. This appeared to be true even in stroke survivors who were not on diuretic therapy.

Aged↗
PubMed2002

Effect of allopurinol on mortality and hospitalisations in chronic heart failure: a retrospective cohort study.

OBJECTIVE: To examine whether allopurinol is associated with any alteration in mortality and hospitalisations in patients with chronic heart failure (CHF). This hypothesis is based on previous data that a high urate concentration is independently associated with mortality with a risk ratio of 4.23 in CHF. DESIGN: Retrospective cohort study. SETTING: Medicines Monitoring Unit, Ninewells Hospital, Dundee, UK. PATIENTS: 1760 CHF patients divided into four groups: those on no allopurinol, those on long term low dose allopurinol, those on short term low dose allopurinol, and those on long term high dose allopurinol. MAIN OUTCOME MEASURES: Total mortality, cardiovascular mortality, cardiovascular hospitalisations, cardiovascular mortality or hospitalisations. RESULTS: Long term low dose allopurinol was associated with a significant worsening in mortality over those who never received allopurinol (relative risk 2.04, 95% confidence interval (CI) 1.48 to 2.81). This may be because low dose allopurinol is insufficient to negate the adverse effect of a high urate concentration. However, long term high dose (> or = 300 mg/day) allopurinol was associated with a significantly better mortality than longstanding low dose allopurinol (relative risk 0.59, 95% CI 0.37 to 0.95). This may mean that high dose allopurinol can fully negate the adverse effect of urate and return the mortality to normal. CONCLUSIONS: Long term high dose allopurinol may be associated with a better mortality than long term low dose allopurinol in patients with CHF because of a dose related beneficial effect of allopurinol against the well described adverse effect of urate. Further work is required to substantiate or refute this finding.

Aged↗
PubMed2002

Adherence to statin treatment and readmission of patients after myocardial infarction: a six year follow up study.

OBJECTIVE: To investigate patients' adherence to statin treatment prescribed following their first myocardial infarction (MI) and to estimate the effect of adherence to statins on recurrence of MI and all cause mortality. DESIGN: Cohort study using a record linkage database. SETTING: Tayside, Scotland, UK. PATIENTS: Patients who experienced their first MI between January 1990 and November 1995. MAIN OUTCOME MEASURES: Percentage of statin use and adherence to statins by patients after an MI and the relative risk of hospitalisation for recurrent MI. The effect of adherence on all cause mortality was also examined. The covariates used were age, sex, socioeconomic deprivation, serum cholesterol concentration, diabetes mellitus, cardiovascular drug use, and other hospitalisations. RESULTS: Of 5590 patients who experienced an incident MI, 717 (12.8%) experienced at least one further MI. Only 7.7% of patients used statins after an MI during the study period. Compared with those not taking statins, those who had 80% or better adherence to statin treatment had an adjusted relative risk of recurrent MI of 0.19 (95% confidence interval (CI) 0.08 to 0.47) and all cause mortality of 0.47 (95% CI 0.22 to 0.99). There was no significant reduction in either end point for those who were less than 80% adherent to statins. CONCLUSIONS: Despite the infrequent use of statin during the study period, good adherence to statin treatment was associated with lower risk of recurrent MI.

Adult↗
PubMed2002

Perindopril improves six minute walking distance in older patients with left ventricular systolic dysfunction: a randomised double blind placebo controlled trial.

OBJECTIVE: To evaluate the effects of the angiotensin converting enzyme inhibitor perindopril on six minute walking distance and quality of life in very old patients with left ventricular systolic dysfunction. DESIGN: Prospective, double blind placebo controlled trial. SETTING: Medicine for the elderly day hospital. PATIENTS: 66 patients (average age 81) with left ventricular systolic dysfunction identified by echocardiography. INTERVENTIONS: 10 weeks of treatment with titrated doses of perindopril or placebo. MAIN OUTCOME MEASURES: Six minute walking distance 10 weeks following treatment, quality of life measurements including the Minnesota living with heart failure questionnaire and the 36 item short form health survey. RESULTS: In patients with left ventricular systolic dysfunction, six minute walking distance was significantly increased in the treatment group (37.1 m) compared with the placebo group (-0.3 m, p < 0.001). The medication was well tolerated and there were no significant adverse events. CONCLUSIONS: Six minute walking distance is improved considerably by treatment with perindopril in older patients with heart failure caused by left ventricular systolic dysfunction.

Aged↗
PubMed2002

Increasing plasma potassium with amiloride shortens the QT interval and reduces ventricular extrasystoles but does not change endothelial function or heart rate variability in chronic heart failure.

OBJECTIVES: To test whether simply increasing plasma potassium with amiloride would exert any of the same beneficial effects on "surrogate outcome measures" that are seen with spironolactone. The latter has been shown to improve mortality in chronic heart failure, possibly as a result of improvements in endothelial dysfunction, vascular angiotensin converting enzyme (ACE), autonomic function, myocardial fibrosis, ventricular arrhythmias, and QT interval indices. DESIGN: Randomised, placebo controlled trial. SETTING: Teaching hospital. PATIENTS AND INTERVENTIONS: Double blind crossover study involving 10 patients with New York Heart Association functional class II-III chronic heart failure comparing 5 mg/day amiloride (one month) with placebo. MAIN OUTCOME MEASURES: Endothelial function, vascular ACE, collagen markers, 24 hour ECG, and QT interval results. RESULTS: The amiloride induced increase in serum potassium (0.4 mmol/l) did not significantly change endothelial dysfunction, vascular ACE, collagen markers, or heart rate variability. However, amiloride significantly improved QT interval indices, reducing both QT dispersion (from 65.7 ms to 50.9 ms, p = 0.001) and mean maximal corrected QT (from 445 ms to 435 ms, p = 0.008). Amiloride also reduced ventricular extrasystoles (p < 0.05). CONCLUSIONS: Amiloride shortens QT interval length and reduces ventricular extrasystoles in chronic heart failure, implying that this effect is caused by potassium retention per se. However, unlike spironolactone, amiloride did not improve endothelial dysfunction, vascular ACE, heart rate variability, or myocardial fibrosis, implying that spironolactone improves these latter effects by aldosterone blockade rather than by simply increasing serum potassium. Therefore, amiloride has fewer beneficial mechanistic effects than spironolactone, but it does share with spironolactone the ability to shorten the QT interval and reduce ventricular extrasystoles.

Aged↗
PubMed2001

Circadian variation in the effects of aldosterone blockade on heart rate variability and QT dispersion in congestive heart failure.

OBJECTIVES: The study was designed to comprehensively evaluate the circadian effects of aldosterone blockade on autonomic tone and QT dispersion in chronic heart failure (CHF). BACKGROUND: Spironolactone therapy given in addition to angiotensin-converting enzyme inhibitors improved survival in CHF, but the mechanism of its benefit is uncertain. Experimental evidence suggests that aldosterone may have detrimental effects on the autonomic nervous system, especially during the morning hours. METHODS: Twenty-eight patients with New York Heart Association class II to IV CHF received spironolactone 50 mg daily and placebo for four weeks each in a double-blind crossover fashion. After each treatment phase, a full circadian assessment was undertaken of spironolactone's autonomic effects. The assessment included monitoring heart rate, QT dispersion, continuous Holter recordings, heart rate variability (HRV) and norepinephrine kinetics. RESULTS: Spironolactone significantly reduced all indices of QT dispersion. The reductions in QTcmax, QTd and QTcd were greatest at 6 AM. In addition, spironolactone had favorable autonomic effects, which were limited to the morning (6-10 AM), including heart rate reduction and an improvement in HRV. CONCLUSIONS: Spironolactone reduced heart rate and improved HRV and QT dispersion in CHF. Its effects were particularly prominent during the morning hours.

Circadian Rhythm↗
PubMed2001

Exercise blood pressure correlates with the maximum heart rate corrected QT interval in hypertension.

Submaximal exercise systolic blood pressure (ExSBP) is a recognised predictor of cardiac mortality. This study examined the possibility that this might be related to increased QT dispersion or prolonged maximum QT(c) interval (QTcmax). Twenty-nine untreated hypertensive subjects were assessed. Each subject underwent an echocardiographic examination and a 24-h ambulatory blood pressure (ABP). ExSBP was measured during a 3-min lightweight submaximal Dundee step test. In multiple regressional analyses, only left ventricular mass index significantly predicted QT dispersion (R2 = 22.4%, P = 0.018) and QT(c) dispersion (R(2) = 25.3%, P = 0.012). However, with respect to QTcmax, ExSBP (R2 = 21.6%, P = 0.02) emerged as the sole significant predictor of this index. Five (17.2%) out of the 29 subjects had prolonged QTcmax > or = 430 ms and these subjects were not differentiated by 24-h ABP (146 (s.d. 21)/83 (16) vs 140 (14)/88 (11) mm Hg, P = Ns) but by ExSBP (226 (15) vs 188 (24) mm Hg, P = 0.002). In conclusion, systolic blood pressure measured during exercise correlated with QT(c) max in hypertension. This finding may partly explain the prognostic value of exercise blood pressure.

Adult↗
PubMed2001

Cigarette smoking in men and vascular responsiveness.

AIMS: Smoking is a major risk factor for developing atherosclerosis. In order to understand the vascular abnormalities observed in smokers, we investigated vascular responsiveness in cigarette smokers. METHODS: We performed two consecutive matched group comparative studies to investigate vascular responsiveness using venous occlusion plethysmography. The mean effects of three incremental doses of each vasoactive agent are presented. Both studies compared smokers with nonsmokers. RESULTS: The first investigated 68 subjects (smokers = 29; mean +/- s.d. ages; 24 +/- 6 vs 25 +/- 5 years; P = NS) and found smoking was associated with a significant blunting of the flow ratio between treated and untreated arms to endothelium-dependent vasodilatation to acetylcholine (mean +/- s.d., nonsmokers vs smokers) 4.07 +/- 2.18 vs 3.42 +/- 1.79 (P = 0.04, 95% CI 0.02, 1.12). By contrast, there was no significant difference in the responses to the endothelium-independent vasodilators sodium nitroprusside and verapamil. Smoking was also associated with a significant impairment in endothelium-dependent vasoconstriction induced by monomethyl-L-arginine (L-NMMA) 0.78 +/- 0.22 vs 0.87 +/- 0.21 (P = 0.006, 95% CI -0.14, -0.02) and a trend to blunted endothelium-independent vasoconstrictor responses to noradrenaline. In the second study we investigated the response to angiotensin I and II in 23 subjects (smokers = 12; mean +/- s.d. ages; 34 +/- 10 vs 32 +/- 11 years). There was significant impairment in smokers of the mean vasoconstrictor response to angiotensin I 0.51 +/- 0.15 vs 0.59 +/- 0.16 (nonsmokers vs smokers; P = 0.003, 95% CI -0.13, -0.03) and a nonsignificant trend towards impairment of the response to angiotensin II. CONCLUSIONS: Cigarette smoking in male volunteers is associated with blunted basal and stimulated nitric oxide bioactivity. Endothelial independent vasodilator responses (to nitroprusside and verapamil) were unaltered in smokers. A defect in the vasoconstrictor response to angiotensin I was also seen.

Acetylcholine↗
PubMed2001

A placebo-controlled study examining the effect of allopurinol on heart rate variability and dysrhythmia counts in chronic heart failure.

AIMS: Allopurinol improves endothelial function in chronic heart failure by reducing oxidative stress. We wished to explore if such an effect would attenuate autonomic dysfunction in CHF in line with many other effective therapies in CHF. METHODS: We performed a prospective, randomized, double-blind cross-over study in 16 patients with NYHA Class II-IV chronic heart failure (mean age 67 +/- 10 years, 13 male, comparing allopurinol (2 months) at a daily dose of 300 mg (if creatinine < 150 micromol l-1) or 100 mg (if creatinine > 150 micromol l-1) with matched placebo. Mean heart rate and dysrhythmia counts were recorded from 24 h Holter tapes at monthly intervals for 6 months. We assessed autonomic function using standard time domain heart rate variability parameters (HRV): SDNN, SDANN, SDNN index, rMSSD and TI. RESULTS: Allopurinol had no significant effect on heart rate variability compared with placebo; the results are expressed as a difference in means +/- s.d. with 95% confidence interval (CI) between allopurinol and placebo: SDNN mean = 6.5 +/- 4.8 ms, P = 0.18 and 95% CI (-3.7, 17); TI mean = -2.1 +/- 1.4, P = 0.16 and 95% CI (-5.2, 0.8); SDANN mean = -2.8 +/- 7 ms, P = 0.68 and 95% CI (-18, 12); SDNNi mean = 2 +/- 6.6, P = 0.7 and 95% CI (-12, 16); RMSSD mean = -0.9 +/- 2, P = 0.68 and 95% CI (-5.6, 3.7). For mean heart rate the corresponding results were 0.9 +/- 1.4, P = 0.5 and 95% CI (-2, 3.8). Log 24 h ventricular ectopic counts (VEC) were 0.032 +/- 0.37, P = 0.7 and 95% CI (-0.1, 0.2). Patient compliance with study medication was good since allopurinol showed its expected effect of reducing plasma uric acid (P < 0.001). CONCLUSIONS: Allopurinol at doses, which are known to reduce oxidative stress appear to have no significant effect on resting autonomic tone, as indicated by time domain heart rate variability or on dysrhythmia count in stable heart failure patients.

Aged↗