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Biomedical subjects

A D Struthers

Publications and source records attributed to A D Struthers.

At least 55 records · Page 3Linked to original sources
PubMed2001

Careful screening to target interventions to prevent sudden cardiac death.

1. Cardiac death is due not only to coronary artery disease, but also to left ventricular (LV) abnormalities (fibrosis, dysfunction) and arrhythmogenic triggers, such as autonomic imbalance. 2. Nitric oxide deficiency could be a key mediator leading not only to coronary atherosclerosis, but also to LV abnormalities and autonomic imbalance. 3. It may be possible to screen for the above abnormalities (e.g. echocardiography and brain natriuretic peptide levels for LV abnormalities, 24 h tapes for autonomic imbalance and QT interval analysis). 4. Once individuals are identified as being at high risk, a range of interventions is possible (e.g. intensive statin therapy or angiotensin-converting enzyme inhibitors if LV abnormalities or autonomic imbalance are found).

Death, Sudden, Cardiac↗
PubMed2001

Differential expression and synthesis of natriuretic peptides determines natriuretic peptide receptor expression in primary cultures of human proximal tubular cells.

INTRODUCTION: The natriuretic peptides and natriuretic peptide receptors may play a beneficial role in hypertension and heart failure and possibly in opposing associated detrimental cellular changes in the heart, vasculature and kidney. These responses may be, in part, modulated by the natriuretic peptide clearance receptor rather than the natriuretic peptide receptors (NPR-A or NPR-B). OBJECTIVE: To investigate the expression of the natriuretic peptide receptors (NPR-A,-B,-C) and the natriuretic peptides (ANP, BNP, CNP) in primary cultures of human proximal tubular cells and the role played by endogenously released natriuretic peptides in natriuretic peptide receptor expression. RESULTS: Northern analysis demonstrated that freshly isolated human proximal tubular cells express the NPR-C only. However, at confluence mRNA transcripts for both the NPR-A and -B were expressed, accompanied by a significant cyclic guanosine monophosphate (cGMP) response to ANP and CNP, indicating the development of functionally active receptors. A significant increase in immunoreactive ANP, BNP and CNP in the cell supernatant accompanied the appearance of these receptors. Incubation of freshly isolated cells with exogenous ANP, BNP, CNP or with the NPR-C specific ligand C(4.23)ANF induced similar changes in receptor expression, suggesting that these changes were mediated via the NPR-C rather than the NPR-A or -B. CONCLUSIONS: Significant changes in peptide and receptor expression occur during cell culture and may be integrally linked, with functionally active NPR-A and -B occurring in response to an increase in the expression of the natriuretic peptides possibly acting at the NPR-C.

Atrial Natriuretic Factor↗
PubMed2001

Adverse cardiac effects of salt with fludrocortisone in hypertension.

The effect of salt on blood pressure (BP) is controversial. A more important question is whether salt can produce cardiac target-organ damage, irrespective of its effect on BP. We assessed the effect of salt with fludrocortisone on QT dispersion and echocardiographic left ventricular diastolic function in a prospective interventional study involving 29 hypertensive subjects with a raised aldosterone/renin ratio who were hospitalized for investigation of possible primary aldosteronism. Each subject over 4 days was given a total of 28.8 g (480 mmol) of sodium chloride and 1.5 mg of fludrocortisone with potassium supplementation. Baseline and posttreatment 12-lead ECGs and echocardiograms were obtained. There were no significant changes in body weight, pulse rate, or BP after treatment with salt and fludrocortisone. Plasma sodium was significantly increased from 141.4 (SD 2.1) to 142.6 (SD 2.4) mmol/L (P:=0.001). QT and QTc dispersion both significantly increased: +19.6 (SD 16.5) ms (95% CI, 13.4 to 25.9) (P:<0.001) and +19.8 (SD 20.9) ms (95% CI, 11.8 to 27.7) (P:<0.001), respectively. There were no significant changes in (n=15) left ventricular dimensions or systolic function, but all diastolic filling indexes, including the preload-independent index, flow propagation velocity (55.49 [SD 10.91] to 48.96 [SD 11.40] cm/s, P:=0.018) worsened, suggesting significant deterioration of left ventricular diastolic function with salt and fludrocortisone. In conclusion, a combination of salt with fludrocortisone increased QT dispersion and impaired left ventricular diastolic relaxation in hypertensive patients with high aldosterone/renin ratios. This raises the possibility that salt may have BP-independent adverse cardiac effects in susceptible hypertensive subjects.

Aldosterone↗
PubMed2001

Lisinopril improves endothelial function in chronic cigarette smokers.

Cigarette smoking is a pernicious risk factor for the pathogenesis of coronary artery disease, and endothelial dysfunction is an important antecedent event in this process. This is important, as cigarette smoke is directly toxic to endothelial cells. Inhibitors of angiotensin-converting enzyme (ACE) have been shown to improve endothelial function in diabetes and hypercholesterolaemia, and are a promising option in smokers. We treated 23 subjects (age 38+/-12 years; mean+/-S.D.) for 8 weeks with 20 mg of lisinopril in a randomized controlled trial. Endothelial function was assessed by measurement of forearm blood flow responses to intra-arterial infusions of endothelial-dependent and -independent vasodilators and an endothelial-dependent vasoconstrictor [acetylcholine, sodium nitroprusside and monomethyl-L-arginine (L-NMMA) respectively] using venous occlusion plethysmography. Lisinopril significantly increased the forearm blood flow response to acetylcholine by 20% [lisinopril, 3.12+/-0.37 (mean+/-S.E.M.); placebo, 2.58+/-0.25; P=0.02, 95% confidence intervals (CI) 0.09, 1.06] (values given are ratios of flow in the infused arm to that in the control arm); there was no effect on the response to sodium nitroprusside (lisinopril, 3.97+/-0.40; placebo, 3.92+/-0.39; P=0.84; 95% CI -0.50, 0.61). The vasoconstrictor response to L-NMMA demonstrated a significant improvement (lisinopril, 0.77+/-0.06; placebo, 0.95+/-0.05; P<0.001; 95% CI -0.09, -0.27). In conclusion, these results indicate that ACE inhibition can improve endothelial function in cigarette smokers. We show that lisinopril improves both receptor-mediated and tonic NO release. The mechanism could be either that lisinopril limits the angiotensin II-induced production of superoxide radicals which would normally inactivate NO, or that lisinopril may increase bradykinin-mediated NO release.

Acetylcholine↗
PubMed2000

Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure.

BACKGROUND: The RALES study showed that spironolactone, added to conventional therapy for chronic heart failure, dramatically reduced mortality. We tested the hypothesis that this benefit was partially due to improvement in endothelial function and/or to amplified suppression of the vascular renin-angiotensin axis. METHODS AND RESULTS: We performed a randomized, placebo-controlled, double-blind crossover study on 10 patients with NYHA class II to III chronic heart failure on standard diuretic/ACE inhibitor therapy, comparing 50 mg/d spironolactone (1 month) versus placebo. Forearm vasculature endothelial function was assessed by bilateral forearm venous occlusion plethysmography using acetylcholine and N-monomethyl-L-arginine (L-NMMA), with sodium nitroprusside as a control vasodilator. Also, vascular ACE activity was assessed by use of angiotensin (Ang) I, with Ang II as a control vasoconstrictor. Spironolactone significantly increased the forearm blood flow response to acetylcholine (percentage change in forearm blood flow [mean+/-SEM], 177+/-29% versus 95+/-20%, spironolactone versus placebo; P<0.001), with an associated increase in vasoconstriction due to L-NMMA (-35+/-6% versus -18+/-4%; P<0.05). The Ang I response was also significantly reduced with spironolactone (P<0.05), with Ang II responses unaltered. CONCLUSIONS: Spironolactone improves endothelial dysfunction, increases NO bioactivity, and inhibits vascular Ang I/Ang II conversion in patients with heart failure, providing novel mechanisms for its beneficial effect on cardiovascular mortality.

Aged↗
PubMed2000

Effect of phenylephrine with and without atropine on QT dispersion in healthy normotensive men.

The present study examined if changes in cardiac after-load would affect QT interval dispersion. QT dispersion (QTd) on the 12-lead electrocardiogram is believed to be a noninvasive measure of electrical inhomogeneity in the heart and has recently been identified as a sensitive predictor of sudden cardiac death. In experimental models, an increase in cardiac afterload has been shown to alter action potential durations through mechanoelectrical feedback. This may result in an altered dispersion of action potential repolarization in the ventricle. Until now, there has been little evidence for this occurring in man in vivo. In the present study, the effects of afterload on QTd were examined in 10 healthy male volunteers (mean age [SD] 25 years [4.5]) who received an intravenous infusion of phenylephrine (0.2 to 3.6 microg/kg/min) given in incremental doses, and placebo in a blinded, crossover fashion. Because phenylephrine is known to alter heart rate (HR) significantly (via a reflex vagal response), the study was performed with and without atropine. We found a significant positive correlation between acute changes in blood pressure (BP) and changes in all QTd indexes (deltaQTd/delta systolic BP and deltaQTcd/deltasystolic BP r values 0.67 and 0.60, respectively; p <0.001). This relation was independent of HR changes or reflex vagal activity. Atropine had no significant effect on QTd. These observations have important clinical implications and may partly account for why sudden deaths and arrhythmic complications occur so frequently in conditions associated with increased after-load, such as hypertension and heart failure.

Adrenergic alpha-Agonists↗
PubMed2000

Ovarian hormones in man: their effects on resting vascular tone, angiotensin converting enzyme activity and angiotensin II-induced vasoconstriction.

AIMS: Oestrogens in women have been shown to cause vasodilation which may reflect alterations in the activity of vascular angiotensin converting enzyme (ACE) and/or sensitivity to angiotensin II. The aim of this study was to assess the effect of ovarian hormones on vascular tone, vascular ACE activity and vasoconstriction to angiotensin II in males. METHODS: Eight volunteers were randomised in a crossover design to oestradiol, medroxy-progesterone, and placebo. Vasoconstriction to angiotensin I and angiotensin II was assessed by forearm plethysmography. RESULTS: Although baseline forearm flow was increased with oestradiol, suggesting generalized vasodilation, there were no changes in the vasoconstrictor responses to angiotensin I or angiotensin II. Medroxy-progesterone affected neither baseline flow nor vasoconstrictor responses. The results expressed as percentage reduction in flow (mean +/- s.d.) were: angiotensin I 48 pmol ml-1: placebo -48 +/- 14%; oestradiol -42 +/- 16%; medroxyprogesterone -43 +/- 8% and for angiotensin II 16 pmol ml-1: placebo -42 +/- 10%; oestradiol -39 +/- 11%; medroxyprogesterone -46 +/- 13%. CONCLUSIONS: Acute administration of oestradiol caused vasodilation in males, the effect was not due to alterations in vascular ACE activity or to altered sensitivity to angiotensin II.

Adult↗
PubMed2000

Task-based learning: the answer to integration and problem-based learning in the clinical years.

INTRODUCTION: Integrated teaching and problem-based learning (PBL) are powerful educational strategies. Difficulties arise, however, in their application in the later years of the undergraduate medical curriculum, particularly in clinical attachments. Two solutions have been proposed - the use of integrated clinical teaching teams and time allocated during the week for PBL separate from the clinical work. Both approaches have significant disadvantages. Task-based learning (TBL) is a preferred strategy. In TBL, a range of tasks undertaken by a doctor are identified, e.g. management of a patient with abdominal pain, and these are used as the focus for learning. Students have responsibility for integrating their learning round the tasks as they move through a range of clinical attachments in different disciplines. They are assisted in this process by study guides. METHOD: The implementation of TBL is described in one medical school. One hundred and thirteen tasks, arranged in 16 groups, serve to integrate the student learning as they rotate through 10 clinical attachments. RESULTS: This trans-disciplinary approach to integration, which incorporates the principles of PBL offers advantages to both teachers and students. It recognizes that clinical attachments in individual disciplines can offer rich learning opportunities and that such attachments can play a role in an integrated, as well as in a traditional, curriculum. In TBL, the contributions of the clinical attachments to the curriculum learning outcomes must be clearly defined and tasks selected which will serve as a focus for the integration of the students' learning over the range of attachments.

Clinical Clerkship↗