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Biomedical subjects

J N Townend

Publications and source records attributed to J N Townend.

At least 19 recordsLinked to original sources
PubMed2001

Vagus nerve stimulation decreases left ventricular contractility in vivo in the human and pig heart.

1. Studies of the effect of vagus nerve stimulation on ventricular myocardial function in mammals are limited, particularly in the human. 2. The present study was designed to determine the effect of direct electrical stimulation of the left vagus nerve on left ventricular contractile state in hearts paced at 10 % above the natural rate, in anaesthetised pigs and anaesthetised human subjects undergoing open chest surgery for coronary artery bypass grafting. 3. Contractility of the left ventricle was determined from a series of pressure-volume loops obtained from a combined pressure and conductance (volume) catheter placed in the left ventricle. From the measurements a regression slope of the end-systolic pressure-volume relationship was determined to give end-systolic elastance (Ees), a load-independent measure of contractility. 4. In six anaesthetised open chest pigs, stimulation of the peripheral cut end of the left cervical vagus nerve induced a significant decrease in Ees of 26 +/- 14 %. 5. In nine patients electrical stimulation of the left thoracic vagus nerve close to its cardiac branch resulted in a significant drop in Ees of 38 +/- 16 %. 6. The effects of vagal stimulation were blocked by the muscarinic antagonist glycopyrronium (5 mg kg(-1)). 7. Administration of the beta-adrenoreceptor antagonist esmolol (1 mg kg(-1)) also attenuated the effect of vagal stimulation, indicating a degree of interaction of vagal and sympathetic influences on contractility. 8. These studies show that in the human and pig heart the left vagus nerve can profoundly decrease the inotropic state of the left ventricular myocardium independent of its bradycardic effect.

Animals↗
PubMed2001

A randomized double-blind placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease.

OBJECTIVES: This study was designed to determine the effects of folic acid therapy on endothelial function in patients with coronary artery disease (CAD). BACKGROUND: Hyperhomocysteinemia, a risk factor for CAD, may cause atherosderosis by oxidative endothelial injury. Folic acid reduces plasma homocysteine, but the effect on adverse vascular events is unknown. METHODS: In a double-blind placebo-controlled trial, 90 patients (mean age [range] 63 [46 to 79] years, 79 men) with CAD were randomized to either folic acid 5 mg or placebo daily for 12 weeks. Endothelial function was assessed by measuring: 1) flow-mediated endothelium-dependent dilation (EDD) of the brachial artery; 2) combined serum nitrite/nitrate (NOx) concentrations and; 3) plasma von Willebrand factor (vWF) concentration. RESULTS: At the end of the study, plasma homocysteine was lower in the folic acid group compared with the placebo group (mean [95% confidence interval] 9.3 (8.5 to 10.1) vs. 12.3 [11.3 to 13.4] micromol/l, p < 0.001). Although there were no significant differences in EDD, serum NOx or plasma vWF between the two groups, there was a greater increase in EDD from baseline in the folic acid group compared to placebo (1.2 [0.7 to 1.8] vs. 0.4 [-0.3 to 1.1]%, p = 0.07). CONCLUSIONS: Folic acid reduced plasma homocysteine and was associated with a trend toward improved endothelial function in patients with CAD. The absence of an unequivocally positive result may have been due to inadequate sample size or chance. This reinforces the need for the results of large randomized controlled trials before the implementation of routine folic acid supplementation.

Aged↗
PubMed2001

The elective use of the seven-cell NIR stent in coronary arteries < 2.75 mm in diameter: clinical and angiographic results at 6-month follow-up.

The outcome of interventional procedures has been improved by the use of coronary stents in vessels > 3.0 mm in diameter. We report a single-center prospective study of elective coronary stenting in 39 consecutive patients with de novo lesions and reference diameters < 2.75 mm. Seven-cell NIR stents were deployed with standard antiplatelet therapy, but without routine use of IIb/IIIa inhibitors or intravascular ultrasound. There was one case of acute stent thrombosis, but no cases of subacute thrombosis. The binary restenosis rate was 27.8% (10/36 lesions) and the target lesion revascularization rate was 19.4%. Symptoms improved markedly as judged by Canadian Cardiovascular Society and questionnaire scores and the use of antianginal therapy. This pilot study suggests that the elective use of coronary stents in vessels < 2.75 mm in diameter is safe with acceptable long-term results. A randomized trial comparing outcomes after stents and balloon angioplasty in small vessels is required.

Aged↗
PubMed2001

Nitric oxide and hypertension: not just an endothelium derived relaxing factor!

The importance of endothelial nitric oxide (NO) generation in sustaining a tonic systemic vasodilatation is well established. Inhibiting NO production produces hypertension in animals and in humans and not surprisingly there has been considerable interest in establishing whether deficiencies of endothelial NO pathway activity are implicated in the aetiology of essential hypertension. The results of these investigations have been inconsistent with some suggestion that observed deficiencies of both basal and stimulated endothelial NO generation in hypertensive subjects may be an effect rather than the cause of raised arterial pressure. It is increasingly recognised that neuronal production of NO also influences cardiovascular homeostasis through its action as a neuromodulator within the autonomic nervous system. Overall NO has been shown to have sympatho-inhibitory and vagotonic effects, acting by both central and peripheral mechanisms. Sympathetic overactivity, coupled with the permissive role of a depressed level of baroreflex mediated cardiac vagal control, may play a significant role in the genesis of human hypertension. Early work in hypertensive rats suggests that neuronal NO production is impaired at a number of key central sites concerned with autonomic cardiovascular regulation. This data is consistent with the pattern of autonomic dysfunction observed in human hypertension. The possibility that neuronal rather than endothelial production of NO might play a significant role in the aetiology of essential hypertension is a promising area for future human research.

Autonomic Nervous System↗
PubMed2001

ACE inhibition in aortic stenosis: dangerous medicine or golden opportunity?

Conventionally angiotensin-converting enzyme (ACE) inhibitors are contraindicated in patients with aortic stenosis. Abundant evidence is now available showing that angiotensin II has a central role in the development of left ventricular hypertrophy (LVH), myocardial contractile failure and diastolic dysfunction in response to pressure overload. In animal models, ACE inhibitors have been shown to attenuate these pathological responses. In humans there is no such evidence available, however uncontrolled studies have shown that these agents are not only tolerated but are associated with acute improvements in haemodynamics and diastolic function. Further studies are merited to assess the possible role of ACE inhibitors in aortic stenosis both before and after valve replacement. Potential benefits may include prevention of LVH, improved diastolic function, reduction of arrhythmias and preservation of left ventricular function.

Adult↗
PubMed2001

Epidemiological evaluation of known and suspected cardiovascular risk factors in chronic renal impairment.

Patients with chronic renal impairment (CRI) are at greatly increased risk for premature vascular disease; however, little is known about its evolution. This paper describes a cohort of patients with CRI and reports study design, baseline demographic and biochemical data, and comparisons with two contemporaneous age- and sex-matched control groups, one with established coronary artery disease and the other without overt vascular disease. Among 369 individuals (median age, 63 years; range, 18 to 88 years; 67% men) with CRI, 34% had a history of vascular disease and 21% had electrocardiographic left ventricular hypertrophy (LVH). Even in those with mild renal impairment (serum creatinine < 2.1 mg/dL), approximately one third had vascular disease and 12% had LVH. A history of hypertension was present in 76% of the CRI group, but as compared with controls, systolic and diastolic blood pressures were not elevated. Low-density lipoprotein (LDL) cholesterol concentration also was not elevated, but CRI was associated with elevated serum triglyceride and plasma homocysteine levels and reduced high-density lipoprotein (HDL) cholesterol, hemoglobin, and serum albumin concentrations. Across the spectrum of CRI, more severe renal dysfunction was associated with lower levels of diastolic blood pressure, LDL and HDL cholesterol, albumin, and hemoglobin, but increased levels of plasma homocysteine. This cross-sectional analysis shows that vascular disease is common in individuals with mild CRI attending a nephrology program and also suggests trends in the levels of a number of potential vascular risk factors with respect to severity of renal dysfunction. These results will be further quantified in a prospective biennial follow-up.

Adolescent↗
PubMed2001

Effects of coronary revascularisation on myocardial blood flow and coronary vasodilator reserve in hibernating myocardium.

OBJECTIVE: Previous studies have suggested that resting myocardial blood flow is within normal limits in most chronically dysfunctional left ventricular segments which improve function after coronary artery revascularisation (hibernating myocardium). The aim of this study was to assess myocardial blood flow and coronary vasodilator reserve in hibernating myocardium before and after coronary revascularisation. PATIENTS AND METHODS: 30 patients with multivessel coronary disease undergoing coronary revascularisation (21 patients with bypass grafting and nine with coronary angioplasty), and 21 age and sex matched healthy volunteers (controls). Myocardial blood flow (MBF, ml/min/g) was measured by positron emission tomography using oxygen-15 water at rest and after dipyridamole (MBFdip, 0.56 mg/kg in four minutes). Coronary vasodilator reserve was calculated as MBFdip/MBF. Regional wall motion was assessed with echocardiography. RESULTS: Before revascularisation there were 48 remote and 275 dysfunctional myocardial segments, of which 163 (59%) improved function after revascularisation (hibernating). In hibernating segments coronary vasodilator reserve before revascularisation was significantly lower than in remote segments (1.97 (0.7), p < 0.0001) and controls (3.2 (1.5), p < 0.0001). In hibernating segments, myocardial blood flow remained unchanged after revascularisation (0.94 (0.3) v 0.95 (0.3) ml/min/g, p = 0.3) while coronary vasodilator reserve increased (1. 47 (0.7) v 1.98 (1.0), p < 0.0001). Myocardial blood flow was similar in remote, hibernating segments before and after revascularisation and in controls. CONCLUSIONS: This study confirms that myocardial blood flow at rest in hibernating myocardium is within normal limits in most segments, and that hibernating myocardium is characterised by an impaired coronary vasodilator reserve which improves significantly after coronary revascularisation.

Adult↗
PubMed2001

Incremental shuttle walk test in the assessment of patients for heart transplantation.

OBJECTIVE: To compare the incremental shuttle walk test (ISWT) with treadmill exercise testing (TT) derived measurement of peak oxygen consumption (peak VO(2)) in patients undergoing assessment for cardiac transplantation. DESIGN: Prospective comparison. All investigations occurred during a single period of admission for transplant assessment. SETTING: Single UK cardiothoracic transplantation unit. PATIENTS: 25 patients recruited (21 men). Mean age was 53 years. INTERVENTIONS: Patients underwent two TT of peak VO(2) using the modified Naughton protocol and three (one practice) ISWT. Investigations were performed on consecutive days. MAIN OUTCOME MEASURES: Main outcome measures were repeatability of TT and ISWT assessments; relation between peak VO(2) and distance walked in the ISWT; and receiver operating characteristic (ROC) analysis to establish a distance walked in the ISWT that predicted which patients would have a peak VO(2) greater than 14 ml/min/kg. RESULTS: Both the ISWT and the TT were highly reproducible. Following the first practice walk, mean (SD) ISWT distances were 400.0 (146) m (ISWT2) and 401.3 (129) m (ISWT3), r = 0.90, p < 0.0001. Mean peak VO(2) by TT was 15.2 (4.4) ml/kg/min (TT1) and 15.0 (4.4) ml/kg/min (TT2), r = 0.83, p < 0.0001. The results revealed a strong correlation between distance covered in the ISWT and peak VO(2) obtained during TT (r = 0.73, p = 0.0001). ROC analysis showed that a distance walked of 450 m allowed the selection of patients with a peak VO(2) of over 14 ml/min/kg. CONCLUSIONS: This work confirms the utility of the ISWT in the assessment of exercise capacity in patients with severe heart failure undergoing assessment for cardiac transplantation. ISWT may provide a widely applicable surrogate measure for peak VO(2) estimation in this population. Shuttle distance walked may therefore allow the convenient, serial assessment of patients with heart failure before referral for transplantation.

Exercise Test↗
PubMed2001

Effects of angiotensin II (AT1) receptor blockade on cardiac vagal control in heart failure.

The objective of the present study was to determine the autonomic effects of angiotensin II (AT(1)) receptor blocker therapy in heart failure. In a randomized double-blind cross-over study, we compared the effects of candesartan and placebo on baroreflex sensitivity and on heart rate variability at rest, during stress and during 24 h monitoring. Acute effects were assessed 4 h after oral candesartan (8 mg) and chronic effects after 4 weeks of treatment (dose titrated to 16 mg daily). The study group comprised 21 patients with heart failure [mean (S.E.M.) ejection fraction 33% (1%)], in the absence of angiotensin-converting enzyme (ACE) inhibitor therapy. We found that acute candesartan was not different from placebo in its effects on blood pressure or mean RR interval. Chronic candesartan significantly reduced blood pressure [placebo, 137 (3)/82 (3) mmHg; candesartan, 121 (4)/75 (2) mmHg; P<0.001; values are mean (S.E.M.)], but had no effect on mean RR interval [placebo, 857 (25) ms; candesartan, 857 (21) ms]. Compared with placebo there were no significant effects of acute or chronic candesartan on heart rate variability in the time domain and no consistent effects in the frequency domain. Baroreflex sensitivity assessed by the phenylephrine bolus method was significantly increased after chronic candesartan [placebo, 3.5 (0.5) ms/mmHg; candesartan, 4.8 (0.7) ms/mmHg; P<0.05], although there were no changes in cross-spectral baroreflex sensitivity. Thus, in contrast with previous results with ACE inhibitors, angiotensin II receptor blockade in heart failure did not increase heart rate variability, and there was no consistent effect on baroreflex sensitivity.

Aged↗
PubMed2000

Suppression of inflammation in primary systemic vasculitis restores vascular endothelial function: lessons for atherosclerotic disease?

BACKGROUND: Chronic inflammatory rheumatic disorders are associated with excess cardiovascular mortality. This may result from arteriosclerosis following inflammatory damage to the vessel wall by vasculitis. Our hypothesis that vasculitis results in arteriosclerosis by causing vascular endothelial dysfunction was tested in patients with primary systemic necrotizing vasculitis (SNV). METHODS AND RESULTS: Endothelial function was assessed in cross-sectional and longitudinal studies of patients with primary SNV by measuring flow-mediated, endothelium-dependent brachial artery vasodilatation. These patients exhibited marked endothelial dysfunction compared with controls. Remission induction in patients with active primary SNV restored endothelial function. CONCLUSIONS: Endothelial function is significantly impaired in adults with primary SNV, supporting the hypothesis that premature arteriosclerosis in chronic inflammatory rheumatic disorders results from endothelial dysfunction secondary to vasculitis. Normalization of endothelial function after the treatment of primary SNV suggests that early suppression of disease activity in chronic inflammatory rheumatic disorders may reduce long-term vascular damage. The role of inflammation in atheroma formation is increasingly appreciated; this work raises questions regarding the potential for anti-inflammatory therapy in atherosclerosis itself.

Brachial Artery↗
PubMed2000

Does folic acid decrease plasma homocysteine and improve endothelial function in patients with predialysis renal failure?

BACKGROUND: Considerable evidence suggests that hyperhomocysteinemia is an independent vascular risk factor that promotes atherosclerosis by inducing endothelial dysfunction. Although folic acid reduces hyperhomocysteinemia, the effect on adverse vascular events is unknown. We hypothesized that in patients with chronic renal failure, a condition associated with both hyperhomocysteinemia and atherosclerosis, treatment with folic acid would improve endothelial function. METHODS AND RESULTS: In a prospective, double-blind protocol, 100 patients (mean age 62 years, 67 men) with predialysis chronic renal failure were randomized to 5 mg folic acid or placebo daily for 12 weeks. Endothelial function was assessed by measuring (1) endothelium-dependent dilation of the brachial artery, (2) combined serum nitrite/nitrate concentrations, and (3) plasma von Willebrand factor concentration. Baseline characteristics of the 2 groups were similar. At the end of the study, both serum and red cell folate concentrations were greater in the folic acid group than the placebo group [mean (95% CI) 39.0 (29.8 to 51.0) versus 7.7 (6.6 to 8.9) microg/L and 739 (613 to 891) versus 220 (184 to 262) microg/L, respectively; both P<0.001]. Despite a reduction in hyperhomocysteinemia in the folic acid group compared with the placebo group [15.1 (14.1 to 16.2) versus 20.1 (18.2 to 22.2) micromol/L; P<0.001], there were no significant differences in endothelium-dependent dilation, combined serum nitrite/nitrate concentrations, or plasma von Willebrand factor concentration between the 2 groups. CONCLUSIONS: High-dose folic acid lowers but fails to normalize hyperhomocysteinemia in patients with predialysis chronic renal failure. This was not accompanied by an improvement of endothelial function and suggests that treatment with folic acid may not reduce the burden of vascular disease in uremia.

Aged↗
PubMed2000

Abnormalities of endothelial function in patients with predialysis renal failure.

BACKGROUND: Endothelial dysfunction plays an important role in the development of atherosclerotic vascular disease, which is the leading cause of mortality in patients with chronic renal failure. OBJECTIVE: To examine the relation between predialysis renal failure and endothelial function. DESIGN: Two groups were studied: 80 patients with non-diabetic chronic renal failure and 26 healthy controls, with similar age and sex distributions. Two indices of endothelial function were assessed: high resolution ultrasonography to measure flow mediated endothelium dependent dilatation of the brachial artery following reactive hyperaemia, and plasma concentration of von Willebrand factor. Endothelium independent dilatation was also assessed following sublingual glyceryl trinitrate. The patients were divided into those with and without overt atherosclerotic vascular disease. RESULTS: Although patients with chronic renal failure had significantly impaired endothelium dependent dilatation compared with controls (median (interquartile range), 2.6% (0.7% to 4.8%) v 6.5% (4.8% to 8.3%); p < 0.001) and increased von Willebrand factor (254 (207 to 294) v 106 (87 to 138) iu/dl; p < 0.001), there was no difference between renal failure patients with and without atherosclerotic vascular disease. Within the chronic renal failure group, endothelium dependent dilatation and von Willebrand factor were similar in patients in the upper and lower quartiles of glomerular filtration rate (2.7% (0.7% to 6.7%) v 2.8% (1.1% to 5.0%); and 255 (205 to 291) v 254 (209 to 292) iu/dl, respectively). Endothelium independent dilatation did not differ between the renal failure or control groups and was also similar in patients with renal failure irrespective of the degree of renal failure or the presence of atherosclerotic vascular disease. CONCLUSIONS: Endothelial function is abnormal in chronic renal failure, even in patients with mild renal insufficiency and those without atherosclerotic vascular disease, suggesting that uraemia may directly promote the development of atherosclerosis early in the progression of chronic renal failure.

Arteriosclerosis↗
PubMed2000

Hibernating myocardium: morphological correlates of inotropic stimulation and glucose uptake.

BACKGROUND: In patients with postischaemic left ventricular dysfunction, segments recovering function after revascularisation (hibernating myocardium) may not respond during dobutamine echocardiography, despite preserved [(18)F] 2-fluoro-2-deoxy-D-glucose (FDG) uptake at positron emission tomography. OBJECTIVE: To investigate whether this lack of response might reflect the degree of ultrastructural change in hibernating myocardium. METHODS: Transmural biopsies were obtained from 22 dysfunctional segments in 22 patients during coronary artery bypass grafting and examined by light and electron microscopy. Wall motion scores and coronary vasodilator reserve were assessed before and after coronary artery bypass grafting (CABG). RESULTS: Mean (SD) wall motion score improved in all segments following CABG (from 2.24 (0.4) to 1.55 (0.4); p < 0.0001), confirming hibernating myocardium. In these segments myocardial blood flow (positron emission tomography with H(2)(15)O) before CABG was similar to that in normal volunteers (1.02 (0.24) v 1.02 (0.23) ml/min/g), while the coronary vasodilator reserve was blunted (1.26 (0.7) v 3.2 (1.6); p < 0.0001). Myocardial blood flow was unchanged after CABG, whereas coronary vasodilator reserve increased to 2.10 (0.90) (p < 0.0007). In hibernating myocardium myofibrillar loss, interstitial fibrosis, and glycogen-rich myocytes were more marked than in control donor hearts. On the basis of the response to dobutamine before CABG, two functional groups were identified: group A, segments with inotropic reserve (n = 15); group B, segments without inotropic reserve (n = 7). FDG uptake was similar in group A and group B (0.40 (0.1) v 0.44 (0.1) micromol/min/g). In group B there was more myofibrillar loss (26 (8)% v 11 (5)%; p = 0.0009) and glycogen-rich myocytes (28 (11)% v 17 (10)%; p = 0.02), whereas interstitial fibrosis, myocardial blood flow, and coronary vasodilator reserve were similar in the two groups. Myofibrillar loss was the only independent predictor of inotropic reserve (p = 0.01). CONCLUSIONS: Hibernating myocardium is characterised by a reduced coronary vasodilator reserve which improves on revascularisation and shows a spectrum of ultrastructural changes that influence the response to dobutamine, while FDG uptake is invariably preserved.

Adult↗