Showing papers by "Philip A. Poole-Wilson published in 1994"
TL;DR: It is likely to be increasingly difficult to reduce mortality with newer treatments without specifically targeting the underlying processes leading to left ventricular dysfunction, and this is a valid area for therapeutic intervention, but one in which objective measurements of benefit have proved difficult to obtain.
Abstract: Heart failure is a common and debilitating condition with a high mortality.' Reductions in mortality in this condition have been achieved by treatment with vasodilators, in particular the angiotensin converting enzyme (ACE) inhibitors, but there remains a considerable burden of disability and mortality. The other mainstay, diuretic treatment, has never been shown to reduce mortality in heart failure but its ability to relieve life threatening pulmonary oedema and to help relieve fluid retention and dyspnoea in chronic heart failure is not seriously questioned. It is likely to be increasingly difficult to reduce mortality with newer treatments without specifically targeting the underlying processes leading to left ventricular dysfunction. There remain, however, many unrelieved symptoms in optimally treated patients, with a correspondingly low quality of life. This is a valid area for therapeutic intervention, but one in which objective measurements of benefit have proved difficult to obtain. Therapeutic strategies have also been limited by our poor understanding of the physiological bases of the cardinal symptoms, dyspnoea and fatigue.
303 citations
TL;DR: High- and low-frequency power showed a similar circadian pattern in Syndrome X patients and control subjects and an inverse correlation between heart rate and measures of heart rate variability was found in syndrome X but not in control subjects.
Abstract: Anomalies of autonomic control of the coronary circulation may play a role in the development of syndrome X (angina pectoris, ischemic-appearing results on exercise test, and normal coronary arteriograms). Twenty-six patients with syndrome X and 20 healthy sex- and age-matched control subjects were studied by means of analysis of heart rate variability during 24-hour Holter monitoring. Spectral and nonspectral parameters of heart rate variability were investigated. Mean heart rate was similar in patients with syndrome X and in control subjects. Patients with syndrome X had significantly lower standard deviation of all normal RR intervals, a lower percentage of adjacent normal RR intervals > 50 ms in difference (126.4 +/- 22 vs 149 +/- 43 ms, p < 0.05; 6.3 +/- 4 vs 11.2 +/- 7%, p < 0.05; respectively), and a trend toward lower values of time-domain parameters. Lower values of total power and low frequency were also observed in patients with syndrome X (1273 +/- 693 vs 1790 +/- 989 ms2, p < 0.05; 406 +/- 176 vs 729 +/- 455 ms2, p < 0.01, respectively). An inverse correlation between heart rate and measures of heart rate variability was found in syndrome X but not in control subjects. High- and low-frequency power showed a similar circadian pattern in syndrome X patients and control subjects. Patients and control subjects were then allocated into 2 groups according to the median RR duration: syndrome X1 and control 1 with high mean heart rate, and syndrome X2 and control 2 with low mean heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)
89 citations
72 citations
46 citations
TL;DR: The 9-minute walking test on a self-powered treadmill is a sensitive, reproducible, safe, and inexpensive method of assessing functional capacity in patients with all grades of heart failure.
Abstract: OBJECTIVES--To assess the efficacy of a 9-minute walking test on a self-powered treadmill in a group of patients with various degrees of heart failure, to investigate the reproducibility of the technique, and to establish the safety of the technique. PATIENTS AND METHODS--24 controls and 37 patients with various grades of heart failure were studied. Peak oxygen consumption was measured in patients and controls. The distance walked in 9 minutes on a self-powered treadmill was measured in all groups and the test was repeated to assess reproducibility. RESULTS--The distance walked in 9 minutes correlated with peak oxygen consumption in patients, controls, and both groups combined. There was a significant difference in the distance walked by controls and patients and in the distance walked by patients with severe rather than with mild or moderate heart failure. There was no significant difference between the results of successive 9-minute walking tests in any group. No serious adverse reaction was seen in any patient during or after the test. CONCLUSION--The 9-minute walking test on a self-powered treadmill is a sensitive, reproducible, safe, and inexpensive method of assessing functional capacity in patients with all grades of heart failure.
24 citations
TL;DR: It is suggested that lemakalim reduces systolic [free Ca2+]i by activating ATP sensitive potassium channels which results in a decrease of action potential duration in guinea pig and human ventricular myocytes.
Abstract: OBJECTIVE The aim was to investigate the effects of lemakalim on action potential duration, intracellular free calcium ([free Ca2+]i), and cell contraction in human and guinea pig cardiac myocytes. In addition, the possible modulation by pH of lemakalim induced activation of ATP sensitive potassium (KATP) channels was assessed. METHODS Single ventricular myocytes were enzymatically dissociated from adult male guinea pigs (300-600 g). Single myocytes were isolated from human ventricular tissues. Cells were loaded with the acetoxymethyl ester form of fura-2 to monitor changes in [free Ca2+]i and subjected to conventional electrophysiological techniques. RESULTS In guinea pig cells, lemakalim (3, 10, 30 microM) reduced action potential duration in a concentration dependent manner. This decrease was accompanied by hyperpolarisation of the resting membrane potential. Lemakalim (3, 10, 30 microM) reduced the systolic fura-2 fluorescence ratio without having a significant effect on diastolic fluorescence and also reduced the cell contraction in concentration dependent manner. Glibenclamide (1 microM), a specific inhibitor of KATP channels, did not affect action potential duration, fura-2 fluorescence ratio, or cell contraction in the absence of lemakalim. However, the same dose of glibenclamide markedly inhibited the lemakalim induced decrease in action potential duration, fura-2 fluorescence ratio, and cell contraction. Reducing extracellular pH enhanced the decrease in action potential duration induced by lemakalim. In human ventricular myocytes, lemakalim (3, 10 and 30 microM) caused a decrease in action potential duration and systolic fura-2 fluorescence ratio. The reduction in action potential duration and fura-2 fluorescence ratio was also reversed by glibenclamide (1 microM). CONCLUSIONS These results suggest that lemakalim reduces systolic [free Ca2+]i by activating ATP sensitive potassium channels which results in a decrease of action potential duration in guinea pig and human ventricular myocytes. The reduction in [free Ca2+]i mediates the negative inotropic effect induced by lemakalim. In addition, pH may modulate the KATP channel activation by the channel opener.
23 citations
TL;DR: Compared in man the effects of acetylcholine with substance P, which appears to be a pure endothelium-dependent vasodilator, on epicardial and resistance coronary arteries in patients with idiopathic dilated cardiomyopathy and 10 control subjects.
Abstract: Attenuation of the increase in blood flow caused by acetylcholine in the peripheral vasculature and coronary circulation of patients with heart failure has been interpreted as an impairment of endothelium-dependent vasodilation. The aim of this study was to compare in man the effects of acetylcholine, which also has endothelium-independent actions, with substance P, which appears to be a pure endothelium-dependent vasodilator, on epicardial and resistance coronary arteries in patients with idiopathic dilated cardiomyopathy. The effects of intracoronary acetylcholine (10(-7) M and 10(-6) M) and substance P (5, 10 and 25 pmol.min-1) on epicardial coronary artery diameter and coronary blood flow velocity were measured with an intracoronary Doppler flow probe and quantitative coronary angiography in 11 patients with idiopathic dilated cardiomyopathy and 10 control subjects. Epicardial coronary artery diameter did not change with acetylcholine but increased significantly with substance P in both groups (cardiomyopathy patients: 3.3 +/- 0.2 mm (mean +/- SEM) at baseline vs 3.9 +/- 0.2 mm with substance P25 pmol.min-1, P < 0.01; controls: 3.1 +/- 0.2 mm at baseline vs 3.9 +/- 0.3 mm with substance P25 pmol.min-1, P < 0.05). Coronary flow ratios with acetylcholine were lower in cardiomyopathy patients (10(-7) M: 1.4 +/- 0.1 vs 2.3 +/- 0.4, P = 0.05; 10(-6) M: 1.8 +/- 0.2 vs 3.2 +/- 0.5, P = 0.05 vs controls).(ABSTRACT TRUNCATED AT 250 WORDS)
20 citations
TL;DR: The role of the sympathetic system is indicated by the parallels between myocytes from failing human heart and those from the noradrenaline-treated guinea-pig, which show beta-adrenoceptor desensitization, a post-receptor defect and reduced basal cyclic AMP levels.
Abstract: Ventricular myocytes from failing human hearts have a similar maximum contraction amplitude in high Ca2+ to those from non-failing heart at low stimulation rates (0.2 Hz, 32 degrees C), but do not exhibit the same positive frequency-interval relationship. At higher stimulation rates (1 Hz) therefore, the amplitude is depressed in cells from failing hearts compared to controls. Slow relaxation is seen in myocytes from failing ventricle at all stimulation rates, and contraction velocity is also slightly reduced. beta-adrenoceptor desensitization is evident, and increases with severity of disease. There is also a post-receptor defect in myocytes from failing heart since responses to forskolin and cyclic AMP analogues are reduced, and this is accompanied by decreased cyclic AMP levels in myocardium from patients in end-stage disease. Pertussis toxin treatment, which inactivates Gi, reverses most of the alterations in the beta-adrenoceptor pathway. The role of the sympathetic system is indicated by the parallels between myocytes from failing human heart and those from the noradrenaline-treated guinea-pig, which show beta-adrenoceptor desensitization, a post-receptor defect and reduced basal cyclic AMP levels. However, relaxation velocities are not slowed in these guinea-pig myocytes, indicating that basal cyclic AMP does not have a tonic role in speeding relaxation.
15 citations
TL;DR: The report by Uretsky et al .
9 citations
TL;DR: The DEFIANT-II study as mentioned in this paper showed that the effect of nisoldipine on left ventricular (LV) size and function after acute myocardial infarction.
Abstract: The DEFIANT-I study (Doppler Flow andEchocardiography inFunctional cardiacInsufficiency:Assessment ofNisoldipineTherapy) was a multicenter, multinational double-blind randomized study of the effects of the new calcium channel blocking drug nisoldipine on left ventricular (LV) size and function after acute myocardial infarction. Randomization to placebo or to long-acting nisoldipine core coat (20 mg once daily) was performed in 135 eligible patients with mild to moderate systolic LV dysfunction (LV ejection fraction ≤50%) 20 days (range 7–35) after infarction, with serial clinical, echocardiographic, and Doppler cardiographic measurements during a 4 week follow-up period. At the end of the follow-up period, exercise capacity was determined by bicycle ergometry. Nisoldipine improved indices of diastolic LV function. Early diastolic transmitral blood flow velocity increased, with an increase in peak E wave of 0.06 m/sec (95% confidence intervals [CI], 0.01, 0.11) and an increase in time velocity integral of 1.2 cm (95% CI, 0.16, 2.27). Isovolumic relaxation time was reduced by 14.7 msec (95% CI, −22.5, −6.9), a change not explained by the very small (and not significant) changes in systemic arterial pressure, heart rate, or cardiac output. There was no change in systolic and diastolic LV volume, nor in LV ejection fraction. Exercise capacity was greater by 12 watts (95% CI, 0.8, 23.3) in patients receiving nisoldipine, while the incidence of ≥1 mm ST-segment depression (relative occurrence 0.54, 95% CI, 0.30–0.97) and the incidence of angina pectoris (relative occurrence 0.67, 95% CI, 0.42–1.08) during exercise testing tended to be lower in this group. Although the relations were not exact, peak exercise workload 7 weeks after infarction correlated with resting measurements of diastolic LV function. Exercise workload was inversely related to peak late diastolic transmitral blood flow velocity (A wave, slope, −86.6; 95% CI, −120.9, −52.2) and directly to the E/A ratio (slope, 20.5, 95% CI, 6.0, 35.1). The relations between exercise workload and peak late diastolic flow velocity remained significant after correction for age, sex, resting heart rate, and usage of beta-blocking drugs or nisoldipine. Exercise capacity was not related to measurements of systolic LV function (LV end-diastolic and end-systolic volume, LV ejection fraction, stroke volume, cardiac index). In summary, the calcium channel blocker nisoldipine improved measurements of diastolic LV function in patients recovering from acute myocardial infarction. Exercise capacity was higher in patients receiving the drug, and there was less exercise induced ischemia. In both placebo and nisoldipine groups, exercise capacity was related to measurements of resting diastolic LV function. The observed changes in diastolic LV function during nisoldipine therapy may reflect the antiischemic effect of the drug and/or be due to an improvement in myocardial relaxation. The DEFIANT-II study, presently in progress, will examine the effect of higher doses of nisoldipine on LV function and exercise performance after acute myocardial infarction, with a longer (6 month) follow-up period.
6 citations
TL;DR: Patients who present to the cardiologist with pain typical of angina often undergo coronary angiography regardless of whether other tests such as an exercise tolerance test or a radionuclide investigation have been undertaken or provide supporting evidence of a cardiac origin for the pain.
Abstract: Patients who present to the cardiologist with pain typical of angina often undergo coronary angiography regardless of whether other tests such as an exercise tolerance test or a radionuclide investigation have been undertaken or provide supporting evidence of a cardiac origin for the pain. Between 10% and 20% of coronary angiograms are interpreted as being normal1; the paradox of a normal coronary angiogram and typical angina chest pain was clearly identified in 19672. Many phrases have been used to describe patients with chest pain suggestive of angina. These include Da Costa’s syndrome, effort syndrome3, neurocirculatory asthenia4, anxiety neurosis, chest wall syndrome5, hyperventilation syndrome6, syndrome X7 and microvascular angina8. Many of these phrases hint at a particular cause for the chest pain but the variety of terminology suggests an unresolved clinical problem. The possible causes extend from the mind9,10 to bones, muscle, oesophagus11–13, lung14, metabolism15, the endocrine system16 and the heart17–19. Though the prognosis of these patients is excellent17,20, they usually continue to have clinical problems and consume medical resources21. Only a minority go on to develop any cardiac problem including cardiomyopathy22.