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Biomedical subjects

S M Cobbe

Publications and source records attributed to S M Cobbe.

At least 91 records · Page 5Linked to original sources
PubMed1995

Activation and inhibition of the endogenous opioid system in human heart failure.

BACKGROUND: In a canine model of congestive heart failure beta endorphin concentrations were high and opioid receptor antagonists exerted beneficial haemodynamic effects. In humans previous studies have suggested that opioid peptides may modify the perception of breathlessness and fatigue in heart failure. METHODS: Plasma concentrations of beta endorphin were measured in patients with acute and chronic heart failure and cardiogenic shock. A subgroup of eight patients with New York Heart Association (NYHA) class III-IV heart failure was assessed for acute haemodynamic effects of naloxone, an opioid receptor antagonist. A separate group of 10 patients with class II-III heart failure, was randomised to a double blind placebo controlled study of the effects of intravenous naloxone on cardiopulmonary exercise performance. RESULTS: Plasma concentrations of beta endorphin were usually normal in patients with chronic heart failure and did not correlate with severity as assessed by NYHA class. In 29% of patients with acute heart failure and 71% of those with cardiogenic shock beta endorphin concentrations were high. The median concentration in the cardiogenic shock group was significantly higher than in either of the two heart failure groups and there was some evidence of a relation between beta endorphin concentrations and survival. At the doses tested, naloxone was unable to modify systemic haemodynamics, exercise performance, or symptoms in patients with chronic congestive heart failure. CONCLUSIONS: Circulating concentrations of beta endorphin are usually normal in patients with chronic congestive heart failure. Inhibition of the endogenous opioid system is unlikely to have therapeutic potential in heart failure.

Acute Disease↗
PubMed1995

Heart rate variability in left ventricular hypertrophy.

BACKGROUND: Electrocardiographic left ventricular hypertrophy and strain are associated with increased cardiac morbidity and mortality. Impaired cardiac autonomic function, assessed non-invasively by spontaneous heart rate variability on Holter monitoring, is associated with an increased risk of sudden death after myocardial infarction. AIM: To study the effect of left ventricular hypertrophy on heart rate variability. PATIENTS: 36 controls and 154 patients with left ventricular hypertrophy (94 with hypertension and 60 with aortic valve disease). SETTING: Tertiary referral centre. METHODS: Heart rate variability was measured on 24 h Holter recordings by non-spectral methods. Left ventricular mass index and fractional shortening were measured by echocardiography. RESULTS: Patients with left ventricular hypertrophy had a higher left ventricular mass index (P < 0.001) and reduced heart rate variability (P < 0.001) compared with those of the controls. A continuous inverse relation was apparent between heart rate variability and left ventricular mass index (r = -0.478, P < 0.001). Heart rate variability was not affected by age, the presence of coronary artery disease in patients with left ventricular hypertrophy, or beta blocker treatment for hypertension. Multivariate analysis showed that left ventricular mass index is the most important determinant of heart rate variability. CONCLUSION: Heart rate variability is significantly reduced in patients with left ventricular hypertrophy secondary to hypertension or aortic valve disease. A continuous inverse relation exists between heart rate variability and left ventricular mass index. Impaired cardiac autonomic function in left ventricular hypertrophy may contribute to the mechanism of sudden death.

Aortic Valve Stenosis↗
PubMed1995

Do radionuclide and echocardiographic techniques give a universal cut off value for left ventricular ejection fraction that can be used to select patients for treatment with ACE inhibitors after myocardial infarction?

OBJECTIVE: To determine whether echocardiography and radionuclide angiography give comparable results when the left ventricular ejection fraction is measured early after myocardial infarction and thus whether, irrespective of the method used, a single value for the ejection fraction could be used as a guide for starting treatment with an angiotensin converting enzyme inhibitor. DESIGN: Prospective comparison of measurement of left ventricular ejection fraction by echocardiography and radionuclide angiography. SETTING: Coronary care units of two university teaching hospitals in Glasgow. PATIENTS: 99 patients studied within 36 hours of acute myocardial infarction. OUTCOME MEASURES: Left ventricular ejection fraction assessed by echocardiography and radionuclide angiography. RESULTS: 70 (77%) of the 99 patients had ejection fraction measured by both echocardiographic and radionuclide techniques, 30 in centre 1 and 40 in centre 2. In centre 1 the mean difference (SD) in ejection fraction (radionuclide angiography--echocardiography) was -8 (10%); 95% CI -12 to -4%. In centre 2 the mean difference was -14 (11%); 95% CI -17 to -11%. If patients had been treated with an ACE inhibitor on the basis of a radionuclide ejection fraction of < 40% then 93% in centre 1 (28 of 30) and 98% in centre 2 (39 of 40) would have been treated. This compares with 63% (19 of 30) and 50% (20 of 40), respectively if echocardiography had been used as a guide. CONCLUSION: Measurement of ejection fraction is highly dependent on the method used and it is therefore impossible to quote a universally applicable figure for left ventricular ejection fraction below which an ACE inhibitor should be used after myocardial infarction.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

The electrophysiology of rabbit hearts with left ventricular hypertrophy under normal and ischaemic conditions.

OBJECTIVES: To examine the cardiac electrophysiological effects of left ventricular hypertrophy (LVH) and to determine whether any observed differences are modified by global zero-flow ischaemia. METHODS: LVH was induced by perinephritic hypertension in New Zealand White rabbits. Transmembrane action potential recordings were made using conventional floating glass microelectrodes and effective refractory periods (ERP) determined by programmed stimulation in isolated arterially perfused interventricular septa during normal perfusion and a 30-min period of global ischaemia. The electrophysiological data were pooled into 6-min periods during ischaemia. RESULTS: The post-operative blood pressure was 76(2) mmHg (mean(s.e.m.)) and 113(2) mmHg (P < 0.0005) in the sham and perinephritic rabbits respectively. The left ventricular to body weight ratio was 0.27(0.01) g kg-1 in the sham and 0.36(0.02) g kg-1 in the perinephritic group (P < 0.005) representing 33% hypertrophy. In the isolated septa, prior to ischaemia, the hypertrophied group exhibited significant prolongations in action potential duration to 50% and 90% repolarisation (APD50, APD90) and ERP of 20%, 12% and 19% respectively (P < 0.005) without any differences in resting membrane potential (Em), upstroke velocity (dV/dtmax) or amplitude (APA) of the action potential. During ischaemia Em, APA and dV/dtmax progressively decreased to a similar extent in both groups. Ischaemia resulted in shortenings in APD50, APD90 and ERP in the hypertrophy group of 122(9) ms, 131(8) ms and 99 (6) ms respectively which were greater than those observed in the control group (84 (7) ms, 115 (7) ms and 50 (13) ms, P < 0.05). These differences resulted in loss of the preischaemic prolongation of repolarisation and refractoriness in the hypertrophy group. CONCLUSIONS: There was enhanced shortening of APD and ventricular refractoriness in hypertrophied muscle during global ischaemia. This could increase the dispersion of repolarization and refractoriness between normal and ischaemic hypertrophied muscle during regional ischaemia which may explain the increased susceptibility of hypertrophied hearts to arrhythmias.

Action Potentials↗
PubMed1995

Sarcoplasmic reticulum and myofilament function in chemically-treated ventricular trabeculae from patients with heart failure.

OBJECTIVES: Assessment of sarcoplasmic reticulum calcium-loading ability, myofilament force production and myofilament calcium sensitivity in ventricular trabeculae from patients with heart failure. METHODS: Right ventricular trabeculae (diameter 150-250 microns) were obtained from 18 patients undergoing elective cardiac transplantation. These were mounted for isometric tension measurement and treated with saponin which permeabilises the sarcolemma leaving the sarcoplasmic reticulum (SR) functionally intact. The trabecula was bathed in a mock intracellular solution containing ATP and weakly buffered [Ca2+] at various concentrations (150-400 nM). The amplitude of caffeine-induced contractures was used as a quantitative measure of the SR calcium content and was correlated with the clinical severity of heart failure. The same trabecula was then exposed to a solution containing Triton-X100 (1%) which destroys all cell membranes leaving only the myofilaments intact. The maximum calcium-activated force (Cmax) and myofilament responsiveness to calcium was assessed. RESULTS: Patients with ischaemic heart disease (IHD) and severe heart failure (PCWP > 20 mm Hg, ejection fraction < 15%, n = 8) demonstrated low SR Ca(2+)-loading ability compared with patients with IHD and moderate heart failure (PCWP-20 mmHg, LV ejection fraction > 20%, n = 6). Patients with dilated cardiomyopathy (DCM) (n = 4) demonstrated SR Ca(2+)-loading ability which was lower than either of the two IHD groups. Myofilament force production (per unit cross-sectional area) was not significantly different between the three groups. Myofilament responsiveness to Ca2+ demonstrated no relationship with severity of heart failure. CONCLUSIONS: In human heart failure, SR Ca(2+)-loading ability diminishes with increasing severity of heart failure. Myofilament force production and sensitivity to calcium are unaffected by severity of heart failure.

Actin Cytoskeleton↗
PubMed1995

Adenosine increases potassium conductance in isolated rabbit atrioventricular nodal myocytes.

OBJECTIVE: To study the actions of adenosine on the electrophysiology of spontaneously active, rod-shaped cells enzymatically isolated from rabbit atrioventricular (AV) node. METHODS: Calcium-tolerant myocytes were isolated from the region of the AV node by enzymatic and mechanical dispersion. They were rod- or spindle-shaped, with spontaneous activity at 35-37 degrees C, and had higher membrane resistances (776 +/- 283 M omega, n = 13), compared to atrial cells (41 +/- 18.2 M omega, n = 7; P < 0.001). Membrane potential, spontaneous action potentials and transmembrane ionic currents were studied using the whole-cell patch-clamp technique, in current-clamp and voltage-clamp mode. RESULTS: Adenosine (0.1-50 microM) slowed or abolished the spontaneous activity, with hyperpolarisation of the membrane potential. Voltage-clamp experiments showed that adenosine induced an inwardly rectifying time-independent current. The adenosine-induced current was shown to be carried by potassium ions by the effect of increasing external potassium, which altered the reversal potential in accordance with the calculated potassium equilibrium potential. The A1 adenosine receptor antagonist, CPDPX (8-cyclopentyl-1,3-dypropylxanthine), reversed the effects of adenosine and an A1 receptor agonist, R-PIA [R(-)N(6)-(2-phenylisopropyl)adenosine] had effects similar to adenosine. Adenosine also caused a small decrease in inward calcium current (ICa) in some AV nodal cells. CONCLUSIONS: These results indicate that adenosine acts at A1 adenosine receptors to suppress spontaneous activity, hyperpolarise membrane potential and induce a time-independent potassium current in AV nodal cells. These actions, combined with reduction in inward calcium current in some cells, may underlie the negative chronotropic and dromotropic actions of adenosine on rabbit AV nodal cells.

Adenosine↗
PubMed1994

A clinical and in vitro study on the possible interaction of intravenous nitrates with heparin anticoagulation.

It has been reported that intravenous nitrates inhibit the anticoagulant effect of heparin. This possible interaction has potentially serious implications for the management of patients with acute coronary ischemic syndromes. This possible interaction was assessed prospectively in a clinical and in an in vitro study involving 24 patients receiving both drugs for the management of unstable angina pectoris. There was a small inhibitory effect of intravenous glyceryl trinitrate or isosorbide dinitrate on the anticoagulant effect of heparin in 3 of 24 cases in vivo, as assessed by activated partial thromboplastin time measurements. Nitrates or propylene glycol had no effect on heparin activity in vitro. It was concluded that there may be an inhibitory effect of nitrates on anticoagulation in a small minority of patients, but close attention to detail in monitoring heparin anticoagulation is far more important.

Angina, Unstable↗
PubMed1994

The causative rhythm in out-of-hospital cardiac arrests witnessed by the emergency medical services in the Heartstart Scotland Project.

Out-of-hospital defibrillation has been shown to improve survival in out-of-hospital cardiac arrests. The maximum performance of defibrillation-based systems is dependent on the proportion of cardiac arrests due to tachyarrhythmias. We reviewed 4248 reported arrests in the Heartstart Scotland database. We identified 3489 arrests due to cardiac or unknown cause. From this group we selected 258 cases known to be conscious on arrival of the crew. We were able to retrieve electrocardiographic data on the period within 2 min of the arrest in 106 cases. The first recorded rhythm at the arrest was ventricular fibrillation in 64%, ventricular tachycardia 4%, bradycardia in 28% and electromechanical dissociation in 4%. Defibrillatory shocks were delivered to 96% of patients in ventricular fibrillation and 60% of these patients survived. None of the patients with bradycardic arrests survived. Preceding chest pain was noted in 79% of patients subsequently developing ventricular fibrillation as the cause of arrest compared to only 37% of those suffering bradycardic arrests. It would appear that public awareness of the importance of early contact with the emergency services after the onset of chest pain could substantially improve the survival from out-of-hospital arrests.

Aged↗
PubMed1994

Effects of contraction-excitation feedback on electrophysiology and arrhythmogenesis in rabbits with experimental left ventricular hypertrophy.

OBJECTIVE: The aim was to investigate the influence of contraction-excitation feedback on myocardial electrophysiology and arrhythmia susceptibility in the setting of experimental left ventricular hypertrophy. METHODS: New Zealand White rabbits with perinephritis hypertension were used. With the hearts perfused in vitro, left ventricular monophasic action potential duration and local effective refractory periods were determined at three sites, namely the anterior, apical, and posterior wall, together with ventricular tachycardia inducibility and ventricular fibrillation threshold under different loading conditions. RESULTS: The left ventricular dry weight to body weight ratio was increased by 31% in the hypertrophied group (3.863 x 10(-4), v 2.955 x 10(-4) in the controls). Left ventricular hypertrophy was associated with prolongation of action potential duration when the left ventricle was not loaded and under normal loading conditions. Changing from unloaded Langendorff to baseline working heart perfusion resulted in a consistent decrease in action potential duration and effective refractory period at all left ventricular sites in both hypertrophied and control hearts. Subsequent manipulations of myocardial loading resulted in decreases in action potential duration and effective refractory period in both groups of hearts. Ventricular tachycardia could not be induced in any heart in Langendorff mode. Under different increased loading conditions, a total of four hypertrophied hearts (44%) became inducible, while control hearts remained non-inducible. The ventricular fibrillation threshold under conditions of increased load tended to be lower in the hypertrophied hearts than the control hearts; in the setting of increased preload the hypertrophied group showed significantly increased vulnerability to ventricular fibrillation (median threshold currents 35 mA v > 100 mA, p < 0.05). CONCLUSIONS: Left ventricular hypertrophy is associated with a prolongation of action potential duration and effective refractory period and an increased arrhythmia susceptibility in the setting of increased myocardial loading. There were no marked differences between the groups in the magnitude of the changes in action potential duration, effective refractory period, or dispersion of repolarisation and refractoriness resulting from manipulations of myocardial loading that could have been implicated in the increased arrhythmia susceptibility of the hypertrophied hearts during changes in load.

Action Potentials↗
PubMed1994

Drug therapy of supraventricular tachyarrhythmias--based on efficacy or futility?

The clinical spectrum of supraventricular tachyarrhythmias ranges from infrequent, brief and well tolerated episodes of arrhythmia to attacks resulting in cardiovascular collapse. Many patients have such infrequent episodes that prophylactic or ablative therapy is not indicated. In those with more troublesome symptoms, an initial trial of medical therapy is common unless the arrhythmia has major prognostic or vocational importance. Thus despite the recent advances in catheter ablation techniques, there remains a place for antiarrhythmic drug therapy in supraventricular tachyarrhythmias. Furthermore, ablation therapy in atrial fibrillation is currently unable to control arrhythmias except by destruction of the normal conduction system. In contrast to the therapy goals in ventricular tachyarrhythmias, safety considerations far outweigh those of efficacy in the drug management of supraventricular tachycardias. Many patients with supraventricular tachyarrhythmias are young and have no serious underlying heart disease. Although symptomatic recurrences of arrhythmia are troublesome, these should be regarded as acceptable if the alternative is serious drug-related toxicity. There are relatively few well conducted clinical trials of the efficacy of drug therapy in supraventricular tachycardia. Existing study data and new trial information on the efficacy of propafenone are reviewed.

Atrial Fibrillation↗
PubMed1994

Failure to reproduce the in vitro cardiac electrophysiological effects of naloxone in humans.

1. Opioid receptor antagonists such as naloxone have shown antiarrhythmic activity in animal models of coronary artery occlusion. Studies have indicated that these effects are stereospecific but both isomers of naloxone prolong action potential duration and refractoriness in guinea-pig and rabbit isolated ventricular myocardium (Class III effect). 2. This study was performed to identify whether this Class III effect of naloxone could be reproduced in human myocardium in vivo. Twenty patients with coronary artery disease received intravenous racemic naloxone (1-40 micrograms kg-1 min-1). Surface electrocardiographic parameters were measured and refractory periods were determined during fixed rate pacing by programmed stimulation. 3. The corrected QT interval during sinus rhythm (SR-QTc) was prolonged by 5(3)% (P = 0.06) at a dose of 20 micrograms kg-1 min-1 and by 9(10)% at 40 micrograms kg-1 min-1 (P = 0.03). These small changes were lost at higher paced heart rates. No significant effects on atrial, atrioventricular nodal or ventricular refractoriness were seen. 4. Plasma naloxone concentrations well into the micromolar range were achieved with both of the higher doses of naloxone administered. Plasma beta-endorphin concentrations invariably increased following naloxone infusion. There was no statistical relationship between peak plasma naloxone concentrations and the absolute or percent prolongation of SR-QTc. 5. It seems unlikely that racemic naloxone would have any clinical utility as an antiarrhythmic agent. Racemic naloxone may enhance cardiac adrenergic nerve activity and this receptor mediated effect may have prevented the demonstration of any nonreceptor mediated prolongation of cardiac refractoriness. Studies with the individual stereoisomers of naloxone would be of interest.

Action Potentials↗
PubMed1994

Increase in plasma beta endorphins precedes vasodepressor syncope.

BACKGROUND: Endogenous opioids have a tonic inhibitory effect on sympathetic tone and have been implicated in the pathophysiology of vasodepressor syncope. Plasma beta endorphin concentrations increase after vasodepressor syncope induced by exercise or by fasting. AIMS: To take frequent samples for plasma beta endorphin estimation during tilt testing, and to determine whether plasma beta endorphin increased before the start of syncope. PATIENTS: 24 patients undergoing tilt testing for investigation of unexplained syncope. SETTING: Tertiary referral centre. METHODS: Blood samples were obtained during 70 degrees head up tilt testing. Plasma beta endorphin concentrations were estimated by radioimmunoassay (mean(SD) pmol/l). RESULTS: Patients with a positive test showed a rise in beta endorphin concentrations before syncope baseline 4.4(1.5) v start of syncope 8.5(3.1), p < 0.002). In contrast, patients with a negative test showed no change in beta endorphin concentrations (baseline 3.4(1.0) v end of test 4.5(2.3), NS). After syncope all patients showed a large secondary increase in beta endorphins (32.3(18.6)). CONCLUSION: An increase in plasma beta endorphins precedes vasodepressor syncope. This finding supports a pathophysiological role for endogenous opioids.

Adolescent↗
PubMed1994

QT interval dispersion: a non-invasive marker of susceptibility to arrhythmia in patients with sustained ventricular arrhythmias?

OBJECTIVE: To assess QT interval dispersion on the surface electrocardiogram in patients with sustained ventricular arrhythmias. DESIGN: A retrospective and prospective blinded controlled study of patients referred for investigation of ventricular arrhythmias at a tertiary cardiac centre. PATIENTS AND METHODS: 89 consecutive patients with sustained ventricular arrhythmias due to chronic ischaemic heart disease, cardiomyopathy, or ventricular tachycardia (VT) in a normal heart. 32 patients did not meet the inclusion criteria; therefore 57 patients were compared with a control group of 40 patients with myocardial disease but no history of arrhythmias and 12 normal controls with no myocardial disease. Standard 12 lead electrocardiograms were enlarged, the QT intervals for each lead measured, and QT dispersion calculated. RESULTS: There was a significantly greater mean QT dispersion (77 ms) in patients with sustained ventricular arrhythmias compared with the control group (38 ms, p < 0.01). This held for all groups; after myocardial infarction VT (82 (22) ms v control 38 (10) ms; p < 0.01), dilated cardiomyopathy VT (76 (18) ms v control 40 (11) ms, p < 0.01), and normal heart VT (65 (7) ms v control 32 (8), p < 0.05). There was also a greater QT dispersion in patients with impaired left ventricular function and VT, with a correlation between left ventricular function and QT dispersion in patients with VT (r = 0.56, p < 0.01). CONCLUSION: QT interval dispersion may be a further non-invasive marker of susceptibility to ventricular arrhythmias.

Arrhythmias, Cardiac↗