Biomedical subjects
W J Penny
Publications and source records attributed to W J Penny.
Microvascular angina may be a legacy of coronary thrombolysis.
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Hirudin, heparin, and placebo during deep arterial injury in the pig. The in vivo role of thrombin in platelet-mediated thrombosis.
Three dosages (0.3, 0.7, and 1.0 mg/kg) of recombinant hirudin, a specific inhibitor of thrombin, were compared with heparin (50 units/kg) and placebo for reducing thrombus formation in the carotid arteries of 50 pigs after deep injury by balloon dilatation. Each drug was administered as a bolus followed immediately by a continuous infusion of the same dose per hour. Major end points were quantitative indium-111-labeled platelet and iodine-125-labeled fibrinogen deposition and the incidence of mural thrombosis. This study showed that heparin, at a dose that prolonged the activated partial thromboplastin time (APTT) to twice the control time, did not prevent mural thrombosis or significantly reduce platelet deposition compared with placebo but did reduce fibrinogen deposition. Recombinant hirudin markedly reduced platelet and fibrinogen deposition in a dose-related manner and totally eliminated mural thrombosis at an APTT of two to three times that of control. Platelet deposition (x 10(6)/cm2, mean +/- SEM) in areas of deep arterial injury for the placebo, heparin, and 0.3, 0.7, and 1.0 mg/kg hirudin groups was 54 +/- 21, 33 +/- 9, 22 +/- 6, 8 +/- 1, and 7 +/- 1, respectively; electron microscopy showed a single layer (or less) of platelets at the two highest hirudin dosages. The incidence of macroscopic mural thrombosis was 76% with placebo, 57% with heparin, 46% with 0.3 mg/kg hirudin; there were no thrombi with 0.7 or 1.0 mg/kg hirudin (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Nifedipine is excreted in human milk.
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Post-infarction ventricular septal defect: the importance of right ventricular coronary perfusion in determining surgical outcome.
Mortality from a post-infarction ventricular septal defect (VSD) can be reduced by surgery, selection for which would be helped by knowledge of factors affecting the postoperative prognosis. We reviewed our 9-year experience (1978-1987) of 40 surgically treated patients, comparing preoperative characteristics in those who died postoperatively (n = 15, 37%) and those who survived (n = 25, 63%), all still alive. Sex, age, infarct size as assessed by peak serum creatine kinase values, left ventricular end-diastolic pressure and pulmonary/systemic flow ratio (2.9 +/- 0.2 vs 3.1 +/- 0.3) were similar. Survivors had a lower incidence of inferior infarct than those who died (6, 24% vs 9, 60%, P less than 0.05), a lower incidence of cardiogenic shock (7, 28% vs 10, 67%, P less than 0.05), less elevation of right ventricular end-diastolic pressure (10.1 +/- 0.9 vs 14.7 +/- 1.0 mm Hg, P less than 0.01) and less impairment of right ventricular coronary supply as determined by a coronary angiography-derived myocardial score (0.9 +/- 0.3 vs 4.7 +/- 0.7, P less than 0.001). The data suggest that right ventricular coronary perfusion influences prognosis. The proposed angiographic score may help to identify preoperatively those patients most likely to benefit from surgery.
Effects of thrombin inhibition on the development of acute platelet-thrombus deposition during angioplasty in pigs. Heparin versus recombinant hirudin, a specific thrombin inhibitor.
The effect of recombinant hirudin and the dosage of heparin on acute platelet-thrombus deposition during carotid angioplasty in anesthetized pigs was prospectively assessed. Fifty-five animals (mean weight, 33.9 kg) were randomized to one of six heparin dosages: heparin boluses of 35, 50, 100, 150, 200, or 250 units/kg followed by a continuous infusion of 35, 50, 100, 150, 200, or 250 units/kg/hr, respectively. Another five pigs received a bolus of 1 mg/kg hirudin (recombinant desulphatohirudin), a specific thrombin inhibitor, followed by an infusion of 1 mg/kg/hr. Bilateral carotid angioplasty was performed in all pigs 20 minutes after starting the infusion; they were sacrificed 57 +/- 12 minutes after the procedure. Deep medial arterial injury was present in approximately 75% of the dilated segments, and subendothelial injury in the remaining 25%. Mean log of number of platelets and molecules of fibrinogen per centimeter squared of deep injury in segments from all the animals treated with heparin were 4.74 +/- 1.03 and 5.02 +/- 0.64, respectively. A regression analysis showed an inverse correlation of the log of platelet deposition with the heparin group (r = -0.56, p = 0.0001) with administered total units of heparin (r = -0.55, p = 0.0003) and with mean plasma heparin concentration (r = -0.55, p = 0.0004) in deeply injured arteries. Similar inverse relations were obtained for fibrinogen. In contrast, the deposition of platelets and fibrinogen in subendothelial injury was very low and independent of the heparin administered.(ABSTRACT TRUNCATED AT 250 WORDS)
The sign of the flashing wheal in aortic regurgitation.
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A possible drug interaction between rifampicin and enalapril.
When a 35-year-old man with essential hypertension was treated with antibiotics for brucellosis his blood pressure rose significantly. While all other treatment was kept constant rifampicin was discontinued. On rechallenge rifampicin did not alter serum concentrations of enalapril or the area under the curve (AUC) between 0 and 7 h, but it did reduce the AUC of the active metabolite enalaprilat by 31%. These observations suggest that there may be an interaction between rifampicin and enalapril, causing reduced hypotensive efficacy of enalapril. The mechanism of such an interaction merits further study, but it could be due to enhanced renal clearance of enalaprilat.
Importance of adequate heparin dosage in arterial angioplasty in a porcine model.
Acute occlusion after a successful angioplasty is a severe complication that has been reported in 2-12% of patients. Therefore, to determine whether there was a relation between the dosage of heparin and the presence of mural thrombosis, we studied in a pig model the relation between the dosage of heparin and acute platelet-thrombus deposition on the site of arterial injury. We retrospectively analyzed the effect of three heparin regimens on platelet deposition in 32 normal pigs (mean weight, 32.7 kg) that underwent bilateral carotid angioplasty and were sacrificed 90 +/- 26 minutes later. Pigs in protocol 1 (n = 7) received an intravenous bolus injection of 4,000 units heparin 10 minutes before angioplasty. Pigs in protocol 2 (n = 11) received two bolus injections of 4,000 units heparin 40 minutes apart; the angioplasty was performed immediately after the second bolus. Pigs in protocol 3 (n = 14) had an initial 4,000-unit bolus injection of heparin followed immediately by an infusion of 4,000 units/hr; angioplasty was performed 20 minutes after starting the infusion. 111In-labeled platelet deposition on deeply injured (torn into the media) arterial segments were 86.3 +/- 68, 56.2 +/- 56.9, and 37.7 +/- 37.7 X 10(6)/cm2 for protocols 1, 2, and 3, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Antithrombotic therapy for patients with cardiac disease.
The use and type of antithrombotic therapy for patients with cardiac disease are described based on an understanding of the pathophysiologic mechanisms involved, the risk of thromboembolism, and the evidence from prospective and, if necessary, retrospective clinical trials. The indications and intensity of anticoagulant therapy in patients with valvular heart disease and prosthetic valves are first discussed. We recommend that the prothrombin time be reported as a ratio and standardized using the International Normalized Ratio. The pivotal role of platelets and the clotting system in the initiation and progression of atherosclerosis and the acute coronary syndromes is described. There is no evidence to date that antiplatelet therapy is of value in primary prevention or in patients with stable angina, but the value of aspirin in patients with unstable angina was clearly shown in two well-designed studies. Adequate prophylactic therapy to prevent the thrombotic complications of acute myocardial infarction (i.e., venous thrombosis and intracardiac thrombosis) is described, and the available data on the prevention of coronary reocclusion after thrombolysis reviewed. There is now convincing evidence from studies in animals and in patients that vascular injury during aortocoronary vein bypass graft surgery requires antitihrombotic therapy starting before the procedure to minimize acute platelet thrombus deposition and prevent occlusion. Restenosis after arterial angioplasty appears to be related to acute platelet thrombus deposition on the site of deep arterial injury. Therapeutic interventions should probably involve both anticoagulants and platelet inhibitor therapy. Implications derived from recent animal studies are discussed.
The incidence and significance of early pericardial effusion after open heart surgery.
The presence and severity of postoperative pericardial effusions were studied echocardiographically in 114 consecutive patients (70 males, 44 females; mean age 56 +/- 10 years). An effusion was present in 35 patients at 3-5 days. An effusion was less common when a drainage tube was inserted for 24-36 h in the posterior as well as the anterior mediastinum than when only an anterior drain was used. Patients with effusions differed from those without in having more supraventricular arrhythmias, more wound infections, smaller total blood drainage and longer postoperative hospital stay. Three patients with posterior pericardial effusions developed cardiac tamponade 5-18 days postoperatively. The data show that pericardial effusions are associated with postoperative complications and suggest that effusion formation can be reduced by using posterior as well as anterior chest drains.
Arrhythmogenic and electrophysiological effects of alpha adrenoceptor stimulation during myocardial ischaemia and reperfusion.
To examine possible arrhythmogenic effects of alpha adrenoceptor stimulation, we studied the effects of methoxamine 10(-6) M on arrhythmias and cellular electrophysiology during global myocardial ischaemia and reperfusion in isolated Langendorff perfused guinea-pig hearts. To avoid interference from release of endogenous catecholamines during ischaemia or reperfusion, experiments were performed using catecholamine depleted hearts (myocardial noradrenaline = 11% of control). Catecholamine depletion markedly reduced the incidence of VT and VF during ischaemia and reperfusion and perfusion with methoxamine significantly reversed this. This arrhythmogenic effect of methoxamine was only observed during ischaemia or reperfusion, was independent of beta adrenoceptor blockade and H2 receptor blockade but was abolished by alpha adrenoceptor blockade with phentolamine. Catecholamine depletion blunted the ischaemia induced fall in action potential amplitude and Vmax and prolonged action potential duration and refractory period. Perfusion with methoxamine either partially or completely reversed these effects. Thus, alpha adrenoceptor stimulation has little effect on normally perfused myocardium, but may induce VT or VF during ischaemia or reperfusion.
Adenosine causes transient dilatation of coronary arteries in man.
We investigated the effects of i.v. adenosine on coronary blood flow in 10 normal subjects undergoing investigation for chest pain. Coronary flow transiently doubled after greater than or equal to 3.5 mg adenosine without increase in perfusion pressure, systolic load or inotropic state at a constant, paced heart rate. The data provide direct evidence that adenosine dilates coronary arteries in man. The transience of the effect suggests a possible role for adenosine in repeated estimations of coronary flow reserve.
Left main coronary artery occlusion with preserved left ventricular function: a report of three cases.
Three patients with angina pectoris are reported in whom occlusion of the left main coronary artery was found at coronary arteriography. In these three patients left ventricular function was well preserved. In all three the right coronary artery was dominant and there were prominent epicardial and septal collateral vessels to the territories normally supplied by the left anterior descending and circumflex arteries. It seems reasonable to suggest that this coronary artery anatomy and collateral vessel formation accounted for the preservation of the left ventricular myocardium in these patients.
Cardiorespiratory response to exercise before and after acute beta-adrenoreceptor blockade in nonsmokers and chronic smokers.
To evaluate the effects of chronic smoking on exercise performance we studied 5 smokers and 7 nonsmokers of comparable age and physical characteristics. The resting heart rate in smokers (75 +/- 3 beats/min; mean +/- SD) was significantly (P less than 0.01) higher than in nonsmokers (64 +/- 5). During exercise on a bicycle ergometer the heart rate remained significantly (P less than 0.01) higher in smokers than in nonsmokers. After exercise, the heart rate in nonsmokers settled to 78 +/- 9 beats/min at 10 minutes compared with 105 +/- 11 (P less than 0.01) in smokers. Oxygen consumption was similar in both groups throughout. Beta-adrenergic blockade reduced the exercise tachycardia in both groups but the heart rate for the same workload remained significantly (P less than 0.01) higher in smokers. Beta-blockade significantly reduced (P less than 0.05) oxygen consumption in nonsmokers but not in smokers who also incurred a significantly (P less than 0.05) greater oxygen debt and had higher serum lactate levels. These differences were attributed mainly to carboxyhaemoglobinaemia and partly to the effect of prolonged smoking on the heart and on intermediary metabolism.
Electrophysiological disturbances associated with acute myocardial infarction.
By the time most patients reach hospital with acute myocardial infarction the risk of developing ventricular fibrillation (VF) is receding and Q wave evolution is complete. While these changes are the culmination of a single irreversible ischaemic insult, this may follow several reversible episodes of ischaemia associated with marked ECG changes during the preceding hours or days and further ischaemic episodes may follow the development of Q waves. Cellular electrophysiological changes associated with experimental myocardial ischaemia in an isolated guinea pig preparation were a reduction in refractory period and action potential amplitude, Vmax and duration while conduction time and QRS width were prolonged. Spontaneous recovery in action potential amplitude and Vmax was observed after 12 min of ischaemia and depended on the presence of residual coronary flow. Electrophysiological recovery commenced rapidly on reperfusion but with further shortening of action potential duration. Reperfusion VF was most likely to occur when the associated ischaemic insult was 20-30 min in duration. Myocardial catecholamine depletion significantly reduced these arrhythmias and this antiarrhythmic action was associated with marked attenuation of the electrophysiological effects of ischaemia and reperfusion.
Prevalence of inflammatory bowel disease amongst Mormons in Britain and Ireland.
The prevalence of Crohn's disease (79/10(5)), ulcerative colitis (389/10(5)) and appendicectomy (2751/10(5)) were measured in a survey of the Mormon church in Britain and Ireland. Details were obtained from 230 of the 342 branches in Britain which had a membership of 56,000 people although only 17,700 people were active members. The prevalence of Crohn's disease was comparable to that reported from various centres in Britain, but ulcerative colitis was significantly commoner amongst Mormons while the frequency of appendicectomy was significantly reduced.
Antiarrhythmic and electrophysiological effects of alpha adrenoceptor blockade during myocardial ischaemia and reperfusion in isolated guinea-pig heart.
An isolated buffer perfused guinea-pig heart preparation has been used to study the antiarrhythmic and cellular electrophysiological effects of alpha adrenoceptor blockade during myocardial ischaemia and reperfusion. Phentolamine 5 X 10(-6) M and indoramin 2 X 10(-6) M significantly reduced the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) during ischaemia and reperfusion. Both drugs prolonged action potential duration (APD) and refractory period and reduced Vmax during normal perfusion and these effects were maintained during ischaemia. Reperfusion led to prompt recovery in all hearts but with initial transient shortening of APD. Phentolamine and indoramin abolished shortening of the APD whether added prior to ischaemia or immediately prior to reperfusion, and attenuated the reduction in refractory period, due to higher values at the end of ischaemia. Myocardial catecholamine depletion also significantly reduced ventricular tachycardia and ventricular fibrillation during ischaemia and reperfusion. Catecholamine depletion had similar effects on APD, refractory period and conduction, but phentolamine produced no additional effects when added to catecholamine depleted hearts suggesting that the effects observed here are mediated via adrenergic rather than direct myocardial effects.