G.M. Rees

High-dose aspirin inhibits shear-induced platelet reaction involving thrombin generation.

BackgroundA unifying concept of explaining all pharmacological actions of aspirin by the irreversible blockage of the enzyme cyclooxygenase and therefore the inhibition of prostaglandin biosynthesis has left many unanswered questions. Methods and ResultsTwo hundred ninety-four patients taking 75 mg/day aspirin were tested 3 months after coronary artery bypass surgery. Platelet thromboxane formation (whole blood aggregation to arachidonate) was completely prevented in 80% of patients. Compared with matched healthy controls (n = 95), a significant platelet hyperreactivity was observed in patients (p<0.0001 versus <0.002). Ninety patients were advised to increase their daily dose of aspirin from 75 mg to 300 mg. Platelet reactivity retested 1 month after increasing the dose has significantly decreased (p = 0.0008; <0.0001), whereas it remained unchanged in those patients (n = 84) who continued with the same dose regimens. In normal subjects, ingestion of a single 600-mg aspirin significantly inhibited shear-induced platelet reaction. ConclusionsIt is concluded that aspirin does affect the platelet response to shear forces, but this requires higher dosage (>300 mg/day), suggesting a mechanism probably different from that of interference with thromboxane formation.

Cryothermal mapping and cryoablation in the treatment of refractory cardiac arrhythmias.

SUMMARYCryoablation was applied to the treatment of 15 refractory tachyarrhythmias in 12 patients, Wolff-Parkinson-White atrioventricular reentrant tachycardia (WPW) in five patients, paroxysmal atrial fibrillation (PAF) in five patients, chronic atrial fibrillation (CAF) in one patient, paroxysmal atrial tachycardia (PAT) in two patients and paroxysmal ventricular tachycardia (PVT) in two patients. At operation the accessory pathway in four patients with left-sided WPW was located by intraluminal coronary sinus and epicardial electrographic mapping techniques. Epicardial cryothermal mapping during tachycardia terminated the arrhythmias in one patient. In three patients endocardial cryothermal mapping was necessary to abolish ventriculoatrial accessory pathway conduction. In four patients with PAF and one patient with PAT the AV node/His bundle was located by both electrographic and cryothermal mapping. In one patient with concealed WPW, one with PAT, and the patient with CAF, electrographic mapping was impossible. Cryothermal mapping accurately located the AV node/His bundle in two of these patients.Electrographic mapping during PVT revealed earliest ventricular activation on the lateral left ventricular epicardium in one patient and on the right side of the intraventricular septum in the other. Cryothermal mapping at the point of earliest activation terminated both tachycardias. In all cases cryoablation was achieved by cooling to −65°C for 2 minutes.In nine patients there has been no recurrence of symptomatic tachycardia during the follow-up period of 4- 20 months but there were three partial failures when His bundle conduction resumed immediately, at 10 days, and at 2 months. The technique of electrographic mapping, cryothermal mapping and cryoablation has proved a simple and successful method.

Elevated plasma lipid hydroperoxides in patients with coronary artery disease.

Sustained presence of lipid peroxides in the circulation and their plasma carrier is a controversial issue. Particularly, there is no firm evidence for an increased plasma lipid peroxide level in patients with atherosclerosis. In this study, a strong correlation was found between plasma total lipid hydroperoxide and lipid hydroperoxide content of LDL cholesterol (r = 0.882; p < 0.001; n = 16). Lipid hydroperoxides in plasma were carried almost exclusively (89%) in LDL. In 70 patients tested 3 months after coronary artery bypass graft surgery with a specific assay, plasma lipid hydroperoxide levels were significantly increased when compared with matched healthy controls (4.31 +/- 0.23 nmol/ml and 2.34 +/- 0.13 nmol/ml, p < 0.0001, patients vs controls, respectively). These concentrations are 10 times lower than those detected by the nonspecific thiobarbituric acid assay. However, considering the in vitro concentration range in which oxidized LDL exerts important atherogenic effects, the elevated plasma lipid hydroperoxide levels measured in atherosclerotic patients have pathologic significance.

Reduction of heparin binding to and inhibition of platelets by aprotinin

The direct effect of aprotinin on in vitro platelet function was assessed by hemostatometry (n = 10). No significant enhancement was demonstrated. However, aprotinin reduced platelet inhibition secondary to heparin. Hemostatometry demonstrated a significant preservation of in vitro platelet function (n = 25) (p = 0.04), which was particularly marked (p = 0.003) in the subgroup (n = 7) demonstrating a severe inhibition of platelet function with heparin. Aprotinin significantly reduced the binding of tritium-labeled heparin to both nonactivated (n = 25) (p = 0.004) and activated platelets (n = 25) (p < 0.0001). We conclude that interference with heparin-induced inhibition of platelet function by aprotinin may be one of its hemostatic actions in cardiac surgery. This effect is probably secondary to aprotinin reducing binding of heparin to platelets.

Left ventricular aneurysm and congestive heart failure: value of exercise stress and isosorbide dinitrate in predicting hemodynamic results of aneurysmectomy.

In 12 patients with left ventricular aneurysm and chronic congestive heart failure, left ventricular functional reserve was assessed from the hemodynamic response to exercise stress after administration of isosorbide dinitrate. Two to 23 months (mean 8.6 months) after left ventricular aneurysmectomy hemodynamic measurements were made with the patient at rest and during exercise and were analyzed with respect to preoperative data. Left ventricular aneurysmectomy reduced mean left ventricular filling pressure from 25 to 17 mm Hg at rest (p < 0.02) and from 39 to 32 mm Hg during exercise (p < 0.05). There was no significant change in mean stroke volume index at rest or during exercise. Changes in resting and exercise hemodynamic indexes of left ventricular function produced by aneurysmectomy were inversely related to preoperative left ventricular function. Hence, hemodynamic status was less likely to improve In patients with good preoperative left ventricular function. Similarly, resting and exercise values for left ventricular function tended to improve in patients with reduced ejection fraction of the contractile section of the left ventricle. Left ventricular aneurysmectomy was generally effective in reducing left ventricular filling pressure but failed to achieve clinically important improvement in left ventricular performance during exercise. In patients with chronic congestive heart failure, left Ventricular aneurysmectomy should be performed only after careful assessment of preoperative left ventricular functional reserve.

Preoperative hemostatic activity and excessive bleeding after cardiopulmonary bypass

The rationale for predicting the risk of excessive postoperative bleeding by assessing the hemostatic status of a patient before cardiopulmonary bypass was investigated. A novel, rapid, overall test (hemostatometry) consisting of a physiologically relevant test of platelet function (shear-induced hemostasis) and coagulation was performed using nonanticoagulated blood and compared with the routine coagulation screen. Two hundred five patients undergoing elective coronary revascularization were studied 3 to 4 days before operation. Forty-nine bled excessively for nonsurgical reasons; none were predicted by the routine coagulation tests. Using a stepwise discriminant analysis, hemostatometry correctly predicted 31 of 49 (63%). Thirty of 156 predicted as bleeders by hemostatometry did not bleed. Thus, preoperative hemostatometry predicted 77% of the true outcome. The false predictions suggest, however, that certain bleeding abnormalities probably acquired during cardiopulmonary bypass cannot be predicted. These findings do not justify the routine use of preoperative tests in assessing the bleeding risk in patients undergoing cardiopulmonary bypass.

Combined exercise radionuclide and hemodynamic evaluation of left ventricular aneurysmectomy

Twelve patients were studied by rest and exercise radionuclide ventriculography following left ventricular aneurysmectomy (LVA). Left ventricular filling pressure (LVFP) was also measured. Nine patients had been studied pre-LVA at rest and exercise before and after isosorbide dinitrate (ISDN). Resting ejection fraction (LVEF) improved after LVA (p less than 0.25), but exercise LVEF did not. End-diastolic volume (EDV) and resting LVFP also fell after LVA (p less than 0.25 for EDV, p less than 0.05 for LVFP) and although exercise LVFP fell (p less than 0.02), the values were abnormal in all patients. Ejection fraction of contractile segment (EFCS) from the resting radionuclide study pre-LVA was related to resting LVEF post-LVA (r = 0.71 p less than 0.02), although postoperative LVEF could not be predicted from preoperative EFCS in individual patients. Deterioration in LVEF and LVFP from rest to exercise post-LVA occurred both in patients with single-vessel occlusion and in those with multivessel coronary disease, irrespective of whether or not revascularization had been performed. Thus LVA is effective in improving resting ventricular function; exercise performance may remain abnormal even in patients without residual coronary disease.

Evidence against hypercoagulability in coronary artery disease

The strong epidemiological association between elevated plasma clotting factors and coronary artery disease is generally interpreted as evidence that patients with coronary atherosclerosis are in a procoagulant (hypercoagulable) state. A dynamic global test was used to assess the overall coagulation status of 761 patients with coronary artery disease scheduled for coronary artery bypass grafting and compared to healthy matched controls (n = 100). Platelet reactivity to shear-stress was simultaneously measured from identical, non-anticoagulated blood samples. Contrary to expectation, the overall coagulation in cardiac patients did not differ significantly from that of controls. Furthermore, the coagulation status of patients bore no relationship to the severity of coronary atherosclerosis. The latter is in contrast with platelet reactivities, which were significantly increased in patients with > or = 2 vessel disease as compared with single vessel disease. The present results do not necessarily conflict with the finding of elevated plasma clotting factors in cardiac patients. However, they do not support the claim that these markers are a reflection of a hypercoagulable state. Indeed, this study confirms that such patients are in a prothrombotic state, which is related to enhanced platelet reactivities, and not to a prothrombotic imbalance of the coagulation mechanism.

Incessant atrioventricular tachycardia involving an accessory pathway: preoperative and intraoperative electrophysiologic studies and surgical correction.

Abstract In three patients with incessant supraventricular tachycardia, the anatomic substrate was a left-sided atrioventricular (A-V) accessory pathway. In two patients there was no expression of anterograde conduction through this pathway during spontaneous or induced atrial rhythms. The three patients had had increasingly frequent palpitations for more than 10 years despite adequate antiarrhythmic drug therapy. Preoperative intracardiac studies indicated that a left lateral accessory pathway was utilized in the retrograde limb of supraventricular tachycardia in all three patients. The spontaneous initiation of supraventricular tachycardia was due to (1) frequent spontaneous ventricular premature beats in two patients, (2) increase in sinus rate in two patients, and (3) ventriculoatrial reentry without preceding changes in sinus rate or intracardiac conduction intervals in one patient. At operation the accessory pathway was located in two patients with epicardial and endocardial electrographic mapping and cryothermal mapping. In one patient the His bundle was located with electrographic and cryothermal mapping. The accessory pathway (two patients) or the His bundle (one patient) were cryoablated by freezing over the area of the conducting tissue for 120 seconds at a temperature of −65 ° C. Attempts to reinitiate supraventricular tachycardia after this procedure were unsuccessful. The operation was without significant morbidity. During follow-up for 3 to 10 months, no patient has experienced any further attacks of supraventricular tachycardia or required antiarrhythmic drugs. These observations confirm that an A-V accessory pathway may be the anatomic substrate for incessant or persistently repetitive tachycardias that may be resistant to medical and pacing therapy. Surgical interruption or cryothermal ablation of part of the reentrant circuit may abolish tachycardia, thus providing proof of the underlying mechanism.

The Effect of Nitrous Oxide on the Cell Cycle in Human Bone Marrow

Summary. The effect of 24 h exposure to nitrous oxide on the cell division cycle in human bone marrow has been studied in vivo using the technique of DNA flow microfluorimetry. All patients who received nitrous oxide showed a significant increase in the proportion of early S‐phase cells with a decrease in late S, G2 and mitotic cells. These changes resemble those seen following the use of S‐phase‐specific cytotoxic drugs. Control patients showed no such effect. Parallel studies have suggested that interference with the function of vitamin B12 underlies this response. Nitrous oxide may provide a convenient method for studying the cell kinetic aspects of acute B12 deficiency and the possibility of using it to increase the therapeutic index of antitumour drugs is discussed.