S. De Servi

Increased expression of neutrophil and monocyte adhesion molecules in unstable coronary artery disease.

BackgroundA rapid increase in leukocyte adhesion to endothelial cells is one of the first events in the acute inflammatory response and in the pathogenesis of vascular diseases. A subgroup of cell surface glycoproteins (the CD11/CD18 complex) play a major role in the leukocyte adhesion process; in particular, the CD11b/CD18 receptor can be upregulated severalfold in response to chemotactic factors. The purpose of this study was to assess whether upmodulation of granulocyte and monocyte CD11b/CD18 receptors takes place during the passage of blood through the coronary tree of patients with clinical manifestations of ischemic heart disease. Methods and ResultsThirty-nine patients who underwent diagnostic coronary arteriography were studied. Group 1 (15 patients) had a clinical diagnosis of unstable angina, group 2 (14 patients) had stable exertional angina, and group 3 (10 patients) had atypical chest pain. Simultaneous sampling from the coronary sinus and aorta was obtained before coronary arteriography. Cell surface receptors were detected by direct immunofluorescence evaluated by flow cytofluorimetry using monoclonal antibodies tagged with fluorescent markers. Leukocytes were stained in unseparated blood to avoid in vitro manipulation that could activate phagocytes. Group 1 and 2 patients had significant coronary artery disease (>50%o coronary narrowing in at least one major coronary vessel), whereas group 3 patients had normal coronary arteries. In group 1, granulocytes and monocytes showed a significantly higher expression of the CD11b/CD18 adhesion receptor in the coronary sinus than in the aorta (both P<.01), whereas no difference in CD11b/CD18 expression was seen in groups 2 and 3. ConclusionPatients with unstable angina have an increased expression of granulocyte and monocyte CD11b/CD18 adhesion receptors, indicating that an inflammatory reaction takes place within their coronary tree. Activation of these leukocytes may induce coronary vasoconstriction, favor thrombotic processes, and further activate platelets, thus having potential implications on the pathogenesis of unstable coronary artery disease.

A new method for quantitation of mitral regurgitation based on color flow Doppler imaging of flow convergence proximal to regurgitant orifice.

BackgroundImaging of the flow convergence region (FCR) proximal to a regurgitant orifice has been shown to provide a method for quantifying the regurgitant flow rate. According to the continuity principle, the FCR is constituted by concentric hemispheric isovelocity surfaces centered at the orifice. The flow rate is constant across all isovelocity surfaces and equals the flow rate through the orifice. For any isovelocity surface the flow rate (Q) is given by: Q = 2n−r2 Vr, where 2wrr2 is the area of the hemisphere and Vr is the velocity at the radial distance (r) from the orifice. Methods and ResultsWe studied 52 consecutive patients with mitral regurgitation (mean age, 49 years; age range, 21–66 years) verified by left ventricular angiography using color flow mapping. The FCR r was measured as the distance between the first aliasing limit-at a Nyquist limit obtained by zero-shifting the velocity cutoff to 38 cm/sec and the regurgitant orifice. Seven patients without evidence of an FCR had only grade 1 + mitral regurgitation angiographically. There was a significant relation between the Doppler-derived maximal instantaneous regurgitant flow rate and the angiographic degree of mitral regurgitation in the other patients (rs = 0.91, p < 00.001). The regurgitant flow rate by Doppler also correlated with the angiographic regurgitant volume (r = 0.93, SEE = 123 ml/sec) in the 15 patients in normal sinus rhythm and without other regurgitant lesions in whom it could be measured. The correlation between regurgitant jet area within the left atrium and the angiographic grade was only fair (rs = 0.75, p < 0.001). ConclusionsColor flow Doppler provides new velocity information about the proximal FCR in patients with mitral regurgitation. According to the continuity principle, the maximal instantaneous regurgitant flow rate, obtained with the FCR method, may provide a quantitative estimate of the severity of mitral regurgitation, which is relatively independent of technical factors.

A new method for estimating left ventricular dP/dt by continuous wave Doppler-echocardiography. Validation studies at cardiac catheterization.

In this study, we explored the use of continuous wave Doppler-echocardiography guided by color Doppler flow-mapping as a method for noninvasively calculating the rate of pressure rise (RPR) in the left ventricle. Continuous wave Doppler determination of the velocities in mitral regurgitant jets allows calculation of instantaneous pressure gradients between the left ventricle and the left atrium. Left atrial pressure variations in early systole can be considered negligible; therefore, the rising segment of the mitral regurgitation velocity curve should reflect left ventricular pressure increase. We studied 50 patients (mean age, 51 years; range, 25-66 years) in normal sinus rhythm with color Doppler-proven mitral regurgitation and compared the Doppler-derived left ventricular RPR with peak dP/dt obtained at cardiac catheterization. Doppler studies were performed simultaneously with cardiac catheterization in 11 patients and immediately before in the remaining cases. Two points were arbitrarily selected on the steepest rising segment of the continuous wave mitral regurgitation velocity curve (point A, 1 m/sec, point B, 3 m/sec), and the time interval (t) between them was measured. Following the Bernoulli relation, the pressure rise between points A and B is 32 mm Hg (4vB2-4vA2) and the RPR is 32 mm Hg/t. Results showed a linear correlation between the Doppler RPR and peak dP/dt (r = 0.87, SEE = 316 mm Hg/sec). The RPR in the left ventricle can be derived from the continuous wave Doppler mitral regurgitation velocity curve.

Coronary arterial spasm as a cause of exercise-induced ST-segment elevation in patients with variant angina.

Four patients with variant angina pectoris exhibited reproducible exercise-induced chest pain ST-segment elevation. Coronary arterial spasm was documented with arteriography during exerciseinduced ST-segment elevation (three patients) or after intravenous administration of ergonovine maleate (one patient). Our observations show that in patients with variant angina exercise can trigger coronary arterial spasm, thus inducing anginal pain ST-segment elevation.

Trapidil (triazolopyrimidine), a platelet-derived growth factor antagonist, reduces restenosis after percutaneous transluminal coronary angioplasty. Results of the randomized, double-blind STARC study. Studio Trapidil versus Aspirin nella Restenosi Coronarica.

BackgroundTrapidil is an antiplatelet drug with specific platelet- derived growth factor antagonism and antiproliferative effects in the rat and rabbit models after balloon angioplasty. Methods and ResultsThe Studio Trapidil versus Aspirin nella Restenosi Coronarica (STARC) is a multicentric, randomized, double-blind trial to assess the effects of trapidil in angiographic restenosis prevention after percutaneous transluminal coronary angioplasty (PTCA). Patients received either trapidil 100 mg TID or aspirin at the same dosage at least 3 days before angioplasty and for 6 months thereafter. Coronary angiograms before PTCA, after PTCA, and at 6-month follow-up were quantitatively analyzed with manual calipers. Of the initial 384 patients recruited, 254 were evaluable for restenosis analysis (128 trapidil, 126 aspirin). Restenosis, defined as a loss of initial percent gain after PTCA of at least 50% (primary end point), occurred in 24.2% of the trapidil group and 39.7% of the aspirin group (P < .01). A similar result was obtained when restenosis per vessel was considered (trapidil, 23.3%; aspirin, 36.9%; P = .018). Clinical events at follow-up were similar in the two groups except that recurrent angina was significantly more frequent in the aspirin group, 43.7% versus 25.8% in the trapidil group (P < .01). Trapidil was well tolerated: only 6 patients had to discontinue the drug because of side effects, which was not different from the aspirin group. ConclusionsTrapidil reduces restenosis after PTCA at the dosage of 100 mg TID and favorably influences the clinical outcome thereafter.

Granulocyte activation after coronary angioplasty in humans.

To determine whether percutaneous transluminal coronary angioplasty (PTCA) would lead to neutrophil activation with subsequent discharge of proteolytic enzymes, like elastase, and oxygen free radicals, like superoxide anion, blood samples were taken from the coronary sinus and aorta in 14 patients with stable angina and one-vessel disease who underwent PTCA. Neutrophils were separated by means of the Ficoll-Hypaque system and were stimulated to detect release of elastase and generation of superoxide anion. Plasma levels of elastase were also measured by an immunoenzymatic method. PTCA was successful in all patients. Plasma elastase levels increased significantly at the end of the procedure compared with pre-PTCA values both in the coronary sinus (from 129.2 +/- 16.6 to 286.6 +/- 39.7 micrograms/l, p less than 0.005) and in the aorta (from 117.4 +/- 13.6 to 258.1 +/- 41.3 micrograms/l, p less than 0.005). On the other hand, superoxide anion released in the supernatants after neutrophil stimulation by phorbol-myristate-acetate decreased after PTCA in the coronary sinus (before PTCA, 60.1 +/- 7.1; after PTCA, 40.7 +/- 6.8 nmol 1 x 10(7) granulocytes/ml/15 min, p less than 0.05), whereas a mild but not significant decrease was observed in the aorta (from 58.3 +/- 10.9 to 55.3 +/- 8.6 nmol 1 x 10(7) granulocytes/ml/15 min, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of nifedipine on coronary hemodynamic findings during exercise in patients with stable exertional angina.

To investigate the mechanism by which nifedipine improves exercise tolerance in patients with coronary artery disease, we studied 14 patients with stable exertional angina and left anterior descending artery disease by measuring great cardiac vein flow (GCVF) and calculating anterior regional coronary resistance (ARCR) during exercise before and after sublingual administration of 20 mg of nifedipine. After nifedipine seven patients (group I) had no increase in exercise capacity and showed a similar magnitude of ST segment depression at peak exercise, while another seven patients (group II) had prolonged exercise duration (p less than .001) with less ST segment depression at peak exercise (p less than .01). Such effects were achieved despite a significant increase in double product, an indirect index of myocardial oxygen consumption. In group I patients no significant change was induced by nifedipine in GCVF or in ARCR either at rest or at peak exercise. In contrast, in group II patients nifedipine significantly increased GCVF at rest (p less than .05) and at peak exercise (p less than .001). Moreover, resting ARCR was decreased (p less than .01) and remained significantly lower at peak exercise (p less than .01) compared with the prenifedipine values. These data show that nifedipine may increase GCVF and decrease ARCR at rest and at peak exercise in patients with left anterior descending artery disease. Such increase in myocardial oxygen supply seems the most likely mechanism by which nifedipine may improve exercise capacity in patients with stable exertional angina.

The exercise test in variant angina: results in 114 patients.

One hundred fourteen patients with variant angina performed bicycle exercise stress tests, and were divided into three groups. Group 1 included 37 patients with a normal exercise test. Coronary arteriography revealed absence of significant coronary stenoses in 18 patients, one‐vessel disease in 17 and involvement of two or more vessels in two. Group 2 consisted of 40 patients who had ST‐segment elevation during or just after exercise. Coronary arteriography in these cases revealed absence of significant coronary stenoses in nine patients, one‐vessel disease in 18 and disease of two or more vessels in 13. Group 3 included 37 patients who had ST‐segment depression during exercise. Absence of coronary artery disease was found in only two patients, one‐vessel disease was found in 19 and disease of two or more vessels was found in 16. Sixty‐one patients repeated the exercise test after a mean of 18 months after hospital discharge. Exerciseinduced ST‐segment elevation was no longer present in surgically or medically treated patients; ST‐segment depression was still evident in all the medically treated patients, but was absent in eight of 13 patients who underwent aortocoronary bypass surgery. Exercise testing can be useful in the follow‐up of patients with variant angina and in selecting patients most likely to be helped by bypass surgery.

Significance of exercise-induced ST-segment elevation in patients without myocardial infarction.

SUMMARY Sixteen patients with exercise-induced ST-segment elevation and without a history of myocardial infarction or left ventricular aneurysm were studied. Fourteen complained of angina at rest, which was associated with ST-segment elevation in the same leads where it was recorded during exercise, and two patients had only exertional angina. Exercise-induced ST-segment elevation was generally reproducible in subsequent exercise tests performed in different hours of the day, but exercise tests repeated a mean of 15 months later did not induce this electrocardiographic abnormality. All patients had a marked susceptibility to coronary spasm, as shown by the response to the ergonovine test (12 positive tests in 12 patients) and by the occurrence of spontaneous spasm during coronary arteriography in two patients. In addition, coronary arteriography, performed in seven patients at the time of exercise-induced ST-segment elevation, revealed spasm of a major coronary vessel in all. In two patients we documented that exercise-induced ST-segment elevation was accompanied by a decreased coronary blood flow and increased coronary vascular resistance. We conclude that exercise-induced ST-segment elevation in patients without a history of myocardial infarction or left ventricular aneurysm is caused by coronary spasm of a major coronary vessel.

Different susceptibility to the development of nitroglycerin tolerance in the arterial and venous circulation in humans. Effects of N-acetylcysteine administration.

BackgroundTolerance to the effects of organic nitrates develops rapidly during continuous exposure to these drugs; its main mechanism seems to be an intracellular sulfhydryl group depletion. However, the relative susceptibility to the development of nitroglycerin tolerance of the arterial or venous circulation in humans is still a matter of dispute. Methods and ResultsTwenty patients with coronary artery disease underwent a continuous 24-hour nitroglycerin infusion followed by a bolus administration of N-acetylcysteine. Forearm blood flow (ml/100 ml/min) and venous volume (ml/100 ml) were measured by strain gauge plethysmography under control conditions, at the end of nitroglycerin titration, after 24-hour infusion, and after N-acetylcysteine; vascular resistance was calculated as mean cuff blood pressure divided by flow. After 24 hours of nitroglycerin infusion, the initial increase in venous volume was reduced 48% (p<0.01), whereas the acute effects on vascular resistance were not attenuated in the whole group. N-Acetylcysteine completely restored nitroglycerin venodilator effects in all 10 patients in whom attenuation of the venous effects was observed during the infusion period. ConclusionsThe data indicate that the susceptibility to the development of nitrate tolerance in humans is higher in the venous than in the arterial circulation, and that the sulfhydryl group donor N-acetylcysteine is extremely effective in reversing nitroglycerin tolerance in the venous circulation in humans.