Hassan El-Tamimi

Role of adenosine in pathogenesis of anginal pain.

The intravenous infusion of adenosine provokes anginalike chest pain. To establish its origin, an intracoronary infusion of increasing adenosine concentrations was given in 22 patients with stable angina pectoris. During adenosine infusion, 20 patients had chest pain without electrocardiographic signs of ischemia. They all reported that the chest pain was similar to their usual anginal pain. In 10 of the 22 patients adenosine was also infused into the right atrium, but it never produced symptoms at the doses that had provoked chest pain during intracoronary infusion. In seven other patients, the intracoronary adenosine infusion was repeated after intravenous administration of aminophylline, an antagonist of adenosine P1-receptors. Aminophylline decreased the severity of adenosine-induced chest pain (assessed with a visual analog scale) from 42 +/- 22 to 23 +/- 17 mm (p less than 0.002). In the remaining five of the 22 patients, monitoring of blood oxygen saturation in the coronary sinus during intracoronary adenosine administration showed that maximum coronary vasodilation was achieved at doses lower than those responsible for chest pain. A single-blind, placebo-controlled, randomized trial of the effect of aminophylline on exercise-induced chest pain was also performed in 20 other patients with stable angina. Aminophylline, compared with placebo, decreased the severity of chest pain at peak exercise from 67 +/- 21 to 51 +/- 23 mm (p less than 0.02), despite the achievement of a similar degree of ST-segment depression. Finally, the effect of intravenous adenosine was compared in 10 patients with predominantly painful myocardial ischemia and in 10 patients with predominantly silent ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of coronary angiographic findings in acute and chronic first presentation of ischemic heart disease.

BackgroundIt is generally assumed that the clinical manifestations of ischemic heart disease occur randomly on the same underlying pathological process. Therefore, coronary angiographic findings should be similar whether the first presentation of ischemic heart disease is acute myocardial infarction or uncomplicated chronic stable angina Methods and ResultsWe studied 102 patients (men ≤60 years old, women ≤65 years old) presenting with either acute myocardial infarction as first manifestation of coronary artery disease with a concomitant coronary angiogram (55 patients; mean age, 50.2 years) or stable angina for at least 2 years with no history, ECG, or left ventriculographic evidence of any acute event and with an angiogram performed at least 2 years after initial symptoms (47 patients; mean age at symptom onset, 51.7 years). These angiograms were evaluated blindly for severity (number of vessels diseased, stenoses ≥50%, occlusions), extent of disease (with an index derived by assigning a score of 0-3 per segment, depending on the proportion of lumen length irregularity and dividing the sum by the number of visualized segments), and pattern (discrete: three or fewer loci of disease never involving more than 50%7e of the length of any segment or diffuse: anything exceeding this). Patients with unheralded myocardial infarction had fewer vessels diseased, fewer stenoses and occlusions, and a lower extent index than those with uncomplicated stable angina (mean±SD of 1.3±0.8 versus 2.1±0.8, p<0.001; 2.1±1.8 versus 3.9±1.8, p<0.001; 0.6±0.6 versus 1.0±0.9, p<0.02; and 0.6±0.5 versus 1.2±0.5, p<0.001, respectively). A discrete pattern was present in 54.5% of patients with unheralded infarction and in only 8.5% of those with uncomplicated angina (p<0.001). ConclusionThese very different angiographic findings suggest that unheralded acute myocardial infarction and uncomplicated chronic stable angina do not occur randomly on a common atherosclerotic background but rather that additional factors, such as a varying propensity to thrombosis, may predispose to one or the other of these two clinical syndromes. (Circulation 1993;87:1938-1946)

Response of angiographically normal and atherosclerotic left anterior descending coronary arteries to acetylcholine

Acetylcholine-induced constriction of human coronary arteries in vivo is commonly attributed to endothelial dysfunction. To examine the effects of 2 other important determinants of vascular responses--namely, agonist concentration and the segment of circulation under study--the diameters of proximal, middle and distal segments of the left anterior descending artery (LAD) and coronary sinus oxygen saturation were measured in 10 patients with angiographically normal coronary arteries (group 1) and in 7 patients with coronary atherosclerosis (group 2) after intracoronary acetylcholine was infused at concentrations from 10(-7)M to between 10(-4)M and 10(-2)M. In group 1, acetylcholine caused minor (less than or equal to 6%) but progressive dilatation of the LAD up to 10(-4)M, but constriction, particularly of the distal segments and tertiary branches, occurred at higher concentrations. Over the same concentration range, coronary sinus oxygen saturation rose progressively from a basal level of 36 +/- 3% to a maximum of 72 +/- 3% in the absence of changes in heart rate and blood pressure, suggesting marked progressive dilatation of resistance vessels. Concentrations greater than or equal to 10(-3)M caused intense constriction of distal epicardial vessels and, in some cases, anginal pain and objective signs of ischemia. Conversely, in group 2, acetylcholine (infused only up to 10(-4)M for ethical reasons) failed to cause significant changes in LAD diameter. These data suggest that the local acetylcholine concentration and coronary vascular segment under study may determine the observed response to at least an equivalent extent as does the presence or absence of coronary atherosclerosis, raising the question of whether a constrictor response to intracoronary acetylcholine reliably indicates the presence of coronary atherosclerosis.

Very early prediction of restenosis after successful coronary angioplasty: Anatomic and functional assessment

To investigate the time course of restenosis, serial treadmill exercise testing was performed in the absence of medical therapy by 31 patients with single vessel coronary disease who underwent successful angioplasty. Exercise tests were performed before angioplasty and at 3 days and 1, 3 and 6 months after angioplasty; if the test was positive, it was repeated after administration of 10 mg of intravenous verapamil. At arteriography 6 months after coronary angioplasty, 17 patients (group 1) showed no restenosis but 14 patients (group 2) did. Before angioplasty all 31 patients had a positive exercise test with ST segment depression greater than or equal to 1 mm. At 3 days after angioplasty, three patients in group 1 had a positive exercise test compared with 11 patients in group 2 (p = 0.08). At 1, 3 and 6 months, 1 patient in group 1 had a positive exercise test compared with 14 patients in group 2 (p less than 0.01). The heart rate-blood pressure product (beats/min.mm Hg) calculated at 1 mm ST segment depression, or at peak exercise if the test was negative, was used as an index of the ischemic threshold. In group 1 (no restenosis) the ischemic threshold increased progressively from 14,840 +/- 1,075 (mean value +/- SEM) before angioplasty to 21,210 +/- 1,049 at 3 days and to 25,140 +/- 1,177 (p less than 0.001) at 6 months. In group 2 (restenosis) the ischemic threshold increased from 16,270 +/- 828 before angioplasty to 20,400 +/- 984 (p less than 0.0004) at 3 days but decreased to 16,090 +/- 1,298 (p less than 0.006) at 6 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal vasomotor changes early after coronary angioplasty. A quantitative arteriographic study of their time course.

BackgroundTo study the impact of percutaneous transluminal coronary angioplasty (PTCA) on coronary vasomotion, we prospectively analyzed spontaneous changes in coronary diameter and the response to the cold pressor test and intracoronary nitroglycerin in 11 patients subjected to successful single-vessel PTCA. Methods and ResultsAll antianginal medications were stopped 48 hours before each study. The minimum diameter of the PTCA segment and the diameter of a distal segment in the angioplastied vessel and of a segment in a control vessel not manipulated by the balloon catheter or guide wire were measured by computerized edge detection immediately before PTCA and 5 minutes after, 4 hours after, and 8 days after PTCA. At 4 hours, PTCA and distal segments were constricted by 38 ± o9% and 16 + 5%, respectively, compared with the values at 5 minutes (p < 0.01). Before angioplasty, the cold pressor test caused vasoconstriction of PTCA and distal segments by 23 ± 6% (p < 0.0001) and 15 ± 4% (p < 0.008), respectively, but no constrictor response was elicited at 5 minutes or 4 hours after angioplasty. Eight days after PTCA, the basal coronary diameters were similar to those observed 5 minutes after PTCA and the response to the cold pressor test was similar to that observed before PTCA. All segments dilated significantly with nitroglycerin at all times, and no vasoconstriction changes were found in the control segments. ConclusionsFour hours after PTCA, transient spontaneous vasoconstriction of the PTCA and distal segments occurs, which is so intense that the cold pressor test does not cause any further constriction. These abnormalities resolve within 8 days of PTCA.

Inappropriate constriction of small coronary vessels as a possible cause of a positive exercise test early after successful coronary angioplasty.

BackgroundThe mechanism responsible for exercise-induced myocardial ischemia early after successful coronary angioplasty (PTCA) is poorly understood. Methods and ResultsTwelve patients who underwent one-vessel PTCA were studied. Exercise testing was performed before and on day 7 after PTCA, which was repeated after 10 mg sublingual isosorbide dinitrate if the test was positive. Quantitative coronary arteriography was also performed on day 8 after PTCA in the basal state, after intracoronary infusion of 0.9% saline, 1, 5, 10, and 20 jig ergonovine, and after 300 gg nitroglycerin. All patients had a positive exercise test before PTCA but on day 7, six-patients had a positive exercise test (group 1) and six patients (group 2) had a negative exercise test. In group 1, all positive exercise tests on day 7 became negative when repeated after isosorbide dinitrate. Intracoronary ergonovine was associated with a dose-dependent constriction of the PTCA segment, a segment distal to it, and a control segment, with no significant difference in the magnitude of the response between the two groups; maximum constriction for group 1 was 19 ± 3%, 23 ± 2%, and 16 ± 3% (p < 0.001 versus basal), and in group 2 was 20 ± 4%, 18 % 4%, and 9 ± 2% (p < 0.01 versus basal). No angina, ischemic ST segment changes, occlusive, or subocclusive spasm occurred in any patient of either group. ConclusionsWe could find no evidence that exercise-induced myocardial ischemia early after PTCA is related to the presence of fixed angiographic restenosis or to dynamic constriction of any epicardial coronary segment. Therefore, inappropriate small coronary vessel constriction responsive to nitrates should be considered as a possible alternative explanation.

Optimal control of myocardial ischaemia: the benefit of a fixed combination of atenolol and nifedipine in patients with chronic stable angina.

Objective—To study the effects on myocardial ischaemia of 50 mg of atenolol, 20 mg of slow release nifedipine, and their fixed combination given 12 hourly. Design—A treadmill exercise test and 24 hour ambulatory electrocardiographic monitoring were carried out after a period of five days off treatment (control) and at the end of three weeks of each treatment period. Patients—23 patients with stable angina pectoris, documented coronary artery disease, and a positive exercise test were randomised in a double blind, three way, cross over study. Results—Compared with the control, nifedipine significantly induced an increase in resting heart rate of (mean (SEM)) 14 (2) beats/min whereas atenolol and the combination significantly reduced it by 24 (2) and 20 (1) beats/min respectively. The number of exercise tests rendered negative after each intervention was five for nifedipine, nine for atenolol, and 11 for the combination. Compared with the control the time to the start of myocardial ischaemia (1 mm ST segment depression) during exercise significantly increased by 3·2 (0·6) min after nifedipine, by 4·6 (0·4) min after atenolol, and by 4·6 (0·5) min after the combination; rate-pressure product (beats/min. mm Hg) at 1 mm ST segment depression increased by 2824 (970) after nifedipine but fell by 4436 (900) and 4501 (719) after atenolol and the combination. The weekly frequency of angina was reduced from a mean of five while taking nifedipine, to three while taking atenolol, and to two while taking the combination. The total ischaemic time during ambulatory monitoring was significantly reduced from 69 (17) min during control to 37·5 (9·8) min during nifedipine, to 15·6 (5·5) min during atenolol, and to 6·5 (2·7) min during the combination. Conclusion—The undesirable effect of a high basal heart rate induced by nifedipine was neutralised by its combination with atenolol. Whereas atenolol and the combination were equally efficacious in controlling exercise induced ischaemia, the combination was more effective in reducing total ischaemic burden.

Comparative effects of theophylline and isosorbide dinitrate on exercise capacity in stable angina pectoris, and their mechanisms of action☆

While the role of nitrates in the prevention and treatment of myocardial ischemia is well established, the use of theophylline, proposed almost a century ago, is still controversial. Also controversial is its mechanism of action, initially thought to be coronary dilation. In this randomized, single-blind study, the acute effects on exercise capacity of sublingual isosorbide dinitrate (10 mg) and of intravenous theophylline ethylenediamine (7 mg/kg) were assessed in 10 patients with chronic stable angina and positive exercise test. After the administration of theophylline, the time to onset of angina, the heart rate-blood pressure product at 1-mm ST-segment depression and the exercise duration were similar to that after isosorbide dinitrate administration (9.8 +/- 2.3 vs 9.3 +/- 1.7 minutes, 207 +/- 41 vs 207 +/- 48 beats/min.mm Hg.10(-2) and 10.8 +/- 2 vs 10.4 +/- 2 minutes, respectively). Both drugs significantly (p less than 0.001) improved all these parameters compared to the baseline exercise test. The effect of the 2 drugs on the diameters of angiographically normal segments of large epicardial coronary arteries was then assessed using computerized quantitative angiography in 10 other patients with stable angina. Whereas theophylline failed to increase the coronary diameters compared to that in the baseline angiogram (2.9 +/- 0.6 vs 2.9 +/- 0.6 mm, respectively), the subsequent administration of isosorbide dinitrate resulted in an increase up to 3.2 +/- 0.7 mm (p less than 0.02). Thus, in patients with stable angina, theophylline delays the onset of angina, increases the ischemic threshold and prolongs the exercise duration to the same degree as isosorbide dinitrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of theophylline, atenolol and their combination on myocardial ischemia in stable angina pectoris

The effects of theophylline (400 mg twice a day), atenolol (50 mg twice a day) and their combination on myocardial ischemia were studied in 9 patients with stable angina pectoris in a randomized, single-blind, triple crossover trial. Placebo was administered to the patients during the run-in and the run-off periods. A treadmill exercise test and 24-hour ambulatory electrocardiographic monitoring were obtained at the end of each treatment period. Compared with placebo, theophylline significantly improved the time to onset of myocardial ischemia (1 mm of ST-segment depression) from 7.8 +/- 3.7 to 9.5 +/- 3.7 minutes (p less than 0.03) and the exercise duration from 9 +/- 3.4 to 10.1 +/- 3.5 minutes (p less than 0.04). During atenolol and during combination treatment, the time to the onset of ischemia and the exercise duration were similar (10.8 +/- 4.2 and 11.2 +/- 3.2 minutes, 11.2 +/- 3.6 and 11.5 +/- 3.2 minutes, respectively) and longer than during theophylline administration (p less than 0.05). Ambulatory electrocardiographic monitoring showed that, during theophylline administration, the heart rate was higher than during placebo throughout the 24 hours (p less than 0.05). During atenolol and during combination treatment the heart rate was similar and in both cases lower than during placebo (p less than 0.05). Compared with placebo, theophylline decreased the total ischemic time from 97 +/- 110 to 70 +/- 103 minutes (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of diltiazem alone or with isosorbide dinitrate or with atenolol both acutely and chronically for stable angina pectoris

To establish the contribution of combination therapy in stable angina, the short- and long-term effects of diltiazem (120 mg and 360 mg/day, respectively), and the additive effects of sublingual isosorbide dinitrate, 10 mg, and atenolol, 100 mg, were studied in 11 patients with chronic stable angina using an open-label sequential design. All patients underwent exercise testing without therapy, and with each drug and their combinations. Exercise time and heart rate-blood pressure product were measured at 1-mm ST-segment depression, or at peak exercise if the test result was negative. Exercise time increased from a control value of 8.0 +/- 2.3 minutes (mean +/- standard deviation) to 11.4 +/- 2.4 minutes (p less than 0.0001) after the administration of isosorbide dinitrate, to 11.3 +/- 1.8 minutes (p less than 0.001) after short-term diltiazem and to 12.4 +/- 1.5 minutes (p less than 0.001) after long-term diltiazem. The rate-pressure product increased from a control value of 19,070 +/- 3,564 to 24,431 +/- 4,795 beats/min X mm Hg (p less than 0.0001) after isosorbide dinitrate, to 22,287 +/- 4,753 beats/min X mm Hg (p less than 0.01) after short-term diltiazem and to 21,812 +/- 3,976 beats/min X mm Hg (p less than 0.007) after long-term diltiazem. The addition of atenolol to long-term diltiazem significantly reduced the rate-pressure product compared with long-term diltiazem alone (21,812 +/- 3,976 vs 13,926 +/- 2,880 beats/min X mm Hg, (p less than 0.002), although there was no further significant increase in exercise time (12.4 +/- 1.5 vs 13.3 +/- 1.6 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)