Filippo Crea

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)

Transient myocardial ischemia during daily life in patients with syndrome X

Nineteen patients with syndrome X (typical exertional angina, positive exercise test response [at least 0.1 mV of ST-segment depression], no evidence of coronary spasm and angiographically normal coronary arteries) underwent continuous 48-hour electrocardiographic (ECG) monitoring during unrestricted daily life. Fifty-eight ischemic episodes of at least 0.1 mV of ST-segment depression were observed in the same ECG leads that showed ST depression during stress testing: 28 (48%) were accompanied by anginal pain and 30 (52%) were asymptomatic. No significant differences were found between painful and silent ST-segment depression with regard to the number of episodes, their temporal distribution, magnitude, duration or heart rate (HR) at onset of ST-segment depression. In the minute preceding ischemic ST shifts, HR did not change in 33% of episodes or increased by less than 10 beats/min in 28%. HR at onset of ST depression was significantly lower during ambulatory ECG monitoring than during exercise testing (98 +/- 18 vs 117 +/- 18 beats/min, p less than 0.01). During ambulatory monitoring, 85 episodes of sinus tachycardia (exceeding by 10 to 80 beats/min the HR that triggered ischemia during exercise testing) occurred in the absence of angina or ST-segment shifts. The results of this study suggest that in patients with syndrome X, myocardial ischemia frequently develops during daily life; silent ischemia is an important component of this syndrome; and increased oxygen demand in the presence of impaired coronary vasodilatory capacity is not the only cause of myocardial ischemia. Active mechanisms that transiently reduce coronary flow may act and explain occurrence of angina at rest and with minimal exertion.

Failure of thromboxane A2 blockade to prevent attacks of vasospastic angina.

Thromboxane A2 (TxA2), released by aggregating platelets, has been proposed as a potential mediator of coronary vasospasm. We studied six patients with variant angina, a clinical syndrome due to coronary vasospasm, and one patient with frequent recurrent episodes of transient ST-segment depression at rest in whom the spasm was demonstrated angiographically. All patients underwent continuous ECG monitoring for 2 days before and 2 days after a single, low, i.v. dose of aspirin (2 mg/kg), which reduced TxB2 (the stable metabolite of TxA2) to less than 3% of the control values. There were 129 transient ischemic episodes during control and 146 after aspirin, when platelet TxB2 was reduced to negligible levels. The duration, severity and incidence of symptomatic episodes were not significantly affected by TxA2 blockade. We conclude that platelet TxA2 is probably not responsible for the initiation of coronary vasospasm.

Effects of intravenous prostacyclin in variant angina.

A lack in prostacyclin (PGI2) production due to atherosclerosis may play a role in the pathophysiology of some of the clinical manifestations of ischemic heart disease and, in particular, of coronary vasospasm. We therefore evaluated the effects of i.v. PGI, in nine patients with variant angina and six normal volunteers. In normal subjects, PGI2 (2.5, 5, 10 and 20 jg/kg/min) had significant antiplatelet effects, caused a dosedependent decrease in both systolic and diastolic arterial pressure and a decrease in pulmonary resistance. Heart rate increased in a dose-dependent manner, but no consistent effects on myocardial contractility (evaluated by ultrasound) were observed. Side effects were negligible and readily reversible. Although producing obvious antiplatelet and vasodilatory effects, PGI2 did not affect the number, severity and duration of spontaneous ischemic episodes due to coronary vasospasm in five patients and ergonovineinduced spasm in three. However, the number of ischemic episodes was consistently reduced in one patient during four consecutive periods of PGI2 infusion alternated with placebo. A severe, prolonged ischemic episode with ST elevation and pain was consistently observed in this patient every time PGI2 was discontinued. In the appropriate environment, PGI2 can be administered safely to patients with ischemic heart disease. Occasionally, PGI2 may result in a complete disappearance of ischemic episodes due to coronary vasospasm, but usually it is ineffective. These conflicting results could be related to different etiologies of coronary spasm.

Failure of transdermal nitroglycerin to improve chronic stable angina: A randomized, placebo-controlled, double-blind, double crossover trial

We assessed the effect of transdermal nitroglycerin (NTG-TTS), releasing 5 mg/24 hr, in 11 patients with chronic stable angina during a randomized, placebo-controlled, double-blind, double crossover trial of four 1-week periods. All patients had a positive exercise test and coronary artery disease prior to entry into the study. Efficacy was assessed weekly by anginal diaries, ambulatory ST segment recordings, and computerized exercise testing 2 to 4 hours after renewal of NTG-TTS. One patient withdrew in the first week (placebo) and was excluded from all analysis. The weekly frequency of anginal attacks was 9 +/- 11 (mean +/- SD) and 9 +/- 10 during the 2 placebo weeks and 11 +/- 14 and 9 +/- 11 during NTG-TTS; the time to 1 mm ST segment depression (seconds) was 268 +/- 178 and 303 +/- 217 with placebo and 228 +/- 221 and 285 +/- 178 with NTG-TTS; exercise duration (seconds) was 375 +/- 230 and 467 +/- 254 during placebo and was 394 +/- 233 and 412 +/- 236 during NTG-TTS. The weekly number of episodes of ST depression was 11 +/- 9 and 8 +/- 5 during placebo and 8 +/- 5 and 9 +/- 7 during NTG-TTS. Our study failed to show any consistent differences in patients treated with placebo or NTG-TTS.

Comparison of regional myocardial blood flow in syndrome X and one-vessel coronary artery disease

Myocardial blood flow (MBF) was measured using continuous inhalation of oxygen-15-labeled carbon dioxide, and positron emission tomography before and after intravenous dipyridamole in 13 patients with syndrome X (angina pectoris, angiographically normal coronary arteries, positive exercise test and negative ergonovine test), 7 healthy subjects and 8 patients with 1-vessel coronary artery disease (CAD). In patients with syndrome X, baseline MBF was greater than in healthy subjects and patients with CAD (1.24 +/- 0.27 vs 0.87 +/- 0.07 and 1.03 +/- 0.23 ml/g/min, respectively; p < 0.05), and more heterogeneous (34 +/- 7 vs 26 +/- 5 and 25 +/- 6, respectively; p < 0.05) as assessed by the coefficient of variation among myocardial regions < or = 2.3 cm3. After dipyridamole, MBF in patients with syndrome X was similar to that in healthy subjects (2.95 +/- 0.75 vs 3.40 +/- 0.82 ml/g/min; p = NS) and greater than in patients with CAD (1.78 +/- 0.76 ml/g/min; p < 0.05). However in patients with both syndrome X and CAD, MBF was more heterogeneous than in healthy subjects (48 +/- 12 and 48 +/- 11, respectively, vs 30 +/- 7; p < 0.01). Thus, in patients with syndrome X, MBF is abnormally heterogeneous both at baseline and after dipyridamole. These findings are compatible with the presence of dynamic alterations of small coronary arteries. Because these alterations appear to be very sparse within the myocardium, they can be undetected when myocardial perfusion, function and metabolism are assessed using conventional methods that are unable to detect small myocardial regions.

Spontaneous coronary artery spasm in variant angina is caused by a local hyperreactivity to a generalized constrictor stimulus

To assess whether spontaneous coronary artery spasm in patients with variant angina results from local coronary hyperreactivity to a generalized constrictor stimulus or from a stimulus generated only at the site of the hyperreactive segment, the behavior of spastic and nonspastic coronary segments was studied in six patients with variant angina in whom focal coronary spasm developed spontaneously during cardiac catheterization. None of the patients had critical (greater than 50% luminal diameter reduction) organic coronary stenoses. Coronary diameters were measured by computerized quantitative arteriography during control, spontaneous spasm and ergonovine-induced spasm and after intracoronary nitrates were given. During spontaneous spasm, the luminal diameter of spastic and both proximal and distal nonspastic coronary segments was significantly reduced from control values, 64.2%, 13.2% and 14.8%, respectively. Average diameter reduction of unrelated arteries was 12.3%. Ergonovine, which was also administered to four patients, provoked focal spasm at the same site as spontaneous spasm. During intravenous ergonovine, luminal diameter of spastic segments was reduced by 91.5%, that of nonspastic proximal segments by 17.8% and that of nonspastic distal segments by 11.5%. Luminal diameter of unrelated arteries during ergonovine-induced spasm was reduced by 17.7%. Constriction of spastic segments was greater during ergonovine-induced spasm (p less than 0.05), whereas the extent of diameter reduction of nonspastic segments was not significantly different during spontaneous spasm and ergonovine-induced spasm. Intracoronary isosorbide dinitrate dilated spastic and nonspastic coronary segments to a similar extent from control (20.7%, 18% and 16.5%, respectively; p = NS).(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.

EFFECT OF THEOPHYLLINE ON EXERCISE-INDUCED MYOCARDIAL ISCHAEMIA

In a single-blind, placebo-controlled, randomised trial in 20 patients with stable angina pectoris, intravenous theophylline ethylenediamine (aminophylline), 7 mg/kg, increased the time to onset of angina by 46%, the heart-rate/blood-pressure product (an index of myocardial oxygen consumption) at 1 mm ST segment depression by 22%, and exercise duration by 24%. In a subsequent double-blind placebo-controlled trial in 8 patients a single oral dose of theophylline (375 mg) increased the time to onset of angina by 56%, the heart-rate/blood-pressure product at 1 mm ST segment depression by 22%, and the exercise duration by 35%. Infusion of theophylline ethylenediamine during angiography (10 patients) did not affect the diameter of epicardial coronary arteries. The beneficial effects of theophylline may be due to redistribution of coronary blood flow from non-ischaemic to ischaemic myocardium.

Lack of evidence for alpha-adrenergic receptor-mediated mechanisms in the genesis of ischemia in syndrome X

Patients with syndrome X (typical angina pectoris, positive exercise tests [greater than or equal to 1 mm of ST-segment depression], no evidence of coronary spasm and angiographically normal coronary arteries) have a reduced coronary flow reserve due to inappropriate dilatation of small resistive vessels. To assess whether alpha-adrenergic mechanisms play a role in the genesis of ST-ischemic changes in syndrome X, 12 patients with this syndrome (2 men and 10 women, mean age 50 +/- 6 years) underwent exercise testing and 24-hour ambulatory electrocardiographic monitoring. They were done off treatment and after alpha blockade with prazosin and clonidine on 2 separate weeks. Despite treatment, all exercise tests remained positive and patients were stopped because of progressive angina pain. Compared to the off-treatment tests, exercise duration and heart rate-blood pressure product at 1 mm of ST-segment depression did not change significantly after prazosin (617 +/- 203 vs 663 +/- 203 seconds and 23,857 +/- 6,125 vs 22,098 +/- 4,816 beats/min X mm Hg, respectively) and clonidine (684 +/- 148 vs 649 +/- 80 seconds and 25,514 +/- 2,386 vs 24,567 +/- 2,001 beats/min X mm Hg, respectively). Ambulatory monitoring showed similar results regarding number of episodes of ST-segment depression greater than or equal to 0.1 mV during control and after prazosin (39 vs 38) or clonidine (26 vs 23) treatment. None of the 8 patients who also underwent provocative testing with phenylephrine had ischemic electrocardiographic changes; only 2 experienced chest pain during the test.(ABSTRACT TRUNCATED AT 250 WORDS)