Sergio Chierchia

Local coronary supersensitivity to diverse vasoconstrictive stimuli in patients with variant angina.

It has been shown in different groups of patients with variant angina that coronary spasm can be reproduced by physiologic maneuvers and pharmacologic agents. It is not known, however, to what extent different stimuli can induce spasm in the same patient. To investigate whether coronary arterial spasm results from specific abnormal agonist-receptor interactions or from a local nonspecific coronary supersensitivity to different stimuli, 28 patients with vasospastic angina were submitted to a series of diverse vasoconstrictive stimuli known to provoke coronary spasm. Ergonovine, hyperventilation, handgrip, cold pressor, and exercise-tests, were carried out in all 28 patients. In the last 15 patients histamine was also administered. Spasm was provoked by ergonovine in 96% of patients, by hyperventilation in 54%, by histamine in 47%, by exercise in 46%, and by the cold pressor and handgrip tests in 11% and 7%, respectively. No significant differences were found in the responses to provocative tests of patients with normal coronary arteries or nonsignificant stenoses and those with significant lesions. In the same individual, spasm was induced by at least two vasoconstrictive stimuli, although with a different mechanism of action, in 82% of patients and spasm was induced by three or more stimuli in 39%. Tests were repeated in at least 23 patients and short-term reproducibility paralleled sensitivity. These results suggest that in patients with variant angina, a local nonspecific supersensitivity rather than an abnormal specific agonist-receptor interaction plays a major role in the genesis of coronary arterial spasm.

Importance of generalized defective perception of painful stimuli as a cause of silent myocardial ischemia in chronic stable angina pectoris

Growing evidence indicates that most patients with coronary artery disease frequently have episodes of painless myocardial ischemia. Previous studies from our institution show that the severity and duration of myocardial ischemia are necessary but not sufficient factors to explain the occurrence of anginal pain. The responses to a battery of painful stimuli were studied in 12 patients with predominantly painless (group A) and in 15 patients with predominantly painful (group B) ischemic episodes. The severity of myocardial ischemia as assessed by the measurement of ST-segment depression during exercise stress testing and during ambulatory electrocardiographic monitoring was comparable in the 2 groups. Patients in group A had a significantly higher threshold and tolerance for forearm ischemia (+32%, p less than 0.05; +120%, p less than 0.001), cold (+100%, p less than 0.05; +180%, p less than 0.01) and electrical skin stimulation (+145%, p less than 0.01; +109%, p less than 0.01), but the overlap between the 2 groups was often appreciable. In the 6 patients with the longest tolerance times for forearm ischemic pain (all in group A) and in the 5 having the shortest tolerance times (all in group B), plasma levels of beta endorphin, met-enkephalin, noradrenaline and adrenaline were similar during both the basal state and the induction of forearm ischemic pain. Thus, a generalized defective perception of painful stimuli plays an important role in many patients with predominantly painless myocardial ischemia. Other mechanisms, however, may also be important, particularly in patients whose threshold and tolerance values overlap with those of patients who have predominantly painful myocardial ischemia.

Induction of coronary artery spasm by a direct local action of ergonovine.

To investigate whether ergonovine acts directly on coronary arteries or via remote neurohumoral reflexes, we administered small titrated increments of intracoronary ergonovine up to a maximum cumulative dose of 50 micrograms to 15 patients. In six patients with variant angina (group 1), ischemic electrocardiographic ST changes, angina, and localized coronary spasm (local coronary diameter reduction of 87.8 +/- 18.9% [mean +/- SD]) followed after 6 to 50 micrograms (mean 20.7) cumulative intracoronary ergonovine. In nine patients with atypical chest pain, normal baseline coronary arteriograms, and no evidence of variant angina (group 2), there was no ischemic ST segment change or localized coronary spasm after 6 to 50 micrograms (mean 31.6) intracoronary ergonovine. Coronary diameter of proximal vessels of patients in group 2 was reduced by 16.2 +/- 6.5% and did not differ from the response of nonspastic vessels of comparable size of group 1 (20.5 +/- 13.8%; p = .7). There was no significant difference in the median effective dose values in the dose-response curves of the spastic and nonspastic segments between groups 1 and 2. Ergonovine causes coronary spasm by a direct local effect, which seems to be caused by localized arterial hyperreactivity rather than supersensitivity. Intracoronary delivery may be safer than intravenous administration because negligible drug recirculation may prevent perpetuation of spasm and selective coronary administration can avoid branches with critical stenoses.

alpha-Adrenergic receptors and coronary spasm: an elusive link.

In 14 consecutive patients with variant angina we investigated the possible role of coronary alpha-adrenergic receptors in the genesis of coronary spasm. In eight patients, computerized, beat-by-beat analysis of the electrocardiogram recorded during continuous Holter monitoring failed to reveal any increase of heart rate and corrected QT interval (both indexes of cardiac sympathetic activation) in the period preceding the onset of ST segment changes in 197 episodes of ischemia caused by coronary spasm. In the same patients, analysis of the circadian distribution of ischemic episodes revealed a significantly higher incidence in the early morning hours, when sympathetic activity is at the lowest level. Twelve patients underwent serial provocative testing with cold pressor, phenylephrine, or norepinephrine infusion and administration of ergonovine maleate. Ergonovine consistently reproduced coronary spasm in all 12 patients, while results of cold pressor testing were positive in only one. Infusion of phenylephrine (eight patients) or norepinephrine after beta-blockade (four patients) failed to precipitate myocardial ischemia. In five patients infusion of phentolamine at the highest tolerated dose did not reduce significantly the number of ischemic attacks when compared with placebo. In contrast to results of previous reports, our data seem to rule out the hypothesis that an increase of sympathetic outflow to the heart plays an important role in the genesis of coronary spasm. We cannot, however, exclude the possibility of localized alpha-stimulation of epicardial arteries.

Mixed angina pectoris

Patients who present with episodes of angina caused both by an increase in oxygen demand and by transient impairment of supply have a mixed form of angina. Distinctive clinical features allow the classification of patients in everyday practice. At one end of the spectrum are patients who have angina only and always when they exercise beyond an essentially fixed level; their angina is fairly predictable and has been termed secondary angina. At the other end of the spectrum are patients who have a normal exercise tolerance but have angina at rest or during activities usually well tolerated that must be caused by a transient impairment of coronary blood flow; their angina is typically unpredictable and has been termed primary angina. We adopted the term primary to emphasize the possible existence of multiple causes of impairment of coronary flow, which together are to be contrasted with the traditional prevailing concept of angina being secondary to excessive increase in demand. In between these ends of the spectrum are most of the patients with angina pectoris encountered in clinical practice: they have a rather predictable ceiling of exercise that they cannot exceed without developing angina, but they also have a variable proportion of unpredictable anginal attacks that occur spontaneously or at levels of activity that are usually well tolerated. We introduced the concept of mixed forms of angina when we became aware that the same patient could experience angina both as a result of an excessive increase in myocardial demand, i.e., secondary angina, and as a result of the transient impairment of coronary blood flow supply, i.e., primary angina.

Pathophysiology of coronary occlusion in acute infarction.

Coronary angiography has proved beyond doubt that complete coronary occlusion is the rule in the very early hours of infarction. The 60% to 80% rate of coronary recanalization after thrombolytic therapy has proved that thrombosis is a major component of the occlusion at the time when the procedure is performed a few hours after the onset of symptoms. However, the trigger for coronary thrombosis and the causes of failure of thrombolytic therapy are still a matter of speculation. The relatively rare occurrence of acute coronary occlusion in the life of an individual with even severe coronary disease can be explained on the basis of the necessity of either extremely powerful isolated stimuli, which only occurs rarely, or the casual simultaneous presence in one coronary arterial segment of multiple unfavorable events, such as plaque fissuring, enhanced reactivity of coronary smooth muscle to constrictor stimuli and displacement of the thrombotic-thrombolytic equilibrium toward thrombosis. Coronary artery constriction possibly caused by vasoconstrictor substances released by thrombus, represents the potential element of a vicious cycle causing persistent coronary occlusion and reocclusion when reflow occurs with thrombolysis.

Ergonovine-induced myocardial ischemia: no role for serotonergic receptors?

Because ergonovine appears to produce coronary contractions by a serotonergic (5-HT) mechanism, we attempted to prevent ergonovine-induced ischemia in patients with vasospastic angina by pretreatment with ketanserin, a new selective 5-HT blocker. We studied seven patients with consistently positive results of ergonovine testing (ST segment elevation in three and ST segment depression in four). Ergonovine testing was performed before and after a bolus of 10 mg of ketanserin (all patients) and infusion of 2 to 4 mg/hr for 8 hr (six patients). To assess 5-HT blockade during ketanserin infusion, the constrictor response of hand veins to 5-HT was tested before and after ketanserin. Despite evidence of 5-HT blockade in hand veins, ergonovine-induced ischemia was not prevented by ketanserin in any patient, and there was no significant change in the dose of ergonovine required to provoke ischemia. In one patient, four spontaneous episodes of ST segment elevation occurred during infusion of ketanserin. The plasma concentrations of ketanserin at the time of ergonovine testing ranged from 61 to 127 ng/ml (mean 102) and were well above those that completely inhibit canine coronary 5-HT contractions in vitro. Although human coronary arteries may differ in their responsiveness to 5-HT or ketanserin, these data suggest that ischemia from ergonovine-induced coronary vasospasm is not mediated by 5-HT receptors.

ROLE OF HEART RATE IN PATHOPHYSIOLOGY OF CHRONIC STABLE ANGINA

11 patients with chronic, stable, effort angina, off medication apart from glyceryl trinitrate, were monitored continuously by electrocardiogram (ECG) during normal, unrestricted daily activity. Computerised ECG analysis demonstrated during 33 twenty-four hour periods of monitoring, 278 episodes of transient ischaemic ST segment depression of which 52 were associated with angina. In the 15 minutes preceding the onset of ischaemia, heart rate did not increase in 164 episodes, increased slightly (greater than or equal to 5 beats/min) in 61, and increased moderately or markedly (greater than or equal to 10 beats/min) in 53. Findings were similar when episodes with or without angina or episodes of different severity were analysed separately. In all patients, periods of sinus tachycardia exceeding the control rate by more than 30 beats/min and lasting more than 10 minutes, often occurred in the absence of angina and/or ST segment depression. Also, in 65% of the ischaemic episodes, heart rate at the beginning of the ST change was either below or less than 10 beats/min above the modal value of the twenty-four hour heart rate. This suggests that increased myocardial demand is not necessarily the only or the most common cause of acute ischaemia in patients with chronic effort angina during unrestricted daily activity. Factors which only transiently interfere with myocardial oxygen supply are probably important in this syndrome.

Mechanisms of ischemic cardiac pain and silent myocardial ischemia

The mechanisms of cardiac ischemic pain remain obscure. It is unknown whether ischemia causes cardiac pain by the release of chemical substances or by mechanical stretching. It is also unknown whether ischemia activates specific nociceptors and pain fibers or mechanoreceptors and chemoreceptors. In patients who have both painful and painless ischemic episodes, a certain minimal duration and severity of ischemia are necessary but insufficient to explain the presence of pain, since very severe ischemia of long duration can be silent. Thus, central transmission of painful stimuli and the pain perception threshold appear to play major roles in determining the presence or absence of pain. The emotional state and psychologic expectations of patients may affect their perception and threshold of pain considerably.

Limitations of dipyridamole-echocardiography in effort angina pectoris

The sensitivity of dipyridamole--2-dimensional (2-D) echocardiography was assessed for detection and localization of ischemia in 21 patients with severe chronic stable angina pectoris, a clearly positive exercise stress test response and multivessel coronary atherosclerosis. Regional wall motion during dipyridamole infusion (0.6 mg/kg intravenously over 4 minutes) was compared with control and recovery by 2 blinded observers in consensus. Transient regional wall motion abnormalities were observed in 11 patients. Angina and ST-segment changes occurred in 9 of these 11 patients with positive responses, but in none of those who showed no transient abnormality of regional wall motion. Localization of regional wall motion abnormalities correlated well with angiographic severity of coronary lesions. Endocardial area contraction, evaluated by a computerized system, was reduced significantly after dipyridamole administration in patients with a positive response (from 51 +/- 10% to 35 +/- 11%, p less than 0.001), whereas it did not change significantly in the others (from 43 +/- 6% to 42 +/- 8%). In the 11 patients with a positive response, coronary reserve assessed by exercise testing (modified Bruce protocol) was more impaired than in those with a negative response (time to 1 mm of ST depression 177 +/- 148 seconds and 472 +/- 179 seconds, respectively, p less than 0.01). In patients with severe angina and multivessel coronary artery disease, dipyridamole--2-D echocardiography appears to identify the vessel in which flow reserve is most limited. Although this information may be valuable, indications for the test are restricted to patients with severely limited exercise capacity.