Dipyridamole infusion can provoke myocardial ischemia in coronary patients. Two-dimensional echocardiographic monitoring has been used in conjunction with infusion of this drug to detect coronary artery disease (1-3) and in evaluating the efficacy of antiischemic therapy (4-6). Transient dipyridamole myocardial asynergies, identified by two-dimensional echocardiographic monitoring, have been shown to represent a specific sign of acute ischemia. Moreover, the dipyridamole echocardiography test has been proposed as a clinically useful tool for assessing the organic coronary reserve by eliminating the variability in coronary tone related to the exercise stress test (7).
To the best of our knowledge, no prospective studies are available concerning the effects of verapamil on dipyridamole-induced myocardial ischemia. Verapamil has been shown to exert a direct protective action on the ischemic myocardium by both decreasing myocardial oxygen consumption and increasing myocardial oxygen supply (8). The drug in vivo has a negative chronotropic effect at rest (9-11), reduces myocardial oxygen demand during exercise (12), increases the threshold of effort angina (13,14), and is highly effective in the relief of coronary spasm in patients with variant angina (15). Furthermore the Danish Verapamil Infarction Trial II (DAVIT II; 16) and the Calcium Antagonist Reinfarction Italian Study (CRIS; 9), two double-blind placebo-controlled studies of verapamil after myocardial infarction, demonstrated a significant reduction in angina pectoris in patients given verapamil compared with a placebo group.
In this study, we evaluated the effects of this calcium antagonist on dipyridamole-induced transient wall-motion abnormalities as detected by two-dimensional echocardiographic monitoring in patients with coronary artery disease.
We prospectively studied 28 hospitalized patients (16 men and 12 women; mean age, 60 ± 7 years) with angiographic evidence of significant coronary artery disease, positive dipyridamole echocardiography test result at baseline condition, and adequate echocardiographic windows. The dipyridamole echocardiography test was repeated in each patient on two consecutive days and showed a reproducibility of 100%. Patients with previous myocardial infarction, valvular heart disease, congestive heart failure, atrioventricular conduction defects, cardiomyopathy, or severe ventricular arrhythmias were excluded from the study. All subjects gave informed consent, and the protocol was approved by the hospital's Ethics Committee. β-Adrenergic blocking drugs, nitrates, and angiotensin-converting enzyme inhibitors were discontinued ≥7 days before dipyridamole testing and were not given throughout the study period except sublingual nitroglycerine, as required. Calcium antagonists were discontinued ≥7 days before dipyridamole testing and were not given at basal condition or during placebo treatment. Patients were randomized to verapamil (360 mg/day) or placebo treatment, given in three divided doses daily for 7 days; at the end of this time, each patient crossed over to the alternate regimen. Dipyridamole echocardiographic testing was repeated at the end of each treatment period. Patients drank no coffee or tea for ≥3 h before the dipyridamole echocardiographic test.
Dipyridamole was infused through a 21-gauge butterfly needle inserted into a large anterocubital vein at a rate of 0.56 mg/kg body weight over 4 min followed by a 4-min pause and then 0.28 mg/kg over 2 min. The cumulative dose was therefore 0.84 mg/kg over 10 min. Twelve-lead electrocardiograms and blood pressure measurements were obtained at baseline and at 1-min intervals during the first 15 min of the study and at 20, 25, and 30 min. Parenteral aminophylline (240 mg) and nitroglycerin were available to reverse significant side effects of dipyridamole. The following side effects were considered significant: chest pain, dyspnea, ST-segment depression >1 mV, or appearance of myocardial asynergies detected by echocardiography. For safety reasons, aminophylline was administered in all patients despite positivity or negativity of the dipyridamole echocardiographic test.
The electrocardiographic criteria for a positive test were horizontal or downsloping ST-segment depression of ≥0.1 mV occurring at the J point and lasting 80 ms. Real-time echocardiographic examination was performed before, during, and after dipyridamole infusion, with the patient in a 30-60° left lateral decubitus position, by using a wide-angle (105°) phased-array imaging system (model 77020 AC, Hewlett Packard, Andover, MA, U.S.A., 3- to 5-MHz transducer). Images were obtained from standard parasternal and apical transducer positions. Particular attention was given to the apical four- and two-chamber views and to the parasternal short-axis plane. A wall-motion score index was derived for rest and peak dipyridamole echocardiograms in each patient. The left ventricle was divided into 11 segments, as proposed by the Italian Society of Echocardiography (17) and used in the GISSI 2 multicenter trial, in the subproject "Residual Ischemia" (which included performing a dipyridamole-echo test early after uncomplicated acute myocardial infarction; 18). The 11 segments are apex, anterior septum (proximal and distal), inferior septum (proximal and distal), anterior wall (proximal and distal), lateral wall (proximal and distal), and inferior wall (proximal and distal). Segmental wall motion was graded as follows: normal, normal motion at rest, with normal or increased wall motion (hyperkinesia) after dipyridamole (score = 1); hypokinetic, marked reduction of endocardial motion (score = 2); akinetic, virtual absence of inward motion (score = 3); and dyskinetic, paradoxical wall motion away from the center of the ventricle in systole (score = 4). The wall-motion score index was derived by summing individual segment scores and dividing by the number of segments interpreted. Inadequately visualized segments were not scored. A digital cine-loop system was available to evaluate the appearance of new wall-motion abnormalities, considered a valid criterion for a positive echocardiographic test (19). The images were displayed in real time at a rate of 58 frames/s and were recorded by a 0.25-inch (0.64 cm) VHS tape cassette recorder. Digital images at basal condition and during dipyridamole testing were analyzed independently by two observers unaware of treatment type (verapamil or placebo). In case of disagreement, a third observer reviewed the images, and majority judgment was binding. Interobserver variability was 4.8%. Intraobserver agreement was 100% in the studies reanalyzed by the same observer 1 week after the first evaluation.
Coronary arteriography was conducted by the Sones technique the morning after an overnight fast. Intramuscular diazepam (10 mg) was administered 30 min before the study. Selective coronary arteriography was performed in the standard projection and analyzed for quantitative evaluation of stenosis severity. For each coronary artery, the frame showing the most significant percentage narrowing in any projection over the length of that artery was selected and enlarged 10 times. The diameter of the stenosis and that of the most nearly "normal" proximal or distal segments were measured with a digital caliper. The ratio of the two measurements was taken as the percentage narrowing of that artery. For each vessel, the projection selected for this evaluation was agreed on by three experienced angiographers. Significant coronary artery disease was defined as ≥70% reduction in luminal diameter of one or more of the major coronary arteries.
Statistical analysis was performed by using a paired t test and Wilcoxon test as required. Values were expressed as mean ± standard deviation, and p < 0.05 was considered significant.
Dipyridamole test: echocardiographic and hemodynamic findings
No patients needed to use nitroglycerin to reverse dipyridamole side effects. Clinical and angiographic data of the study population are shown in Table 1. Hemodynamic findings during dipyridamole infusion of the patients in verapamil and placebo-treated groups are shown in Table 2. At basal condition, heart rate and rate-pressure product were significantly lower in the verapamil group than in placebo-treated patients. At peak dipyridamole infusion, heart rate and rate-pressure product increased with respect to baseline in both groups. Heart rate and rate-pressure product were significantly lower in the verapamil group than in the placebo group, whereas no difference was observed in other parameters. Dipyridamole-induced wall-motion score index was significantly reduced by verapamil with respect to placebo (1.7 ± 0.4 vs. 1.3 ± 0.2; p < 0.001; Fig. 1).
Our results show that verapamil significantly reduces the dipyridamole-induced wall-motion score index, a quantitative marker of acute myocardial ischemia.
Our hemodynamic data confirm that this drug is able to reduce myocardial oxygen demand at rest by decreasing rate-pressure product, the most important determinant of O2 consumption. In particular, they show that the drug decreases the rate-pressure product under dipyridamole at peak because it reduces heart-rate baseline values without changing the hemodynamic response during dipyridamole infusion. For these reasons, absolute values of rate-pressure product at the peak of the dipyridamole test are lower than placebo. These hemodynamic findings confirm those of a previous report (5) in which administration of β-adrenoceptor blockade reduced the development of transient dipyridamole-induced myocardial ischemia and decreased the determinants of O2 consumption, both at basal condition and at peak of dipyridamole infusion. We did not observe a significant reduction in blood pressure, even if this drug was given at the dose of 360 mg. It is important to note that our patients are not hypertensive. Oral administration of verapamil does not produce significant changes in systolic and diastolic blood pressure in normotensive subjects, as suggested by Buhler et al. (20) and Leonetti et al. (21).
It is not easy to explain the beneficial effects of verapamil on dipyridamole-induced ischemia on the basis of its mechanism. In fact dipyridamole infusion induces only a very slight increase in rate-pressure product, and the increase in myocardial oxygen consumption has rarely been considered responsible for dipyridamole-induced ischemia. However, Chambers and Brown (22) suggested that an increase in rate-pressure product is a significant multivariate predictor of dipyridamole-induced ST-segment depression, an electrical marker of ischemia.
The beneficial effects of verapamil on dipyridamole-induced myocardial ischemia could be explained by other mechanisms of action, as well as the vasodilatatory effect or sympathetic modulation. In theory, the vasodilatatory effect of verapamil on large coronary arteries could worsen the dipyridamole-induced "coronary steal" phenomenon. However, previous studies, by using a different calcium antagonist (diltiazem), suggested a major improvement of blood flow in areas of ischemic myocardium at rest or during exercise (23). Chew et al. (24) showed that verapamil is able to increase the coronary sinus blood flow in patients with fixed coronary occlusion. They found that verapamil moderately dilates the systemic and coronary small vessel resistance bed without apparently increasing myocardial metabolic demand. Experimental studies reported that after coronary occlusion, verapamil increased regional myocardial blood flow in moderately ischemic zones in anesthetized dogs, and that it increased collateral blood flow in conscious dogs (25). Even if a decrease in heart rate and heart rate-systolic blood pressure product (indicating a reduction in myocardial oxygen consumption) was observed, the most significant finding of the study was the verapamil-induced reduction of regional coronary resistance and increase in perfusion of the ischemic zone. On the basis of these observations, it was hypothesized that the effects of verapamil could be attributed mainly to increased blood flow in collateral channels.
Flow maldistribution, due to inappropriate coronary arteriolar vasodilatation, has been thought to play a central role in dipyridamole-induced ischemia (3,26). In particular, in patients with multivessel disease or coronary occlusion or both, the dipyridamole-induced reduction in collateral blood flow could be the mechanism mainly responsible for drug-induced ischemia. Therefore, dilatation in the coronary collateral circulation induced by verapamil could account for the beneficial effects of this drug.
Lucarini et al. (27) showed that dipyridamole triggers a sympathetic excitatory reflex by a positive modulation of sympathetic outflow. Although the level of sympathetic activation with dipyridamole infusion is much lower than that observed with dynamic stress test (28), they found a dipyridamole-induced increase in plasma norepinephrine, an index of neuronal activity, of ∼70%. Phenylalkylamines such as verapamil have been demonstrated to limit efferent sympathetic outflow of catecholamines, to deplete catecholamine vescicular stores (29,30), and to depress norepinephrine release (31,32), resulting in an attenuation of reflex tachycardia (33). Moreover, verapamil has been found in cerebrospinal fluid after oral administration (34), suggesting an influence on sympathetic outflow after crossing the blood-brain barrier. Kailasam et al. (11) recently compared short- and long-term effects of dihydropyridine and phenylalkylamine calcium channel antagonist classes on autonomic function in human hypertension. These authors found a significant decrease in plasma norepinephrine and chromogranin A after prolonged verapamil administration, confirming a suppressive effect on sympathetic outflow. They also demonstrated a divergent effect of verapamil (phenylalkylamine type/calcium antagonist) and felodipine (dihydropyridine type/calcium antagonist) on hemodynamic indexes of autonomic function, suggesting that verapamil is able to depress sympathetic activity. In our study, the sympathetic modulation induced by verapamil could be responsible of further protective effect on dipyridamole-induced ischemia.
We conclude that verapamil is able to reduce dipyridamole-induced ischemia, as detected by two-dimensional echocardiographic monitoring, in patients with coronary artery disease by reducing, at least partially, myocardial oxygen consumption. Moreover, its beneficial action could be related to effects of the drug on coronary collateral circulation and on sympathetic modulation. However, further investigations are needed to clarify the mechanism of action of verapamil on dipyridamole-induced myocardial ischemia.
Acknowledgment: We thank Giovanna Santopietro for her technical assistance and Mary Spears for manuscript revision.
This study was partially supported by a 40% grant from the Ministry of University and Scientific and Technological Research (MURST), Rome, Italy.
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