International Journal of Cardiology, 33 (1991) 75-82 0 1991 Elsevier Science Publishers B.V. All rights reserved 0167-5273/91/%03.50 ADONIS 016752739100212X
75
CARD10 01320
Exercise cardiovascular
responses to gallopamil in ischemic heart disease
P. Terrosu ‘, G.V. Ibba ‘, R. Pes ‘, G.M. Contini ‘, A. Delpini ‘, V. Franceschino D. Fantoccoli 2 and M. Magri 2
‘,
’ Department of Cardiology, General Hospital, U.S.L. N o 1. Sassari, Italy; 2 Division of Medical Research, Knoll, Milan. Italy (Received 23 November 1990; revision accepted 3 April 1991)
Terrosu P, Ibba GV, Pes R, Contini GM, Delpini A, Franceschino V, Fantoccoli D, Magri M. Exercise cardiovascular responses to gallopamil in ischemic heart disease. Int J Cardiol 1991;33:75-82. In a single-blind, placebo-controlled, crossover trial versus diltiazem, we evaluated the influence of gallopamil on cardiovascular responses evoked by bycicle exercise. Twelve patients with chronic stable angina were enrolled. After a 5 days placebo run-in period, patients were randomly assigned either to gallopamil (50 mg thrice daily) or diltiazem (60 mg thrice daily) for 10 days. Then, patients were changed to the alternative drug. After placebo, and at the end of each subsequent period, all subjects underwent right heart catheterization by means of a Swan-Ganz thermodilution catheter. Hemodynamics were determined in 3 ways: supine, standing and during a multistage exercise test. Results: angina1 attacks were reduced to a similar degree by gallopamil (2.1 k 1 /week versus 5.8 & 2.8/week during placebo, p < 0.01) and diltiazem (2.0 f 0.8/week versus 5.8 f 2.8/week during placebo, P < 0.01). At rest, gallopamil caused a significant decrease in heart rate and a slight fall in systemic vascular resistance. Cardiac index rose during exercise and was higher with respect to placebo at peak exercise P < 0.05). As a consequence, stroke volume index and stroke work index both (6.7 vs 5.6 l/min/m2, increased at maximum workload (P < 0.05). Compared to placebo, exercise time was significantly improved by gallopamil ( +50%, P < 0.02) and diltiazem ( +38%, P < 0.05). Likewise, time to onset of ST-segment depression was prolonged by 70% with gallopamil (P < 0.01) and by 64% with diltiazem (P < 0.02). The rate-pressure product was significantly lowered by gallopamil at maximum comparable workload (16.8 f 5.8 versus 20.9 * 4.4 during placebo, P < 0.05). However, there was no difference between gallopamil and placebo at peak exercise. Notably, the index of left ventricular work at peak exercise was higher with respect to placebo. In conclusion, therefore, gallopamil and diltiazem both improve exercise test tolerance to a similar degree. Although gallopamil reduced the double product at comparable workloads, it does not impare left ventricular function. On the contrary, myocardial performance and maximum left ventricular workload increase, thus suggesting that gallopamil produces a direct improvement of the myocardial supply/demand ratio. Key words: Gallopamil; Exercise cardiovascular
Correspondence
response; Stable angina
to: P. Terrosu, M.D., Dept. ?f Cardiology, Via Principessa Jolanda 29, 07100 Sassari, Italy.
Introduction In the last decades, calcium-antagonists have gained a wide-spread use for the treatment of the myocardial ischemia. Despite our considerable knowledge of the cardiovascular effects of these drugs, however, much still has to be learned about their mechanism of action. Moreover, it should be pointed out that calcium channel blockers are widely heterogeneous in their chemical structure and differ considerably in their relative cardiodepressant, electrophysiologic and peripheral vasodilating actions. Gallopamil, a methoxyderivative of verapamil, is reported to have maximal anti-ischemic effects [l-6] despite a minor activity on the automaticity of the sinus node and on vascular smooth cells. Further, in contrast to other currently available calcium-blockers (such as verapamil), gallopamil has been proven to reduce transport of calcium across mitochondrial membranes [7,8]. This evidence supports the hypothesis that gallopamil may preserve myocardial function during ischemia by preventing mitochondrial calcium overload. Accordingly, this study was designed to compare the hemodynamic effects of gallopamil with diltiazem in patients with coronary arterial disease. In addition, we specifically evaluated the mechanisms underlying the action of gallopamil with particular regard as to whether the antiischemic properties of the drug may be due to direct changes in myocardial metabolism rather than to indirect influences on left ventricular load or coronary blood flow. Patient selection The study group comprised 12 patients with coronary arterial disease. They were all males, ranging from 40 to 64 years of age. All patients had history of angina on effort and > 1 mm of horizontal or downsloping STsegment depression during maximal bicycle-exercise test. Seven patients who had undergone coronary angiography showed at least 70% luminal diame-
ter narrowing on one vessel. In the other five patients, the diagnosis of ischemic heart disease was confirmed by thallium myocardial scintigraphy. Patients with myocardial infarction within the previous three months, unstable angina, significant hypertension (diastolic blood pressure > 110 mmHg or systolic blood pressure > 190 mmHg), valvar heart disease, or electrocardiographic abnormalities precluding interpretation of exerciseinduced ST-segment changes were not considered for the study. All antianginal drugs except sublingual nitroglycerine and all cardiovascular drugs that interfere with the interpretation of ST-segment changes were discontinued for at least 5 half-lives before the pre-study exercise test and withheld during the study. All patients gave their informed consent before entering in the study. Study design Before randomization, all patients received placebo (three times daily) for 5 days, while baseline angina1 frequency and sublingual nitroglycerin consumption were assessed (placebo run-in). At the conclusion of this period, a multistage bicycle exercise test was performed, against which subsequent exercise tests during diltiazem or gallopamil were compared. At the end of the run-in period, patients were randomly assigned to receive either diltiazem (60 mg thrice daily) or gallopamil (50 mg thrice daily). After 10 days of treatment, each patient crossed over to the alternative drug therapy for remaining 10 days. Exercise tests and hemodynamic recordings were taken on the fifth day of placebo and at the end of each treatment period. To avoid physician bias, the investigators who performed the cardiac catheterizations and the exercise tests were unaware of which drug was being administered at the time of recording of data. A diary record of angina1 frequency and consumption of nitroglycerin was kept by all patients during the control and treatment periods.
Exercise testing Exercise testing was performed in the postabsorptive state with an electrically braked bicycle ergometer in the upright position. Exercise was started at 25 watts and was increased by 25 watts every 3 minutes until fatigue, seiere angina or more than 0.25 mV ST-segment depression occurred, or 90% of the age predicted maximal heart rate was reached. Blood pressure was monitored with a standard cuff sphygmomanometer. A 12-lead electrocardiography was continuously recorded before, during and up to 10 minutes after exercise. ST-segment depression was measured at 80 msec after the J-point. The depth of ST depression was reported from the same lead for each test, the one that showed the most ST depression. Total exercise duration, time to 1 mm ST-depression, heart rate, blood pressure, rate-pressure product, time to angina were assessed. The “maximum comparable workload”. was defined as the highest identical workload achieved during both placebo and active treatment. Peak exercise represented the maximum workload achieved at termination of exercise.
Hemodynamic recordings Before each exercise test, a Swan-Ganz thermodilution catheter was introduced percutaneously by the subclavian route. Pressures were recorded by means of a Statham P23ID manometer using a g-channel polygraph (Mingograf 804 Siemens). Cardiac output was measured by thermodilution (Edwards 9620). Systemic vascular resistance, pulmonary vascular resistance and total pulmonary resistance were expressed in dynes. sec. crnm5 and were calculated as follows: systemic vascular resistance = (mean aortic pressure-mean right atria1 pressure) * go/cardiac outPW
pulmonary vascular resistance = (mean pulmonary arterial pressure-pulmonary wedge pressure) . go/cardiac output; total pulmonary resistance = mean pulmonary artery pressure . go/cardiac output. Left ventric-
ular stroke work index, expressed in g. m/m2, was calculated as stroke volume index. (mean aortic pressure-pulmonary wedge pressure) . (0.0136). Data were acquired over a 2 minute period before exercise in the supine and erect postures and during the last 2 minutes of each 3 minute exercise test stage.
Statistical analysis Values are reported as mean k standard deviation. Data were evaluated using 2 way analysis of variance for repeated measures. Multiple comparison were performed using Student’s test with Bonferroni correction, as appropriate. A level of P < 0.05 was considered significant.
Results Clinical response to therapy All 12 male patients completed the protocol without complication or adverse effects. The average number of angina1 attacks/ week decreased from 5.8 k 2.8 at baseline to 2.1 + 1 with gallopamil (P < 0.01) and 2.0 + 0.8 with diltiazem (P < 0.01). There was a reduction in the number of glyceryl trinitrate tablets taken compared to the prestudy measurement (from 7 f 2 to 2 + 0.5 with both drugs). Hemodynamic parameters (Table 1) Compared to placebo, gallopamil treatment resulted in a reduction in heart rate at rest (from 82 to 71 beats/min, P < 0.05) and at comparable workload (P < 0.05). Concomitantly there was no significant difference in systemic vascular resistance either at rest or at peak exercise. Cardiac index was unchanged at rest but rose during exercise and was higher with respect to placebo at peak exercise (6.7 vs 5.6 l/min/m’, P < 0.05). As a consequence, stroke volume index and stroke work index both increased at maximum workload (P < 0.05). Relative to reduction of heart rate and aortic pressure, the rate-pressure product was markedly
Diltiazem 68 *12 * 2.7kO.4 93 *9 8.7k2.8 8.4 * 2.5 1454 rt234 41 *9 47.7+ 12
Placebo
82 + 9.5 2.7kO.5 100 +14 7.6*4 10.8 f 2.2 1538 f268 34.7 f 5.6 43.7+ 10
Rest erect
71 _+11* 2.8kO.4 95 +11 8.5 + 3.9 9.1 k2.2 1430 + 182 40 +7.5 47 *9
Gallopamil 121 *I4 5.6kO.8 115 +15 17.8k8.6 20.9 + 4.4 888 k149 45.4*6 60 +9
Placebo
108 f18 * 5.9*1.3 112 _+6 15.553.8 16.8k5.8 * 833 *130 52.8f 12 * 69.3 + 8
Gallopamil
127 +14 5.6kO.8 115 *15 17.8 + 8.6 20.9 f 4.4 888 * 149 45.4_+6 60 +9
Placebo
Peak exercise
PWP = pulmonary wedge pressure;
110 + 15 * 5.7* 1.1 111 _+14 15 +_6.4 18 k3.7 819 k158 51 +8 66.5 f 15
Diltiazem
Maximum comparable workload
* P < 0.05 vs placebo. HR = heart rate; CI = cardiac index; MAP = mean aortic pressure; SVR = systemic vascular resistance; SVI = stroke volume index; SW1 = stroke work index.
MM hnmHg) PWP (mmHg) DP (x 10,000) SVR (dynes.sec.cm-5) SVI (ml/min/m’/cycle) SWI (g/mitt/m”)
CI (I/min/m’)
HR (bpm)
Hemodynamic parameters.
TABLE 1
product;
127 +15 6.7k1.6 * 120 *5 15 *3 21.7k3.6 778 +145 51.5& 12 73.5 f 18.7 *
Gallopamil
DP = rate pressure
128 523 6.3+ 1.4 118 f13 15.8 + 6.7 20.6+6.7 794 * 168 48.9 f 5 67.9 * 12.7
Diltiazem
79
TABLE 2
Discussion
Exercise test results
Two general types of calcium antagonists are described. The first, is drugs such as diltiazem or Total time verapamil, whose action on heart and smooth 12.2 k2.9 ** exercised (min) 8.3 f 2.3 11.7 + 3.6 * muscle are roughly equivalent. The second group Time exercised is made up of calcium blockers, more active on before 1 mm vascular smooth muscle than on cardiac muscle ST depression (such as dihydropiridines) [9,11]. (min) 6.2+3 10.2 +3.6 * 10.5 +3.7 * The highest As a final result, the effects on cardiac electricomparable cal and mechanical function depend on the comST segment plex interplay between the direct effect and the depression indirect influence of reduction of afterload and 2.1kO.9 0.54kO.6 *** 0.54kO.8 *** (mm) sympathetic stimulation mediated through re* P < 0.05 vs placebo; * * P < 0.02 vs placebo; * * * P < 0.01 flexes involving baroreceptors. vs placebo. Differences in the biological effects of the many calcium entry blockers have led investigators to postulate the theoretical advantages of some over others when treating patients with reduced by gallopamil at comparable workload angina pectoris. This study shows that gallopamil levels (from 20.9 + 4.4 to 16.8 A 5.8, P < 0.05). has similar antianginal effects in comparison with However, at peak exercise the rate pressure proddiltiazem. uct reached a value similar to that found during At the doses used, both drugs exerted an equal placebo. No significant difference was found besuppression of the frequency of angina1 attacks tween gallopamil and diltiazem, although stroke and improved similarly the tolerance to exercise. work index had a less and not statistical increase No adverse reaction was described with treatwith diltiazem therapy. This was because diltiment with gallopamil, while only one patient on azem tended to produce minor changes in puldiltiazem experienced a significative systemic hymonary wedge pressure and cardiac. index. potension during the exercise test. Notably, gallopamil increased the cardiac index, whereas there was no significant change in Exercise test results (Table 2) the pulmonary wedge pressure. This evidence has some important implications. First, gallopamil is All exercise test parameters were significantly devoid of significant myocardial depressant efimproved by both gallopamil and diltiazem. fects even in the presence of coronary arterial There were marked increases in exercise duradisease. Second, the drug seems to improve left tion and peak workload compared to placebo ventricular end-diastolic compliance, probably with gallopamil (+50% and +38% vs placebo because of its antiischemic effects. respectively, both P < 0.02) and diltiazem ( + 41% The mechanism by which gallopamil improves and +28% vs placebo, both P < 0.05). exercise tolerance in patients with stable angina As shown in Table 2, there was an approxiremains controversial. According to previous remate 50% decrease in magnitude of ST-depresports [3-6,12-161, gallopamil reduces the ratesion at similar workload in patients taking galpressure product at rest as well as at comparable lopamil or diltiazem compared to placebo. submaximal workload. Such a reduction in rateMoreover, time to 1 mm ST-depression was pressure product, an indirect index of myocardial significantly prolonged by gallopamil (+ 70%, P oxigen demand, permitted patients to work to a < 0.01) and diltiazem (+64%, P < 0.02) comhigher work level before the onset of ischemia. pared to placebo. These findings support the hypothesis that dePlacebo
Diltiazem
Gallopamil
80
creased myocardial consumption of oxygen may be a major contributing factor in the antianginal effects of gallopamil at submaximal exercise levels. Gallopamil, nonetheless, did not influence the rate-pressure product at maximal peak exercise in comparison with placebo, because the capacity to increase heart rate and systemic pressure was blunted but not abolished. Surprisingly, gallopamil was found to increase maximal left ventricular work with respect to placebo and diltiazem, despite a similar peak of rate-pressure product. This was mainly due to an increase in the cardiac index and, therefore, in the myocardial performance. It may be assumed that gallopamil exerts a direct myocardial anti-ischemic effect and improves contraction in ischemic regions. Our data also agree with the results of a previous study performed with intravenous gallopamil, which demonstrated that this drug reverts contractile dysfunction in the ischemic myocardium
n71. As the effects of the drug on ventricular function become evident under conditions leading to myocardial ischemia, it is obvious that these effects appear to be more important during peak exercise. We postulate that gallopamil may improve perfusion to ischemic areas by relieving exercise induced coronary vaso~nstriction or by redistribution of coronary flow. In addition, it may exert a beneficial effect on intracellular energetic processes by preventing ischemia-induced calcium overload of the mitochondria. In summary, gallopamil increased exercise tolerance (subm~imum and maximum workload), as well as the time to the onset of electrocardiographic ischemia in all patients. Moreover, exercise cardiac performance improved and there was no evidence of adverse inotropic effects. Therefore, the theoretical negative inotropic action of the drug may be, even in patients with ischemic left ventricular dysfunction, counterbalanced by a direct favorable action on regional wall motion. These findings could be an expression of a direct beneficial effect of gallopamil on metabolism of the ischemic myocardium.
References 1 Khurmi NS, O’Hara MJ, Bowles MJ, Baia Subramanian V, Raftery EB. Randomised double-blind comparison of gallopamil and propanolol in stable angina pectoris. Am J Cardiol 1984;53:684-688. 2 Scrutinio D, Lagioia R, Accettura D, Preziusi N, Mastropasqua E, Rizzon P. Dose-response effectiveness of gallopamil for the treatment of chronic stable effort angina pectoris: comparison with propanolol. Curr Ther Res 1985;37:830-838. 3 Scrutinio D, Lagioia R, Mangini SG et al. Objective evaluation of ~aliopamil in patients with chronic stabte angina. Exercise testing, Hoher monitoring, cross-sectional echocardiograpby and plasma levels. Eur Heart J 1989; 10: 168-176. 4 Tartagni F, Maiello L, Marchetti G et al. Clinical and hemodynamic effects of long-term administration of gallopamil in patients with coronary artery disease and normal or impaired left ventricular function. Am J Cardiol 1989;63:291-295. 5 Rettig G, Sen S. Akut- und ~n~eite~ekte von Gallopamil bei Patienten mit stabiler Angina Pectoris. In: Kahenbach M, Hopf R, eds. Gallopamil; pharmakologisches und klinisches Wirkungspro~l eines Kalziumantagonisten. Berlin, Heidelberg, Tokyo: Sponger-Verlag, 1984, 136-142. 6 Theisen F, Jahrmarker H. Wirkung von Gallopamil (D-600) auf das belastungs EKG bei koronarer Herzerkrankung. In: Kaltenbach M, Hopf R, eds. Gallopamil: pharmakologisches und klinisches Wirkungspro~l eines ~lziumantagonisten. Berfin, Heidelberg, Tokyo: Springer-Verlag, 1984, 117-131. 7 Ferrari R, Raddino R, Dei Cas L, Ciampalini G, Visioli 0. I nuovi farmaci calcio antagonisti in cardiologia. In: Atti de1 21” Corso di Aggiornamento “Cardiologia 1987” Milano. Librex, 1987, 386-401. 8 Ferrari R, Boffa GM, Ciampalini G, Cecconi C. Meccanismo di azione cellulare miocardico dei “calcioantagonisti”. Cardiologia 1985;30:9-13. 9 Millard RW, Grupp G, Grupp IL, Disalvo J, Depover A, Schwartz A. Chronotropic, inotropic and vasodilator actions of diltiazem, nifedipine and verapamil. Circ Res 1983;52:1-29-39. 10 Stone PH, Antman EM, Muller JE, Branwald E. Calcium channel blocking drugs in the treatment of cardiovascular disorders. II. Hemodynamic effects and clinical applications. Ann Intern Med 1980;93:886-891. 11 Janis RA, Rampe D, Su CM, Triggle DJ. Cat+ channel. ~gand-induced antagonism and activation. In: Godfraind T, Vanhoutte PM, Govorri S, Paoletti R, eds. Calcium entry blockers and tissue protection. New York Raven Press, 1985, 21-30. 12 Specchia G, Cobelii F, Tavazzi L et al. Beurteilungen von Gallopamil (D600) bei Patienten mit chronisch stabiler Angina Pectoris. Ergebnisse einer plazebokontrollierten Einfachblindstudie. In: Bender F, Meesmann W, eds.
81 Therapie mit Gallopamil. Darmstadt: Steinkopf Verlag, 1987, 179-186. 13 Brisse P, Weber M, Bender F. Untersuchung der Gallopamilwirkung mit dem Nuklearstethoskop bei Patienten mit koronaner Herzkrankheit. In: Bender F, Meesmann W, eds. Therapie mit Gallopamil. Darmstadt, 1987, 131137. 14 Tartagni F, Marchetti G, Maiello L, Dondi M, Franchi R, Magnani B. Profilo dell’ effetto emodinamico de1 gallopamil a riposo e sotto sforzo mediante studio angiocardioscintigrafico: dati preliminari. Cardiologia 1987; 32:1249-1253.
15 De Servi S, Ferrario M, Ghio S et al. Coronary haemodynamic effects of short term intravenous administration of gallopamil in patients with stable exertional angina. Br Heart J 1987;57:226-231. 16 Sangiorgio P, Rubboli A, Brunelli D, Bracchetti D. I1 gallopamil nell’ angina stabile da sforzo. Effetti di due diversi dosaggi. G Ital Cardiol 1989;19:40-45. 17 Stauch M, Grossmann G, Schmidt A, Richter P, Waitzinger J, Wanjura D, Adam WE, Konig W. Effect of gallopamil on left ventricular function in regions with and without ischaemia. Br Heart J 1987; 8 (suppl G): 77-83.
75
CARD10 01320
Exercise cardiovascular
responses to gallopamil in ischemic heart disease
P. Terrosu ‘, G.V. Ibba ‘, R. Pes ‘, G.M. Contini ‘, A. Delpini ‘, V. Franceschino D. Fantoccoli 2 and M. Magri 2
‘,
’ Department of Cardiology, General Hospital, U.S.L. N o 1. Sassari, Italy; 2 Division of Medical Research, Knoll, Milan. Italy (Received 23 November 1990; revision accepted 3 April 1991)
Terrosu P, Ibba GV, Pes R, Contini GM, Delpini A, Franceschino V, Fantoccoli D, Magri M. Exercise cardiovascular responses to gallopamil in ischemic heart disease. Int J Cardiol 1991;33:75-82. In a single-blind, placebo-controlled, crossover trial versus diltiazem, we evaluated the influence of gallopamil on cardiovascular responses evoked by bycicle exercise. Twelve patients with chronic stable angina were enrolled. After a 5 days placebo run-in period, patients were randomly assigned either to gallopamil (50 mg thrice daily) or diltiazem (60 mg thrice daily) for 10 days. Then, patients were changed to the alternative drug. After placebo, and at the end of each subsequent period, all subjects underwent right heart catheterization by means of a Swan-Ganz thermodilution catheter. Hemodynamics were determined in 3 ways: supine, standing and during a multistage exercise test. Results: angina1 attacks were reduced to a similar degree by gallopamil (2.1 k 1 /week versus 5.8 & 2.8/week during placebo, p < 0.01) and diltiazem (2.0 f 0.8/week versus 5.8 f 2.8/week during placebo, P < 0.01). At rest, gallopamil caused a significant decrease in heart rate and a slight fall in systemic vascular resistance. Cardiac index rose during exercise and was higher with respect to placebo at peak exercise P < 0.05). As a consequence, stroke volume index and stroke work index both (6.7 vs 5.6 l/min/m2, increased at maximum workload (P < 0.05). Compared to placebo, exercise time was significantly improved by gallopamil ( +50%, P < 0.02) and diltiazem ( +38%, P < 0.05). Likewise, time to onset of ST-segment depression was prolonged by 70% with gallopamil (P < 0.01) and by 64% with diltiazem (P < 0.02). The rate-pressure product was significantly lowered by gallopamil at maximum comparable workload (16.8 f 5.8 versus 20.9 * 4.4 during placebo, P < 0.05). However, there was no difference between gallopamil and placebo at peak exercise. Notably, the index of left ventricular work at peak exercise was higher with respect to placebo. In conclusion, therefore, gallopamil and diltiazem both improve exercise test tolerance to a similar degree. Although gallopamil reduced the double product at comparable workloads, it does not impare left ventricular function. On the contrary, myocardial performance and maximum left ventricular workload increase, thus suggesting that gallopamil produces a direct improvement of the myocardial supply/demand ratio. Key words: Gallopamil; Exercise cardiovascular
Correspondence
response; Stable angina
to: P. Terrosu, M.D., Dept. ?f Cardiology, Via Principessa Jolanda 29, 07100 Sassari, Italy.
Introduction In the last decades, calcium-antagonists have gained a wide-spread use for the treatment of the myocardial ischemia. Despite our considerable knowledge of the cardiovascular effects of these drugs, however, much still has to be learned about their mechanism of action. Moreover, it should be pointed out that calcium channel blockers are widely heterogeneous in their chemical structure and differ considerably in their relative cardiodepressant, electrophysiologic and peripheral vasodilating actions. Gallopamil, a methoxyderivative of verapamil, is reported to have maximal anti-ischemic effects [l-6] despite a minor activity on the automaticity of the sinus node and on vascular smooth cells. Further, in contrast to other currently available calcium-blockers (such as verapamil), gallopamil has been proven to reduce transport of calcium across mitochondrial membranes [7,8]. This evidence supports the hypothesis that gallopamil may preserve myocardial function during ischemia by preventing mitochondrial calcium overload. Accordingly, this study was designed to compare the hemodynamic effects of gallopamil with diltiazem in patients with coronary arterial disease. In addition, we specifically evaluated the mechanisms underlying the action of gallopamil with particular regard as to whether the antiischemic properties of the drug may be due to direct changes in myocardial metabolism rather than to indirect influences on left ventricular load or coronary blood flow. Patient selection The study group comprised 12 patients with coronary arterial disease. They were all males, ranging from 40 to 64 years of age. All patients had history of angina on effort and > 1 mm of horizontal or downsloping STsegment depression during maximal bicycle-exercise test. Seven patients who had undergone coronary angiography showed at least 70% luminal diame-
ter narrowing on one vessel. In the other five patients, the diagnosis of ischemic heart disease was confirmed by thallium myocardial scintigraphy. Patients with myocardial infarction within the previous three months, unstable angina, significant hypertension (diastolic blood pressure > 110 mmHg or systolic blood pressure > 190 mmHg), valvar heart disease, or electrocardiographic abnormalities precluding interpretation of exerciseinduced ST-segment changes were not considered for the study. All antianginal drugs except sublingual nitroglycerine and all cardiovascular drugs that interfere with the interpretation of ST-segment changes were discontinued for at least 5 half-lives before the pre-study exercise test and withheld during the study. All patients gave their informed consent before entering in the study. Study design Before randomization, all patients received placebo (three times daily) for 5 days, while baseline angina1 frequency and sublingual nitroglycerin consumption were assessed (placebo run-in). At the conclusion of this period, a multistage bicycle exercise test was performed, against which subsequent exercise tests during diltiazem or gallopamil were compared. At the end of the run-in period, patients were randomly assigned to receive either diltiazem (60 mg thrice daily) or gallopamil (50 mg thrice daily). After 10 days of treatment, each patient crossed over to the alternative drug therapy for remaining 10 days. Exercise tests and hemodynamic recordings were taken on the fifth day of placebo and at the end of each treatment period. To avoid physician bias, the investigators who performed the cardiac catheterizations and the exercise tests were unaware of which drug was being administered at the time of recording of data. A diary record of angina1 frequency and consumption of nitroglycerin was kept by all patients during the control and treatment periods.
Exercise testing Exercise testing was performed in the postabsorptive state with an electrically braked bicycle ergometer in the upright position. Exercise was started at 25 watts and was increased by 25 watts every 3 minutes until fatigue, seiere angina or more than 0.25 mV ST-segment depression occurred, or 90% of the age predicted maximal heart rate was reached. Blood pressure was monitored with a standard cuff sphygmomanometer. A 12-lead electrocardiography was continuously recorded before, during and up to 10 minutes after exercise. ST-segment depression was measured at 80 msec after the J-point. The depth of ST depression was reported from the same lead for each test, the one that showed the most ST depression. Total exercise duration, time to 1 mm ST-depression, heart rate, blood pressure, rate-pressure product, time to angina were assessed. The “maximum comparable workload”. was defined as the highest identical workload achieved during both placebo and active treatment. Peak exercise represented the maximum workload achieved at termination of exercise.
Hemodynamic recordings Before each exercise test, a Swan-Ganz thermodilution catheter was introduced percutaneously by the subclavian route. Pressures were recorded by means of a Statham P23ID manometer using a g-channel polygraph (Mingograf 804 Siemens). Cardiac output was measured by thermodilution (Edwards 9620). Systemic vascular resistance, pulmonary vascular resistance and total pulmonary resistance were expressed in dynes. sec. crnm5 and were calculated as follows: systemic vascular resistance = (mean aortic pressure-mean right atria1 pressure) * go/cardiac outPW
pulmonary vascular resistance = (mean pulmonary arterial pressure-pulmonary wedge pressure) . go/cardiac output; total pulmonary resistance = mean pulmonary artery pressure . go/cardiac output. Left ventric-
ular stroke work index, expressed in g. m/m2, was calculated as stroke volume index. (mean aortic pressure-pulmonary wedge pressure) . (0.0136). Data were acquired over a 2 minute period before exercise in the supine and erect postures and during the last 2 minutes of each 3 minute exercise test stage.
Statistical analysis Values are reported as mean k standard deviation. Data were evaluated using 2 way analysis of variance for repeated measures. Multiple comparison were performed using Student’s test with Bonferroni correction, as appropriate. A level of P < 0.05 was considered significant.
Results Clinical response to therapy All 12 male patients completed the protocol without complication or adverse effects. The average number of angina1 attacks/ week decreased from 5.8 k 2.8 at baseline to 2.1 + 1 with gallopamil (P < 0.01) and 2.0 + 0.8 with diltiazem (P < 0.01). There was a reduction in the number of glyceryl trinitrate tablets taken compared to the prestudy measurement (from 7 f 2 to 2 + 0.5 with both drugs). Hemodynamic parameters (Table 1) Compared to placebo, gallopamil treatment resulted in a reduction in heart rate at rest (from 82 to 71 beats/min, P < 0.05) and at comparable workload (P < 0.05). Concomitantly there was no significant difference in systemic vascular resistance either at rest or at peak exercise. Cardiac index was unchanged at rest but rose during exercise and was higher with respect to placebo at peak exercise (6.7 vs 5.6 l/min/m’, P < 0.05). As a consequence, stroke volume index and stroke work index both increased at maximum workload (P < 0.05). Relative to reduction of heart rate and aortic pressure, the rate-pressure product was markedly
Diltiazem 68 *12 * 2.7kO.4 93 *9 8.7k2.8 8.4 * 2.5 1454 rt234 41 *9 47.7+ 12
Placebo
82 + 9.5 2.7kO.5 100 +14 7.6*4 10.8 f 2.2 1538 f268 34.7 f 5.6 43.7+ 10
Rest erect
71 _+11* 2.8kO.4 95 +11 8.5 + 3.9 9.1 k2.2 1430 + 182 40 +7.5 47 *9
Gallopamil 121 *I4 5.6kO.8 115 +15 17.8k8.6 20.9 + 4.4 888 k149 45.4*6 60 +9
Placebo
108 f18 * 5.9*1.3 112 _+6 15.553.8 16.8k5.8 * 833 *130 52.8f 12 * 69.3 + 8
Gallopamil
127 +14 5.6kO.8 115 *15 17.8 + 8.6 20.9 f 4.4 888 * 149 45.4_+6 60 +9
Placebo
Peak exercise
PWP = pulmonary wedge pressure;
110 + 15 * 5.7* 1.1 111 _+14 15 +_6.4 18 k3.7 819 k158 51 +8 66.5 f 15
Diltiazem
Maximum comparable workload
* P < 0.05 vs placebo. HR = heart rate; CI = cardiac index; MAP = mean aortic pressure; SVR = systemic vascular resistance; SVI = stroke volume index; SW1 = stroke work index.
MM hnmHg) PWP (mmHg) DP (x 10,000) SVR (dynes.sec.cm-5) SVI (ml/min/m’/cycle) SWI (g/mitt/m”)
CI (I/min/m’)
HR (bpm)
Hemodynamic parameters.
TABLE 1
product;
127 +15 6.7k1.6 * 120 *5 15 *3 21.7k3.6 778 +145 51.5& 12 73.5 f 18.7 *
Gallopamil
DP = rate pressure
128 523 6.3+ 1.4 118 f13 15.8 + 6.7 20.6+6.7 794 * 168 48.9 f 5 67.9 * 12.7
Diltiazem
79
TABLE 2
Discussion
Exercise test results
Two general types of calcium antagonists are described. The first, is drugs such as diltiazem or Total time verapamil, whose action on heart and smooth 12.2 k2.9 ** exercised (min) 8.3 f 2.3 11.7 + 3.6 * muscle are roughly equivalent. The second group Time exercised is made up of calcium blockers, more active on before 1 mm vascular smooth muscle than on cardiac muscle ST depression (such as dihydropiridines) [9,11]. (min) 6.2+3 10.2 +3.6 * 10.5 +3.7 * The highest As a final result, the effects on cardiac electricomparable cal and mechanical function depend on the comST segment plex interplay between the direct effect and the depression indirect influence of reduction of afterload and 2.1kO.9 0.54kO.6 *** 0.54kO.8 *** (mm) sympathetic stimulation mediated through re* P < 0.05 vs placebo; * * P < 0.02 vs placebo; * * * P < 0.01 flexes involving baroreceptors. vs placebo. Differences in the biological effects of the many calcium entry blockers have led investigators to postulate the theoretical advantages of some over others when treating patients with reduced by gallopamil at comparable workload angina pectoris. This study shows that gallopamil levels (from 20.9 + 4.4 to 16.8 A 5.8, P < 0.05). has similar antianginal effects in comparison with However, at peak exercise the rate pressure proddiltiazem. uct reached a value similar to that found during At the doses used, both drugs exerted an equal placebo. No significant difference was found besuppression of the frequency of angina1 attacks tween gallopamil and diltiazem, although stroke and improved similarly the tolerance to exercise. work index had a less and not statistical increase No adverse reaction was described with treatwith diltiazem therapy. This was because diltiment with gallopamil, while only one patient on azem tended to produce minor changes in puldiltiazem experienced a significative systemic hymonary wedge pressure and cardiac. index. potension during the exercise test. Notably, gallopamil increased the cardiac index, whereas there was no significant change in Exercise test results (Table 2) the pulmonary wedge pressure. This evidence has some important implications. First, gallopamil is All exercise test parameters were significantly devoid of significant myocardial depressant efimproved by both gallopamil and diltiazem. fects even in the presence of coronary arterial There were marked increases in exercise duradisease. Second, the drug seems to improve left tion and peak workload compared to placebo ventricular end-diastolic compliance, probably with gallopamil (+50% and +38% vs placebo because of its antiischemic effects. respectively, both P < 0.02) and diltiazem ( + 41% The mechanism by which gallopamil improves and +28% vs placebo, both P < 0.05). exercise tolerance in patients with stable angina As shown in Table 2, there was an approxiremains controversial. According to previous remate 50% decrease in magnitude of ST-depresports [3-6,12-161, gallopamil reduces the ratesion at similar workload in patients taking galpressure product at rest as well as at comparable lopamil or diltiazem compared to placebo. submaximal workload. Such a reduction in rateMoreover, time to 1 mm ST-depression was pressure product, an indirect index of myocardial significantly prolonged by gallopamil (+ 70%, P oxigen demand, permitted patients to work to a < 0.01) and diltiazem (+64%, P < 0.02) comhigher work level before the onset of ischemia. pared to placebo. These findings support the hypothesis that dePlacebo
Diltiazem
Gallopamil
80
creased myocardial consumption of oxygen may be a major contributing factor in the antianginal effects of gallopamil at submaximal exercise levels. Gallopamil, nonetheless, did not influence the rate-pressure product at maximal peak exercise in comparison with placebo, because the capacity to increase heart rate and systemic pressure was blunted but not abolished. Surprisingly, gallopamil was found to increase maximal left ventricular work with respect to placebo and diltiazem, despite a similar peak of rate-pressure product. This was mainly due to an increase in the cardiac index and, therefore, in the myocardial performance. It may be assumed that gallopamil exerts a direct myocardial anti-ischemic effect and improves contraction in ischemic regions. Our data also agree with the results of a previous study performed with intravenous gallopamil, which demonstrated that this drug reverts contractile dysfunction in the ischemic myocardium
n71. As the effects of the drug on ventricular function become evident under conditions leading to myocardial ischemia, it is obvious that these effects appear to be more important during peak exercise. We postulate that gallopamil may improve perfusion to ischemic areas by relieving exercise induced coronary vaso~nstriction or by redistribution of coronary flow. In addition, it may exert a beneficial effect on intracellular energetic processes by preventing ischemia-induced calcium overload of the mitochondria. In summary, gallopamil increased exercise tolerance (subm~imum and maximum workload), as well as the time to the onset of electrocardiographic ischemia in all patients. Moreover, exercise cardiac performance improved and there was no evidence of adverse inotropic effects. Therefore, the theoretical negative inotropic action of the drug may be, even in patients with ischemic left ventricular dysfunction, counterbalanced by a direct favorable action on regional wall motion. These findings could be an expression of a direct beneficial effect of gallopamil on metabolism of the ischemic myocardium.
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