JACC Vol. 18, No . 3 Semember 1991 :876-8
876
Editorial Comment the ischemic myocardium ; that is, for any given duration of ischemia, there is a well documented inverse relation be-
Experimental Infarct Size Reduction With Calcium Channel Blockers*
tween extent of necrosis and myocardial blood flow during occlusion (5). One puzzling aspect of the present study (1) is the apparent absence of this relation between blood flow and infarct size, even in the control group . Although the reasons for this are unclear, it may be due to the uniformly high
ROBERT KLONER, MD, PHD, FACC,
values of collateral blood flow observed by Higginson et al . (I) . In addition, the complex (and atypical) premeditation
KARIN
PRZYKLENK,
PHD
Los Angeles, California
and anesthetic regimen used in their study may have altered the expected relation between blood flow and infarct size. They observed that intracoronary diltiazem reduced infarct size even when treatment was initiated shortly before reper-
The present study. Higginson et al. (1), in this issue of the Journal, report on the effect of intracoronary diltiazem on infarct size and contractile function in an anesthetized canine model of 90 min of left anterior descending coronary
fusion . This observation suggests that diltiazem may have prevented so-called reperfusion injury-that is, injury at the time of reflow, whereby myocytes reversibly injured at the end of a period of ischenda become irreversibly damaged by
artery occlusion followed by 4 h of reperfusion. Infusion of the act of reperfusion itself. However, the concept that diltiazem into the distal artery bed was initiated either diltiazem prevented lethal reperfusion injury must be viewed "early" (at the time of occlusion) or "late" (beginning with caution because the agent was also present during the 15 min before reperfusion) and maintained throughout the final 15 min of ischemia . initial 60 to 135 min of reflow . It is important to note that the Calcium channel Mockers and the stunned myocardium . dose and rate of diltiazem infusion were chosen such that The second major finding reported by Higginson et al, (1) is hemodynamic variables and myocardial blood flow were not that early treatment with diltiazem enhanced recovery of altered by drug treatment. Higginson et al . (1) report that regional contractile function after reperfusion . Furthermore, both early and late infusion of diltiazem reduced the size of this enhanced segmental shortening in the subendocardium the myocardial infarct. occurred even in the presence of a small subendocardial These results are in general agreement with several infarction . Because this improvement in function of the previous experimental studies (2) in which verapamil, nifed"stunned myocardium" occurred without significant ipine and other calcium channel blockers were shown to changes in hemodynamics or regional myocardial blood reduce myocardial infarct size in models of ischemia and flow, these data suggest that diltiazem exerted a direct effect reperfusion. However, the efficacy of these agents clearly on the remaining viable myocytes . depends on the experimental model used, the duration of Using a 1S-min occlusion and reperfusion protocol, we ischemia, the duration of reperfusion, the route of drug have observed improvements in function of stunned myoadministration and the length of time the drug is on board . For example, Reimer and Jennings (3) observed that intra-
cardium with both verapamil (6) and nifedipine (7). The beneficial effects of intravenous verapamil were most strik-
venous verapamil reduced myocardial infarct size in a 40ing when the agent was administered before and during min model of occlusion and reperfusion but failed to reduce coronary occlusion and less striking when given only during infarct size when the duration of ischemia was extended rpetfusion . However, nifedipine administered either intrato 3 h. Lo et al . (4) found that in a 3-h occlusion and 3-h venously or by an intracoronary i ,'rte (7) restored contracreperfusion protocol, intracoronary verapamilinfused durtile function of the stunned myocardium to baseline preocing ischemia and reperfusion reduced infarct size . In conelusion values even when given after reperfusion . trast, when intracoronary verapamil was administered only Our data are similar to those of Higginson et al . (I) in that during reperfusion, no reduction in infarct size was obtained . a very small dose of intracoronary nifedipine restored wall It is well recognized that infarct size in the canine model motion to essentially normal values without altering hemois highly dependent on the degree of collateral blood flow to dynamics or regional myocardial blood flow . Again, this raises the Interesting possibility that the calcium channel blacker was having a direct effect on the myocyte, rather 'Editorials published in Journal ofthe American College f Cardiology reflect the views of the authors and do not necessarily represent the elews of JACC or the American College of Cardiology. From the Heart Institute Research Department, Hospital of the Sood Samaritan and the Section of Cardiology, university of Southern California Medical School . Los Angeles. California . Address for morinti: Robert A. Matter, MD, PhD, The Heart Institute, Hospital of the Good Samaritan, 616 South Witmer, Los Angeles, California 90017. 01991 by the American College of Cardiology
than simply exerting a peripheral hemodynamic or vascular effect . In fact, Martian (8) demonstrated that the stunned myocardium is characterized by an increase in calcium transients and a decreased responsiveness of the myofilaments to calcium . Thus, it is possible that calcium antagonists reduce these calcium transients and improve the sensitivity of the myofilaments to calcium .
0735-1097191153 .50
JACC Vol . I8 . No . 3 September 1991 :876-u
Clinical aspects of calcium channel blockers and acute myocardial infarction . Although thrombolytic agents are unquestionably the treatment of choice in acute myocardial infarction, the search continues for adjuvant therapy that will further improve the benefits of reperfusion . Aspirin . heparin, beta-adrenergic blockers and angiotensin-converting enzyme inhibitors have all been used as adjuvant therapy, with some modest success in improving clinical outcome (9) . Calcium channel blockers have consistently been shown to be efficacious for the treatment of brief ischemic episodes (that is, angina) ; however, their ability to improve outcome associated with acute myocardial infarction has been disappointing in most clinical studies (10-14) . Clinical studies (10-14) performed in the 1980s (and before the standard use of thrombolysis) found that calcium channel blockers neither reduced myocardial infarct size nor improved survival . In patients with potential acute myocardial infarction or unstable angina . calcium channel blockers did not prevent myocardial infarction (I1). Some studies did suggest. however, that these agents might reduce reinfarction after non-Q wave infarction (as shown with diltiazem) (15) and reduce postmyocardial infarction angina (as shown with diltiazem and nifedipine) (15 .16). The feat trials that have assessed rite effects of calriroos channel blockers as adjunctive therapy to thronbolvsislmre also been disappointing . For example. Erbel et al. (17)
failed to show improvement in left ventricular ejection fraction or survival in patients who received nifedipine along with thrombolysis for acute myocardial infarction . Ellis et al. (18) reported the effects of long-term beta-adrenergic or calcium channel blockade in patients who received coronary angioplasty within 12 h of onset of symptoms of myocardial infarction and found that patients receiving a beta-blocker at the time of infarction had a lower mortality rate than those not receiving a beta-blocker . In contrast . calcium channel blockade did not affect survival . Given the large number of experimental studies that have documented a beneficial effect of calcium channel blockers on infarct size and cardiac function in models of ischemia and reperfusion, it is surprising that more clinical studies have not addressed this issue . Perhaps the major reason for lack of enthusiasm in studying calcium channel blockers as possible adjunctive therapy with thrombolysis is the negative studies in the 1980s and recent studies (19-21) showing a wor;eoing of congestive heart failure with calcium antagonist therapy in instances of underlying left ventricular dysfunction. It is unlikely that calcium channel blockers will be used as standard adjunctive therapy in the selling of acute Q wave myocardial infarction in the immediate future . At present . these agents are not routinely recommended in acute Q wave myocardial infarction and should be used only if there is a specific indication such as postinfarction angina and hypertension . Furthermore . they should be used with great caution in patients with severe left ventricular dysfunction.
KLONeRAND PRZYKLENK EDITORIAL COMMENT
877
What Factors might account for the apparent discrepancy between animal studies that have shown reductions in infarct size with calcium channel blockers and the general lack of efficacy of these agents in patients with acute myocardial infarction! It is possible that in some of the clinical studies, too high a dose may have been used, resulting in decreased coronary perfusion pressure . This reduction in blood pressure may further result in reflex tachycardia. which could increase the severity of ischemia . i n a ddition . it appears likely that . in some instances, calcium channel blockers may have stimulated neurohumoral mechanisms that may have caused worsened heart failure (20) . Effect of long-term calcium channel blacker therapy . Calcium channel blockers have also been administered as maintenance therapy after acute myocardial infarction to deternine whether they would enhance survival. In one study (221, dihiazem administered on a long-term basis after infarction failed to improve overall survival . In fact, subgroup analysis revealed that patients in the diltiazem group with underlying pulmonary congestion had a higher cardiac event rate than untreated patients. perhaps because of its negative inotropic effect . However . patients without pulmonary congestion did demonstrate an improved outcome . Similarly, in a trial 1121 utilizing the cacicm channel blocker nifedipine, there was no dttference in 10-month mortality or nonfatal reinfarction rates between treated and untreated patients . In contrast. the recent Danish Vempamil lnfaretisn Trial II (DAVIT 11) 1241 reported a nonsignificant trend toward lower mortality and significant reduction in major cardiac events in patients who received verapamil beginning 2 weeks after infarction . Of n ote . in patients without heart failure while in the coronary care unit . verapamil reduced the mortality rate significantly from 11 .8% in the placebo group to 7 .7% in the verapamil group (p = 0.021 . However. there was no difference in mortality or major event rates with •terapamil in patients with heart failure . Thus, alttough the results from these three major trials are not definitive, data from DAVIT It raise the possibility that verapamil may limit the incidence of major cardiac events after myocardial infarction . Implications. Although clinical studies have, in general, not shown calcium channel blockers to be capable of reducing infarct size or improving survival after infarction, experimental data (6,7) suggest that these agents may improve function of the stunned myocardium in patients who puffer from briefer episodes of ischemia, such as patients eith angina . Stunned myocardium has been described (25) both in patients with unstable angina and in those with chronic stable angina after exercise testing . Although this issue remains to be investigated, experimental results imply that calcium channel blockers may be more likely to improve regional wail motion abnormalities in the setting of brief ischemia than in acute myocardial infarction . We g,,,,&dly acknowledge Ire eeerttem typing skillsofCathy Davisson . whc
helped prepare he manuscnpl .
678
KL(JNEII ANG PRZYKLENK 11)1IGIJIAl .It1MMEN F
References 1 . Hiainson L . Tang A, Knoll G . Calvin l . Effect of intrucoronary Jihiazem an infer .: siac and reaiorl£1 myorcrdlal Rlnellon In the ISehemie reperfused canine hear-J Am Coll Cardiol 1591 Ii 867-74 . 2- Koner RA, Braunwald E. EAeas rf oakium aotagnnisl, on infarcbng myocardium . Am J Cardiol 1987 ;59:&JB-94B . 3 . Reimer KA . Jennings RB . Vempamil in two reperftsion models of myocardial fnfarcrion. temporary protection of severely ischemic myo . medium wilhonl Iimimtim of ultimate infect size. Lob Invest 1984 :51 : 655-66. 4, Lo NM, Kloner RA, Dmunwsld E, Effect of mtracoron,ry vcrapamfl on infarct size in theIschemic .repnMaott aniseheart :criticalimportanceof the timing of ireaimerd- Am J Cardiol 1985 ;56,672-1. 9 Reimm KA . Jmrdngs RR, (-.an, FR, er al. Animal models for protecting is, hemic myossediam . R- 11s of the NHLBI Cooperative Study : com.--s end conscious dog models . Cite Res 1985 :56: parison of am 651-5 . 0 . PrzykIenkK .KlmerRA .Effect afvempaeiiloopostischemic"stunasd" myocardium- impedance of noting of treatment . J A . Call Cardi.1 14 -24 . 7. K, Ghaf i GB. Eilzoszn DT . Kloner RA . Nifedipine adettnisscred postreperfusion ablates cyanotic contractile dysfunction of postisehesdc "scanned" myocardium . J Am Coll Cardiol 1989:13:1176-83. 8 . Martian E . Myacardial ituaning and bibemaling . The physiology behind Iho cnllnq-aialism . Circulation 1991 :83:681-8 . 9 . infarction Kloner RA . Adjuvanl pharmaatlngio therapy for soot[ myocardial . Heap Fomiulary 1991 ;20 :108-17. 10 . Skolntck AE, Fdshman WH. Calcium channel blockers in myocardial infarctian .Arci later. Med 1989.149,1669-77. I- Yasuf S . An overview of the clinical trials of agents (other than betaMockercy shat polomially limit myocardial infarct size . J Cardinvase Phatmacol 1988:12isuppl7I:948-55. 12 . Roberts R . Review of calcium anlagomsl trials in acute myocardial infarction . Clin Cordial l989 :12Isuppl IIIf:111-4-47. 17 . Roberts R. Throetbolye :s and its sequelae: calcium antagonists as amen Jot ad ceclive therapy . Circulation 1989$Olsuppl IVI'IV-93-101 . 14 . Held PH, Yumf S, Furber_e CD . Calcium channel blockers in acute
JACC Vol. II . No. 3 September 1991 :916-II myanrdiai infarction and utable angina: en oversew . Br Med J 1989:299:1187-92 . 15, Gibson IS . Bodes WE, Therooe P . el al. Lrhiazeen and reinfarctton in patients with non-Q wave myocardial intarclimr roaulta oFadouhlnblind . randomized . multicenter trial . N Eel I Med 1985 ;315:423-9 16. Stone PH . Mailer SE. Nifedipfne therapy for reconvert ischemie polo following myocardial infarction, din Cardiol 198! ;7-2!l-30 . 17 . EmelR .POpT,MeinertzT.DlehaunertRV,eal .Combination ofoaleiuee channel block,, and thrambolylic therapy in acme mY .-JalidremAHt198 ;115 :529 -3& 18. Ellie SG, Mailer DW, Topn1 FJ . P,-,,Me survival benefit from rnncnnitant halt, but not calcium-antagonist therapy duringreperfinion fat acute myecardial infarclion. Am J Cardiol I99u ;f•6925-R. 19. Goldstein RE . Doauzzi ST. Cness D . Newel S . Diltiamm mesons lute .onsel congestive hear failure in pnstirdarclion patients with emly reduction in ejection fraction . Circulation 1931;85 :32-60 . 20. Packer M. Calcium channel bhocken in dvonie heart failure : the Asks of "physiolagically rational" therapy . Circularom t99O ;82 :2254-7. 21 . Elkayem V. Amin 1 . Mehm A, Vuques 1, Weber L, Rahimroolr SH . A prospective, randomized. double-hind, crossover study to carry re the efficacy and safety of chronic ndedipete therapy with that of isasatoSde dinitrnle and their combination in the treatment of chronic congestive heart failure . Circulation 1997-82 :1954-61 . 22. The Multicenter Diltiazem Poaieferelion Teml Research Group. The effect of diltiazem on mortality and reinlarce:on after mywcardisl irdarc. tion. N Eoel S Med 1988;319:385 .92 . 23. The Israeli Sprint Study Group, Securldaty Prevembon Reinfarctfon Israeli Nifedipine Teal (SPRINTI : a randomized intervention trial of niiedipine in patients with acute myocardial iefenction . Ear Heart I 19819 :354-64 . 24. TheLaniehStudy GrauponVeopamilinMy diallnfacdon .ERecof verapamil on mortality and major events of er acute myocardialin auction (the Danish Vempamil Infarction Trial It-DAVIT II) . Am J Cadol 1990 :66:779-85 . 25. Kloner RA, Allen J . Zheng Y . Ruiz C . Myocardial stmcirg folbwhrg exercise treadmill testing in man (abstrl . J Am Call Cardiol IhRO 7SIsuppl AI203A.
876
Editorial Comment the ischemic myocardium ; that is, for any given duration of ischemia, there is a well documented inverse relation be-
Experimental Infarct Size Reduction With Calcium Channel Blockers*
tween extent of necrosis and myocardial blood flow during occlusion (5). One puzzling aspect of the present study (1) is the apparent absence of this relation between blood flow and infarct size, even in the control group . Although the reasons for this are unclear, it may be due to the uniformly high
ROBERT KLONER, MD, PHD, FACC,
values of collateral blood flow observed by Higginson et al . (I) . In addition, the complex (and atypical) premeditation
KARIN
PRZYKLENK,
PHD
Los Angeles, California
and anesthetic regimen used in their study may have altered the expected relation between blood flow and infarct size. They observed that intracoronary diltiazem reduced infarct size even when treatment was initiated shortly before reper-
The present study. Higginson et al. (1), in this issue of the Journal, report on the effect of intracoronary diltiazem on infarct size and contractile function in an anesthetized canine model of 90 min of left anterior descending coronary
fusion . This observation suggests that diltiazem may have prevented so-called reperfusion injury-that is, injury at the time of reflow, whereby myocytes reversibly injured at the end of a period of ischenda become irreversibly damaged by
artery occlusion followed by 4 h of reperfusion. Infusion of the act of reperfusion itself. However, the concept that diltiazem into the distal artery bed was initiated either diltiazem prevented lethal reperfusion injury must be viewed "early" (at the time of occlusion) or "late" (beginning with caution because the agent was also present during the 15 min before reperfusion) and maintained throughout the final 15 min of ischemia . initial 60 to 135 min of reflow . It is important to note that the Calcium channel Mockers and the stunned myocardium . dose and rate of diltiazem infusion were chosen such that The second major finding reported by Higginson et al, (1) is hemodynamic variables and myocardial blood flow were not that early treatment with diltiazem enhanced recovery of altered by drug treatment. Higginson et al . (1) report that regional contractile function after reperfusion . Furthermore, both early and late infusion of diltiazem reduced the size of this enhanced segmental shortening in the subendocardium the myocardial infarct. occurred even in the presence of a small subendocardial These results are in general agreement with several infarction . Because this improvement in function of the previous experimental studies (2) in which verapamil, nifed"stunned myocardium" occurred without significant ipine and other calcium channel blockers were shown to changes in hemodynamics or regional myocardial blood reduce myocardial infarct size in models of ischemia and flow, these data suggest that diltiazem exerted a direct effect reperfusion. However, the efficacy of these agents clearly on the remaining viable myocytes . depends on the experimental model used, the duration of Using a 1S-min occlusion and reperfusion protocol, we ischemia, the duration of reperfusion, the route of drug have observed improvements in function of stunned myoadministration and the length of time the drug is on board . For example, Reimer and Jennings (3) observed that intra-
cardium with both verapamil (6) and nifedipine (7). The beneficial effects of intravenous verapamil were most strik-
venous verapamil reduced myocardial infarct size in a 40ing when the agent was administered before and during min model of occlusion and reperfusion but failed to reduce coronary occlusion and less striking when given only during infarct size when the duration of ischemia was extended rpetfusion . However, nifedipine administered either intrato 3 h. Lo et al . (4) found that in a 3-h occlusion and 3-h venously or by an intracoronary i ,'rte (7) restored contracreperfusion protocol, intracoronary verapamilinfused durtile function of the stunned myocardium to baseline preocing ischemia and reperfusion reduced infarct size . In conelusion values even when given after reperfusion . trast, when intracoronary verapamil was administered only Our data are similar to those of Higginson et al . (I) in that during reperfusion, no reduction in infarct size was obtained . a very small dose of intracoronary nifedipine restored wall It is well recognized that infarct size in the canine model motion to essentially normal values without altering hemois highly dependent on the degree of collateral blood flow to dynamics or regional myocardial blood flow . Again, this raises the Interesting possibility that the calcium channel blacker was having a direct effect on the myocyte, rather 'Editorials published in Journal ofthe American College f Cardiology reflect the views of the authors and do not necessarily represent the elews of JACC or the American College of Cardiology. From the Heart Institute Research Department, Hospital of the Sood Samaritan and the Section of Cardiology, university of Southern California Medical School . Los Angeles. California . Address for morinti: Robert A. Matter, MD, PhD, The Heart Institute, Hospital of the Good Samaritan, 616 South Witmer, Los Angeles, California 90017. 01991 by the American College of Cardiology
than simply exerting a peripheral hemodynamic or vascular effect . In fact, Martian (8) demonstrated that the stunned myocardium is characterized by an increase in calcium transients and a decreased responsiveness of the myofilaments to calcium . Thus, it is possible that calcium antagonists reduce these calcium transients and improve the sensitivity of the myofilaments to calcium .
0735-1097191153 .50
JACC Vol . I8 . No . 3 September 1991 :876-u
Clinical aspects of calcium channel blockers and acute myocardial infarction . Although thrombolytic agents are unquestionably the treatment of choice in acute myocardial infarction, the search continues for adjuvant therapy that will further improve the benefits of reperfusion . Aspirin . heparin, beta-adrenergic blockers and angiotensin-converting enzyme inhibitors have all been used as adjuvant therapy, with some modest success in improving clinical outcome (9) . Calcium channel blockers have consistently been shown to be efficacious for the treatment of brief ischemic episodes (that is, angina) ; however, their ability to improve outcome associated with acute myocardial infarction has been disappointing in most clinical studies (10-14) . Clinical studies (10-14) performed in the 1980s (and before the standard use of thrombolysis) found that calcium channel blockers neither reduced myocardial infarct size nor improved survival . In patients with potential acute myocardial infarction or unstable angina . calcium channel blockers did not prevent myocardial infarction (I1). Some studies did suggest. however, that these agents might reduce reinfarction after non-Q wave infarction (as shown with diltiazem) (15) and reduce postmyocardial infarction angina (as shown with diltiazem and nifedipine) (15 .16). The feat trials that have assessed rite effects of calriroos channel blockers as adjunctive therapy to thronbolvsislmre also been disappointing . For example. Erbel et al. (17)
failed to show improvement in left ventricular ejection fraction or survival in patients who received nifedipine along with thrombolysis for acute myocardial infarction . Ellis et al. (18) reported the effects of long-term beta-adrenergic or calcium channel blockade in patients who received coronary angioplasty within 12 h of onset of symptoms of myocardial infarction and found that patients receiving a beta-blocker at the time of infarction had a lower mortality rate than those not receiving a beta-blocker . In contrast . calcium channel blockade did not affect survival . Given the large number of experimental studies that have documented a beneficial effect of calcium channel blockers on infarct size and cardiac function in models of ischemia and reperfusion, it is surprising that more clinical studies have not addressed this issue . Perhaps the major reason for lack of enthusiasm in studying calcium channel blockers as possible adjunctive therapy with thrombolysis is the negative studies in the 1980s and recent studies (19-21) showing a wor;eoing of congestive heart failure with calcium antagonist therapy in instances of underlying left ventricular dysfunction. It is unlikely that calcium channel blockers will be used as standard adjunctive therapy in the selling of acute Q wave myocardial infarction in the immediate future . At present . these agents are not routinely recommended in acute Q wave myocardial infarction and should be used only if there is a specific indication such as postinfarction angina and hypertension . Furthermore . they should be used with great caution in patients with severe left ventricular dysfunction.
KLONeRAND PRZYKLENK EDITORIAL COMMENT
877
What Factors might account for the apparent discrepancy between animal studies that have shown reductions in infarct size with calcium channel blockers and the general lack of efficacy of these agents in patients with acute myocardial infarction! It is possible that in some of the clinical studies, too high a dose may have been used, resulting in decreased coronary perfusion pressure . This reduction in blood pressure may further result in reflex tachycardia. which could increase the severity of ischemia . i n a ddition . it appears likely that . in some instances, calcium channel blockers may have stimulated neurohumoral mechanisms that may have caused worsened heart failure (20) . Effect of long-term calcium channel blacker therapy . Calcium channel blockers have also been administered as maintenance therapy after acute myocardial infarction to deternine whether they would enhance survival. In one study (221, dihiazem administered on a long-term basis after infarction failed to improve overall survival . In fact, subgroup analysis revealed that patients in the diltiazem group with underlying pulmonary congestion had a higher cardiac event rate than untreated patients. perhaps because of its negative inotropic effect . However . patients without pulmonary congestion did demonstrate an improved outcome . Similarly, in a trial 1121 utilizing the cacicm channel blocker nifedipine, there was no dttference in 10-month mortality or nonfatal reinfarction rates between treated and untreated patients . In contrast. the recent Danish Vempamil lnfaretisn Trial II (DAVIT 11) 1241 reported a nonsignificant trend toward lower mortality and significant reduction in major cardiac events in patients who received verapamil beginning 2 weeks after infarction . Of n ote . in patients without heart failure while in the coronary care unit . verapamil reduced the mortality rate significantly from 11 .8% in the placebo group to 7 .7% in the verapamil group (p = 0.021 . However. there was no difference in mortality or major event rates with •terapamil in patients with heart failure . Thus, alttough the results from these three major trials are not definitive, data from DAVIT It raise the possibility that verapamil may limit the incidence of major cardiac events after myocardial infarction . Implications. Although clinical studies have, in general, not shown calcium channel blockers to be capable of reducing infarct size or improving survival after infarction, experimental data (6,7) suggest that these agents may improve function of the stunned myocardium in patients who puffer from briefer episodes of ischemia, such as patients eith angina . Stunned myocardium has been described (25) both in patients with unstable angina and in those with chronic stable angina after exercise testing . Although this issue remains to be investigated, experimental results imply that calcium channel blockers may be more likely to improve regional wail motion abnormalities in the setting of brief ischemia than in acute myocardial infarction . We g,,,,&dly acknowledge Ire eeerttem typing skillsofCathy Davisson . whc
helped prepare he manuscnpl .
678
KL(JNEII ANG PRZYKLENK 11)1IGIJIAl .It1MMEN F
References 1 . Hiainson L . Tang A, Knoll G . Calvin l . Effect of intrucoronary Jihiazem an infer .: siac and reaiorl£1 myorcrdlal Rlnellon In the ISehemie reperfused canine hear-J Am Coll Cardiol 1591 Ii 867-74 . 2- Koner RA, Braunwald E. EAeas rf oakium aotagnnisl, on infarcbng myocardium . Am J Cardiol 1987 ;59:&JB-94B . 3 . Reimer KA . Jennings RB . Vempamil in two reperftsion models of myocardial fnfarcrion. temporary protection of severely ischemic myo . medium wilhonl Iimimtim of ultimate infect size. Lob Invest 1984 :51 : 655-66. 4, Lo NM, Kloner RA, Dmunwsld E, Effect of mtracoron,ry vcrapamfl on infarct size in theIschemic .repnMaott aniseheart :criticalimportanceof the timing of ireaimerd- Am J Cardiol 1985 ;56,672-1. 9 Reimm KA . Jmrdngs RR, (-.an, FR, er al. Animal models for protecting is, hemic myossediam . R- 11s of the NHLBI Cooperative Study : com.--s end conscious dog models . Cite Res 1985 :56: parison of am 651-5 . 0 . PrzykIenkK .KlmerRA .Effect afvempaeiiloopostischemic"stunasd" myocardium- impedance of noting of treatment . J A . Call Cardi.1 14 -24 . 7. K, Ghaf i GB. Eilzoszn DT . Kloner RA . Nifedipine adettnisscred postreperfusion ablates cyanotic contractile dysfunction of postisehesdc "scanned" myocardium . J Am Coll Cardiol 1989:13:1176-83. 8 . Martian E . Myacardial ituaning and bibemaling . The physiology behind Iho cnllnq-aialism . Circulation 1991 :83:681-8 . 9 . infarction Kloner RA . Adjuvanl pharmaatlngio therapy for soot[ myocardial . Heap Fomiulary 1991 ;20 :108-17. 10 . Skolntck AE, Fdshman WH. Calcium channel blockers in myocardial infarctian .Arci later. Med 1989.149,1669-77. I- Yasuf S . An overview of the clinical trials of agents (other than betaMockercy shat polomially limit myocardial infarct size . J Cardinvase Phatmacol 1988:12isuppl7I:948-55. 12 . Roberts R . Review of calcium anlagomsl trials in acute myocardial infarction . Clin Cordial l989 :12Isuppl IIIf:111-4-47. 17 . Roberts R. Throetbolye :s and its sequelae: calcium antagonists as amen Jot ad ceclive therapy . Circulation 1989$Olsuppl IVI'IV-93-101 . 14 . Held PH, Yumf S, Furber_e CD . Calcium channel blockers in acute
JACC Vol. II . No. 3 September 1991 :916-II myanrdiai infarction and utable angina: en oversew . Br Med J 1989:299:1187-92 . 15, Gibson IS . Bodes WE, Therooe P . el al. Lrhiazeen and reinfarctton in patients with non-Q wave myocardial intarclimr roaulta oFadouhlnblind . randomized . multicenter trial . N Eel I Med 1985 ;315:423-9 16. Stone PH . Mailer SE. Nifedipfne therapy for reconvert ischemie polo following myocardial infarction, din Cardiol 198! ;7-2!l-30 . 17 . EmelR .POpT,MeinertzT.DlehaunertRV,eal .Combination ofoaleiuee channel block,, and thrambolylic therapy in acme mY .-JalidremAHt198 ;115 :529 -3& 18. Ellie SG, Mailer DW, Topn1 FJ . P,-,,Me survival benefit from rnncnnitant halt, but not calcium-antagonist therapy duringreperfinion fat acute myecardial infarclion. Am J Cardiol I99u ;f•6925-R. 19. Goldstein RE . Doauzzi ST. Cness D . Newel S . Diltiamm mesons lute .onsel congestive hear failure in pnstirdarclion patients with emly reduction in ejection fraction . Circulation 1931;85 :32-60 . 20. Packer M. Calcium channel bhocken in dvonie heart failure : the Asks of "physiolagically rational" therapy . Circularom t99O ;82 :2254-7. 21 . Elkayem V. Amin 1 . Mehm A, Vuques 1, Weber L, Rahimroolr SH . A prospective, randomized. double-hind, crossover study to carry re the efficacy and safety of chronic ndedipete therapy with that of isasatoSde dinitrnle and their combination in the treatment of chronic congestive heart failure . Circulation 1997-82 :1954-61 . 22. The Multicenter Diltiazem Poaieferelion Teml Research Group. The effect of diltiazem on mortality and reinlarce:on after mywcardisl irdarc. tion. N Eoel S Med 1988;319:385 .92 . 23. The Israeli Sprint Study Group, Securldaty Prevembon Reinfarctfon Israeli Nifedipine Teal (SPRINTI : a randomized intervention trial of niiedipine in patients with acute myocardial iefenction . Ear Heart I 19819 :354-64 . 24. TheLaniehStudy GrauponVeopamilinMy diallnfacdon .ERecof verapamil on mortality and major events of er acute myocardialin auction (the Danish Vempamil Infarction Trial It-DAVIT II) . Am J Cadol 1990 :66:779-85 . 25. Kloner RA, Allen J . Zheng Y . Ruiz C . Myocardial stmcirg folbwhrg exercise treadmill testing in man (abstrl . J Am Call Cardiol IhRO 7SIsuppl AI203A.
