- Email: [email protected]
Calcium antagonists and myocardial protection
Glen J. Kowalchuk, MD, and Richard W. Nesto, MD
Painfid and asymptomatic ischemla has been assoelated with left ventrkuW dysfunction, an important varlabk re@ed to survival ii9 patients With coronary artery disease. The treatment of patknts withcoMnaryarterydlsea~withagentssucha8 cakhnchannelblockershasbeendlrectedatreduelng ischemia by rest&kg the balance between rntitial oxygei~ supply and demand, which ultimately s&ves to protect against myocardial dysflmdlon.Dnceischemikoccurred,eakbun ehann@l blockers may protect myocardlal cellular integrity and functki. By reducing intracdkrbr &Icium ov&ad king Ischsmia, niito&ondrial functlon Is preserved and adenosine trlphosphate stures are malntsin’ed. Numerous in vitro and Isoiated heart preparations have shown thqt ischemia In the presence of cakium blockade is ass&elatedwlth thaninthssltuationof lesscellulardy~ ischemia In the abssnce of calcium channsl blodtade. (Am J Can#d1989;64:10F-17F)
n important relation exists between ventricular function and survival in patients with coronary artery disease. Numerous studies have shown that left ventricular function is an im@rtant independent variable related to mortality in the setting of aate myocardial infarction, unstable angina. and chronic stable angina.1-3Treatment efforts in patients with coronary artery diseaseare directed at reducing ischemiaby restoring the balance between myocardial oxygen supply and demand,which ultimately servesto protect against myocardial dysfunction. It was once believedthat only a prolonged symptomatic ischemicinsult led to myocardial necrosiswith resultant abnormalities of ventricular function. It is now known, however,that ventiicular dysfunction is not limited to symptomatic or prolongedischemicevents.Asymp tomatic ischemia may be associatedwith left ventricular dysfunction to a degreethat is similar to that of painful episodes.4v5 Changes in left ventiicular compliance, as well as abnormalities of regional wall motion, often precedeischemicelectrocardiographicchangesand angina,6 and havebeenfound to persistwell beyondthe resolution of ischemia.7,8In addition, becausesilent ischemia may occur up to 4 times as often as painful attacks, angina thus is an insensitive and unreliable indicator of myocardial ischemia.9 The cumulative effect of ischemic eventson ventricular function and their relation to patient survival is only speculative. It has been postulated that repeated, brief episodesof ischemia may lead to a stunning of the myocardium with chronic postischemicleft ventricular dysfunction.*OGiven the impact of left ventricular function in the prognosisof patients with coronary artery disease, numerousinvestigationshavesought to identify the mediators of cellular injury.
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CALCIUM
AND CELL INJURY
In the resting myocyte, the intracellular calcium concentration is maintained at several thousand times less than the extracellular concentration.” The maintenance of this concentration gradient is dependenton an intact cell membraneas well as proper functioning of ion-selective channels and energy-dependention pump mechanisms.12J3 Normally, calcium may enter the cell by several routes. Sites of passivediffusion, sodiuin-calcium exchangeand slow calcium channelshave all beencited as possibleentry mechanisms.11~12~14~15 However, the greatest contributor to free cytosolic calcium may result from calcium-triggered releaseof calcium from storage sites From the Department of Medicine, Cardiology Se&&, Harvard Medi- within the sarcoplasmic reticulum.16 During ischemia, cal School,and the New England De&ness Hqvital, Boston,Massathe cytosolic calcium concentration increase~.~~J~ The chusetts. Address for reprints: Richard W. Nesto, MD, New England Dea- initiating factor responsiblefor this increaseis not completely understood,but may be due to ischemia-induced conessHospital, 185pilgrim Road, Boston,Massachusetts02215. 1OF
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64
t [W Mitochondrial Ca Overload
t Activity of Ca ATPases
+ ATP Production
ATP Depletion /
Loss of Ion Pump Function and Contractile Function
depletion of cellular adenosine triphosphate (ATP).19 The mode of this calcium increase may involve alterations in one or more of the calcium regulatory mechanismspreviously mentioned. It is this increasein cytosolic calcium that is thought to result in myocardial cell death.*O Cell death involves both energy expenditure and organelle destruction. In animal models, an uncontrolled increase in cytosolic calcium concentration results in ATP depletion by way of the activation of calcium-dependentATPase.l 9This decreasein cellular energystores impairs the function of the energy-dependentcalcium pump responsible for retrieving calcium, and may decreasecalcium reuptake by the sarcoplasmicreticulum. In addition, endogenousproteasesand phospholipasesare activated, which may lead to damageof the intracellular organelles and loss of mitochondrial membrane integrity.*‘,** The final blow to cellular homeostasisis mitochondrial calcium overload, resulting in the inhibition of ATP generation (Fig. 1).12~17J9~23 Pharmacologic agents that limit intracellular calcium concentration may, therefore, protect against ischemia-inducedATP depletion and preserve cellular function. The mechanismof action of calcium channel antagonists involves the inhibition of calcium influx at the slow channel site, thereby protecting against cell damage or death.l4 Unfortunately, there are severalreasonsto doubt that transmembranecalcium influx through the slow calcium channel is the predominant sourceof calcium overload during ischemia. The observednumber and conductance of the calcium channel do not account for the total gain in cytosolic calcium noted after ischemia. Furthermore, the slow channel requires phosphorylation in order to function properly; but during periods of ischemia,cellular ATP reservesare depleted and thus it is unlikely that the calcium channel operatesat full capacity. Normal operation of the calcium channel also dependson maintenance of physiologic intracellular pH and normal intracellular calcium concentration, both of which are altered by ischemia.1sJ9,23-26
4 Protease Activitv
‘4 Lipase and Phospholipase
Membrane Disruption
Progressive Ca Overload
Contkture
Arachidonic Acid Metabolites
Loss of Ionic Gradients
Despite these observations,pharmacologic blockade of the calcium channels may reduce cellular calcium overload early in the ischemic process.In fact, in experimental models of ischemia, calcium channel-blocking agentsreducedcellular calcium overloadby an estimated 40% when administered before reoxygenation after hypoxemia.17In addition, the administration of nifedipine and verapamil before reperfusion of ischemic myocardiurn has been demonstrated to decreasemitochondrial calcium overload and improve postischemicrecovery of ventricular function (Fig. 2).17J9One mechanism by which mechanicalfunction is preservedis maintenanceof myocardial ATP stores.27y2s Calcium channel blockers are known to reduce high-energy phosphatebreakdown during hypoxia. Moreover, thii effect appearsto be independentof any negative inotropic action of the drug.29s30 CARDIOPULMONARY BYPASS During cardiopulmonary bypass,global ischemia occurs in myocardium, with time- and temperature-dependent changesto myocardial cells resulting in postoperative impairment of ventricular function.31 To minimize myocellular injury during cardiac surgery, electivecardiac arrest using hypothermic, hyperkalemic cardioplegia is frequently used. Despite cardioplegia, however, left ventricular dysfunction and myocardial necrosiscontinue to pose a problem during prolonged cardiopulmonary bypass.Becausereperfusion after periods of regional or global ischemia is associatedwith excesscalcium flux across the sarcolemma, a drug that could retard this influx might offer additional myocardial protection and decreaseperioperative morbidity and mortality. Clark et aP* constructeda dog model for cardiopulmonary bypass in order to test this hypothesis.A standard hyperkalemic cardioplegic solution was comparedwith an identical solution to which nifedipine had beenadded.After 2 hours of hypothermic cardiac arrest, the dogs were weaned from bypass.The nifedipine-treated group was found to have significantly better indexesof left ventricular function when compared with the control group (Fig. 3).
THE AMERICAN JOURNAL OF CARDIOLOGY SEPTEMBER 19, 1989
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Untreated Mitochondrial Calcium (nmolslmg protein)
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These drug-treated dogs were more easily weanedfrom bypass,required lesspressorsupport, and had lesshistologic evidenceof ischemicinjury than the untreated dogs. The protection afforded by nifedipine in this setting extends to other calcium channel blockers. Verapamil was found to be equally as effective as potassiumcardioplegia in preserving high-energy phosphate stores and systolic function under normothermic conditions.33In another study, the benefits of diltiazem exceededthose of ice in hypothermic dogs when left ventricular performance was assessed.34 Clark et a135extendedtheseobservationsin animals to an evaluation of calcium blockers as cardioplegicsin humans. The first American clinical trial of nifedipine in cardioplegia evaluated47 patients at high risk for cardiac surgery. Thesepatients receivedstandard cold hyperkalemic cardioplegia solution either with or without 275 pg/ liter of nifedipine. Immediate postbypasshemodynamic
monitoring demonstrated that the nifedipine-treated group had higher cardiac output, larger stroke volume and lower pulmonary and peripheral vascular resistance (Fig. 4). Evidence suggesting a cardioprotective effect was observed in the drug-treated group and included lower creatine kinase release and fewer abnormalities demonstrable on postoperative technetium pyrophosphate scans. An extendedtrial of 205 high-risk patients36included a randomized subsetof 74 patients, of whom 39 received nifedipine cardioplegia and 35 receivedstandard cardioplegia. There were no significant differencesin preoperative hemodynamicsnoted betweenthe 2 groups. The nifedipine-treatedpatients had a nearly 100?6improvement in postoperative cardiac output, left ventricular stroke volume and stroke work index when compared with the control group. This improvement in postoperative left ventricular function was reflected in a mortality rate of
1OOr
FIGURE 3. Change from pmidmdc vduesincontrot(n=7)8nddntg-treated@ =6)degsferkft(Lv) end-db stdcpreum,shkewerk,imdLvdP/ &.AbeidRwasdedford3vdhles aRer?hou%of --ill thedfedlpb-tmatedm&naba. (Repro-
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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64
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only 4%, an almost threefold reduction when compared with the control group. A later study also examined the role of calcium channel blockers in providing myocardial protection during cardiopulmonary bypass.37Thirty-nine women undergoing coronary artery bypass procedures were randomly assigned to either a standard cardioplegic group or a verapamil-nifedipine group.37Patients received 1 mg of verapamil added to each liter of cardioplegia as well as oral postoperative nifedipine. A significantly lower creatine kinasevalue and serum aspartateaminotransferase were noted postoperatively in the women treated with calcium blockers (Fig. 5). A trend toward fewer episodes of postoperativeventricular tachyarrhythmias wasnoted, with the control group experiencing 3 fatal ventricular fibrillation arrests; no such events were seenin the patients treated with verapamil and nifedipine. Thesestudies provide clinical data to support the theory that the effect of ischemia on myocardial function may be attenuated by calcium channel-blocking agents.
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PERCUTANEOUS TRANSLUMINAI. CORONARY ANGIOPLASTY Coronary angioplasty offers an opportunity to study the effectsof flow-related regional ischemiaon myocardial function. After the acute interruption of coronary blood flow, a cascadeof pathophysiologiceventsensues. Abnormalities of diastolic function occur within seconds of balloon occlusion, followed in sequenceby systolic dysfunction, electrocardiographic signs of ischemia, and finally the subjective appreciation of ischemia-angina pectoris.‘j Such abnormalities of systolic and diastolic function may resolvebefore angina is triggered and may persist well beyond the restoration of coronary flow. Limited studies are available to show that calcium channel blockersare cardioprotectiveduring angioplasty, and there is even less information to support that this protection is the direct result of calcium infhtx. An investigation performed by Serruys et aPs showedthat intracoronary nifedipine administered before percutaneous transluminal coronary angioplasty (PTCA) reducesthe
1
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THE AMERICAN JOURNAL OF CARDIOLOGY SEPTEMBER 19, 1989
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severity of myocardial ischemia.They initially compared the effects of nifedipine injected into the left main coronary artery with results from balloon occlusionof the left anterior descendingartery in patients with isolated obstructive lesions and preserved systolic function. Both interventions produced a similar depressionin myocardial diastolic and systolic function. The patients taking nifedipine, however, had an increase in coronary sinus and great cardiac vein blood flow asmeasuredby therrnodilution techniques. It was concluded that the transient depressionof mechanicalfunction producedby nifedipine was due to a regional “cardioplegic” effect, an effect that is associatedwith a reduction in myocardial oxygen consumption, an increasein coronary blood flow and vasodilation of epicardial vessels.38,39 In a second group of patients, Serruys et aP* also determined that this reduction in contractile function was paralleled by an improvement in metabolic parameters of ischemia. Measurements of myocardial lactate production were obtained before FTCA, after PTCA without nifedipine, and after F’TCA with intracoronary nifedipine pretreatment. Lactate production wasnoted to increase dramatically after left anterior descendingartery occlusion.However, pretreatment with nifedipine all but suppressedthis effect. Summary data suggestedthat nifedipine preventedmyocytesfrom becominganaerobic due to its effectson contractile energyexpenditure,there by preventing tissue damage during flow-related ischel&.W9 Fujibayashi et al@examined the effectsof nifedipine on recoverytime of left ventricular dysfunction after brief coronary occlusion during angioplasty. Intravenous nifedipine was administered either beforeor during 1- or 2minute occlusions of the left anterior descendingcoronary artery in dogs.Two-dimensional echocardiography was performed to document the return of diastolic and
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THE AMERICANJOURNALOF CARDIOLOGY VOLUME64
aRuwardforadmdstmatedwRhintravenousdediphe(dwhgaccbion,n=6 n=6shdfes) m--, andforcontdahals(n= 12studks.) RedtS-~arrYarh umnbdpinegroup6mnhthewntrolanhldS.(ReproduccdWRhpannbdontrom IACC.‘o)
systolic function. Without drug treatment, diastolic function was noted to be abnormal for up to 75 minutes after l-minute occlusions (Fig. 6) and for up to 105 minutes after 24nute occlusions.Although still delayed,shorter recovery periods were recorded for indexes of systolic function. Treatment with nifedipine significantly accelerated the recovery of both diastolic and systolic function. When nifedipine was given before coronary occlusion, recovery of both systolic and diastolic function was ap parent as early as within 2 minutes of either occlusion period. Administration of nifedipine during occlusion again significantly acceleratedrecovery of both diastolic and systolic function, with both values returning to normal within 15 minutes. Although hemodynamic benefit was gained with nifedipine administration either before or during ischemia, a greater responsewas gained by pretreatment. Independent studies have demonstratedthat calcium channel blockersadministered either intravenously or by way of the intracoronary route prolong the time to ischemia during coronary angioplasty. Feldman et a141found that pretreatment with intravenousnicardipine prevented or delayed the onset of ischemic ST-segment shifts in most patients after left anterior descendingartery occlusion. Investigations by Amende et a142with intracoronary nisoldipine not only confirmed that calcium channel blockers delay onset of ischemic ST-segment changes, but also demonstrateda significant decreasein the magnitude of ST-segmentshift, thereby supporting the concept of cardioprotection. Extrapolation from these studies using angioplastyinduced ischemiato the clinical setting is difficult. During balloon inflation, there is total interruption of coronary blood flow, whereas in ambulatory patients, most ischemit eventsare secondaryto a “low-flow” state and are usually longer, as demonstrated on Holter monitoring,
10
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Further studies are neededto seeif the beneficial effects of calcium channel blockers observedin the angioplasty model of ischemia can be applied to patients with chronic coronary artery diseasewho are taking calcium channel blockers. ACUTE MYOCARDIAL INFARCTION When myocardial blood flow is reduced beyond a critical level for prolonged periods of time, severeischemia develops;when left uncorrected, myocardial infarction occurs.The severity of the resulting ventricular dysfunction is directly proportional to the extent of myocardial tissue necrosis.43T44Current therapy of acute myocardial infarction is aimed at reducing the extent of necrosis by reestablishing blood flow to ischemic zones and reducing oxygen demand. Both thrombolysis and angioplasty have been successful in this regard.45-47 These interventions are effective only if used soon after the onsetof myocardial infarction. Pharmacologicagents capable of retarding cell death may reduce the extent of ischemic injury. Calcium channel blockershave also beenfound capable of reducing the extent of necrosis in a laboratory setting of experimentally induced myocardial infarction. In animal studies,isolated heart preparationsusing verapamil, nifedipine and diltiazem have shown that all 3 compoundsdecreasethe extent of infarction asmeasured by cumulative lactate dehydrogenasereleaseafter core nary occlusion (Fig. 7) .48This reduction wasindependent of the agents’ chronotropic effects, sincebenefit was unchangedwhen the hearts were electrically pacedat rates that approximated the heart rate of a control group. Reimer et a149evaluated the effect of verapamil pretreatment on the infarct size of dogs subjected to 40 minutes of left circumflex occlusion.After 48 to 96 hours of reperfusion, animals pretreated with lower dosesof verapamil demonstrated a significant reduction in the histologic extent of necrosis compared with untreated animals. As with thrombolytic therapy, the benefits achievedwith the useof calcium channel blockersduring
infarction appear to be dependenton the timing of their administration. Klein et a150studied 3 groups of pigs that underwent 75 minutes of left anterior descendingartery occlusion followed by 4 hours of reperfusion. The first group received no drug treatment, the second received diltiazem before coronary occlusion,and the third group received the samedoseof diltiazem after 79 minutes of ischemia.Both drug-treated groups showeda significant reduction in infarct size when compared with control animals. The greatest reduction, however, was demonstrated in the group that receiveddiltiazem before coronary occlusion. Similar findings were reported by Lo et al,51when infarct sizein dogswasexaminedafter 3 hours of left anterior descendingartery occlusion with 3 hours of reperfusion. Dogs treated with verapamil 90 minutes into occlusionwere found to havea significant decreasein the areaof necrosiswhen comparedwith dogsnot administered verapamil. This benefit was lost when verapamil treatment was delayed until just before reperfusion. Although more studies are neededto determine the effectsof calcium channel blockersasmodifiers of infarct size in humans, results of severaltrials to date in which calcium channel blockers were administered within 12 hours of onset of symptomsshowedno difference in infarct size.52-54 Results of another clinical study, however, suggesteda reduction in myocardial infarct size by calcium channel blocker administration. Bussmann et alS5 randomized 29 patients to receiveintravenousverapamil a mean of 8 hours after the onset of chest pain, with an additional 25 patients serving as controls. Peak creatine kinaseand creatine kinaseMB activity derivedfrom time activity curves were consistently and significantly lower in the verapamil-treated group than in the control group. Mathematic conversion of creatine kinase values to weight equivalents calculated to an approximate 30% reduction in infarct size. Although animal data suggestthat calcium channel blockersdelay the onsetof cellular injury, it appearsthat without reperfusion, cell death is inevitable. It is quite possible, however, that the administration of calcium
THE AMERICAN JOURNAL OF CARDIOLOGY SEPTEMBER 19, 1989
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channel blockers earlier than in the studies mentioned previously may limit the extent of necrosisor reduce the size of the periiiarction ischemic zone. CONCLUSIONS In laboratory studies, calcium antagonists have been shown to conserveATP, reduce mitochondrial calcium overload, and enhance recovery of ventricular function. Application of these findings to clinical situations has yielded data supporting cardioprotection during both cardiopulmonary bypassand flow-related regional ischemia. In both of these situations, optimal effects are obtained when ischemia is followed by reperfusion. In models of regional ischemia, when calcium antagonistsare administered late in the courseof occlusion,or when ischemiais not followed by reperfusion, calcium antagonistsare less effective. Calcium channel blockersare of considerablevalue in reducing myocardial ischemia. These drugs have been demonstrated to alter favorably the balance between myocardial supply and demand by decreasingleft ventricular afterload, reducing myocardial contractility, and dilating the coronary arterial tree.56>57 Additionally, these agentshave the potential for protecting the myocardium against ischemically mediated injury by virtue of their effect on calcium flux acrosscell membranesor within cellular compartments. REFERENCES
1. The Veterans Administration Coronary Artery BypassSurgery Cooperative Study Group. Eleven-year survival in the Veterans Administration random&d trial of coronary bypasssurgery for stableangina.N Engl J Med 1984;311:13331339. 2. Luchi RJ, Scott SM, Deupree RH. Comparison of medical and surgical treatment for unstable angina pectoris. N Engl J Med 1987;316.977-984. 3. The Multicenter Postinfarction ResearchGroup. Risk stratification and survival after myocardial infarction. N Engl J Med 1983;309:331-336. 4. Cohn PF, Brown EJ, Wymte J, Holman BL, Atkins HL. Global and regional left ventricular ejection fraction abnormalities during exercise in patients with silent myozudial ischemia.JACC 1983;1.931-933. S. Chierchii S, Laxzari M, FreedmanB, Brunelli C, Maseri A. Impairment of myocardiil perfusion and function during painlessmyocardiil iscbemia.JACC 1983;1:924-930. 6. Nest0 RW, Kowalchuk GJ. The ischemic cascade:temporal sequenceof hemodynamic,electrocardiographic and symptomatic expressionsof ischemia. Am J Cardiol 1987;57:23C-3OC. 7. Wijns W, Serruys P, Slager CJ, Grimm J, Krayenbuehl HP, Hugenholtz PG, HessOM. Effect of coronary occlusionduring percutaneoustransluminal am& plasty in humans on left ventricular chamber stiffness and regional diastolic press~radius relations. JACC 1986;7:455-463. 2. Carbon EB, Hmohara T, Morris KG. Recovery of systolic and diastolic left ventricular function after a 60-secondcoronary arterial occlusionduring percutaneous transluminal coronary angioplasty for angina pcctoris. Am J Cardiol 1987,6&460-466. 9. Schang SJ Jr, Pepine CJ. Transient asymptomatic ST-segmentdepression during daiiy activity. Am J Med 1977;39:3%-402. 10. Braunwald E, Kloner RA. The stunnedmyccardium:prolonged,postischemic ventricular dysfunction. Circulation 1982x56:1 146-I 149. 11. Carafoli E. How calcium crossesplasmamembranesincluding the sarcolemma. In: Gpie LH, ed. Calcium Antagonists and Cardiovascular Dii. New York Ranen Press, 1984:29-41. 12. JenningsRB, Reimer KA. Lethal myocardial ischemicinjury. Am J Pathof 1981;102:241-255. 13. Caroni P, Carafoli E. Regulation of Cast-pumping ATPase of heart sarco lemma by a phmphorylation-dephmphorylationprocess.J Biol Chem 1981;256: 9371-9373. 14. Antman EM, StonePH. Muller JE, Braunwald E. Calcium channelblocking agenta in the treatment of cardiovascular disorders. Part 1: Basic and clinical electrophysiologic effects Ann Intern Med 1980,93:875-88X 15. SperelakisN, SchneiderJA. A metabolic control mechanismfor calcium ion influx that may protect the ventricular myocardial cell. Am J Cardiol 1976;
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37:1079-1085. 16. Fabiato A, Fabiato F. Calcium releasefrom the sarcoplasmicreticulum. Circ Res 1977;40:119-129. 17. Nayler WG, Ferrari R, Williams A. Protective effect of pretreatment with verapamil, nifedipine and propranolol on mitochondrial function in the ischemic and reperfuscd myocardium. Am J Cardiol 1980:46:242-M. 16. Shen AC, JenningsRB. Myocardiil calcium and magnesiumin acute ischemit injury. Am J Pathol 1972,67:417-433. IS. Naylor WG. The role of calcium in myocardial ischemiaand cell death. In: StonePH, Antman EM, eds.Calcium ChannelBlocking Agentsin the Treatment of CardiovascularDisorders.Mount Kisco, NY: Futura Publishing, 1983:81-105. 20. Katz AM, Reuter H. Cellular calcium and cardiac cell death. Am J Cardiol 1979;44:188-190. 21. Dayton WR, Schollmeyer JV. Isolation from porcine cardiac muscleof a Ca*+-activated proteasethat partially degradesmyotibrib. J I401 Cell Cardiol 1980;12:533-551. 22. Vasdev SC, Kako KJ, Biio GP. Phmpholipid compositionof cardiac mitechondria and lyscuomesin experimental myocardial ischemiain the dog. J Mel Cell Cardiol 1979;l I:1 195-l-1200. 23. Murphy JG, Marsh JD, Smith TW. The role of calcium in ischemicmyocardial injury. Circulation 1987;75:supplKV-15-V-24. 24. Krishtal OA, Pidoplichko VI, ShakhovalovYA. Conductanceof the calcium channel in the membraneof snail neurones.J Pfiysiol 1981;310:423-434. 25. Shimoni Y. Parametersaffecting the slow inward channelreprinting process in frog atrium. J PhysiolI981;320:269-291. 26. Elz JS, Naylor WG. The effect of cellular Ca*+ on Ca2+overload (abstr). J Mel Cell Cardiol 1985;17:suppl3x58. 27. WeishaarR, Ashikawa K, Sing RJ. Effect of diltiaxem, a calcium antagonist, on mywardial ischemia.Am J Cardiol 1979;43:1137-1143. 28. Lange R, Ingwall J, Hale SL, Alker KJ, Braunwald E, Kloner RA. Preservation of high-energyphosphatesby verapamil in reperfusedmyocardium.Circzdation 1984;70:734-741. 23. Mori H, Nagata M, Miyazaki T, Sakurai K, Ogawa S, Hattori S, Takahashi M, Nakamura Y. Protection of hypoxic myocardium by intracoronary administration of verapamil in open-chestdogs. Circulation 1984;70:742-747. 30. Hugenholtx BG, Verdourv PD. deJong JW, Serruys PW. Nifedipine for anginaand acute myocardial ischemia.In: Opie LH, cd. Calcium Antagonistsand Cardiovascular Disease.New York: Raven Press, 1984:237-255. 31. Maloney JV, Nelson RL. Mywardial preservationduring cardiopulmonary bypass.J Thorac Cardiwasc Surg 1975:70:1040-1050. 32. Clark RE, FergusonTB, West PN, ShuchleibRC, Henry PD. Pharmacological preservation of the ischemicheart. Ann Thorac Surg 1977:24:307-314. 33. Robb-Nicholson C, Currie WD, Wechsler AS. Effects of verapamil on myocardiil tolerancetc ischemicarrest.Comparisonto potassiumarrest. Circulation 1978;58::1119-1124. 34, Vouhe PR, Helias J, Grondin CM. Myocardial protection through cold cardioplegia using diltiaxem, a calcium channel blocker. Ann Thorac Surg 1980;30:342-348. 315.Clark RE, Christlieb IY, FergusonTB, Weldon CS, Marbarger JP, Biello DR. Roberts R, Ludbrook PA, Sob-e.1 BE. The first American cliiical trial of nifedipine in cardioplegia: a report of the first 12 month experience.J Thorac Cardiovax Surg 1981;82:848-859. 36. Clark RE, Magovem GJ, Christlieb IY, Boe S. Niiedipine cardioplegia experience: results of a 3-year cooperative clinical study. Ann Thorac Surg 1983:36.x554-662. 37. Hicks GL, Jr., Salley RK, DeWecse JA. Calcium channel blockers: an intraoperative and postoperativetrial in women.Ann Thorac Surg 1984;37:319323. 33. Serruys PW, van der Brand M, Brewer RW, Hugenholtz PG. Regional cardioplegiaand cardioprotcction during transluminal angioplasty,which role for nifedipine? Eur Heart J 1983;4:supplC:ll5-121. 39. Serruys PW, Hooghoudt TEH, Reiber JHC, Slager C, Brewer RW, Hugenholtx PG. Influence of intracoronary nifedipine on left ventricular function, corenay vasomotility, and myocardial oxygenconsumption.Br Heart J 1983;49;42740.’ Fujibayashi Y, Yamaxaki S, Chang BL, Rajagopalan RE, Meerbaum S, Corday E. Comparative echccardiographicstudy of recovery of diastolic versus systolic function after brief periods of coronary occlusion:differential effects of intravenous nifcdipine administered before and during occulsion. JACC 1985; 6:1289-l 298. 41. Feldman RL, MacDonald RG, Hill JA, PepineCJ. Effect of nicardipine on determinantsof myocardial ischemiaoccurring during acute coronary occlusion produced by percutaneoustransluminal coronary angioplasty. Am J Cardiol 1987,60:267-270. 42. Amende I, Herrmann G, Simon R. Differential effects of nisoldipine and nitroglycerin on myocardial ischemiaduring coronary angioplasty (abstr). Circulation 1987;IWV-183. 43. Fletcher PJ, Pfeffer JM, Pfeffer MA, Braunwald E. Left ventricular diastolic pressure-volumerelations in rats with healed myocardial infarction. Effects on systolic function. Circ Res 1981;49.618-626. 44. Pfeffer MA, Pfeffer JM, FishbeinMC, Fletcher PJ, SpadaroJ, Kloner RA, Braunwald E. Myocardial infarct size and ventricular function in rats. Circ Res
1979:44:503-512. 45. ChesebroJH, Knatterud G, Roberta R, Borer J, Cohen IS, Dalen J, Dodge
HT. Francis CK, Hillii D, Ludbrook P, Markis JE, Mueller H, PassamaniER, Powers ER, Rao AK, Robertson T, Ross A, Ryan TJ, Sobel BE, Willerson J, Williams DO, Zaret BL, Braunwald E. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase:clinical findings through hospital discharge. Circulation 1987:76:142-154. 46. Gruppo Italian0 Per Lo Studio Della StreptochinasiNell ‘Infarto Miocardio (GISSI). Effectivenessof intravenousthrombolytic treatment in acutemyocardial infarction. Lnncel 1986;1:397-401, 47. Topol EJ, O’Neill WW, Langburd AB, Walton JA, Bourdillon PDV, Bates ER, Grinea CL, Schork AM, Kline E, Pitt B. A randomized,placebo-controlled trial of intravenousrecombinanttissue-typeplasminogenactivator andemergency coronary angioplasty in patients with acute myocardial infarction. Circulation 1987;75:420-428. 48. Hamm CW, Opie LH. Protection of infarcting myocardiumby slow channel
inhibitors. Comparative effects of verapamil, nifedipine, and diltiazem in the coronary-ligated, isolated working rat heart. Circ Res 1983;52:supp/ 1:129-138. 49. Reimer KA, Lowe JE, JenningsRB. Eff& of the calcium antagonistverapamil on necrosisfollowing temporary coronary artery occlusionin dogs.Circularion 1977;55:581-587.
50. Klein HH, Schubothe M, Nebendahl K, Kreuzer H. The effect of two different diltiazem treatments on infarct size in ischemic, reperfused porcine hearts. Circulalion 1984.69:1CW-I 005.
51. Lo HM, Kloner RA, Braunwald E. Effect of intracoronary verapamil on infarct size in the ischemic,reperfusedcanine heart: critical importance of the timing of treatment. Am J Cardiol 198536:672-677. 52. Sirncs PA, Overskeid K, PedersenTR, Bathen J, Drivenes A, Froland GS, Kjekshus JK, Landmark K, Rokscth R. Sirnes KE, Sundoy A, Torjussen BR, Wcstlund KM, Wik BA. Evolution of infarct size during the early useof nifcdipine in patients with acute myocardial infarction: The Norwegian Nifedipine Multicenter Trial. Circulation 1984;70:638-644. 53. Muller JE, Morrison J, Stone PH. Rude RE, Rosner B, Roberts R, Pearle DL, Turi ZG, SchneiderJF, Serfas DH, Tate C, ScheinerE, Sobel BE, HennekensCH, Braunwald E. Nifedipine therapy for patientswith threatenedandacute myocardial infarction: a randomized,double-blind, placebo-controlledcomparison. Circulalion 1984,69:740-747. 54. ThuesenL, JrgensenL, Kristgaard HJ, SrensenJA, Vaeth M, JensenEB, JensenJJ, Hagerup L. Effect of verapamil on enzymereleaseafter early intravenousadministrationin acutemyocardial infarction: doubleblind randomizedtrial. Br Med J 1983;286:1107-1108,
55. BussmannW, Seher W, Gruengras M. Reduction of creatine kinase and creatine kinase-MB indexesof infarct size by intravenousverapamil. Am J Cardial 198434:1224-l
230.
58. Ferlinz J. Nifedipine in myocardial ischemia, systemic hypertension,and other cardiovascular disorders.Ann Intern Med 1986;105:714-729. 57. StonePH. Antman EM, Muller JE, Braunwald E. Calcium channelblocking agentsin the treatment of cardiovasculardisorders.Part II: hemodynamiceffects and clinical applications. Ann Intern Med 198093:886-904.
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Painfid and asymptomatic ischemla has been assoelated with left ventrkuW dysfunction, an important varlabk re@ed to survival ii9 patients With coronary artery disease. The treatment of patknts withcoMnaryarterydlsea~withagentssucha8 cakhnchannelblockershasbeendlrectedatreduelng ischemia by rest&kg the balance between rntitial oxygei~ supply and demand, which ultimately s&ves to protect against myocardial dysflmdlon.Dnceischemikoccurred,eakbun ehann@l blockers may protect myocardlal cellular integrity and functki. By reducing intracdkrbr &Icium ov&ad king Ischsmia, niito&ondrial functlon Is preserved and adenosine trlphosphate stures are malntsin’ed. Numerous in vitro and Isoiated heart preparations have shown thqt ischemia In the presence of cakium blockade is ass&elatedwlth thaninthssltuationof lesscellulardy~ ischemia In the abssnce of calcium channsl blodtade. (Am J Can#d1989;64:10F-17F)
n important relation exists between ventricular function and survival in patients with coronary artery disease. Numerous studies have shown that left ventricular function is an im@rtant independent variable related to mortality in the setting of aate myocardial infarction, unstable angina. and chronic stable angina.1-3Treatment efforts in patients with coronary artery diseaseare directed at reducing ischemiaby restoring the balance between myocardial oxygen supply and demand,which ultimately servesto protect against myocardial dysfunction. It was once believedthat only a prolonged symptomatic ischemicinsult led to myocardial necrosiswith resultant abnormalities of ventricular function. It is now known, however,that ventiicular dysfunction is not limited to symptomatic or prolongedischemicevents.Asymp tomatic ischemia may be associatedwith left ventricular dysfunction to a degreethat is similar to that of painful episodes.4v5 Changes in left ventiicular compliance, as well as abnormalities of regional wall motion, often precedeischemicelectrocardiographicchangesand angina,6 and havebeenfound to persistwell beyondthe resolution of ischemia.7,8In addition, becausesilent ischemia may occur up to 4 times as often as painful attacks, angina thus is an insensitive and unreliable indicator of myocardial ischemia.9 The cumulative effect of ischemic eventson ventricular function and their relation to patient survival is only speculative. It has been postulated that repeated, brief episodesof ischemia may lead to a stunning of the myocardium with chronic postischemicleft ventricular dysfunction.*OGiven the impact of left ventricular function in the prognosisof patients with coronary artery disease, numerousinvestigationshavesought to identify the mediators of cellular injury.
A
CALCIUM
AND CELL INJURY
In the resting myocyte, the intracellular calcium concentration is maintained at several thousand times less than the extracellular concentration.” The maintenance of this concentration gradient is dependenton an intact cell membraneas well as proper functioning of ion-selective channels and energy-dependention pump mechanisms.12J3 Normally, calcium may enter the cell by several routes. Sites of passivediffusion, sodiuin-calcium exchangeand slow calcium channelshave all beencited as possibleentry mechanisms.11~12~14~15 However, the greatest contributor to free cytosolic calcium may result from calcium-triggered releaseof calcium from storage sites From the Department of Medicine, Cardiology Se&&, Harvard Medi- within the sarcoplasmic reticulum.16 During ischemia, cal School,and the New England De&ness Hqvital, Boston,Massathe cytosolic calcium concentration increase~.~~J~ The chusetts. Address for reprints: Richard W. Nesto, MD, New England Dea- initiating factor responsiblefor this increaseis not completely understood,but may be due to ischemia-induced conessHospital, 185pilgrim Road, Boston,Massachusetts02215. 1OF
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64
t [W Mitochondrial Ca Overload
t Activity of Ca ATPases
+ ATP Production
ATP Depletion /
Loss of Ion Pump Function and Contractile Function
depletion of cellular adenosine triphosphate (ATP).19 The mode of this calcium increase may involve alterations in one or more of the calcium regulatory mechanismspreviously mentioned. It is this increasein cytosolic calcium that is thought to result in myocardial cell death.*O Cell death involves both energy expenditure and organelle destruction. In animal models, an uncontrolled increase in cytosolic calcium concentration results in ATP depletion by way of the activation of calcium-dependentATPase.l 9This decreasein cellular energystores impairs the function of the energy-dependentcalcium pump responsible for retrieving calcium, and may decreasecalcium reuptake by the sarcoplasmicreticulum. In addition, endogenousproteasesand phospholipasesare activated, which may lead to damageof the intracellular organelles and loss of mitochondrial membrane integrity.*‘,** The final blow to cellular homeostasisis mitochondrial calcium overload, resulting in the inhibition of ATP generation (Fig. 1).12~17J9~23 Pharmacologic agents that limit intracellular calcium concentration may, therefore, protect against ischemia-inducedATP depletion and preserve cellular function. The mechanismof action of calcium channel antagonists involves the inhibition of calcium influx at the slow channel site, thereby protecting against cell damage or death.l4 Unfortunately, there are severalreasonsto doubt that transmembranecalcium influx through the slow calcium channel is the predominant sourceof calcium overload during ischemia. The observednumber and conductance of the calcium channel do not account for the total gain in cytosolic calcium noted after ischemia. Furthermore, the slow channel requires phosphorylation in order to function properly; but during periods of ischemia,cellular ATP reservesare depleted and thus it is unlikely that the calcium channel operatesat full capacity. Normal operation of the calcium channel also dependson maintenance of physiologic intracellular pH and normal intracellular calcium concentration, both of which are altered by ischemia.1sJ9,23-26
4 Protease Activitv
‘4 Lipase and Phospholipase
Membrane Disruption
Progressive Ca Overload
Contkture
Arachidonic Acid Metabolites
Loss of Ionic Gradients
Despite these observations,pharmacologic blockade of the calcium channels may reduce cellular calcium overload early in the ischemic process.In fact, in experimental models of ischemia, calcium channel-blocking agentsreducedcellular calcium overloadby an estimated 40% when administered before reoxygenation after hypoxemia.17In addition, the administration of nifedipine and verapamil before reperfusion of ischemic myocardiurn has been demonstrated to decreasemitochondrial calcium overload and improve postischemicrecovery of ventricular function (Fig. 2).17J9One mechanism by which mechanicalfunction is preservedis maintenanceof myocardial ATP stores.27y2s Calcium channel blockers are known to reduce high-energy phosphatebreakdown during hypoxia. Moreover, thii effect appearsto be independentof any negative inotropic action of the drug.29s30 CARDIOPULMONARY BYPASS During cardiopulmonary bypass,global ischemia occurs in myocardium, with time- and temperature-dependent changesto myocardial cells resulting in postoperative impairment of ventricular function.31 To minimize myocellular injury during cardiac surgery, electivecardiac arrest using hypothermic, hyperkalemic cardioplegia is frequently used. Despite cardioplegia, however, left ventricular dysfunction and myocardial necrosiscontinue to pose a problem during prolonged cardiopulmonary bypass.Becausereperfusion after periods of regional or global ischemia is associatedwith excesscalcium flux across the sarcolemma, a drug that could retard this influx might offer additional myocardial protection and decreaseperioperative morbidity and mortality. Clark et aP* constructeda dog model for cardiopulmonary bypass in order to test this hypothesis.A standard hyperkalemic cardioplegic solution was comparedwith an identical solution to which nifedipine had beenadded.After 2 hours of hypothermic cardiac arrest, the dogs were weaned from bypass.The nifedipine-treated group was found to have significantly better indexesof left ventricular function when compared with the control group (Fig. 3).
THE AMERICAN JOURNAL OF CARDIOLOGY SEPTEMBER 19, 1989
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Untreated Mitochondrial Calcium (nmolslmg protein)
-r
NEXT STEP
Nifedipine treated
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These drug-treated dogs were more easily weanedfrom bypass,required lesspressorsupport, and had lesshistologic evidenceof ischemicinjury than the untreated dogs. The protection afforded by nifedipine in this setting extends to other calcium channel blockers. Verapamil was found to be equally as effective as potassiumcardioplegia in preserving high-energy phosphate stores and systolic function under normothermic conditions.33In another study, the benefits of diltiazem exceededthose of ice in hypothermic dogs when left ventricular performance was assessed.34 Clark et a135extendedtheseobservationsin animals to an evaluation of calcium blockers as cardioplegicsin humans. The first American clinical trial of nifedipine in cardioplegia evaluated47 patients at high risk for cardiac surgery. Thesepatients receivedstandard cold hyperkalemic cardioplegia solution either with or without 275 pg/ liter of nifedipine. Immediate postbypasshemodynamic
monitoring demonstrated that the nifedipine-treated group had higher cardiac output, larger stroke volume and lower pulmonary and peripheral vascular resistance (Fig. 4). Evidence suggesting a cardioprotective effect was observed in the drug-treated group and included lower creatine kinase release and fewer abnormalities demonstrable on postoperative technetium pyrophosphate scans. An extendedtrial of 205 high-risk patients36included a randomized subsetof 74 patients, of whom 39 received nifedipine cardioplegia and 35 receivedstandard cardioplegia. There were no significant differencesin preoperative hemodynamicsnoted betweenthe 2 groups. The nifedipine-treatedpatients had a nearly 100?6improvement in postoperative cardiac output, left ventricular stroke volume and stroke work index when compared with the control group. This improvement in postoperative left ventricular function was reflected in a mortality rate of
1OOr
FIGURE 3. Change from pmidmdc vduesincontrot(n=7)8nddntg-treated@ =6)degsferkft(Lv) end-db stdcpreum,shkewerk,imdLvdP/ &.AbeidRwasdedford3vdhles aRer?hou%of --ill thedfedlpb-tmatedm&naba. (Repro-
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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64
-
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2.6 FIGURE 4. Average cardiac index (Lhnin/ mqfavp&athtetreatadwilh-WV&plegia(n= 15)mdforpathtslreated withthsarKilonof~lnecuaopkgia(n=Z2to23).Valuesaregivenasa functhofeventdllme~andaRer swgay. ICU = llltodwcare!urH;Inbe -.(RepmhmdwithpemWion km J IBorac Cardiovasc Surg.3s)
2.2 Average Cardiac Index (Llminlm 2)
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only 4%, an almost threefold reduction when compared with the control group. A later study also examined the role of calcium channel blockers in providing myocardial protection during cardiopulmonary bypass.37Thirty-nine women undergoing coronary artery bypass procedures were randomly assigned to either a standard cardioplegic group or a verapamil-nifedipine group.37Patients received 1 mg of verapamil added to each liter of cardioplegia as well as oral postoperative nifedipine. A significantly lower creatine kinasevalue and serum aspartateaminotransferase were noted postoperatively in the women treated with calcium blockers (Fig. 5). A trend toward fewer episodes of postoperativeventricular tachyarrhythmias wasnoted, with the control group experiencing 3 fatal ventricular fibrillation arrests; no such events were seenin the patients treated with verapamil and nifedipine. Thesestudies provide clinical data to support the theory that the effect of ischemia on myocardial function may be attenuated by calcium channel-blocking agents.
I I I I ’ After Before After Before 4 HR lnduc Bypass Bypass ICU ICU
I I 12 HR 24 HR ICU ICU
PERCUTANEOUS TRANSLUMINAI. CORONARY ANGIOPLASTY Coronary angioplasty offers an opportunity to study the effectsof flow-related regional ischemiaon myocardial function. After the acute interruption of coronary blood flow, a cascadeof pathophysiologiceventsensues. Abnormalities of diastolic function occur within seconds of balloon occlusion, followed in sequenceby systolic dysfunction, electrocardiographic signs of ischemia, and finally the subjective appreciation of ischemia-angina pectoris.‘j Such abnormalities of systolic and diastolic function may resolvebefore angina is triggered and may persist well beyond the restoration of coronary flow. Limited studies are available to show that calcium channel blockersare cardioprotectiveduring angioplasty, and there is even less information to support that this protection is the direct result of calcium infhtx. An investigation performed by Serruys et aPs showedthat intracoronary nifedipine administered before percutaneous transluminal coronary angioplasty (PTCA) reducesthe
1
1100 1000 900 800 700 flGURE 5. Poshpesathe cm&c enzyme levekin3SwomeminGbesbdy.AST= sevum~amlnotr~cPK= phosphoklnaoe; V-N = vesonancvoaths group; *p
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THE AMERICAN JOURNAL OF CARDIOLOGY SEPTEMBER 19, 1989
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Ocdusion without Nifedipine Niiedipine during Occlusion Niiypine prior to Occlusion
FIGURE 6. Redts of Pdhe~bnd eadolgrylNcmfor*~m bry~--~grclph depictsthethnecaa-seiofracolwryef meanvekcRyof~dkstol&awadmnge(VLAC)asmindexofdiastokftmdolhvLACbrhormafter1 mhwteefkRmlterkr~-
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severity of myocardial ischemia.They initially compared the effects of nifedipine injected into the left main coronary artery with results from balloon occlusionof the left anterior descendingartery in patients with isolated obstructive lesions and preserved systolic function. Both interventions produced a similar depressionin myocardial diastolic and systolic function. The patients taking nifedipine, however, had an increase in coronary sinus and great cardiac vein blood flow asmeasuredby therrnodilution techniques. It was concluded that the transient depressionof mechanicalfunction producedby nifedipine was due to a regional “cardioplegic” effect, an effect that is associatedwith a reduction in myocardial oxygen consumption, an increasein coronary blood flow and vasodilation of epicardial vessels.38,39 In a second group of patients, Serruys et aP* also determined that this reduction in contractile function was paralleled by an improvement in metabolic parameters of ischemia. Measurements of myocardial lactate production were obtained before FTCA, after PTCA without nifedipine, and after F’TCA with intracoronary nifedipine pretreatment. Lactate production wasnoted to increase dramatically after left anterior descendingartery occlusion.However, pretreatment with nifedipine all but suppressedthis effect. Summary data suggestedthat nifedipine preventedmyocytesfrom becominganaerobic due to its effectson contractile energyexpenditure,there by preventing tissue damage during flow-related ischel&.W9 Fujibayashi et al@examined the effectsof nifedipine on recoverytime of left ventricular dysfunction after brief coronary occlusion during angioplasty. Intravenous nifedipine was administered either beforeor during 1- or 2minute occlusions of the left anterior descendingcoronary artery in dogs.Two-dimensional echocardiography was performed to document the return of diastolic and
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THE AMERICANJOURNALOF CARDIOLOGY VOLUME64
aRuwardforadmdstmatedwRhintravenousdediphe(dwhgaccbion,n=6 n=6shdfes) m--, andforcontdahals(n= 12studks.) RedtS-~arrYarh umnbdpinegroup6mnhthewntrolanhldS.(ReproduccdWRhpannbdontrom IACC.‘o)
systolic function. Without drug treatment, diastolic function was noted to be abnormal for up to 75 minutes after l-minute occlusions (Fig. 6) and for up to 105 minutes after 24nute occlusions.Although still delayed,shorter recovery periods were recorded for indexes of systolic function. Treatment with nifedipine significantly accelerated the recovery of both diastolic and systolic function. When nifedipine was given before coronary occlusion, recovery of both systolic and diastolic function was ap parent as early as within 2 minutes of either occlusion period. Administration of nifedipine during occlusion again significantly acceleratedrecovery of both diastolic and systolic function, with both values returning to normal within 15 minutes. Although hemodynamic benefit was gained with nifedipine administration either before or during ischemia, a greater responsewas gained by pretreatment. Independent studies have demonstratedthat calcium channel blockersadministered either intravenously or by way of the intracoronary route prolong the time to ischemia during coronary angioplasty. Feldman et a141found that pretreatment with intravenousnicardipine prevented or delayed the onset of ischemic ST-segment shifts in most patients after left anterior descendingartery occlusion. Investigations by Amende et a142with intracoronary nisoldipine not only confirmed that calcium channel blockers delay onset of ischemic ST-segment changes, but also demonstrateda significant decreasein the magnitude of ST-segmentshift, thereby supporting the concept of cardioprotection. Extrapolation from these studies using angioplastyinduced ischemiato the clinical setting is difficult. During balloon inflation, there is total interruption of coronary blood flow, whereas in ambulatory patients, most ischemit eventsare secondaryto a “low-flow” state and are usually longer, as demonstrated on Holter monitoring,
10
a Cumulative LDHrelease (U/g/hour)
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L N=l(
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Further studies are neededto seeif the beneficial effects of calcium channel blockers observedin the angioplasty model of ischemia can be applied to patients with chronic coronary artery diseasewho are taking calcium channel blockers. ACUTE MYOCARDIAL INFARCTION When myocardial blood flow is reduced beyond a critical level for prolonged periods of time, severeischemia develops;when left uncorrected, myocardial infarction occurs.The severity of the resulting ventricular dysfunction is directly proportional to the extent of myocardial tissue necrosis.43T44Current therapy of acute myocardial infarction is aimed at reducing the extent of necrosis by reestablishing blood flow to ischemic zones and reducing oxygen demand. Both thrombolysis and angioplasty have been successful in this regard.45-47 These interventions are effective only if used soon after the onsetof myocardial infarction. Pharmacologicagents capable of retarding cell death may reduce the extent of ischemic injury. Calcium channel blockershave also beenfound capable of reducing the extent of necrosis in a laboratory setting of experimentally induced myocardial infarction. In animal studies,isolated heart preparationsusing verapamil, nifedipine and diltiazem have shown that all 3 compoundsdecreasethe extent of infarction asmeasured by cumulative lactate dehydrogenasereleaseafter core nary occlusion (Fig. 7) .48This reduction wasindependent of the agents’ chronotropic effects, sincebenefit was unchangedwhen the hearts were electrically pacedat rates that approximated the heart rate of a control group. Reimer et a149evaluated the effect of verapamil pretreatment on the infarct size of dogs subjected to 40 minutes of left circumflex occlusion.After 48 to 96 hours of reperfusion, animals pretreated with lower dosesof verapamil demonstrated a significant reduction in the histologic extent of necrosis compared with untreated animals. As with thrombolytic therapy, the benefits achievedwith the useof calcium channel blockersduring
infarction appear to be dependenton the timing of their administration. Klein et a150studied 3 groups of pigs that underwent 75 minutes of left anterior descendingartery occlusion followed by 4 hours of reperfusion. The first group received no drug treatment, the second received diltiazem before coronary occlusion,and the third group received the samedoseof diltiazem after 79 minutes of ischemia.Both drug-treated groups showeda significant reduction in infarct size when compared with control animals. The greatest reduction, however, was demonstrated in the group that receiveddiltiazem before coronary occlusion. Similar findings were reported by Lo et al,51when infarct sizein dogswasexaminedafter 3 hours of left anterior descendingartery occlusion with 3 hours of reperfusion. Dogs treated with verapamil 90 minutes into occlusionwere found to havea significant decreasein the areaof necrosiswhen comparedwith dogsnot administered verapamil. This benefit was lost when verapamil treatment was delayed until just before reperfusion. Although more studies are neededto determine the effectsof calcium channel blockersasmodifiers of infarct size in humans, results of severaltrials to date in which calcium channel blockers were administered within 12 hours of onset of symptomsshowedno difference in infarct size.52-54 Results of another clinical study, however, suggesteda reduction in myocardial infarct size by calcium channel blocker administration. Bussmann et alS5 randomized 29 patients to receiveintravenousverapamil a mean of 8 hours after the onset of chest pain, with an additional 25 patients serving as controls. Peak creatine kinaseand creatine kinaseMB activity derivedfrom time activity curves were consistently and significantly lower in the verapamil-treated group than in the control group. Mathematic conversion of creatine kinase values to weight equivalents calculated to an approximate 30% reduction in infarct size. Although animal data suggestthat calcium channel blockersdelay the onsetof cellular injury, it appearsthat without reperfusion, cell death is inevitable. It is quite possible, however, that the administration of calcium
THE AMERICAN JOURNAL OF CARDIOLOGY SEPTEMBER 19, 1989
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channel blockers earlier than in the studies mentioned previously may limit the extent of necrosisor reduce the size of the periiiarction ischemic zone. CONCLUSIONS In laboratory studies, calcium antagonists have been shown to conserveATP, reduce mitochondrial calcium overload, and enhance recovery of ventricular function. Application of these findings to clinical situations has yielded data supporting cardioprotection during both cardiopulmonary bypassand flow-related regional ischemia. In both of these situations, optimal effects are obtained when ischemia is followed by reperfusion. In models of regional ischemia, when calcium antagonistsare administered late in the courseof occlusion,or when ischemiais not followed by reperfusion, calcium antagonistsare less effective. Calcium channel blockersare of considerablevalue in reducing myocardial ischemia. These drugs have been demonstrated to alter favorably the balance between myocardial supply and demand by decreasingleft ventricular afterload, reducing myocardial contractility, and dilating the coronary arterial tree.56>57 Additionally, these agentshave the potential for protecting the myocardium against ischemically mediated injury by virtue of their effect on calcium flux acrosscell membranesor within cellular compartments. REFERENCES
1. The Veterans Administration Coronary Artery BypassSurgery Cooperative Study Group. Eleven-year survival in the Veterans Administration random&d trial of coronary bypasssurgery for stableangina.N Engl J Med 1984;311:13331339. 2. Luchi RJ, Scott SM, Deupree RH. Comparison of medical and surgical treatment for unstable angina pectoris. N Engl J Med 1987;316.977-984. 3. The Multicenter Postinfarction ResearchGroup. Risk stratification and survival after myocardial infarction. N Engl J Med 1983;309:331-336. 4. Cohn PF, Brown EJ, Wymte J, Holman BL, Atkins HL. Global and regional left ventricular ejection fraction abnormalities during exercise in patients with silent myozudial ischemia.JACC 1983;1.931-933. S. Chierchii S, Laxzari M, FreedmanB, Brunelli C, Maseri A. Impairment of myocardiil perfusion and function during painlessmyocardiil iscbemia.JACC 1983;1:924-930. 6. Nest0 RW, Kowalchuk GJ. The ischemic cascade:temporal sequenceof hemodynamic,electrocardiographic and symptomatic expressionsof ischemia. Am J Cardiol 1987;57:23C-3OC. 7. Wijns W, Serruys P, Slager CJ, Grimm J, Krayenbuehl HP, Hugenholtz PG, HessOM. Effect of coronary occlusionduring percutaneoustransluminal am& plasty in humans on left ventricular chamber stiffness and regional diastolic press~radius relations. JACC 1986;7:455-463. 2. Carbon EB, Hmohara T, Morris KG. Recovery of systolic and diastolic left ventricular function after a 60-secondcoronary arterial occlusionduring percutaneous transluminal coronary angioplasty for angina pcctoris. Am J Cardiol 1987,6&460-466. 9. Schang SJ Jr, Pepine CJ. Transient asymptomatic ST-segmentdepression during daiiy activity. Am J Med 1977;39:3%-402. 10. Braunwald E, Kloner RA. The stunnedmyccardium:prolonged,postischemic ventricular dysfunction. Circulation 1982x56:1 146-I 149. 11. Carafoli E. How calcium crossesplasmamembranesincluding the sarcolemma. In: Gpie LH, ed. Calcium Antagonists and Cardiovascular Dii. New York Ranen Press, 1984:29-41. 12. JenningsRB, Reimer KA. Lethal myocardial ischemicinjury. Am J Pathof 1981;102:241-255. 13. Caroni P, Carafoli E. Regulation of Cast-pumping ATPase of heart sarco lemma by a phmphorylation-dephmphorylationprocess.J Biol Chem 1981;256: 9371-9373. 14. Antman EM, StonePH. Muller JE, Braunwald E. Calcium channelblocking agenta in the treatment of cardiovascular disorders. Part 1: Basic and clinical electrophysiologic effects Ann Intern Med 1980,93:875-88X 15. SperelakisN, SchneiderJA. A metabolic control mechanismfor calcium ion influx that may protect the ventricular myocardial cell. Am J Cardiol 1976;
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37:1079-1085. 16. Fabiato A, Fabiato F. Calcium releasefrom the sarcoplasmicreticulum. Circ Res 1977;40:119-129. 17. Nayler WG, Ferrari R, Williams A. Protective effect of pretreatment with verapamil, nifedipine and propranolol on mitochondrial function in the ischemic and reperfuscd myocardium. Am J Cardiol 1980:46:242-M. 16. Shen AC, JenningsRB. Myocardiil calcium and magnesiumin acute ischemit injury. Am J Pathol 1972,67:417-433. IS. Naylor WG. The role of calcium in myocardial ischemiaand cell death. In: StonePH, Antman EM, eds.Calcium ChannelBlocking Agentsin the Treatment of CardiovascularDisorders.Mount Kisco, NY: Futura Publishing, 1983:81-105. 20. Katz AM, Reuter H. Cellular calcium and cardiac cell death. Am J Cardiol 1979;44:188-190. 21. Dayton WR, Schollmeyer JV. Isolation from porcine cardiac muscleof a Ca*+-activated proteasethat partially degradesmyotibrib. J I401 Cell Cardiol 1980;12:533-551. 22. Vasdev SC, Kako KJ, Biio GP. Phmpholipid compositionof cardiac mitechondria and lyscuomesin experimental myocardial ischemiain the dog. J Mel Cell Cardiol 1979;l I:1 195-l-1200. 23. Murphy JG, Marsh JD, Smith TW. The role of calcium in ischemicmyocardial injury. Circulation 1987;75:supplKV-15-V-24. 24. Krishtal OA, Pidoplichko VI, ShakhovalovYA. Conductanceof the calcium channel in the membraneof snail neurones.J Pfiysiol 1981;310:423-434. 25. Shimoni Y. Parametersaffecting the slow inward channelreprinting process in frog atrium. J PhysiolI981;320:269-291. 26. Elz JS, Naylor WG. The effect of cellular Ca*+ on Ca2+overload (abstr). J Mel Cell Cardiol 1985;17:suppl3x58. 27. WeishaarR, Ashikawa K, Sing RJ. Effect of diltiaxem, a calcium antagonist, on mywardial ischemia.Am J Cardiol 1979;43:1137-1143. 28. Lange R, Ingwall J, Hale SL, Alker KJ, Braunwald E, Kloner RA. Preservation of high-energyphosphatesby verapamil in reperfusedmyocardium.Circzdation 1984;70:734-741. 23. Mori H, Nagata M, Miyazaki T, Sakurai K, Ogawa S, Hattori S, Takahashi M, Nakamura Y. Protection of hypoxic myocardium by intracoronary administration of verapamil in open-chestdogs. Circulation 1984;70:742-747. 30. Hugenholtx BG, Verdourv PD. deJong JW, Serruys PW. Nifedipine for anginaand acute myocardial ischemia.In: Opie LH, cd. Calcium Antagonistsand Cardiovascular Disease.New York: Raven Press, 1984:237-255. 31. Maloney JV, Nelson RL. Mywardial preservationduring cardiopulmonary bypass.J Thorac Cardiwasc Surg 1975:70:1040-1050. 32. Clark RE, FergusonTB, West PN, ShuchleibRC, Henry PD. Pharmacological preservation of the ischemicheart. Ann Thorac Surg 1977:24:307-314. 33. Robb-Nicholson C, Currie WD, Wechsler AS. Effects of verapamil on myocardiil tolerancetc ischemicarrest.Comparisonto potassiumarrest. Circulation 1978;58::1119-1124. 34, Vouhe PR, Helias J, Grondin CM. Myocardial protection through cold cardioplegia using diltiaxem, a calcium channel blocker. Ann Thorac Surg 1980;30:342-348. 315.Clark RE, Christlieb IY, FergusonTB, Weldon CS, Marbarger JP, Biello DR. Roberts R, Ludbrook PA, Sob-e.1 BE. The first American cliiical trial of nifedipine in cardioplegia: a report of the first 12 month experience.J Thorac Cardiovax Surg 1981;82:848-859. 36. Clark RE, Magovem GJ, Christlieb IY, Boe S. Niiedipine cardioplegia experience: results of a 3-year cooperative clinical study. Ann Thorac Surg 1983:36.x554-662. 37. Hicks GL, Jr., Salley RK, DeWecse JA. Calcium channel blockers: an intraoperative and postoperativetrial in women.Ann Thorac Surg 1984;37:319323. 33. Serruys PW, van der Brand M, Brewer RW, Hugenholtz PG. Regional cardioplegiaand cardioprotcction during transluminal angioplasty,which role for nifedipine? Eur Heart J 1983;4:supplC:ll5-121. 39. Serruys PW, Hooghoudt TEH, Reiber JHC, Slager C, Brewer RW, Hugenholtx PG. Influence of intracoronary nifedipine on left ventricular function, corenay vasomotility, and myocardial oxygenconsumption.Br Heart J 1983;49;42740.’ Fujibayashi Y, Yamaxaki S, Chang BL, Rajagopalan RE, Meerbaum S, Corday E. Comparative echccardiographicstudy of recovery of diastolic versus systolic function after brief periods of coronary occlusion:differential effects of intravenous nifcdipine administered before and during occulsion. JACC 1985; 6:1289-l 298. 41. Feldman RL, MacDonald RG, Hill JA, PepineCJ. Effect of nicardipine on determinantsof myocardial ischemiaoccurring during acute coronary occlusion produced by percutaneoustransluminal coronary angioplasty. Am J Cardiol 1987,60:267-270. 42. Amende I, Herrmann G, Simon R. Differential effects of nisoldipine and nitroglycerin on myocardial ischemiaduring coronary angioplasty (abstr). Circulation 1987;IWV-183. 43. Fletcher PJ, Pfeffer JM, Pfeffer MA, Braunwald E. Left ventricular diastolic pressure-volumerelations in rats with healed myocardial infarction. Effects on systolic function. Circ Res 1981;49.618-626. 44. Pfeffer MA, Pfeffer JM, FishbeinMC, Fletcher PJ, SpadaroJ, Kloner RA, Braunwald E. Myocardial infarct size and ventricular function in rats. Circ Res
1979:44:503-512. 45. ChesebroJH, Knatterud G, Roberta R, Borer J, Cohen IS, Dalen J, Dodge
HT. Francis CK, Hillii D, Ludbrook P, Markis JE, Mueller H, PassamaniER, Powers ER, Rao AK, Robertson T, Ross A, Ryan TJ, Sobel BE, Willerson J, Williams DO, Zaret BL, Braunwald E. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase:clinical findings through hospital discharge. Circulation 1987:76:142-154. 46. Gruppo Italian0 Per Lo Studio Della StreptochinasiNell ‘Infarto Miocardio (GISSI). Effectivenessof intravenousthrombolytic treatment in acutemyocardial infarction. Lnncel 1986;1:397-401, 47. Topol EJ, O’Neill WW, Langburd AB, Walton JA, Bourdillon PDV, Bates ER, Grinea CL, Schork AM, Kline E, Pitt B. A randomized,placebo-controlled trial of intravenousrecombinanttissue-typeplasminogenactivator andemergency coronary angioplasty in patients with acute myocardial infarction. Circulation 1987;75:420-428. 48. Hamm CW, Opie LH. Protection of infarcting myocardiumby slow channel
inhibitors. Comparative effects of verapamil, nifedipine, and diltiazem in the coronary-ligated, isolated working rat heart. Circ Res 1983;52:supp/ 1:129-138. 49. Reimer KA, Lowe JE, JenningsRB. Eff& of the calcium antagonistverapamil on necrosisfollowing temporary coronary artery occlusionin dogs.Circularion 1977;55:581-587.
50. Klein HH, Schubothe M, Nebendahl K, Kreuzer H. The effect of two different diltiazem treatments on infarct size in ischemic, reperfused porcine hearts. Circulalion 1984.69:1CW-I 005.
51. Lo HM, Kloner RA, Braunwald E. Effect of intracoronary verapamil on infarct size in the ischemic,reperfusedcanine heart: critical importance of the timing of treatment. Am J Cardiol 198536:672-677. 52. Sirncs PA, Overskeid K, PedersenTR, Bathen J, Drivenes A, Froland GS, Kjekshus JK, Landmark K, Rokscth R. Sirnes KE, Sundoy A, Torjussen BR, Wcstlund KM, Wik BA. Evolution of infarct size during the early useof nifcdipine in patients with acute myocardial infarction: The Norwegian Nifedipine Multicenter Trial. Circulation 1984;70:638-644. 53. Muller JE, Morrison J, Stone PH. Rude RE, Rosner B, Roberts R, Pearle DL, Turi ZG, SchneiderJF, Serfas DH, Tate C, ScheinerE, Sobel BE, HennekensCH, Braunwald E. Nifedipine therapy for patientswith threatenedandacute myocardial infarction: a randomized,double-blind, placebo-controlledcomparison. Circulalion 1984,69:740-747. 54. ThuesenL, JrgensenL, Kristgaard HJ, SrensenJA, Vaeth M, JensenEB, JensenJJ, Hagerup L. Effect of verapamil on enzymereleaseafter early intravenousadministrationin acutemyocardial infarction: doubleblind randomizedtrial. Br Med J 1983;286:1107-1108,
55. BussmannW, Seher W, Gruengras M. Reduction of creatine kinase and creatine kinase-MB indexesof infarct size by intravenousverapamil. Am J Cardial 198434:1224-l
230.
58. Ferlinz J. Nifedipine in myocardial ischemia, systemic hypertension,and other cardiovascular disorders.Ann Intern Med 1986;105:714-729. 57. StonePH. Antman EM, Muller JE, Braunwald E. Calcium channelblocking agentsin the treatment of cardiovasculardisorders.Part II: hemodynamiceffects and clinical applications. Ann Intern Med 198093:886-904.
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