Silent Myocardial lschemia After Acute Myocardial Infarction Ernst E. Van der Wall,
MD,
Volkert Manger Cats,
6llentkchenl&aftermyocardal-has butshwldbe M-P-lnmpMedwlthlnthecontextofother~ kwlcstorr.The-fortherapcnrticmthkbased4inthe --of s2entkchemlaandthepobntHydeMdous cdlbctofrepeatedepkodesofkchemlaonthe lntegmyofthelef&-.we-redparametersoflscbmla In2Opathtswhoshowed ~lSCh@lW6T-Tcha~Oll~X-
testhgIntheemlyphaseaft8rmyocadMinfare tkn.AfterdWazemadmlnlstdion,aredudon Ofex-sT-TdeprewknRom 23 + OS to 0.7 f 0.6 mm (p < 0.01) occwrd, andr8@onalwahdlon scOreat8X~,dS -n@dw-amimmwY,knpnnr~ dgnlfkantly (p e 0.02). llwse and other observatlonswamJntfurtherstudleelnwhkhtheduratlon,severltyand eapKmcyofthelschemkeplsodesshou#bequanthdandcordabdwlth prognohaRermyocaHalinfwctbn. (AmJCadoll992~l9624B)
From the Department of Cardiology, University Hospital, Rijnsburgenveg, L.&den, The Netherlands. Address for reprints: Ernst E. Van der Wall, Department of Cardiology, University Hospital, Bldg 1, C5, Rijnsburgerweg 10, 2333 AA L.eiden, The Netherlands.
MD,
and Albert V.G. Bruschke,
MD
I
schemia following an episode of myocardial infarction, particularly if it is asymptomatic or silent, is more difficult to define and recognize than is ischemia in the chronic stages of coronary artery disease. In view of the variability that is commonly seen in the evolving myocardial infarction, particularly the accompanying electrocardiographic changes (e.g., ST-segment depression or elevation or evolution of Q-waves),’ it is not practical to use the term “silent ischemia” in the first days of myocardial infarction. On the other hand, after a certain period of time, the clinical picture becomes indistinguishable from that of chronic coronary artery disease. For a meaningful definition of postinfarction ischemia, it is, therefore, necessaryto define a time frame. In our studies we have chosen the period between days 4 and 31 after the acute event. Evidence of postinfarction ischemia encompassesa range of manifestations, from symptoms of early recurrent angina pectoris to a positive but “silent” stress test (that is, a stress test showing unequivocal evidence of ischemia in the absenceof angina pectoris or other symptoms; Table I). In the literature on silent myocardial ischemia, relatively little attention is given to the definition of electrocardiographic evidence of ischemia. Nevertheless, spontaneously occurring nonspecific electrocardiographic ST-T changes are relatively common after acute myocardial infarction and do not always indicate the presence of ischemia. Further, exercise tests using electrocardiographic criteria may be difficult to interpret in the presence of marked repolarization disturbances at rest. To be considered evidence of myocardial ischemia with acceptable accuracy, postinfarction electrocardiographic changes at Holter monitoring or exercise testing should fulfill criteria for ischemia that have proven to be sufficiently specific.” It has long been recognized that in risk stratitication after myocardial infarction, evidence of ischemia at exercise testing is one of the major indicators of the future occurrence of reinfarction and death. Indeed, for many years this has been the A SYMPOSIUM: MYOCARDIAL ISCHEMIA
188
TABLE
I Manifestation
of Postmyocardial
Infarction
lschemia
1. Spontaneous transient tischemic) ECG changes, including recurring or extending ST elevations 2. Early recurrent angina pectoris 3. Positive ECG exercise test 4. Positive isotope tests showing reversible perfusion defects or deterioration of left ventricular function during exercise ECG
DlLllAZEM FOR SLEM SCHEMA DIVEN EARLY AFRiR MYOCARDIAL INFARCTION
= electrocardiographic.
basis of strategies in the management of postinfarction patients.& More recently, emphasis has been placed on the prognostic significance of asymptomatic or silent myocardial ischemia. Various studies have demonstrated that silent ischemia following myocardial infarction-detected by Holter monitoring or electrocardiographic exercise testing,“14 or demonstrated at exercise testing by perfusion defects and increased lung uptake by thallium-201 scintigraphy,‘5s’6or seen as a decrease of global ejection fraction and the development of wall motion abnormalities using radionuclide angiogra-has prognostic implications similar to those PhY16,” following the occurrence of symptomatic ischemia. Manifestations of silent ischemia may be abolished by drugs commonly used to treat angina pectoris. After acute myocardial infarction, calcium antagonists, by virtue of their vasodilating and afterload reducing properties, appear to be a logical choice to treat ischemic episodes. This assumption is supported by the Multicenter Diltiazem Postinfarction Trial (MDPIT), which showed a reduction of postmyocardial infarction mortality in patients who had received diltiazem and had no left ventricular dysfunction, although an increase in mortality was noted in patients who had evidence of pulmonary congestion.18~‘g Diltiazem was also shown in the Diltiazem Reinfarction Study to be effective in preventing early reinfarction and severe angina after non-Q-wave infarction.20 How80 70
ever, in neither study were patients stratified according to the presence of residual or silent ischemia, and the effect of diltiazem on the occurrence of silent ischemia was not studied.
f@j control Diltiazem
To determine the efficacy and safety of administration of diltiazem early after myocardial infarction in patients with residual silent ischemia, we studied 20 postinfarction patients who showed > l-mm asymptomatic ST-T depression during exercise testing with radionuclide angiography.*’ The patients underwent repeated exerciseradionuelide angiography 2 days later, 2 hours after oral intake of 120 mg diltiazem. The double product was not significantly altered before or after diltiazem, both at rest and during exercise. Maximal ST-T depression after diltiazem was reduced from 2.3 + 0.8 to 0.7 + 0.6 mm (p < 0.01). Left ventricular ejection fraction at rest before diltiazem was 54.4 & 8.7% and after diltiazem 56.2 + 11.3% (difference not significant). During exercise, left ventricular ejection fraction improved after diltiazem from 43.2 f 12.2% to 49.8 f 10.5% (p ~0.05) (Figure 1). Regional wall motion score (1 = normal, 4 = dyskinetic, x3 segments) at rest before diltiazem was 9.6 2 2.0 and after diltiazem 9.1 rt 1.8 (difference not significant). During exercise, regional wall motion score improved after diltiazem from 5.8 & 1.3 to 4.3 & 1.1 (p < 0.02). In conclusion, the study showed diltiazem to have beneficial effects on electrocardiographic ST-T depression and on both global and regional left ventricular function in postinfarction patients with silent myocardial ischemia.
l p < 0.05 T
60 3
50
LL ?i
40 30 20 10 0
202
THE AMERICAN
Rest JOURNAL
OF CARDIOLOGY
Exercise VOLUME
69
MARCH
6, 1992
SllENf ISCREMIA AS A MARKER OF PROWOSS AFfER MYOCARDW. INFARCTION Silent &hernia has proven to be a valuable predictor of the occurrence of cardiac events following acute myocardial infarction. However, it is just one parameter in a series of factors that are known to be of prognostic significance (Table II). Among these, the size of infarction, that is, the amount of myocardial tissue loss, appears to have the highest predictive power in both the acute and the chronic Therefore, treatment of acute myocarstages.4*22-25 dial infarction is primarily directed toward reduction of infarct size by early reperfusion.24225Loss of pump function is dependent, to a large extent, on infarct size but is also subject to other mechanisms such as postinfarction “remodeling” of the left ventricle.%% Infarct localization also has partly independent prognostic significance.29 After myocardial infarction, coronary anatomy appears to have less predictive value than the left ventricular angiogram. However, in the early 1970s it had already been demonstrated that the predictive power of the combination of left ventricular and coronary angiograms was greater than the predictive power of either one alone or in combination with clinical data.30 In a more recent study Proudfit et al= showed that in patients with previous myocardial infarction without subsequent angina, similar to group C of the Coronary Artery Surgery Study (CASS), prognosis was related to impairment of left ventricular function and extent of coronary artery disease. Weiner et ak31using the CASS registry data, showed that within the subset of patients with silent ischemia the coronary arteriogram retained significant prognostic power. Since >50% of their patients had prior myocardial infarction, these findings are also valid for postinfarction patients. Electrocardiographic markers of prognosis relate to QRS morphology and cardiac rhythm. The prognosis after Q-wave infarction appears to be different from that after non-Q-wave infarction, although the differences are in part dependent on age and previous myocardial infarction.32-34Bundle branch block complicating acute myocardial infarction adds to the postmyocardial infarction risk, particularly in the period shortly after the acute event.35 Developments in signal-averaging techniques (high-resolution electrocardiogram) have made it possible to record and identify late potentials, which are markers for propensity to ventricular arrhythmias. Therefore, late potentials merit a place in risk stratification after myocardial infarction.36 Recently, in experimental and clinical stud-
TABLE II Infarction
Prognostic
Indicators
After Acute
Myocardial
1. 2. 3. 4. 5. 6.
Size of infarction Localization of infarction Residual pump function Coronary artery obstructions Myocardial ischemia (silent or symptomatic) Electrocardiographic a. Changes of QRS complex Q-waves lntraventricular conduction disturbances Late potentials b. Rhythm disturbances Ventricular tachycardia and ventricular fibrillation Premature ventricular contractions Supraventricular rhythm disturbances Heart rate variability 7. Risk factors (hypertension, hyperlipidemia, diabetes mellitus, smoking, etc.)
ies, attention has also been focused on the prognos, tic significance of heart rate variability, in particular after myocardial infarction.37 Commonly recognized risk factors for the development of coronary atherosclerosis, such as hypercholesterolemia, also appear to have an influence on the prognosis of postinfarction patients, although their importance in secondary prevention is less marked than it is in primary prevention.38 Therefore, in our opinion the prognostic significance of postinfarction ischemia, whether silent or symptomatic, should be interpreted within the context of the entire risk profile of the individual patient to achieve an optimal risk stratification. Using the presence or absence of silent myocardial ischemia as the sole or major determinant of prognosis should be avoided, particularly in patients who have a history of acute myocardial infarction. TREATMENT OF POSllNFARCTiON SILENT ISCHEMIA The rationale for treatment of silent myocardial ischemia rests on two considerations: the prognostic significance of ischemia and the possibility that silent ischemia itself may exert harmful effects. It has been postulated (but not yet proven) that episodes of ischemia may cause microscopic myocardial necrosis and that repeated episodes may eventually lead to deterioration of left ventricular function. It is difficult to assess the potentially deleterious effect of episodes of ischemia in postinfarction patients because these patients are also prone to have progression of coronary artery disease. In an angiographic follow-up study including 300 patients with mainly stable coronary artery disease, Visser et a139observed deterioration of left ventricular contractions only in patients who had A SYMPOSIUM:
MYOCARDIAL
ISCHEMIA
21B
severe progression of their coronary artery obstructions. In essence the same may be true in postmyocardial infarction patients once the process of remodeling is completed, which is after about 1 month.28 Clinical studies of this problem are cumbersome because they require not only follow-up of left ventricular function but also repeated assessments of coronary anatomy by coronary arteriography. If ischemia, whether silent or symptomatic, causes myocardial necrosis, this can only occur if the episodes of ischemia are severe and the duration of ischemia is long enough. Silent ischemia may be more prone to cause myocardial damage than does symptomatic ischemia because of its characteristic lack of a warning mechanism. These assumptions, however, are purely hypothetical and require further investigation. Other potentially deleterious effects include induction and modulation of rhythm disturbances. This could be one of the mechanisms that may cause life-threatening arrhythmias and unexpected sudden death. The occurrence of mild rhythm disturbances in association with silent ischemia may be a warning sign, and, conversely, maintenance of normal sinus rhythm during episodes of marked ischemia may indicate a low risk. These aspects should be given particular consideration in the interpretation of Holter recordings and electrocardiographic exercise tests. In summary, the question whether silent ischemia requires treatment cannot be answered unconditionally but is subject to the severity and duration of the ischemic episodes and a variety of other factors. This, of course, relates mainly to patients who exhibit solely silent ischemia; the decisionmaking process is considerably less complicated in patients who also experience episodes of angina pectoris. If a decision is made to treat a patient with silent ischemia, the most direct approach is to eliminate the source of ischemia by surgical or catheter revascularization. There are no indications that the atherosclerotic changes of the coronary arteries in patients who have had a myocardial infarction are different in those who exhibit silent ischemia compared with those who do not, and, therefore, the same results of coronary revascularization may be anticipated. This is substantiated by the good results of percutaneous transluminal coronary angioplasty (PTCA) and coronary surgery in patients with silent ischemia.@ If the coronary obstructions are not amenable to revascularization or revascularization is not feasible or desirable for other reasons, then medical management should be considered. Nitrates may 22B
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
suppress evidence of silent ischemia41;in postinfarction patients isosorbide mononitrate was shown to be effective and well tolerated.42 Beta-blocking agents were shown to improve left ventricular function as assessed by radionuclide studies in patients with silent ischemia by Cohn and Lawson.” Willich et al” determined the effects of metoprolol on silent ischemia and platelet aggregability in patients with proven coronary artery disease; metoprolol decreased the number and duration of ischemic episodes, but the mechanism of action was not related to inhibition of platelet aggregation. Mahony45 showed in 6 patients with silent ischemia and documented coronary artery disease that aspirin decreased the number of episodes of myocardial ischemia. This finding suggests that platelet aggregation is one of the causative mechanisms in silent ischemia. Cohn et alM treated patients with combinations of drugs in the Nifedipine Total Ischemia Awareness Program study. Best results were seen after nifedipine was added to nitrates or @blocking agents in patients with either frequent or long episodes of silent ischemia. Mulcahy et a147found in patients with proven coronary artery disease that nifedipine, unlike atenolol, had little effect on either the frequency or total duration of ischemic episodes and did not alter the circadian distribution of ischemic episodes; the authors concluded that this finding is against the theory that ambulatory ischemia is mainly caused by alterations in coronary vasomotor tone. Frishman and Teicher48 found that diltiazem reduced the number of episodes of silent ischemia in patients with chronic stable angina, whereas combination therapy with nifedipine provided no further advantage. In our study the result of a single oral dose of diltiazem in patients with silent ischemia after myocardial infarction was impressive.” It is difficult to explain this result exclusively by a vasodilatory or afterload reducing effect, particularly since hemodynamic monitoring revealed no significant reduction of the double product. Redistribution of coronary flow with restoration of a normal epicardial-endocardial gradient as was demonstrated in an experimental model by Bathe and Dymek,49 may have played a role, or there may have been a direct calcium-entry blocking effect at the myocyte level. Further studies are required to determine whether treatment with diltiazem results in sustained relief of ischemic episodes and, eventually, to improvement of prognosis. MARCH 6, 1992
REFERENCES L Boden WE, Gibson RS, SchechtmanKB, Kleiger RE, Schwartz DJ, Capone RJ, Roberts R, Dihiazem Reinfarction Study Group. ST segment shii are pcor predictots of subsequentQ wave evolution in acute myocardial infarction. A natural history of early non-Q wave infarction. Circularion 1989;79537-548. 2. Amsterdam IS, Marts&&e R, Laslett IJ, Rutledge JC, Vera 2 Symptomatic and silent myocardial ischemia during exercise testing in coronary artery dii. Am J Can&l 19%,58343B46B. 2. Rijneke RD, Ascoop CA, Tahnon JL. CIinicaI signiicance of upSropingST segmentsin exercise electrocardiography.Circulation 1980,61:671-678. 4.DeBusk RF. Specialized testing after recent acute myocamial infarction. Ann h&m md 1989$10:47@481. 8. DeBwk RF, Kraemer HC, Nash E, Berger WE III, Lew H. Stepwise risk stratification soon after acute myocardial inkctim. Am J Cmn!h’ 1983;52:1161-
1166. 6. DeBusk RF, Blomqvist CG, Kouchoukcs NT, Luepker RV, Miher HS, Moss AJ, PoIkxk MI+ Reeves TJ, Selvester RI-I, Stason WB, Wagner GS, Wii VL Identification and treatment of low-risk patients after acute myocardial infarction and coronary-artery bypass graft surgery. N Ed J Med 1986,314:161-166. 7. Tzivoni D, Gavish A, Zin D, Gottlieb S, Moriel M, Rexen A, Banai S, Stern S. Prognosticsigahkance of ischemicepisodesin patients with previous myocardii infarction. Am J Canliol1988,62:661-664. 8. Fox JP, Beattie JM, &Iii MM, Davies MR, Littler WA, Murray MG. Silent ischemiafoUowing myocardii infarction: frequency, characteristicsand progno sis.Ew Heari J 1988,9(sup~lN):108-113. 8. Gottlieb SO, Gottheb SH, AchutI SC, Baumgardner R, Mellits ED, Weisfeldt ML, Gerstenbhth G. Silent ischemiaon Hoher monitoring predicts mortality in hi-risk postinfarction patients.JW 1988;259:1030-1035. 10. Weiner DA, Ryan TJ, McCabe CH, Luk S, Chaitman BR, Sheffield LT, Tristani F, Fisher LD. Significance of silent myocardial ischemia during exercise testing in patients with coronary artery disease.Am J Cardid 198759X25729. ll. Ouyang P, Chandra NC, Gottlieb SO. Frequency and importance of silent myocardial ischemia identitied with ambulatory electrocardiographic monitoring in the early in-hcepitai period after myocanhai infarction. Am J C&l 1990;65:267-270. 12 Ouyang P, Shapiro EP, Char&a NC, Gottlieb SH, Chew PH, Gottlieb SO. An angiographicand functional compariron of patientswith silent and symptomatic treadmiU ischemia early aher myocardial infarction. Am J Curdid 198739: 730-734. 18. M-ad KW, Grodecki JR, Dubiel JP, Curylo AM. Silent myocardiai ischemia in Holter monitoring and exercise stress testing alter a first myocardial infarction. EurHec~2 J 1988;9(supplN):llCllB. l4. De Feyter PJ, Van Eenige MJ, Diiton DH, Visser FC, De Jong J, Ram JP. Progncmicvalue of exercise testing, coronary angiographyand left ventriculography 6-8 weeks after myocardii infarction. Cim&ticn 1982;66:527-536. lS. Gibson RS, Watson DD, Craddock GB, Crampton RS, Raiser DL, Denny MJ, Belier GA Prediion of cardiac events after uncomplicated myocardii infarction: a prospective study comparing predkcharge exercise thallium-201 scintigraphy and coronaty angiography.Cinrulntin 1983;68:321-336. l8. Hung J, Goris ML, Nash E, Kraemer HC, DeBusk RF, Berger WE III, Lew H. Comparative value of maximaI treadmill testing, exercise thallium m-dial perfusion scintigraphy and exercise radionuclide ventriculogmphy for distinguishing high- and low-risk patients soon aI& acute myocardiai infarction. Am J Cardid 1984;53:1221-1227. 17. Marzotta G, Borrow RO, Pace L, Brittain E, Epstein SE. Relation between exertional ischemia and progntxis in mikily symptomatic patients with single or double vessel coronary artery dii and left ventrimlar dysfunction at rest. JAm Coil Cardid 1989;13:567-573. l8. The Multicenter Diltiazem P&infarction Trial Research Group. The effect of diItiazem on mortality and reinfarction after myocardial infarction. N E&J Med 1988;319:385-392. l9. Moss AJ, Oakes D, Benhorin J, Carleen E, Mu&enter Diltiaze.m PostInfarction Research Group. The interaction between dihiazem and left ventricular function after myocardial h&r&on. Cirnrlation 1989;8o:IV-RI?-IV-106. #). Gibson RS, Boden WE, Therow P, StraussHD, Pratt CM, Gheorghiade M, Capone RJ, Crawford MH, Schlant RC, Kleiger RE, Young PM Schechtman K, Penyman MB, Roberts R, the Diltiazem Reinfarction Group. Dihiazem and reinfarction in patients with non-Q-wave myocardiai infarction. N En.& J Med 1986;315:423-429. 2L Van der Wag EE, Manger Cats V, Blokland JAR, Bosker HA, Arndt JW, Pauwels EKJ, Brurchke AVG. The effects of dihiarem on cardiac function in silent ischemiaafter myocardial infarction. Am Heart J 1989,118:655-661.
22.The Muhicenter Postinfarction Research Group. Risk stratilication and N Engl J Med 1983m331-336. 22. Proudfit WI., Kramer JR, Bott-Siiverman C, Goormastic M. Survival of non-surgical patients with miId angina or myccanhal h&rction without angina BrHeatt J 1986;56:213-221. 24. Simoons ML, Serruys PW, Van den Brand M, Res J, Verheugt FWA, Krauss XH, Remme WJ, B& F, de Zwaan C, van der Laatse A, Vermeer F, L&en J. Early thmmbolysis in acute myocardial infarction: limitation of infarct size and improved survival.JAm Cull cardid 1986;7:717-728 25. Van der Laame A, Rerkhof PLM, Vermeer F, Serruys PW, Hermens WT, Verheugt FWA, Bar FW, Rrauas XI-I, Van der Wag EE, Siins ML Relation between infarct size and left ventticuIar performance amessedin patients with first acute myocardial infarcdon randomized to intracoronaty thrombolytic therapy or to conventional treatment.Am J C&Z 1988;61:1-7. 26. White HD, Norris RM, Bmwn MA, Brandt PWT, Whitlock RI& Wild CT. Left ventrictdar end-systolic volume as the major determinant of smvivaI after recovety from myocardial infarction. Cinr&ion 1987;76:44-51. 27. Baur LH, Schiirheyn JJ, Baan J, Van der Laarse A, Buis B, Van der WaU EE, Manger Cats V, Van Dijk AD, Blokland JA, Fr6Iich M, Bruschke AVG. Intluence of angiotensinconverting enzymeinhibition on pump function and cardiac contractihty in patients with chronic congestive heart failure. Br Heart J 1991;65:137-142. 28. Sharpe N, Smith I-I, WhaUey G, Murphy J, Greaves S, Gamble G. EarIy preventive treatment of left ventricular dysfunction following myocardial infaro tion (abstr). JAm Cdl Cur&d 1991;173115A 28. Hands ME, Lloyd BL, Robii JS, De KIerk N, Thompson PL. Pmgnostic signIIcance of electrocardiographic site of infarction atIer correction for enzymaticsire of infarction. Cirarlaabn 1986;73:885-891. 28. Bruschke AVG, Proudfit WL, SonesFM Jr. Progressstudy of 5% consecutive nonsurgicai cases of coronary disease followed 5-9 years II. VentricuIo graphic and other correlations. Circulation 1973;47:1154-1163. 2l. Weiner DA, Ryan TJ, McCabe CH, Ng G, Chaitman BR, Sheffield T, Tristani FE, Fisher LD. Risk of developing an acute m infarction or sudden coronary death in patients with exercise-induced silent myocardiai ischemia A report from the Coronary Artery Surgery Study (CASS) registry. survival after myocardial inkction.
Am J C&d
1988;621155-1158.
82 Nicod P, GiIpin E, D&rich H, Poiikar R, Hjahnamon A, Blacky AR, Hemring H, Ross JJ. Short- and long-term clinical outcome after Q-wave and non-Q-wave myocardiai infarction in a large patient population. Cinw/arifm 1989$?52&536. 22. Gibson RS, BeIIer GA, Gheorghiade M, Nygaard TW, Watson DD, Huey BL, Sayre SI, Raiser DL The prevalence and clinical significanceof residual myocardiai ischemia 2 weeks after uncomplicated non-Q-wave hrfarction: a prospectivenatural history study. Cbculanbn19%,73:118&11%. 81. Ferlinz J. Acute myuc&ial infarct& does the lack of Q waves help or hinder? JAm Cdl Cc& 19%;15:12t&l211. B& Hauer RNW, Lie RI, Liem KL, Durrer D. Long-term prognosisin patients with bundle branch block complicathrg acute anteroseptal infarction. Am J Cardid 1982;49:1581-1585.
a Fetch TH, Pieterson AH, Borggrefe M, Breithardt G. Clinicai indications for signal-averagedelectmmrdtographic analysis cw Alrery Lxv 1991;23341. 27. Malik M, Farrell T, Cripps T, Camm AJ. Heart rate variability in relation to prognosis after myocardial infarction: selection of optimai processingtechniques.Eur Hecur J 1989;10:106&1074. 28. Rossouw JE, Lewis B, Rifkind BM. The value of knvering cholesterol after myomrdU infarction. N Engl Jhfed 1990;323:1112-1119. 28. Viaser RF, Van Der Wed T, Ascoop CAPL, Btuschke AVG. The inlluence of anatomic ew~lution of oxonaty artery disease on leti ventticuIar contraction: an am&graphic follow-up study of 300 nonoperated patients.Am Heart J 1986;112%3-972. 48. Tuacu EM, Niianci Y, Simpfendorfer C, Domsti I& France I, Holhnan J, Whitlow P. Percutaneoustranshtminal coronary angioplasty in silent ischemia. Am Heat J 199ik119797-so1. 4l. Schnemeiss A, Marmor A. Transdermai nitroglycerin patches for silent myocardii ischemia during andanghmltreatment. Am J Cdid 1988,61:36E?38E. 42. Fen J, Feng XII, SchneeweissA. Efficacy of iscmrbide-5-mononitrate on painful and silent myocardiaI ischemia after myccudial infambm. Am J Cardid 199065z32J-35J. 42. Cohn PF, Lawson WE. Effects of long-actingpropranolol on A.M. and P.M. peak in silent lnyocardial ischemia.Am J Cardid 1989@872-873. 44. Willich SN, Pohjola-Sintonen S, Bhatia SJS, Shook THL, To8er GH, MuiIer JE, Curtis DG, WilIiams GH, Stone PH. Suppressionof silent ischemia A SYMPOSIUM:
MYOCARDIAL
ISCHEMIA
?BB
by metoprolol without alteration of morning increaseof platelet aggregabilityin patients with stable coronaq artety disease.Ce 1989;79:557-565. 46. Mahony CH. Effect of aspirin on myocardial ischemia. Am J Cam&i 1989;64:387-389. 46. Cohn PF, Vetrovec GW, Nest0 R, Gerber FR, the Total IschemiaAwareness Program Investigators. The Nifedipine+TotaI Ischemia Awarenes Program: a national survey of painful and painless myocxdial ischemia including results of antiischemictherapy.Am J Canlid 1989;63:534-539. 47. M&&y D, Conningham D, Crean P, Wright CH, Keegan J, Quyyumi 4 Park A, Fox K. Ciidii variation of total ischaemicburden and its alteration with antianginal agents.Lancer 1988$755-759. 48. Frishman WH, Teicher M. Antianginal drug therapy for silent myocardial ischemia./lm HecutJ 1987,114:14&147. 49. Bathe RJ, Dymek DJ. Effect of dltiazem on myocardial blood flow. Circulanbn 1982;65:1.19-1.26.
DISCUSSIDN
Question: Recently, it has been observed that administration of certain anti-ischemic agents to patients with symptomatic ischemia is associated with a great reduction in frequency and duration of ischemic episodes. However, there is no difference when it comes to silent ischemia. This raises the question: What are the differences between symptomatic and asymptomatic ischemia, if indeed there are any? Dr. Brusdmke: These data are exactly opposite what we found in our study, and I have no explanation for them. However, in some publications it is suggested that silent ischemia is an entity that should be treated differently from ischemia in general. I prefer to believe that ischemia is isch-
246
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
emia and that silent and symptomatic ischemias differ only in their manifestations. Question: In post-transplant patients, it has been found that ischemia is always silent. Yet, when examined on autopsy, it can be seen that these patients can have very serious infarction, and sudden death frequently occurs as a result of ischemia and infarction. Does this suggest to you that ischemia, whether silent or painful, is a very important factor to consider, or that detection of ST-segment depression on Holter monitoring does not provide sufficient information and that better ways of detecting ischemia should be developed? Dr. Brus&ke: Yes, but then it must be decided what it is we want to treat. Do we want to treat the ischemia or the underlying coronary artery disease? In this setting, ischemia is a powerful marker of the presence of coronary artery disease and the results achieved through interventions such as PTCA or surgery. However, I am not certain at all whether ischemia itself deserves treatment when it is painless in post-transplant patients because ischemia is essentially a symptom of a disease. If no arrhythmias are present when ischemia occurs, ischemia may have no other consequences than being a very powerful marker of underlying coronary disease that must be treated.
MARCH 6, 1992
MD,
Volkert Manger Cats,
6llentkchenl&aftermyocardal-has butshwldbe M-P-lnmpMedwlthlnthecontextofother~ kwlcstorr.The-fortherapcnrticmthkbased4inthe --of s2entkchemlaandthepobntHydeMdous cdlbctofrepeatedepkodesofkchemlaonthe lntegmyofthelef&-.we-redparametersoflscbmla In2Opathtswhoshowed ~lSCh@lW6T-Tcha~Oll~X-
testhgIntheemlyphaseaft8rmyocadMinfare tkn.AfterdWazemadmlnlstdion,aredudon Ofex-sT-TdeprewknRom 23 + OS to 0.7 f 0.6 mm (p < 0.01) occwrd, andr8@onalwahdlon scOreat8X~,dS -n@dw-amimmwY,knpnnr~ dgnlfkantly (p e 0.02). llwse and other observatlonswamJntfurtherstudleelnwhkhtheduratlon,severltyand eapKmcyofthelschemkeplsodesshou#bequanthdandcordabdwlth prognohaRermyocaHalinfwctbn. (AmJCadoll992~l9624B)
From the Department of Cardiology, University Hospital, Rijnsburgenveg, L.&den, The Netherlands. Address for reprints: Ernst E. Van der Wall, Department of Cardiology, University Hospital, Bldg 1, C5, Rijnsburgerweg 10, 2333 AA L.eiden, The Netherlands.
MD,
and Albert V.G. Bruschke,
MD
I
schemia following an episode of myocardial infarction, particularly if it is asymptomatic or silent, is more difficult to define and recognize than is ischemia in the chronic stages of coronary artery disease. In view of the variability that is commonly seen in the evolving myocardial infarction, particularly the accompanying electrocardiographic changes (e.g., ST-segment depression or elevation or evolution of Q-waves),’ it is not practical to use the term “silent ischemia” in the first days of myocardial infarction. On the other hand, after a certain period of time, the clinical picture becomes indistinguishable from that of chronic coronary artery disease. For a meaningful definition of postinfarction ischemia, it is, therefore, necessaryto define a time frame. In our studies we have chosen the period between days 4 and 31 after the acute event. Evidence of postinfarction ischemia encompassesa range of manifestations, from symptoms of early recurrent angina pectoris to a positive but “silent” stress test (that is, a stress test showing unequivocal evidence of ischemia in the absenceof angina pectoris or other symptoms; Table I). In the literature on silent myocardial ischemia, relatively little attention is given to the definition of electrocardiographic evidence of ischemia. Nevertheless, spontaneously occurring nonspecific electrocardiographic ST-T changes are relatively common after acute myocardial infarction and do not always indicate the presence of ischemia. Further, exercise tests using electrocardiographic criteria may be difficult to interpret in the presence of marked repolarization disturbances at rest. To be considered evidence of myocardial ischemia with acceptable accuracy, postinfarction electrocardiographic changes at Holter monitoring or exercise testing should fulfill criteria for ischemia that have proven to be sufficiently specific.” It has long been recognized that in risk stratitication after myocardial infarction, evidence of ischemia at exercise testing is one of the major indicators of the future occurrence of reinfarction and death. Indeed, for many years this has been the A SYMPOSIUM: MYOCARDIAL ISCHEMIA
188
TABLE
I Manifestation
of Postmyocardial
Infarction
lschemia
1. Spontaneous transient tischemic) ECG changes, including recurring or extending ST elevations 2. Early recurrent angina pectoris 3. Positive ECG exercise test 4. Positive isotope tests showing reversible perfusion defects or deterioration of left ventricular function during exercise ECG
DlLllAZEM FOR SLEM SCHEMA DIVEN EARLY AFRiR MYOCARDIAL INFARCTION
= electrocardiographic.
basis of strategies in the management of postinfarction patients.& More recently, emphasis has been placed on the prognostic significance of asymptomatic or silent myocardial ischemia. Various studies have demonstrated that silent ischemia following myocardial infarction-detected by Holter monitoring or electrocardiographic exercise testing,“14 or demonstrated at exercise testing by perfusion defects and increased lung uptake by thallium-201 scintigraphy,‘5s’6or seen as a decrease of global ejection fraction and the development of wall motion abnormalities using radionuclide angiogra-has prognostic implications similar to those PhY16,” following the occurrence of symptomatic ischemia. Manifestations of silent ischemia may be abolished by drugs commonly used to treat angina pectoris. After acute myocardial infarction, calcium antagonists, by virtue of their vasodilating and afterload reducing properties, appear to be a logical choice to treat ischemic episodes. This assumption is supported by the Multicenter Diltiazem Postinfarction Trial (MDPIT), which showed a reduction of postmyocardial infarction mortality in patients who had received diltiazem and had no left ventricular dysfunction, although an increase in mortality was noted in patients who had evidence of pulmonary congestion.18~‘g Diltiazem was also shown in the Diltiazem Reinfarction Study to be effective in preventing early reinfarction and severe angina after non-Q-wave infarction.20 How80 70
ever, in neither study were patients stratified according to the presence of residual or silent ischemia, and the effect of diltiazem on the occurrence of silent ischemia was not studied.
f@j control Diltiazem
To determine the efficacy and safety of administration of diltiazem early after myocardial infarction in patients with residual silent ischemia, we studied 20 postinfarction patients who showed > l-mm asymptomatic ST-T depression during exercise testing with radionuclide angiography.*’ The patients underwent repeated exerciseradionuelide angiography 2 days later, 2 hours after oral intake of 120 mg diltiazem. The double product was not significantly altered before or after diltiazem, both at rest and during exercise. Maximal ST-T depression after diltiazem was reduced from 2.3 + 0.8 to 0.7 + 0.6 mm (p < 0.01). Left ventricular ejection fraction at rest before diltiazem was 54.4 & 8.7% and after diltiazem 56.2 + 11.3% (difference not significant). During exercise, left ventricular ejection fraction improved after diltiazem from 43.2 f 12.2% to 49.8 f 10.5% (p ~0.05) (Figure 1). Regional wall motion score (1 = normal, 4 = dyskinetic, x3 segments) at rest before diltiazem was 9.6 2 2.0 and after diltiazem 9.1 rt 1.8 (difference not significant). During exercise, regional wall motion score improved after diltiazem from 5.8 & 1.3 to 4.3 & 1.1 (p < 0.02). In conclusion, the study showed diltiazem to have beneficial effects on electrocardiographic ST-T depression and on both global and regional left ventricular function in postinfarction patients with silent myocardial ischemia.
l p < 0.05 T
60 3
50
LL ?i
40 30 20 10 0
202
THE AMERICAN
Rest JOURNAL
OF CARDIOLOGY
Exercise VOLUME
69
MARCH
6, 1992
SllENf ISCREMIA AS A MARKER OF PROWOSS AFfER MYOCARDW. INFARCTION Silent &hernia has proven to be a valuable predictor of the occurrence of cardiac events following acute myocardial infarction. However, it is just one parameter in a series of factors that are known to be of prognostic significance (Table II). Among these, the size of infarction, that is, the amount of myocardial tissue loss, appears to have the highest predictive power in both the acute and the chronic Therefore, treatment of acute myocarstages.4*22-25 dial infarction is primarily directed toward reduction of infarct size by early reperfusion.24225Loss of pump function is dependent, to a large extent, on infarct size but is also subject to other mechanisms such as postinfarction “remodeling” of the left ventricle.%% Infarct localization also has partly independent prognostic significance.29 After myocardial infarction, coronary anatomy appears to have less predictive value than the left ventricular angiogram. However, in the early 1970s it had already been demonstrated that the predictive power of the combination of left ventricular and coronary angiograms was greater than the predictive power of either one alone or in combination with clinical data.30 In a more recent study Proudfit et al= showed that in patients with previous myocardial infarction without subsequent angina, similar to group C of the Coronary Artery Surgery Study (CASS), prognosis was related to impairment of left ventricular function and extent of coronary artery disease. Weiner et ak31using the CASS registry data, showed that within the subset of patients with silent ischemia the coronary arteriogram retained significant prognostic power. Since >50% of their patients had prior myocardial infarction, these findings are also valid for postinfarction patients. Electrocardiographic markers of prognosis relate to QRS morphology and cardiac rhythm. The prognosis after Q-wave infarction appears to be different from that after non-Q-wave infarction, although the differences are in part dependent on age and previous myocardial infarction.32-34Bundle branch block complicating acute myocardial infarction adds to the postmyocardial infarction risk, particularly in the period shortly after the acute event.35 Developments in signal-averaging techniques (high-resolution electrocardiogram) have made it possible to record and identify late potentials, which are markers for propensity to ventricular arrhythmias. Therefore, late potentials merit a place in risk stratification after myocardial infarction.36 Recently, in experimental and clinical stud-
TABLE II Infarction
Prognostic
Indicators
After Acute
Myocardial
1. 2. 3. 4. 5. 6.
Size of infarction Localization of infarction Residual pump function Coronary artery obstructions Myocardial ischemia (silent or symptomatic) Electrocardiographic a. Changes of QRS complex Q-waves lntraventricular conduction disturbances Late potentials b. Rhythm disturbances Ventricular tachycardia and ventricular fibrillation Premature ventricular contractions Supraventricular rhythm disturbances Heart rate variability 7. Risk factors (hypertension, hyperlipidemia, diabetes mellitus, smoking, etc.)
ies, attention has also been focused on the prognos, tic significance of heart rate variability, in particular after myocardial infarction.37 Commonly recognized risk factors for the development of coronary atherosclerosis, such as hypercholesterolemia, also appear to have an influence on the prognosis of postinfarction patients, although their importance in secondary prevention is less marked than it is in primary prevention.38 Therefore, in our opinion the prognostic significance of postinfarction ischemia, whether silent or symptomatic, should be interpreted within the context of the entire risk profile of the individual patient to achieve an optimal risk stratification. Using the presence or absence of silent myocardial ischemia as the sole or major determinant of prognosis should be avoided, particularly in patients who have a history of acute myocardial infarction. TREATMENT OF POSllNFARCTiON SILENT ISCHEMIA The rationale for treatment of silent myocardial ischemia rests on two considerations: the prognostic significance of ischemia and the possibility that silent ischemia itself may exert harmful effects. It has been postulated (but not yet proven) that episodes of ischemia may cause microscopic myocardial necrosis and that repeated episodes may eventually lead to deterioration of left ventricular function. It is difficult to assess the potentially deleterious effect of episodes of ischemia in postinfarction patients because these patients are also prone to have progression of coronary artery disease. In an angiographic follow-up study including 300 patients with mainly stable coronary artery disease, Visser et a139observed deterioration of left ventricular contractions only in patients who had A SYMPOSIUM:
MYOCARDIAL
ISCHEMIA
21B
severe progression of their coronary artery obstructions. In essence the same may be true in postmyocardial infarction patients once the process of remodeling is completed, which is after about 1 month.28 Clinical studies of this problem are cumbersome because they require not only follow-up of left ventricular function but also repeated assessments of coronary anatomy by coronary arteriography. If ischemia, whether silent or symptomatic, causes myocardial necrosis, this can only occur if the episodes of ischemia are severe and the duration of ischemia is long enough. Silent ischemia may be more prone to cause myocardial damage than does symptomatic ischemia because of its characteristic lack of a warning mechanism. These assumptions, however, are purely hypothetical and require further investigation. Other potentially deleterious effects include induction and modulation of rhythm disturbances. This could be one of the mechanisms that may cause life-threatening arrhythmias and unexpected sudden death. The occurrence of mild rhythm disturbances in association with silent ischemia may be a warning sign, and, conversely, maintenance of normal sinus rhythm during episodes of marked ischemia may indicate a low risk. These aspects should be given particular consideration in the interpretation of Holter recordings and electrocardiographic exercise tests. In summary, the question whether silent ischemia requires treatment cannot be answered unconditionally but is subject to the severity and duration of the ischemic episodes and a variety of other factors. This, of course, relates mainly to patients who exhibit solely silent ischemia; the decisionmaking process is considerably less complicated in patients who also experience episodes of angina pectoris. If a decision is made to treat a patient with silent ischemia, the most direct approach is to eliminate the source of ischemia by surgical or catheter revascularization. There are no indications that the atherosclerotic changes of the coronary arteries in patients who have had a myocardial infarction are different in those who exhibit silent ischemia compared with those who do not, and, therefore, the same results of coronary revascularization may be anticipated. This is substantiated by the good results of percutaneous transluminal coronary angioplasty (PTCA) and coronary surgery in patients with silent ischemia.@ If the coronary obstructions are not amenable to revascularization or revascularization is not feasible or desirable for other reasons, then medical management should be considered. Nitrates may 22B
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
suppress evidence of silent ischemia41;in postinfarction patients isosorbide mononitrate was shown to be effective and well tolerated.42 Beta-blocking agents were shown to improve left ventricular function as assessed by radionuclide studies in patients with silent ischemia by Cohn and Lawson.” Willich et al” determined the effects of metoprolol on silent ischemia and platelet aggregability in patients with proven coronary artery disease; metoprolol decreased the number and duration of ischemic episodes, but the mechanism of action was not related to inhibition of platelet aggregation. Mahony45 showed in 6 patients with silent ischemia and documented coronary artery disease that aspirin decreased the number of episodes of myocardial ischemia. This finding suggests that platelet aggregation is one of the causative mechanisms in silent ischemia. Cohn et alM treated patients with combinations of drugs in the Nifedipine Total Ischemia Awareness Program study. Best results were seen after nifedipine was added to nitrates or @blocking agents in patients with either frequent or long episodes of silent ischemia. Mulcahy et a147found in patients with proven coronary artery disease that nifedipine, unlike atenolol, had little effect on either the frequency or total duration of ischemic episodes and did not alter the circadian distribution of ischemic episodes; the authors concluded that this finding is against the theory that ambulatory ischemia is mainly caused by alterations in coronary vasomotor tone. Frishman and Teicher48 found that diltiazem reduced the number of episodes of silent ischemia in patients with chronic stable angina, whereas combination therapy with nifedipine provided no further advantage. In our study the result of a single oral dose of diltiazem in patients with silent ischemia after myocardial infarction was impressive.” It is difficult to explain this result exclusively by a vasodilatory or afterload reducing effect, particularly since hemodynamic monitoring revealed no significant reduction of the double product. Redistribution of coronary flow with restoration of a normal epicardial-endocardial gradient as was demonstrated in an experimental model by Bathe and Dymek,49 may have played a role, or there may have been a direct calcium-entry blocking effect at the myocyte level. Further studies are required to determine whether treatment with diltiazem results in sustained relief of ischemic episodes and, eventually, to improvement of prognosis. MARCH 6, 1992
REFERENCES L Boden WE, Gibson RS, SchechtmanKB, Kleiger RE, Schwartz DJ, Capone RJ, Roberts R, Dihiazem Reinfarction Study Group. ST segment shii are pcor predictots of subsequentQ wave evolution in acute myocardial infarction. A natural history of early non-Q wave infarction. Circularion 1989;79537-548. 2. Amsterdam IS, Marts&&e R, Laslett IJ, Rutledge JC, Vera 2 Symptomatic and silent myocardial ischemia during exercise testing in coronary artery dii. Am J Can&l 19%,58343B46B. 2. Rijneke RD, Ascoop CA, Tahnon JL. CIinicaI signiicance of upSropingST segmentsin exercise electrocardiography.Circulation 1980,61:671-678. 4.DeBusk RF. Specialized testing after recent acute myocamial infarction. Ann h&m md 1989$10:47@481. 8. DeBwk RF, Kraemer HC, Nash E, Berger WE III, Lew H. Stepwise risk stratification soon after acute myocardial inkctim. Am J Cmn!h’ 1983;52:1161-
1166. 6. DeBusk RF, Blomqvist CG, Kouchoukcs NT, Luepker RV, Miher HS, Moss AJ, PoIkxk MI+ Reeves TJ, Selvester RI-I, Stason WB, Wagner GS, Wii VL Identification and treatment of low-risk patients after acute myocardial infarction and coronary-artery bypass graft surgery. N Ed J Med 1986,314:161-166. 7. Tzivoni D, Gavish A, Zin D, Gottlieb S, Moriel M, Rexen A, Banai S, Stern S. Prognosticsigahkance of ischemicepisodesin patients with previous myocardii infarction. Am J Canliol1988,62:661-664. 8. Fox JP, Beattie JM, &Iii MM, Davies MR, Littler WA, Murray MG. Silent ischemiafoUowing myocardii infarction: frequency, characteristicsand progno sis.Ew Heari J 1988,9(sup~lN):108-113. 8. Gottlieb SO, Gottheb SH, AchutI SC, Baumgardner R, Mellits ED, Weisfeldt ML, Gerstenbhth G. Silent ischemiaon Hoher monitoring predicts mortality in hi-risk postinfarction patients.JW 1988;259:1030-1035. 10. Weiner DA, Ryan TJ, McCabe CH, Luk S, Chaitman BR, Sheffield LT, Tristani F, Fisher LD. Significance of silent myocardial ischemia during exercise testing in patients with coronary artery disease.Am J Cardid 198759X25729. ll. Ouyang P, Chandra NC, Gottlieb SO. Frequency and importance of silent myocardial ischemia identitied with ambulatory electrocardiographic monitoring in the early in-hcepitai period after myocanhai infarction. Am J C&l 1990;65:267-270. 12 Ouyang P, Shapiro EP, Char&a NC, Gottlieb SH, Chew PH, Gottlieb SO. An angiographicand functional compariron of patientswith silent and symptomatic treadmiU ischemia early aher myocardial infarction. Am J Curdid 198739: 730-734. 18. M-ad KW, Grodecki JR, Dubiel JP, Curylo AM. Silent myocardiai ischemia in Holter monitoring and exercise stress testing alter a first myocardial infarction. EurHec~2 J 1988;9(supplN):llCllB. l4. De Feyter PJ, Van Eenige MJ, Diiton DH, Visser FC, De Jong J, Ram JP. Progncmicvalue of exercise testing, coronary angiographyand left ventriculography 6-8 weeks after myocardii infarction. Cim&ticn 1982;66:527-536. lS. Gibson RS, Watson DD, Craddock GB, Crampton RS, Raiser DL, Denny MJ, Belier GA Prediion of cardiac events after uncomplicated myocardii infarction: a prospective study comparing predkcharge exercise thallium-201 scintigraphy and coronaty angiography.Cinrulntin 1983;68:321-336. l8. Hung J, Goris ML, Nash E, Kraemer HC, DeBusk RF, Berger WE III, Lew H. Comparative value of maximaI treadmill testing, exercise thallium m-dial perfusion scintigraphy and exercise radionuclide ventriculogmphy for distinguishing high- and low-risk patients soon aI& acute myocardiai infarction. Am J Cardid 1984;53:1221-1227. 17. Marzotta G, Borrow RO, Pace L, Brittain E, Epstein SE. Relation between exertional ischemia and progntxis in mikily symptomatic patients with single or double vessel coronary artery dii and left ventrimlar dysfunction at rest. JAm Coil Cardid 1989;13:567-573. l8. The Multicenter Diltiazem P&infarction Trial Research Group. The effect of diItiazem on mortality and reinfarction after myocardial infarction. N E&J Med 1988;319:385-392. l9. Moss AJ, Oakes D, Benhorin J, Carleen E, Mu&enter Diltiaze.m PostInfarction Research Group. The interaction between dihiazem and left ventricular function after myocardial h&r&on. Cirnrlation 1989;8o:IV-RI?-IV-106. #). Gibson RS, Boden WE, Therow P, StraussHD, Pratt CM, Gheorghiade M, Capone RJ, Crawford MH, Schlant RC, Kleiger RE, Young PM Schechtman K, Penyman MB, Roberts R, the Diltiazem Reinfarction Group. Dihiazem and reinfarction in patients with non-Q-wave myocardiai infarction. N En.& J Med 1986;315:423-429. 2L Van der Wag EE, Manger Cats V, Blokland JAR, Bosker HA, Arndt JW, Pauwels EKJ, Brurchke AVG. The effects of dihiarem on cardiac function in silent ischemiaafter myocardial infarction. Am Heart J 1989,118:655-661.
22.The Muhicenter Postinfarction Research Group. Risk stratilication and N Engl J Med 1983m331-336. 22. Proudfit WI., Kramer JR, Bott-Siiverman C, Goormastic M. Survival of non-surgical patients with miId angina or myccanhal h&rction without angina BrHeatt J 1986;56:213-221. 24. Simoons ML, Serruys PW, Van den Brand M, Res J, Verheugt FWA, Krauss XH, Remme WJ, B& F, de Zwaan C, van der Laatse A, Vermeer F, L&en J. Early thmmbolysis in acute myocardial infarction: limitation of infarct size and improved survival.JAm Cull cardid 1986;7:717-728 25. Van der Laame A, Rerkhof PLM, Vermeer F, Serruys PW, Hermens WT, Verheugt FWA, Bar FW, Rrauas XI-I, Van der Wag EE, Siins ML Relation between infarct size and left ventticuIar performance amessedin patients with first acute myocardial infarcdon randomized to intracoronaty thrombolytic therapy or to conventional treatment.Am J C&Z 1988;61:1-7. 26. White HD, Norris RM, Bmwn MA, Brandt PWT, Whitlock RI& Wild CT. Left ventrictdar end-systolic volume as the major determinant of smvivaI after recovety from myocardial infarction. Cinr&ion 1987;76:44-51. 27. Baur LH, Schiirheyn JJ, Baan J, Van der Laarse A, Buis B, Van der WaU EE, Manger Cats V, Van Dijk AD, Blokland JA, Fr6Iich M, Bruschke AVG. Intluence of angiotensinconverting enzymeinhibition on pump function and cardiac contractihty in patients with chronic congestive heart failure. Br Heart J 1991;65:137-142. 28. Sharpe N, Smith I-I, WhaUey G, Murphy J, Greaves S, Gamble G. EarIy preventive treatment of left ventricular dysfunction following myocardial infaro tion (abstr). JAm Cdl Cur&d 1991;173115A 28. Hands ME, Lloyd BL, Robii JS, De KIerk N, Thompson PL. Pmgnostic signIIcance of electrocardiographic site of infarction atIer correction for enzymaticsire of infarction. Cirarlaabn 1986;73:885-891. 28. Bruschke AVG, Proudfit WL, SonesFM Jr. Progressstudy of 5% consecutive nonsurgicai cases of coronary disease followed 5-9 years II. VentricuIo graphic and other correlations. Circulation 1973;47:1154-1163. 2l. Weiner DA, Ryan TJ, McCabe CH, Ng G, Chaitman BR, Sheffield T, Tristani FE, Fisher LD. Risk of developing an acute m infarction or sudden coronary death in patients with exercise-induced silent myocardiai ischemia A report from the Coronary Artery Surgery Study (CASS) registry. survival after myocardial inkction.
Am J C&d
1988;621155-1158.
82 Nicod P, GiIpin E, D&rich H, Poiikar R, Hjahnamon A, Blacky AR, Hemring H, Ross JJ. Short- and long-term clinical outcome after Q-wave and non-Q-wave myocardiai infarction in a large patient population. Cinw/arifm 1989$?52&536. 22. Gibson RS, BeIIer GA, Gheorghiade M, Nygaard TW, Watson DD, Huey BL, Sayre SI, Raiser DL The prevalence and clinical significanceof residual myocardiai ischemia 2 weeks after uncomplicated non-Q-wave hrfarction: a prospectivenatural history study. Cbculanbn19%,73:118&11%. 81. Ferlinz J. Acute myuc&ial infarct& does the lack of Q waves help or hinder? JAm Cdl Cc& 19%;15:12t&l211. B& Hauer RNW, Lie RI, Liem KL, Durrer D. Long-term prognosisin patients with bundle branch block complicathrg acute anteroseptal infarction. Am J Cardid 1982;49:1581-1585.
a Fetch TH, Pieterson AH, Borggrefe M, Breithardt G. Clinicai indications for signal-averagedelectmmrdtographic analysis cw Alrery Lxv 1991;23341. 27. Malik M, Farrell T, Cripps T, Camm AJ. Heart rate variability in relation to prognosis after myocardial infarction: selection of optimai processingtechniques.Eur Hecur J 1989;10:106&1074. 28. Rossouw JE, Lewis B, Rifkind BM. The value of knvering cholesterol after myomrdU infarction. N Engl Jhfed 1990;323:1112-1119. 28. Viaser RF, Van Der Wed T, Ascoop CAPL, Btuschke AVG. The inlluence of anatomic ew~lution of oxonaty artery disease on leti ventticuIar contraction: an am&graphic follow-up study of 300 nonoperated patients.Am Heart J 1986;112%3-972. 48. Tuacu EM, Niianci Y, Simpfendorfer C, Domsti I& France I, Holhnan J, Whitlow P. Percutaneoustranshtminal coronary angioplasty in silent ischemia. Am Heat J 199ik119797-so1. 4l. Schnemeiss A, Marmor A. Transdermai nitroglycerin patches for silent myocardii ischemia during andanghmltreatment. Am J Cdid 1988,61:36E?38E. 42. Fen J, Feng XII, SchneeweissA. Efficacy of iscmrbide-5-mononitrate on painful and silent myocardiaI ischemia after myccudial infambm. Am J Cardid 199065z32J-35J. 42. Cohn PF, Lawson WE. Effects of long-actingpropranolol on A.M. and P.M. peak in silent lnyocardial ischemia.Am J Cardid 1989@872-873. 44. Willich SN, Pohjola-Sintonen S, Bhatia SJS, Shook THL, To8er GH, MuiIer JE, Curtis DG, WilIiams GH, Stone PH. Suppressionof silent ischemia A SYMPOSIUM:
MYOCARDIAL
ISCHEMIA
?BB
by metoprolol without alteration of morning increaseof platelet aggregabilityin patients with stable coronaq artety disease.Ce 1989;79:557-565. 46. Mahony CH. Effect of aspirin on myocardial ischemia. Am J Cam&i 1989;64:387-389. 46. Cohn PF, Vetrovec GW, Nest0 R, Gerber FR, the Total IschemiaAwareness Program Investigators. The Nifedipine+TotaI Ischemia Awarenes Program: a national survey of painful and painless myocxdial ischemia including results of antiischemictherapy.Am J Canlid 1989;63:534-539. 47. M&&y D, Conningham D, Crean P, Wright CH, Keegan J, Quyyumi 4 Park A, Fox K. Ciidii variation of total ischaemicburden and its alteration with antianginal agents.Lancer 1988$755-759. 48. Frishman WH, Teicher M. Antianginal drug therapy for silent myocardial ischemia./lm HecutJ 1987,114:14&147. 49. Bathe RJ, Dymek DJ. Effect of dltiazem on myocardial blood flow. Circulanbn 1982;65:1.19-1.26.
DISCUSSIDN
Question: Recently, it has been observed that administration of certain anti-ischemic agents to patients with symptomatic ischemia is associated with a great reduction in frequency and duration of ischemic episodes. However, there is no difference when it comes to silent ischemia. This raises the question: What are the differences between symptomatic and asymptomatic ischemia, if indeed there are any? Dr. Brusdmke: These data are exactly opposite what we found in our study, and I have no explanation for them. However, in some publications it is suggested that silent ischemia is an entity that should be treated differently from ischemia in general. I prefer to believe that ischemia is isch-
246
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
emia and that silent and symptomatic ischemias differ only in their manifestations. Question: In post-transplant patients, it has been found that ischemia is always silent. Yet, when examined on autopsy, it can be seen that these patients can have very serious infarction, and sudden death frequently occurs as a result of ischemia and infarction. Does this suggest to you that ischemia, whether silent or painful, is a very important factor to consider, or that detection of ST-segment depression on Holter monitoring does not provide sufficient information and that better ways of detecting ischemia should be developed? Dr. Brus&ke: Yes, but then it must be decided what it is we want to treat. Do we want to treat the ischemia or the underlying coronary artery disease? In this setting, ischemia is a powerful marker of the presence of coronary artery disease and the results achieved through interventions such as PTCA or surgery. However, I am not certain at all whether ischemia itself deserves treatment when it is painless in post-transplant patients because ischemia is essentially a symptom of a disease. If no arrhythmias are present when ischemia occurs, ischemia may have no other consequences than being a very powerful marker of underlying coronary disease that must be treated.
MARCH 6, 1992
