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Silent myocardial ischemia
Silent Myocardial .Ischemia Mechanisms and Rationale for Therapy GLEN
J.
KOWALCHUK,
M.D., RICHARD W. NESTO, M.D. Boston,
Massachusetts
The widespread use of Holter monitoring has demonstrated that the majority of ischemic episodes occur during activities that do not require exertion. These episodes tend to occur at only minimal increases in heart rate above resting levels, well below the level of myocardial oxygen demand required to produce ischemia on formal exercise tolerance testing. In all likelihood, therefore, most ischemic events in ambulatory patients are due to a combination of flow-limiting coronary stenosis and superimposed vasoactive or thrombotic elements. Asymptomatic ischemic events are common in subsets of patients with angina pectoris. Traditionally, treatment with calcium channel blockers, beta-blockers, and long-acting nitrates has been aimed at reducing episodes of angina pectoris. Despite a reduction in angina1 symptoms, however, it is likely that patients continue to experience silent ischemia, particularly at rest and during activities of daily living. The strategy for treatment in such patients should include the abolition of the patients’ “total ischemic activity.” It is conceivable that more aggressive anti-ischemic therapy may improve prognosis, as patients with ambulatory ST-segment depression experience frequent cardiac events. Other potential benefits of more aggressive treatment include the prevention of myocardial hibernation, which occurs as a result of a chronic ischemic state, and a reduction in episodes of myocardial stunning. This approach may lead to protection against transient and chronic left ventricular dysfunction, which is associated with a poor prognosis in patients with symptomatic coronary artery disease.
From the Department of Medlclne. Cardiology Secbon, Harvard Medical School, and the New England Deaconess Hospital, Boston, Massachusetts. Requests for reprints should be addressed to Dr. Richard W. Nesto, New England Deaconess Hospital, 185 Pllgrlm Road, Boston, Massachusetts 02115.
reatment of coronary artery disease has been T based primarily on relief of symptoms. Recent evidence, however, has demonstrated that most ischemic episodes in patients with symptomatic coronary artery disease are painless [1,2]. The importance of these findings is underscored by the fact that 20 to 25 percent of myocardial infarctions may occur without angina [3,4]. Furthermore, a change in angina1 pattern may not precede myocardial infarction in patients who do experience chest pain.
PAINFULVERSUSPAINLESSISCHEMICEVENTS Several hypotheses have been proposed to explain why certain ischemic episodes lead to angina, whereas others do not. Myocardial ischemia results from an imbalance between myocardial oxygen supply and demand. The onset of this imbalance is followed by a sequence of pathophysiologic events that culminates in the subjective appreciation of ischemia-angina pectoris [5]. A series of subclinical metabolic, mechanical, and electrocardiographic abnormalities occurs before ischemia is clinically recognized [6]. Furthermore, a given episode of myocardial ischemia may resolve before reaching the angina1 threshold, leaving ischemia undetected. Hill and Pepine [7] have referred to the time delay between the initiation of supply/demand imbalance and its clinical recognition as the “ischemic gap.” Viewed in this light, all episodes of ischemia can be considered to have a silent phase. Other factors acting alone or in concert have been proposed to account for variation in the perception of angina among individual patients and among individual ischemic events. In one theory involving alterations in neural pathways, it is suggested that the afferent sympathetic nerve fibers responsible for pain conduction from the heart are either impaired or damaged [81. Proponents of this argument cite the higher incidence of asymptomatic ischemia in patients who may suffer de-enervation of the autonomic nervous system, for example, many diabetic patients [g-111. A second theory holds that patients who experience silent myocardial ischemia exhibit hyposensibility to painful stimuli [12]. Independent studies have indicated that patients with asymptomatic coronary artery disease tend to have a higher pain threshold and a higher pain tolerance than patients with symptomatic ischemia [ 13,141. Recent investigations have suggested that endorphins may play a role in the mechanism responsible for this difference [15,16]. A third theory proposes that the mass of myocardium at jeopardy during silent ischemia is quantitatively less than that at risk during symptomatic events. Unfortunately, when the extent and severity of ischemia have been analyzed, a considerable overlap has been found between symptomatic and asymptomatic patients; thus, firm conclusions cannot be drawn [17-191. January 16. 1989
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PROGNOSTIC SIGNIFICANCE OF ASYMF’TOMATIC ISCHEMIA Although the cause of asymptomatic ischemic events has not been clearly defined, the detection of such episodes has been shown to have prognostic significance. Indeed, in one study, angina, myocardial infarction, or death developed within five years in 24 percent of men who were found to have asymptomatic coronary disease [20]. Longer follow-up has demonstrated a 42 percent incidence of cardiac events by eight to ten years [21]. Patients with stable angina who experience asymptomatic ST-segment depression detected on ambulatory Holter monitoring are noted to have an increased frequency of cardiac death, myocardial infarction, and need for revascularization over the ensuing nine months [22]. This observation has been extended to post-myocardial infarction patients, among whom silent ischemia on Holter monitoring has been correlated with an incidence of cardiac events in 51 percent of patients over a 2%month follow-up period, a value that is four times greater than that noted among persons without such a finding [23]. Perhaps the most ominous prognostic data gathered from studies in which silent ischemia has been monitored involve patients presenting with unstable angina. In this situation, asymptomatic ischemia has been associated with an incidence of myocardial infarction that is six times greater over the subsequent month and thus serves as a powerful predictor of the need for coronary revascularization [241. PATHOPHYSIOLOGY OF ASYMPTOMATIC ISCHEMIA Observations of episodes of asymptomatic ischemia may offer insights into their pathophysiology and adverse prognosis, but may also afford insights into possible means of treatment. The major diagnostic and prognostic tool used in the evaluation of patients with coronary artery disease has been the exercise treadmill. Through graded increases in cardiac workloads, exercise testing has provided a reproducible method of inducing demand-related myocardial ischemia. Ambulatory Holter monitoring has revealed that most silent ischemic events occur during usual daily activity at times when heart rate is not significantly elevated [1,2,25]. This suggests that the predominant mechanism of asymptomatic ischemia is a decrease in myocardial oxygen supply rather than an increase in oxygen demand. Further evidence supporting a primary decrease in coronary blood flow has come from studies in which painless myocardial perfusion abnormalities were noted during cigarette smoking, mental stress, and exposure to cold [26-281. It is too simplistic to postulate that painful ischemia results only from demand-related states and that painless ischemia results primarily from flow-related mechanisms. Ischemia cannot be considered as purely a demand- or a flow-related phenomenon, but rather should be thought of as a flow-limiting fixed disease combined with superimposed vasoconstrictive or thrombotic elements. To understand how these two processes are interrelated, a re-examination of myocardial supply/demand imbalance is necessary. In patients with coronary artery disease, the mechanisms thought to be primarily responsible for myocardial ischemia have involved the concept of a fixed coronary flow reserve. According to this concept, patients with 10
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coronary stenosis have a flow reserve that, though reduced, allows for adequate myocardial perfusion as long as metabolic demands are not exceeded; only when oxygen demand exceeds coronary reserve capabilities does ischemia develop. Although this concept provides an adequate explanation for demand-related myocardial ischemia, it does not address episodes of ischemia that occur with low heart rate/blood pressure products. The realization that coronary flow may change in response to a variety of physical, metabolic, and pharmacologic stimuli has necessitated a modification of this scheme [29-311. Maseri [32] has postulated that coronary flow reserve may be both reduced and variable. Changes in coronary resistance at the site of a fixed stenosis may thus produce dramatic reductions in myocardial blood flow that result in ischemia at times when oxygen demand is low. This concept allows an explanation for ischemia occurring during high-oxygen-demand states, such as exercise, and during low-oxygen-demand states, as has been demonstrated during asymptomatic ischemia detected with ambulatory Holter monitoring. Proof of the dynamic nature of coronary stenoses has been provided in the work by Brown et al [331. Using sophisticated angiographic methods, these investigators demonstrated a 35 percent change in the luminal area of stenotic vessels during isometric exercise and nitroglycerin treatment, resulting in even more dramatic changes in trans-stenotic coronary resistance. This variation in lesion reactivity may vary among individual patients and among individual coronary lesions. Changes in stenosis size and vessel resistance are therefore not limited to patients with classic spasm but are typical of the majority of all coronary stenoses [341. TREATMENT OF MYOCARDIAL ISCHEMIA These findings present concerns that must be addressed in considering the treatment of all episodes of myocardial ischemia, including the treatment of silent ischemia. Agents that reduce ischemia by reducing myocardial oxygen consumption may not be fully effective in eliminating all ischemic events. First, as noted previously, the majority of episodes of asymptomatic ischemia occur with low heart rate/blood pressure products. The ideal anti-ischemic medication should be able to eliminate angina and these silent episodes by improving coronary arterial perfusion. Second, a circadian clustering of ischemic episodes has been noted, with the majority of events occurring during the early morning hours after awakening [351. Thus, the traditional dosing regimen of anti-angina1 therapy can leave patients unprotected during the peak incidence of ischemic activity at a time when there is a trough level of anti-angina1 activity. Third, there is little correlation between the severity of a patient’s symptoms and the severity of underlying coronary artery disease [36]. Moreover, in persons with stable angina, there are few data to suggest that improvement in angina1 class or exercise treadmill duration can result in an improvement in survival. Therefore, conventional medical treatment of coronary artery disease aimed at the control of angina1 symptoms should be re-evaluated. Perhaps therapy directed toward the elimination of all ischemic activity, both silent and symptomatic, is warranted.
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Previous investigations have demonstrated that such an end point is possible. By prescribing antiangina1 medication at higher doses it may be possible to produce a further reduction in ischemlc activity and abolish silent as well as symptomatic events. An example of such an effect was reported by Dargie et al [37] in their study of 16 patients with stable angina pectoris and positive exercise test results. After a two-week run-in period receiving placebo, patients were randomly assigned to receive nifedipine 30 or 60 mg per day, propranolol240 or 480 mg per day, or the combination of nifedipine and propranolol, 30 mg per day with 240 mg per day or 60 mg per day with 480 mg per day, respectively, in single-blind fashion. Both the frequency of angina and the number of nitroglycerin tablets consumed per day were reduced significantly by each active drug compared with placebo. The combination of high doses of both propranolol and nifedipine produced an even larger percentage reduction than did either drug alone in the number of STsegment depressions detected by ambulatory electrocardiographic monitoring. In this study [37], aggressive medical management of ischemic heart disease beyond that needed to control patients’ symptomatic states produced a further decrease in total ischemic activity. In light of the concerns surrounding abnormalities in vessel tone and coronary flow in the majority of patients with “fixed” coronary disease, it would appear that agents that improve myocardial blood flow are particularly well suited as anti-angina1 medication. Calcium antagonists constitute one class of medications that have been useful in the treatment of both flow- and demand-related ischemic events. These agents have been shown to decrease myocardial vascular resistance, increase coronary collateral flow, and decrease myocardial oxygen consumption [38,391. In clinical situations in which marked variations in coronary vascular tone predominate, such as vasospastic angina, calcium antagonists have been effective antiangina1 agents [40-421. Nesto et al [43] studied the effect of nifedipine on ischemia as measured by exercise testing and ambulatory Holter monitoring. In a double-blind, randomized, crossover trial, nifedipine was compared with placebo in 10 patients with angiographically documented coronary disease and positive treadmill test results. Patients underwent a baseline exercise tolerance test and 4%hour Holter monitoring, after which they were randomly assigned to receive either nifedipine or placebo. A one-week titration phase was followed by one week of maintained therapy. Repeat exercise tolerance testing and 4%hour Holter monitoring were performed at the end of the first treatment period, after which patients were crossed over to the other treatment period with a similar one-week titration and one-week maintenance phase. At the end of the second treatment period, Holter monitoring and exercise tests were repeated. The mean dose of nifedipine was 80 mg per day. On baseline Holter recordings, there were 5.5 episodes of silent ischemia compared with 2.2 episodes during nifedipine treatment, with five patients experiencing a 50 percent reduction in ischemia and five patients a 100 percent reduction, and 6.8 episodes during placebo treatment. The total time of ischemia was signiticantly reduced during nifedipine treatment from 96
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minutes at baseline to only 35 minutes during treatment, compared with 97 minutes at baseline and 117 minutes during placebo treatment. Exercise capacity and time to ST-segment depression were also increased with nifedipine by virtue of a reduction in double product at submaximal exercise. In this study 1431, indices of both demand- and flow-related ischemia were significantly reduced during nifedipine treatment; this effect was presumably mediated by the ability of nifeclipine to increase coronary flow and reduce myocardial oxygen demand.
MYOCARDIAL ISCHEMIA AND LEFT VENTRICULAR FUNCTION Potential problems with maximized therapy, however, include additional patient-care costs and possible exposure to more severe side effects. Although it has not been proved that abolition of silent and symptomatic ischemia translates into an improvement in patient survival, there is reason to believe that this relationship exists. The magnitude of left ventricular dysfunction associated with myocardial ischemia is similar regardless of the presence or absence of chest pain [44-461. Therefore, patients with frequent bouts of asymptomatic ischemia experience frequent bouts of transient left ventricular dysfunction. When such events, which are insufficient to produce myocellular necrosis, are repeated, they may lead to a “stunning” of the myocardium by altering biochemical processes and injuring the cellular ultrastructure [47,481. Chronic impairment of coronary blood flow may lead to hibernation, a condition of persistent left ventricular dysfunction [49]. The key feature of hibernation is the reversibility of the functional abnormalities that occur with restoration of flow. In selected subgroups of patients with chronic ischemia, improvement in myocardial perfusion by either surgical or medical means can result in improvement in contractile function [50]. Therapy for myocardial ischemia would safeguard against these episodes and protect patients against the possibility of chronic ischemic left ventricular dysfunction. Given the prognostic importance of ejection fraction on survival in patients with coronary disease, it is conceivable that pharmacologic management that limits ischemia also will have a favorable impact on the long-term prognosis. Fujibayashi et al [51] have shown that calcium antagonists may protect the ventricle from ischemically mediated dysfunction. Using a closed-chest canine model, these workers administered intravenous nifedipine at various times before or during transient occlusion of the left anterior descending artery. After reperfusion, nifedipine was found to enhance the recovery of both diastolic and systolic function. Animals receiving drug treatment earlier in the course of coronary occlusion experienced the greatest benefits. Since similar mechanical events accompany silent myocardial ischemia, a comparable benefit might be expected. Thus, treatment of ischemia with calcium antagonists may provide a dual benefit: a decrease in the number of ischemic episodes, and minimization of the magnitude of left ventricular dysfunction that occurs secondary to these events.
MYOCARDIAL ISCHEMIA AND VENTRICULAR ARRHYTHMIA The association between myocardial
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ventricular arrhythmia also may have clinical relevance. Approximately 25 percent of persons who experience sudden death and in whom coronary artery disease is proved at autopsy never experience clinical symptoms associated with coronary artery disease [52]. Although it is premature to assume that treatment of coronary artery disease can alter the risk of sudden death in these patients, an association does exist between ischemia and arrhythmic events. Data from studies in animals indicate that the ventricular fibrillation threshold is markedly reduced during coronary occlusion [53]. Extension of these observations to human subjects has indicated that in certain subgroups of patients who survive cardiac arrests, myocardial ischemia may be a requirement for the induction of ventricular tachycardia by programmed electrical stimulation [54]. A closer link between arrhythmia and ischemia has been suggested recently by a study in which potentially life-threatening arrhythmias in patients with stable angina pectoris were shown to be closely related to severe, repetitive, and occasionally asymptomatic ischemic episodes [55].
CONCLUSIONS Further investigation of large patient groups will be necessary to determine whether treatment can alter the unfavorable prognosis associated with silent myocardial ischemia. Examination of the events surrounding asymptomatic ischemia raises interesting questions regarding future goals in the medical management of coronary artery disease and offers a rationale for the aggressive management of patients with silent and symptomatic myocardial ischemia.
REFERENCES 1. Schang SJ Jr, Peprne Cl: Transient asymptomatrc ST-segment depressron during dally achvlty. Am J Cardtol 19q 39: 396-402. 2. Deanfreld JE, Selwyn AP, Chrerchra S, et al: Myocardial rschaemra during dally kfe In patrents wrth stable angina: Its relatron to symptoms and heart rate changes. Lancet 1983; II: 753-758. 3. Kannel WB. Abbott RD. lncrdence and prognoses of unrecognrzed myocardial Infarctron: an update on the Framrngham Study. N Engl J Med 1984; 311: 11441147. 4. Rosenman RH, Frredman M, Jenkrns CD, Sttaus R. Wurm M, Kositchek R: Clrnrcally unrecognrzed myocardlal mfarction rn the Western Collaborative Group Study. Am J Cardrol 1967; 19: 776-782. 5. Nesto RW. Kowalchuk GJ: The rschemlc cascade: temporal sequence of hemodynamrc, electrocardrographic and symptomatrc expressrons of ischemra. Am J Cardrol 1987; 59: 23C-30C. 6. Stgwart U, Grbrc M, Payot M, Goy J-J, Esslnger A, Fischer A: lschemrc events durrng coronary artery balloon obstructton. in: Rubshauser W, Roskamm H, eds. Srlent Myocardral Ischemra. Berlrn, New York Sprrnger-Verlag. 1984; 29-36. 7. Hrll JA, Peprne C.: Myocardral tschemra and chest parn: a mrsunderstood and oversrmplrfled relahonshrp? Cardrol Clan 1986; 4: 621-625. 8. Mallranr A, Lombard1 F: Consrderatron of the fundamental mechanrsms elicrttng cardrac pain. Am Heart J 1982; 103: 575-578. 9. Nesto RW, Phrlkps RT: Asymptomahc myocardral rschemra rn drabetrc patients. Am J Med 1986; 80 (suppl 4C), 40-47. 10. Nesto RW, Phrllkps RT, Kett KG, et a/: Angrna and exerhonal myocardral tschemra In diabetic and nondiabebc pabents: assessment by exercrse thallium scrntigraphy. Ann Intern Med 1988; 108: 170-175. 11. Farerman I, Faccro E, Mile1 J, et a/: Autonomrc neuropathy and patnless myocardral Infarctron rn drabetrc patients: hrstologrc evrdence of their relationshrp. Diabetes 19R 26: 1147-1158. 12. Cohn PF: Possrble mechanrsms responsrble for srlent myocardial tschemia: do patients with srlent myocardral rschemra have altered pawnthresholds? Cardiol Clan 1986; 4: 727711 13. Droste C, Roskamm H: Experrmental parn measurement rn pabents with asymptomahc myocardral rschemra. J Am Coil Cardiol 1983; 1: 940-945. 14. Glazier JJ, Chlerchra S, Brown MJ, Maser1 A: Importance of generalrzed defective perceptton of parnful stlmulr as a cause of srlent myocardial rschemra rn chronic stable angrna pectotrs. Am J Cardrol 1986; 58: 667-672. 15. Sheps DS, Adams KF, HInderliter A, era/ Endorphrns are related to parn perception rn
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coronary artery dtsease Am J Cardrol 1987, 59: 523-527. 16. Van Rrfn T, Rabkrn SW: Effect of naloxone, a specrflc optold antagonist on exercise Induced anglna pectorrs (abstr). Clrculatron 1981; 4: l-45 17. Selwyn AP, Deanfield J, Shea M, Jones T. Different pathophystology of parnful and srlent myocardral lschemra (abstr). Circulatron 1986; 74: 11-57. 18. Amsterdam EA, Martschrnske R, Laslett LJ Rutledge JC. Vera 2: Symptomatrc and srlent myocardral rschemra durrng exercrse testrng rn coronary artery disease Am J Cardrol 1986; 58: 438-468. 19. Cecchr AC, Dovelknr EV, March1 F. PUCCIP, Santoro GM, Fazzrn F: Srlent myocardral rschemra durrng ambulatory electrocardrographrc monltorrng rn patients wrth effort angrna. J Am Coil Cardrol 1983; 1: 934-939. 20. Hrckman JR Jr, Uhl GS. Cook RL. Engel PJ, Hopkrrk A: A natural hrstory study of asymptomatrc coronary drsease (abstr). Am J Cardrol 1980; 45: 422. 21. Errkssen J, Thaulow E: Follow-up of pabents with asymptomahc myocardral ischemra. In. Rutrshauser W. Roskamm H. eds. Silent Myocardral Ischemia. Berlrn, New York: Sprrnger-Verlag 1984; 156-164. 22. Rocco MB, Nabel EG, Campbell S, et al: Prognostic Importance of myocardral rschemra detected by ambulatory monltorrng rn patients wrth coronary drsease (abstr). J Am Coil Cardrol 1987; 9: 68A 23. Tzrvon~ D, Gavrsh A, Zrm D. et a/: Prognostrc srgnrfrcance of rschemrc epcsodes In patrents wrth prevrous myocardral Infarctron. Am J Cardrol 1988; 62: 661-664. 24. Gottlreb SO, Wersfeldt ML, Ouyang P, MelIlts ED, Gerstenbkth G: Silent rschemra as a marker for early unfavorable outcomes in patients wrth unstable angma. N Engl J Med 1986; 314: 1214-1219. 25. Chterchra S, Smrth G, Morgan M. eta/: Role of heart rate rn pathophystology of chronrc stable angina. Lancet 1984; II: 1353-1357. 26. Deanfteld JE. Shea M, Rrbrero P, eta/;Transrent ST-segment depressron as a marker of myocardral rschemla during dally kfe. Am J Cardrol 1984; 54: 1195-1200. 27. Deanfreld JE. Kensett M. Wrlson RA. et al: Stlent myocardial ischaemra due to mental stress. Lancet 1984; II: 1001-1004. 28. Deanfreld JE, Shea MJ, Nesto RA, Horlock P, Landsheere CM, Selwyn AP: Drrect effects of smoking on the heart srlent tschemrc disturbances of coronary flow. Am J Cardlol 1986: 57: 1005-1009. 29. Masen A. Chrerchra S: Coronary artery spasm: demonstration dehnrbon. dragnosis, and consequences Prog Cardrovasc DIS 1982; 25: 169-192. 30. Ginsburg R, Bristow MR, Davts K, Drbiase A, Bilkngham ME: Quantrtatrve pharmacologrc responses of normal and atherosclerohc Isolated human eprcardral coronary arteries. Crrculatron 1984: 69: 430-440. 31. Yasue H, Nagao M, Omote S, Takrzawa A, Mrwa K, Tanaka S: Coronary arterial spasm and Prinzmetal’s variant form of angina Induced by hyperventilabon and tns-buffer rnfusron. Crrculatron 1978; 58: 56-62. 32. Maser1 A: Role of coronary artery spasm rn symptomatrc and silent myocardral rschemra J Am Coil Cardrol 1987; 9: 249-262. 33. Brown BG, Lee AB, Bolson EL, Dodge HT: Reflex constrrction of signrfrcant coronary stenosis as a mechanrsm contrrbuting to rschemrc left ventrrcular dysfunction during ISOmetrrc exercrse. Crrculatron 1984; 70: 18-24. 34. Brown BG, Bolson EL, Dodge HT: Dynamrc mechanrsms In human coronary steno%. Crrculatron 1984: 70: 917-922. 35. Rocco MB, Nabel EG. Selwyn AP: Crrcadran rhythms and coronary artery drsease. Am J Cardrol 1987: 59: 13C-17C. 36. Hultgren HN, Peduzzl P: Relation of severrty of symptoms to prognoses rn stable angrna pectorrs. parbcrpants of the Veterans Admrnrstratron cooperatrve study of surgery for coronary arterial occlusrve drsease. Am J Cardiol 1984; 54: 988-993. 37. Dargre HJ, Lynch PG, Krrkler DM. Harns L, Knkler S: Nrfedrprne and propranolol: a benefrcral drug Interactron. Am J Med 1981; 71: 676-682. 38. Stone PH, Antman EM, Muller JE, Braunwald E: Calcrum channel blocking agents In the treatment of cardiovascular dtsorders. Part II: Hemodynamrc effects and clrnical appkcatrons. Ann Intern Med 1980: 93: 886-904. 39. Ferlrnz J, Nrfedipme rn myocardral rschemra, systemtc hypertenston, and other cardrovascular drsorders. Ann Intern Med 1986; 105: 714-729. 40. Johnson SM, Mauntson DR, Wrllerson JT, Hrlks LD: A controlled trral of verapamrl for Pnnzmetal’s varrant angina. N Engl J Med 1981: 304: 862-866. 41. Antman E, Muller J. Goldberg S, et at Ntfedipine therapy for coronary-artery spasm: experrence In 27 patients. N Engl J Med 1980; 302: 1269-1273. 42. Wtnnrford MD, Johnson SM, Maurrtson DR, et a/: Verapamrl therapy for Prrnzmetal’s vanant angrna: comparison wrth placebo and nrfedrprne. Am J Cardrol 1982; 50: 913-918. 43. Nesto RW, Kett KJ McAulrffee LS: Effect of nrfedlprne on srlent rschemra rn patrents wrth stable angrna and those wtth asymptomatic coronary artery disease. In: Srngh BN, ed. Srlent Myocardial lschemra and Angina. New York: Pergamon Press 1988; 263-271. 44. Chierchra S: Left ventricular perfusron and function during transrent asymptomatlc STsegment changes. In: Rutishauser W, Roskamm H. eds. Srlent Myocardral Ischemra. Berlrn, New York: Springer-Verlag 1984: 24-28. 45. Hlrzel HO, Leutwyler R, Krayenbuehl HP: Silent myocardral rschemra: hemodynamic changes durrng dynamrc exercrse in patrents wrth proven coronary artery drsease desprte absence of angrna pectons. J Am Coll Cardrol 1985; 6: 275-284. 46. Cohn PF, Brown EJ Jr, Wynne J, Holman BL, Atkrns HL: Global and regional left ventrrcular electron fraction abnormalrbes during exercise rn patrents wrth silent myocardral rschemra. J Am Colt Cardiol 1983; 1: 931-933. 47. Pate1 B, Kloner RA, Przyklenk K, Braunwald E: Postischemrc myocardral “stunnrng:” a clrnrcally relevant phenomenon. Ann Intern Med 1988; 108: 626-628. 48. Braunwald E, Kloner RA: The stunned myocardrum: prolonged, postrschemrc ventncular dysfunction. Crrculation 1982; 66: 1146-1149.
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SYMPOSIUM 49. Braunwald E. Rutherford JD: Reversible rschemrc left ventrrcular dysfuncbon: evidence for the “hibernatrng myocardrum.” J Am Coil Cardrol 1986: 8: 1467-1470. 50. Nesto RW, Cohn LH, Collins JJ, Wynne J. Holman L, Cohn PP lnotroprc contractrle reserve’ a useful predrctor of Increased 5 year survrval and Improved postoperatrve left ventrrcular fun&on in patrents wrth coronary artery disease and reduced eJectron fraction. Am J Card0 1982: 50: 39-44. 51. Fufrbayashl Y. Yamazakr S, Chang B-L, Rajagopalan RE, Meerbaum S. Corday E: Corn. paratrve echocardrographrc study of recovery of drastolrc versus systolrc functron after brref periods of coronary occlusron: drfferentral effects of Intravenous nrfedrprne admrnrs tered before and during occlusion. J Am Coil Cardrol 1985: 6: 1289-1298.
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52. Lown ET:Sudden cardiac death, the major challenge confrontrng contemporary cardrology Am J Cardiol 1979; 43: 313-328. 53. Axelrod PJ. Vervrer RL, Lown B: Vuinerabikty to ventrrcular frbrrllatron durrng acute coronary arterral occlusron and release. Am J Cardtol 1975; 36: 776-782. 54. Morady F. DrCarlo LA Jr. Krol RB, et al: Role of myocardial rschemra during programmed strmulation In suIvrvors of cardrac arrest wrth coronary artery disease. J Am Cot1 Cardiol 1987; 9, 1004-1012. 55. Carbon1 GP, Lahrrr A, Cashman M, Raftery EB: Mechanrsms of arrhythmias accompanyrng ST-segment depressron on ambulatory monrtorrng rn stable angina pectorrs. Am J Cardrol 1987: 60: 1246-1253
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The widespread use of Holter monitoring has demonstrated that the majority of ischemic episodes occur during activities that do not require exertion. These episodes tend to occur at only minimal increases in heart rate above resting levels, well below the level of myocardial oxygen demand required to produce ischemia on formal exercise tolerance testing. In all likelihood, therefore, most ischemic events in ambulatory patients are due to a combination of flow-limiting coronary stenosis and superimposed vasoactive or thrombotic elements. Asymptomatic ischemic events are common in subsets of patients with angina pectoris. Traditionally, treatment with calcium channel blockers, beta-blockers, and long-acting nitrates has been aimed at reducing episodes of angina pectoris. Despite a reduction in angina1 symptoms, however, it is likely that patients continue to experience silent ischemia, particularly at rest and during activities of daily living. The strategy for treatment in such patients should include the abolition of the patients’ “total ischemic activity.” It is conceivable that more aggressive anti-ischemic therapy may improve prognosis, as patients with ambulatory ST-segment depression experience frequent cardiac events. Other potential benefits of more aggressive treatment include the prevention of myocardial hibernation, which occurs as a result of a chronic ischemic state, and a reduction in episodes of myocardial stunning. This approach may lead to protection against transient and chronic left ventricular dysfunction, which is associated with a poor prognosis in patients with symptomatic coronary artery disease.
From the Department of Medlclne. Cardiology Secbon, Harvard Medical School, and the New England Deaconess Hospital, Boston, Massachusetts. Requests for reprints should be addressed to Dr. Richard W. Nesto, New England Deaconess Hospital, 185 Pllgrlm Road, Boston, Massachusetts 02115.
reatment of coronary artery disease has been T based primarily on relief of symptoms. Recent evidence, however, has demonstrated that most ischemic episodes in patients with symptomatic coronary artery disease are painless [1,2]. The importance of these findings is underscored by the fact that 20 to 25 percent of myocardial infarctions may occur without angina [3,4]. Furthermore, a change in angina1 pattern may not precede myocardial infarction in patients who do experience chest pain.
PAINFULVERSUSPAINLESSISCHEMICEVENTS Several hypotheses have been proposed to explain why certain ischemic episodes lead to angina, whereas others do not. Myocardial ischemia results from an imbalance between myocardial oxygen supply and demand. The onset of this imbalance is followed by a sequence of pathophysiologic events that culminates in the subjective appreciation of ischemia-angina pectoris [5]. A series of subclinical metabolic, mechanical, and electrocardiographic abnormalities occurs before ischemia is clinically recognized [6]. Furthermore, a given episode of myocardial ischemia may resolve before reaching the angina1 threshold, leaving ischemia undetected. Hill and Pepine [7] have referred to the time delay between the initiation of supply/demand imbalance and its clinical recognition as the “ischemic gap.” Viewed in this light, all episodes of ischemia can be considered to have a silent phase. Other factors acting alone or in concert have been proposed to account for variation in the perception of angina among individual patients and among individual ischemic events. In one theory involving alterations in neural pathways, it is suggested that the afferent sympathetic nerve fibers responsible for pain conduction from the heart are either impaired or damaged [81. Proponents of this argument cite the higher incidence of asymptomatic ischemia in patients who may suffer de-enervation of the autonomic nervous system, for example, many diabetic patients [g-111. A second theory holds that patients who experience silent myocardial ischemia exhibit hyposensibility to painful stimuli [12]. Independent studies have indicated that patients with asymptomatic coronary artery disease tend to have a higher pain threshold and a higher pain tolerance than patients with symptomatic ischemia [ 13,141. Recent investigations have suggested that endorphins may play a role in the mechanism responsible for this difference [15,16]. A third theory proposes that the mass of myocardium at jeopardy during silent ischemia is quantitatively less than that at risk during symptomatic events. Unfortunately, when the extent and severity of ischemia have been analyzed, a considerable overlap has been found between symptomatic and asymptomatic patients; thus, firm conclusions cannot be drawn [17-191. January 16. 1989
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PROGNOSTIC SIGNIFICANCE OF ASYMF’TOMATIC ISCHEMIA Although the cause of asymptomatic ischemic events has not been clearly defined, the detection of such episodes has been shown to have prognostic significance. Indeed, in one study, angina, myocardial infarction, or death developed within five years in 24 percent of men who were found to have asymptomatic coronary disease [20]. Longer follow-up has demonstrated a 42 percent incidence of cardiac events by eight to ten years [21]. Patients with stable angina who experience asymptomatic ST-segment depression detected on ambulatory Holter monitoring are noted to have an increased frequency of cardiac death, myocardial infarction, and need for revascularization over the ensuing nine months [22]. This observation has been extended to post-myocardial infarction patients, among whom silent ischemia on Holter monitoring has been correlated with an incidence of cardiac events in 51 percent of patients over a 2%month follow-up period, a value that is four times greater than that noted among persons without such a finding [23]. Perhaps the most ominous prognostic data gathered from studies in which silent ischemia has been monitored involve patients presenting with unstable angina. In this situation, asymptomatic ischemia has been associated with an incidence of myocardial infarction that is six times greater over the subsequent month and thus serves as a powerful predictor of the need for coronary revascularization [241. PATHOPHYSIOLOGY OF ASYMPTOMATIC ISCHEMIA Observations of episodes of asymptomatic ischemia may offer insights into their pathophysiology and adverse prognosis, but may also afford insights into possible means of treatment. The major diagnostic and prognostic tool used in the evaluation of patients with coronary artery disease has been the exercise treadmill. Through graded increases in cardiac workloads, exercise testing has provided a reproducible method of inducing demand-related myocardial ischemia. Ambulatory Holter monitoring has revealed that most silent ischemic events occur during usual daily activity at times when heart rate is not significantly elevated [1,2,25]. This suggests that the predominant mechanism of asymptomatic ischemia is a decrease in myocardial oxygen supply rather than an increase in oxygen demand. Further evidence supporting a primary decrease in coronary blood flow has come from studies in which painless myocardial perfusion abnormalities were noted during cigarette smoking, mental stress, and exposure to cold [26-281. It is too simplistic to postulate that painful ischemia results only from demand-related states and that painless ischemia results primarily from flow-related mechanisms. Ischemia cannot be considered as purely a demand- or a flow-related phenomenon, but rather should be thought of as a flow-limiting fixed disease combined with superimposed vasoconstrictive or thrombotic elements. To understand how these two processes are interrelated, a re-examination of myocardial supply/demand imbalance is necessary. In patients with coronary artery disease, the mechanisms thought to be primarily responsible for myocardial ischemia have involved the concept of a fixed coronary flow reserve. According to this concept, patients with 10
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coronary stenosis have a flow reserve that, though reduced, allows for adequate myocardial perfusion as long as metabolic demands are not exceeded; only when oxygen demand exceeds coronary reserve capabilities does ischemia develop. Although this concept provides an adequate explanation for demand-related myocardial ischemia, it does not address episodes of ischemia that occur with low heart rate/blood pressure products. The realization that coronary flow may change in response to a variety of physical, metabolic, and pharmacologic stimuli has necessitated a modification of this scheme [29-311. Maseri [32] has postulated that coronary flow reserve may be both reduced and variable. Changes in coronary resistance at the site of a fixed stenosis may thus produce dramatic reductions in myocardial blood flow that result in ischemia at times when oxygen demand is low. This concept allows an explanation for ischemia occurring during high-oxygen-demand states, such as exercise, and during low-oxygen-demand states, as has been demonstrated during asymptomatic ischemia detected with ambulatory Holter monitoring. Proof of the dynamic nature of coronary stenoses has been provided in the work by Brown et al [331. Using sophisticated angiographic methods, these investigators demonstrated a 35 percent change in the luminal area of stenotic vessels during isometric exercise and nitroglycerin treatment, resulting in even more dramatic changes in trans-stenotic coronary resistance. This variation in lesion reactivity may vary among individual patients and among individual coronary lesions. Changes in stenosis size and vessel resistance are therefore not limited to patients with classic spasm but are typical of the majority of all coronary stenoses [341. TREATMENT OF MYOCARDIAL ISCHEMIA These findings present concerns that must be addressed in considering the treatment of all episodes of myocardial ischemia, including the treatment of silent ischemia. Agents that reduce ischemia by reducing myocardial oxygen consumption may not be fully effective in eliminating all ischemic events. First, as noted previously, the majority of episodes of asymptomatic ischemia occur with low heart rate/blood pressure products. The ideal anti-ischemic medication should be able to eliminate angina and these silent episodes by improving coronary arterial perfusion. Second, a circadian clustering of ischemic episodes has been noted, with the majority of events occurring during the early morning hours after awakening [351. Thus, the traditional dosing regimen of anti-angina1 therapy can leave patients unprotected during the peak incidence of ischemic activity at a time when there is a trough level of anti-angina1 activity. Third, there is little correlation between the severity of a patient’s symptoms and the severity of underlying coronary artery disease [36]. Moreover, in persons with stable angina, there are few data to suggest that improvement in angina1 class or exercise treadmill duration can result in an improvement in survival. Therefore, conventional medical treatment of coronary artery disease aimed at the control of angina1 symptoms should be re-evaluated. Perhaps therapy directed toward the elimination of all ischemic activity, both silent and symptomatic, is warranted.
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Previous investigations have demonstrated that such an end point is possible. By prescribing antiangina1 medication at higher doses it may be possible to produce a further reduction in ischemlc activity and abolish silent as well as symptomatic events. An example of such an effect was reported by Dargie et al [37] in their study of 16 patients with stable angina pectoris and positive exercise test results. After a two-week run-in period receiving placebo, patients were randomly assigned to receive nifedipine 30 or 60 mg per day, propranolol240 or 480 mg per day, or the combination of nifedipine and propranolol, 30 mg per day with 240 mg per day or 60 mg per day with 480 mg per day, respectively, in single-blind fashion. Both the frequency of angina and the number of nitroglycerin tablets consumed per day were reduced significantly by each active drug compared with placebo. The combination of high doses of both propranolol and nifedipine produced an even larger percentage reduction than did either drug alone in the number of STsegment depressions detected by ambulatory electrocardiographic monitoring. In this study [37], aggressive medical management of ischemic heart disease beyond that needed to control patients’ symptomatic states produced a further decrease in total ischemic activity. In light of the concerns surrounding abnormalities in vessel tone and coronary flow in the majority of patients with “fixed” coronary disease, it would appear that agents that improve myocardial blood flow are particularly well suited as anti-angina1 medication. Calcium antagonists constitute one class of medications that have been useful in the treatment of both flow- and demand-related ischemic events. These agents have been shown to decrease myocardial vascular resistance, increase coronary collateral flow, and decrease myocardial oxygen consumption [38,391. In clinical situations in which marked variations in coronary vascular tone predominate, such as vasospastic angina, calcium antagonists have been effective antiangina1 agents [40-421. Nesto et al [43] studied the effect of nifedipine on ischemia as measured by exercise testing and ambulatory Holter monitoring. In a double-blind, randomized, crossover trial, nifedipine was compared with placebo in 10 patients with angiographically documented coronary disease and positive treadmill test results. Patients underwent a baseline exercise tolerance test and 4%hour Holter monitoring, after which they were randomly assigned to receive either nifedipine or placebo. A one-week titration phase was followed by one week of maintained therapy. Repeat exercise tolerance testing and 4%hour Holter monitoring were performed at the end of the first treatment period, after which patients were crossed over to the other treatment period with a similar one-week titration and one-week maintenance phase. At the end of the second treatment period, Holter monitoring and exercise tests were repeated. The mean dose of nifedipine was 80 mg per day. On baseline Holter recordings, there were 5.5 episodes of silent ischemia compared with 2.2 episodes during nifedipine treatment, with five patients experiencing a 50 percent reduction in ischemia and five patients a 100 percent reduction, and 6.8 episodes during placebo treatment. The total time of ischemia was signiticantly reduced during nifedipine treatment from 96
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minutes at baseline to only 35 minutes during treatment, compared with 97 minutes at baseline and 117 minutes during placebo treatment. Exercise capacity and time to ST-segment depression were also increased with nifedipine by virtue of a reduction in double product at submaximal exercise. In this study 1431, indices of both demand- and flow-related ischemia were significantly reduced during nifedipine treatment; this effect was presumably mediated by the ability of nifeclipine to increase coronary flow and reduce myocardial oxygen demand.
MYOCARDIAL ISCHEMIA AND LEFT VENTRICULAR FUNCTION Potential problems with maximized therapy, however, include additional patient-care costs and possible exposure to more severe side effects. Although it has not been proved that abolition of silent and symptomatic ischemia translates into an improvement in patient survival, there is reason to believe that this relationship exists. The magnitude of left ventricular dysfunction associated with myocardial ischemia is similar regardless of the presence or absence of chest pain [44-461. Therefore, patients with frequent bouts of asymptomatic ischemia experience frequent bouts of transient left ventricular dysfunction. When such events, which are insufficient to produce myocellular necrosis, are repeated, they may lead to a “stunning” of the myocardium by altering biochemical processes and injuring the cellular ultrastructure [47,481. Chronic impairment of coronary blood flow may lead to hibernation, a condition of persistent left ventricular dysfunction [49]. The key feature of hibernation is the reversibility of the functional abnormalities that occur with restoration of flow. In selected subgroups of patients with chronic ischemia, improvement in myocardial perfusion by either surgical or medical means can result in improvement in contractile function [50]. Therapy for myocardial ischemia would safeguard against these episodes and protect patients against the possibility of chronic ischemic left ventricular dysfunction. Given the prognostic importance of ejection fraction on survival in patients with coronary disease, it is conceivable that pharmacologic management that limits ischemia also will have a favorable impact on the long-term prognosis. Fujibayashi et al [51] have shown that calcium antagonists may protect the ventricle from ischemically mediated dysfunction. Using a closed-chest canine model, these workers administered intravenous nifedipine at various times before or during transient occlusion of the left anterior descending artery. After reperfusion, nifedipine was found to enhance the recovery of both diastolic and systolic function. Animals receiving drug treatment earlier in the course of coronary occlusion experienced the greatest benefits. Since similar mechanical events accompany silent myocardial ischemia, a comparable benefit might be expected. Thus, treatment of ischemia with calcium antagonists may provide a dual benefit: a decrease in the number of ischemic episodes, and minimization of the magnitude of left ventricular dysfunction that occurs secondary to these events.
MYOCARDIAL ISCHEMIA AND VENTRICULAR ARRHYTHMIA The association between myocardial
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ventricular arrhythmia also may have clinical relevance. Approximately 25 percent of persons who experience sudden death and in whom coronary artery disease is proved at autopsy never experience clinical symptoms associated with coronary artery disease [52]. Although it is premature to assume that treatment of coronary artery disease can alter the risk of sudden death in these patients, an association does exist between ischemia and arrhythmic events. Data from studies in animals indicate that the ventricular fibrillation threshold is markedly reduced during coronary occlusion [53]. Extension of these observations to human subjects has indicated that in certain subgroups of patients who survive cardiac arrests, myocardial ischemia may be a requirement for the induction of ventricular tachycardia by programmed electrical stimulation [54]. A closer link between arrhythmia and ischemia has been suggested recently by a study in which potentially life-threatening arrhythmias in patients with stable angina pectoris were shown to be closely related to severe, repetitive, and occasionally asymptomatic ischemic episodes [55].
CONCLUSIONS Further investigation of large patient groups will be necessary to determine whether treatment can alter the unfavorable prognosis associated with silent myocardial ischemia. Examination of the events surrounding asymptomatic ischemia raises interesting questions regarding future goals in the medical management of coronary artery disease and offers a rationale for the aggressive management of patients with silent and symptomatic myocardial ischemia.
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coronary artery dtsease Am J Cardrol 1987, 59: 523-527. 16. Van Rrfn T, Rabkrn SW: Effect of naloxone, a specrflc optold antagonist on exercise Induced anglna pectorrs (abstr). Clrculatron 1981; 4: l-45 17. Selwyn AP, Deanfield J, Shea M, Jones T. Different pathophystology of parnful and srlent myocardral lschemra (abstr). Circulatron 1986; 74: 11-57. 18. Amsterdam EA, Martschrnske R, Laslett LJ Rutledge JC. Vera 2: Symptomatrc and srlent myocardral rschemra durrng exercrse testrng rn coronary artery disease Am J Cardrol 1986; 58: 438-468. 19. Cecchr AC, Dovelknr EV, March1 F. PUCCIP, Santoro GM, Fazzrn F: Srlent myocardral rschemra durrng ambulatory electrocardrographrc monltorrng rn patients wrth effort angrna. J Am Coil Cardrol 1983; 1: 934-939. 20. Hrckman JR Jr, Uhl GS. Cook RL. Engel PJ, Hopkrrk A: A natural hrstory study of asymptomatrc coronary drsease (abstr). Am J Cardrol 1980; 45: 422. 21. Errkssen J, Thaulow E: Follow-up of pabents with asymptomahc myocardral ischemra. In. Rutrshauser W. Roskamm H. eds. Silent Myocardral Ischemia. Berlrn, New York: Sprrnger-Verlag 1984; 156-164. 22. Rocco MB, Nabel EG, Campbell S, et al: Prognostic Importance of myocardral rschemra detected by ambulatory monltorrng rn patients wrth coronary drsease (abstr). J Am Coil Cardrol 1987; 9: 68A 23. Tzrvon~ D, Gavrsh A, Zrm D. et a/: Prognostrc srgnrfrcance of rschemrc epcsodes In patrents wrth prevrous myocardral Infarctron. Am J Cardrol 1988; 62: 661-664. 24. Gottlreb SO, Wersfeldt ML, Ouyang P, MelIlts ED, Gerstenbkth G: Silent rschemra as a marker for early unfavorable outcomes in patients wrth unstable angma. N Engl J Med 1986; 314: 1214-1219. 25. Chterchra S, Smrth G, Morgan M. eta/: Role of heart rate rn pathophystology of chronrc stable angina. Lancet 1984; II: 1353-1357. 26. Deanfteld JE. Shea M, Rrbrero P, eta/;Transrent ST-segment depressron as a marker of myocardral rschemla during dally kfe. Am J Cardrol 1984; 54: 1195-1200. 27. Deanfreld JE. Kensett M. Wrlson RA. et al: Stlent myocardial ischaemra due to mental stress. Lancet 1984; II: 1001-1004. 28. Deanfreld JE, Shea MJ, Nesto RA, Horlock P, Landsheere CM, Selwyn AP: Drrect effects of smoking on the heart srlent tschemrc disturbances of coronary flow. Am J Cardlol 1986: 57: 1005-1009. 29. Masen A. Chrerchra S: Coronary artery spasm: demonstration dehnrbon. dragnosis, and consequences Prog Cardrovasc DIS 1982; 25: 169-192. 30. Ginsburg R, Bristow MR, Davts K, Drbiase A, Bilkngham ME: Quantrtatrve pharmacologrc responses of normal and atherosclerohc Isolated human eprcardral coronary arteries. Crrculatron 1984: 69: 430-440. 31. Yasue H, Nagao M, Omote S, Takrzawa A, Mrwa K, Tanaka S: Coronary arterial spasm and Prinzmetal’s variant form of angina Induced by hyperventilabon and tns-buffer rnfusron. Crrculatron 1978; 58: 56-62. 32. Maser1 A: Role of coronary artery spasm rn symptomatrc and silent myocardral rschemra J Am Coil Cardrol 1987; 9: 249-262. 33. Brown BG, Lee AB, Bolson EL, Dodge HT: Reflex constrrction of signrfrcant coronary stenosis as a mechanrsm contrrbuting to rschemrc left ventrrcular dysfunction during ISOmetrrc exercrse. Crrculatron 1984; 70: 18-24. 34. Brown BG, Bolson EL, Dodge HT: Dynamrc mechanrsms In human coronary steno%. Crrculatron 1984: 70: 917-922. 35. Rocco MB, Nabel EG. Selwyn AP: Crrcadran rhythms and coronary artery drsease. Am J Cardrol 1987: 59: 13C-17C. 36. Hultgren HN, Peduzzl P: Relation of severrty of symptoms to prognoses rn stable angrna pectorrs. parbcrpants of the Veterans Admrnrstratron cooperatrve study of surgery for coronary arterial occlusrve drsease. Am J Cardiol 1984; 54: 988-993. 37. Dargre HJ, Lynch PG, Krrkler DM. Harns L, Knkler S: Nrfedrprne and propranolol: a benefrcral drug Interactron. Am J Med 1981; 71: 676-682. 38. Stone PH, Antman EM, Muller JE, Braunwald E: Calcrum channel blocking agents In the treatment of cardiovascular dtsorders. Part II: Hemodynamrc effects and clrnical appkcatrons. Ann Intern Med 1980: 93: 886-904. 39. Ferlrnz J, Nrfedipme rn myocardral rschemra, systemtc hypertenston, and other cardrovascular drsorders. Ann Intern Med 1986; 105: 714-729. 40. Johnson SM, Mauntson DR, Wrllerson JT, Hrlks LD: A controlled trral of verapamrl for Pnnzmetal’s varrant angina. N Engl J Med 1981: 304: 862-866. 41. Antman E, Muller J. Goldberg S, et at Ntfedipine therapy for coronary-artery spasm: experrence In 27 patients. N Engl J Med 1980; 302: 1269-1273. 42. Wtnnrford MD, Johnson SM, Maurrtson DR, et a/: Verapamrl therapy for Prrnzmetal’s vanant angrna: comparison wrth placebo and nrfedrprne. Am J Cardrol 1982; 50: 913-918. 43. Nesto RW, Kett KJ McAulrffee LS: Effect of nrfedlprne on srlent rschemra rn patrents wrth stable angrna and those wtth asymptomatic coronary artery disease. In: Srngh BN, ed. Srlent Myocardial lschemra and Angina. New York: Pergamon Press 1988; 263-271. 44. Chierchra S: Left ventricular perfusron and function during transrent asymptomatlc STsegment changes. In: Rutishauser W, Roskamm H. eds. Srlent Myocardral Ischemra. Berlrn, New York: Springer-Verlag 1984: 24-28. 45. Hlrzel HO, Leutwyler R, Krayenbuehl HP: Silent myocardral rschemra: hemodynamic changes durrng dynamrc exercrse in patrents wrth proven coronary artery drsease desprte absence of angrna pectons. J Am Coll Cardrol 1985; 6: 275-284. 46. Cohn PF, Brown EJ Jr, Wynne J, Holman BL, Atkrns HL: Global and regional left ventrrcular electron fraction abnormalrbes during exercise rn patrents wrth silent myocardral rschemra. J Am Colt Cardiol 1983; 1: 931-933. 47. Pate1 B, Kloner RA, Przyklenk K, Braunwald E: Postischemrc myocardral “stunnrng:” a clrnrcally relevant phenomenon. Ann Intern Med 1988; 108: 626-628. 48. Braunwald E, Kloner RA: The stunned myocardrum: prolonged, postrschemrc ventncular dysfunction. Crrculation 1982; 66: 1146-1149.
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SYMPOSIUM 49. Braunwald E. Rutherford JD: Reversible rschemrc left ventrrcular dysfuncbon: evidence for the “hibernatrng myocardrum.” J Am Coil Cardrol 1986: 8: 1467-1470. 50. Nesto RW, Cohn LH, Collins JJ, Wynne J. Holman L, Cohn PP lnotroprc contractrle reserve’ a useful predrctor of Increased 5 year survrval and Improved postoperatrve left ventrrcular fun&on in patrents wrth coronary artery disease and reduced eJectron fraction. Am J Card0 1982: 50: 39-44. 51. Fufrbayashl Y. Yamazakr S, Chang B-L, Rajagopalan RE, Meerbaum S. Corday E: Corn. paratrve echocardrographrc study of recovery of drastolrc versus systolrc functron after brref periods of coronary occlusron: drfferentral effects of Intravenous nrfedrprne admrnrs tered before and during occlusion. J Am Coil Cardrol 1985: 6: 1289-1298.
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52. Lown ET:Sudden cardiac death, the major challenge confrontrng contemporary cardrology Am J Cardiol 1979; 43: 313-328. 53. Axelrod PJ. Vervrer RL, Lown B: Vuinerabikty to ventrrcular frbrrllatron durrng acute coronary arterral occlusron and release. Am J Cardtol 1975; 36: 776-782. 54. Morady F. DrCarlo LA Jr. Krol RB, et al: Role of myocardial rschemra during programmed strmulation In suIvrvors of cardrac arrest wrth coronary artery disease. J Am Cot1 Cardiol 1987; 9, 1004-1012. 55. Carbon1 GP, Lahrrr A, Cashman M, Raftery EB: Mechanrsms of arrhythmias accompanyrng ST-segment depressron on ambulatory monrtorrng rn stable angina pectorrs. Am J Cardrol 1987: 60: 1246-1253
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