Hemodynamic and electrocardiographic correlates of symptomatic and silent myocardial ischemia: Pathophysiologic and therapeutic implications

Hemodynamic and Electrocardiographic Correlatesof SymptomaticandSilent Myocardiallschemia: Pathophysiologic andTherapeuticImplications BRAMAH N. SINGH, MD, DPhil, FRCP, KOONLAWEE NADEMANEE, JAIME FIGUERAS, MD, and MARTIN A. JOSEPHSON, MD

Numerous hemodynamic, electrocardiographic, metabolic and radionuclide measurements in various subsets of patients wlth coronary artery disease (CAD) reveal that ischemia does not always occur on the basis of increases in myocardial oxygen consumption. Continuous hemodynamic monitoring indicates that most episodes of myocardial ischemia are not preceded by increases in such major determinants of oxygen consumption as heart rate or blood pressure, but that these usually increase in response to the development of &hernia. The development of pain during ischemia is a late feature and most episodes are silent. There are no significant differences in the hemodynamic characteristics of symptomatic versus asymptomatic episodes of myocardial ischemia in patients with angina at rest or between those associated with ST-segment depression and those with ST-segment elevation. Continuous Holter recordings analyzed by compact analog technique in hospitalized and ambulatory patients with ischemic heart disease indicate that in both unstable and chronic stable angina, over two-thirds of myocardial ischemic episodes are clinically silent. Symptomatic

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hen a coronary artery is transiently occluded in an experimental animal certain reversible electrophysiologic, metabolic, inotropic and hemodynamic alterations ensue.1,2 The electrocardiographic (ECG] From the Cardiology Section, Veterans Administration Wadsworth Medical Center, West Los Angeles, and Department of Medicine, University of California-Los Angeles School of Medicine, Los Angeles, California. This study was supported in part by grants from the Medical Research Services of the Veterans Administration and the American Heart Association, Greater Los Angeles Affiliate. Dr. Figueras’ present address is Unidad Coronaria, Ciudad Sanitaria, Valle Hebron de la Seguridad Social, Paseo Valle de Hebron, s/n, Barcelona, Spain. Address for reprints: Bramah N. Singh, MD, Cardiology Section (691/111E), Wadsworth Veterans Administration Hospital, Wilshire and Sawtelle Boulevard, Los Angeles, California 90073.

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and silent episodes do not differ significantly with respect to duration. Most symptomatic and asymptomatic episodes are not triggered by increases in the determinants of oxygen demand. Such episodes may arise on the basis of a critical reduction in the lumen of the diseased coronary artery leading to a primary reduction in blood flow. Intermittent obstruction due to changes in coronary vasomobility or possibly formation of thrombi may be a common mechanism for the pathogenesis of myocardial ischemia in patients with a varying spectrum of coronary artery lesions. At present, the precise clinical and prognostic significance of silent ischemia in CAD is not completely defined. However, emerging data indicate that silent myocardial ischemia documented on Holter recordings is associated with significant CAD. These data also suggest the possibility that elimination of silent ischemia may be a desirable adjunctive goal for the therapy of ischemic heart disease and an additional endpoint for the evaluation of the antiischemic effects of antianginal compounds. (Am J Cardiol 1988;58:3B-108)

changes are characterized by T-wave augmentation, ST-segment elevations and depressions, R-wave augmentation and heart rate acceleration. Before these changes, there is depression of myocardial contractility, reduction in ventricular compliance, elevation of the filling pressures of the ventricles and reduction in cardiac index. Accompanying these alterations is an increase in lactate concentrations in the venous effluent from the ischemic region, another hallmark of myocardial ischemia.3 Various invasive and noninvasive techniques have now established that these overall correlates of myocardial ischemia can also be identified in man when a transient imbalance develops in oxygen supply-and-demand, particularly in the setting of obstructive coronary artery disease [CAD]. Relatively little attention has been paid to the possibility that an accurate determination of the temporal sequence of the changes in the major determinants of 38

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myocardial oxygen consumption may provide insight into the nature of individual episodes of transient ischemia in patients with CAD. Interest in this possibility has burgeoned recently with the demonstration that many episodes of ischemia in various myocardial ischemit syndromes may arise on the basis of a primary reduction blood flowe4 It has also become clear that myocardial ischemic syndromes such as chronic stable angina, unstable angina and Prinzmetal’s angina form a continuum in terms of fundamental mechanisms of causation.+0 There appears to be a complex interaction between atherosclerotic disease and coronary vasomotion.@ The dynamic nature of such an interaction has received increasing attention in recent years.6J-10 From various clinical studies in recent years 2 significant observations have emerged. First, it has become clear that in patients with CAD who are subject to angina, no less than two-thirds of ischemic episodes are clinically siIent.11-27 Second, a similar proportion of episodes in both unstable angina and chronic stable angina is not triggered by increases in the major determinants of myocardial oxygen consumption.18JgJ3-27 This article will discuss some of the evidence from our own studies on the hemodynamic and ECG changes in patients with angina in relation to the evidence from other studies, which indicate that myocardial ischemia in patients with CAD may result from both increases in oxygen demand and primary decreases in myocardial blood flow. Another aim is to reexamine the validity of the traditional concept of the pathogenesis of myocardial ischemia in CAD in light of newer observations, Finally, we will examine the therapeutic implications of the frequency and dura-

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tion of myocardial ischemia with particular emphasis on the silent episodes. The prognostic implications are discussed elsewhere in this issue but will be mentioned in brief herein for completeness.

Methods Study poptilations: The study population comprised 3 discrete subsets of patients who have been described previously. In the first, there were 23 patient.9 who were admitted to the coronary care unit for the evaluation and therapy of angina at rest as a component of unstable angina syndrome. These patients underwent continuous hemodynamic monitoring to ascertain the precise temporal sequence of the hemodynamic and ECG abnormalities accompanying episodes of symptomatic and asymptomatic myocardial ischemia. In the second,23 there were 30 patients with unstable angina (24 with CAD and 6 with normal coronary vessels but with spasm). One or more 24hour Holter recording was obtained in these patients and analyzed by compact analog technique (to be described]. In the final study! there were 22 patients26 with chronic stable angina and documented CAD and 12 patients without CAD. Patients with chronic stable angina had positive exercise treadmill test results for ischemia and those without CAD had negative treadmill tests. A11 34 patients underwent seria1 exercise treadmill tests during Holter recordings when they were not taking specific antianginal therapy. The exercise treadmill test was performed according to symptom-limited, multistage, modified Bruce protocol. Hemodynamic measurements: Arterial pressure via an indwelling radial artery cannula, right-sided heart pressures (and cardiac output intermittently) by

FIGURE 1. Sequential changes in systolic arterial pressure (SAP), diastolic arterial pressure (DAP), pulmonary artery diastolic pressure (PADP) and heart rate (HR) in patients 3 and 7 during 3 different episodes of angina at rest. Clockwise from left, the values plotted correspond to the following points obtained from continuous recordings: (1) control measurements 2 minutes before the onset of ischemic electrocardiographic changes, (2) onset of ischemic electrocardiographic changes, (3) onset of pain (A and A), (4) maximal changes and (5) after relief of pain. Note the reproducibility of the changes in SAP, DAP and PADP in both patients throughout the different episodes. Reproduced with permission from the American Heart Association.i5

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Swan-Ganz thermodilution catheter and electrocardiogram were recorded on a magnetic tape continuously for 24 to 72 hours when the patients were not taking antianginal drugs. The data were subsequently analyzed in real time in relation to the clinical events.15 Holter recordings and analysis: Twenty-four-hour Holter recordings were obtained (Del Mar Avionics Electrocardiocorder, model 445). This was loaded with a new reel of magnetic tape and a l-mV calibration test signal was recorded for 5 minutes. After the patient cable had been attached to the reel-to-reel Holter recorder, the timing clock built into the recorder was set and the patient was instructed to press the event signal button if and when chest pain supervened. In addition, the patient was requested to maintain a written diary of symptoms and activities during the entire monitoring period. The Hoiter leads used were those corresponding to V1 or VZ and V5 or lead II of the electrocardiogram. The analysis of ST-T wave changes using the compact analog technique has been described elsewhere.27 In brief, the alterations in the ST-T wave segments from the reel-to-reel recordings were analyzed by playing the tapes back on to an Oxford PB-2 d&k (Oxford Medical Instruments) into the Pathfinder electrocardiographic high-speed analyzer (Reynolds Medical] with an ST-segment plotter. The ST-segment plotter &timated the magnitude of the deviation [upward or downward) in amplitude from the baseline indicated by the horizontal line between the 2 points. The ST-segment analog signal was fed into the linear recorder at paper speed of 30 cm/hour of real-time recording. The signal was validated by printout of the abnormalities in real time.

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veloped a finite period after the onset of myocardial ischemia and over 70% of the episodes were entirely painless. Of particular interest was the finding that at the onset of the ECG and hemodynamic changes and before the onset of pain, the rate-pressure product was unchanged in 7 patients and increased slightly in 4. Transient myocardial ischemia in unstable angina: The data from Halter recordings analyzed by the compact analog technique in 30 patients with unstable angina revealed 407 episodes of transient myocardial ischemia. Only 28% were symptomatic. The frequen-

Results Hemodynamic correlates of angina at rest: During the study, 11 of the 23 patients developed reproducible episodes of ischemic pain. In every individual patient, the pattern of changes in heart rate, mean pulmonary wedge prebsure [as indicated by pulmonary artery diastolic pressure) and systolic and diastolic pressures preceding and accompanying the ischemic episodes were highly reproducible (Fig. 1). The pattern of hemodynamic alterations in symptomatic and asymptomatic episodes of ischemia was identical (Fig. 2), although those that were “silent” tended to be less severe and of a shorter duration. There was, however, considerable overlap even in the same patients; the reason why some episodes were associated with pain and others were not could not be accounted for solely by the duration of individual episodes of myocardial ischemia. Moreover, there was no detectable hemodynamic differende between the episodes of ischemia associated with ST-segment depression and those with ST-segment elevation (Fig. 3). In 7 of the 11 patients, the pulmonary artery systolic pressure was the first hemoclynamic variable to change (Fig. 2); in the remaining 4 patients, there was a coticomitant increase in the mean arterial pressure, which also increased in most patients after the onset of the ischemia as indicated by ECG changes. In all episodes, chest pain de-

FIGURE 2. The temporal sequence and the magnitude and duration of changes in heart rate (HR), arterial blood pressure (ABP) and pulmonary artery pressure (PAP) are compared in a symptbmatic, A, and an asymptomatic episode, 6, of myocardial ischemia In the same patient with angina at rest. Note the overall similarities between the 2 episodes (with a longer duration of changes in the symptomatic episodes). Based on data from Figueras et aLI

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cy of ST-segment depression was somewhat greater than that of ST-segment elevation, In 310 episodes the temporal sequence of changes in heart rate relative to the onset of &hernia indicated that in only 32 (107’0) was there a heart rate increase of 26 beats/min preceding the onset of the ischemia. In the remaining 278 episodes, there was either no change or a decrease, but during the peak of ischemia, heart rate increased in all 310 episodes. It was of particular interest that in 10 of the 30 patients given verapamil or nitrates, Holter recordings showed a mean reduction of ischemic episodes of 76%. Transient myocardial ischemia in chronic stable angiua: Twenty-four Holter recordings from 22 pa-

tients with chronic stable angina with positive exercise stresstestsand from 12patients with negative exercise stress tests and normal coronary arteries were available for analysis. Eighty-one Holter tapes (representing 1,862 hours of recording) were analyzed by the compact Holter analog technique for the frequency and duration of transient myocardial ischemia in relation to the temporal sequence of heart rate changes. Spontaneous ischemia was found to have the same characteristics as those developing during treadmill exercise [Fig. 4). Of the 58 episodes of ischemia during treadmill, 42 (72%) were associated with pain; in contrast, only 23 (16%) of the 144episodes of spontaneously occurring episodes of ischemia documented during Holter monitoring were associated with chest pain. Only 10% of the spontaneously occurring myocardial ischemic episodes had heart rate increases of 210 beats/min before the onset of ischemia. None of the patients with negative treadmill testsor normal coronary arteries had typical crescendo-decrescendo patterns of ECG or heart rate changes that were found

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with symptomatic or asymptomatic episodes of myocardial ischemia in patients with CAD.

DisGussion The overall data from our studies in patients with angina at rest, unstable angina and chronic stable angina subjected to ECG and hemodynamic monitoring or to serial Holter recordings have revealed a number of significant findings. First, episodes of myocardial ischemia in all these subsetsof patients with CAD, but not in those patients with normal coronaries, have a characteristic pattern of ST-segment and heart rate changes. The abnormalities tend to increase in a crescendo fashion to a peak and decrease in a corresponding manner. The accompanying hemodynamic abnormalities, such as in blood pressure and pulmonary artery diastolic or mean wedge pressure, exhibited a similar pattern. Second, most episodes in all the ischemic syndromes were silent. Third, over 80% to 90% of the episodes of ischemia were not preceded by significant increases in heart rate. These findings, which confirm and extend previous observations, have important clinical implications. Nature of symptomatic and silent ischemia in angina at rest and unstable angina: The evidence is now

compelling that Prinzmetal’s or variant angina results from a primary reduction in blood flow in patients regardless of whether or not they have CAD.5,28,2g That most episodes of myocardial ischemia in hospitalized patients with angina at rest and unstable angina also occur without being triggered by increases in myocardial oxygen demand is emphasized by our data. Such data have also been derived by others from reasonably precise evaluation of the temporal sequence of changes in the ECG, hemodynamic and metabolic ac-

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companiments of ischemia monitored continuously for deprolonged periods of time 5~8,~~s with intermittent termination of perfusion deficits by radionuclide scintigraphy.lgJg The findings are in accord with results of Berndt et a1,30 who reported that the rate-pressure product was significantly lower at the onset of spontaneous ischemia than that at angina1 threshold during atria1 pacing in patients with CAD with unstable angina. These overall data are clearly consistent with the possibility that a primary reduction in myocardial perfusion may represent a fundamental mechanism of angina at rest in many patients with CAD. Maseri,2g Chierchialg and their co-workers found that thallium201 myocardial scintigrams obtained during spontaneous angina1 episodes revealed a reversible defect in tracer uptake. This is also consistent with a reduction in regional myocardial blood flow during an episode of ischemia. Numerous angiographic studies during attacks of spontaneous angina have consistently showed reversible coronary artery spasm.5 Particularly convincing are the observations of Chierchia et al,lg who continuously monitored the electrocardiogram, left ventricular pressure and its first derivative and great cardiac vein oxygen saturation by a fiberoptic catheter system in patients with frequent attacks of angina at rest. In all cases of anterior wall ischemia, whether symptomatic or silent, the onset of ECG and hemodynamic alterations was preceded by a large decrease in oxygen saturation in the great cardiac vein. Such changes were followed consistently by signs of left ventricular dysfunction (increases in left ventricular end-diastolic pressure and in negative and positive left ventricular (dP/dt) but were never preceded by detectable increases in the hemodynamic determinants of myocardial oxygen consumption. Thus, one must conclude that a significant number of episodes of ischemia in patients with angina at rest are produced by primary alterations in regional myocardial blood flow rather than by increases in the oxygen demand. This finding has therapeutic significance. Our data from Holter monitoring in patients with unstable angina-indicating that most episodes of ischemia in this syndrome are clinically silent and not triggered by increases in heart rate-are in agreement with those previously reported. For example, Biagini et all8 analyzed 520 episodes of transient myocardial ischemia (180 with ST-segment elevation, 73 with STsegment depressions and 267 with T-wave alterations] in 11 patients monitored over 89 days in the coronary care unit. They found only 12% of the episodes were symptomatic. In 7 patients, an ergonovine test done during coronary angiography induced angina, ST-T wave changes and coronary spasm, suggesting a marked overlap with Prinzmetal’s angina. Symptomatic and asymptomatic episodes of myocardial ischemia in chronic stable angina: Continuous ambulatory monitoring has been applied sporadica11ylW427,30,31 t o evaluate ST-T wave changes in patients with CAD since Stern and his colleaguesllJ2 pioneered its use in the detection of transient myocardial ischemia during daily activities. In recent years,

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interest in this technique has burgeoned especially with the availability of improved recorders and scanning techniques17,22*23-27 and with the growing interest in defining the pathogenetic mechanisms producing ischemia in the setting of CAD. As with angina at rest and unstable angina, 2 salient features have emerged. Although the occurrence of silent myocardial ischemia in patients with CAD has been known for many years,11J2 it is now clear that, in number, silent episodes in chronic stable angina greatly exceed those associated with chest pain or its equivalents.21J2~26 Our most recent data are concordant. Unexpectedly, most episodes of transient ischemia detected by continuous ambulatory monitoring in chronic stable angina do not appear to be triggered by increases in the major determinants of myocardial oxygen consumption.21,26 Similar data have been reported by Cecchi,21 Deanfield22 and their co-workers. Cecchi et al21 found that asymptomatic episodes in patients with effort angina were more frequent than symptomatic ones; they were of a shorter duration and tended to have a greater STsegment depression although there was a considerable overlap in both parameters between symptomatic and asymptomatic episodes. Deanfield et a122subjected 30 patients with chronic stable angina and positive stress tests to long-term Holter monitoring during daily life.

FIGURE 4.’ Examples of myocatdial ischemic episodes from compact analog analysis of Holter recordings from a patient with chronic stable angina. A, shows changes in heart rate and ST segment during treadmill exercise; S, shows spontaneous transient ischemia episode wtth pain; C, shows that an episode of &hernia occurring spontaneously is similar to that with exercise, but the heart rate at peak ST-segment change is slower. Both episodes demonstrate the crescendo-decrescendo pattern of electrocardiographic abnormality characteristic of myocardial ischemia. TM = transient myocardial ischemia.

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They found further support for the concept that most dromes in the setting of significant coronary artery episodes in such patients are produced by primary lesions, myocardial ischemia appears to develop as a decreases in myocardial blood flow. Of the 1,934 epi- result of changes in coronary vasomotion4 or possibly sodes of ischemia identified in 446 days of ambulatory as a consequence of intermittent thrombus formaECG recordings, only 470 (24%) were associated with tion.33The precise mechanisms governing such alterangina. The fact that the asymptomatic episodes were ations in individual patients with angina remain to be indeed ischemic in origin was confirmed by positron elucidated. emission tomography because there was no significant A current perspective that encompasses the interdifference between symptomatic and asymptomatic actions among the morphologic characteristics of the episodes with respect to regional myocardial ischemia. atherosclerotic plaque, blood flow across the stenosis In terms of the mechanism of ischemia production, it and the potential mechanisms of coronary vasomotion was found that the heart rate at the beginning of both was recently summarized by Brown6 and Brown et The essential features are illustrated in Figure 5. symptomatic and asymptomatic episodes of spontane- a1.8Tg ous ischemia was significantly lower than that at the It provides a conceptual framework for the genesis of onset of ST-segment depression during exercise test- myocardial ischemia in CAD and for evaluating the ing. Because heart rate increase was uncommon be- mechanisms of antiischemic and antianginal drugs. fore the onset of myocardial ischemia in this study as The central feature is that most of the human coronary well as in othersz1J6previously discussed, it is clear stenosesare compliant. It has been shown that in about that most episodes of myocardial ischemia occurring 70% of significantly narrowed histologic sections of during daily life in patients with chronic stable angina human coronary arteries the lumen is eccentrically are unlikely to be due to increases in myocardial oxy- constricted, being partially circumscribed by an arc of about 60’ of normal arterial wa11.34The presence of gen demand. such a pliable arc of normal wall in 70% of arterial Dynamic behavior of coronary artery stenosis in man and development of myocardial ischemia: The stenoses has the potential to alter stenosis flow resisevidence discussed so far clearly suggeststhat in the tance in the event of a change in intraluminal pressure development of ischemia in various myocardial isch- or coronary vasomotor tone. Detailed studies in man emit syndromes (such as Prinzmetal’s angina, unsta- by Brown et al* using computer-assisted quantitative ble angina and chronic stable angina] in patients with angiography and a large number of physiologic and CAD, a primary reduction in myocardial blood flow pharmacologic vasodilator and vasoconstrictor interplays a significant role. Such a reduction may be relat- ventions have established the dynamic nature of the ed to a focal “spasm” due to localized hypersensitivity coronary artery stenosis behavior. These observations of a segment of a coronary artery; this phenomenon is in the intact coronary circulation are in line with the best demonstrated in the relatively few patients who quantitative pharmacologic responses of normal and have Prinzmetal’s angina in the context of little or no atherosclerotic isolated human epicardial coronary aratherosclerotic lesions.32However, it is possible that in teries removed from patients undergoing transplantamost patients with various ischemic myocardial syn- tion.35 As suggested by Brown8 an interaction among RELATING LESION STRUCTURE TO CLINICAL PRESENTATION IN THE SPECTRUM OF ANGINA SYNDROMES MORPHOLOGIC YOUNG, IN-TWA

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FIGURE 5. Relation of lesion structure to clinical presentation in the spectrum of angina syndromes; effects of ordlnary vasoconstrlction In normal and diseased coronary arteries. In portions of the vessel with relatively normal wall, transient 10% lsovolumetrlc circumferential shortening may cause dramatic changes in lumen caliber. Percentage of dlameter reduction Is relative to orlglnal 2.9-mm lumen and corresponds to absolute luminal area and an associated angina1 syndrome: 49% stenosis, 1.7 mm*, no Symptoms; 00%, 1.0 mm’, exertional angina; 76%, 0.35 mm*, subendocardial infarction. Reproduced with permission from Arch Intern Med.6

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stenosis morphology, stenosis severity and degrees of constriction of the normal arterial segments provides the basis for a plausible hypothesis to account for the development of myocardial &hernia in patients with angina at rest, unstable angina, chronic stable angina or in those with so-called mixed angina. The mechanism for the development of ischemia in nocturnaP5 or postprandial angina16 is also likely to be similar. It is evident that if ischemia were precipitated by vasoconstriction alone or by intermittent thrombus formation, the change in heart rate at the onset of the ischemic episode will either be little or none. However, because an increase in heart rate is almost invariable following the onset of ischemia, an increase in oxygen demand engendered by cardiac acceleration is likely to aggravate further the existing ischemia. Prognostic and therapeutic implications of silent ischemia: Two significant questions arise when discussing the prognostic and therapeutic implications of these newer findings. First, what is the prognostic implication of the large number of asymptomatic episodes of myocardial ischemia detected by continuous Holter monitoring in various subsets of patients with CAD? Second, what is the clinical significance of the observation that most episodes of myocardial ischemia, asymptomatic and symptomatic, in such patients are not initiated by increases in the major determinants of myocardial oxygen consumption? Both issues are of much practical importance. Two related issues need to be considered. The first is the endpoint of therapy of CAD. Before the advent of surgery for CAD, the major emphasis was the relief of symptoms referable to myocardial ischemia by pharmacologic therapy. The demonstration that adequate myocardial revascularization can prolong survival in certain subsets of patients has raised the question of whether this can also be achieved by appropriate medical therapy. The most convincing evidence for this stems from the data from the numerous clinical trials in the survivors of acute myocardial infarction given prophylactic p blockade. 36 The fundamental mechanism underlying the reduction in sudden death and reinfarction induced by @ blockade in such patients remains uncertain. It is not clear whether the salutary effect stems from a reduction in ischemic episodes or from a primary antiarrhythmic action or other associated effects of fl-adrenergic blocking drugs. If the beneficial effect were mediated through the elimination of myocardial ischemia, clearly then the endpoint of medical therapy of CAD should focus not only on the relief of symptoms but also on the elimination of symptomatic and asymptomatic episodes of myocardial ischemia. The preliminary data from studies of patients with unstable angina by Johnson,37 Nademanee25 and their co-workers indicate that the elimination of symptoms alone may not ensure favorable outcome. The experience of Nademanee et a125 suggests that silent ischemia persisting after symptomatic control had been attained by medical therapy was associated with clinically significant coronary events. Thus it appears that therapy may need to be designed not only to alleviate symptoms of ischemia but also the

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ischemia itself to prevent the occurrence of myocardial infarction and sudden death. For this reason, in evaluating newer medical therapies of angina the endpoints to define efficacy should include the reduction or elimination of both silent and symptomatic episodes of myocardial ischemia in patients with CAD. The second issue pertains to the question of the efficacy of various antianginal [which should probably be termed antiischemic) agents in controlling myocardial ischemia relative to the finding that most episodes of ischemia in unstable and stable angina are not triggered by increases in the determinants of myocardial oxygen consumption. Whether such episodes are triggered by platelet thrombi or by alterations in vasomotor tone of the coronary arteries remains uncertain. It is known that such agents as nitrates7 and calcium antagonist&38,39 dilate coronary artery lesions and lesion dilatation may constitute a significant mode of antiischemic action of these classes of drugs. If changes in coronary vasomotor tone were a major mechanism for the initiation of ischemia in man, then the use of coronary vasodilators should be considered an integral part of the overall regimen for the treatment of patients with angina. Nevertheless, it is of interest that a recent multicenter cooperative study has demonstrated that aspirin, a platelet-active agent, was superior to placebo in preventing myocardial infarction in patients with unstable angina .40 There is also the possibility that in those subsets of patients in whom ischemia arises solely on the basis of focal spasm, ,&adrenergic blocking drugs may be ineffective or possibly deleterious. This was reported in Prinzmetal’s angina;41 however, a detailed but limited study comparing the efficacy of propranolol and verapamil in unstable angina also indicated that the p blocker had no effect on symptomatic and asymptomatic episodes of ischemia whereas the calcium antagonists reduced them both significantly.42 Beta-blocking drugs have been used widely for over 2 decades in the control of angina, yet controlled data documenting their potential to aggravate ischemia have not been reported. They could exert a beneficial effect even in episodes of ischemia triggered by abnormal vasomotor tone by attenuating the heart rate increases following the onset of ischemia, thereby curtailing the overall duration of individual episodes of ischemia. Clearly, further carefully controlled studies are needed to define the precise mode of actions of various antianginal agents relative to the genesis of different ischemic myocardial syndromes in patients with CAD. Such studies could provide a rational basis for the medical therapy of ischemic heart disease. Also, if the growing data on the significance of the frequency and duration of myocardial ischemia determined by continuous ECG monitoring are substantiated, a major change in the endpoints for judging efficacy of therapy of angina and for evaluating the newer antianginal/antiischemic compounds will result. Acknowledgment: We are indebted to Lawrence Kimble for secretarial assistance and to Medical Media of the Wadsworth Veterans Administration Hospital for illustrations and photography.

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References 1. Hess ML, Barnhart GR, Crute S, Komwatana P, Krause S, Greenfield LJ. Mechanical and biochemical effects of transient myocardial ischemia. J Surg Res 1979;26:175-184. 2. Heyndricks GR, Millard RW, McRitchie RJ, Maroko PR, Vatner SF. Regional myocardial functional artery occlusions in conscious dogs. f Clin Invest 1975;56:978-985. 3. Braasch W, Gudbjarnason S, Puri PS, Ravens KG, Bing RJ. Early changes in energy metabolism in the myocardium following acute coronary artery occlusion in anesthetized dogs. Circ Res 1968;23:429-438. 4. Maseri A. Pathogenetic mechanisms of angina pectoris: expanding views. Br Heart f1980;43:648-660. 5. Maseri A, Severi S, De Nes M, L’Abbate A, Chierchia S, Marzili M, Ballestra AM, Parodi 0, Biagini A, Distante A. “Variant angina”: one aspect of a continuous spectrum of vasaspastic myocardial ischemia. Am J Cardiol 1978;42:1019-1025. 6. Brown BG. Coronary vasospasm: observations linking the clinical spectrum of ischemic heart disease to the dynamic pathology of coronary atherosclerosis. Arch Intern Med 1981;141:716-722. 7. Brown BG. Bolson EL, Peterson RB, Pierce CD, Dodge DT. The mechanisms of nitroglycerin action: stenosis vasodilation as a major component of the drug response. Circulation 1981;64:1089-1094. 6. Brown BG, Bolson EL, Dodge HT. Dynamic mechanisms in human coronary stenosis. Circulation 1984;70:917-922. 9. Brown BG, Lee AB, Bolson EL, Dodge HT. Reflex constriction of significant coronary stenosis as a mechanism contributing to ischemic left ventricular dysfunction during isometric exercise. Circulation 1984;70:18-25. 10. MacAlpin RN. Relation of coronary arterial spasm to sites of organic stenosis. Am 1 Cardiol1980;46:143-149. 11. Wolf E, Tzivoni D, Stern S. Comparison of exercise stress tests and 24-hour ambulatory electrocardiographic monitoring of ST-T changes. Br Heart / 1980;86:501-506. 12. Stern S, Tzivoni D. Early detection of silent ischaemic heart disease by24 hour electrocardiographic monitoring of active subjects. Br Heart f 1974;36: 481-485.

13. Allen RD. Gettes LS, Phalan C, Avington D. Painless ST-segment depression in patients with angina pectoris. Chest 1976;69:467-473. 14. Schang SJ, Pepine CJ. Transient asymptomatic ST segment depression during daily activity. Am J Cardiol1977;39:297-302. 15. Figueras J, Singh BN, Ganz W, Char& Y, Swan HJC. Mechanism of rest and nocturnal angina: observations during continuous hemodynamic and electrocardiographic monitoring. Circulation 1979;59:955-966. 16. Figueras J, Singh BN, Ganz W, Swan HJC. Hemodynamic and electrocardiographic accompaniments of resting postprandial angina. Br Heart J 1979;42:402-410. 17. Bala Subramanian V, Lahiri A. Green HL, Stott FD, Raftery EB. Ambulatory ST segment monitoring: problems, pitfalls, solutions and clinical applications. Br Heart f1980;44:419-425. 16. Biaaini A, Mazzei MG, Carpeggiani C, Testsa R, Antonelli R, Michelassi _ __ C, L’Agbate A, Maseri A. Vasospastic ischemic mechanism of frequent asymptomatic transient ST-T changes during continuous electrocardiographic monitoring in selected untable angina patients. Am Heart J 1980;103:13-19. 19. Chierchia S, Brunelli C. Simonetti I, Lazzari M, Maseri A. Sequence of events in angina at rest: primary reduction in coronary flow. Circulation 1980;61:759-764. 20. Cocco G, Brown G, Strozzi C, Leishman B, Chu B, Rochat N. Asymptomatic myocardial ischaemio in patients with stable and typical angina pectoris. Clin Cardiol1982;5:403-408. 21. Cecchi A, Dovellini EV, Morchi F, Pucci P, Santa-oro GM, Fazzini PF. Silent myocardial ischemia during ambulatory electrocardiographic monitoring in patients with effort angina. JACC 1983;1:934-939. 22. Deanfield JE. Maseri A, Selwyn AP, Ribeiro P, Chierchia S, Krikler S, Morgan M. Myocardial ischaemia during daily life in patients with stable angina: its relation to symptoms and heart rate changes. Lancet 1983;2: 753-758.

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