New Insights into the Management of Myocardial lschemia Alan C. Yeung,
MD,
Khether E. Raby,
MD,
EpisodesofSTdepressionarecloselyrelatedto transient deaeaws in regional myocardial perfusion during physkal or mental stress. At the onset of these events, there is transient constrktionofaUwosclerotk&enoses,wtthan increase in myocardial demand as reflected by i-ses in heart rate and blood pressure. Recent research has shown that normal epicardial coronary arterks respond to these provocations andtoi -ing blood flow with progressive vasodilation. In contrast, atherosclerotkvessels lose this ability to dilate and may show paradoxical constrktion. This abnormal constrktion parallels the response of the arteries to acetykholine, whkh can be used to assess the ability of the coronary endothelium to regulate vasodilation. The loss of eWothelhnndependent vasodilation appears to be an important functional manifestation of coronary athe rosdemsls and a potential triggeri~ mechanism for transient ischemia. Dysfunctional endothelium may also result In a procoagulant surface, wRh cell adherence and local thrombus formation. Restoration of normal endothelial function is likely to emerge as an important therapeutic objectfve in the management of myocardlal ischemia and coronary atherosclerosis. (Am J Cardiol1992;70:8ol3G)
From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. Address for reprints: Andrew P. Selwyn, MD, Cardiovascular Division, L2, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. 80
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
Peter Ganz,
MD,
and Andrew P. Selwyn,
MD
T
ransient myocardial ischemia is an important functional expression of coronary artery disease. Although angina is a typical herald of ischemia, it does not occur prior to the majority of adverse coronary events. Episodes of ST depression are closely related to transient decreases in regional myocardial perfusion in response to such provocations as exercise, exposure to cold, and mental stress. Recent research indicates that atherosclerotic arteries lose their ability to dilate in response to such stimuli and instead constrict inappropriately. Experimental and clinical studies suggest that the loss of endotheliumdependent vasodilation is an important consequence of hypercholesterolemia and coronary atherosclerosis and represents a potential pathogenic mechanism for transient myocardial ischemia. These findings may prove of value in the treatment of myocardial ischemia, the control of atherosclerosis, and the prevention of adverse coronary events. TRANSIENT ISCHEMIA: PROGNOSIS
PREVALENCE AND
Most clinicians would agree that, in patients with coronary artery disease, the presence and severity of transient ischemia provide a measure of the risk of adverse coronary events. A familiar clinical problem is that, although the majority of ischemic episodes that occur in middle-aged individuals with cardiovascular risk factors are completely asymptomatic, these transient events are also highly associated with the presence of atherosclerotic stenoses in the proximal epicardial arteries. The prevalence of ischemia varies greatly, depending on the clinical diagnosis. It is important to emphasize that this prevalence is < 10% in unselected populations with no symptoms, no history of coronary artery disease, and few risk factors. For this reason, screening is not worthwhile in these open populations. In contrast, active ischemia during exercise testing or ambulatory monitoring is quite frequent in populations with chronic stable
NOVEMBER 27, 1992
coronary disease or unstable angina and among survivors of myocardial infarction, coronary artery bypass grafting, or cardiac arrest.’ Even in patients who present with peripheral vascular disease, ambulatory monitoring and dipyridamole thallium studies reveal a 16-20% prevalence of unsuspected but active ischemia.*y3 Thus, in these high-risk populations, the prevalence of ischemic episodes must be considered, whether or not an individual complains of angina. In patients with chronic stable coronary artery disease, the severity and extent of ischemia on thallium stress testing correlate with the event rate on subsequent follow-up.4 It is interesting to note that the risk of myocardial infarction or death is extremely low for approximately 2 years in patients with chronic stable coronary disease who have positive exercise tests and proven atherosclerosis but who show no active ischemia on ambulatory monitoring while off medication.5 After 2 years, however, these patients begin to experience adverse events, presumably because of progression of the underlying coronary disease. In contrast, the occurrence of active ischemia on Holter monitoring is associated with a worse prognosis, even when it is the single distinguishing clinical feature. Patients with asymptomatic ischemia show better event-free survival than those with symptomatic ischemia at the outset, but this advantage is lost within 3 years (Figure 1). By 5 years, patients with asymptomatic and symptomatic ischemia experience the same prognosis.
suggests that endothelial dysfunction in atherosclerosis permits the growth of stenotic lesions and the appearance of paradoxical constriction. The coronary vascular endothelium is a responsive organ that, in and of itself, can transduce signals from the intravascular environment, including blood pressure, pulse pressure, and acetylcholine stimulation of muscarinic receptors. In addition, many products of platelets and thrombin can stimulate the endothelium to exert its own local vasodilating effect on vascular smooth muscle cells. Thus, in the healthy intact organism, the endothelium regulates a defensive local vasodilating response. Within the endothelial cell, in response to appropriate stimuli, nitric oxide is cleaved off the terminal guanidino group of the amino acid L-arginine. The short-lived nitric oxide then diffuses locally, reaching the vascular smooth muscle cells, where it acts on cyclic adenosine monophosphate, producing vasodilation through a mechanism not dissimilar to the therapeutic effects of nitroglycerin. We know from experimental studies that this very fragile and easily disturbed vasodilator system can be impaired by increased levels of low-density lipoprotein (LDL), particularly oxidized LDL; by hypertension; and by the early changes of atherosclerosis. These findings are directly relevant to coronary artery disease in our patients. Smooth coronary arteries can exhibit endothelium-dependent vasodilation in response to acetylcholine (1O-s-1O-6 M), a local and specific test of endothelial function, or in response to more complex sympathetic stimuli such as mental stress (Figure 2A). Our group has demonstrated in patients undergoing diagnostic catheterization that atherosclerotic coronary arteries lose their dilator response and develop constriction in response to either acetylcholine or mental stress (Figure 2B).6 Interestingly, the vasomotor response to mental stress correlates with the
ATHEROSCLEROSIS, ENDOTHEUAL DYSFUNCTION, AND VASOCONSTRlCTlON Sympathetic stimulation: What is the role of increased myocardial oxygen demand and decreased coronary blood supply in causing the ischemia associated with such common events as exercise, mental stress, and exposure to cold? These events are almost always accompanied by an increase in neural and circulating sympathetic activity, blood pressure, and heart rate, resulting in 25 vs 7 events increased myocardial demand. At the same time, ‘4yp = 0.009 normal epicardial coronary arteries respond to this increase in demand associated with sympathetic stress with increased coronary blood flow and modest vasodilation of the large epicardial vessels. 0 20 40 60 80 Atherosclerotic vessels, in contrast, lose this vasodiFollow-up months lator response and develop constriction of varying degrees during sympathetic arousal. Interestingly, FlWREl.PrdcUvevahmofSTdepmdonInpatknts however, these vessels retain their ability to dilate wtth chronk stde anglna. --- = no ST depmeskn; - = ST depmsdon, abymptomatlc; -.-. = ST depm, in response to nitroglycerin. Evidence from basic as well as clinical research
--_ I
A SYMPOSIUM:
OPTIMIZING
ANTIANGINAL
THERAPY
St?
I
I
1
I
I
I
I
I
C ACh ACh ACh Ret MS NTG 1o-6 1o-7 1o-6
Molar 20 B q e $ %
lo-
FIGURE PA Response of a s4noothldtantdordescwhg (~)aMB~a-W chollno(ACh)andmmtalstroas (MG). G. Reqanse ofastenotk leltanblor -WI am-toandmeMdstressC=contrd; gfzlL=r mkshlkomNEn@JMed.@)
o-
.s -10 n d -20 -30
I
C
I
I
I
ACh ACh Ret 10-6 10”
I
MS
lNTG
Molar
response to acetylcholine (r = 0.58, p 220 mg/dL, endothelial function is lost even in coronary arteries without angiographic evidence of atherosclerotic lesions. There is both clinical and experimental evidence that endothelial dysfunction occurs very early in the development of atherosclerosis.” In the macaque monkey, endothelium-dependent vasodilation is lost with hypercholesterolemia but can be restored if hyperchol15
esterolemia is corrected, even in the presence of subintimal thickening, which takes a longer time to regress.12Clinical research studies in patients are currently investigating whether endothelial abnormalities can be reversed and appropriate vasodilator and anticoagulant functions restored in patients with atherosclerosis by administering antioxidants such as probucol, by decreasing LDL levels, and in the future by increasing high-density lipoprotein levels. Studies in patients show that lowering plasma cholesterol, particularly LDL cholesterol, results in very modest physical regression of coronary atherosclerosis but much more substantial reductions in adverse coronary events.13 This suggests that improvements in the functional aspects of the physiology of atherosclerosis are not only possible but are likely more important in patients. The Multiple Risk Factor Intervention Trial (MRFIT), for example, demonstrated that patients with manifest coronary artery disease will benefit from cholesterol lowering, blood pressure control, and smoking cessation. l4 Further support for this concept comes from the more recent Familial Atherosclerosis Treatment Study (FATS),15 which showed that intensive lipid-lowering therapy reduces the frequency of progression of coronary lesions and the incidence of cardiovascular events in men with coronary artery disease who are at high risk. EFFECTS OF ANTI-ISCHEMIC THERAPY ON PROGNOSIS Much more is known about the effects of antiangina1 drugs on ischemia than about their influence on patient outcome. For example, it is known that any decrease in the frequency of ischemic episodes achieved by a l3 blocker or a dihydropyri-
1
l
,I
-5 -10 -15 -20 -25 -30 100
150
200
Total cholesterol
A SYMPOSIUM:
OPTIMIZING
250
300
(mg/dL)
ANTIANGINAL
THERAPY
iiQ
dine calcium antagonist, or a combination of the 2, is significant and dose-dependent and that various antianginal agents have differential effects on ischemia occurring at low heart rates versus high heart rates. Studies in patients using ambulatory electrocardiographic monitoring have demonstrated that (3 blockers may actually increase the incidence of ischemic events at low heart rates but exert a beneficial effect on ischemia at intermediate and high heart rates. l6 In contrast, transcutaneous nitroglycerin reduces ischemia at low heart rates but worsens the events at high heart rates. These opposite but complementary actions may stem not only from the drugs’ overall effects on heart rate and myocardial demands, but also from differences in their effects on coronary blood supply. A multicenter study funded by the National Heart, Lung, and Blood Institute is underway and addresses the issue of whether the relief of ischemia can reduce adverse coronary events in patients. At present, there is only minimal evidence that medical therapy affects prognosis, with the exception of l3 blockers and aspirin in certain subsets of coronary patients.17 Surgical treatment has been shown to improve survival relative to medical treatment in patients with obvious evidence of ischemia in noninvasive test results, although it offered no advantage in those who had normal or only mildly abnormal test results, i.e., no ischemia.18 CONCLUSION The dysfunctional endothelium that characterizes coronary atheroslerosis results in the loss of normal endothelium-mediated vasodilator responses to physical and mental provocations and also leads to the development of a procoagulant surface, with cell adherence and local thrombus formation. Active ischemia in patients with coronary lesions appears to arise from this disordered cell biology, i.e., abnormal growth of stenosis, constriction, and thrombosis, all of which increase the patient’s risk of adverse outcomes. In the future, the restoration of normal endothelial functions is likely to become a major goal in the long-term control of coronary atherosclerosis and prevention of adverse coronary events. REFERENCES L Selwyn AP, Yeung AC, Ryan TJ, Raby KE, Bany J, Ganz P. Pathophysiology of ischemia in patients with coronary artery disease.F?wgCardiovuscDis 199&35:27-39. 2. Raby KE, Goldman L, Creager MA, Cook EF, We&berg MC, Whittemore AD, Sem AP. Correlation between preoperative ischemiaand major cardiac eventsafter peripheral vascular surgery.N EnglJMed 1989;321:1296-1300.
I20
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
3. Mangano DT, Browner WS, Hollenberg M, London MJ, Tubau JF, Tateo IM. Association of perioperative myocardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac surgery. The study of perioperative ischemiaresearchgroup. N Engl J Med 1990;323:1781-1788. ALadenheim ML, Pollock BH, Rozanski A, Berman DS, Staniloff HM, Forrester JS, Diamond GA. Extent and severity of myocardial hypoperfusion as predictors of prognosisin patients with suspectedcoronary artery disease.J Am Cd cardio119863464-471. 5. Yeung AC, Bany JB, Orav J, BonassinE, Raby KE, Selwyn AP. Effects of asymptomaticischemia on long-term prognosis in chronic stable coronary dis ease.circulation 1991;83:1598-1604. 6. Yeung AC, Vekshtein VI, Krantz DS, Vita JA, Ryan TJ Jr., Ganz P, Selwyn AP. The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress.N Engl J Med 1991;325:1551-1556. 7. Gordon JB, Ganz P, Nabel EG, Fish RD, ikbede J, Mudge GH, Alexander RW, Selwyn AP. Atherosclerosis influences the vasomotor responseof epicardial wronaly arteries to exercise.J ChinInvest 1989;83:1946-1952. 8. Zeiier AM, Drexler H, WoIlschlager H, Just H. Modulation of coronary vasomotor tone in humans. Progressiveendothelial dysfunction with different early stagesof coronary atherosclerosis.Circulation 1991;83:391401. 9. Vita JA, Treasure CB, Yeung AC, Vekshtein VI, Fantasia GM, Fish RD, Ganz P, Sehvyn AP. Patients with evidence of endothelial dysfunction as assessedby acetylcholine infusion demonstrate a marked increasein sensitivity to the constrictor effects of catecholamines.Cirrulahon 1992,85:13~1397. 10. Martin W, Furchgott RF, Viiani GM, Jothiinandan D. Depression of wntractik responsesin rat aorta by spontaneouslyreleased endothelium derived relaxing factor. JPhys E~J 7’kr 1986;237:529-538. Li Heistad DD, Armstrong ML, Marcus ML, Piegors DJ, Mark AL. Augmented responsesto vasownstrictor stimuli and hypercholesterolemiain atherosclerotic monkeys.Circ Res 1984;54:711-718. l2.Harrison DJ, Armstrong ML, Freiman PC, Heistad DD. Restoration of endothelimn dependent relaxation by dietary treatment of atherosclerosis.J CIin Invest 1987;80:1808-1811. 13. Tyroler Hk Cholesterol and cardiovasculardisease.An ovetiew of Lipids Research Clinics (LRC) epidemiologic studies as background for the LRC coronary primary prevention trial.dm J Cardid 1984;54314C-19C. iA The Multiple Riik Factor Intervention Trials (MRFIT). A national study of primary prevention of coronary heart disease.JAMA 197@235:82.%27. lS. Buxvn G, Albers JJ, Fisher LD, Schaefer SM, Lm J-T, Kaplan C, Zhao X-Q, B&on BD, Fitzpatrick VF, Dodge HT. Regression of wronary artery diseaseas a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990,323:128%1298. l6. McLenachan JM, Weidmger FS, Barry J, Yeung A, Nabel EG, Rocw MB, Seh+ynAP. Relations behveen heart rate, ischemia, and drug therapy during daily life in patients with coronary artery disease. Cimdafion 1991;83:12631270. 17. Lim R, Dyke L Dymond DS. Effect on prognosisof abolition of exercise induced painlessmyocardial ischemiaby medical therapy.Am J Car&~ 1992,69: 733-735.
18. VamauskasE, and the European Coronary Surgery Study Group. Twelveyear follow-up of survival in the randomized European Coronary Surgery Study. N Engl J Med 1988;319:332-337. 19. Vita JA, Treasure CB, Nabel EG, McLenachan JM, Fish RD, Yeung AC, Vekshtein VI, Selwyn AP, Ganz P. Coronary vasomotor responseto acetylcholine relates to risk factors for coronary artery disease.Circu’afion 1990;81:491497.
DISCUSSION Participant: Does hypertriglyceridemia, in the absence of hypercholesterolemia, alter the endothelial response to acetylcholine? Dr. Amlrew Selwyn: That is an interesting point, since in some clinical settings hypertriglyceridemia is an independent risk factor for atherosclerosis and for coronary events. There is very little information about the influence of triglycerides on endothelial function, since the majority of studies to date have examined the effects of increased LDL, oxidized LDL, and, to a lesser extent, shear force and blood pressure. NOVEMBER 27, 1992
Partldpant: Have you attempted to block the action of nitric oxide to confirm that it is actually an endothelial function that mediates the vascular response to stress? Dr. sehvyn: Administration of very small quantities of free hemoglobin and monomethylarginine into the coronary circulation abolishes the vasodilator response to stress, increased blood flow, and acetylcholine. Most studies have shown that the change from dilation to constriction depends on the function or dysfunction of the endothelium. This is not to say that endothelial dysfunction is the only abnormality in atherosclerosis, but it does appear to be a reasonable barometer of atherosclerotic damage. Partidpant: Do atherosclerotic coronary arteries constrict in response to stress because they are more sensitive to circulating catecholamines? Dr. Selwyn: According to the work of Martin et al,1° in the healthy endothelium, there is continuous basal release of endothelium-derived relaxing factor (ERDF) under normal conditions and pulsed release in response to stress. Loss of the ability of the endothelium to release EDRF accounts for the shift in the vascular dose-response curve to norepinephrine and to phenylephrine. Partidpant: Could you summarize your perspective on the heart rate changes that precede episodes of ischemia? Dr. Selwyn: Most ambulatory monitoring studies have shown that a small increase in heart rate (a median of 15 beats/min) precedes the onset of >70% of episodes of ST-segment depression. These periods of increased heart rate last an average of 30 minutes. In contrast, equal increases in heart rate that are short lived are not associated with ischemia. Thus, unlike ischemic episodes observed during the Bruce protocol, the majority of ischemic episodes that occur outside the hospital appear to be associated with modest increases in heart rate of long duration. Partidpant: You described differences in therapeutic response based on the resting heart rate. Are there any differences in heart rate changes in individuals with low versus intermediate versus high heart rates?
Dr. Selwyn: It is difficult to distinguish between the effect of the l3 blocker because they reduce heart rate throughout the day but could also modify the mechanisms at the onset of ischemia. Beta blockers can reduce heart rate below the range that precedes ischemia. Despite this, ischemia continues to occur at lower heart rates. The puzzle is that the incidence of ischemic events at low heart rates actually increases with l3 blockade. Partidpant Could you speculate about the adverse effects of the p blockers in increasing atherogenesis at the same time that they protect against rapid heart rates? Dr. Selwyn: The effect of the l3 blockers actually represents the net effect of several different actions, including antiarrhythmic activity, anti-ischemit activity, and decreased myocardial oxygen consumption (MV02). Theoretically, there is reason to believe that B blockade removes the dilating effect of p stimulation on the epicardial arteries, leaving (Yconstriction unopposed. In fact, coronary resistance is slightly worse at rest during B blocker therapy. However, these effects are balanced by the stronger effect of decreased MV02 throughout the day. Thus, the net effect is a significant reduction in the overall frequency and duration of ischemia, despite the increased frequency of low heart rate ischemic episodes. Partkipant: Could you comment on the clinical implications of the increased frequency of low heart rate ischemic episodes? Dr. Selwyn: One possibility is that p blockade eliminates high heart rate ischemic events, so that the ischemia that remains simply appears in the lower heart rate range. A second possibility is that B blockers are more effective in abolishing ischemit events triggered largely but not exclusively by an increase in MV02. Thus, the remaining ischemit episodes are caused primarily by problems with coronary blood supply. It might be of interest to investigate whether such supply-side ischemic events provide important prognostic information and whether they reveal anything about the pathophysiologic activity of the coronary disease at the time they occur.
A SYMPOSIUM:
OPTIMIZING
ANTIANGINAL
THERAPY
130
MD,
Khether E. Raby,
MD,
EpisodesofSTdepressionarecloselyrelatedto transient deaeaws in regional myocardial perfusion during physkal or mental stress. At the onset of these events, there is transient constrktionofaUwosclerotk&enoses,wtthan increase in myocardial demand as reflected by i-ses in heart rate and blood pressure. Recent research has shown that normal epicardial coronary arterks respond to these provocations andtoi -ing blood flow with progressive vasodilation. In contrast, atherosclerotkvessels lose this ability to dilate and may show paradoxical constrktion. This abnormal constrktion parallels the response of the arteries to acetykholine, whkh can be used to assess the ability of the coronary endothelium to regulate vasodilation. The loss of eWothelhnndependent vasodilation appears to be an important functional manifestation of coronary athe rosdemsls and a potential triggeri~ mechanism for transient ischemia. Dysfunctional endothelium may also result In a procoagulant surface, wRh cell adherence and local thrombus formation. Restoration of normal endothelial function is likely to emerge as an important therapeutic objectfve in the management of myocardlal ischemia and coronary atherosclerosis. (Am J Cardiol1992;70:8ol3G)
From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. Address for reprints: Andrew P. Selwyn, MD, Cardiovascular Division, L2, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. 80
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
Peter Ganz,
MD,
and Andrew P. Selwyn,
MD
T
ransient myocardial ischemia is an important functional expression of coronary artery disease. Although angina is a typical herald of ischemia, it does not occur prior to the majority of adverse coronary events. Episodes of ST depression are closely related to transient decreases in regional myocardial perfusion in response to such provocations as exercise, exposure to cold, and mental stress. Recent research indicates that atherosclerotic arteries lose their ability to dilate in response to such stimuli and instead constrict inappropriately. Experimental and clinical studies suggest that the loss of endotheliumdependent vasodilation is an important consequence of hypercholesterolemia and coronary atherosclerosis and represents a potential pathogenic mechanism for transient myocardial ischemia. These findings may prove of value in the treatment of myocardial ischemia, the control of atherosclerosis, and the prevention of adverse coronary events. TRANSIENT ISCHEMIA: PROGNOSIS
PREVALENCE AND
Most clinicians would agree that, in patients with coronary artery disease, the presence and severity of transient ischemia provide a measure of the risk of adverse coronary events. A familiar clinical problem is that, although the majority of ischemic episodes that occur in middle-aged individuals with cardiovascular risk factors are completely asymptomatic, these transient events are also highly associated with the presence of atherosclerotic stenoses in the proximal epicardial arteries. The prevalence of ischemia varies greatly, depending on the clinical diagnosis. It is important to emphasize that this prevalence is < 10% in unselected populations with no symptoms, no history of coronary artery disease, and few risk factors. For this reason, screening is not worthwhile in these open populations. In contrast, active ischemia during exercise testing or ambulatory monitoring is quite frequent in populations with chronic stable
NOVEMBER 27, 1992
coronary disease or unstable angina and among survivors of myocardial infarction, coronary artery bypass grafting, or cardiac arrest.’ Even in patients who present with peripheral vascular disease, ambulatory monitoring and dipyridamole thallium studies reveal a 16-20% prevalence of unsuspected but active ischemia.*y3 Thus, in these high-risk populations, the prevalence of ischemic episodes must be considered, whether or not an individual complains of angina. In patients with chronic stable coronary artery disease, the severity and extent of ischemia on thallium stress testing correlate with the event rate on subsequent follow-up.4 It is interesting to note that the risk of myocardial infarction or death is extremely low for approximately 2 years in patients with chronic stable coronary disease who have positive exercise tests and proven atherosclerosis but who show no active ischemia on ambulatory monitoring while off medication.5 After 2 years, however, these patients begin to experience adverse events, presumably because of progression of the underlying coronary disease. In contrast, the occurrence of active ischemia on Holter monitoring is associated with a worse prognosis, even when it is the single distinguishing clinical feature. Patients with asymptomatic ischemia show better event-free survival than those with symptomatic ischemia at the outset, but this advantage is lost within 3 years (Figure 1). By 5 years, patients with asymptomatic and symptomatic ischemia experience the same prognosis.
suggests that endothelial dysfunction in atherosclerosis permits the growth of stenotic lesions and the appearance of paradoxical constriction. The coronary vascular endothelium is a responsive organ that, in and of itself, can transduce signals from the intravascular environment, including blood pressure, pulse pressure, and acetylcholine stimulation of muscarinic receptors. In addition, many products of platelets and thrombin can stimulate the endothelium to exert its own local vasodilating effect on vascular smooth muscle cells. Thus, in the healthy intact organism, the endothelium regulates a defensive local vasodilating response. Within the endothelial cell, in response to appropriate stimuli, nitric oxide is cleaved off the terminal guanidino group of the amino acid L-arginine. The short-lived nitric oxide then diffuses locally, reaching the vascular smooth muscle cells, where it acts on cyclic adenosine monophosphate, producing vasodilation through a mechanism not dissimilar to the therapeutic effects of nitroglycerin. We know from experimental studies that this very fragile and easily disturbed vasodilator system can be impaired by increased levels of low-density lipoprotein (LDL), particularly oxidized LDL; by hypertension; and by the early changes of atherosclerosis. These findings are directly relevant to coronary artery disease in our patients. Smooth coronary arteries can exhibit endothelium-dependent vasodilation in response to acetylcholine (1O-s-1O-6 M), a local and specific test of endothelial function, or in response to more complex sympathetic stimuli such as mental stress (Figure 2A). Our group has demonstrated in patients undergoing diagnostic catheterization that atherosclerotic coronary arteries lose their dilator response and develop constriction in response to either acetylcholine or mental stress (Figure 2B).6 Interestingly, the vasomotor response to mental stress correlates with the
ATHEROSCLEROSIS, ENDOTHEUAL DYSFUNCTION, AND VASOCONSTRlCTlON Sympathetic stimulation: What is the role of increased myocardial oxygen demand and decreased coronary blood supply in causing the ischemia associated with such common events as exercise, mental stress, and exposure to cold? These events are almost always accompanied by an increase in neural and circulating sympathetic activity, blood pressure, and heart rate, resulting in 25 vs 7 events increased myocardial demand. At the same time, ‘4yp = 0.009 normal epicardial coronary arteries respond to this increase in demand associated with sympathetic stress with increased coronary blood flow and modest vasodilation of the large epicardial vessels. 0 20 40 60 80 Atherosclerotic vessels, in contrast, lose this vasodiFollow-up months lator response and develop constriction of varying degrees during sympathetic arousal. Interestingly, FlWREl.PrdcUvevahmofSTdepmdonInpatknts however, these vessels retain their ability to dilate wtth chronk stde anglna. --- = no ST depmeskn; - = ST depmsdon, abymptomatlc; -.-. = ST depm, in response to nitroglycerin. Evidence from basic as well as clinical research
--_ I
A SYMPOSIUM:
OPTIMIZING
ANTIANGINAL
THERAPY
St?
I
I
1
I
I
I
I
I
C ACh ACh ACh Ret MS NTG 1o-6 1o-7 1o-6
Molar 20 B q e $ %
lo-
FIGURE PA Response of a s4noothldtantdordescwhg (~)aMB~a-W chollno(ACh)andmmtalstroas (MG). G. Reqanse ofastenotk leltanblor -WI am-toandmeMdstressC=contrd; gfzlL=r mkshlkomNEn@JMed.@)
o-
.s -10 n d -20 -30
I
C
I
I
I
ACh ACh Ret 10-6 10”
I
MS
lNTG
Molar
response to acetylcholine (r = 0.58, p 220 mg/dL, endothelial function is lost even in coronary arteries without angiographic evidence of atherosclerotic lesions. There is both clinical and experimental evidence that endothelial dysfunction occurs very early in the development of atherosclerosis.” In the macaque monkey, endothelium-dependent vasodilation is lost with hypercholesterolemia but can be restored if hyperchol15
esterolemia is corrected, even in the presence of subintimal thickening, which takes a longer time to regress.12Clinical research studies in patients are currently investigating whether endothelial abnormalities can be reversed and appropriate vasodilator and anticoagulant functions restored in patients with atherosclerosis by administering antioxidants such as probucol, by decreasing LDL levels, and in the future by increasing high-density lipoprotein levels. Studies in patients show that lowering plasma cholesterol, particularly LDL cholesterol, results in very modest physical regression of coronary atherosclerosis but much more substantial reductions in adverse coronary events.13 This suggests that improvements in the functional aspects of the physiology of atherosclerosis are not only possible but are likely more important in patients. The Multiple Risk Factor Intervention Trial (MRFIT), for example, demonstrated that patients with manifest coronary artery disease will benefit from cholesterol lowering, blood pressure control, and smoking cessation. l4 Further support for this concept comes from the more recent Familial Atherosclerosis Treatment Study (FATS),15 which showed that intensive lipid-lowering therapy reduces the frequency of progression of coronary lesions and the incidence of cardiovascular events in men with coronary artery disease who are at high risk. EFFECTS OF ANTI-ISCHEMIC THERAPY ON PROGNOSIS Much more is known about the effects of antiangina1 drugs on ischemia than about their influence on patient outcome. For example, it is known that any decrease in the frequency of ischemic episodes achieved by a l3 blocker or a dihydropyri-
1
l
,I
-5 -10 -15 -20 -25 -30 100
150
200
Total cholesterol
A SYMPOSIUM:
OPTIMIZING
250
300
(mg/dL)
ANTIANGINAL
THERAPY
iiQ
dine calcium antagonist, or a combination of the 2, is significant and dose-dependent and that various antianginal agents have differential effects on ischemia occurring at low heart rates versus high heart rates. Studies in patients using ambulatory electrocardiographic monitoring have demonstrated that (3 blockers may actually increase the incidence of ischemic events at low heart rates but exert a beneficial effect on ischemia at intermediate and high heart rates. l6 In contrast, transcutaneous nitroglycerin reduces ischemia at low heart rates but worsens the events at high heart rates. These opposite but complementary actions may stem not only from the drugs’ overall effects on heart rate and myocardial demands, but also from differences in their effects on coronary blood supply. A multicenter study funded by the National Heart, Lung, and Blood Institute is underway and addresses the issue of whether the relief of ischemia can reduce adverse coronary events in patients. At present, there is only minimal evidence that medical therapy affects prognosis, with the exception of l3 blockers and aspirin in certain subsets of coronary patients.17 Surgical treatment has been shown to improve survival relative to medical treatment in patients with obvious evidence of ischemia in noninvasive test results, although it offered no advantage in those who had normal or only mildly abnormal test results, i.e., no ischemia.18 CONCLUSION The dysfunctional endothelium that characterizes coronary atheroslerosis results in the loss of normal endothelium-mediated vasodilator responses to physical and mental provocations and also leads to the development of a procoagulant surface, with cell adherence and local thrombus formation. Active ischemia in patients with coronary lesions appears to arise from this disordered cell biology, i.e., abnormal growth of stenosis, constriction, and thrombosis, all of which increase the patient’s risk of adverse outcomes. In the future, the restoration of normal endothelial functions is likely to become a major goal in the long-term control of coronary atherosclerosis and prevention of adverse coronary events. REFERENCES L Selwyn AP, Yeung AC, Ryan TJ, Raby KE, Bany J, Ganz P. Pathophysiology of ischemia in patients with coronary artery disease.F?wgCardiovuscDis 199&35:27-39. 2. Raby KE, Goldman L, Creager MA, Cook EF, We&berg MC, Whittemore AD, Sem AP. Correlation between preoperative ischemiaand major cardiac eventsafter peripheral vascular surgery.N EnglJMed 1989;321:1296-1300.
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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
3. Mangano DT, Browner WS, Hollenberg M, London MJ, Tubau JF, Tateo IM. Association of perioperative myocardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac surgery. The study of perioperative ischemiaresearchgroup. N Engl J Med 1990;323:1781-1788. ALadenheim ML, Pollock BH, Rozanski A, Berman DS, Staniloff HM, Forrester JS, Diamond GA. Extent and severity of myocardial hypoperfusion as predictors of prognosisin patients with suspectedcoronary artery disease.J Am Cd cardio119863464-471. 5. Yeung AC, Bany JB, Orav J, BonassinE, Raby KE, Selwyn AP. Effects of asymptomaticischemia on long-term prognosis in chronic stable coronary dis ease.circulation 1991;83:1598-1604. 6. Yeung AC, Vekshtein VI, Krantz DS, Vita JA, Ryan TJ Jr., Ganz P, Selwyn AP. The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress.N Engl J Med 1991;325:1551-1556. 7. Gordon JB, Ganz P, Nabel EG, Fish RD, ikbede J, Mudge GH, Alexander RW, Selwyn AP. Atherosclerosis influences the vasomotor responseof epicardial wronaly arteries to exercise.J ChinInvest 1989;83:1946-1952. 8. Zeiier AM, Drexler H, WoIlschlager H, Just H. Modulation of coronary vasomotor tone in humans. Progressiveendothelial dysfunction with different early stagesof coronary atherosclerosis.Circulation 1991;83:391401. 9. Vita JA, Treasure CB, Yeung AC, Vekshtein VI, Fantasia GM, Fish RD, Ganz P, Sehvyn AP. Patients with evidence of endothelial dysfunction as assessedby acetylcholine infusion demonstrate a marked increasein sensitivity to the constrictor effects of catecholamines.Cirrulahon 1992,85:13~1397. 10. Martin W, Furchgott RF, Viiani GM, Jothiinandan D. Depression of wntractik responsesin rat aorta by spontaneouslyreleased endothelium derived relaxing factor. JPhys E~J 7’kr 1986;237:529-538. Li Heistad DD, Armstrong ML, Marcus ML, Piegors DJ, Mark AL. Augmented responsesto vasownstrictor stimuli and hypercholesterolemiain atherosclerotic monkeys.Circ Res 1984;54:711-718. l2.Harrison DJ, Armstrong ML, Freiman PC, Heistad DD. Restoration of endothelimn dependent relaxation by dietary treatment of atherosclerosis.J CIin Invest 1987;80:1808-1811. 13. Tyroler Hk Cholesterol and cardiovasculardisease.An ovetiew of Lipids Research Clinics (LRC) epidemiologic studies as background for the LRC coronary primary prevention trial.dm J Cardid 1984;54314C-19C. iA The Multiple Riik Factor Intervention Trials (MRFIT). A national study of primary prevention of coronary heart disease.JAMA 197@235:82.%27. lS. Buxvn G, Albers JJ, Fisher LD, Schaefer SM, Lm J-T, Kaplan C, Zhao X-Q, B&on BD, Fitzpatrick VF, Dodge HT. Regression of wronary artery diseaseas a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990,323:128%1298. l6. McLenachan JM, Weidmger FS, Barry J, Yeung A, Nabel EG, Rocw MB, Seh+ynAP. Relations behveen heart rate, ischemia, and drug therapy during daily life in patients with coronary artery disease. Cimdafion 1991;83:12631270. 17. Lim R, Dyke L Dymond DS. Effect on prognosisof abolition of exercise induced painlessmyocardial ischemiaby medical therapy.Am J Car&~ 1992,69: 733-735.
18. VamauskasE, and the European Coronary Surgery Study Group. Twelveyear follow-up of survival in the randomized European Coronary Surgery Study. N Engl J Med 1988;319:332-337. 19. Vita JA, Treasure CB, Nabel EG, McLenachan JM, Fish RD, Yeung AC, Vekshtein VI, Selwyn AP, Ganz P. Coronary vasomotor responseto acetylcholine relates to risk factors for coronary artery disease.Circu’afion 1990;81:491497.
DISCUSSION Participant: Does hypertriglyceridemia, in the absence of hypercholesterolemia, alter the endothelial response to acetylcholine? Dr. Amlrew Selwyn: That is an interesting point, since in some clinical settings hypertriglyceridemia is an independent risk factor for atherosclerosis and for coronary events. There is very little information about the influence of triglycerides on endothelial function, since the majority of studies to date have examined the effects of increased LDL, oxidized LDL, and, to a lesser extent, shear force and blood pressure. NOVEMBER 27, 1992
Partldpant: Have you attempted to block the action of nitric oxide to confirm that it is actually an endothelial function that mediates the vascular response to stress? Dr. sehvyn: Administration of very small quantities of free hemoglobin and monomethylarginine into the coronary circulation abolishes the vasodilator response to stress, increased blood flow, and acetylcholine. Most studies have shown that the change from dilation to constriction depends on the function or dysfunction of the endothelium. This is not to say that endothelial dysfunction is the only abnormality in atherosclerosis, but it does appear to be a reasonable barometer of atherosclerotic damage. Partidpant: Do atherosclerotic coronary arteries constrict in response to stress because they are more sensitive to circulating catecholamines? Dr. Selwyn: According to the work of Martin et al,1° in the healthy endothelium, there is continuous basal release of endothelium-derived relaxing factor (ERDF) under normal conditions and pulsed release in response to stress. Loss of the ability of the endothelium to release EDRF accounts for the shift in the vascular dose-response curve to norepinephrine and to phenylephrine. Partidpant: Could you summarize your perspective on the heart rate changes that precede episodes of ischemia? Dr. Selwyn: Most ambulatory monitoring studies have shown that a small increase in heart rate (a median of 15 beats/min) precedes the onset of >70% of episodes of ST-segment depression. These periods of increased heart rate last an average of 30 minutes. In contrast, equal increases in heart rate that are short lived are not associated with ischemia. Thus, unlike ischemic episodes observed during the Bruce protocol, the majority of ischemic episodes that occur outside the hospital appear to be associated with modest increases in heart rate of long duration. Partidpant: You described differences in therapeutic response based on the resting heart rate. Are there any differences in heart rate changes in individuals with low versus intermediate versus high heart rates?
Dr. Selwyn: It is difficult to distinguish between the effect of the l3 blocker because they reduce heart rate throughout the day but could also modify the mechanisms at the onset of ischemia. Beta blockers can reduce heart rate below the range that precedes ischemia. Despite this, ischemia continues to occur at lower heart rates. The puzzle is that the incidence of ischemic events at low heart rates actually increases with l3 blockade. Partidpant Could you speculate about the adverse effects of the p blockers in increasing atherogenesis at the same time that they protect against rapid heart rates? Dr. Selwyn: The effect of the l3 blockers actually represents the net effect of several different actions, including antiarrhythmic activity, anti-ischemit activity, and decreased myocardial oxygen consumption (MV02). Theoretically, there is reason to believe that B blockade removes the dilating effect of p stimulation on the epicardial arteries, leaving (Yconstriction unopposed. In fact, coronary resistance is slightly worse at rest during B blocker therapy. However, these effects are balanced by the stronger effect of decreased MV02 throughout the day. Thus, the net effect is a significant reduction in the overall frequency and duration of ischemia, despite the increased frequency of low heart rate ischemic episodes. Partkipant: Could you comment on the clinical implications of the increased frequency of low heart rate ischemic episodes? Dr. Selwyn: One possibility is that p blockade eliminates high heart rate ischemic events, so that the ischemia that remains simply appears in the lower heart rate range. A second possibility is that B blockers are more effective in abolishing ischemit events triggered largely but not exclusively by an increase in MV02. Thus, the remaining ischemit episodes are caused primarily by problems with coronary blood supply. It might be of interest to investigate whether such supply-side ischemic events provide important prognostic information and whether they reveal anything about the pathophysiologic activity of the coronary disease at the time they occur.
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