Daily Life lschemia
and Nitrate Therapy
Carl J. Pepine,
Daily life ischemia has generated considerable interest because most of it is silent and associated wlth increased risk of adverse outcome. Coronary vasomotiin, as well as increases in myocardial oxygen demand, seem important in the pathogenesis of this form of ischemia, so treatment with nitrates seems rational. Administration of subliwal nitro@yceHn hourly, over 12 hours, was shown to decrease both silent and painful ischemic episodes in patients with effort angina. Subsequently, isosorbide dinitrate or mononitrate, glven either as an intravenous infusion or orally, was shown to decrease both silent and painful ischemic episodes in patients with unstable rest angina and in those with severe angina. More recently, 6 studii have reported using transdermal nitroglycerin for daily lii ischemia. Three of these reported open-label uncontrolled observatiis and suggested that ischemia frequency may be reduced approximately 6% 66% during treatment with doses of 16-36 mg/ day, with a duration of treatment ranging from 1 hour to 14 days. In 2 of these reports the duration of ischemia also decreased. The other 3 studies were randomized, double-blind, placebo-controlled studies with a total enrollment of 66 patllnts. These studii provkled mixed results. One suggested that evidence for partial tolerance develops within 1 day of treatment, using large continuous or intermittent doses (mean, 62 mg/ day). Another suggested that no tolerance develops to intermittent doslne[ (18 mg/l6 hr out of 24 hr) durlng exercise testiw but no effect is seen on daily life ischemia. The remaining study suggested that tolerance does not develop using small doses (W mg/day) continuously over l4 days for lschemia duriM daily lii, and that thii response is diirentfrom that observed using the calcium antagonist nifediplne. Those limited
From the University of Florida, College of Medicine, and the Veterans Atfairs Medical Center, Gainesville, Florida. Address for reprints: Carl J. Pepine, MD, Professor of Medicine, University of Florida, College of Medicine, Department of Medicine, Division of Cardiology, P.O. Box 100277, Gainesville, Florida 32610.
54B
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
70
MD
observations and confliing results underscore a need for additional larger controlled trials, employing topsCal nltrate therapy in low intermktent doses for daily lii ischemia. (Am J Cardiil1662;70:64&638)
T
he recent acceptance of silent myocardial &hernia as a problem associated with increased risk of adverse outcome has attracted considerable attention, particularly relative to its treatment with nitrates and other agents.l Before specifically addressing nitrate treatment issues, it is appropriate to review briefly the clinical problem of silent or asymptomatic ischemia. The concept of silent ischemia is not new and dates back to when asymptomatic ischemic-type ST-segment responses were first observed during Masters-type exercise testing. These patients were thought to have “latent,” “asymptomatic,” or “silent” coronary artery disease and to be in an early phase of their disease and not at risk for ischemia unless they were undergoing high-level stress. The development of sensitive and accurate ambulatory electrocardiographic (ECG) recorders led to the observation that patients with coronary artery disease, some of whom were never symptomatic, frequently have episodes of ischemia during activities of daily life.2 It is now clear that most daily life ischemia occurs in the absence of symptoms and that daily life ischemia can occur in patients with various clinical subsets of coronary artery disease (e.g., asymptomatic, angina, postmyocardial infarction, and survivors of sudden death). The presence of this form of ischemia, even in patients with angina, has recently been identified as an independent marker for adverse outcome.‘9 If we could better understand the pathogenesis of daily life ischemia, we could gain further insight into the mechanisms responsible for both ischemia and the interaction between ischemia and adverse outcome. Then, perhaps, we could begin to identify factors that are important to this interaction and design therapy to modify them. Although this review will focus on therapy with nitrates to modify SEPTEMBER
24, 1992
daily life ischemia, discussion of pathophysiologic mechanisms of daily life &hernia is pertinent to understand how nitrates and other anti-ischemic agents operate.
our understanding of coronary reactivity nent as it relates to activities of daily life.
is perti-
CORONARY VASOMOTlON AND SYMPATHlEClC STlMUlATlON Multiple factors that could be operative during PATHOPHYSIOWGY OF DA&Y WE SILENT daily life ischemia are known to influence coronary ISCHEMlA vascular tone. These include the autonomic ne,rEarly studies, using detailed daily diaries and vous system, catecholamines, and local effects ‘of ambulatory electrocardiographic monitoring, first vasoactive substances released from platelets as documented that most ischemic activity occurred well as blood flow and even the arterial wall itself. while patients were awake but during periods of Numerous angiographic studies, including many usual or nonexertional activities. In our index from our laboratory, have identified coronary arstudies, 72% of the episodes occurred during the tery disease patients who have dynamic coronary daytime when patients were sitting at ease and artery constriction. These changes in the coronary mentally or emotionally active, rather than physibed may result in primary decreases in blood cally active.2 We estimated the approximate metasupply and contribute to both acute and chronic constrictor rebolic costs of the activities when most ischemia ischemic syndromes. 8 Abnormal occurred and found them to be ~50% of the sponses in both large and smaller vessels may also metabolic cost associated with exercise-induced cause severe cardiac ischemia and such responses ischemia in the same subject. Recently, Barry and have been demonstrated in response to malny common daily life stimuli. coworkers4 confirmed and extended our observations on the relation between physical activities Mudge and coworkers9 suggested that cardiovalscular reactivity, evoked by cold pressor stress, and perceived mental stress to daily life ischemia. Most (58%) daily life ischemic activity occurred increased coronary vascular resistance in some during usual or low physical activities and high or coronary artery disease patients as well as heant usual mental activities. When the duration of rate and blood pressure in all patients. We conischemia was normalized for time spent in each firmed this abnormal vasoconstrictor response and activity category, increasing mental as well as extended their observations. We found that reactivphysical activity was associated with an increasing ity that contributed to the increased coronary duration of ischemia per unit time. They concluded resistance was localized to myocardial regions that the intensity of both perceived psychologic supplied by arteries with significant atherosclerotic and physical states had important influences on disease, but not to regions supplied by angiographdaily ischemic activity. Also, we had found that an ically normal-appearing coronary arteries.lO We individual patient’s daily life ischemic activity often also measured coronary artery size and found that occurred at a heart rate that was significantly lower the distal coronary segments, in the range of than the heart rate observed at the onset of 1.0-1.5 mm in diameter, appeared to be the most ischemia during exercise testing.2 This finding has reactive to cold pressor stress.ll Large coronary been confirmed by others5-7 and adds strong sup- artery reactivity alone did not appear to be of port to the concept that daily life ischemia involves sufficient magnitude to explain all of the increase coronary vascular alterations that limit oxygen observed in coronary resistance. This conclusion delivery as well as increases in myocardial oxygen was based on the observation that the cold pressorconsumption. induced resistance changes persisted even when Taken collectively, these findings indicate that the larger coronary vessels were dilated by nitroglycthe pathophysiology of daily life ischemia is likely erin pretreatment.12 Subsequently, Gunther et all3 to be much more complex than previously thought. reported that nifedipine, a potent smaller coronary The concept that a “fixed” plaquelike coronary artery and arteriolar dilator with little large vessel obstruction limits coronary flow at a relatively effect, completely prevented the abnormal constricconstant ceiling in response to increasing myocartion expected to occur in response to cold pressor dial oxygen demand to result in ischemia expressed stress. as angina is clearly not the complete picture. It Thus, the foregoing studies documented th.at follows that better treatment will result from a the patient with a diseased coronary circulation more complete understanding of all of the promay have some coronary beds that react in a cesses involved in daily life ischemia. To this end, different manner than the other beds to a common A SYMPOSIUM:
NITROGLYCERIN
THERAPY
!%5B
daily life form of stress (e.g., cold pressor). Some diseased coronary vascular beds react to cold pressor stress with an abnormal increase in tone. The major component of this paradoxical response lies in the smaller coronary arteries and arterioles. Nabel and coworkers14 have recently examined the large coronary artery responses to cold pressor stress in more detail. They found that regions of large coronary arteries, with an endothelial surface that appeared smooth by angiography, dilated in response to cold pressor stress, but other regions with severe narrowings or irregular endothelial surfaces as demonstrated by angiography constricted. More recently, others showed that regions of large arteries demonstrating angiographic abnormalities, attributed to a disordered endothelium, constricted following low-dose acetylcholine,15 whereas, acetylcholine regularly dilated angiographically normal-appearing regions of coronary arteries or regions of arteries without important surface irregularities attributed to a diseased endothelium. Nitroglycerin, on the other hand, dilated coronary arteries with and without endothelial surface irregularities and reversed the acetylcholine-induced constriction. Thus, evidence for regional endothelial dysfunction localized to one area of a coronary artery was established in these patients. Vita et all6 suggested that this type of endothelial dysfunction leads to increased constriction of a coronary artery region in response to catecholamine administration. Zeiher and coworkers17 have described the large and small coronary artery vasomotor responses to cold pressor stress, acetylcholine, and catecholamines in a large group of patients. They found that the dilation of normal-appearing and constriction of atherosclerotic coronary artery segments with cold pressor stress mirrored the responses observed to the endothelium-dependent vasodilator acetylcholine. Stenotic and irregular artery segments displaying evidence for endothelial dysfunction (e.g., constriction after low-dose acetylcholine) lost their normal dilator responses to cold pressor stress and constricted. Interestingly, p-adrenergic blockade with propranolol did not affect either the vasodilator or constrictor responses. Thus, all of these findings indicate that certain regions of the coronary artery react differently to a variety of stimuli common to daily life stimuli. The functional integrity of the coronary artery endothelium in a certain region seems to be a major determinant of the coronary vascular bed response to these different forms of stress. The response of the bed includes a localized coronary segment 568
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
70
response and the response of the smaller coronary arteries and arterioles in a region. If this finding is shown in response to other pathophysiologic interventions, regional endothelial dysfunction could determine the susceptibility to vasoconstrictor responses resulting from other forms of daily life stress. If this proves to be true, the presence of daily life ischemia may prove to be a sensitive marker for coronary artery endothelial dysfunction and disordered coronary reactivity. Local coronary reactivity has been related to adverse outcome in patients with clinical syndromes of variant angina or unstable angina. Hence, disordered reactivity could provide the link between daily life ischemia present in many clinical coronary disorders and adverse outcome. If this theory is proven, therapy directed to endothelial dysfunction could prove useful not only to modify and prevent daily life ischemia, but also, perhaps, to modify adverse outcome. ANIMAL MODELS SILENT ISCHEMlA
RELEVANT TO DALY LIFE AND NITRATE EFFECTS
Support for the theory that coronary endothelium is involved in the pathogenesis of abnormal coronary vasomotor responses to daily life ischemia also comes from animal models. Uchida et a11*J9 were among the first to describe cyclic coronary flow reductions after application of a partial constriction to a dog coronary artery. They proposed that coronary artery spasm at, and distal to, the constriction was the mechanism responsible for flow reduction, since nitroglycerin prevented flow reductions. Folts et a120 later found fibrinplatelet thrombi at the site of partial coronary obstruction in dogs and noted that the reversible flow reductions were prevented by aspirin pretreatment. Folts et a121then tested topical applications of nitroglycerin (0.5 mg) over the stenotic area of the coronary artery and found no change in either the magnitude or frequency of the cyclic flow reductions, although a transient fall in blood pressure occurred. Recently, in closed-chest dogs permitted to range freely, a model analogous to daily life ischemia, cyclic flow changes were also found following application of a partial constriction.22 Importantly, these flow changes could be prevented by thromboxane inhibitors. Most recently, similar cyclic flow reductions have been demonstrated in humans.23 In consideration of the previous discussion, it is interesting to note that Uchida et a118219 maintained that fibrin-platelet aggregates were not the only mechanisms responsible, since such aggregates SEPTEMBER
24,
1992
were found in partially constricted dog coronary arteries without cyclic flow reductions. The fact that cyclic flow reductions were prevented with nitroglycerin, a finding now recently confirmed by Folts and coworkers,24 suggests that a more complex mechanism than simply platelet aggregation may be operative. Small amounts of nitroglycerin are now known to act on coronary vascular smooth muscle by conversion to nitric oxide (NO), the same compound as endothelium-derived relaxing factor (EDRF). Thus, it seems that endothelial damage, perhaps induced at the time of application of the coronary artery stenosis or caused by increased shear at the site of narrowing, may be responsible for both the platelet aggregation and constriction. In addition, platelet thrombus formation may be inhibited by the organic nitrate.24 Thus, addition of an exogenous source of NO could compensate for loss of endogenous NO, due to endothelial cell dysfunction, and act to both prevent smooth muscle activation and restore local antiplatelet aggregation. The fact that Folts et a121 did not observe prevention of the cyclic flow reductions with topical nitroglycerin, could be explained by the fact that delivery of NO to the vascular smooth muscle site of the constriction was not complete. Also, the decrease in blood pressure observed could have aggravated the degree of obstruction by causing the stenosis to collapse.
EFFECTS
OF NITRATES
ON SILENT ISCHEMIA
Before reviewing the human silent ischemia data relative to nitrates, it is important to note that, in addition to well-known effects acting to redu.ce determinates of myocardial oxygen demand, there are now ample data showing that nitrates improve myocardial oxygen supply (see also article by Abrams, this symposium). The first convincing data supporting improved blood supply came from data showing improved collateral blood flow.25>26More recent work has focused on the direct vascular action of organic nitrates on patent atherosclerotic arteries. We and others have demonstrated that hemodynamically important coronary vasodilatilon occurs in response to nitroglycerin.27>28 This response is seen whether nitroglycerin is administered systemically or directly in small intracoronary doses. In fact, in a recent study of ours, extremely small doses (5 pg) caused important coronary vasodilation28 (Figure 1). We have also demonstrated that nitroglycerin reverses asymptomatic global and regional left ventricular hemodynamic dysfunction seen in patients with coronary artery disease.29 In this study, patients with important coronary artery stenoses who had left ventricular dyskinesia and no symptoms were given a bolus of intravenous nitroglycerin. Patients who responded to intravenous nitroglycerin with an increase in wall motion, in a previously dyskinetic region, were
flGURE 1. Dose+eqwnse relatkwshlp for cross-sectional area after intracoronmy nRro&cerln (cumulative dose) In nonstenotlc coronary artery segments. Note that all proximal and distal left coronary artery segments dilate In response to very low dose (5 ccg) nitroglycerin. Asterisk Indlcates p
and Nitrate Therapy
Carl J. Pepine,
Daily life ischemia has generated considerable interest because most of it is silent and associated wlth increased risk of adverse outcome. Coronary vasomotiin, as well as increases in myocardial oxygen demand, seem important in the pathogenesis of this form of ischemia, so treatment with nitrates seems rational. Administration of subliwal nitro@yceHn hourly, over 12 hours, was shown to decrease both silent and painful ischemic episodes in patients with effort angina. Subsequently, isosorbide dinitrate or mononitrate, glven either as an intravenous infusion or orally, was shown to decrease both silent and painful ischemic episodes in patients with unstable rest angina and in those with severe angina. More recently, 6 studii have reported using transdermal nitroglycerin for daily lii ischemia. Three of these reported open-label uncontrolled observatiis and suggested that ischemia frequency may be reduced approximately 6% 66% during treatment with doses of 16-36 mg/ day, with a duration of treatment ranging from 1 hour to 14 days. In 2 of these reports the duration of ischemia also decreased. The other 3 studies were randomized, double-blind, placebo-controlled studies with a total enrollment of 66 patllnts. These studii provkled mixed results. One suggested that evidence for partial tolerance develops within 1 day of treatment, using large continuous or intermittent doses (mean, 62 mg/ day). Another suggested that no tolerance develops to intermittent doslne[ (18 mg/l6 hr out of 24 hr) durlng exercise testiw but no effect is seen on daily life ischemia. The remaining study suggested that tolerance does not develop using small doses (W mg/day) continuously over l4 days for lschemia duriM daily lii, and that thii response is diirentfrom that observed using the calcium antagonist nifediplne. Those limited
From the University of Florida, College of Medicine, and the Veterans Atfairs Medical Center, Gainesville, Florida. Address for reprints: Carl J. Pepine, MD, Professor of Medicine, University of Florida, College of Medicine, Department of Medicine, Division of Cardiology, P.O. Box 100277, Gainesville, Florida 32610.
54B
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
70
MD
observations and confliing results underscore a need for additional larger controlled trials, employing topsCal nltrate therapy in low intermktent doses for daily lii ischemia. (Am J Cardiil1662;70:64&638)
T
he recent acceptance of silent myocardial &hernia as a problem associated with increased risk of adverse outcome has attracted considerable attention, particularly relative to its treatment with nitrates and other agents.l Before specifically addressing nitrate treatment issues, it is appropriate to review briefly the clinical problem of silent or asymptomatic ischemia. The concept of silent ischemia is not new and dates back to when asymptomatic ischemic-type ST-segment responses were first observed during Masters-type exercise testing. These patients were thought to have “latent,” “asymptomatic,” or “silent” coronary artery disease and to be in an early phase of their disease and not at risk for ischemia unless they were undergoing high-level stress. The development of sensitive and accurate ambulatory electrocardiographic (ECG) recorders led to the observation that patients with coronary artery disease, some of whom were never symptomatic, frequently have episodes of ischemia during activities of daily life.2 It is now clear that most daily life ischemia occurs in the absence of symptoms and that daily life ischemia can occur in patients with various clinical subsets of coronary artery disease (e.g., asymptomatic, angina, postmyocardial infarction, and survivors of sudden death). The presence of this form of ischemia, even in patients with angina, has recently been identified as an independent marker for adverse outcome.‘9 If we could better understand the pathogenesis of daily life ischemia, we could gain further insight into the mechanisms responsible for both ischemia and the interaction between ischemia and adverse outcome. Then, perhaps, we could begin to identify factors that are important to this interaction and design therapy to modify them. Although this review will focus on therapy with nitrates to modify SEPTEMBER
24, 1992
daily life ischemia, discussion of pathophysiologic mechanisms of daily life &hernia is pertinent to understand how nitrates and other anti-ischemic agents operate.
our understanding of coronary reactivity nent as it relates to activities of daily life.
is perti-
CORONARY VASOMOTlON AND SYMPATHlEClC STlMUlATlON Multiple factors that could be operative during PATHOPHYSIOWGY OF DA&Y WE SILENT daily life ischemia are known to influence coronary ISCHEMlA vascular tone. These include the autonomic ne,rEarly studies, using detailed daily diaries and vous system, catecholamines, and local effects ‘of ambulatory electrocardiographic monitoring, first vasoactive substances released from platelets as documented that most ischemic activity occurred well as blood flow and even the arterial wall itself. while patients were awake but during periods of Numerous angiographic studies, including many usual or nonexertional activities. In our index from our laboratory, have identified coronary arstudies, 72% of the episodes occurred during the tery disease patients who have dynamic coronary daytime when patients were sitting at ease and artery constriction. These changes in the coronary mentally or emotionally active, rather than physibed may result in primary decreases in blood cally active.2 We estimated the approximate metasupply and contribute to both acute and chronic constrictor rebolic costs of the activities when most ischemia ischemic syndromes. 8 Abnormal occurred and found them to be ~50% of the sponses in both large and smaller vessels may also metabolic cost associated with exercise-induced cause severe cardiac ischemia and such responses ischemia in the same subject. Recently, Barry and have been demonstrated in response to malny common daily life stimuli. coworkers4 confirmed and extended our observations on the relation between physical activities Mudge and coworkers9 suggested that cardiovalscular reactivity, evoked by cold pressor stress, and perceived mental stress to daily life ischemia. Most (58%) daily life ischemic activity occurred increased coronary vascular resistance in some during usual or low physical activities and high or coronary artery disease patients as well as heant usual mental activities. When the duration of rate and blood pressure in all patients. We conischemia was normalized for time spent in each firmed this abnormal vasoconstrictor response and activity category, increasing mental as well as extended their observations. We found that reactivphysical activity was associated with an increasing ity that contributed to the increased coronary duration of ischemia per unit time. They concluded resistance was localized to myocardial regions that the intensity of both perceived psychologic supplied by arteries with significant atherosclerotic and physical states had important influences on disease, but not to regions supplied by angiographdaily ischemic activity. Also, we had found that an ically normal-appearing coronary arteries.lO We individual patient’s daily life ischemic activity often also measured coronary artery size and found that occurred at a heart rate that was significantly lower the distal coronary segments, in the range of than the heart rate observed at the onset of 1.0-1.5 mm in diameter, appeared to be the most ischemia during exercise testing.2 This finding has reactive to cold pressor stress.ll Large coronary been confirmed by others5-7 and adds strong sup- artery reactivity alone did not appear to be of port to the concept that daily life ischemia involves sufficient magnitude to explain all of the increase coronary vascular alterations that limit oxygen observed in coronary resistance. This conclusion delivery as well as increases in myocardial oxygen was based on the observation that the cold pressorconsumption. induced resistance changes persisted even when Taken collectively, these findings indicate that the larger coronary vessels were dilated by nitroglycthe pathophysiology of daily life ischemia is likely erin pretreatment.12 Subsequently, Gunther et all3 to be much more complex than previously thought. reported that nifedipine, a potent smaller coronary The concept that a “fixed” plaquelike coronary artery and arteriolar dilator with little large vessel obstruction limits coronary flow at a relatively effect, completely prevented the abnormal constricconstant ceiling in response to increasing myocartion expected to occur in response to cold pressor dial oxygen demand to result in ischemia expressed stress. as angina is clearly not the complete picture. It Thus, the foregoing studies documented th.at follows that better treatment will result from a the patient with a diseased coronary circulation more complete understanding of all of the promay have some coronary beds that react in a cesses involved in daily life ischemia. To this end, different manner than the other beds to a common A SYMPOSIUM:
NITROGLYCERIN
THERAPY
!%5B
daily life form of stress (e.g., cold pressor). Some diseased coronary vascular beds react to cold pressor stress with an abnormal increase in tone. The major component of this paradoxical response lies in the smaller coronary arteries and arterioles. Nabel and coworkers14 have recently examined the large coronary artery responses to cold pressor stress in more detail. They found that regions of large coronary arteries, with an endothelial surface that appeared smooth by angiography, dilated in response to cold pressor stress, but other regions with severe narrowings or irregular endothelial surfaces as demonstrated by angiography constricted. More recently, others showed that regions of large arteries demonstrating angiographic abnormalities, attributed to a disordered endothelium, constricted following low-dose acetylcholine,15 whereas, acetylcholine regularly dilated angiographically normal-appearing regions of coronary arteries or regions of arteries without important surface irregularities attributed to a diseased endothelium. Nitroglycerin, on the other hand, dilated coronary arteries with and without endothelial surface irregularities and reversed the acetylcholine-induced constriction. Thus, evidence for regional endothelial dysfunction localized to one area of a coronary artery was established in these patients. Vita et all6 suggested that this type of endothelial dysfunction leads to increased constriction of a coronary artery region in response to catecholamine administration. Zeiher and coworkers17 have described the large and small coronary artery vasomotor responses to cold pressor stress, acetylcholine, and catecholamines in a large group of patients. They found that the dilation of normal-appearing and constriction of atherosclerotic coronary artery segments with cold pressor stress mirrored the responses observed to the endothelium-dependent vasodilator acetylcholine. Stenotic and irregular artery segments displaying evidence for endothelial dysfunction (e.g., constriction after low-dose acetylcholine) lost their normal dilator responses to cold pressor stress and constricted. Interestingly, p-adrenergic blockade with propranolol did not affect either the vasodilator or constrictor responses. Thus, all of these findings indicate that certain regions of the coronary artery react differently to a variety of stimuli common to daily life stimuli. The functional integrity of the coronary artery endothelium in a certain region seems to be a major determinant of the coronary vascular bed response to these different forms of stress. The response of the bed includes a localized coronary segment 568
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
70
response and the response of the smaller coronary arteries and arterioles in a region. If this finding is shown in response to other pathophysiologic interventions, regional endothelial dysfunction could determine the susceptibility to vasoconstrictor responses resulting from other forms of daily life stress. If this proves to be true, the presence of daily life ischemia may prove to be a sensitive marker for coronary artery endothelial dysfunction and disordered coronary reactivity. Local coronary reactivity has been related to adverse outcome in patients with clinical syndromes of variant angina or unstable angina. Hence, disordered reactivity could provide the link between daily life ischemia present in many clinical coronary disorders and adverse outcome. If this theory is proven, therapy directed to endothelial dysfunction could prove useful not only to modify and prevent daily life ischemia, but also, perhaps, to modify adverse outcome. ANIMAL MODELS SILENT ISCHEMlA
RELEVANT TO DALY LIFE AND NITRATE EFFECTS
Support for the theory that coronary endothelium is involved in the pathogenesis of abnormal coronary vasomotor responses to daily life ischemia also comes from animal models. Uchida et a11*J9 were among the first to describe cyclic coronary flow reductions after application of a partial constriction to a dog coronary artery. They proposed that coronary artery spasm at, and distal to, the constriction was the mechanism responsible for flow reduction, since nitroglycerin prevented flow reductions. Folts et a120 later found fibrinplatelet thrombi at the site of partial coronary obstruction in dogs and noted that the reversible flow reductions were prevented by aspirin pretreatment. Folts et a121then tested topical applications of nitroglycerin (0.5 mg) over the stenotic area of the coronary artery and found no change in either the magnitude or frequency of the cyclic flow reductions, although a transient fall in blood pressure occurred. Recently, in closed-chest dogs permitted to range freely, a model analogous to daily life ischemia, cyclic flow changes were also found following application of a partial constriction.22 Importantly, these flow changes could be prevented by thromboxane inhibitors. Most recently, similar cyclic flow reductions have been demonstrated in humans.23 In consideration of the previous discussion, it is interesting to note that Uchida et a118219 maintained that fibrin-platelet aggregates were not the only mechanisms responsible, since such aggregates SEPTEMBER
24,
1992
were found in partially constricted dog coronary arteries without cyclic flow reductions. The fact that cyclic flow reductions were prevented with nitroglycerin, a finding now recently confirmed by Folts and coworkers,24 suggests that a more complex mechanism than simply platelet aggregation may be operative. Small amounts of nitroglycerin are now known to act on coronary vascular smooth muscle by conversion to nitric oxide (NO), the same compound as endothelium-derived relaxing factor (EDRF). Thus, it seems that endothelial damage, perhaps induced at the time of application of the coronary artery stenosis or caused by increased shear at the site of narrowing, may be responsible for both the platelet aggregation and constriction. In addition, platelet thrombus formation may be inhibited by the organic nitrate.24 Thus, addition of an exogenous source of NO could compensate for loss of endogenous NO, due to endothelial cell dysfunction, and act to both prevent smooth muscle activation and restore local antiplatelet aggregation. The fact that Folts et a121 did not observe prevention of the cyclic flow reductions with topical nitroglycerin, could be explained by the fact that delivery of NO to the vascular smooth muscle site of the constriction was not complete. Also, the decrease in blood pressure observed could have aggravated the degree of obstruction by causing the stenosis to collapse.
EFFECTS
OF NITRATES
ON SILENT ISCHEMIA
Before reviewing the human silent ischemia data relative to nitrates, it is important to note that, in addition to well-known effects acting to redu.ce determinates of myocardial oxygen demand, there are now ample data showing that nitrates improve myocardial oxygen supply (see also article by Abrams, this symposium). The first convincing data supporting improved blood supply came from data showing improved collateral blood flow.25>26More recent work has focused on the direct vascular action of organic nitrates on patent atherosclerotic arteries. We and others have demonstrated that hemodynamically important coronary vasodilatilon occurs in response to nitroglycerin.27>28 This response is seen whether nitroglycerin is administered systemically or directly in small intracoronary doses. In fact, in a recent study of ours, extremely small doses (5 pg) caused important coronary vasodilation28 (Figure 1). We have also demonstrated that nitroglycerin reverses asymptomatic global and regional left ventricular hemodynamic dysfunction seen in patients with coronary artery disease.29 In this study, patients with important coronary artery stenoses who had left ventricular dyskinesia and no symptoms were given a bolus of intravenous nitroglycerin. Patients who responded to intravenous nitroglycerin with an increase in wall motion, in a previously dyskinetic region, were
flGURE 1. Dose+eqwnse relatkwshlp for cross-sectional area after intracoronmy nRro&cerln (cumulative dose) In nonstenotlc coronary artery segments. Note that all proximal and distal left coronary artery segments dilate In response to very low dose (5 ccg) nitroglycerin. Asterisk Indlcates p
