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The revival of coronary spasm
The Revival of Coronary Spasm ATILIO
MASERI,
C of “variant”
oronary vasospasm has become accepted as a cause angina, and it has also been convincingly demonstrated in angina with S-T segment depression. This mechanism of angina, postulated over a century ago, fell into disrepute when nearly all patients with angina were found to have severe coronary atherosclerotic narrowing at autopsy. The present revival of coronary vasospasm affects our approach to patients with angina both directly, because of its therapeutic implications, and indirectly, because of its contribution in demolishing the mental barrier which for decades protected the notion that the only respectable cause of angina was an excessive increase of demand in the presence of organic coronary artery narrowing. The extrapolation of this notion, although favoring the development of methods for the detection of stenosis, of interventions aimed at reducing myocardial oxygen consumption, and of the widespread diffusion of coronary artery by-pass surgery, prevented learning: when a stenosis was found it was automatically taken as the cause of angina. EXPANDING UNDERSTANDING
OF ANGINA
In my opinion three sets of data are opening the way to a better understanding of angina pectori$ and of ischemit heart disease. (1) Recurring angina1 attacks in patients admitted to coronary care units for the severity of their symptoms were shown not to be caused by an excessive increase of myocardial demand as traditionally assumed. It was the search for the cause of these attacks that stimulated studies which demonstrated a reduction of coronary blood flow preceding [l] and accompanying [2] the ischemic episodes and the role of coronary vasospasm [3]. Although several observations confirmed and extended these findings in different institutions, no conflicting report can be found so far in the literature. (2) Angina1 attacks can be caused by a transient reduction of regional coronary blood flow in the presence of a wide variability of coronary atherosclerosis-from angiographically normal to severely stenosed vessels.
M.D.*
Thus, in the presence of organic stenoses, angina can be caused by different mechanisms even in the same patient on different occasions: by a sudden impairment of coronary flow at rest or during levels of exertion usually well tolerated, and by excessive increase of demand. Therefore, in the patient with coronary atherosclerotic obstructions, assessment of the level of maximal residual coronary flow reserve becomes an essential step in his diagnostic evaluation: attacks which occur clearly below this level can be assumed to be caused by a transient impairment of coronary blood supply: those occurring clearly beyond this level, by an excessive increase of myocardial oxygen demand [a]. (3) Transient elevation of the S-T segment does not represent the exclusive marker of ischemic episodes caused by impairment of coronary blood supply because S-T segment elevation, depression and T wave changes are often observed in the same patients if enough ischemit episodes are recorded. Furthermqre, complete occlusion of a small branch, diffuse coronary narrowing or even complete occlusion of a large branch in the presence of collaterals may result in S-T segment depression which, therefore, is more frequent than elevation in patients with multivessel disease [5]. Usually the transient electrocardiographic chaages follow the reduction of blood flaw and the beginning of ventricular function impairment, but they precede by minutes the onset of pain, which is only a late and inconstant marker of acute myocardial ischemia and, therefore, should not necessarily condition therapeutic decisions [1,6] ROLE OF CORONARY VASOSPASM ISCHEMIC HEART DISEASE
The study of patients with recurrent spontaneous angina
provided valuable information also on the possible role of coronary vasospasm in sudden death and in infarction. Angina Pectoris. The precise role of coronary vasospasm in angina is still ill-defined because its existence became accepted too recently for patients to be widely examined with a view to this possible mechanism and because its diagnosis is not easy. The assessment of the
From Fisiolo ia Clinica, Laboratorio dei Consiglio Nazionale, Delle Ricerche, Piss. Italy. Requests for reprints s a ould be addressed to Dr. Atilio Maseri. * Present address: Cardiovascular Research Unit, Hammersmith Hospital, Du Cane Road, London WI2 OHS England.
752
April 1981
The American Journal of Medicine
IN
Volume 70
EDITORIALS-MASER1
frequency of angina caused by transient impairment of coronary supply relative to angina caused by excessive demand could be taken as a provisional starting point. Transient impairment of coronary flow may turn out to be a much more common cause of angina than generally thought when considered in the light of whether the attacks occur clearly above or clearly below the maximal level of coronary flow reserve of the patient [angina secondary to excessive increased demand or “secondary” angina in the first case, and angina caused by impairment of supply or “primary” angina in the latter
[41). Once it is established that attacks are not caused by excessive increase of demand, it remains to be ascertained whether they are caused by (11 coronary vasospasm, broadly intended as inappropriate active constriction of epicardial coronary arteries-such a broad definition may be provisionally justified because so far we have no clue indicating that different mechanisms are responsible for different degrees of changes in vasomotor tone, even though it is obvious that, although major changes are required for impairment of flow in arteries with normal lumen, minimal changes in tone can affect flow through a stenotic artery; (2) constriction or failure of vasodilatation at the level of resistive coronary arteries: (3) platelet aggregation: (4) unidentified mechanisms [hence the preliminary general classification as “primary” angina for angina not secondary to excessive increase of demand [4]]. For practical purposes coronary vasospasm can be assumed with reasonable confidence to play a role in “variant” angina, and in the cases in which the usual symptoms of the patient associated with transient electrocardiographic changes, S-T segment elevation or depression and T-wave changes, can be reproduced by intravenous injection of ergonovine during a waxing phase of symptoms (even without angiographic demonstration]. For the other cases, vasospasm can only be suspected and directly demonstrated at angiography during spontaneous or induced ischemic episodes, or it might be inferred from the favorable results obtained by treatment with drugs known to be effective in vasospastic angina. The development of more specific and sensitive methods for the precise identification of the causes of transient impairment of coronary blood supply requires a more precise understanding of the different mechanisms responsible for vasospasm and investigations into the possible alternative mechanisms of impairment of supply. Sudden Coronary Death. Episodes of ventricular tachycardia, fibrillation and atrioventricular block are relatively common during episodes of acute myocardial ischemia with S-T segment elevation (with or without pain) and, hence, are most likely to be caused by transient coronary spasm. The frequency of these possible mechanisms of arrhythmic death may not be negligible if it contributes to the number of survivors who col-
April 1981
lapsed with chest pain and who were resuscitated without subsequent evidence of acute infarction. Myocardial Infarction. The most stimulating clue to a possible pathogenetic mechanism of infarction was obtained in patients who could be studied immediately before the infarction developed. The irreversible ischemit episode was preceded by several reversible episodes of ischemia in the same myocardial area, caused by reduced supply and with an onset indistinguishable from that of the final, irreversible episode. In some cases these transient episodes could be shown to be caused by coronary vasospasm [7]. In our limited experience the irreversible episode could not be reversed by intracoronary nitrates, but the vessel was open 24 hours later with the appearance of a partially recanalized vessel in two cases and open at postmortem in a third in which there was a mural platelet thrombus just distal to the site in which the spasm was observed at angiography. As a working hypothesis we proposed that repeated and/or prolonged spasm may damage the intima, cause plaque rupture, hemorrhage, blood stagnation and initiate a vicious circle with platelet aggregation and thrombus formation leading to potentiation of vasospasm and diffuse, prolonged occlusion [8]. The intravascular occlusion may subsequently extend and organize in a permanent obstruction over a variable length of the vessel or be lysed partially or completely. This hypothesis is compatible with the variable response to therapy with intracoronary nitrates [9], with the results of intracoronary fibrinolytic agents [lo] and with the variable frequency of vascular obstruction observed after infarction [ll]. These mechanisms may have preventive implications if we consider that infarction is often preceded by one or more episodes of angina. MECHANISMS AND TREATMENT CORONARY SPASM
OF
We proposed as a working hypothesis that spasm may result from a variable combination of a triggering stimulus acting on hypersensitive vessels. Autonomic nervous system stimulation, histamine, serotonin, thromboxane AZ, ergometrine can induce vasospasm in susceptible vessels, but the susceptibility to spasm can vary considerably in time in the same patient [8]. Until the relative role of triggering factors is better understood, a rational therapy can only be based on drugs which aspecifically raise the threshold for spasm, such as nitrates and slow channel blockers, which appear to give remarkable results both in acute and chronic phases [12]. The results of surgical denervation are still too preliminary to allow conclusions. Following bypass coronary surgery, attacks of vasospastic angina may disappear, at least for some time, but it is difficult to understand the mechanisms of this improvement, in particular in those patients in whom, according to our clinical experience, waxing phases of the disease tend to be associated with inability to cope and breakdown
The American
Journal
of Medicine
Volume
70
753
EDITORIALS-MASER1
in adaptation, and waning phases with reassurance and feelings of security. CONCLUSIONS
3. 4. 5.
The demonstration that impairment of supply caused by transient, potentially reversible, obstruction of the coronary lumen may represent a frequent cause of acute myocardial ischemia is opening new horizons. Although prognosis is obviously heavily influenced by the severity of the underlying coronary organic lesions, diagnosis, treatment and prevention of ischemic heart disease must no longer be centered only on coronary atherosclerosis. Modulating factors, superimposed on a fixed obstruction of varying severity and transiently interfering with coronary blood flow, such as coronary vasospasm, may play a relevant role in the genesis of the clinical manifestations of the disease.
6. 7.
8. 9. 10.
REFERENCES 1. 2.
754
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: 759-767. Maseri A. Parodi 0, Severi S. Pesola A: Transient transmural reduction of myocardial blood flow, demonstrated by thallium-201 scintigraphy. a cause of variant angina. Circulation 1976; 54:280-288.
April 1981
The American
Journal of Medicine
11.
12.
Volume 70
Maseri A, L’Abbatc A, Pesola A. et al.: Coronarv vasosnasm in angina pectoris. Lancet 1977: 1: 713-717. _ _ Maseri A: Pathoaenetic mechanisms of annina pectoris: expanding views. Br Heart J 1980: 43: 6; 6418-666. Maseri A, Severi S. De Nes M, et al.: “Variant” angina: one aspect of a continuous spectrllm of vasospastic myocardial ischemia. Pathogenetic mechanisms, estimated incidence and clinical and coronarv arterionraohic findinns in 138 patients. Am J Cardiol 1958: 42; l&9-1035. Maseri A, Mimmo R, Chierchia S, Marchesi C, Pesola A, L’Abbate A: Coronary artcry spasm as a cause of acute mvocardial ischemia in man. Chest 1975: 68; 625-633. Maseri A. L’Abbate A, Baroldi G. et al.: Coronary vasospasm as a possible cause of myocardial infarction. A conclusion derived from the studv of “ureinfarction” angina. N Enel J Med 1978: 299; 127111278: Maseri A, Chierchia S, L’Abbate A: Pathogenetic mechanisms underlying the clinical events associated with atherosclerotic heart disease. Circulation 1980; 62: ISUDDI):3-13. Oliva PB, Breckenridge 1C: Arteriographicevidence of coronary arterial spasm in acute myocardial infarction. Circulation 1977; 56: 366-374. Rentroo KP. Blanke H. Karsch KR. et al.: Acute mvocardial ‘infarction: intracoronary application of nitroglycerin and streptokinase. Clin Cardiol 1979; 2: 354-363. DeWdod MA, Spores J, Notske R, et al.: Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980; 16: 897-902. Severi S, Davies Gj, Maseri A. Marzullo P. L’Abbate A: Long-term prognosis of variant angina with medical treatment. Am J Cardioll980: 46; 226-231.
MASERI,
C of “variant”
oronary vasospasm has become accepted as a cause angina, and it has also been convincingly demonstrated in angina with S-T segment depression. This mechanism of angina, postulated over a century ago, fell into disrepute when nearly all patients with angina were found to have severe coronary atherosclerotic narrowing at autopsy. The present revival of coronary vasospasm affects our approach to patients with angina both directly, because of its therapeutic implications, and indirectly, because of its contribution in demolishing the mental barrier which for decades protected the notion that the only respectable cause of angina was an excessive increase of demand in the presence of organic coronary artery narrowing. The extrapolation of this notion, although favoring the development of methods for the detection of stenosis, of interventions aimed at reducing myocardial oxygen consumption, and of the widespread diffusion of coronary artery by-pass surgery, prevented learning: when a stenosis was found it was automatically taken as the cause of angina. EXPANDING UNDERSTANDING
OF ANGINA
In my opinion three sets of data are opening the way to a better understanding of angina pectori$ and of ischemit heart disease. (1) Recurring angina1 attacks in patients admitted to coronary care units for the severity of their symptoms were shown not to be caused by an excessive increase of myocardial demand as traditionally assumed. It was the search for the cause of these attacks that stimulated studies which demonstrated a reduction of coronary blood flow preceding [l] and accompanying [2] the ischemic episodes and the role of coronary vasospasm [3]. Although several observations confirmed and extended these findings in different institutions, no conflicting report can be found so far in the literature. (2) Angina1 attacks can be caused by a transient reduction of regional coronary blood flow in the presence of a wide variability of coronary atherosclerosis-from angiographically normal to severely stenosed vessels.
M.D.*
Thus, in the presence of organic stenoses, angina can be caused by different mechanisms even in the same patient on different occasions: by a sudden impairment of coronary flow at rest or during levels of exertion usually well tolerated, and by excessive increase of demand. Therefore, in the patient with coronary atherosclerotic obstructions, assessment of the level of maximal residual coronary flow reserve becomes an essential step in his diagnostic evaluation: attacks which occur clearly below this level can be assumed to be caused by a transient impairment of coronary blood supply: those occurring clearly beyond this level, by an excessive increase of myocardial oxygen demand [a]. (3) Transient elevation of the S-T segment does not represent the exclusive marker of ischemic episodes caused by impairment of coronary blood supply because S-T segment elevation, depression and T wave changes are often observed in the same patients if enough ischemit episodes are recorded. Furthermqre, complete occlusion of a small branch, diffuse coronary narrowing or even complete occlusion of a large branch in the presence of collaterals may result in S-T segment depression which, therefore, is more frequent than elevation in patients with multivessel disease [5]. Usually the transient electrocardiographic chaages follow the reduction of blood flaw and the beginning of ventricular function impairment, but they precede by minutes the onset of pain, which is only a late and inconstant marker of acute myocardial ischemia and, therefore, should not necessarily condition therapeutic decisions [1,6] ROLE OF CORONARY VASOSPASM ISCHEMIC HEART DISEASE
The study of patients with recurrent spontaneous angina
provided valuable information also on the possible role of coronary vasospasm in sudden death and in infarction. Angina Pectoris. The precise role of coronary vasospasm in angina is still ill-defined because its existence became accepted too recently for patients to be widely examined with a view to this possible mechanism and because its diagnosis is not easy. The assessment of the
From Fisiolo ia Clinica, Laboratorio dei Consiglio Nazionale, Delle Ricerche, Piss. Italy. Requests for reprints s a ould be addressed to Dr. Atilio Maseri. * Present address: Cardiovascular Research Unit, Hammersmith Hospital, Du Cane Road, London WI2 OHS England.
752
April 1981
The American Journal of Medicine
IN
Volume 70
EDITORIALS-MASER1
frequency of angina caused by transient impairment of coronary supply relative to angina caused by excessive demand could be taken as a provisional starting point. Transient impairment of coronary flow may turn out to be a much more common cause of angina than generally thought when considered in the light of whether the attacks occur clearly above or clearly below the maximal level of coronary flow reserve of the patient [angina secondary to excessive increased demand or “secondary” angina in the first case, and angina caused by impairment of supply or “primary” angina in the latter
[41). Once it is established that attacks are not caused by excessive increase of demand, it remains to be ascertained whether they are caused by (11 coronary vasospasm, broadly intended as inappropriate active constriction of epicardial coronary arteries-such a broad definition may be provisionally justified because so far we have no clue indicating that different mechanisms are responsible for different degrees of changes in vasomotor tone, even though it is obvious that, although major changes are required for impairment of flow in arteries with normal lumen, minimal changes in tone can affect flow through a stenotic artery; (2) constriction or failure of vasodilatation at the level of resistive coronary arteries: (3) platelet aggregation: (4) unidentified mechanisms [hence the preliminary general classification as “primary” angina for angina not secondary to excessive increase of demand [4]]. For practical purposes coronary vasospasm can be assumed with reasonable confidence to play a role in “variant” angina, and in the cases in which the usual symptoms of the patient associated with transient electrocardiographic changes, S-T segment elevation or depression and T-wave changes, can be reproduced by intravenous injection of ergonovine during a waxing phase of symptoms (even without angiographic demonstration]. For the other cases, vasospasm can only be suspected and directly demonstrated at angiography during spontaneous or induced ischemic episodes, or it might be inferred from the favorable results obtained by treatment with drugs known to be effective in vasospastic angina. The development of more specific and sensitive methods for the precise identification of the causes of transient impairment of coronary blood supply requires a more precise understanding of the different mechanisms responsible for vasospasm and investigations into the possible alternative mechanisms of impairment of supply. Sudden Coronary Death. Episodes of ventricular tachycardia, fibrillation and atrioventricular block are relatively common during episodes of acute myocardial ischemia with S-T segment elevation (with or without pain) and, hence, are most likely to be caused by transient coronary spasm. The frequency of these possible mechanisms of arrhythmic death may not be negligible if it contributes to the number of survivors who col-
April 1981
lapsed with chest pain and who were resuscitated without subsequent evidence of acute infarction. Myocardial Infarction. The most stimulating clue to a possible pathogenetic mechanism of infarction was obtained in patients who could be studied immediately before the infarction developed. The irreversible ischemit episode was preceded by several reversible episodes of ischemia in the same myocardial area, caused by reduced supply and with an onset indistinguishable from that of the final, irreversible episode. In some cases these transient episodes could be shown to be caused by coronary vasospasm [7]. In our limited experience the irreversible episode could not be reversed by intracoronary nitrates, but the vessel was open 24 hours later with the appearance of a partially recanalized vessel in two cases and open at postmortem in a third in which there was a mural platelet thrombus just distal to the site in which the spasm was observed at angiography. As a working hypothesis we proposed that repeated and/or prolonged spasm may damage the intima, cause plaque rupture, hemorrhage, blood stagnation and initiate a vicious circle with platelet aggregation and thrombus formation leading to potentiation of vasospasm and diffuse, prolonged occlusion [8]. The intravascular occlusion may subsequently extend and organize in a permanent obstruction over a variable length of the vessel or be lysed partially or completely. This hypothesis is compatible with the variable response to therapy with intracoronary nitrates [9], with the results of intracoronary fibrinolytic agents [lo] and with the variable frequency of vascular obstruction observed after infarction [ll]. These mechanisms may have preventive implications if we consider that infarction is often preceded by one or more episodes of angina. MECHANISMS AND TREATMENT CORONARY SPASM
OF
We proposed as a working hypothesis that spasm may result from a variable combination of a triggering stimulus acting on hypersensitive vessels. Autonomic nervous system stimulation, histamine, serotonin, thromboxane AZ, ergometrine can induce vasospasm in susceptible vessels, but the susceptibility to spasm can vary considerably in time in the same patient [8]. Until the relative role of triggering factors is better understood, a rational therapy can only be based on drugs which aspecifically raise the threshold for spasm, such as nitrates and slow channel blockers, which appear to give remarkable results both in acute and chronic phases [12]. The results of surgical denervation are still too preliminary to allow conclusions. Following bypass coronary surgery, attacks of vasospastic angina may disappear, at least for some time, but it is difficult to understand the mechanisms of this improvement, in particular in those patients in whom, according to our clinical experience, waxing phases of the disease tend to be associated with inability to cope and breakdown
The American
Journal
of Medicine
Volume
70
753
EDITORIALS-MASER1
in adaptation, and waning phases with reassurance and feelings of security. CONCLUSIONS
3. 4. 5.
The demonstration that impairment of supply caused by transient, potentially reversible, obstruction of the coronary lumen may represent a frequent cause of acute myocardial ischemia is opening new horizons. Although prognosis is obviously heavily influenced by the severity of the underlying coronary organic lesions, diagnosis, treatment and prevention of ischemic heart disease must no longer be centered only on coronary atherosclerosis. Modulating factors, superimposed on a fixed obstruction of varying severity and transiently interfering with coronary blood flow, such as coronary vasospasm, may play a relevant role in the genesis of the clinical manifestations of the disease.
6. 7.
8. 9. 10.
REFERENCES 1. 2.
754
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: 759-767. Maseri A. Parodi 0, Severi S. Pesola A: Transient transmural reduction of myocardial blood flow, demonstrated by thallium-201 scintigraphy. a cause of variant angina. Circulation 1976; 54:280-288.
April 1981
The American
Journal of Medicine
11.
12.
Volume 70
Maseri A, L’Abbatc A, Pesola A. et al.: Coronarv vasosnasm in angina pectoris. Lancet 1977: 1: 713-717. _ _ Maseri A: Pathoaenetic mechanisms of annina pectoris: expanding views. Br Heart J 1980: 43: 6; 6418-666. Maseri A, Severi S. De Nes M, et al.: “Variant” angina: one aspect of a continuous spectrllm of vasospastic myocardial ischemia. Pathogenetic mechanisms, estimated incidence and clinical and coronarv arterionraohic findinns in 138 patients. Am J Cardiol 1958: 42; l&9-1035. Maseri A, Mimmo R, Chierchia S, Marchesi C, Pesola A, L’Abbate A: Coronary artcry spasm as a cause of acute mvocardial ischemia in man. Chest 1975: 68; 625-633. Maseri A. L’Abbate A, Baroldi G. et al.: Coronary vasospasm as a possible cause of myocardial infarction. A conclusion derived from the studv of “ureinfarction” angina. N Enel J Med 1978: 299; 127111278: Maseri A, Chierchia S, L’Abbate A: Pathogenetic mechanisms underlying the clinical events associated with atherosclerotic heart disease. Circulation 1980; 62: ISUDDI):3-13. Oliva PB, Breckenridge 1C: Arteriographicevidence of coronary arterial spasm in acute myocardial infarction. Circulation 1977; 56: 366-374. Rentroo KP. Blanke H. Karsch KR. et al.: Acute mvocardial ‘infarction: intracoronary application of nitroglycerin and streptokinase. Clin Cardiol 1979; 2: 354-363. DeWdod MA, Spores J, Notske R, et al.: Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980; 16: 897-902. Severi S, Davies Gj, Maseri A. Marzullo P. L’Abbate A: Long-term prognosis of variant angina with medical treatment. Am J Cardioll980: 46; 226-231.