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Prinzmetal's variant angina
LETTERS TO THE EDITOR
LYMPHATICS
AND
MYOCARDIAL
FUNCTION
The patient with extensive subendocardial fibroelastosis described by Libanoff and McMahon’ merits some discussion. I believe that he manifested certain findings compatible with disease involving the lymphatics of the heart. The lymphatics of the mammalian heart drain from the endocardium to the epicardium, and on the ventricular surface the collecting lymphatics follow the veins.2 There is evidence that diffuse disease of the myocardium, as well as disease of the myocardial lymphatics, can interfere with lymph drainage from heart muscle and lead to endocardial fibroelastosis in man.:’ Studies in dogs have shown that interference with lymph flow from the heart results in endocardial fibroelastosis.4 It is known that interference with lymph flow predisposes to the laying down of fibrous tissue in the affected tiss&m7 and that fibrotic processes related to wound healing are also a1tered.s The phrase “delayed immunologic reaction” used by Libanoff and McMahon is a type of hazy terminology that does not tell us about the mechanism by which an inflammatory reaction might lead to severe endocardial fibroelastosis. In the patient presented such a reaction could have injured lymphatics and might then have interfered with lymphatic drainage by direct lymphatic obstruction. Additionally, because of an epicarditis, there could have been interference with the lymphatic drainage vessels on the surface of the heart. The mechanism of formation of pericardial effusions has also been related to impaired lymph and venous blood flow from the myocardium,g and the epicarditis in the patient described would be consistent with this concept. Thus, a “delayed immunologic reaction” might cause endocardial fibroelastosis through diffuse direct injury to lymphatics and an inflammatory epicardial process, both causing interference with lymph flow. Certain viral infections may act in a similar manner. The lymphatics of the heart are technically difficult to study, and much of the thinking surrounding their function in pathophysiology is indeed speculative. But enough work has been done to merit for them a role in our thinking. It is my opinion that they play an integral part in myocardial function in health and disease.“)
6. Rusmyak I. Foldi M, Szaba G: Lymphatic5 and Lymph Circulation. New York, Pergamon Press, 1960 7. Kline IK. Miller AJ. Katz LN: Cardiac lvmph flow impairment and mvocardial fib,“=‘=. effects of chronic obstruction in dogs: A&h Pathol’76:424-433. 1463 6. Kline IK. Miller AJ. Pick R. et al: The effects of chronic impairment of cardiac I”mnh flow on myocardial reacti& after coronary artery ligations in dogs. Am Heart;“& 515-523. 1964 9. Miller AJ: Some observations concerning pericardial effusions and their relationship to the venous and lymphatic circulation of the heart. Lymphology 2~76-70. 1970 10. Miller AJ, Pick R, Katz LN: The importance of the lymphatics of the mammalian heart: experimental observations and scwne speculations. Circulation 29:465-467, 1964 ._G,O.
REPLY
We stated early in our article: “Eosinophilia occurs as a manifestation of many different disease processes; however, the mechanism by which it is induced has remained enigmatic.” Our intention in the Discussion was to relate the endomyocardial fibrosis (a late phenomenon) to the eosinophilia (an early phenomenon). Other early manifestations of endomyocardial disease were of a diffuse nature involving the liver, spleen, lymph nodes and bone marrow. It should be noted that the lymph nodes were involved; perhaps the lymphatics were related to that involvement. This would be consistent with Miller’s view that lymphatic obstruction of the heart caused the endomyocardial fibrosis. It is interesting that interference with lymph flow in the heart of the dog causes endomyocardial fibrosis. Let us assume that a diffuse inflammatory reaction of the myocardium caused obstruction to the lymphatic flow. This could have been responsible for the endomyocardial fibrosis. Questions persist concerning etiology. What caused the diffuse myocardial inflammation? What role can one attribute to the eosinophil in the origin of this inflammation? Does the eosinophilia occur in response to the inflammation or as an initial response to some other stimulus? I agree that the Iymphatics merit a role in our thinking about pathologic findings of the heart, and I feel somewhat remiss in not considering their possible role in endomyocardial fibrosis. A. J. Libanoff, MD Internal Medicine
and Cardiology
Montclair,
California
VARIANT
ANGINA
Albert J. Miller, MD Department Northwestern Chicago,
of Medicine University
Medical
References 1. Libanolf AJ, McMahon NJ: Eosinophilla and endomyocardial fibrosis. Am J Cardiol 37:436-441. 1976 2. Patek PR: The morphology of the lymphatics of the mammalian heart. Am J Anat 64:203-249, 1939 3 Kline IK. Miller AJ, Pick R, et al: The relationship between human endocardial fibroelastosis and obstruction of the cardiac lymphatics Circulation 30:726-735, 1964 4. Miller AJ, Pick R, Katz LN: Ventricular endomyocardial changes after impairment of cardiac lymph flow in dogs Etr Heart J 25.182-190, 1963 5. Yofle JM. Courtice FC: Lymphatics. Lymph and the Lymphomyeloid Complex New York, Academic Press, 1970
964
December 1976
PRINZMETAL’S
School
Illinois
The American Journal of CARDIOLOGY
Higgins et al.’ leave the reader with the impression that two separate pathogenetic mechanisms caused variant angina in their 17 patients. They describe a group of eight subjects without important fixed coronary obstructive disease whose angina1 attacks are attributed (quite reasonably) to coronary arterial spasm. In a second group of nine patients high grade fixed coronary arterial stenosis is considered the pathogenetic mechanism for the attacks of variant angina. I disagree with this latter conclusion. Their Table I shows that none of the patients in the group with severe coronary obstruction had a history of angina on
Volume 36
exertion. Moreover, the authors did not document whether attacks at rest in this group were associated with tachycardia or elevated arterial pressure, which would increase myocardial oxygen requirements. They have thus failed to explain adequately what actually did cause these patients to have severe myocardial ischemia while at rest. There is justification for the belief that coronary arterial spasm was the pathogenetic mechanism in most if not all of their cases, even those with high grade fixed obstruction. The elegant angiographic and physiologic observations of Maseri et al.zJ are consistent with this view, as are my own angiographic observations in two patients in whom coronary spasm superimposed on high grade fixed stenosis produced transient complete coronary occlusion, which reproduced the symptoms and electrocardiographic changes that had been seen on the ward before arteriography. In Prinzmetal’s variant angina one can find a complete spectrum of coronary obstructive disease from no arteriographically discernible disease to high grade multivessel obstruction. What binds these arteriographically diverse conditions into a distinct clinical syndrome is the recurrent development of localized transmural myocardial ischemia (injury) when myocardial oxygen needs are low, and the usual absence of ischemia when the metabolic needs of the heart are high. The best information available indicates that the proximate cause of this syndrome is coronary spasm whether or not high grade fixed coronary obstruction is also present. The underlying causes of such spontaneous coronary spasm are not known. This is of clinical importance. Patients with symptoms due to coronary spasm tend to get operated upon when they have some high grade coronary obstructive disease but not when there are no fixed obstructions. This form of treatment may be justified when good medical therapy fails to control symptoms. But the results of coronary bypass surgery are not as good with this syndrome as with classic angina pectoris because coronary spasm often persists after placement of a bypass graft; spasm may involve the vessel distal to the graft or occur in ungrafted vessels, and even may be responsible for thrombosis of the graft. It is possible that some of the unsatisfactory results of surgery in these cases can be avoided by the routine intraoperative administration of vasodilators and by continuing such administration in the postoperative period even in the absence of symptoms. An effective surgical method for abolishing coronary arterial spasm would be an appropriate prelude to bypassing fixed obstruction in these cases, but such a method is currently not known. Rex MacAlpin, MD Department of Medicine The School of Medicine The Center for the Health Sciences University of California, Los Angeles Los Angeles, California
1
Higgins CB, Wexler L, Silverman JF, et al: Clinical and arteriographic features of Prinzmetal’s variant angina: documentation of etiologic factors. Am J Cardiol 37: 631-639. 1976 2. Maseri A, Pesola A, Mimmo R, et al: Pathogenetic mechanisms of angina at rest. Circulation 52:Suppl ll:li-69. 1975 3. Maseri A, Mlmmo R, Chlerchia S, et al: Coronary artery spasm as a cause of acute myocardial ischemia in man. Chest 68:625-633. 1975
REPLY
The 17 patients in our study had in common the occurrence of chest pain while at rest and S-T segment elevation during painful episodes. Coronary arteriography in nine patients revealed obstructive lesions that, according to current concepts, were sufficiently severe to be responsible for angina under situations of augmented myocardial oxygen requirements. In eight of these nine patients the luminal diameter of at least one coronary artery was narrowed by more than 85 percent. Luminal narrowing of the cross-sectional diameter of a coronary artery by more than 85 percent has been demonstrated in canine preparations to be sufficient to impede distal coronary blood flow at rest.’ Therefore, it is not possible to state that fixed obstructions of this severity were not solely responsible for episodes of angina. In our minds, and as stated in a recent compilation of knowledge on this subject,2 spasm as the proximate mechanism of ischemia in all patients with variant angina is not as clearly established as MacAlpin apparently believes. However, we, like MacAlpin, have developed the feeling that coronary arterial spasm, in some instances, is superimposed on significant lesions and have recently documented this notion by coronary arteriography in two patients. Coronary arterial spasm occurred spontaneously during arteriography at the site of a 60 percent stenosis of the proximal left anterior descending coronary artery, resulting in near total occlusion in one patient. In the other patient, spasm appeared at the site of an 80 percent stenosis of the mid right coronary artery, producing total occlusion. In conclusion, we agree that spasm may be superimposed on lesions of any severity. However, given the current state of knowledge on this topic, one can be relatively confident that spasm is the responsible mechanism eventuating in myocardial ischemia only in those patients with clearly nonsignificant fixed stenoses. Charles B. Higgins, MD Department of Radiology University Hospital University of California, San Diego San Diego, California References 1. Gould KL, Lipscomb K, Calverf C: Compensatory changes of the distal cwonary vascular bed during progressive coronary constriction. Circulation 51:1085-1094. 1975 2. Scherf D, Cohen J: “Variant” angina pectoris. Circulation 49:767-769. 1974
December 1976
The American Journal of CARDIOLOGY
Volume 38
965
LYMPHATICS
AND
MYOCARDIAL
FUNCTION
The patient with extensive subendocardial fibroelastosis described by Libanoff and McMahon’ merits some discussion. I believe that he manifested certain findings compatible with disease involving the lymphatics of the heart. The lymphatics of the mammalian heart drain from the endocardium to the epicardium, and on the ventricular surface the collecting lymphatics follow the veins.2 There is evidence that diffuse disease of the myocardium, as well as disease of the myocardial lymphatics, can interfere with lymph drainage from heart muscle and lead to endocardial fibroelastosis in man.:’ Studies in dogs have shown that interference with lymph flow from the heart results in endocardial fibroelastosis.4 It is known that interference with lymph flow predisposes to the laying down of fibrous tissue in the affected tiss&m7 and that fibrotic processes related to wound healing are also a1tered.s The phrase “delayed immunologic reaction” used by Libanoff and McMahon is a type of hazy terminology that does not tell us about the mechanism by which an inflammatory reaction might lead to severe endocardial fibroelastosis. In the patient presented such a reaction could have injured lymphatics and might then have interfered with lymphatic drainage by direct lymphatic obstruction. Additionally, because of an epicarditis, there could have been interference with the lymphatic drainage vessels on the surface of the heart. The mechanism of formation of pericardial effusions has also been related to impaired lymph and venous blood flow from the myocardium,g and the epicarditis in the patient described would be consistent with this concept. Thus, a “delayed immunologic reaction” might cause endocardial fibroelastosis through diffuse direct injury to lymphatics and an inflammatory epicardial process, both causing interference with lymph flow. Certain viral infections may act in a similar manner. The lymphatics of the heart are technically difficult to study, and much of the thinking surrounding their function in pathophysiology is indeed speculative. But enough work has been done to merit for them a role in our thinking. It is my opinion that they play an integral part in myocardial function in health and disease.“)
6. Rusmyak I. Foldi M, Szaba G: Lymphatic5 and Lymph Circulation. New York, Pergamon Press, 1960 7. Kline IK. Miller AJ. Katz LN: Cardiac lvmph flow impairment and mvocardial fib,“=‘=. effects of chronic obstruction in dogs: A&h Pathol’76:424-433. 1463 6. Kline IK. Miller AJ. Pick R. et al: The effects of chronic impairment of cardiac I”mnh flow on myocardial reacti& after coronary artery ligations in dogs. Am Heart;“& 515-523. 1964 9. Miller AJ: Some observations concerning pericardial effusions and their relationship to the venous and lymphatic circulation of the heart. Lymphology 2~76-70. 1970 10. Miller AJ, Pick R, Katz LN: The importance of the lymphatics of the mammalian heart: experimental observations and scwne speculations. Circulation 29:465-467, 1964 ._G,O.
REPLY
We stated early in our article: “Eosinophilia occurs as a manifestation of many different disease processes; however, the mechanism by which it is induced has remained enigmatic.” Our intention in the Discussion was to relate the endomyocardial fibrosis (a late phenomenon) to the eosinophilia (an early phenomenon). Other early manifestations of endomyocardial disease were of a diffuse nature involving the liver, spleen, lymph nodes and bone marrow. It should be noted that the lymph nodes were involved; perhaps the lymphatics were related to that involvement. This would be consistent with Miller’s view that lymphatic obstruction of the heart caused the endomyocardial fibrosis. It is interesting that interference with lymph flow in the heart of the dog causes endomyocardial fibrosis. Let us assume that a diffuse inflammatory reaction of the myocardium caused obstruction to the lymphatic flow. This could have been responsible for the endomyocardial fibrosis. Questions persist concerning etiology. What caused the diffuse myocardial inflammation? What role can one attribute to the eosinophil in the origin of this inflammation? Does the eosinophilia occur in response to the inflammation or as an initial response to some other stimulus? I agree that the Iymphatics merit a role in our thinking about pathologic findings of the heart, and I feel somewhat remiss in not considering their possible role in endomyocardial fibrosis. A. J. Libanoff, MD Internal Medicine
and Cardiology
Montclair,
California
VARIANT
ANGINA
Albert J. Miller, MD Department Northwestern Chicago,
of Medicine University
Medical
References 1. Libanolf AJ, McMahon NJ: Eosinophilla and endomyocardial fibrosis. Am J Cardiol 37:436-441. 1976 2. Patek PR: The morphology of the lymphatics of the mammalian heart. Am J Anat 64:203-249, 1939 3 Kline IK. Miller AJ, Pick R, et al: The relationship between human endocardial fibroelastosis and obstruction of the cardiac lymphatics Circulation 30:726-735, 1964 4. Miller AJ, Pick R, Katz LN: Ventricular endomyocardial changes after impairment of cardiac lymph flow in dogs Etr Heart J 25.182-190, 1963 5. Yofle JM. Courtice FC: Lymphatics. Lymph and the Lymphomyeloid Complex New York, Academic Press, 1970
964
December 1976
PRINZMETAL’S
School
Illinois
The American Journal of CARDIOLOGY
Higgins et al.’ leave the reader with the impression that two separate pathogenetic mechanisms caused variant angina in their 17 patients. They describe a group of eight subjects without important fixed coronary obstructive disease whose angina1 attacks are attributed (quite reasonably) to coronary arterial spasm. In a second group of nine patients high grade fixed coronary arterial stenosis is considered the pathogenetic mechanism for the attacks of variant angina. I disagree with this latter conclusion. Their Table I shows that none of the patients in the group with severe coronary obstruction had a history of angina on
Volume 36
exertion. Moreover, the authors did not document whether attacks at rest in this group were associated with tachycardia or elevated arterial pressure, which would increase myocardial oxygen requirements. They have thus failed to explain adequately what actually did cause these patients to have severe myocardial ischemia while at rest. There is justification for the belief that coronary arterial spasm was the pathogenetic mechanism in most if not all of their cases, even those with high grade fixed obstruction. The elegant angiographic and physiologic observations of Maseri et al.zJ are consistent with this view, as are my own angiographic observations in two patients in whom coronary spasm superimposed on high grade fixed stenosis produced transient complete coronary occlusion, which reproduced the symptoms and electrocardiographic changes that had been seen on the ward before arteriography. In Prinzmetal’s variant angina one can find a complete spectrum of coronary obstructive disease from no arteriographically discernible disease to high grade multivessel obstruction. What binds these arteriographically diverse conditions into a distinct clinical syndrome is the recurrent development of localized transmural myocardial ischemia (injury) when myocardial oxygen needs are low, and the usual absence of ischemia when the metabolic needs of the heart are high. The best information available indicates that the proximate cause of this syndrome is coronary spasm whether or not high grade fixed coronary obstruction is also present. The underlying causes of such spontaneous coronary spasm are not known. This is of clinical importance. Patients with symptoms due to coronary spasm tend to get operated upon when they have some high grade coronary obstructive disease but not when there are no fixed obstructions. This form of treatment may be justified when good medical therapy fails to control symptoms. But the results of coronary bypass surgery are not as good with this syndrome as with classic angina pectoris because coronary spasm often persists after placement of a bypass graft; spasm may involve the vessel distal to the graft or occur in ungrafted vessels, and even may be responsible for thrombosis of the graft. It is possible that some of the unsatisfactory results of surgery in these cases can be avoided by the routine intraoperative administration of vasodilators and by continuing such administration in the postoperative period even in the absence of symptoms. An effective surgical method for abolishing coronary arterial spasm would be an appropriate prelude to bypassing fixed obstruction in these cases, but such a method is currently not known. Rex MacAlpin, MD Department of Medicine The School of Medicine The Center for the Health Sciences University of California, Los Angeles Los Angeles, California
1
Higgins CB, Wexler L, Silverman JF, et al: Clinical and arteriographic features of Prinzmetal’s variant angina: documentation of etiologic factors. Am J Cardiol 37: 631-639. 1976 2. Maseri A, Pesola A, Mimmo R, et al: Pathogenetic mechanisms of angina at rest. Circulation 52:Suppl ll:li-69. 1975 3. Maseri A, Mlmmo R, Chlerchia S, et al: Coronary artery spasm as a cause of acute myocardial ischemia in man. Chest 68:625-633. 1975
REPLY
The 17 patients in our study had in common the occurrence of chest pain while at rest and S-T segment elevation during painful episodes. Coronary arteriography in nine patients revealed obstructive lesions that, according to current concepts, were sufficiently severe to be responsible for angina under situations of augmented myocardial oxygen requirements. In eight of these nine patients the luminal diameter of at least one coronary artery was narrowed by more than 85 percent. Luminal narrowing of the cross-sectional diameter of a coronary artery by more than 85 percent has been demonstrated in canine preparations to be sufficient to impede distal coronary blood flow at rest.’ Therefore, it is not possible to state that fixed obstructions of this severity were not solely responsible for episodes of angina. In our minds, and as stated in a recent compilation of knowledge on this subject,2 spasm as the proximate mechanism of ischemia in all patients with variant angina is not as clearly established as MacAlpin apparently believes. However, we, like MacAlpin, have developed the feeling that coronary arterial spasm, in some instances, is superimposed on significant lesions and have recently documented this notion by coronary arteriography in two patients. Coronary arterial spasm occurred spontaneously during arteriography at the site of a 60 percent stenosis of the proximal left anterior descending coronary artery, resulting in near total occlusion in one patient. In the other patient, spasm appeared at the site of an 80 percent stenosis of the mid right coronary artery, producing total occlusion. In conclusion, we agree that spasm may be superimposed on lesions of any severity. However, given the current state of knowledge on this topic, one can be relatively confident that spasm is the responsible mechanism eventuating in myocardial ischemia only in those patients with clearly nonsignificant fixed stenoses. Charles B. Higgins, MD Department of Radiology University Hospital University of California, San Diego San Diego, California References 1. Gould KL, Lipscomb K, Calverf C: Compensatory changes of the distal cwonary vascular bed during progressive coronary constriction. Circulation 51:1085-1094. 1975 2. Scherf D, Cohen J: “Variant” angina pectoris. Circulation 49:767-769. 1974
December 1976
The American Journal of CARDIOLOGY
Volume 38
965