CASE REPORTS
Small Vessel Disease of the Heart Resulting in Myocardial Necrosis and Death Despite Angiographically Normal Coronary Arteries
JAY W. MASON, MD, FACC AARON STREFLING, MD Stanford. California
A 46 year old man who had undergone cardiac transplantation
1 year previously had progressive congestive heart failure without evidence of cardiac rejection. Cardiac catheterization and angiography revealed a reduced ejectionfraction and cardiac output caused by diffuse left ventricular hypokinegia, but the epicardial coronary arteries were widely patent. The transit time of injected contrast material across the coronary arterial tree was greatly slowed. Within a few days cardiogenic shock and death occurred. The large epicardial coronary vessels were grossly patent at autopsy, although nonstenosing arteriosclerotic plaques were identifiable histologically. However, intramyocardial vessels showed severe arteriosclerotic narrowing, resulting in multiple, diffuse microinfarcts.
An adequate mass of evidence exists now to prove unequivocally the occurrence of myocardial infarction despite normal coronary arteriograms,l-s although opinions to the contrary have been offered.7s8 Considerable, in fact exhaustive, speculation has been offered, but the etiology of such infarction, with rare exceptions,2 is entirely undetermined. In this report we document the occurrence of occlusive disease of the small intramural coronary arteries in the absence of angiographically demonstrable epicardial arterial disease with resultant myocardial infarction and death. Case History A 46 year old man was referred to the Stanford University Medical Center for cardiac transplantation. For 9 months before referral he had experienced pro-
From the Division of Cardiology and Department of Pathology, Stanford University School of Medicine, Stanford, California. This work was supported in part by Grants f-L-5866 and HL- 13 108-09 from the National institutes of Health, Bethesda, Maryland. Manuscript received December 12, 1978; revised manuscript received January 3, 1979, accepted February 1, 1979. Address for reprints: Jay W. Mason, MD, Division of Cardiology, Stanford University Medical Center, Stanford, California 94305.
gressive cardiac dilatation and failure without historical or angiographic evidence of myocardial infarction or coronary artery disease. Endomyocardial biopsy at Stanford was consistent with congestive cardiomyopathy. Cardiac transplantation was accomplished 2 months after referral. Examination of the excised heart confirmed the absence of disease of both epicardial and intramyocardial vessels. The findings were consistent with idiopathic myocardial disease. The donor heart was obtained from a 19 year old man who had had brain death and had no evidence of premortem cardiac disease. At the time of transplantation, gross examination of the donor heart showed no abnormal findings, and cardiac function after transplantation was normal. The early posttransplant course was uncomplicated. Only two epjspdes of cardiac rejection were documented and easily treated.
One year after transplantation the patient returned for annual investigations, and at that time it became clear that congestive heart failure had been developing over the past month. He was on maintenance doses of immunosuppressive agents, including prednisone, 20 mg daily, and azathioprine, 200 mg daily. The electrocardiogram now revealed a modest decrease in QRS voltage as well as a mild left axis shift, prolongation of the P-R interval and S-T segment
July 1979
The American Journal of CARDIOLOGY
Volume 44
171
SMALL VESSEL CORONARY DISEASE-MASON
AND STREFLING
and T wave changes (Fig. 1). The possibility of acute cardiac rejection was entertained and myocardial biopsy performed,g but no histologic evidence of rejectionlO was found despite cardiac enlargement and clinical signs of congestive heart failure. Endomyocardial biopsy of both the right and left ventricles was repeated but again showed no evidence of acute rejection, although ongoing interstitial fibrosis was found on this second biopsy. Except for capillaries, small vessels were
not identified in any of the biopsy specimens. Angiography was then undertaken (see later). The left ventricular enddiastolic pressure was increased and the cardiac index reduced, hut coronary disease was not present. Standard therapy for congestive heart failure was instituted but the progressive deterioration was unrelenting and 1 year and 17 days after cardiac transplantation the patient died. Angiographic findings: A sinus tachycardia of 120 beats/min was present during angiography. The left ventriculogram revealed moderate left ventricular cavity enlargement and diffuse moderately severe left ventricular hypokinesia (Fig. 2). Coronary angiography unequivocally demonstrated widely patent epicardial coronary vessels. However, with both right and left coronary injections, contrast runoff in the distal vessels was profoundly delayed beyond the permissible tine recording time (Fig. 3 and 4). The small coronary vessels usually visible in high quality coronary arteriograms were normal. Pathologic findings: The heart was edematous and weighed 410 g. There was extensive, diffuse recent hemorrhage. The pericardial space was obliterated by mild fibrinous adhesions. The epicardial coronary vessels appeared grossly
FfGURE 1. Electrocardiograms taken at full standardization. A, obtained 3 months after cardiac transpiantatiot?, demonstrating diffuse S-T segment and T wave abnormalities, which are commonly present in the electrocaridiograms after transplantation. 6. taken the day before the patient’s death. A marked decrease in CFtS voltage is apparent. The frontal GRS axis has shifted toward the left. The sinus rate has increased from 104 to 130 beats/min, and the P-R interval has increased from 0.15 to 0.27 second. Mild S-T segment elevation is now present in lead VI, as well as diffuse S-T segment depression.
172
July 1979
The American Journal of CARDIOLOGY
Volume 44
FIGURE 2. End-systolic (top) and end-diastolic (bottom) left ventriculographic frames. There is moderately severe global depression of left ventricular contraction.
SMALL
normal. On light microscopy, sections from all four cardiac chambers showed hemorrhage. Infrequent perivascular mononuclear cell infiltrates and occasional aggregates of lymphocytes and plasma cells were found in the subendocardium. Some sections of the anterior descending, left circumflex and right coronary arteries showed mild intimal proliferation (Fig.
VESSEL CORONARY
DISEASE-MASON
AND STREFLING
5), but no lesions appeared t,o compromise their luminal diameter significantly. Most striking was the severe degree of intimal proliferation noted in virtually all of the intramyocardial branches of both coronary arteries seen microscopitally. In many arteries there was almost total obliteration of the lumen (Fig. 6). Finally, sections from both ventricles
FIGURE 3. Right coronary angiogram. A, frame showing the right coronary artery partially opacified at the end of contrast injection. B, a frame taken four heartbeats and 2 seconds later. The distal right coronary artery is now fully opacified and contrast agent remains in the more proximal vessel (black arrow). C, frame obtained seven heartbeats and 1.5 seconds after B. Contrast agent remains both in the proximal vessel (black arrow) and in the distal coronary artery (white anow). D, obtained after three more heartbeats and 1.6 seconds had passed; considerable contrast material is still visible in the proximal right coronary artery a full 5.1 seconds and 10 cardiac contractions after completion of the injection.
July 1979
The American Journal of CARDIOLOGY
Volume 44
173
SMALL VESSEL CORONARY DISEASE-MASON
AND STREFLING
FIGURE 4. Left coronary angiogram. The left frame shows the opacified left coronary system in the right anterior oblique projection at the completion of contrast injection. The right frame shows persistence of contrast medium in both the proximal and distal left anterior descending system, five beats (3.2 seconds) later.
showed early focal necrosis of myocardial fibers (Fig. 7). Such pathologic findings have never been observed by us in over 100 autopsies of transplanted hearts of human beings.
Myocardial infarction or necrosis in the absence of coronary occlusive disease is a challenging enigma. In autopsy cases in which normal coronary arterial anatomy is demonstrated, thromboembolism with subsequent clot lysis, thrombosis in situ with recanalization, abnormal affinity of hemoglobin for oxygen,’ coronary arterial spasm and excessive myocardial oxygen demand1’J2 have all been considered potential causes. There has been direct and circumstantial evidence to support each of these theories, but there has also been compelling evidence against each of them. Multiple,
independent causes of nonatherosclerosis-induced myocardial infarction are likely. Small coronary vessel disease as a cause of myocardial infarction: In those cases where autopsy has not ruled it out an additional etiology has been entertained: occlusive disease of the small, intramural coronary arteries. Although a number of disease processes may involve the small coronary arteries (systemic vasculitis, amyloidosis, hereditary medial necrosis and diabetes mellitus), it is not clear whether any of these disorders can so selectively involve the small vessels as to result in myocardial infarction with angiographically normal epicardial coronary vessels. Exclusive involvement of the intramural coronary branches has been noted in dogs,13 and descriptions of these lesions are strikingly similar to findings in our
FIGURE 5. Mild intimal proliferation in the circumflex branch of the left coronary artery. (Hematoxylin-eosin X30, reduced by 33 percent.)
FIGURE 6. A typical intramyocardial artery showing severe atherosclerotic narrowing. Note the marked intimal proliferation with lipid deposition (hematoxylin-eosin X 192, reduced by 33 percent.)
Discussion
174
July 1979
The American Journal of CARDIOLOGY
Volume 44
SMALL VESSEL CORONARY DISEASE-MASON
patient. Similar preferential involvement of the deep myocardial vessels has been described in a variety of mammals and birds.i4 The etiology of this lesion is unknown, but an inflammatory process has been suggested.14 Inflammation has previously been considered a possible cause of all forms of arteriosclerosis.15 More recently, pathologic evidence has been presented of an inflammatory lesion of the small coronary vessels in patients with large vessel atherosclerosis.16 It is also possible that small vessel coronary disease simply represents an unusual manifestation of the same coronary atherosclerotic process that involves the larger vessels. This appeared to be the case in our patient. Coronary artery disease in the transplanted heart: This may be the only reported case of fatal small
vessel coronary arteriopathy associated with a normal coronary arteriogram. In addition, it is a special instance of this process because it occurred in a transplanted heart. Coronary arteriosclerosis of the transplanted heart is common, and may be present in some degree in 20 percent or more of patients within 3 years of transplantation.17 Interestingly, a heart recipient’s preoperative cardiac diagnosis (end stage coronary artery disease versus cardiomyopathy) has no bearing on the incidence, nature or severity of this lesion after transplantation. l7 A reasonable hypothesis holds that coronary vascular intimal injury, resulting from acute, overt rejection or perhaps from a more chronic, clinically inapparent rejection process, renders the coronary vessel susceptible to the “normal” atherosclerotic process. Although we have seen similar severe small vessel involvement in two other cardiac grafts and less severe involvement in others, proportionately extensive epicardial vessel involvement, with abnormal coronary arteriograms, was present in these cases (unpublished observation by Margaret E. Billingham, MD). The small
FIGURE 7. Myocardium from the left ventricle. showing early focal ischemic necrosis. The muscle fibers are swollen with cross striations that are blurred and coarsened and their nuclei have disappeared. A large contraction band is present (arrows). Neutrophils are almost undetectable in the interstitial tissue. Hematoxylin-eosin X 192, reduced by 33 percent.)
AND STREFLING
vessel disease noted in other recipients, aside from this patient and the two described earlier, has been minimal, nonocclusive and not associated with infarction. It is worthwhile noting that our patient did, in fact, have atherosclerotic disease involving the proximal epicardial vessels. However, that involvement was relatively minor and nonocclusive, and therefore was not detected on coronary arteriography. It should be noted that epicardial coronary disease is seen on angiography in approximately 20 percent of patients, after cardiac transplantation, and can also lead to myocardial infarction. Significance of retarded clearance of contrast agent on coronary angiography: The only coronary
angiographic abnormality found in this patient was greatly retarded clearance of the contrast agent from the coronary vessels. This finding may relate to reduced coronary flow, but other explanations are tenable. For example, if for some reason the total capacity of the transplant recipient’s coronary arterial bed was abnormally increased, then flow volume might be normal despite a decreased flow velocity. Previous studies in our transplant recipients have documented essentially normal flow volumes in the resting state.18 However, because of total anatomic cardiac denervation, and resultant removal of resting neural alpha adrenergic tone,18 it is in fact plausible that a greater arterial capacity is present. This possibility could account for the fact that slowed disappearance of contrast medium from the coronary arteries has been seen in other transplant recipients without large or known small vessel coronary disease. Another possible explanation might be the existence of abnormal mixing of the contrast agent with the transplant recipient’s blood, or an affinity of the agent for the recipient’s coronary vessel wall, although there are no data or theories to support these latter two speculations. Premortem identification of the form of small vessel arteriopathy presented herein may be difficult. Our findings suggest that a reduced rate of removal of contrast material during angiography from the coronary arteries in the absence of proximal stenoses may be a clue to the presence of microvascular occlusive disease, although the sensitivity and specificity of such a finding are untested. It might be possible to detect this lesion with endomyocardial biopsy, although arterioles of the size affected in our patient are usually not seen in endomyocardial biopsy specimens. Clinical implications: It is not known whether there is a correlate of the small vessel disease described in our case in the nontransplanted, nondenervated heart. However, this case serves to demonstrate clearly that severe small vessel disease can occur in man in the presence of angiographically normal epicardial coronary arteries. In addition, our experience with other transplant patients demonstrates that large vessel involvement may occur simultaneously with intramural vessel disease. Thus, one should recognize this possibility when considering patients with “routine” coronary artery disease, especially when angiographic and electrocardiographic or historical data conflict.
July 1979
The American Journal of CARDIOLOGY
Volume 44
175
SMALL VESSEL CORONARY DISEASE-MASON
AND STREFLING
References 1. Eliot RS, BratlO: The paradox of myocardial ischemia and necrosis in young women with normal coronary arteriograms. Am J Cardiol 23:633-638, 1969 2. Bruschke AVG, Bruyneel KJJ, Bloch A, van Herpen G: Acute myocardial infarction without obstructive coronary artery disease demonstrated by selective cinearteriography. Br Heart J 33: 585-594, 1971 3. Khan AH, Haywood LJ: Myocardial infarction in nine patients with radiologically patent coronary arteries. N Engl J Med 35:427-430. 1974 4. Clraulo DA: Recurrent myocardial infarction and angina in a woman with normal coronary angiograms. Am J Cardiol 35923-928, 1975 5. Rosenblatt A, Seizer A: The nature and clinical features of myocardial infarction with normal coronary arteriogram. Circulation 55578-580, 1977 6. kifchaelson SP, Karsh DL, Wolfson S, Lebson RE, Cohen LS: Recurrent myocardlal infarction with normal coronary arteriography. N Engl J Med 297:916-918, 1977 7. James TN: Angina without coronary disease (sic). Circulation 62:189-191, 1970 8. Arnett EN, Roberts WC: Acute myocardial infarction and angiographically normal coronary arteries. Circulation 53:395-399, 1976 9. Mason JW: Techniques for right and left ventricular endomyocardial biopsy. Am J Cardiol41:882-892, 1978 10.. Caves PK, Bllllngham ME, Stlnson EB, Shumway NE: Serial
178
July 1979
The American Journal of CARDIOLOGY
Volume 44
i 1.
12.
13. 14.
15. 16. 17.
18.
19.
transvenous biopsy of the transplanted human heart: improved management of acute rejection episodes. Lancet 2:821-826, 1974 Arbogaef R, Sourasa MO: fvlyocardialfunction during atrial pacing in patients with angina pectoris and normal coronary arteriograms. Am J Cardiol 32:257-263, 1973 Mammohanslngh P, Parker JO: Angina pectoris with normal coronary arteriograms: hemodynamic and metabolic response to atrial pacing. Am Heart J 90:555-561, 1975 Luglnbuhl H, Detweller DK: Cardiovascular lesions in d>gs. Ann NY Acad Sci 127:517-540, 1966 Ratcliffe HL, Yerasfmkles TG, Elliott GA: Changes in the character and iocation of arterial lesions in mammals and birds in the Philadelphia Zoological Garden. Circulation 21:730-738, 1960 Soyd AN: Inflammatory basis for coronary thrombosis. Am J Pathol 4:15-18, 1928 Saphir 0, Dhrlnger L: Changes in the intramural coronary branches in coronary arteriosclerosis. Arch Pathol 62: 159- 170, 1956 Griepp RB, Stlnson EB, Bleber CP, Reltr BA, Copeland JG, Oyer PE, Shumway NE: Control of graft arteriosclerosis in human heart transplant recipients. Surgery 81:262-269. 1977 Orllck AE, Ricci DR, Alderman EL, Stinson EB, Harrison DC: Effects of alpha-adrenergic blockade on coronary hemodynamics. J Clin Invest 62:459-467, 1978 Bllllngham ME, Schwartz BD, Rider AK, Harrison DC: An ultrastructural study of age-related changes in intramyocardial arterioles (abstr). Lab Invest 36:3, 1977
Small Vessel Disease of the Heart Resulting in Myocardial Necrosis and Death Despite Angiographically Normal Coronary Arteries
JAY W. MASON, MD, FACC AARON STREFLING, MD Stanford. California
A 46 year old man who had undergone cardiac transplantation
1 year previously had progressive congestive heart failure without evidence of cardiac rejection. Cardiac catheterization and angiography revealed a reduced ejectionfraction and cardiac output caused by diffuse left ventricular hypokinegia, but the epicardial coronary arteries were widely patent. The transit time of injected contrast material across the coronary arterial tree was greatly slowed. Within a few days cardiogenic shock and death occurred. The large epicardial coronary vessels were grossly patent at autopsy, although nonstenosing arteriosclerotic plaques were identifiable histologically. However, intramyocardial vessels showed severe arteriosclerotic narrowing, resulting in multiple, diffuse microinfarcts.
An adequate mass of evidence exists now to prove unequivocally the occurrence of myocardial infarction despite normal coronary arteriograms,l-s although opinions to the contrary have been offered.7s8 Considerable, in fact exhaustive, speculation has been offered, but the etiology of such infarction, with rare exceptions,2 is entirely undetermined. In this report we document the occurrence of occlusive disease of the small intramural coronary arteries in the absence of angiographically demonstrable epicardial arterial disease with resultant myocardial infarction and death. Case History A 46 year old man was referred to the Stanford University Medical Center for cardiac transplantation. For 9 months before referral he had experienced pro-
From the Division of Cardiology and Department of Pathology, Stanford University School of Medicine, Stanford, California. This work was supported in part by Grants f-L-5866 and HL- 13 108-09 from the National institutes of Health, Bethesda, Maryland. Manuscript received December 12, 1978; revised manuscript received January 3, 1979, accepted February 1, 1979. Address for reprints: Jay W. Mason, MD, Division of Cardiology, Stanford University Medical Center, Stanford, California 94305.
gressive cardiac dilatation and failure without historical or angiographic evidence of myocardial infarction or coronary artery disease. Endomyocardial biopsy at Stanford was consistent with congestive cardiomyopathy. Cardiac transplantation was accomplished 2 months after referral. Examination of the excised heart confirmed the absence of disease of both epicardial and intramyocardial vessels. The findings were consistent with idiopathic myocardial disease. The donor heart was obtained from a 19 year old man who had had brain death and had no evidence of premortem cardiac disease. At the time of transplantation, gross examination of the donor heart showed no abnormal findings, and cardiac function after transplantation was normal. The early posttransplant course was uncomplicated. Only two epjspdes of cardiac rejection were documented and easily treated.
One year after transplantation the patient returned for annual investigations, and at that time it became clear that congestive heart failure had been developing over the past month. He was on maintenance doses of immunosuppressive agents, including prednisone, 20 mg daily, and azathioprine, 200 mg daily. The electrocardiogram now revealed a modest decrease in QRS voltage as well as a mild left axis shift, prolongation of the P-R interval and S-T segment
July 1979
The American Journal of CARDIOLOGY
Volume 44
171
SMALL VESSEL CORONARY DISEASE-MASON
AND STREFLING
and T wave changes (Fig. 1). The possibility of acute cardiac rejection was entertained and myocardial biopsy performed,g but no histologic evidence of rejectionlO was found despite cardiac enlargement and clinical signs of congestive heart failure. Endomyocardial biopsy of both the right and left ventricles was repeated but again showed no evidence of acute rejection, although ongoing interstitial fibrosis was found on this second biopsy. Except for capillaries, small vessels were
not identified in any of the biopsy specimens. Angiography was then undertaken (see later). The left ventricular enddiastolic pressure was increased and the cardiac index reduced, hut coronary disease was not present. Standard therapy for congestive heart failure was instituted but the progressive deterioration was unrelenting and 1 year and 17 days after cardiac transplantation the patient died. Angiographic findings: A sinus tachycardia of 120 beats/min was present during angiography. The left ventriculogram revealed moderate left ventricular cavity enlargement and diffuse moderately severe left ventricular hypokinesia (Fig. 2). Coronary angiography unequivocally demonstrated widely patent epicardial coronary vessels. However, with both right and left coronary injections, contrast runoff in the distal vessels was profoundly delayed beyond the permissible tine recording time (Fig. 3 and 4). The small coronary vessels usually visible in high quality coronary arteriograms were normal. Pathologic findings: The heart was edematous and weighed 410 g. There was extensive, diffuse recent hemorrhage. The pericardial space was obliterated by mild fibrinous adhesions. The epicardial coronary vessels appeared grossly
FfGURE 1. Electrocardiograms taken at full standardization. A, obtained 3 months after cardiac transpiantatiot?, demonstrating diffuse S-T segment and T wave abnormalities, which are commonly present in the electrocaridiograms after transplantation. 6. taken the day before the patient’s death. A marked decrease in CFtS voltage is apparent. The frontal GRS axis has shifted toward the left. The sinus rate has increased from 104 to 130 beats/min, and the P-R interval has increased from 0.15 to 0.27 second. Mild S-T segment elevation is now present in lead VI, as well as diffuse S-T segment depression.
172
July 1979
The American Journal of CARDIOLOGY
Volume 44
FIGURE 2. End-systolic (top) and end-diastolic (bottom) left ventriculographic frames. There is moderately severe global depression of left ventricular contraction.
SMALL
normal. On light microscopy, sections from all four cardiac chambers showed hemorrhage. Infrequent perivascular mononuclear cell infiltrates and occasional aggregates of lymphocytes and plasma cells were found in the subendocardium. Some sections of the anterior descending, left circumflex and right coronary arteries showed mild intimal proliferation (Fig.
VESSEL CORONARY
DISEASE-MASON
AND STREFLING
5), but no lesions appeared t,o compromise their luminal diameter significantly. Most striking was the severe degree of intimal proliferation noted in virtually all of the intramyocardial branches of both coronary arteries seen microscopitally. In many arteries there was almost total obliteration of the lumen (Fig. 6). Finally, sections from both ventricles
FIGURE 3. Right coronary angiogram. A, frame showing the right coronary artery partially opacified at the end of contrast injection. B, a frame taken four heartbeats and 2 seconds later. The distal right coronary artery is now fully opacified and contrast agent remains in the more proximal vessel (black arrow). C, frame obtained seven heartbeats and 1.5 seconds after B. Contrast agent remains both in the proximal vessel (black arrow) and in the distal coronary artery (white anow). D, obtained after three more heartbeats and 1.6 seconds had passed; considerable contrast material is still visible in the proximal right coronary artery a full 5.1 seconds and 10 cardiac contractions after completion of the injection.
July 1979
The American Journal of CARDIOLOGY
Volume 44
173
SMALL VESSEL CORONARY DISEASE-MASON
AND STREFLING
FIGURE 4. Left coronary angiogram. The left frame shows the opacified left coronary system in the right anterior oblique projection at the completion of contrast injection. The right frame shows persistence of contrast medium in both the proximal and distal left anterior descending system, five beats (3.2 seconds) later.
showed early focal necrosis of myocardial fibers (Fig. 7). Such pathologic findings have never been observed by us in over 100 autopsies of transplanted hearts of human beings.
Myocardial infarction or necrosis in the absence of coronary occlusive disease is a challenging enigma. In autopsy cases in which normal coronary arterial anatomy is demonstrated, thromboembolism with subsequent clot lysis, thrombosis in situ with recanalization, abnormal affinity of hemoglobin for oxygen,’ coronary arterial spasm and excessive myocardial oxygen demand1’J2 have all been considered potential causes. There has been direct and circumstantial evidence to support each of these theories, but there has also been compelling evidence against each of them. Multiple,
independent causes of nonatherosclerosis-induced myocardial infarction are likely. Small coronary vessel disease as a cause of myocardial infarction: In those cases where autopsy has not ruled it out an additional etiology has been entertained: occlusive disease of the small, intramural coronary arteries. Although a number of disease processes may involve the small coronary arteries (systemic vasculitis, amyloidosis, hereditary medial necrosis and diabetes mellitus), it is not clear whether any of these disorders can so selectively involve the small vessels as to result in myocardial infarction with angiographically normal epicardial coronary vessels. Exclusive involvement of the intramural coronary branches has been noted in dogs,13 and descriptions of these lesions are strikingly similar to findings in our
FIGURE 5. Mild intimal proliferation in the circumflex branch of the left coronary artery. (Hematoxylin-eosin X30, reduced by 33 percent.)
FIGURE 6. A typical intramyocardial artery showing severe atherosclerotic narrowing. Note the marked intimal proliferation with lipid deposition (hematoxylin-eosin X 192, reduced by 33 percent.)
Discussion
174
July 1979
The American Journal of CARDIOLOGY
Volume 44
SMALL VESSEL CORONARY DISEASE-MASON
patient. Similar preferential involvement of the deep myocardial vessels has been described in a variety of mammals and birds.i4 The etiology of this lesion is unknown, but an inflammatory process has been suggested.14 Inflammation has previously been considered a possible cause of all forms of arteriosclerosis.15 More recently, pathologic evidence has been presented of an inflammatory lesion of the small coronary vessels in patients with large vessel atherosclerosis.16 It is also possible that small vessel coronary disease simply represents an unusual manifestation of the same coronary atherosclerotic process that involves the larger vessels. This appeared to be the case in our patient. Coronary artery disease in the transplanted heart: This may be the only reported case of fatal small
vessel coronary arteriopathy associated with a normal coronary arteriogram. In addition, it is a special instance of this process because it occurred in a transplanted heart. Coronary arteriosclerosis of the transplanted heart is common, and may be present in some degree in 20 percent or more of patients within 3 years of transplantation.17 Interestingly, a heart recipient’s preoperative cardiac diagnosis (end stage coronary artery disease versus cardiomyopathy) has no bearing on the incidence, nature or severity of this lesion after transplantation. l7 A reasonable hypothesis holds that coronary vascular intimal injury, resulting from acute, overt rejection or perhaps from a more chronic, clinically inapparent rejection process, renders the coronary vessel susceptible to the “normal” atherosclerotic process. Although we have seen similar severe small vessel involvement in two other cardiac grafts and less severe involvement in others, proportionately extensive epicardial vessel involvement, with abnormal coronary arteriograms, was present in these cases (unpublished observation by Margaret E. Billingham, MD). The small
FIGURE 7. Myocardium from the left ventricle. showing early focal ischemic necrosis. The muscle fibers are swollen with cross striations that are blurred and coarsened and their nuclei have disappeared. A large contraction band is present (arrows). Neutrophils are almost undetectable in the interstitial tissue. Hematoxylin-eosin X 192, reduced by 33 percent.)
AND STREFLING
vessel disease noted in other recipients, aside from this patient and the two described earlier, has been minimal, nonocclusive and not associated with infarction. It is worthwhile noting that our patient did, in fact, have atherosclerotic disease involving the proximal epicardial vessels. However, that involvement was relatively minor and nonocclusive, and therefore was not detected on coronary arteriography. It should be noted that epicardial coronary disease is seen on angiography in approximately 20 percent of patients, after cardiac transplantation, and can also lead to myocardial infarction. Significance of retarded clearance of contrast agent on coronary angiography: The only coronary
angiographic abnormality found in this patient was greatly retarded clearance of the contrast agent from the coronary vessels. This finding may relate to reduced coronary flow, but other explanations are tenable. For example, if for some reason the total capacity of the transplant recipient’s coronary arterial bed was abnormally increased, then flow volume might be normal despite a decreased flow velocity. Previous studies in our transplant recipients have documented essentially normal flow volumes in the resting state.18 However, because of total anatomic cardiac denervation, and resultant removal of resting neural alpha adrenergic tone,18 it is in fact plausible that a greater arterial capacity is present. This possibility could account for the fact that slowed disappearance of contrast medium from the coronary arteries has been seen in other transplant recipients without large or known small vessel coronary disease. Another possible explanation might be the existence of abnormal mixing of the contrast agent with the transplant recipient’s blood, or an affinity of the agent for the recipient’s coronary vessel wall, although there are no data or theories to support these latter two speculations. Premortem identification of the form of small vessel arteriopathy presented herein may be difficult. Our findings suggest that a reduced rate of removal of contrast material during angiography from the coronary arteries in the absence of proximal stenoses may be a clue to the presence of microvascular occlusive disease, although the sensitivity and specificity of such a finding are untested. It might be possible to detect this lesion with endomyocardial biopsy, although arterioles of the size affected in our patient are usually not seen in endomyocardial biopsy specimens. Clinical implications: It is not known whether there is a correlate of the small vessel disease described in our case in the nontransplanted, nondenervated heart. However, this case serves to demonstrate clearly that severe small vessel disease can occur in man in the presence of angiographically normal epicardial coronary arteries. In addition, our experience with other transplant patients demonstrates that large vessel involvement may occur simultaneously with intramural vessel disease. Thus, one should recognize this possibility when considering patients with “routine” coronary artery disease, especially when angiographic and electrocardiographic or historical data conflict.
July 1979
The American Journal of CARDIOLOGY
Volume 44
175
SMALL VESSEL CORONARY DISEASE-MASON
AND STREFLING
References 1. Eliot RS, BratlO: The paradox of myocardial ischemia and necrosis in young women with normal coronary arteriograms. Am J Cardiol 23:633-638, 1969 2. Bruschke AVG, Bruyneel KJJ, Bloch A, van Herpen G: Acute myocardial infarction without obstructive coronary artery disease demonstrated by selective cinearteriography. Br Heart J 33: 585-594, 1971 3. Khan AH, Haywood LJ: Myocardial infarction in nine patients with radiologically patent coronary arteries. N Engl J Med 35:427-430. 1974 4. Clraulo DA: Recurrent myocardial infarction and angina in a woman with normal coronary angiograms. Am J Cardiol 35923-928, 1975 5. Rosenblatt A, Seizer A: The nature and clinical features of myocardial infarction with normal coronary arteriogram. Circulation 55578-580, 1977 6. kifchaelson SP, Karsh DL, Wolfson S, Lebson RE, Cohen LS: Recurrent myocardlal infarction with normal coronary arteriography. N Engl J Med 297:916-918, 1977 7. James TN: Angina without coronary disease (sic). Circulation 62:189-191, 1970 8. Arnett EN, Roberts WC: Acute myocardial infarction and angiographically normal coronary arteries. Circulation 53:395-399, 1976 9. Mason JW: Techniques for right and left ventricular endomyocardial biopsy. Am J Cardiol41:882-892, 1978 10.. Caves PK, Bllllngham ME, Stlnson EB, Shumway NE: Serial
178
July 1979
The American Journal of CARDIOLOGY
Volume 44
i 1.
12.
13. 14.
15. 16. 17.
18.
19.
transvenous biopsy of the transplanted human heart: improved management of acute rejection episodes. Lancet 2:821-826, 1974 Arbogaef R, Sourasa MO: fvlyocardialfunction during atrial pacing in patients with angina pectoris and normal coronary arteriograms. Am J Cardiol 32:257-263, 1973 Mammohanslngh P, Parker JO: Angina pectoris with normal coronary arteriograms: hemodynamic and metabolic response to atrial pacing. Am Heart J 90:555-561, 1975 Luglnbuhl H, Detweller DK: Cardiovascular lesions in d>gs. Ann NY Acad Sci 127:517-540, 1966 Ratcliffe HL, Yerasfmkles TG, Elliott GA: Changes in the character and iocation of arterial lesions in mammals and birds in the Philadelphia Zoological Garden. Circulation 21:730-738, 1960 Soyd AN: Inflammatory basis for coronary thrombosis. Am J Pathol 4:15-18, 1928 Saphir 0, Dhrlnger L: Changes in the intramural coronary branches in coronary arteriosclerosis. Arch Pathol 62: 159- 170, 1956 Griepp RB, Stlnson EB, Bleber CP, Reltr BA, Copeland JG, Oyer PE, Shumway NE: Control of graft arteriosclerosis in human heart transplant recipients. Surgery 81:262-269. 1977 Orllck AE, Ricci DR, Alderman EL, Stinson EB, Harrison DC: Effects of alpha-adrenergic blockade on coronary hemodynamics. J Clin Invest 62:459-467, 1978 Bllllngham ME, Schwartz BD, Rider AK, Harrison DC: An ultrastructural study of age-related changes in intramyocardial arterioles (abstr). Lab Invest 36:3, 1977
