Case 9 -

Coronary Hypersensitivity Eosinophilic Arteritis and Thrombosis. Alan G. Rose

Clinical History The patient was a 27-year-old male with dilated cardiomyopathy who underwent cardiac transplantation. The section of coronary artery comes from the explanted recipient heart, which showed a hypersensitivity myocarditis (HSM). No significant coronary atherosclerosis was noted. There was evidence of myocyte hypertrophy consistent with a dilated cardiomyopathy. Sections of the myocardium (not seen on the seminar slide) show multifocal and coalescent interstitial inflammatory infiltrates composed mainly of eosinophils with a minor histiocytic and lymphocytic component. Focal collections of cardiac histiocytes are also evident. A major epicardial coronary artery shows mural infiltration by eosinophils (i.e. evidence of arteritis) plus a superimposed, secondary, bland, mural, organizing fibrin thrombus occluding at least 25% of the lumen of the obliquely sectioned artery. Eosinophils are also present within the organizing thrombus. Hypersensitivity myocarditis [1] is noted not infrequently in explanted hearts from patients undergoing cardiac transplantation for terminal cardiac failure. HSM is believed to reflect a drug related hypersensitivity and many such patients are receiving up to 20 drugs. The commonest drugs implicated have been methyl-dopa, penicillin and the sulfa drugs, but Lewin et al [1] encountered dobutamine, furosemide and Captopril as the commonest administered drugs in their patients with hypersensitivity myocarditis. The same authors found eosinophils in subsequent donor heart biopsies in 4 out of 6 cases and speculated that hypersensitivity myocarditis may also affect the donor heart. A recurrent hypersensitivity reaction immediately following cardiac transplantation has also been reported. [2 ]Prolonged dobutamine infusion has also been postulated as the cause of HSM. [3] HSM does not produce necrotizing vasculitis, but infiltration of vessel walls by inflammatory cells may be seen. Giant cell myocarditis may also be a manifestation of drug hypersensitivity. [4] Eosinophils and the Vascular System Endomyocardial Fibrosis The association between eosinophils and disease of the vascular system has been long recognized, especially with regard to obliterative cardiomyopathy, also termed endomyocardial fibrosis (EMF) and its precursor state, Loffler's parietal endomyocarditis. The association with eosinophils explains the frequency of EMF in parts of the world where parasitic diseases are common, as well as its association with eosinophilic leukemia. Eosinophilic degranulation on the endocardium damages the latter and leads to thrombus. Role of Eosinophils in Arterial Dissection The presence of eosinophils has been reported in association with arterial dissecting aneurysms [5] and some suggest that the mechanical process of dissection may elicit the localized inflammatory reaction. [6] Some cases of "spontaneous" coronary arterial dissection without eosinophils have been familial [7] and such affected arteries have shown medial acid mucopolysaccharide accumulation. This raises the problem for the pathologist of being able to exclude such disorders as Ehlers-Danlos syndrome or segmental mediolytic arteriopathy (previously discussed in Case 1). The case under discussion is an example of non-atheromatous coronary arterial disease, which is said to account for 5-10% of coronary arterial occlusions – the other 90-95% being due to atherosclerosis, usually with superimposed thrombosis. The following is a brief review of non-atheromatous coronary arterial disease. Non-atheromatous Coronary Arterial Disease Congenital Congenital abnormalities of the coronary arteries include the following: Abnormal high origin of the coronary artery with the ostium displaced in the ascending aorta beyond the sinus of Valsalva. This produces a so-called flap valve or intra-aortic course for the proximal portion of the artery, which has been blamed as a source of sudden death in the young. A hemodynamic vise is that situation when a coronary artery arises from an opposite sided sinus of Valsalva and the artery runs between, and is compressed during systole by, the aorta and the pulmonary artery. A coronary-cameral fistula occurs when a coronary artery communicates with a cardiac chamber. In the case of both the atria and the right ventricle there will be a free runoff of blood from the artery into the cardiac chamber. As a result of this shunt the coronary arteries become tortuous and very dilated. A coronary artery which arises from a pulmonary artery (anomalous coronary artery origin) will be similarly induced to act as a shunt due to the lower pressure in the pulmonary artery, but the flow will be reversed in the coronary artery. A similar reversal of coronary arterial blood flow may occur in the right ventricle in congenital pulmonary valve atresia with intact ventricular septum. Here enlarged intra-myocardial "sinusoids" act as a conduit for right ventricular blood to reach the epicardial coronary arteries. Supravalvular aortic stenosis may be associated with intimal thickening or with attachment of the free margin of an aortic valve cusp to the aortic intima. Inflammatory Forms of arteritis, which are known to affect medium sized arteries such as the major coronary arteries, include the following: Kawasaki disease, Takayasu arteritis, polyarteritis nodosa, giant cell arteritis, and septic emboli from infective endocarditis. Coronary arterial narrowing has also been reported in systemic lupus erythematosus, sometimes due to secondary accelerated atherosclerosis. Embolism Coronary thromboembolism may be derived from left-sided bland vegetations (marantic on native heart valves or from artificial heart valves, either mechanical or bioprosthetic) or from infected vegetations from the same sources. Mural thrombi from within the heart (ischemia or cardiomyopathy) may also embolize. Fibroelastoma of a cardiac valve may embolize to a coronary artery. A paradoxical embolus is derived from the right side of the heart, usually via a patent foramen ovale. Dissection A dissecting aneurysm of the aorta may extend down one or more coronary arteries or a primary dissection of a coronary artery may also occur. Syphilitic Aortitis Coronary ostial narrowing may result from tertiary syphilitic involvement of the aortic root. Buerger Syndrome Thromboangiitis obliterans is a rare cause of coronary arterial occlusion and the entity of Buerger syndrome itself remains controversial. Calcification at the Junction of the Tubular and Sinus Portions of a Sinus of Valsalva may obstruct a coronary orifice. Scurvy Metabolic abnormalities do not always produce morphologically recognizable changes despite greatly decreased structural strength in a blood vessel. We have encountered a scorbutic (vitamin C deficient) ballet dancer whose femoral artery was ruptured by the thumb of her male dancing partner who caught her thighs in his hands. A small sample of the ruptured artery appeared normal histologically. References Lewin D, d'Amati G, Lewis W. Hypersensitivity myocarditis: findings in native and transplanted hearts. Cardiovasc Pathol 1992; 1: 225-229. di Gioia CRT, d'Amati G, Grillo P, Laurenti A, Gallo P. Eosinophilic infiltration immediately following transplantation: recurrent hypersensitivity reaction? Cardiovasc Pathol 1999; 8: 297-299. Spear G. Eosinophilic explant carditis with eosinophilia: Hypersensitivity to dobutamine infusion. J Heart Lung Transplant 1995; 14: 755-760. Daniels PR, Berry GJ, Tazelaar HD, Cooper LT. Giant cell myocarditis as a manifestation of drug hypersensitivity. Cardiovascular Pathology 2000; 9: 287-291. Borczuk AC, van Hoeven KH, Factor SM. Review and hypothesis: the eosinophil and peripartum heart disease (myocarditis and coronary artery dissection) – coincidence or pathogenetic significance? Cardiovasc Res 1997; 33: 527-532. Siegel RJ, Koponen M. Spontaneous coronary artery dissection causing sudden death. Mechanical arterial failure or primary vasculitis? Arch Pathol Lab Med 1994; 11: 196- 198. Wisecarver J, Jones J, Goaley T, McManus B. "Spontaneous" coronary artery dissection. The challenge of detection, the enigma of cause. Am J Forensic Med Pathol 1989; 10: 60-62.