ENA = antibody to extractable nuclear antigen; ANCA = antineutrophil cytoplasmic antibody; MPL = IgM phospholipid units; GPL = IgG phospholipid units; fl = femtoliters; ESR = erythrocyte sedimentation rate; HIV = human immunodeficiency virus.
At the heart of the matter: The exceptional case of coronary artery disease in a young man
Article first published online: 30 OCT 2008
Copyright © 2008 by the American College of Rheumatology
Arthritis Care & Research
Volume 59, Issue 11, pages 1676–1681, 15 November 2008
How to Cite
Manek, N. J. and Edwards, W. D. (2008), At the heart of the matter: The exceptional case of coronary artery disease in a young man. Arthritis & Rheumatism, 59: 1676–1681. doi: 10.1002/art.24200
- Issue published online: 30 OCT 2008
- Article first published online: 30 OCT 2008
- Manuscript Accepted: 3 JUL 2008
- Manuscript Received: 23 MAR 2008
Causes of coronary artery vasculitis in young adults, as reported in the literature, are mainly systemic inflammatory diseases like Takayasu disease (1), systemic lupus erythematosus (2), rheumatoid arthritis (3), polyarteritis nodosa (4), and Churg-Strauss syndrome (5). Other reported causes of arteriopathy in young persons include Behçet's disease (6), sarcoidosis (7), drugs (8), and infections (9). In older persons, coronary arteritis may occur in association with giant cell arteritis (GCA) (10). Diagnosis of coronary arteritis may be elusive when initially evaluating patients with large- or medium-vessel vasculitis. It is even more unusual to diagnose vasculitis localized specifically to a vascular bed such as the coronary and internal mammary arteries in the absence of a systemic inflammatory disorder. Here, we report a case of a patient with coronary ischemia who had coronary angiographic findings of premature atherosclerosis and in whom lymphoplasmacytic arteritis was found, affecting the coronary and internal mammary vessels. To our knowledge, this is the first report of medium-vessel vasculitis clinically limited to the coronary and internal mammary arteries with no associated systemic inflammatory disease.
A 25-year-old African American man was referred to our institution for further management of diffuse coronary artery disease (CAD). Six months previously, while playing basketball, he had experienced sudden crushing substernal chest pain with radiation to his left arm associated with nausea and vomiting, for which he presented to his local emergency department. Cardiac catheterization demonstrated total occlusion of the left anterior descending coronary artery with thrombus. Percutaneous coronary intervention with thrombectomy and angioplasty was performed with placement of 2 tacrolimus drug-eluting stents. The patient's left ventricular ejection fraction during the procedure was 35–40%. Four months after his initial procedure, he developed palpitations and diaphoresis and was found to be in new-onset atrial fibrillation. He underwent medical cardioversion with sotalol. Subsequently, he returned to see his cardiologist with intermittent exertional chest discomfort. He underwent nuclear stress testing that showed a large ischemic burden and a left ventricular ejection fraction of 40–45%. A repeat coronary angiogram was significant for very diffuse CAD with a new high-grade left anterior descending artery stenosis. By the time of presentation to our institution, the patient was reporting chest pain at rest. Because he was only 25 years old, concern was raised for possible coronary vasculitis.
His medical history was significant for type 2 diabetes mellitus, hypertension, and hyperlipidemia of only 2 years' duration and all well controlled. On review of systems, he denied a history of fevers, night sweats, weight loss, headache, oral or genital ulcerations, skin rashes, arthralgias or arthritis, myalgias, or claudication. He had no history of arterial or venous thrombosis. Eight months previously, he developed bilateral iritis that was treated by an ophthalmologist with topical steroids and resolved 3 months later. He had a chronic cough sometimes productive of discolored sputum, but no hemoptysis. The patient reported a 10 pack-year history of smoking, recreational marijuana use, and use of creatine monohydrate as a body-building supplement. He denied a history of intravenous drug or cocaine use. He denied promiscuous sexual or homosexual activity. His medications on admission included clopidogrel, aspirin, sotalol, enalapril, metformin, and sublingual nitroglycerin as required. His family history was positive for premature CAD.
Physical examination showed a well-built muscular young male in no distress. Baseline vitals showed a normal body temperature, blood pressure of 120/70 mm Hg at both upper extremities, and a heart rate of 64 beats per minute in a regular rhythm. He had bilateral injected conjunctiva. He did not have scalp tenderness or any induration over the temporal vessels. Auscultation of coronary and subclavian vessels was normal and he demonstrated a normal carotid upstroke. Cardiac examination showed normal first and second heart sounds and no gallop, murmurs, or pericardial rubs. There was no evidence of aneurysmal dilatation of the abdominal aorta. Peripheral pulses in all 4 extremities were strong. The pulmonary, abdominal, joint, cutaneous, and lymphatic systems and neurologic examinations were unremarkable. No abnormalities were noted on ear, nose, and throat examination.
Initial laboratory investigation results were largely normal except for a borderline positive antinuclear antibody test (Table 1). The electrocardiogram performed showed a sinus rhythm with premature ventricular complexes, and his chest radiograph was normal. Coronary angiogram performed at our institution revealed diffuse 3-vessel CAD (Figure 1). Both the left internal mammary artery and right internal mammary artery had mild (20%) discrete lesions, but with normal flow and caliber. An arch aortogram with run-off revealed a normal aortic arch and normal great vessel origins with no evidence of atherosclerotic changes or aortitis. The abdominal aortogram likewise was normal, including the origins of the renal arteries and peripheral renal artery branches. There was no evidence for coronary artery vasospasm on intracoronary adenosine injection.
|Blood urea nitrogen, mg/dl||14||8–24|
|Glycosylated hemoglobin, %||7.2||<6.0|
|Aspartate aminotransferase, units/liter||27||12–31|
|Alanine aminotransferase, units/liter||28||10–45|
|Alkaline phosphatase, units/liter||75||45–115|
|Antinuclear antibodies, units||2.5||≤1.0|
|Anti–double-stranded DNA, IU||7||<25|
|C-reactive protein, mg/dl||0.4||≤0.8|
|Total complement, units/ml||59||30–75|
|IgM phospholipid antibody, MPL units||<4.0||<4.0|
|IgG phospholipid antibody, GPL units||<4.0||<4.0|
|White blood cells, × 109/liter||8.2||3.5–10.5|
|Platelet count, × 109/liter||285||150–450|
|Mean corpuscular volume, fl||81.4||81.2–95.1|
|Neutrophils, × 109/liter||4.89||1.7–7.0|
|Lymphocytes, × 109/liter||2.53||0.9–2.9|
|Eosinophils, × 109/liter||0.27||0.05–0.50|
|Total cholesterol, mg/dl||163||<200|
|Low-density lipoprotein, mg/dl||96||≤100|
|High-density lipoprotein, mg/dl||45||≥40|
|Lipoprotein a, mg/dl||10||<3|
|Urine drug screen||Negative||Negative|
|Hepatitis C antibody||Negative||Negative|
After much discussion as to the most optimal approach for revascularization in this young patient, he underwent coronary artery bypass grafting. Intraoperative inspection revealed diffuse thickening of the coronary arteries as well as the surrounding periarterial tissue. The patient had 4 coronary artery bypass grafts, including a left internal mammary artery to an intermediate coronary artery anastomosis and a right internal mammary artery to a left anterior descending coronary artery. During the course of surgery, segments of coronary and internal mammary arteries were excised and submitted for microscopic evaluation.
Pathologic examination of these specimens showed a diffuse non-atherosclerotic obstructive intimal proliferative process, particularly involving the proximal right internal mammary artery (Figure 2). There was moderate to severely active chronic lymphocytic panarteritis with few scattered plasma cells, neutrophils, and eosinophils, but without giant cells or granulomas (Figure 3). The inflammation was transmural, including the periadventitial tissues. There was no fibrinoid necrosis of the arterial walls and no organisms were identified. A biopsy of the ascending aorta did not show any diagnostic abnormality.
Immunohistochemical staining of the right internal mammary artery using antibodies directed against CD3 (for T cells), CD20/L26 (for B cells), CD163 IM (for dendritic cells and histiocytes), CD15/LEUM1 (for neutrophils and eosinophils), and κ and λ light chains (for plasma cells) showed a primary T cell lymphocyte–mediated process involving the intima, media, and adventitia of the internal mammary vessels. Few B cell lymphocytes, plasma cells, neutrophils, or histiocytes were noted. Plasma cells were found predominantly in the adventitia and included a mixture of cells that stained positive for κ and λ light chains, indicative of a polyclonal reactive non-neoplastic process. Moreover, lymphomatous involvement of the heart never has a transmural histologic appearance as was seen in this case. Immunofluorescence studies for immunoglobulins and complements were not performed because tissues had been previously fixed in formalin.
The patient's treatment course included high-dose oral prednisone at 1 mg/kg/day (80 mg daily) with a slow tapering schedule and oral cyclophosphamide at 1.5 mg/kg/day. Measures aimed at secondary prevention of CAD, including optimization of lipid profile, blood pressure control, and smoking cessation were also initiated. On followup visit to our center 6 months later, the patient denied further anginal symptoms and was otherwise clinically stable. Computed tomographic (CT) coronary angiography demonstrated diffuse disease of the native coronary vessels and evidence for luminal narrowing of a saphenous vein graft. The remainder of the bypass grafts was patent. Eighteen months after his bypass surgery, the patient had experienced some episodes of exertional angina. Coronary angiography performed at his outside institution revealed restenosis of the bypass grafts, and the grafts have been stented. His compliance with cyclophosphamide was questionable, and therefore it is not possible to consider this strategy a treatment failure. Consideration was given for rituximab infusions and he has undergone the first cycle of infusion. He has not developed any features of a systemic autoimmune disorder to date.
This report describes an exceptional case of panarteritis clinically limited to the coronary and internal mammary arteries, resulting in luminal stenosis and mimicking premature atherosclerosis with myocardial ischemia and infarction. To our knowledge, this is the first report of isolated coronary and internal mammary lymphoplasmacytic vasculitis in an otherwise healthy young male. This case is presented for several reasons.
First, the atypical and distinct presentation of medium-vessel arteritis without any systemic involvement provided an extremely challenging diagnostic and treatment dilemma. This patient's clinical evaluation and laboratory results revealed none of the changes usually encountered with active vasculitis such as elevated sedimentation rate, anemia, or hypocomplementemia. Furthermore, the lack of serologic markers of disease activity makes decisions regarding optimal immunosuppression regimen and duration of treatment difficult.
Second, there is paucity of data on invasive management strategies for young adults who present with an acute coronary syndrome secondary to active vasculitis. Revascularization is often unsuccessful, particularly when there is inflammatory disease. Noninvasive cardiac imaging such as CT angiography could be helpful in monitoring coronary disease. However, this is as of yet an emerging radiologic technique not widely available.
Third, this patient defies easy classification. In most cases described in the literature, the etiology of a predominately T cell lymphocytic infiltrate seems to be part of a systemic process (11). This microscopic appearance is not typical for polyarteritis nodosa, but it may be considered consistent with other forms of vasculitis, including Behçet's disease. Aside from iritis, this patient had none of the typical features of Behçet's disease (6, 12). He had injected conjunctiva noted on admission, which resolved without treatment, and he did not require ophthalmologic assessment. He has not had a recurrence of inflammatory ocular disease over 18 months of followup. In light of this patient's age and ethnic background, sarcoidosis was also considered in the differential diagnosis. However, diagnosis of active sarcoid vasculitis requires the presence of typical sarcoid granulomas in or around the walls or arteries or veins. There were no granulomas or giant cells in our case. To implicate sarcoid vasculitis when there is only lymphocytic inflammation present would rarely be justified and furthermore, would require that the unequivocal diagnosis of sarcoidosis had been established elsewhere in the patient, which does not apply in our case. Although the diagnosis of Takayasu arteritis seemed unlikely in our patient, it was not precluded by his sex or ethnic background, because lymphocytic aortitis or arteritis without giant cells can be seen in this entity (1). There was no clinical history or morphologic evidence of systemic lupus erythematosus, rheumatoid arthritis, or Churg-Strauss syndrome. Temporal arteritis has been described in young patients (13), but this was deemed unlikely in our case by the absence of temporal headache and gross craniofacial findings such as scalp tenderness. Other disorders, including toxin-induced medium-vessel vasculitis associated with this histopathologic picture, were excluded (8, 14). Leukocytoclastic vasculitis, a cutaneous small-vessel disorder, would also not apply in this case.
Many questions remain unanswered as to the pathophysiologic mechanisms of vasculitis (9). One can speculate whether the initial stage of disease involves an alteration in vessel substrate rather than an immunologic aberration. Variations in vasculitis disease patterns are influenced by genes, sex, ethnicity, and individual factors (e.g., illnesses, habits, toxins, environmental exposures, and infections) (9). Intimal hyperplasia is a shared mechanism in a diverse set of vasculopathies (15). However, intimal atherosclerosis would include not only inflammatory cells but also foam cells and cholesterol clefts, and perhaps a necrotic core with or without calcification, all of which were absent in this case.
Host factors such as hypertension and tobacco, present in our case, could conceivably promote alteration of vessel substrate and promote proinflammatory alterations in the endothelial phenotype (16). The predominance of T cell infiltrate in the vessels seen in this case is similar to that encountered in GCA (17). Also, GCA causes vessel obstruction through intimal hyperplasia (18). Based on these similarities, one could speculate that this patient presents a case in a spectrum of idiopathic inflammatory arteritis, which has a striking predilection to be located in the thoracic region, and in which no giant cells are necessarily seen in the vessel wall (11).
The mechanisms underlying the selective targeting of specific vascular beds are not understood. Inflammation of internal mammary arteries has been described after bypass surgery or severe blunt trauma, neither of which were factors in this case. It could also be speculated that important hemodynamic differences could have played a role in establishing focal vessel vulnerabilities. Another remote possibility is that an infection played a role in this patient's vasculitis, and limitations in our technology may keep critical clues out of reach as to the recognition, identification, and characterization of unusual infectious microorganisms.
In summary, the etiology and precise mechanisms involved in the pathogenesis of lymphocytic arteritis of the coronary and internal mammary vessels is unknown, but in this case, does not appear to be part of a systemic process. Although monitoring of disease activity is a crucial element in minimizing further activity and treatment associated with morbidity and mortality, the optimal immunosuppression regimen and future cardiac testing are unclear in this case. 2
|Systemic lupus erythematosus|
|Antineutrophil cytoplasmic antibody–associated vasculitis|
|Hairy cell leukemia|
|African tick-bite fever|
Dr. Manek had full access to all of the data in the study and takes responsibility for the integrity of the data.
Acquisition of data. Manek, Edwards.
Analysis and interpretation of data. Manek, Edwards.
Manuscript preparation. Manek, Edwards.
We would like to express our thanks to Dr. David S. Viswanatha in the Department of Laboratory Medicine and Pathology at Mayo Clinic for providing expert opinion regarding the possibility of vascular lymphoma in this case, and to Dr. Edward Letourneau of Stormont Vail HealthCare, Topeka, Kansas, for providing details on this patient's subsequent course.
- 5Acute coronary syndrome associated with Churg-Strauss syndrome. Vasc Health Risk Manag 2007; 3: 775–9., , , , , , et al.