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Takayasu arteritis is a chronic, progressive, autoimmune, idiopathic, large-vessel vasculitis that usually affects young adults. The disease has been reported to occur in all races and ethnicities. The diffuse nature of this vasculitis can affect multiple-organ systems to varying degrees. Herein, we report the case of a young woman whose exertional angina and claudication were the initial presentation of active Takayasu arteritis. During more than 4 years of ongoing treatment, therapy, and follow-up, she has displayed differing disease symptoms of varying intensity. We discuss the challenges of managing Takayasu arteritis in our patient and describe different treatments for this rare vasculitic disorder.
Takayasu arteritis (TA) is an autoimmune, idiopathic, large-vessel vasculitis that usually affects young adults. It was first described in 1908, in a Japanese patient with retinal abnormalities.1,2 Although the disease has most often been reported in young East Asian women (median age of onset, 25 yr), it can affect both sexes and all races. The incidence of TA is estimated to be 2.5 in 1 million people in the United States and 1.3 in 1 million people in Europe.3
The cause of TA is unknown. Examination of its characteristic acute vascular lesions reveals an infiltrative process with mononuclear macrophages and lymphocytes that enter vessel walls through the vasa vasorum. Takayasu arteritis patients constitute a management challenge because treatment options vary, depending on the stage of the disease at the time of its diagnosis. Here, we describe the case of a woman who was diagnosed with TA at 28 years of age, the course of the disease during the next 4 years, and different treatments for the rare disorder.
In September 2005, a 28-year-old Russian woman presented with worsening exertional chest pain that was typical of angina. She also reported palpitations and chest discomfort after eating meals that had a high salt or fat content. Her medical history included hypothyroidism, pregnancy-associated idiopathic thrombocytopenic purpura, and preeclampsia. She had stopped smoking 6 years earlier but had a 5 pack-year history of that habit. Her cardiac risk profile was negative for diabetes mellitus, hypertension, and hyperlipidemia. There was no family history of premature coronary artery disease or connective-tissue disorders. She was very active, exercising for 45 minutes on a treadmill 3 or 4 days per week. On occasion, she would experience bilateral calf claudication, but only after especially vigorous exertion. A review of her systems revealed recurrent and relapsing skin lesions that had been biopsied in the past, and previous granuloma annulare. She reported no history of oral ulcers. Upon physical examination, her blood pressure was 145/70 mmHg in both arms. A cardiovascular examination revealed normal carotid upstrokes with bilateral carotid bruits and a soft right subclavian bruit. Cardiac auscultation revealed normal sounds. There was a mid-abdominal aortic bruit. The femoral pulses were normal, with bilateral femoral bruits. The pedal pulses were equal and palpable bilaterally.
The patient underwent an echocardiographic exercise stress test, during which she completed 7 minutes on a standard Bruce protocol. She achieved a workload of 10 metabolic equivalents and 85% of the age-predicted maximal heart rate. Upon exercise, her electrocardiogram (ECG) showed diffuse 5-mm ST-segment depression, and the echocardiogram showed a substantial decrease in overall left ventricular ejection fraction from a normal baseline, with new inferior and septal hypokinesis.
Magnetic resonance angiography (MRA) of the aorta and lower extremities showed patchy, smooth, nonobstructive narrowing of the ascending and descending aorta, right subclavian artery, and abdominal aorta. Other findings were moderate, bilateral nonobstructive lesions in the renal arteries, bilateral external iliac disease, and nonobstructive common femoral disease primarily on the right side (Fig. 1). The patient underwent an extensive serologic evaluation, including a hepatitis panel and tests for human immunodeficiency virus, C-reactive protein levels, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, antiphospholipid antibodies, anticardiolipin antibodies, and thyroid-stimulating hormone (TSH) and free triiodothyronine. The serologic results were unremarkable except for positive rheumatoid factor, TSH, and antinuclear antibody. The TSH itself was normal, but the level of free triiodothyronine was slightly low.
Given the rapid progression of symptomatic angina, we decided to proceed with cardiac catheterization. Angiography revealed a right coronary artery (RCA) that was occluded at the ostium. The left main coronary artery had a distal 90% stenosis that involved the ostia of the circumflex coronary artery and the left anterior descending coronary artery (LAD) (Fig. 2). Extensive Rentrop grade 3 collateral vessels from the LAD filled the entire RCA. Angiography of the aorta revealed minor irregularities of the descending aorta and the supra-aortic arch. There was mild-to-moderate proximal narrowing of both renal arteries. The right common iliac artery had a 70% proximal stenosis. Angiography of the right and left subclavian system revealed mild tubular irregularities that did not involve the ostia of either of the internal mammary arteries. Both radial arteries also showed diffuse irregularities. Carotid duplex ultrasonography revealed mild, nonobstructive (30%) common carotid disease bilaterally.
The patient developed chest discomfort during the procedure; due to the severity of her disease, she was admitted to the hospital. After dinner that evening, she developed profound chest discomfort with global 4-mm ST-segment depression on ECG. The pain resolved after we administered an intravenous β-blocker and 3 nitroglycerin tablets. Upon the presumptive diagnosis of active vasculitis, she was treated with high-dose intravenous methylprednisolone. She underwent coronary artery bypass grafting (CABG), with the surgical intent of avoiding aorto-ostial anastomoses. Accordingly, the left internal mammary artery (LIMA) was grafted to the mid-LAD. A free radial artery graft was placed, originating from the LIMA body and connecting to the 1st obtuse marginal artery (Fig. 3). The right internal mammary artery was grafted in situ to the distal RCA (Fig. 4). A biopsy of the LIMA revealed active arteritis that involved a large elastic artery. Microscopic sections showed a transmural, predominantly mononuclear inflammatory infiltrate that was associated with moderate intimal hyperplasia, medial scarring, adventitial fibrosis, and extensive fragmentation of elastic lamina, all of which were confirmed upon elastic-tissue staining (Figs. 5 and and6).6). Although no giant cells were identified, the findings were consistent with (but not pathognomonic for) TA.
The patient's postoperative course was uneventful, and she was discharged from the hospital on postoperative day 7 with instructions to take a tapering dose of prednisone. Other medications included aspirin, atorvastatin, and metoprolol. She was referred to a multidisciplinary vasculitis clinic for further evaluation and treatment.
Approximately 6 months after undergoing the CABG, she again began experiencing exertional chest pain. Exercise sestamibi stress-testing revealed a small-to-moderate area of lateral ischemia. Repeat angiography showed patent bypass grafts and no change in the native coronary anatomy from before the time of CABG. The area of ischemia was thought to be secondary to an ungrafted atrioventricular-groove circumflex vessel that supplied a small posterolateral branch, and medical management was advised. A rheumatologist treated the patient with oral steroids, but the dosage was eventually tapered due to the side effects of fluid retention and weight gain.
Subsequently, the patient did quite well and returned to her prior activity level. However, she gradually developed worsening hypertension, which warranted increased dosages of her medications. It was believed that the vasculitis had reactivated itself, and intravenous cyclophosphamide was recommended. However, the patient refused this treatment after being apprised of the side effects of cyclophosphamide, and she was instead treated with oral methotrexate. Follow-up MRA for evaluation of her hypertension showed mild bilateral subclavian arterial irregularities without significant stenoses, mild narrowing at the origins of the great vessels, less than 50% narrowing of the carotid arteries bilaterally, an infrarenal aortic focal narrowing, and a focal narrowing of the right renal artery.
Upon her numerous hospital readmissions for chest pain over the 3 years after CABG, myocardial infarction was always ruled out. Repeat stress tests consistently revealed good exercise tolerance and positive exertional chest discomfort, but no major perfusion abnormality (aside from the previously described lateral-wall defect) upon nuclear imaging. Oral ranolazine substantially improved her anginal symptoms but did not completely resolve the exertional chest discomfort. She was eventually readmitted with unstable angina that was difficult to control due to low blood pressure. No major changes in the coronary anatomy were revealed upon repeat angiography 3.5 years after CABG, but there was mild-to-moderate diffuse disease of the arterial bypass conduits. During this procedure, it was noted that the invasive systolic blood pressure was 30 to 40 mmHg higher than the noninvasive right or left brachial pressure. We presumed that this discrepancy was secondary to bilateral subclavian artery disease and that it justified more aggressive medical management in order to achieve a target systolic blood pressure of 80 to 100 mmHg. The medical therapy resulted in a marked reduction of anginal symptoms.
Four years after CABG, we continue to monitor the patient's status in our outpatient cardiology clinic. Her angina is under adequate control, and she is not limited substantially in her daily activities.
Presentation and Differential Diagnosis. Takayasu arteritis is a systemic disorder that affects multiple organs. The diagnosis of TA can be a challenge, especially in its initial phases: there is no diagnostic serologic test, and symptoms are generally constitutional, including malaise, fever, fatigue, and arthralgia. One common presentation is typical angina in a patient in whom one would not otherwise expect coronary artery disease. The finding of hypertension and arterial bruits in young adults necessitates the examination of pulses and blood pressures in different limbs in order to detect asymmetry. Elevated erythrocyte sedimentation rate is a common finding; however, caution is advised, because up to 50% of patients may have active TA disease and a normal sedimentation rate.3–6
The differential diagnosis can include certain congenital disorders that affect the tissue matrix (for example, Marfan and Ehler-Danlos syndromes); however, these disorders are not associated with stenotic lesions in large vessels, which is the common finding in TA. Although infectious causes of large-vessel aneurysm (mycobacterial, syphilitic, or fungal) should be considered, these are similarly not associated with stenotic arterial lesions. Certain autoimmune illnesses (such as systemic lupus, Cogan syndrome, and Behçet's disease) can be associated with large-vessel vasculitis; however, these more typically have other distinguishing factors and distinct age predilection (such as in Kawasaki disease, and giant-cell arteritis of the elderly). Sarcoidosis should also be included in the differential diagnosis of TA. The correct diagnosis usually depends upon the presence of other characteristic features (skin lesions, hilar adenopathy, or Bell's palsy). The diagnosis of TA is reached on the basis of clinical presentation and imaging results; histopathologic confirmation can be obtained in patients who undergo vascular surgery.
Cardiac Complications. Cardiac complications related to TA are due more to poorly controlled hypertension from aorto-renal arterial disease than to disease of the aorto-ostia of the coronary arteries.3–6 Aortic regurgitation that is secondary to aortic root dilation can occur in up to 20% of patients.7,8 Hypertension occurs in one third of patients and is usually caused by renal artery stenosis.7,8 Coronary artery vasculitis is relatively uncommon, and when it is detected (in fewer than 5% of TA patients), it chiefly affects vessel origins.9 Left ventricular dysfunction caused by myocarditis has been reported in up to 18% of cases.10
Medical Therapy and Surgical Treatment. The mainstay of therapy in TA is immunosuppression, primarily with steroids or methotrexate.3,11,12 Remission occurs in 40% to 60% of patients. Approximately 20% of patients are resistant to any therapy. Nearly 30% of TA patients require surgery, usually for large-vessel vasculitis that warrants CABG or replacement of the aortic root or valve.13,14 Clinically significant coronary artery disease has been treated with angioplasty, although CABG has usually been preferred.3–6 If possible, surgery should be delayed until the acute phase of the disease has passed.
Prognosis and Management of Patients. Takayasu arteritis is a chronic, progressive disease. Its degree of activity varies over time: the intensity of its inflammatory processes typically fluctuates between exacerbation and reduction or remission. Vascular involvement tends to be progressive. Vascular complications of the cardiac, renal, and central nervous systems are the chief causes of morbidity and death in TA, which is usually fatal when it remains untreated. Remission remains the goal of therapy. Identifying comorbid complications (such as hypertension) and initiating aggressive treatment may afford better chances of symptom-free survival. In several follow-up studies, 5-year survival rates of 80% to 90% have been reported.11,15,16 Poor outcome depends chiefly on the presence of such complications as hypertension, aortic regurgitation, and aneurysm, and on a rapidly progressive course. In 1 study, the 15-year survival rate was 66% in patients who had a major complication versus 96% in patients who did not, and 68% in patients with a progressive course versus 93% in patients without.17
As is evidenced by our patient's presentation and the course of her TA, the care of patients who have the disease can be very complex. A fundamental understanding of the pathophysiology of TA is imperative in the choice of optimal care. For example, although no data supported the surgical approach that we used when we performed CABG in our patient, our understanding of the underlying disease process—gained in part through collaboration with other physicians who were involved in our patient's treatment—provided a theoretical advantage in that we knew to avoid aorto-ostial anastomoses. Such a multidisciplinary approach was complementary and educational for us, and beneficial to our patient.
The authors thank David Gang, MD, for his assistance in preparing the histopathologic slides for this manuscript.
Address for reprints: Fadi Saab, MD, Division of Cardiology, Baystate Medical Center–Tufts University School of Medicine, 759 Chestnut St., Springfield, MA 01199 E-mail: email@example.com
Disclosures: Dr. G. Giugliano has served on the Speaker's Bureau for Schering Pharmaceuticals, Merck, Abbott, Pfizer, and Radi, and has served as a consultant for or received research support from The Medicines Company, CV Therapeutics, Cordis, Medtronic, Boston Scientific, Eli Lilly, Novartis, AstraZeneca, and Gerson Lehrman Group. Dr. R. Giugliano has received research support from Daiichi-Sankyo, Schering-Plough, Merck, and Novartis; has served as a consultant for Schering-Plough and Merck; and has received honoraria for CME programs from Pfizer, Sanofi-Aventis, Bristol-Myers Squibb, and Schering-Plough.