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Like a House Afire: Cardiac Sarcoidosis

Published:November 21, 2012DOI:https://doi.org/10.1016/j.amjmed.2012.09.002

      Presentation

      It seemed like an obvious case of acute coronary syndrome—but was it really? A 36-year-old man of Sri Lankan origin presented to his local rural emergency department with severe central chest pain. He described persistent chest tightness radiating to his left arm. This had developed at rest and was unaffected by inspiration or posture. Over the preceding 24 hours, he had several short-lived episodes of similar but milder pain that resolved spontaneously. Otherwise, the patient had been well with no recent viral illness. His medical history was significant for diet-controlled type 2 diabetes mellitus and hypercholesterolemia. He was a smoker and had a strong family history of premature coronary artery disease.

      Assessment

      On examination, the patient was hemodynamically stable. His heart sounds were normal, with no pericardial rub, and his lungs were clear on auscultation. An electrocardiogram (ECG) showed sinus rhythm with 1-mm ST elevation in leads I and aVL. A chest radiograph showed normal cardiac and mediastinal contours with clear lung fields. Serum troponin T at admission was significantly elevated at 4.3 μg/L (normal <0.02 μg/L). A random blood glucose measurement was 14.1 mmol/L, and hemoglobin A1c was raised at 9.2%. The patient's white cell count was mildly elevated at 1.36 x103/mm3, and his C-reactive protein level was 23 mmol/L.
      A diagnosis of acute coronary syndrome was made. Treatment was initiated with aspirin and clopidogrel after a loading dose of clopidogrel, 300 mg. He also received a therapeutic dose of subcutaneous low-molecular-weight heparin and opiate analgesia. He was not given thrombolysis, and no catheterization laboratory facilities were available at this rural location.
      Over the next 24 hours, the patient had ongoing pain requiring opiate analgesia. A repeat ECG demonstrated anterolateral and inferior T-wave inversion, with persisting ST elevation in leads I and aVL (Figure 1) . He was transferred to a tertiary cardiology center for further investigation. Echocardiography showed moderate septal hypertrophy with inferior hypokinesis and mild impairment of left ventricular systolic function. Coronary angiography revealed mild atherosclerosis with a noncontributory 30% stenosis in the mid-left anterior descending artery. No provocative testing was undertaken for coronary spasm due to safety issues associated with performing this test in the setting of a troponin elevation.
      Figure thumbnail gr1
      Figure 1An electrocardiogram (ECG) obtained during the 24 hours following presentation demonstrated 1-mm ST-segment elevation in leads I and aVL with T-wave inversion in the inferolateral leads.

      Diagnosis

      The etiology for this patient's presentation remained uncertain, and cardiac magnetic resonance imaging (MRI) was performed. Transverse black-blood images showed mediastinal lymphadenopathy with multiple enlarged lymph nodes measuring up to 18 × 16 mm (Figure 2A ). Cine imaging displayed mild asymmetrical septal hypertrophy with normal left ventricular volume and severe hypokinesia of the mid-to-apical segments of the inferior, lateral, and anterior walls (ejection fraction, 52%).
      Figure thumbnail gr2
      Figure 2Cardiac magnetic resonance imaging was very useful. A, This transverse image showed mediastinal lymphadenopathy, marked here with an asterisk. B, A T2-weighted image had increased signal at the apex, indicating myocardial edema. C, An inversion recovery horizontal long-axis image exhibits late gadolinium enhancement in the septum and distal lateral walls. Note the differing localization of late enhancement to that of the edema shown in 2B—concomitant sarcoid involvement is reflected, but at different evolutionary stages. D, A short-axis image displays extensive late gadolinium enhancement of the distal anterior and inferior myocardium. Sparing of the subendocardium and the noncoronary distribution (anterior wall involved with proximal septum-sparing) suggest a noncoronary etiology.
      T2-weighted images demonstrated an increased signal in the same territories, indicating acute injury with edema (Figure 2B). Inversion recovery images showed patchy mid-wall late gadolinium enhancement in the septum, with more extensive late enhancement in the segments with regional wall-motion abnormalities (Figures 2C and D). The pericardium appeared normal with no pericardial effusion. This pattern of late gadolinium enhancement, with sparing of the subendocardium, indicated myocardial fibrosis of nonischemic etiology, and in association with the lymphadenopathy, led to a working diagnosis of acute cardiac sarcoidosis, a disease spurred by inflammation.
      High-resolution computed tomography (CT) of the thorax confirmed the mediastinal lymphadenopathy noted on cardiac MRI but showed no evidence of pulmonary fibrosis. Abdominal CT demonstrated lymphadenopathy in the para-aortic, perigastric, epigastric and portacaval regions. Thorough clinical examination for peripheral lymphadenopathy identified 1 palpable right femoral lymph node, which was biopsied. Histopathology showed discrete well-formed granulomas composed of epithelioid histiocytes consistent with sarcoidosis (Figure 3).
      Figure thumbnail gr3
      Figure 3A discrete well-formed granuloma composed of epithelioid histiocytes was evident after hematoxylin and eosin staining.
      The incidence of sarcoidosis varies by ethnicity and geographical region, from 10/100,000 in Caucasians to 40-80/100,000 in African Americans.
      • Rybicki B.A.
      • Iannuzzi M.C.
      Epidemiology of sarcoidosis: recent advances and future prospects.
      Up to 40% also have cardiac involvement determined by cardiac MRI or positron emission tomography.
      • Mehta D.
      • Lubitz S.A.
      • Frankel Z.
      • et al.
      Cardiac involvement in patients with sarcoidosis: diagnostic and prognostic value of outpatient testing.
      The clinical manifestations of cardiac sarcoidosis depend on the activity, distribution, and extent of disease. The most common presentations relate to conduction abnormalities, arrhythmias (ventricular or atrial), sudden cardiac death, or heart failure. Presentation with chest pain mimicking acute coronary syndrome, as in this patient's case, is rare.
      Confirming the diagnosis of cardiac sarcoidosis can be challenging. Diagnostic criteria consisting of histological and major/minor clinical criteria have been produced, but are most relevant in chronic disease.
      • Soejima K.
      • Yada H.
      The work-up and management of patients with apparent or subclinical cardiac sarcoidosis: with emphasis on the associated heart rhythm abnormalities.
      Tissue characterization by cardiac MRI is a useful diagnostic tool with reported sensitivity of 100% and specificity of 78%.
      • Smedema J.P.
      • Snoep G.
      • van Kroonenburgh M.P.
      • et al.
      Evaluation of the accuracy of gadolinium-enhanced cardiovascular magnetic resonance in the diagnosis of cardiac sarcoidosis.
      As with our patient, cardiac MRI can accurately assess wall thickness, regional wall-motion abnormalities, myocardial edema, and fibrosis in acute cardiac sarcoidosis. The thinned, scarred myocardium of chronic disease also is readily detectable by cardiac MRI.
      In fact, cardiac MRI has a valuable role in the investigation of patients with presumed acute coronary syndrome who have normal coronary arteries at angiography. Approximately 10% of patients with ST-elevation myocardial infarction and 30% of biomarker-negative acute coronary syndrome cases have nonobstructive coronary disease.
      • Larson D.M.
      • Menssen K.M.
      • Sharkey S.W.
      • et al.
      “False-positive” cardiac catheterization laboratory activation among patients with suspected ST-segment elevation myocardial infarction.
      A routine “structure and function” cardiac MRI with gadolinium contrast may establish a diagnosis in two-thirds of cases, with exclusion of significant pathology in the remainder.
      • Assomull R.G.
      • Lyne J.C.
      • Keenan N.
      • et al.
      The role of cardiovascular magnetic resonance in patients presenting with chest pain, raised troponin, and unobstructed coronary arteries.
      Diagnoses in such cases include myocarditis, Tako-Tsubo cardiomyopathy and other cardiomyopathies, embolic and transient thrombotic events, as well as interesting rarities, such as acute cardiac sarcoidosis.

      Management

      Treatment is aimed at modifying the inflammatory disease process; other therapies deal with potential complications of the disease. Examples of the latter are antiarrhythmic therapy, implantable cardioverter-defibrillators, pacing, heart failure therapy, or even cardiac transplantation. Medical therapy primarily consists of corticosteroid treatment. The evidence for this is largely based on case series and expert opinion, with no published consensus guidelines. High doses of prednisolone—60-80 mg per day—are often initiated, though lower doses have been shown to be effective.
      • Yazaki Y.
      • Isobe M.
      • Hiroe M.
      • et al.
      Central Japan Heart Study Group
      Prognostic determinants of long-term survival in Japanese patients with cardiac sarcoidosis treated with prednisone.
      Two small trials are ongoing: the Cardiac Sarcoidosis Response to Steroids Trial or NCT01210677, designed to examine the effectiveness of a 3-month course of oral prednisolone, 0.5 mg/kg/day, and the Implantable Cardiac Defibrillators for the Prevention of Sudden Death in Patients with Cardiac Sarcoidosis trial or NCT01013311.
      Our patient was treated with prednisolone, 25 mg daily, with initial symptomatic relief. An angiotensin-converting enzyme inhibitor was prescribed for the left ventricular systolic dysfunction, along with oral hypoglycemic drugs to improve glycemic control. He was discharged with a plan to review his progress in 6 weeks. Unfortunately, over the subsequent month, he had ongoing chest pain and mildly elevated troponin levels resulting in 3 admissions to his local rural hospital. His prednisolone dosage was increased to 50 mg daily with some symptomatic improvement, but over the succeeding months, he developed steroid-related adverse effects; specifically, significant weight gain, insomnia, hyperglycemia requiring insulin administration, and Cushingoid appearance.
      Nearly 6 months after the patient's initial presentation, he re-presented with severe and prolonged chest pain, raised troponin levels, and an abnormal ECG, with deep arrowhead T-wave inversion across the anterior leads (Figure 4A). Repeat coronary angiography was unchanged. Repeat cardiac MRI showed regional wall motion abnormalities as previously identified, but with more extensive late gadolinium enhancement in the septum and anterior wall and a reduction in ejection fraction to 48% (Figure 4B).
      Figure thumbnail gr4
      Figure 4The patient's progress was examined with ECG and cardiac MRI. A, Almost 6 months after initial presentation, despite treatment with prednisolone, the patient's ECG showed new anterolateral T-wave inversion. B, A second cardiac MRI showed more extensive late gadolinium enhancement in the anteroseptum and apex—the same region where edema was identified on the first cardiac MRI. This demonstrates the pathological evolution of cardiac sarcoidosis. C, After the patient was placed on a more intensive immunotherapy regimen, an ECG demonstrated marked improvement with residual abnormalities in aVL only. D, Three months after beginning more powerful treatment, a third cardiac MRI demonstrated improvement in late gadolinium enhancement.
      In view of the patient's progressive disease despite high-dose steroid therapy, he was placed on an intensified immunosuppressive regimen of methotrexate and infliximab, a monoclonal antibody specific for tumor necrosis factor-α. This combination produced marked symptomatic relief accompanied by near-normalization of his ECG (Figure 4D). Follow-up cardiac MRI, undertaken 3 months after escalation of immunotherapy, showed a reduction in late gadolinium enhancement and an improved ejection fraction of 67% (Figure 4C).
      This case illustrates the rare presentation of acute cardiac sarcoidosis mimicking acute coronary syndrome; the utility of cardiac MRI to diagnose disease, direct treatment, and monitor the effect of treatment; and the potential difficulty in managing these challenging cases.

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