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24-Year-Old Man With Acute Chest Pain

      A 24-year-old man presented to the emergency department with a 2-day history of progressively worsening chest pain and shortness of breath. He described the pain as a sharp, substernal sensation occurring at rest, exacerbated by deep inspiration or lying flat on his back, and alleviated by sitting upright leaning forward. He did not report radiation to the neck or left arm. Associated symptoms included nausea, vomiting, and nonproductive cough, which began 2 days before the onset of chest pain. His medical history was notable for systemic lupus erythematosus (SLE) complicated by nephritis and congestive heart failure with reduced ejection fraction. The patient had adhered to recommended treatments, including peritoneal dialysis.
      Physical examination revealed an afebrile, calm man with a heart rate of 94 beats/min and regular rhythm, blood pressure of 117/78 mm Hg, and shallow breathing at 18 breaths/min with associated oxygen saturation of 100% while receiving 2 L of oxygen by nasal cannula. His pharynx was clear, and his neck veins were not distended. Cardiac examination revealed a loud, high-pitched, triphasic friction rub, heard best in the left lower sternal border throughout multiple phases. Lung examination was positive for decreased lung sounds at the bases, with inspiratory rales bilaterally. His abdomen was nontender and nondistended, with a peritoneal dialysis catheter located in the left lower quadrant. Mild pitting edema of both ankles was noted.
      • 1.
        On the basis of the patient's history and physical examination, which one of the following is the most likely cause of his clinical presentation?
        • a.
          Acute coronary syndrome
        • b.
          Transient left ventricular apical ballooning syndrome
        • c.
          Acute pericarditis
        • d.
          Cocaine intoxication
        • e.
          Pulmonary embolism
      Acute coronary syndrome may present with substernal chest, left upper extremity, mandibular, or epigastric discomfort or an ischemic equivalent such as dyspnea. The pain typically worsens with exertion and improves with rest and nitroglycerin. The syndrome generally occurs after the fourth decade of life unless the patient has an inheritable condition, exposure to radiation therapy, coronary vasospasm, inflammation, or recent cocaine use. Initial diagnostic testing may reveal markedly elevated cardiac biomarkers with or without ST-segment changes on electrocardiography (ECG) correlating to a specific coronary artery area.
      Transient left ventricular apical ballooning syndrome, also known as Takotsubo cardiomyopathy, causes chest pain and dyspnea with similar ECG changes and biomarker elevation; however, cardiac catheterization generally does not reveal substantial obstructive lesions in the coronary arteries. The syndrome occurs almost exclusively in postmenopausal women in their sixth to seventh decade of life in the setting of a strong emotional stressor.
      • Pilgrim T.M.
      • Wyss T.R.
      Takotsubo cardiomyopathy or transient left ventricular apical ballooning syndrome: a systematic review.
      Our patient's acute chest pain was typical for pericarditis. Diagnostic criteria for pericarditis include 2 of the 4 following findings: pericarditic chest pain, pericardial rubs, new widespread ECG findings, and pericardial effusion.
      • Adler Y.
      • Charron P.
      • Imazio M.
      • et al.
      2015 ESC Guidelines for the diagnosis and management of pericardial diseases: the Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC); endorsed by: the European Association for Cardio-Thoracic Surgery (EACTS).
      Deep inspiration can exacerbate pleuritis, causing sharp pain, whereas leaning forward reduces stress on the pericardium. A triphasic pericardial friction rub results from the inflamed layers of the pericardium and is highly specific for pericarditis, whereas chest pain can be caused by many other diseases.
      Sympathomimetics such as cocaine may cause a hyperadrenergic state, resulting in chest pain due to arterial vasoconstriction and demand ischemia or stress cardiomyopathy. Given that patients may be reluctant to disclose their use of recreational drugs, physical findings such as tachycardia, hypertension, diaphoresis, dilated pupils, and piloerection are important.
      Although half of the patients who have pulmonary embolism (PE) may present with chest pain, the predominant symptom is dyspnea with associated tachycardia. Patients who have active malignant disease, recent immobilization, hemoptysis, or a history of venous thromboembolism are at higher risk for PE. A D-dimer can be useful for patients who have a low pretest probability of PE, whereas if high-risk features are present, computed tomographic angiography of the pulmonary arteries would be the next reasonable step in diagnosis.
      The patient underwent initial laboratory studies, which revealed the following (reference ranges provided parenthetically): hemoglobin, 8.1 g/dL (12.0-15.5 g/dL); white blood cell count, 5.4 × 109/L (3.5-10.5 × 109/L), with a differential of 85% neutrophils and 9% lymphocytes; platelet count, 299 × 109/L (150-450 × 109/L); creatinine, 10.2 mg/dL (0.6-1.1 mg/dL); blood urea nitrogen, 36 mg/dL (8-24 mg/dL); brain natriuretic peptide, 1750 pg/mL (≤35 pg/mL); troponin, <0.01 ng/mL (0.0-0.1 ng/mL); sedimentation rate, 88 mm/h (0-22 mm/h); and C-reactive protein, 51.8 mg/L (≤8.0 mg/L). An ECG was obtained.
      • 2.
        Which one of the following abnormalities is most likely to be seen on our patient's ECG?
        • a.
          Diffuse ST-segment elevation and T-wave inversions
        • b.
          Pathologic Q waves
        • c.
          Peaked T waves
        • d.
          PR-segment deviations
        • e.
          Diffuse ST-segment elevation and PR-segment deviations
      Although diffuse ST-segment elevation is most commonly seen in pericarditis, T-wave inversions do not generally occur simultaneously ST-segment elevation can be seen in acute ST-elevation myocardial infarction and is usually associated with reciprocal ST-segment changes with T-wave inversions that are regional to the area of ischemia. Additionally, ST-segment elevation with pericarditis is diffusely concave upward, whereas with epicardial injury, it is convex.
      Pathologic Q waves represent areas of previous myocardial ischemia as scar tissue limits electrical conduction, but do not suggest acute pericarditis. Normal septal activation produces an initial anterior vector that is positive in the anterior leads of V1 and V2 and briefly positive in the inferior leads. A physiologic Q wave can result from normal initial activation away from the lead, as seen in inferior leads when the heart is rotated superiorly.
      Peaked T waves greater than 10 mm in all precordial leads and greater than 5 mm in all limb leads are associated with hyperkalemia or early myocardial ischemia. In acute pericarditis, T waves are upright but not peaked unless a secondary process is present, such as renal failure with uremia and hyperkalemia.
      Acute pericarditis manifests in 4 phases on ECG: diffuse ST-segment elevation, resolution of ST-segment changes after several days, T-wave inversions, and normalization of ECG.
      • Troughton R.W.
      • Asher C.R.
      • Klein A.L.
      Pericarditis.
      Although ST-segment elevation is a hallmark of myocardial infarction, this change will be found only in the areas affected by ischemic disease. Additionally, PR-segment depression is seen in acute pericarditis, and reciprocal changes can be evident in aVR leads with ST-segment depression and PR-segment elevation.
      Our patient's ECG revealed PR-segment elevation in aVR with ST-segment elevation in multiple leads without any specific area. Further diagnostic work-up included chest radiography, which revealed an enlarged cardiac silhouette with small bilateral pleural effusions. Transthoracic echocardiography revealed an ejection fraction of 36%, indeterminate diastolic function, and a small circumferential pericardial effusion without evidence of ventricular interdependence.
      • 3.
        Which one of the following is the recommended treatment for our patient's first occurrence of acute pericarditis?
        • a.
          Pericardiectomy
        • b.
          Corticosteroids
        • c.
          Colchicine
        • d.
          Nonsteroidal anti-inflammatory drugs (NSAIDs)
        • e.
          NSAIDs plus colchicine
      Pericardiectomy is rarely indicated in acute pericarditis because the inflammation is usually responsive to medical management. Although pericardiectomy can be considered for patients with severe relapsing pericarditis for whom adequate drug treatment has failed, evidence-based data for its effectiveness are lacking.
      • Adler Y.
      • Charron P.
      • Imazio M.
      • et al.
      2015 ESC Guidelines for the diagnosis and management of pericardial diseases: the Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC); endorsed by: the European Association for Cardio-Thoracic Surgery (EACTS).
      Removal of the pericardium can be helpful in patients who have recurrent cardiac tamponade.
      Systemic corticosteroids are not recommended as a first-line therapy for acute pericarditis owing to an increased incidence of recurrent pericarditis and adverse effects, but they can be considered after other therapies such as NSAIDs and colchicine have failed. An exception is culture-proven Mycobacterium tuberculosis effusion in which systemic corticosteroids decrease the incidence of constrictive pericarditis. Colchicine alone can be used as a first-line therapy in patients who do not tolerate NSAIDs.
      • Imazio M.
      Contemporary management of pericardial diseases.
      Patients who have renal impairment require dose adjustments to prevent serious adverse effects such as myelosuppression and hepatotoxicity. The duration of therapy for acute pericarditis is 3 months. Likewise, monotherapy with NSAIDs is a viable option for acute pericarditis. Ibuprofen, aspirin, and indomethacin at high doses for 1 to 2 weeks are most commonly used. Due to the risk of gastrointestinal adverse effects, concomitant use of proton pump inhibitors is recommended.
      Colchicine in combination with NSAIDs has been found to improve symptoms, reduce risk of recurrent pericarditis, and be well tolerated by patients.
      • Imazio M.
      Contemporary management of pericardial diseases.
      Therefore, dual therapy is recommended for treatment of acute pericarditis. Given our patient's end-stage renal disease requiring dialysis, he was given renally dosed colchicine in combination with aspirin therapy. Initially, his symptoms improved, but after 2 days of therapy, chest pain and dyspnea recurred.
      • 4.
        Which one of the following additional diagnostic tests is most likely to be useful for our patient?
        • a.
          Serum double-stranded deoxyribonucleic acid (ds-DNA)
        • b.
          Pericardiocentesis
        • c.
          Interferon-gamma release assay
        • d.
          Viral studies
        • e.
          Magnetic resonance imaging (MRI) of the heart
      Anti–ds-DNA antibodies in the serum are highly specific for SLE, and the titer will vary on the basis of disease activity. Multiple assays are available for detecting ds-DNA antibodies, with specificity averaging 93% to 97%.
      • Kavanaugh A.F.
      • Solomon D.H.
      Guidelines for immunologic laboratory testing in the rheumatic diseases: anti-DNA antibody tests.
      When autoimmune pericarditis is suspected, this test should be reserved for patients with a positive antinuclear antibody test result to limit the incidence of false-positives. In our patient, SLE had been diagnosed previously but was thought to be well controlled with hydroxychloroquine. Yet, the ds-DNA titer level was markedly elevated, suggesting an active inflammatory state as the culprit in his acute pericarditis.
      A pericardiocentesis can be performed for both diagnostic and therapeutic purposes. Diagnostically, this procedure allows clinicians to name the type of effusion trapped in the pericardium. Effusions can be determined to be transudative, exudative, hemorrhagic, or malignant on the basis of visual inspection and laboratory studies. Although useful, this procedure generally is not performed in acute pericarditis unless tamponade physiology develops, a malignant process is of concern, or a large effusion is present with acute illness requiring verification of the diagnosis.
      Interferon-gamma release assay is a useful blood test to diagnose latent or active tuberculosis (TB), although active TB also requires microbiological confirmation. The enzyme-linked immunosorbent assay looks for specific antigens produced by M tuberculosis and has a specificity greater than 95%.
      • Menzies D.
      • Pai M.
      • Comstock G.
      Meta-analysis: new tests for the diagnosis of latent tuberculosis infection; areas of uncertainty and recommendations for research.
      This study should be reserved for patients from TB-endemic countries and for immunocompromised hosts such as patients infected with human immunodeficiency virus. Serum viral markers, including polymerase chain reaction studies, may help initiate antiretroviral therapy in cases in which suspicion is high for human immunodeficiency virus infection. However, routine use of viral studies for acute pericarditis is not favored, as they have low yield and will not change the course of management for more common viral agents such as enteroviruses or adenoviruses.
      Cardiac MRI provides structural and functional information without the invasiveness of right-sided heart catheterization or the viewing limitations of echocardiography. For acute pericarditis, MRI can visualize thickening of the pericardium and small, loculated effusions, whereas in chronic recurrent pericarditis, MRI can reveal fibrosis or calcifications resulting from fibroblast activity, which can develop into constrictive physiology.
      • Rajiah P.
      Cardiac MRI: Part 2, pericardial diseases.
      Although European guidelines favor consideration of cardiac MRI given its high sensitivity for inflammation of cardiac tissue, this imaging modality is not routinely utilized for acute presentations in the United States.
      • Adler Y.
      • Charron P.
      • Imazio M.
      • et al.
      2015 ESC Guidelines for the diagnosis and management of pericardial diseases: the Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC); endorsed by: the European Association for Cardio-Thoracic Surgery (EACTS).
      • 5.
        Which one of the following is the most appropriate next therapeutic option for our patient?
        • a.
          Anakinra
        • b.
          Corticosteroids plus hydroxychloroquine
        • c.
          Azathioprine
        • d.
          Mycophenolate
        • e.
          Belimumab
      Anakinra is an interleukin 1β receptor antagonist that inhibits systemic inflammatory response mediated by interleukin 1. Corticosteroids plus hydroxychloroquine is the best option in this case. All of the listed immunosuppressive agents are indicated for recurrent SLE pericarditis as second-line and third-line therapies after a trial of corticosteroids plus hydroxychloroquine.
      • Muangchan C.
      • van Vollenhoven R.F.
      • Bernatsky S.R.
      • et al.
      Treatment algorithms in systemic lupus erythematosus.
      Although 1.0 to 1.5 mg/kg of prednisone daily for a minimum of 1 month has been recommended, similar efficacy with lower complication rates may be achieved with a lower dose of 0.2 to 0.5 mg/kg daily.
      • Imazio M.
      • Brucato A.
      • Cumetti D.
      • et al.
      Corticosteroids for recurrent pericarditis: high versus low doses; a nonrandomized observation.
      Hydroxychloroquine is added for its anti-inflammatory effects, which can be beneficial in preventing future flares. Azathioprine and mycophenolate are antimetabolites that disrupt purine synthesis, limiting production of B and T lymphocytes. Belimumab is a monoclonal antibody targeting BLyS (also known as B-cell activating factor), indirectly reducing B-cell survival and formation of autoantibodies.
      • Chiche L.
      • Jourde N.
      • Thomas G.
      • et al.
      New treatment options for lupus—a focus on belimumab.
      The drug was the first biological agent to be approved by the US Food and Drug Administration for SLE; however, its benefits seem to fall short of those of anakinra. If SLE pericarditis becomes corticosteroid refractory, then initiation of the other agents can be considered. Our patient had only a remote exposure to corticosteroids for SLE and therefore was treated with systemic corticosteroids and hydroxychloroquine.

      Discussion

      Noninfectious immunogenic etiologies of pericarditis include SLE, rheumatoid arthritis, scleroderma, and vasculitides.
      • Troughton R.W.
      • Asher C.R.
      • Klein A.L.
      Pericarditis.
      Manifestations of SLE include active inflammation presenting as serositis, arthralgias, rashes, hematologic derangements, and other irregularities with autoantibody markers present in the serum. Serositis will involve the pericardium in 30% of patients with SLE, resulting in acute fibrinous pericarditis and pericardial effusion.
      • Ansari A.
      • Larson P.H.
      • Bates H.D.
      Cardiovascular manifestations of systemic lupus erythematosus: current perspective.
      Patients with SLE may have classic pericardial symptoms including sharp, pleuritic chest pain that varies with position in addition to fever, joint pain, malar rash, and fatigue. By comparison, patients who have infectious pericarditis may present with a history of recent upper respiratory tract illness in addition to chest symptoms. Obtaining a full inventory of medical history and active medication therapies will help guide the diagnostic approach, especially if the patient is being treated for SLE, as in our case.
      Initial diagnostic work-up for all suspected pericarditis cases should include a complete blood cell count, erythrocyte sedimentation rate, measurement of serum C-reactive protein and cardiac biomarker levels, ECG, chest radiography, and echocardiography. When autoimmune reactivity is suspected, serum autoantibody levels of antinuclear antibody, ds-DNA, anti–Smith antibodies, anti-Ro/SSA, anti-La/SSB, and complement levels will quantify level of disease activity, allowing for initiation of anti-inflammatory therapies. With detectable serum markers for SLE, subsequent laboratory testing, including glomerular filtration rate and urinalysis, is appropriate to assess for renal involvement and guide medication options. A pericardial tissue biopsy may reveal immunocomplex deposition under direct immunofluorescence, consistent with type III hypersensitivity, but invasive testing is not required for diagnosis.
      • Doria A.
      • Iaccarino L.
      • Sarzi-Puttini P.
      • Atzeni F.
      • Turriel M.
      • Petri M.
      Cardiac involvement in systemic lupus erythematosus.
      Nonsteroidal anti-inflammatory drugs with adjuvant colchicine, in addition to immunomodulators, are the first-line therapy for mild lupus pericarditis. Although rare, complications include cardiac tamponade, constrictive pericarditis, and purulent pericarditis. High-dose intravenous corticosteroids may be given, along with pericardial draining, for severe cases complicated by cardiac tamponade.
      • Doria A.
      • Iaccarino L.
      • Sarzi-Puttini P.
      • Atzeni F.
      • Turriel M.
      • Petri M.
      Cardiac involvement in systemic lupus erythematosus.
      Ongoing research is being conducted on immunosuppressive agents for treatment of recurrent corticosteroid-refractory disease. After beginning to receive systemic corticosteroids with hydroxychloroquine and showing clinical improvement, our patient was discharged with rheumatology follow-up scheduled for consideration of a corticosteroid-sparing immunosuppressive agent.

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        • Charron P.
        • Imazio M.
        • et al.
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        Contemporary management of pericardial diseases.
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        Guidelines for immunologic laboratory testing in the rheumatic diseases: anti-DNA antibody tests.
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        Meta-analysis: new tests for the diagnosis of latent tuberculosis infection; areas of uncertainty and recommendations for research.
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        Cardiac MRI: Part 2, pericardial diseases.
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        Cardiovascular manifestations of systemic lupus erythematosus: current perspective.
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