American Journal of Therapeutics 23, e1060–e1063 (2016)

Cardiac Amyloidosis Presenting With Cardiogenic Shock Ashwad Afzal, MD,1* Sorin J. Brener, MD,1 Navneet Narula, MD,2 Berhane Worku, MD,3 and Iosif Gulkarov, MD3

Cardiac amyloidosis is an infiltrative disorder of the myocardium. It is the result of one of 4 types of amyloidosis: primary systemic (immunoglobulin light chain), secondary, familial (hereditary), or senile. Cardiac amyloidosis ultimately causes congestive heart failure due to irreversible restrictive cardiomyopathy. Because of the rapid progression of the disease, early recognition and determination of underlying etiology are important for tailored therapy. Current interventions range from conservative heart failure management to autologous stem cell and heart transplantation. We present a case of cardiac amyloidosis accompanying undiagnosed multiple myeloma to illustrate the rapid progression of the disease and the complexities of diagnosing and treating this disorder. Keywords: amyloidosis, cardiac amyloidosis

INTRODUCTION Cardiac amyloidosis is a result of one of the systemic amyloidoses that can often be characterized by nonspecific symptoms, most notably congestive heart failure due to the underlying restrictive cardiomyopathy. Because of the rapid progression of the disease, early recognition and determination of underlying etiology is important for tailored therapy. Current therapies range from conservative management to autologous stem cell transplantation and heart transplant. We present a case of cardiac amyloidosis with underlying myeloma to illustrate the rapid progression of the disease and the complexities of diagnosing and treating this disorder.

CASE DESCRIPTION A 41-year-old Hispanic man without significant medical history presented with recurrent syncope over 1

Department of Medicine, New York Methodist Hospital, Brooklyn, NY; 2Department of Pathology, Weill Cornell Medical Center, New York, NY; and 3Department of Cardiothoracic Surgery, New York Methodist Hospital, Brooklyn, NY. The authors have no conflicts of interest to declare. *Address for correspondence: New York Methodist Hospital, 506 Sixth St, East Pavilion, Brooklyn, NY 11215. E-mail: ashwad. [email protected]

a 10-day span. They were preceded by palpitations and lightheadedness. A few of the episodes were witnessed, and it was reported that he became unresponsive for a few minutes. He also described orthopnea and worsening lower extremity edema. He was an avid basketball player and had to curtail this activity because of these symptoms. He denied fever, chest pain, seizures, tongue biting, weakness of extremities, bladder or bowel incontinence. Review of system was otherwise negative. On physical examination, he was afebrile, blood pressure 87/69 mm Hg, heart rate 88 beats per minute, breathing 20 breaths per minute, oxygen saturation 100% on room air. His jugular venous pressure was elevated at 15 cm with the presence of hepatojugular reflux. Crackles were present in both lung bases. Cardiac examination revealed a regular rate and rhythm without any murmurs or gallops. His abdomen was not tender or distended. There was 2+ lower extremity pitting edema bilaterally extending to his knees. Initial laboratory values are shown in Table 1. Electrocardiogram showed low-voltage QRS complexes (Figure 1). A 2-dimensional transthoracic echocardiogram revealed a normal-sized left ventricle with moderately increased wall thickness and an ejection fraction of 15%–20%. The right ventricle was mildly dilated, and there was marked biatrial dilation. There were trace

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Cardiac Amyloidosis

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Table 1. Admission laboratory values.

Laboratory test WBC, K/mL Hemoglobin, g/dL Hematocrit, % Mean corpuscular volume, fL RDW, % Platelets, K/mL Glucose, mg/dL BUN, mg/dL Creatinine, mg/dL Sodium, mmol/L Potassium, mmol/L Chloride, mmol/L Bicarbonate, mmol/L Calcium, mg/dL Albumin, g/dL Total protein, g/dL Direct bilirubin, mg/dL Total bilirubin, mg/dL Alkaline phosphatase, U/L Alanine aminotransferase, U/L Aspartate aminotransferase, U/L Creatine kinase, MB, ng/mL Magnesium, mg/dL Phosphorous, mg/dL Pro BNP, pg/mL Troponin I, ng/mL

On admission

Normal values

9.6 13.6 40.00 94.4 15.6 159 119 17 1.12 131 6.2 97 22 8.8 3.2 5.7 ,0.1 0.8 63 80 74 3.2 2 5 9316.00 1.65

4.0–10.3 12.5–16.9 38.3–48.5 79.5–98.0 11.9–15.0 117–361 55–100 7.0–18 0.67–1.17 136–145 3.5–5.1 100–108 21–32 8.5–10.1 3.4–5.0 6.4–8.2 0–0.2 0.2–1.0 53–128 8.0–62.0 15–37 0.5–3.6 1.8–2.4 2.5–4.9 ,125 ,0.045

mitral and tricuspid regurgitation. Coronary angiography and electrophysiologic study were normal. Cardiac magnetic resonance imaging revealed diffuse fibrosis. He was suspected of having myocarditis and was treated with appropriate heart failure regimen including angiotensin-converting enzyme inhibitors and beta-blockers. However, he returned 10 days later with recurrent syncope and symptoms of New York Heart Association class III heart failure. There was worsening systolic dysfunction on transthoracic echocardiography. Dobutamine infusion was started. On hospital day 2, he had an episode of cardiopulmonary arrest due to ventricular tachycardia with quick return of spontaneous circulation after treatment with epinephrine, and brief cardiopulmonary resuscitation. Later, he had another episode of pulseless electrical activity, was intubated, and started on venoarterial extracorporeal membrane oxygenation support. Blood tests revealed a kappa to lambda www.americantherapeutics.com

ratio .1000 (normal, 0.26–1.25) along with a decrease in gamma globulin on protein electrophoresis. On hospital day 3, after reviewing the cardiac magnetic resonance imaging from previous admission, an endomyocardial biopsy was scheduled to determine a definitive diagnosis. Hematoxylin and eosin stain revealed a significant amount of amyloid deposits around hypertrophied myocytes (Figure 2A), which was confirmed on Congo red staining (Figure 2B). Immunostain for kappa light-chain antibody showed strong staining in the amyloid deposits (Figure 2C). Despite the absence of hypercalcemia, anemia, and renal failure, a bone marrow biopsy confirmed the presence of multiple myeloma. In retrospect, computerized tomography images revealed bone lytic lesions.

DISCUSSION Amyloidosis is a term used to describe diseases caused by extracellular deposition of insoluble beta-pleated protein fibrils in tissues and organs. There are several types of systemic amyloidosis, but only 4 of which mainly affect the heart. Those include immunoglobulin light chain (AL), serum amyloid A protein (AA), familial (ATTR), and senile systemic amyloid.1–3 The commonest form of amyloidosis in the United States is the AL type, which involves the heart in about 50% of cases.1 AL amyloidosis is a plasma cell dyscrasia that can overlap with multiple myeloma and vice versa; however, only a minority of patients have both conditions.1 The key distinction is whether or not the patient exhibits myeloma-related organ or tissue impairment because of the plasma cell proliferative process characterized by hypercalcemia, anemia, renal insufficiency, or bone lesions.4 Cardiac amyloidosis is a difficult diagnosis to make but should be suspected based on a few clinical and diagnostic measures. Clinically, the most common presenting symptom is that of congestive heart failure, including dyspnea and peripheral edema, due to the restrictive cardiomyopathy underlying the disease. Patients often also have markedly elevated jugular venous pressure with a prominent X and Y descent. The 2 most common findings on electrocardiogram are lower than normal voltage and a pseudoinfarct pattern.5 Transthoracic echocardiography usually reveals hypertrophied walls indicating infiltration of the heart with amyloid.6 Cardiac magnetic resonance shows a characteristic pattern of global, subendocardial late gadolinium enhancement.7,8 The role of cardiac catheterization in cardiac amyloidosis is of limited value and is mainly used to obtain an endocardial biopsy. American Journal of Therapeutics (2016) 23(4)

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Afzal et al

FIGURE 1. Electrocardiogram shows low-voltage QRS predominantly in limb leads.

Tissue diagnosis is obtained in one of the 2 ways: directly from the endomyocardial tissue or a fineneedle aspiration of the abdominal fat correlated with echocardiographic findings of cardiac amyloidosis. Although classically it was thought a fat pad biopsy was sufficient, it has been shown to demonstrate a sensitivity of about 75% in making an accurate diagnosis.9 Endomyocardial biopsy was proven to be more sensitive in not only diagnosing cardiac amyloidosis but also in altering the diagnosis when inaccurately performed through clinical assessment.10 The tissue will demonstrate apple-green birefringence when stained with Congo red and viewed under polarized light. Once tissue diagnosis is confirmed, the confirmation of AL amyloidosis is made by attempting to search for the presence of a plasma cell dyscrasia. The recommended testing is serum-free light-chain assay or

serum and urine immunofixation because of their increased sensitivity over serum and urine electrophoresis.11 In addition, the kappa to lambda ratio can be used to assist in determining the underlying plasma cell dyscrasia in AL amyloidosis. An abnormal ratio, along with free lambda and kappa concentrations, is helpful in confirming the diagnosis. A bone marrow biopsy is also required not only to assess the percentage of plasma cells, but also to exclude Myeloma and Waldenstrom macroglobulinemia. Management of cardiac amyloidosis remains controversial and challenging with the average life expectancy for patients with AL amyloidosis only 13–18 months.12 Initial management typically involves symptomatic relief with diuretics. Angiotensin-converting enzyme inhibitors and angiotensin II inhibitors are noted to be very poorly tolerated in those with AL amyloidosis,

FIGURE 2. (A) Hematoxylin and eosin stain with amyloid (white arrows) and hypertrophied myocytes (black arrows). (B) Congo red stain with amyloid (white arrows) and myocytes (black arrows). (C) Immunostain for kappa light-chain antibody shows strong staining of the amyloid (white arrows) and myoctyes (black arrows). American Journal of Therapeutics (2016) 23(4)

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Cardiac Amyloidosis

leading to profound hypotension attributed to the autonomic neuropathy and the role that angiotensin II receptors play in blood pressure maintenance. Definitive treatment of AL amyloidosis is to stop production of the paraprotein responsible for amyloid formation. Intravenous Melphalan with stem cell transplantation has been shown to result in hematologic remission, improved 5-year survival, and reversal of amyloid-related disease.13 The difficulty with this treatment option is that the disease is often in an advanced stage when diagnosed, leaving most patients unfit for the high-dose chemotherapy required. An ejection fraction of ,40% is generally considered an absolute contraindication to high-dose chemotherapy in cardiac amyloid patients.1 Heart transplantation can also be considered in a subset of patients, although the true efficacy has yet to be established. Regardless of the use of adjunctive chemotherapy, the 5-year survival after heart transplant in those with cardiac AL amyloidosis was less than that after heart transplant for other indications and the progression of the systemic disease contributed to the increased mortality.14

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American Journal of Therapeutics (2016) 23(4)

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Cardiac Amyloidosis Presenting With Cardiogenic Shock.

Cardiac amyloidosis is an infiltrative disorder of the myocardium. It is the result of one of 4 types of amyloidosis: primary systemic (immunoglobulin...
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