Aurora Cardiovascular Services Case of the Month
ACS Editorial Board
Jasbir S. Sra, MD
Andrew Boyle, MD
Tanvir Bajwa, MD
David C. Kress, MD
Bijoy K. Khandheria, MD
A. Jamil Tajik, MD
Steven Port, MD
Masood Akhtar, MD
The Thick Heart
M. Fuad Jan, MBBS, MD; Alexander Mayer, DO; Timothy E. Paterick, MD, JD; Lisa Baratta, MD; Nasir Sulemanjee, MBBS, MD; Rachel Loberg, NP; Ajit Divgi, MD; Vasundhara Ganne, MD; Bijoy K. Khandheria, MD; A. Jamil Tajik, MD
We report the case of a 50-year-old woman whose symptoms had defied a unifying diagnosis for three years. This woman was referred for a second opinion for persistent fatigue, progressive shortness of breath (New York Heart Association class III), bilateral lower-extremity edema, abdominal distension, and a 60-lb weight loss over several months duration.
The patient had been hospitalized five times in the past three years for acute diastolic heart failure, managed each time with aggressive intravenous (IV) diuresis. The patient also had a history of systemic hypertension, diet-controlled diabetes mellitus type 2 (hemoglobin A1C three months prior was 6.7%), anemia of chronic disease, and a recent diagnosis of Graves' disease.
Prior cardiac evaluations included several transthoracic echocardiograms (TTE), and left and right cardiac catheterizations. Of note, her TTE consistently revealed "severe" left ventricular hypertrophy (LVH), grade 2 diastolic dysfunction, and preserved ejection fraction of 60-70%. Recent cardiac catheterization revealed normal coronaries and the following hemodynamic measurements: mean right atrial pressure of 15 mmHg, pulmonary artery pressure of 52/28 with a mean of 37 mmHg, and a capillary wedge pressure of 27 mmHg. Calculated pulmonary vascular resistance was 1.8 Wood units with a cardiac index of 2.1 liters per min per m2. Her drug therapy included: carvedilol 6.25 to 12.5 mg twice daily, lisinopril 5 mg daily and furosemide 60 mg/day. Despite this therapeutic regimen she remained symptomatic.
Physical examination (pertinent positives & negatives): The patient was alert and oriented, weight: 160 lb, regular pulse (rate: 104 beats/min), blood pressure: 140/80 without pulsus paradoxus or alternans, respiratory rate: 14 breaths/min, temperature: 98.1 degrees F, arterial oxygen saturation 99% on room air. She had pallor, jugular venous distension without palpable thyroid enlargement. Cardiac examination revealed normal first and second heart sounds, a fourth heart sound, and a 3/6 ejection systolic murmur best heard at the lower left sternal border without diastolic murmur or rub. Examination of her chest revealed a dull right base with absent breath sounds. Abdominal examination revealed palpable hepatomegaly (5 cm below costal margin), ascites without tenderness, and +3 bilateral lower-extremity edema.
Notable laboratory values included hemoglobin: 11.6 gm/dL, creatinine: 1.02 mg/dL, serum bilirubin: 1.1 mg/dL (0.2-1.0 mg/dL is normal), alkaline phosphatase: 164 U/L (50-136 U/L is normal), and B-type natriuretic peptide (BNP): 717 pg/mL.
An electrocardiogram (ECG) obtained in clinic is depicted in Figure 1. This led to the decision to obtain a comprehensive TTE examination.
Figure 1. A 12-lead electrocardiogram showing the classic LV-mass-to-voltage discrepancy for amyloid cardiomyopathy. Also seen is a pseudoinfarct pattern.
Upon examination of the TTE (Figure 2), an infiltrative cardiomyopathy was identified with a presumptive diagnosis of cardiac amyloidosis based on increased wall thickness, large atria, and pericardial effusion. Next, cardiac magnetic resonance (CMR) imaging (Figure 3) and a cardiac endomyocardial biopsy (Figure 4) were obtained.
A Congo-red stain of myocardial tissue revealed apple-green birefringence indicative of amyloid deposition, while a trichrome stain showed some fibrosis. Subsequently, a bone marrow biopsy showed focal perivascular amyloid, with apple-green birefringence on polarization microscopy. Mass spectrometry-based amyloid typing on the endomyocardial biopsy confirmed the presence of AL-type (lambda light chain) amyloidosis, indicating a plasma cell neoplasia despite the lack of morphologic or immunophenotypic evidence of a clonal plasma cell population in the bone marrow biopsy sample; as well as a normal electrophoretic pattern of serum and urine electrophoresis. Axial and appendicular skeleton X-rays also did not demonstrate any evidence of lytic or blastic lesions. A 24-hour urine exam revealed glomerular proteinuria (predominantly albumin).
Figure 2. Panel A: Apical long-axis view demonstrating increased wall thickness. Panel B: Subcostal view demonstrates increased wall thickness of the LV and RV. Panel C: Four-chamber view demonstrating marked biatrial enlargement. Panel D: Tissue Doppler imaging of the septum demonstrating depressed annular velocity, typical of restrictive cardiomyopathy.
Figure 3. Panel A: A short-axis inversion recovery gadolinium enhancement image showing subtle mid-wall delayed enhancement (arrows) of the anteroseptal, lateral wall and anterior wall of the left ventricle as well as free right ventricular wall. Panel B: A short-axis bright blood cine "FIESTA" (fast imaging employing steady-state acquisition) sequence showing severe hypertrophy of the septal wall (19.2 mm) and of the lateral free wall (18.9 mm) in end-diastole. Also seen is pericardial effusion.
Figure 4. Histological sections from the endomyocardial biopsy and bone marrow. Panel A shows Congo-red stain demonstrating amyloid deposition (black arrow) between myocardial cells. Also seen are areas of fibrosis (green arrow) within the interstitium of the myocardium. Panel B demonstrates perivascular amyloid deposition within the bone marrow.
Medical oncologic consultation was sought: the patient was started on a modified regimen of bortezomib and dexamethasone (bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11, dexamethasone 40 mg total dose on days 1 and 8, and 12 mg IV dexamethasone on days 4 and 11 for the newly diagnosed amyloidosis with plasma cell dyscrasia (myeloma). At the time of this report, the patient has completed one full cycle of therapy without any major complications.
This case illustrates the importance of a comprehensive echocardiographic examination with a broad differential thought process. The echo findings dictated the need for a tissue diagnosis despite normal electrophoretic pattern of serum and urine electrophoresis.
Mass spectrometry-based amyloid typing of the endomyocardial biopsy specimen confirmed the presence of AL-type amyloidosis despite the lack of morphologic or immunophenotypic evidence of clonal plasma cell population in the bone marrow biopsy. This is a common discrepancy in AL-type amyloidosis, occurring in more than 50% of cases.
Cardiac amyloid is the prototypical infiltrative heart disease with increased wall thickness (Figure 5). Cardiac involvement is common in all forms of amyloidosis and is the most frequent cause of morbidity and mortality.1 Cardiac amyloid frequently has symptoms of heart failure, including fatigue, breathlessness, and exercise intolerance. Other cardiac presentations include arrhythmias with conduction block, dynamic ventricular outflow obstruction, and hypotension.
Figure 5: Short-axis view of an autopsied heart showing severe left ventricular hypertrophy. Note the thickened wall. Amyloidosis is a close mimic of hypertrophic cardiomyopathy. (Figure from Seward et al. Infiltrative cardiovascular diseases: cardiomyopathies that look alike. J Am Coll Cardiol 2010;55:1769-79, reproduced with permission from Elsevier.)
Characteristic echocardiographic findings of cardiac amyloid include: increased thickness of both left and right ventricular walls, normal or small LV cavity size, and abnormal myocardial texture (nonspecific granular appearance of the myocardium). Additionally, common findings include: atrial enlargement, thickened papillary muscles and valve leaflets, and small to moderate pericardial effusion. LV compliance gradually decreases as myocardial deposition of amyloid fibrils progresses.2 Progressive diastolic dysfunction is a universal finding resulting/cumulating in restrictive cardiomyopathy.2 Systolic dysfunction is typically evident only in advanced stages of the disease process.3 Doppler echocardiography is used to establish and serially monitor the magnitude of diastolic and systolic dysfunction. CMR will show diffuse late gadolinium enhancement throughout both ventricles, particularly the subendocardium.4
A decrease in QRS complex amplitude results from myocyte atrophy. In spite of increased ventricular wall thickness, 30% to 50% of patients with demonstrable amyloid disease will have normal-voltage QRS complexes, and the remainder show low-voltage QRS complexes. A pseudoinfarction pattern, particularly in the inferoseptal wall, may be observed in the precordial leads.5 Also, there is decreased conduction velocity and dyssynchronous activation of the ventricles resulting from amyloid deposition.6,7
Cardiac amyloidosis is diagnosed either directly by endomyocardial biopsy or indirectly using noninvasive diagnostic tools (two-dimensional echocardiography, magnetic resonance imaging, and ECG) and histologic confirmation of amyloid on a noncardiac tissue specimen.7 Upon unequivocal establishment of the diagnosis and tissue confirmation of amyloid type, prompt therapy is warranted for primary amyloidosis to arrest or reverse cardiac dysfunction. Poor cardiac reserve severely narrows the management strategies in the late stages. Without treatment patients have a median survival of less than six months after the onset of heart failure.8 Drug regimens including melphalan, steroids, immunomodulating agents, such as bortezomib, and stem cell transplantation post chemotherapy yield promising results.9-12 However, the mortality rate of transplantation ranges from 11% to 40%.13,14 In some patients with advanced cardiac involvement, cardiac transplantation may be performed before stem cell transplantation.15,16
- Gertz MA, Lacy MQ, Dispenzieri A. Amyloidosis: recognition, confirmation, prognosis, and therapy. Mayo Clin Proc 1999;74:490-4.
- Klein AL, Hatle LK, Burstow DJ, et al. Doppler characterization of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1989;13:1017-26.
- Bellavia D, Abraham TP, Pellikka PA, et al. Detection of left ventricular systolic dysfunction in cardiac amyloidosis with strain rate echocardiography. J Am Soc Echocardiogr 2007;20:1194-202.
- Syed IS, Glockner JF, Feng D, et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc Imaging 2010;3:155-64.
- Murtagh B, Hammill SC, Gertz MA, Kyle RA, Tajik AJ, Grogan M. Electrocardiographic findings in primary systemic amyloidosis and biopsy-proven cardiac involvement. Am J Cardiol 2005;95:535-7.
- Rahman JE, Helou EF, Gelzer-Bell R, et al. Noninvasive diagnosis of biopsy-proven cardiac amyloidosis. J Am Coll Cardiol 2004;43:410-5.
- Kumar V, Abbas AK, Fausto N, Mitchell RN (eds). Robbins Basic Pathology, 8th edition. Philadelphia: Saunders Elsevier, 2007.
- Seward JB, Casaclang-Verzosa G. Infiltrative cardiovascular diseases: cardiomyopathies that look alike. J Am Coll Cardiol 2010;55:1769-79.
- Kyle RA, Gertz MA, Greipp PR, et al. Long-term survival (10 years or more) in 30 patients with primary amyloidosis. Blood 1999;93:1062-6.
- Palladini G, Russo P, Nuvolone M, et al. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood 2007;110:787-8.
- Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood 2007;109:457-64.
- Kastritis E, Anagnostopoulos A, Roussou M, et al. Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone. Haematologica 2007;92:1351-8.
- Comenzo RL, Gertz MA. Autologous stem cell transplantation for primary systemic amyloidosis. Blood 2002;99:4276-82.
- Rajkumar SV, Gertz MA, Kyle RA, Greipp PR, et al. Current therapy for multiple myeloma. Mayo Clin Proc 2002;77:813-22.
- Lacy MQ, Dispenzieri A, Hayman SR, et al. Autologous stem cell transplant after heart transplant for light chain (Al) amyloid cardiomyopathy. J Heart Lung Transplant 2008;27:823-9.
- Maurer MS, Raina A, Hesdorffer C, et al. Cardiac transplantation using extended-donor criteria organs for systemic amyloidosis complicated by heart failure. Transplantation 2007;83:539-45.
Aurora Cardiovascular Services: Phone: (414) 649-3370 or (800) 649-1989.