Hypertrophic cardiomyopathy and symptomatic conduction system disease in cardiac amyloidosis.

Abstract: Cardiac involvement is the most important prognostic factor in primary amyloidosis (AL). The clinical presentation of amyloid cardiomyopathy is varied and may manifest as heart failure, brady or tachyarrhythmias, syncope, angina and rarely with features of hypertrophic cardiomyopathy and advanced symptomatic conduction system disease. The management of amyloid cardiomyopathy has always been a dilemma, as most of the drugs used in congestive heart failure are contraindicated.

This report describes a 70-year-old woman who presented with syncope, severe diastolic heart failure, features of hypertrophic cardiomyopathy and severe symptomatic conduction system disease requiring a pacemaker. Amyloidosis was diagnosed on endomyocardial biopsy after abdominal fat aspirate was negative for amyloid. The patient eventually expired due to end-stage congestive heart failure.

Key Words: amyloidosis, cardiomyopathy, heart block

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Amyloidosis refers to extracellular deposition of fibrils composed of low molecular weight subunits of a variety of proteins. These fibrils adopt a beta pleated sheet configuration leading to a characteristic histologic change. The incidence of primary amyloidosis is 5 to 12 patients per million person years; it is uncommonly encountered in clinical practice and is often misdiagnosed due to the vague nature of symptoms. (1) The symptoms of amyloidosis depend upon the precursor protein, tissue distribution and the amount of amyloid deposited. Amyloidosis should be considered in the differential diagnosis of multiorgan dysfunction with the most commonly involved organs being the kidney, followed by the heart, liver and peripheral nerves. (2) Patients usually present with fatigue, dyspnea, edema and weight loss. Amyloidosis can be broadly classified into primary, secondary, dialysis-related, heritable (transthyretin associated) amyloidosis and organ-specific amyloid. (3,4) Although amyloidosis is a multisystem disease, the prognosis is determined primarily by the presence or absence of cardiac involvement. (5) We report a case of primary amyloidosis which presented with the unusual combination of severe diastolic heart failure with symptomatic conduction system disease.

Case Report

A 70-year-old white female presented with new syncope and symptoms of biventricular congestive heart failure for the previous three months. She had a prior history of hypertension and her medications included aspirin and furosemide. She was married, did not consume alcohol, but had a 40-pack year smoking history. On examination, her vital signs revealed a pulse of 64 beats per minute and a blood pressure of 106/56 mm Hg without orthostatic change. She was afebrile with an oxygen saturation of 98% on room air. Pertinent clinical findings were increased jugular venous pressure, bibasilar lung crackles, nontender hepatomegaly with a 20 cm liver span and bilateral pitting pedal edema. Cardiac examination revealed normal first and second heart sounds and a Grade 3/6 systolic murmur at the lower left sternal border without radiation. The neurologic examination was normal. Specifically, there was no postural hypotension or evidence of peripheral neuropathy. On further questioning, she denied early satiety or vomiting suggestive of gastroparesis. Laboratory data revealed normal hematocrit, electrolytes and renal functions. Globulins were increased and the albumin to globulin ratio was reversed at 0.6. Troponins were mildly increased. Electrocardiogram showed sinus rhythm and low voltage QRS complexes (QRS voltage less than 5 mm in the limb leads and less than 10 mm in the chest leads). 2-D echocardiogram revealed features of hypertrophic cardiomyopathy with increased ventricular septal wall thickness without outflow tract obstruction and preserved left ventricular systolic function with an ejection fraction of 55 to 60%. There was no evidence of valvular abnormality or pericardial effusion. However, the most prominent abnormality on the echocardiogram was the granular sparkling of the myocardium. Cardiac catheterization and coronary angiography revealed normal coronary anatomy. Though the urine dipstick was negative for protein, she had proteinuria of 2 g/24 hours urine collection. Urine electrophoresis and immunofixation were positive for IgG kappa light chains. Bone marrow biopsy revealed a plasma cell dyscrasia with 10% plasma cells. Abdominal fat pad biopsy was negative for amyloid. An endomyocardial biopsy was positive for amyloid. Immunostaining revealed primary amyloidosis (AL) composed of kappa light chains. The stain for prealbumin (transthyretin) was negative. She developed complete heart block requiring a permanent pacemaker and died 2 weeks later due to refractory congestive heart failure (Figs. 1, 2, and 3).

Discussion

Our patient had primary amyloidosis with renal, cardiac and hepatic involvement. Primary amyloidosis is a type of plasma cell dyscrasia in which 5 to 10% of bone marrow plasma cells have a clonal dominance of a light chain isotype on immunohistochemical staining. These light chains are deposited in tissues to form amyloid. Free monoclonal light chains (Bence Jones proteins) of the lambda and kappa type are also excreted in the urine. The finding of a monoclonal protein by serum and urine electrophoresis and immunofixation necessitates a bone marrow biopsy to confirm a plasma cell dyscrasia. (4) Amyloidosis should always be considered in a patient with plasma cell dyscrasia and multiorgan failure. Tissue diagnosis for amyloidosis is made by demonstration of amyloid protein on Congo red stain, where it shows green birefringence under a polarizing microscope. Tissue can be obtained from dysfunctional organs such as kidney, nerve or clinically uninvolved organs such as subcutaneous fat, minor salivary glands or rectal mucosa.

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Cardiac involvement is both more severe and more frequent in patients with primary amyloidosis, and is invariably fatal. (6) Amyloid can infiltrate the ventricular myocardium, conducting system, intramyocardial or epicardial coronary arteries, heart valves and pericardium. (7) Syncope is not uncommon and the mechanism is often multifactorial, resulting from a combination of tachybrady arrhythmia and autonomic dysfunction with associated postural hypotension. (8) Diastolic dysfunction is the earliest and most common abnormality. Symptomatic conduction system disease requiring a pacemaker and presence of hypertrophic cardiomyopathy, as seen in our patient, is rare. (9,10) Hypertrophic cardiomyopathy may have also been responsible for syncope in our patient. Clinical clues to the presence of amyloid heart disease in our patient were severe diastolic heart failure with normal systolic function and ECG findings of low voltage complexes, with development of complete AV block during hospitalization. Atrial fibrillation or a pseudoinfarct pattern may also be seen on ECG in patients with cardiac involvement. For tissue diagnosis, abdominal fat aspirate is easy to obtain and is positive in 80% of patients when stained with Congo red. (2) Endomyocardial biopsy, though invasiye, is indicated in patients with suspected cardiac amyloidosis and unexplained diastolic heart failure, especially when extracardiac tissue is negative for amyloid. (11,12) Hepatomegaly was also seen in our patient and may occur due to infiltration or passive congestion. Firm, nonpulsatile hepatomegaly with increased alkaline phosphatase, as seen in our patient, suggests an infiltrative disease like amyloid.

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Treatment is usually ineffective and generally consists of supportive measures. Congestive heart failure may initially respond to diuretics. Calcium channel blockers and beta blockers are relatively contraindicated, as is digoxin, which may cause toxicity at therapeutic levels. (13,14,15) Chemotherapy with melphalan and prednisone has been shown to be effective in patients with primary amyloidosis. (16) However, those with cardiac involvement have a very short survival and few receive sufficient therapy to influence survival. (5) Heart transplantation has not been routinely performed in patients with amyloid cardiomyopathy because of the frequently severe extracardiac amyloid deposition and possible recurrence in the transplanted heart. (17) Role of autologous stem cell transplantation is yet to be determined. The mean survival after cardiac involvement is 4 to 6 months in primary amyloidosis, although generally it is much longer in other types of amyloidosis. (5)

Conclusion

The clinical presentation of amyloid cardiomyopathy is varied and includes heart failure, brady or tachyarrhythmias, syncope, angina and rarely, features of hypertrophic cardiomyopathy, sudden cardiac death and symptomatic conduction system disease.

Endomyocardial biopsy is diagnostic and should be considered in selected patients with unexplained diastolic heart failure and evidence of multiorgan involvement, especially when extracardiac tissue is negative for amyloid.

References

1. Kyle RA, Linos A, Beard CM, et al. Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989. Blood 1992;79:1817-1822.

2. Gertz MA, Lacy MQ, Dispenzieri A. Amyloidosis: recognition, confirmation, prognosis, and therapy. Mayo Clin Proc 1999;74:490-494.

3. Rocken C, Schwotzer EB, Linke RP, et al. The classification of amyloid deposits in clinicopathological practice. Histopathology 1996;29:325-335.

4. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Eng J Med 1997;337:898-909.

5. Gertz MA, Kyle RA. Amyloidosis: prognosis and treatment. Semin Arthritis Rheum 1994;24:124-138.

6. Dubrey SW, Skinner M, LaValley M, et al. Familial and primary (AL) cardiac amyloidosis: echocardiographically similar diseases with distinctly different clinical outcomes. Heart 1997;78:74-82.

7. Smith TJ, Kyle RA. Clinical significance of histopathologic patterns of cardiac amyloidosis. Mayo Clin Proc 1984;59:547-555.

8. Chamarthi B, Dubrey SW, Cha K, et al. Features and prognosis of exertional syncope in light-chain associated AL cardiac amyloidosis. Am J Cardiol 1997;80:1242-1245.

9. Mathew V, Olson LJ, Gertz MA, et al. Symptomatic conduction system disease in cardiac amyloidosis. Am J Cardiol 1997;80:1491.

10. Sedlis SP, Saffitz JE, Schwob VS, et al. Cardiac amyloidosis simulating hypertrophic cardiomyopathy. Am J Cardiol 1984;53:969-970.

11. Pellikka PA, Holmes DR Jr, Edwards WD, et al. Endomyocardial biopsy in 30 patients with primary amyloidosis and suspected cardiac involvement. Arch. Intern Med 1988;148:662-666.

12. Arbustini E, Merlini G, Gavazzi A, et al. Cardiac immunocyte-derived (AL) amyloidosis: an endomyocardial biopsy study in 11 patients. Am Heart J 1995;130:528-536.

13. Gertz MA, Falk RH, Skinner M, et al. Worsening of congestive heart failure in amyloid heart disease treated by calcium channel-blocking agents. Am J Cardiol 1985;55:1645.

14. Pollak A, Falk RH. Left ventricular systolic dysfunction precipitated by verapamil in cardiac amyloidosis. Chest 1993;104:618-620.

15. Rubinow A, Skinner M, Cohen AS. Digoxin sensitivity in amyloid cardiomyopathy. Circulation 1981;63:1285-1288.

16. Kyle RA, Gertz MA, Greipp PR, et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Eng J Med 1997;336:1202-1207.

17. Hall R, Hawkins PN. Cardiac transplantation for AL amyloidosis. BMJ 1994;309:1135-1137.

Praveen Garg, MD, Ruchi Gupta, MD, David H. Hsi, MD, Lucy A. Sheils, MD, Michael R. DiSalle, MD, and Timothy J. Woodlock, MD

From the Departments of Medicine and Hematology/Oncology and the Division of Cardiology; Unity Health System, Unity Hospital, and the Department of Pathology, Rochester General Hospital, Rochester, NY.

Reprint requests to Praveen Garg, MD, 9645 Old Baymeadows Road, Apartment 726, Jacksonville, FL 32256. Email: [e-mail]

Accepted June 27, 2006.

RELATED ARTICLE: Key Points

* Amyloid cardiomyopathy can present as heart failure, syncope, arrhythmias or angina.

* Hypertrophic cardiomyopathy and advanced symptomatic conduction system disease are less commonly seen in cardiac amyloidosis.

* Cardiac involvement is more common and more severe in primary amyloidosis.

* Cardiac biopsy is an important diagnostic tool in patients with symptoms suggestive of cardiac amyloidosis, especially when extracardiac tissue is negative for amyloid.