JS, a 45-year-old Caucasian man, was referred to the Mayo Clinic in consultation for progressive congestive heart failure (CHF) of unclear etiology. A year prior to his symptoms, he had been a healthy and active person playing tennis 4 times a week and leading a very busy life as a farmer in the Midwest and as a father of 3 young children with no medical problems except for well-controlled essential hypertension (HTN). Six to eight months prior to presentation he experienced a decline in exercise capacity and gradually gave up tennis. Three months prior to presentation he developed dyspnea on moderate exertion and intermittent swelling of his legs. Medical evaluation included normal renal function, blood counts, and pulmonary computed tomography (CT) angiogram. Nuclear medicine cardiac stress test was normal; pulmonary function tests indicated a mild reversible obstructive defect and 2D echocardiogram revealed mildly thickened left ventricle with an ejection fraction of 60% and borderline diastolic dysfunction. Treatment with bronchodilators was empirically started for a provisional diagnosis of atypical asthma. His symptoms progressed rather rapidly over the course of 2 to 3 weeks and he underwent a coronary angiogram, which demonstrated normal coronary arteries. At his evaluation at Mayo Clinic he was found to be in New York Heart Association (NYHA) class III CHF. Based on the review of his electrocardiograph (ECG) and echocardiogram a diagnosis of infiltrative cardiomyopathy was suspected and further work demonstrated an immunoglobulin lambda light chain gammopathy in the serum with 8% lambda restricted plasma cells in the bone marrow. Congo red staining of the bone marrow and abdominal fat aspirate was positive for extracellular amorphous material that demonstrated apple green birefringence under polarized microscope. He was diagnosed with immunoglobulin lambda light chain amyloidosis (AL) with stage IV cardiac disease.

HISTORY AND INTRODUCTION

Matthias Schleiden, a German botanist, first used the term amyloid in 1838 to describe a normal constituent of plants.¹ In 1858, Rudolph Virchow described amyloid deposits in spleen that stained blue with iodine and sulfuric acid, similar to the chemical reaction markers of starch. Virchow concluded that the substance was composed of starch and used the word amyloid to describe it.² In 1859, Friedreich, Nikolau, and Kekule recognized that the waxy spleen described by Virchow did not contain any starchlike substances and that the deposits probably were derived from modified proteins.³

Amyloidosis, as understood today, is a unique, yet remarkably heterogeneous group of diseases characterized by the deposition of misfolded protein precursors in a beta-pleated sheet configuration in the extracellular space in various tissues. This characteristically conserved structure renders the amyloid fibrils of different origins resistant to proteolytic cleavage under physiological condition and forms the basis of characteristic staining of amyloid fibrils by Congo red, thioflavin T, and Alcian blue, a feature essential for establishing the diagnosis on histopathologic examination (Figure 11-1).⁴ Widely divergent precursor proteins (more than 30 currently known) can cause amyloidosis and can lead to diseases belonging to infectious (prion disease), neoplastic (immunoglobulin light chain systemic amyloidosis), neurodegenerative (Alzheimer disease), and hereditary (familial amyloidosis) groups of disorders (Figure 11-2).⁵ Clinically, amyloidosis manifests as localized or systemic disease with disease manifestations resulting from type and extent of organ involvement. The heart is a frequently involved organ in systemic amyloidosis and amyloid cardiomyopathy is the most common cause of death in these patients.

The heart is one of the most common organs involved in amyloidosis. With the exception of localized atrial amyloidosis derived from natriuretic peptide, cardiac amyloidosis almost always indicates systemic disease.

Amyloidogenic proteins can involve any anatomical region of the heart, including the myocardium (atrial, ventricular, and interventricular septum), valvular tissue, the perivascular space around and within small blood vessels, and the conduction system. Gross pathologic examination of the heart infiltrated with amyloidosis reveals characteristic thickening of all 4 cardiac chambers and interventricular septum (Figure 11-3). Microscopically, amyloid deposition is seen in the extracellular space, which results in separation and distortion of myocardial cells and electromechanical dissociation. Myocardial damage results from physical deposition of the amyloid material and from direct cellular cytotoxicity of the circulating amyloidogenic protein. No histologic pattern is specific for a particular form of amyloid cardiomyopathy and different amyloid proteins can result in similar pathological findings. Cardiac involvement can occur at any stage of the disease and may be the initial presentation, incidentally discovered during evaluation of other symptoms, or discovered on postmortem examination.⁶

COMMON TYPES OF AMYLOID CARDIOMYOPATHIES

All forms of cardiac amyloidosis can result in similar cardiac presentations; however, they progress at different rates and important clinical clues can help to differentiate them (Table 11-1).

Immunoglobulin Light Chain Amyloid Cardiomyopathy

Immunoglobulin light chain amyloidosis (primary systemic amyloidosis or AL), the most common systemic amyloidosis in the United States and western Europe, is a plasma cell dyscrasia, where transformed plasma cells in the bone marrow produce amyloidogenic light chains. With 2500 new cases each year, AL is an orphan disease.⁷ Most commonly, AL occurs de novo, but in a minority of patients it can evolve from preexisting multiple myeloma (the most common plasma cell malignancy) and non-Hodgkin lymphomas such as Waldenström macroglobulinemia. Cardiac involvement is often very advanced and is seen in half of the cases.⁸ AL cardiomyopathy presents with restrictive physiology and patients frequently present with CHF with a nondilated, thickened left ventricle on echocardiogram. Peripheral edema from right heart dysfunction is a very common feature. In advanced stage, ascites, hepatomegaly, and jugular venous distension are common. Atrial dysrhythmias are common and can be complicated by mural atrial thrombus; embolic stroke may be the first presentation of the disease.⁹ Ventricular arrhythmias also occur, but are not a common presenting feature, possibly because patients succumb to sudden cardiac arrest before the diagnosis is established. Angina pectoris from myocardial ischemia from amyloid infiltration of small vessel walls can, at times, be very frustrating as cardiac catheterization reveals normal epicardial coronaries.¹⁰ Multiorgan involvement is very commonly seen in AL patients and kidney, peripheral nerves, autonomic nerves, and the liver and GI tract are frequent extracardiac sites of disease (Table 11-2).⁸ Soft tissue infiltration can give rise to rare but classic clinical exam findings such as shoulder pad sign, muscle infiltration, macroglossia, and raccoon eyes (Figure 11-4, Figure 11-5, Figure 11-6). Small- and medium-sized blood vessel ischemia from involvement by amyloid can cause symptoms of jaw claudication and patients can be misdiagnosed as having giant cell arteritis. Mucocutaneous bleeding due to failure of hemostasis resulting from altered blood vessel wall integrity and acquired deficiency of circulating coagulation factors, in particular factor X, can be a prominent presenting feature.¹¹ AL cardiomyopathy is the most aggressive form of amyloid heart disease and is the sole reason for the poor prognosis associated with amyloidosis.

Senile Systemic Amyloid (Wild-Type ATTR) Cardiomyopathy

Senile systemic amyloidosis (SSA) is caused by systemic deposition of amyloid fibrils derived from a native (wild-type) circulating plasma protein transthyretin (TTR).¹² With the increasing availability and more common use of echocardiography, the incidence of SSA is expected to increase significantly in coming years. Interestingly, for unclear reasons, SSA is almost exclusively seen in men. Autopsy series have commonly identified wild-type TTR amyloid deposits in the hearts of older men with some series reporting an incidence as high as 25% in subjects 80 years of age or older. Many patients with SSA may not develop clinically significant end-organ damage, despite histological or radiological evidence of amyloidosis. When clinically apparent, SSA typically presents with progressive decline in energy and symptoms of CHF, often with normal systolic function.¹³ The diagnosis is often delayed in these patients until they have multiple hospitalizations for CHF. Increased myocardial thickness is often blamed on systemic HTN, a very prevalent condition in this age group. Almost half of SSA patients may have symptomatic median neuropathy presenting as carpal tunnel syndrome. This is in contrast to familial TTR amyloidosis, where manifestations of peripheral neuropathy and gastrointestinal (GI) involvement are frequently seen in addition to cardiomyopathy.

Familial Amyloid Cardiomyopathy

Familial/hereditary amyloidosis results from mutant misfolded forms of several proteins such as TTR, apolipoprotein, fibrinogen, and leukocyte chemotactic factor 2, among others.¹⁴ With more than 100 pathogenic mutations described in the TTR gene on chromosome 18, amyloidosis of TTR type (familial-ATTR) is the most common familial amyloid cardiomyopathy.¹⁵ In familial ATTR, the specific TTR mutant determines the clinical presentation, but peripheral nerves and the heart are the most common sites of involvement. Autonomic dysfunction and GI tract involvement can be severe and can cause significant malabsorption and protein-losing enteropathy.^16,17 One particular variant allele, Val122Ile, is found in 1 out of every 25 African Americans (carrier rate of 4%) and is a frequently overlooked cause of cardiomyopathy in African American men.¹⁸ Despite the high prevalence of this variant, the overall prevalence and incidence of familial amyloid cardiomyopathy in African Americans remains low, possibly owing to failure to recognize the etiology of the CHF. In Caucasians, the Val30Met mutant is the most commonly reported variant with high penetrance presenting as early onset (30-40 years of age) peripheral neuropathy and relatively late onset (50-60 years of age) cardiomyopathy.¹⁹

In addition to TTR, mutant fibrinogen A-α and apoA-I and A-II can involve the heart; however, renal involvement predominates in these very rare forms of non-TTR familial amyloidoses.^20,21

Secondary Systemic Amyloid Cardiomyopathy

Secondary systemic (AA) amyloidosis results from excessive production and misfolding of the acute-phase reactant serum amyloid A protein. AA is a very common form of systemic amyloidosis in developing countries and in the Mediterranean basin due to a high prevalence of chronic infections (chronic osteomyelitis and mycobacterial infections) and auto-inflammatory disorders, such as familial periodic fever syndromes.²² In the United States and Western Europe, it is rare and usually results from unrecognized or untreated chronic autoimmune disorders such as rheumatoid arthritis and inflammatory bowel disease. Nephrotic syndrome is the most common presentation but involvement of GI and hepatobiliary systems leading to malabsorption syndrome and/or hepatosplenomegaly can be a presenting feature. Involvement of endocrine organs, such as the thyroid and adrenal gland, can be seen and may result in adrenal insufficiency.²³ Cardiac involvement in AA is rare and even if severe by echocardiogram, seldom results in clinically significant cardiomyopathy.

Isolated Atrial Amyloidosis

Isolated atrial amyloidosis (IAA) is a relatively recently recognized entity and results from atrial deposits of atrial natriuretic peptide.²⁴ Unlike other cardiac amyloidoses, this is almost always localized to the atria and can be diagnosed only on histologic examination of atrial tissue. The incidence of IAA increases with age and appears to be more common in patients with atrial diseases such as rheumatic heart disease. Intriguingly, recent studies have reported a very high incidence of IAA on the histopathologic examination of the explanted hearts from patients with dilated and hypertrophic cardiomyopathies and raise important questions about the possible role of IAA in the pathogenesis of these conditions.²⁵

DIAGNOSIS OF AMYLOID CARDIOMYOPATHY

Like many rare diseases, amyloid cardiomyopathy is very often diagnosed at late stages. This is especially true in AL where the rapid disease course coupled with a lack of specificity in the patient’s symptoms results in delayed diagnosis and poor outcomes. Amyloidosis should be included in the differential diagnosis of all patients presenting with proteinuria; unexplained CHF (especially diastolic heart failure); new-onset peripheral neuropathy, especially with bilateral carpal tunnel syndrome; new-onset autonomic dysfunction; otherwise unexplained weight loss; and hepatomegaly in the absence of known liver disease (Table 11-2).

Patients suspected of amyloidosis should undergo a thorough physical examination with particular attention to signs of volume overload, orthostatic hypotension, macroglossia, amyloid purpura, hepatosplenomegaly, peripheral edema, and sensory neuropathy. Initial laboratory studies should include complete blood counts, renal and liver function profiles, serum electrolytes, coagulation profile, serum protein electrophoresis with immunofixation, 24-hour urine protein electrophoresis, immunofixation and nephelometric measurement of serum immunoglobulin-free light chains (Table 11-3).²⁶ The common abnormalities noted in these initial studies in amyloidosis, particularly in AL patients, are summarized in (Table 11-4). The diagnosis of amyloidosis must be confirmed by histological examination of an optimal biopsy. Sites for the biopsy include abdominal wall subcutaneous fatty tissue (fat pad aspirate, fat pad biopsy), vascular submucosa of the GI tract (minor salivary glands in mouth, labial soft tissue, rectal biopsy), or bone marrow biopsy. In our experience, at the Mayo Clinic, a combination of bone marrow biopsy and abdominal subcutaneous fat pad aspirate yields the diagnosis of AL amyloidosis in 85% of patients.⁸