Amyloid Heart Disease

Abstract

Amyloidosis comprises a unique group of diseases that share in common the extracellular deposition of insoluble fibrillar proteins in organs and tissues. Cardiovascular amyloidosis can be primary, a part of systemic amyloidosis, or a result of chronic systemic diseases elsewhere in the body. The most common presentations are congestive heart failure—mainly a restrictive infiltrative pattern—and conduction system disturbances. Recent developments in imaging techniques and extracardiac tissue sampling have minimized the need for invasive endomyocardial biopsy for amyloidosis. Despite advances in treatment, the prognosis for patients with amyloidosis is still poor and depends on the underlying disease type. Herein, we present new insights and recent advances in cardiovascular amyloidosis.

Amylon and amylum are the Greek and Latin words for plant amylaceous material, which was first described in 1838 by the German botanist Matthias Schleiden.¹ In 1842, Rokitanski used the term amyloid to describe the enlarged livers and spleens of patients with chronic diseases.² In 1854, Virchow was the first to use iodine stain to study cerebral amylacea under the microscope; he described its appearance as that of starch or cellulose.³ Later, several different proteins were attributed to systemic amyloidosis.³ Herein, we discuss different types of amyloidosis, diagnosis, treatment, and prognosis.

Pathogenesis and Classification of Amyloidosis

The pathogenesis of amyloid fibrils is related to amino acid substitutions in prefibrillar proteins and to protein instability. Protein instability can be provoked by different chemical, electrical, and mechanical stimuli and precipitate out of the serum into the extracellular matrix as amyloid.⁴ Five different types of amyloidosis have been described according to the underlying disease:

1. Immunoglobulin Amyloidosis. Immunoglobulin (AL) amyloidosis, found in all cases where the building block of the amyloid fibril is an immunoglobulin light chain protein, includes primary amyloidosis, multiple myeloma, and other plasma cell dyscrasias such as B-cell lymphoma and Waldenström macroglobulinemia.⁵ Primary amyloidosis is a plasma cell disorder in which approximately 5% to 10% of bone marrow plasma cells have clonal dominance of a light chain isotype.⁴ The number of plasma cells and the degree of clonality and marrow infiltration of those cells have been inversely related to survival.⁶ Generally, immunoglobulin variable region genes influence clinical presentation and outcome in light chain-associated amyloidosis, with a predominance of lambda versus kappa free light chains (3:1) in primary AL amyloidosis (Figs. 1 and 2). In comparison, other plasma cell dyscrasias, such as multiple myeloma, usually have a lambda-to-kappa ratio of 1:2. The light chain isotype in primary amyloidosis does not generally affect survival.⁷ Immunoglobulin amyloidosis constitutes about 85% of all newly diagnosed cases of amyloidosis. Common presenting features include nephrotic syndrome, sensorimotor peripheral neuropathy, hepatomegaly, splenomegaly, and, less often, macroglossia.^8,9

2. Familial Amyloidosis. Familial amyloidosis, or hereditary amyloidosis, is less common than primary amyloidosis and is caused by an autosomal-dominant mutation, most frequently in the transthyretin gene. More than 70 transthyretin mutations have been identified to date, although mutations in other proteins, such as fibrinogen Aa, lysozyme, apolipoprotein A-I, and gelsolin, have been also reported.⁵ Common features include peripheral neuropathy, renal impairment, autonomic dysfunction with mainly gastrointestinal symptoms, and cardiomyopathy.¹⁰ Macroglossia does not occur, and renal involvement is less prevalent than it is in AL amyloidosis.

3. Senile Systemic Amyloidosis. Senile systemic amyloidosis (SSA) affects approximately 25% of patients over the age of 80 and is derived from normal transthyretin.¹¹ This type of amyloidosis mainly involves the atria (91%), and less often is isolated in the aorta or involves the entire heart.^12,13 Senile cardiac amyloidosis is not always a benign condition and can result in heart failure, atrial fibrillation, and other conduction disturbances.^14,15

4. Secondary Amyloidosis. Secondary amyloidosis is characterized by reactive amyloid fibrils, which are acute-phase reactants produced in response to systemic inflammation such as tuberculosis, leprosy, rheumatoid arthritis, familial Mediterranean fever, inflammatory bowel syndrome, chronic lung diseases, and chronic infections.¹⁰

5. Hemodialysis-Associated Amyloidosis. This type of systemic amyloidosis occurs in patients with chronic renal failure who are on hemodialysis and is characterized by the deposition of β₂-microglobulin amyloid fibril subunit (Aβ₂M) in bones and joints.⁹

Fig. 1 Photomicrograph of a gastric biopsy specimen of a patient with primary amyloidosis shows plasma cells with expression of kappa light chain (Immunoperoxidase, orig. ×400).

Fig. 2 Photomicrograph of a gastric biopsy specimen of a patient with primary amyloidosis shows plasma cells lacking expression of lambda light chain (Immunoperoxidase, orig. ×400).

Cardiovascular Manifestations of Amyloidosis

Restrictive cardiomyopathy is the main finding in cardiac amyloidosis and results from the replacement of normal myocardial contractile elements by infiltration and interstitial deposits of amyloid, leading to alterations in cellular metabolism, calcium transport, receptor regulation, and cellular edema. Injury can also occur from circulating light chains in the absence of amyloid fibril formation.¹⁶ Amyloid myocardium becomes firm, rubbery, and noncompliant.¹⁷ This process can also involve the cardiac conduction system and cause different types of heart block and arrhythmias. Amyloid pulmonary vasculature, causing pulmonary hypertension and cor pulmonale, also has been described.¹⁸

Immunoglobulin Amyloidosis. Cardiac involvement is most common in AL amyloidosis, with specific avidity of certain variable genes of the clonal B lymphocyte cells, especially variable (V) lambda II light chain, to cardiac tissues.⁷ About 50% of patients experience some cardiac manifestation related to their disease, and at least 25% have congestive heart failure. Most of these patients die of either congestive cardiac failure or arrhythmia.⁸ Early findings include abnormal myocardial relaxation (Fig. 3) that gradually advances to restrictive patterns (Fig. 4), with signs and symptoms of right-sided heart failure: elevated jugular venous pressure, right-sided gallop, hepatomegaly, and peripheral edema.⁴ Low voltage in the limb leads or poor R wave progression in the precordial leads is the hallmark electrocardiographic (ECG) finding (Fig. 5). The infarct pattern can be found in the presence or absence of obstructive coronary disease, due to amyloid deposition in the microcirculation and the smaller intramyocardial arteries.⁸ Atrial fibrillation and conduction abnormalities are also common. Electrophysiologic abnormalities were detected in 25 patients with biopsy-proven AL amyloidosis in the form of abnormal infra-His conduction times; infra-His prolongation was shown to be an independent predictor of sudden cardiac death.¹⁹ Fibrosis of the sinoatrial and atrioventricular nodes has been correlated with the severity of amyloid deposition elsewhere in the heart and may require pacemaker placement. At least two thirds of the patients with AL amyloidosis have echocardiographic abnormalities, such as abnormal global or regional myocardial relaxation (in the early stage), thickened ventricular walls, abnormal myocardial texture (granular sparkling), atrial dilation, valvular thickening or regurgitation, pericardial effusion (Fig. 6), and a restrictive pattern (late stage) with elevated filling pressures.⁸

Fig. 3 Doppler echocardiographic study of a patient in an early stage of cardiac amyloidosis reveals an impaired relaxation pattern with reversal of E/A ratio.

Fig. 4 Doppler echocardiographic study of a patient in a late stage of cardiac amyloidosis reveals a severe restrictive pattern.

Fig. 5 Electrocardiogram of a patient with cardiac amyloidosis shows a diffuse low-voltage QRS complex.

Fig. 6 Echocardiogram of a patient with immunoglobulin (AL) amyloidosis shows thickened ventricular and atrial walls, abnormal myocardial texture, atrial dilatation, and pericardial effusion.

LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle

Familial or Hereditary Amyloidosis. Cardiac involvement is not as common in familial amyloidosis as in the AL type, and the prognosis is often more favorable.²⁰ The pattern of myocardial involvement varies according to the specific mutation; for example, patients with the Met 30 transthyretin mutation may have only conduction-system abnormalities and often require pacemaker implantation. Patients with the Ala 60 variant have echocardiographic results similar to those of patients with AL amyloidosis but have a lower incidence of heart failure and a better prognosis.⁴ In addition, different kindred groups have been shown to have varying degrees of susceptibility to cardiac amyloid deposition, while other mutational groups are not affected by cardiac involvement.⁵ Substitution of isoleucine for valine at position 122 of the transthyretin gene has been reported in 1 family.²¹

Senile Systemic Amyloidosis. Cardiac involvement in SSA, once thought to be a benign condition and an incidental postmortem finding, has recently been recognized as a cause of severe cardiac dysfunction—mainly congestive heart failure and cardiac death.^22,23 Substitution of isoleucine for valine at position 122 of the transthyretin gene has been linked to several of these cases.²¹ At the Mayo clinic, 237 octogenarian hearts from patients 90 to 105 years old were studied at autopsy; 65% had evidence of senile amyloid deposition, and 32% had extensive ventricular deposition.²⁴ Biophysical analysis of normal transthyretin has suggested that heat-induced conformational changes in transthyretin structure may allow the assembly of prefibrils at physiologic pH.²⁵ Another group²⁶ recently suggested a close relationship between amyloid deposits and the basement membranes of myocardial cells, where heparin sulfate—or potentially another molecule located in the basement membrane—may interact with transthyretin and enable it to accumulate in concentrations sufficient to allow fibril formation and deposition.²⁶

Patients with senile cardiac amyloidosis usually present with congestive heart failure months to several years before the cause is discovered.¹⁵ They may have atrial fibrillation or conduction abnormalities and may require pacemaker implantation. Other ECG findings include low-voltage QRS complexes and pseudoinfarction patterns without evidence of ischemia.

Secondary Amyloidosis

Cardiac disease in secondary amyloidosis is less common than it is in other types of amyloidosis, but it may manifest as significant ventricular wall thickness and wall motion abnormalities on echocardiography.²⁷

Diagnosis

Cardiac amyloidosis should be suspected in any patient who presents with restrictive cardiomyopathy, prominent signs of right-sided heart failure, or left-sided heart failure in the absence of ischemic disease—particularly in patients with known systemic amyloidosis.²⁸

If the combined clinical and echocardiographic picture suggests amyloidosis, then immunocharacterization of the underlying amyloid protein can be obtained less invasively from extracardiac tissue sites.²⁹ However, endomyocardial biopsy remains the definitive diagnostic method for cardiac amyloidosis.³⁰

The pattern of amyloid infiltration is characteristic upon staining with hematoxylin and eosin (Fig. 7), methyl violet, crystal violet, and thioflavin; however, Congo red staining will produce an apple-green birefringence under polarized light and is the most specific stain for amyloid (Fig. 8). The characteristic fibrillar pattern of the amyloid deposits can be seen by electron microscopy (Fig. 9). Immunohistochemical staining can then be used to determine the type of amyloid deposit.³⁰ In systemic amyloid deposition, the underlying disease process can be determined in most cases by staining tissue samples with antibodies directed against the amyloid fibril proteins: amyloid associate (AA), amyloid kappa (Aκ), amyloid lambda (Aλ), Aβ₂M, and amyloid transthyretin (ATTR), or by using electron microscopy to search for amyloid proteins in tissue samples. Then the specific type of protein can be identified using immunoelectron microscopy with staining for Aκ, Aλ (Figs. 1 and 2), serum amyloid A, ATTR, and apolipoprotein A-I.²⁹

Fig. 7 Photomicrograph of an endomyocardial biopsy specimen in a patient with immunoglobulin amyloidosis exhibits interstitial eosinophilic amyloid deposits (arrow) (H & E, orig. ×400).

Fig. 8 Photomicrograph of endomyocardial biopsy specimen in a patient with immunoglobulin amyloidosis exhibits the metachromatic appearance of amyloid (AL) (Congo red stain, orig. ×400).

Fig. 9 Electron micrograph of primary amyloidosis shows the characteristic amyloid fibrils (AL) (Lead citrate, orig. ×1500).

Echocardiography is a useful adjunct to tissue diagnosis. Increased myocardial echogenicity (granular sparkling) has been reported to have a sensitivity of 87% and a specificity of 81% for diagnosing cardiac amyloidosis; in the presence of increased atrial thickness, the specificity can reach 100%.³¹ If amyloid deposition is found in noncardiac biopsy sites along with a characteristic appearance on echocardiography, an endomyocardial biopsy is usually not necessary. These sites include the tongue, subcutaneous fat pads, kidneys, bone marrow, gastric mucosa, and, less commonly, rectal mucosa. Combining a subcutaneous fat pad biopsy and Congo red staining of bone marrow has yielded a tissue diagnosis in 90% of patients with amyloidosis.²⁸

Electrocardiography shows the characteristic feature of low QRS voltage in up to 50% of patients³² and, when coupled with the finding of increased ventricular wall thickness, should raise the suspicion of cardiac amyloidosis, since left ventricular hypertrophy due to other causes shows high QRS voltages.²⁷

Treatment and Prognosis

The treatment and prognosis of cardiac amyloidosis depends in part on the underlying disease process. Certain cardiac medications, such as digoxin, are contraindicated or should be used with extreme caution, because they are bound extracellularly by amyloid fibrils and may cause hypersensitivity and toxicity. Calcium channel blockers and β-blockers also can worsen left ventricular function because of their negative inotropic effects.^33,34 Angiotensin-converting enzyme inhibitors, long-acting nitrate, other vasodilators, and diuretics have been used carefully with varying responses. In the event of atrial fibrillation, ibutalide and amiodarone are effective antiarrhythmic drugs. A pacemaker may be required to treat symptomatic bradycardia and high-grade conduction-system disease. If a patient has atrial fibrillation, anticoagulation is required; otherwise, the benefits of anticoagulants in patients with this disease remain speculative.

Immunoglobulin Amyloidosis.

The prognosis for patients with AL amyloidosis is poor. The median survival rate is 13 months without treatment and can be extended to 17 months with cyclic oral melphalan and prednisone therapy.³⁵ Only 5% of patients survive longer than 10 years.³⁶

Cardiac involvement generally denotes a poor prognosis, regardless of the method of treatment. The median survival rate from the onset of congestive heart failure is only 6 months.³⁷ Syncope indicates a poor prognosis as well, and is often a precursor of sudden cardiac death.³⁸ Left ventricular wall thickness is inversely related to survival and is strongly correlated with the severity of congestive heart failure.³⁹ Right ventricular dilatation is associated with more severe cardiac involvement and a median survival of only 4 months.⁴⁰ One study⁴¹ showed that patients who had elevated levels of troponin I and T at diagnosis had a significantly shorter median survival time than did patients without troponin elevation. In addition, troponin elevation was a better predictor of survival than was symptomatic heart failure or 2-dimensional echocardiography.⁴¹

Recently, high-dose intravenous melphalan in combination with autologous peripheral blood stem-cell transplantation has been advocated for patients with AL amyloidosis by a group from Boston University.⁴² Of 701 patients screened, 312 patients underwent treatment. This approach resulted in significantly decreased end-organ dysfunction, 40% complete hematologic remission at 1 year, and improved median survival to 4.6 years, versus 1 year in the nontreatment group. Patients with cardiac involvement had a median survival of 1.6 years, versus 5 months for the untreated patients. However, 100 days after treatment, the peri-transplant mortality rate was still high, at 13%.⁴²

Cardiac transplantation is another but less favorable approach for cardiac amyloidosis. Worldwide, few patients have received a heart transplant for this condition, with variable survival (32–118 months). The immediate and early postoperative results are comparable to those in patients undergoing transplantation for other reasons. However, in the patients with amyloidosis, the survival rate begins to drop more rapidly 30 months after transplantation.⁴³ One post-transplant study showed that 5 of 8 patients with AL amyloidosis had evidence of allograft amyloid deposits as early as 5 months after transplantation. The 1- and 5-year survival rates in that study were 60% and 30%, which suggests that this method for AL amyloidosis remains a palliative measure.⁴⁴

Familial Amyloidosis

Since the abnormal protein in familial amyloidosis is mainly produced by the liver, liver transplantation is the most important and the only definitive therapeutic intervention for familial amyloidosis that results in improvement of end-organ function.⁴⁵ However, in some patients with substantial cardiac involvement before liver transplantation, the cardiac condition continues to worsen—as measured by echocardiographic left ventricular wall thickness and ejection fraction—in contrast to patients who had no cardiac disease before liver transplantation.⁴⁶ These findings have led to a very small number of combined liver and heart transplantations in cases of hereditary amyloidosis with cardiac involvement. Among patients who survived, there was no progression or recurrence of cardiac disease.⁴⁷

Senile Systemic Amyloidosis

Senile systemic amyloidosis with cardiac disease carries the most favorable prognosis, with a nearly 5-year median survival rate even in presence of heart failure.¹⁵ The congestive heart failure resulting from SSA may be more responsive to medical treatment than that resulting from other types of amyloidosis.¹³

Secondary Amyloidosis.

Cardiac involvement in secondary amyloidosis is not common but, when present, carries a poor prognosis. In 1 study of patients with rheumatic disease who were found to have secondary amyloidosis and cardiac involvement, the survival rate was 31% at 5 years.⁴⁸

Summary

Amyloidosis is a complex disease that can involve many organs and cause end-organ dysfunction. Cardiac involvement worsens the prognosis and may influence treatment strategies; therefore, all patients with known amyloidosis should be screened for cardiac amyloidosis even if they have no cardiac symptoms. Cardiac involvement should be suspected in patients with systemic amyloidosis who develop congestive heart failure and or conduction system abnormalities in the absence of notable coronary artery disease. Restrictive cardiomyopathy and prominent signs and symptoms of right-sided heart failure should raise the suspicion of cardiac amyloidosis. Endomyocardial biopsy is the best diagnostic tool, although a combination of characteristic ECG and echocardiographic findings and a positive extracardiac tissue biopsy may provide an alternative approach. The overall prognosis of cardiac amyloidosis is poor; however, recent advances in treatment, including chemotherapy, autologous stem-cell transplantation, and combined heart and liver transplantation, have offered increased survival and improvement in organ function. Anticipated advances and insights in molecular biology, genomes, imaging techniques, biochemical markers, and quantitative detection of amyloid proteins, along with new treatment strategies, offer hope for the future.