Cardiac Amyloidosis

Updated: Mar 21, 2017
  • Author: Gyanendra K Sharma, MD, FACC, FASE; Chief Editor: Richard A Lange, MD, MBA  more...
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Overview

Background

Cardiac amyloidosis is a clinical disorder caused by extracellular deposition of insoluble fibrils (approximately 7.5-10 nm wide) with beta-pleated sheet configuration. [1] The protein misfolding abnormalities result in amyloid fibrils and may manifest as primary, secondary, or familial amyloidosis. Amyloid deposition can occur in multiple organs (eg, heart, liver, kidney, skin, eyes, lungs, nervous system) resulting in a variety of clinical manifestations. [2] Cardiac involvement is a progressive disorder resulting in early death due to congestive heart failure (CHF) and arrhythmias. Cardiac involvement can occur as part of a systemic disease or as a localized phenomenon. [3, 4]

Educating patients about dietary restrictions and medications is useful. Education about symptoms of heart failure and stroke would be helpful in guiding patients to seek early medical advice.

This article provides an overview of the primary systemic amyloidosis (AL) that predominantly affects the heart. [5]

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Pathophysiology

The characteristic abnormality in amyloidosis is an abnormal folding of a protein, rendering it to be insoluble. [6] These abnormalities may be a result of genetic mutations or excess formation. Various proteins may form amyloid fibrils; light chain amyloidosis (AL) is the most common type of systemic amyloidosis that results from the proliferation of plasma cells in the bone marrow. The plasma cell burden in AL is about 5-10% and is a marker of poor prognosis. [7, 8] Lambda light chains are 3 times more likely involved than kappa chains.

Most cases of AL are associated with a benign monoclonal gammopathy. Only rarely is AL seen in patients with multiple myeloma, lymphoma, or macroglobulinemia. Amyloid deposition in the tissues causes disruption of architecture, induces oxidant stress, and results in organ dysfunction. Multiorgan involvement is common. Cardiac involvement is most common in the AL variety but is also seen in secondary, hereditary, and senile amyloidosis.

Cardiac amyloid deposition is most common in the myocardium but is also seen in the atria, pericardium, endocardium, and vasculature. The myocardium becomes thick (mean weight 500 g) with a rubbery consistency. [9] High-grade infiltration (>50%) of myocardium is most common in the AL variety, and 90% of cases have vascular involvement. [10] Epicardial vessels are typically spared, but microvascular involvement is common, resulting in tissue ischemia and infarction. [11, 12, 13] Resultant myocardial fibrosis adds to the myocardial dysfunction, causing heart failure and cardiac arrhythmias.

The ventricular cavities are typically normal in size, but the ventricles are stiff, which cause restrictive ventricular filling and biatrial enlargement. Pericardial involvement is common and leads to pericardial effusion. [14] Endocardial involvement may result in atrioventricular valve dysfunction. Intracardiac thrombosis is common and seen in about 33% cases in autopsy specimens. [15]  The thickening of the left heart valves is common in patients with AL, is associated with advanced age, and increases all-cause mortality. [16] These patients have poor functional class and worse systolic and diastolic function. [16]

Conduction system abnormalities (ie, bundle branch block and atrioventricular block) are frequent in amyloidosis. In a small series, severe sinoatrial node fibrosis was seen in 30% cases. [17]

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Etiology

Primary amyloidosis (AL) is a type of plasma cell dyscrasia and is the most common type involving the heart.

Secondary systemic amyloidosis seen in chronic inflammatory conditions rarely involves the heart. Organ dysfunction is usually reversible with resolution of the underlying inflammatory disorder.

Senile amyloidosis is common in people over 80 years of age and has a better prognosis.

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Epidemiology

United States statistics

Systemic amyloidosis (AL) is a rare disorder, and it is difficult to estimate the exact incidence due to changing diagnostic criteria. In Olmsted County, Minnesota, only 21 cases were diagnosed from Jan 1950 to Dec 1989. In this first population-based study, the incidence of AL was approximately 8.9 per million person years. [18] In the United States, approximately 2000-2500 cases of AL are diagnosed annually. [19]

International statistics

Amyloidosis is reported as a cause of death in 1 in 1000 of the British population.

Race, sex-, and age-related differences in incidence

AL is uncommon in non-white individuals and persons younger than 40 years, [20]  and it affects men and women equally. Senile amyloidosis, in which wild-type transthyretin (TTR) accumulates in tissue and leads to the development of cardiac dysfunction, [21] is 3 times more common in elderly black patients compared to white patients (8.2% vs 2.7%, respectively). [22] Hereditary cardiac amyloidosis resulting from a mutation in TTR (>100 TTR variants [23] ) is more common in black individuals than white persons; 23% of the patients have this variant. [24]

AL type is usually seen in persons older than age 50 years. Although unusual, it can occur as early as the third decade of life. Late onset amyloidosis (senile) is seen in elderly patients and has a better prognosis than primary amyloidosis.

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Prognosis

In general, cardiac involvement is a marker of poor prognosis. [25, 26] Therefore, any clinical, laboratory or imaging abnormality that suggests increased cardiac involvement will be indicative of a worse prognosis. No consensus has been reached about a single most important prognostic factor. The factors associated with a poor prognosis include the following:

  • Syncope
  • Complex arrhythmia
  • Degree of left ventricular (LV) hypertrophy (More = worse prognosis)
  • Low LV ejection fraction (LVEF)
  • Restrictive hemodynamic
  • Right ventricular dilatation
  • Pulmonary hypertension
  • Low voltage on electrocardiography (ECG)
  • High brain natriuretic peptide (BNP) levels
  • High troponin levels
  • T1 kinetics on gadolinium-enhanced magnetic resonance imaging (MRI) (to demonstrate extent of myocardial involvement)

Morbidity/mortality

Amyloidosis has a poor prognosis, and the median survival without treatment is only 13 months. Cardiac involvement has the worst prognosis and results in death in about 6 months after onset of congestive heart failure. Only 5% of the patients with primary amyloidosis survive beyond 10 years. [27] Among 82 patients with cardiac amyloidosis, New York Heart Association (NYHA) class and right ventricular systolic dysfunction (tricuspid annular plane systolic excursion [TAPSE] <14 mm) independently predicted major adverse cardiac events. [28]

Complications

Complications include the following:

  • Atrial fibrillation
  • Congestive heart failure
  • Embolism and stroke
  • Ventricular arrhythmias
  • Heart block requiring pacemaker implantation
  • Pericardial tamponade
  • Death
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