Cardiac amyloidosis overview
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Cardiac amyloidosis is a well-known progressive condition, which has been reported with varying incidence rates. It refers to extracellular deposition of light chains of some serum proteins, that assume a beta pleated structure. Myocardial involvement results in congestive heart failure and fatal arrhythmias and is the leading cause of death in patients with amyloidosis. Systemic amyloidosis of AL and TTR type is often associated with amyloid deposition in heart valves, in addition to blood vessels and myocardium. In this classical type of valvular amyloidosis, the deposits occur in previously unaltered valves. There is also another type of cardiac amyloidosis restricted entirely to the heart valves (surgically removed for chronic valvular disease) or only the atria (also called isolated atrial amyloidosis). This condition is heavily under-diagnosed because the thickening of ventricles from extracellular deposition of amyloid material in the heart is mostly attributed to chronic hypertension, which is also a feature of cardiac amyloidosis. Cardiac amyloidosis should be suspected in the following scenarios:
- Congestive heart failure and an increase in left ventricular wall thickness (> 12 mm) in the absence of hypertension or other causes of increased left ventricular mass
- Congestive heart failure and an increase in left ventricular wall thickness (> 12 mm) in the absence of hypertension or other causes of increased left ventricular mass in an African-American > 60 years old
- Congestive heart failure with preserved left ventricular ejection fraction fraction (HFPEF) in an individual > 60 years old
- Congestive heart failure in an individual (particularly an elderly male) with unexplained neuropathy, bilateral carpal tunnel syndrome without risk factors, atrial fibrillation
- Individuals with hyperenhancement on Cardiac Magnetic Resonance (CMR) or echogenicity on echocardiography
In 1639, Nicolaus Fontanus autopsied a young man who had ascites, jaundice, liver abscess, and splenomegaly and his report has been the first description of amyloidosis. There is no significant data regarding the historical perspective of amyloidosis throughout the 18th century. Rudolph Virchow and Weber are the prominent figures with substantial work on amyloidosis during the 19th century. In 1922, Bennhold introduced Congo Red staining of amyloid that remains the gold standard for diagnosis.
Cardiac amyloidosis can be classified based on the type of amyloid that infiltrates the heart. The types of amyloid that commonly deposit in the heart are immunoglobulin light chain (AL) and transthyretin (ATTR). These two types of amyloid can result in cardiac AL amyloidosis and cardiac transthyretin amyloidosis.
The characteristic feature of cardiac amyloidosis is abnormal deposition of abnormally folded light chains of several serum proteins, making them insoluble and leading to their accumulation in various organs. This abnormal folding of proteins is most commonly a result of genetic mutations or excessive formation. Involvement of cardiac muscle can lead to heart failure, arrhythmias, and advanced cardiac conduction disorders.
Differentiating Cardiac Amyloidosis from other Diseases
Cardiomyopathy with congestive heart failure is the most common presentation of cardiac amyloidosis. Other common causes of cardiomyopathy should be excluded, and cardiac amyloidosis should be considered in the absence of a history of myocaridal ischemia, myocardial infarction, or presence of coronary artery disease risk factors. Cardiac amyloidosis should be included in the differential diagnoses in patients with unexplained congestive heart failure who have no history of valvular heart disease, long-standing hypertension, or myocardial ischemia.
Epidemiology and Demographics
The incidence rate increased from 18 to 55 per 100,000 person-years from 2000 to 2012. The prevalence rate increased from 8 to 17 per 100 000 person-years from 2000 to 2012. Cardiac amyloidosis commonly presents in adults more than 40 years old. The incidence and prevalence of cardiac amyloidosis have increased among blacks from 2000 to 2012. Over the years, both incidence and prevalence of cardiac amyloidosis have increased among men.
There is insufficient evidence to recommend routine screening for cardiac amyloidosis.
Natural History, Complications, and Prognosis
The presence or absence of cardiac involvement with amyloid is the most important prognostic factor. Untreated cardiac amyloidosis is associated with a very poor prognosis and a high mortality rate. The most common cardiac complications include heart failure, sudden cardiac death due to electromechanical dissociation and pericardial effusion.
Diagnostic Study of Choice
A cardiac biopsy that reveals amyloid, confirms the diagnosis. Biopsy of other tissues may also confirm the diagnosis of a systemic involvement. Amyloidosis is frequently confirmed by biopsy of abdominal fat, rectal submucosa, kidney, or bone marrow.
History and Symptoms
Amyloidosis is a multi-system disease involving many organs simultaneously. Approximately 50% of patients with cardiac amyloidosis present with right heart failure symptoms. The most common symptoms observed in patients with cardiac amyloidosis include fatigue, weight loss, and periorbital purpura.
Cardiac amyloidosis is difficult to diagnose. More than 50% of the patients with cardiac amyloidosis present with signs and symptoms suggestive of right heart failure. Common physical exam findings include elevated jugular venous pressure, third heart sound and pedal edema.
There is no single specific diagnostic test that can be used to diagnose amyloidosis and the diagnosis is based upon the totality of the data. Hence, awareness of the disease is necessary to identify patients with amyloidosis.
The combination of low voltage electrocardiographic pattern and increased thickness of the left ventricular posterior wall and interventricular septum on echocardiogram is highly specific for cardiac amyloidosis. Conduction and rhythm disturbances are common in cardiac amyloidosis, however direct infiltration of the specialized conduction tissue of the heart by the amyloid does not account for the majority of these disturbances.
Amyloidosis is an infiltrative disease resulting in deposition of amyloid in the extracellular spaces of the tissues. Amyloid infiltration of the heart leads to expansion of these extracellular spaces resulting in retainment of gadolinium dye during cardiac magnetic resonance imaging. This retainment of gadolinium leads to signal enhancement in the late washout phase during delayed enhanced cardiac imaging.
Transthoracic echocardiography is most commonly used in the initial evaluation of cardiac amyloidosis. The most common echocardiographic finding is thickening of the left ventricle. Echocardiographic findings strongly correlate with the degree of cardiac dysfunction and disease progression with mildly or moderately increased wall thickness in the early asymptomatic phase and severe thickening and hypokinesia of the left ventricular posterior wall and interventricular septum in clinically apparent cardiac dysfunction. Echocardiographic findings have both diagnostic and prognostic importance.
Other Imaging Findings
Nuclear cardiac scans like MUGA and radionuclide ventriculography (RNV) are not used routinely early in the diagnosis of cardiac amyloidosis. However, when performed, these scans show increased uptake of technetium by the myocardium correlating well with the degree of involvement.
A cardiac biopsy that reveals amyloid confirms the diagnosis. Biopsy of other tissues may also confirm the diagnosis. Amyloidosis is frequently confirmed by biopsy of abdominal fat, rectal submucosa, kidney, or bone marrow.
Major cardiac manifestations of systemic amyloidosis include heart failure and fatal arrhythmias. Therefore treatment of cardiac amyloidosis includes treatment of heart failure and arrhythmias and treatment of the underlying disease. Treatment of heart failure associated with cardiac amyloidosis differs from therapy usually attempted in patients with systolic or diastolic dysfunction.
When heart function is very poor, a heart transplant may be considered for some patients, but not those with AL type amyloidosis since their disease compromises many organs. In one type of secondary amyloidosis, liver transplantation is also required.
Future or Investigational Therapies
New therapies targeting the serum amyloid protein (SAP), which is an excellent immunogen and a universal component of all amyloid deposits, using monoclonal antibodies are currently being investigated.