About Cardiac Amyloidosis
Amyloidosis is a protein misfolding disorder. Proteins are composed of a linear chain of amino acids but they have to fold successively into primary, secondary, tertiary and sometimes quaternary structures. This structural conformation is essential for protein integrity and function. Misfolded proteins are nonfunctional, unstable and can clump together (“aggregate”) to form amyloid fibrils. Currently, about 30 different proteins are known that form amyloid fibrils and cause disease. All amyloid fibrils have a cross-beta pleated structure, irrespective of the protein of origin. This structure gives them the characteristic appearance of apple-green birefringence when stained with the dye Congo-red and viewed with polarized light microscopy.
Amyloid in the heart is usually derived from one of two proteins – transthyretin (ATTR amyloidosis) or immunoglobulin light chains (AL amyloidosis). Other proteins such as apolipoprotein A1 and serum amyloid A can also produce cardiac amyloidosis but do so very rarely.
Transthyretin (abbreviated TTR) is a protein normally present in the blood, and functions as a carrier of the hormone thyroxin and vitamin A. Structurally, the normal form of TTR is a tetramer made of four identical units. However, TTR proteins can dissociate into monomers, which then aggregate to form amyloid fibrils. These amyloid fibrils accumulate in the heart or other tissues and over time impair normal organ function. ATTR amyloidosis is seen under two circumstances: 1) Hereditary TTR amyloidosis which occurs as a result of a genetic mutation, and manifests as a cardiomyopathy and/or polyneuropathy; and 2) wild type ATTR amyloidosis, where tissue deposition of non-mutated TTR occurs for unexplained reasons. Wild type ATTR generally manifests later in life and is therefore, also called senile systemic amyloidosis. The most common manifestations are cardiomyopathy, carpal tunnel syndrome, and tendon ruptures.
In contrast, AL amyloidosis occurs due to the unregulated proliferation of a clone of plasma cells, resulting in excess production of immunoglobulin light chains (Kappa or Lambda) which then form amyloid fibrils. AL amyloidosis is a systemic disease which affects many organs including the heart and the kidney.
Diagnosis
The diagnosis of cardiac amyloidosis requires a high degree of suspicion. Unexplained ventricular hypertrophy in older patients with heart failure should trigger testing for amyloidosis. A pericardial effusion and thickening of the inter-atrial septum increase the likelihood of amyloidosis. The electrocardiogram may show conduction blocks, a pseudoinfarction pattern, or low voltage. Unexplained neuropathic pain, orthostatic hypertension, bilateral carpal tunnel syndrome and atraumatic rupture of a biceps tendon are red flags. Signs such as macroglossia and periorbital purpura are highly suggestive of AL amyloidosis, but occur infrequently. Until recently, a cardiac biopsy was essential for the definitive diagnosis of cardiac amyloidosis. Recent developments in cardiac imaging tests have obviated the need for a cardiac biopsy in most patients. Strain echocardiography, cardiac magnetic resonance (CMR) and nuclear scintigraphy with Tc-99m pyrophosphate imaging (PYP) are now widely used to assist in the diagnosis of cardiac amyloidosis. Tc-99m PYP scans are highly accurate for the diagnosis of cardiac ATTR amyloidosis. In most cases of a positive Tc-99m PYP scan, a confirmatory biopsy is not required. After diagnosis, several therapeutic options are available for ATTR and AL patients that are designed to prevent further amyloid formation and to maintain functionality of the heart and other affected organs. Considerable progress has been made recently in diagnosis and treatment of these diseases. Our center is state of the art and dedicated to further improving management of cardiac amyloidosis in clinical practice and through research.