Amyloidosis is a group of disorders characterized by the misfolding of soluble proteins into insoluble fibers, which accumulate in various organs and tissues. When these abnormal protein deposits, known as amyloid fibrils, accumulate specifically in the heart muscle, the condition is termed cardiac amyloidosis. This infiltration interferes with the heart’s normal function, causing the walls to thicken and stiffen. Cardiac involvement is a serious manifestation of systemic amyloidosis and requires prompt, accurate diagnosis for effective management.
The Mechanism: How Amyloid Protein Damages the Heart
The pathology of cardiac amyloidosis begins with the continuous deposition of misfolded protein fibrils into the extracellular space of the myocardium. These deposits accumulate between heart muscle cells, mechanically disrupting the tissue’s normal architecture. This infiltration causes the ventricular walls to become progressively thicker and abnormally rigid. This stiffness prevents the heart chambers from relaxing fully and filling with blood properly, a condition known as restrictive cardiomyopathy.
The initial damage manifests as diastolic dysfunction, meaning the heart struggles to fill during the resting phase of the cardiac cycle. Although pumping ability (systolic function) may initially be preserved, the heart must work harder, leading to elevated filling pressures. This increased pressure backs up into the lungs and veins, resulting in common heart failure symptoms like shortness of breath and fluid retention. Amyloid fibrils may also be directly toxic to the heart cells, contributing to cellular injury and organ dysfunction.
Identifying the Source: Major Types of Cardiac Amyloidosis
Identifying the specific protein responsible for the amyloid deposits is necessary, as the two major types of cardiac amyloidosis require distinct treatment approaches. Nearly all clinically significant cases are caused by immunoglobulin light chains (AL) or transthyretin (ATTR). The distinction determines both the prognosis and the therapeutic strategy.
Amyloid Light Chain (AL) amyloidosis is derived from monoclonal light chains produced by abnormal plasma cells, often associated with an underlying blood disorder like multiple myeloma. These light chains misfold rapidly and are considered the more aggressive form due to their high toxicity and rapid progression. AL amyloidosis can simultaneously affect multiple organs, including the kidneys, liver, and nervous system.
Transthyretin (ATTR) amyloidosis involves the transthyretin protein, which is primarily made in the liver and functions as a transporter for thyroid hormone and retinol. In this form, the TTR protein tetramer becomes unstable and dissociates, allowing the resulting fragments to misfold into amyloid fibrils. ATTR is further divided into two clinically relevant subtypes.
Wild-Type ATTR (ATTRwt) is an age-related condition where the TTR protein misfolds without a genetic mutation and predominantly affects older men. Hereditary ATTR (ATTRv or ATTRm) is caused by a mutation in the TTR gene, leading to the production of an inherently unstable protein. This genetic form can manifest with significant heart involvement, but it frequently causes nerve damage (polyneuropathy) as well.
The Diagnostic Pathway
The diagnostic process confirms the presence of amyloid and identifies its specific protein type. Initial suspicion often arises from standard screening, such as an echocardiogram revealing abnormal thickening of the heart walls without high blood pressure or aortic stenosis. Elevated cardiac biomarkers, such as N-terminal pro-B-type natriuretic peptide (NT-proBNP), also raise suspicion.
Definitive diagnosis involves a specialized sequence of non-invasive and invasive tests to differentiate between AL and ATTR types. The two most important non-invasive tools are a technetium pyrophosphate (PYP) scan and comprehensive monoclonal protein testing. The PYP scan is a nuclear imaging test using a radioactive tracer that binds specifically to ATTR deposits in the heart. Strong uptake of the tracer is highly suggestive of ATTR cardiac amyloidosis.
The PYP scan is only conclusive for ATTR if a blood and urine workup confirms the absence of a monoclonal protein, which would suggest AL amyloidosis. Monoclonal protein testing, involving serum free light chain analysis and immunofixation, is essential to rule out AL, as the PYP tracer can occasionally show faint uptake in AL. If non-invasive tests are inconclusive, or if AL is strongly suspected, a tissue biopsy remains necessary, typically taken from the abdominal fat pad. Genetic testing is performed in all ATTR cases to determine if the condition is the wild-type or the hereditary variant.
Treatment Options Based on Amyloid Type
Treatment for cardiac amyloidosis depends entirely on the specific protein type identified, as therapies target the source of the misfolded protein. Standard heart failure medications, such as beta-blockers and calcium channel blockers, are often poorly tolerated due to the heart’s restrictive nature. Supportive care relies mainly on the careful use of diuretics for fluid management, while disease-modifying therapies aim to halt the progression of the underlying problem.
For AL amyloidosis, treatment focuses on eliminating the source of the abnormal light chains using chemotherapy regimens similar to those for multiple myeloma. These regimens often combine drugs like Daratumumab, Cyclophosphamide, Bortezomib, and Dexamethasone (Dara-CyBorD) to rapidly suppress abnormal plasma cells in the bone marrow. In highly selected patients, high-dose chemotherapy followed by an autologous stem cell transplant may be used to achieve a deep and lasting response.
Treatment for ATTR amyloidosis employs two main strategies to manage the TTR protein. The first involves TTR stabilizers, such as tafamidis, which bind to the TTR protein and prevent it from breaking apart and misfolding. This action slows the deposition of new amyloid fibrils, thereby slowing the progression of heart damage. The second strategy involves TTR gene silencers, such as Patisiran or Vutrisiran, which are RNA-based therapies that target the TTR messenger RNA in the liver, shutting down the production of the TTR protein.