Amyloidosis is a disease where normally soluble proteins misfold and aggregate into insoluble fibers called amyloid fibrils. These fibrils deposit outside of cells in various organs and tissues, disrupting their normal structure and function. When these deposits specifically target the heart muscle (myocardium), the condition is known as cardiac amyloidosis or amyloid cardiomyopathy. This infiltration is a serious, life-threatening condition that ultimately causes the heart to fail as a pump. Early diagnosis and type-specific treatment are important to slow the disease progression and preserve heart function.
How Amyloid Deposits Affect Heart Function
The core problem in cardiac amyloidosis is the physical infiltration of the heart muscle tissue by amyloid proteins, not a blockage of the arteries. These fibrils accumulate densely in the interstitial spaces between heart muscle cells (myocytes), causing the walls of the ventricles to become rigid and abnormally thickened. This stiffening fundamentally changes heart function, resulting in restrictive cardiomyopathy.
The stiffened ventricles cannot properly relax during diastole, the period between heartbeats when the chambers fill with blood. This impaired relaxation, known as diastolic dysfunction, prevents the ventricles from filling completely. The resistance to filling causes blood to back up, leading to elevated pressures within the heart chambers and pulmonary veins.
This pressure overload results in common symptoms of heart failure. Even if the heart’s squeezing ability (systolic function) is preserved early on, the inefficient filling limits the amount of blood the heart can pump out. Over time, the constant pressure and volume backup can cause the upper chambers (atria) to enlarge, increasing the risk of heart rhythm disturbances like atrial fibrillation.
The Main Types of Cardiac Amyloidosis
Cardiac amyloidosis is categorized based on the specific precursor protein that misfolds, as this dictates the prognosis and necessary treatment. The two primary types are Amyloid Light-chain (AL) and Transthyretin (ATTR) amyloidosis. AL amyloidosis results from a disorder of plasma cells, a type of white blood cell found in the bone marrow.
In AL amyloidosis, plasma cells produce excessive abnormal antibody components called light chains, which misfold and form toxic amyloid fibrils. Since it originates from a plasma cell disorder, AL amyloidosis is considered a systemic disease requiring urgent treatment targeting the bone marrow cells. This type is often rapidly progressive and has a poorer prognosis if not treated swiftly.
The second major category is Transthyretin Amyloidosis (ATTR), which involves the TTR protein produced mainly by the liver. ATTR is divided into two subtypes: wild-type and hereditary. Wild-type ATTR amyloidosis (ATTRwt) is an acquired form linked to the natural instability of the TTR protein that occurs with age, typically affecting older men after age 60.
The hereditary form (ATTRh) is caused by an inherited genetic mutation in the TTR gene, leading to the production of an unstable protein prone to misfolding. This form can affect individuals at a much younger age, sometimes in their 30s or 40s. ATTRh may also cause significant nerve damage in addition to heart involvement.
Recognizing Symptoms and Confirming Diagnosis
The symptoms of cardiac amyloidosis often overlap with those of common types of heart failure, making early diagnosis challenging. Patients frequently experience progressive fatigue and shortness of breath, particularly with exertion. Fluid retention, manifesting as swelling (edema) in the legs, ankles, and abdomen, is also common due to pressure back-up in the veins.
Suspicion is typically raised by initial imaging studies, most commonly an echocardiogram. The echocardiogram often reveals thickened ventricular walls and a characteristic sparkling appearance of the heart muscle, along with evidence of the restrictive filling pattern. A cardiac MRI provides more detailed images, often showing diffuse enhancement of the myocardium after a contrast agent is administered, suggesting amyloid infiltration.
A specialized nuclear imaging test, the technetium-99m pyrophosphate (PYP) scan, is a critical diagnostic step. This non-invasive scan is useful because the radioactive tracer binds specifically to ATTR amyloid deposits in the heart, but not to AL deposits. A positive PYP scan, combined with blood and urine tests ruling out AL amyloidosis, can definitively confirm ATTR cardiomyopathy without a heart biopsy.
Definitive confirmation of amyloidosis still relies on a biopsy, which involves taking a small tissue sample for analysis. While an endomyocardial biopsy is the most direct method, a less invasive fat pad biopsy can sometimes confirm the presence of amyloid fibrils. Specialized staining techniques are then used to identify the specific protein type, which guides the appropriate treatment strategy.
Modern Treatment Strategies
Treatment for cardiac amyloidosis is specific to the type of amyloid protein identified, as the goal is to stop the production of the toxic precursor protein. For AL amyloidosis, treatment aims to eliminate the abnormal plasma cells in the bone marrow producing the misfolded light chains. This is typically accomplished using chemotherapy regimens, often combined with immunotherapy drugs designed to suppress the plasma cell clone.
In select, healthy patients with AL amyloidosis, high-dose chemotherapy followed by an autologous stem cell transplant may be an option for deeper suppression. For ATTR amyloidosis, the approach centers on either stabilizing the TTR protein or silencing the gene responsible for its production. Medications like tafamidis stabilize the TTR protein structure, preventing it from falling apart and forming amyloid fibrils.
Newer treatments for ATTR include gene-silencing therapies, such as RNA interference drugs, which block genetic instructions to the liver cells. These treatments drastically reduce the amount of circulating TTR protein, slowing disease progression. Supportive care remains important for both types, involving diuretics for fluid retention and specialized heart rhythm devices. Standard heart failure medications, such as beta-blockers, are often poorly tolerated or contraindicated due to the unique restrictive physiology of the disease.