Amyloidosis is a group of disorders characterized by the misfolding of specific proteins, which then aggregate and deposit in organs and tissues throughout the body. When these abnormal, insoluble protein deposits accumulate within the heart muscle, the condition is termed cardiac amyloidosis, or amyloid cardiomyopathy. These protein aggregates, called amyloid fibrils, progressively infiltrate the myocardium, the muscular wall of the heart. Cardiac involvement is a serious complication of systemic amyloidosis and, without timely diagnosis, leads to severe heart dysfunction. This condition requires a high index of suspicion because its symptoms frequently mimic those of more common types of heart failure.
The Mechanism of Damage: How Amyloid Proteins Affect the Heart
The fundamental problem is the physical presence of deposited amyloid fibrils in the spaces between the heart muscle cells. This infiltration causes the ventricular walls to thicken and become abnormally stiff, significantly impairing the heart’s ability to relax between beats. This stiffening results in restrictive cardiomyopathy.
The inability of the ventricles to properly relax and fill with blood is termed diastolic dysfunction, typically the earliest physiological change seen in the disease. The restricted filling capacity reduces the overall volume of blood the heart can handle, even if the pumping function (systolic function) is initially preserved. This reduction causes blood to back up, ultimately leading to heart failure symptoms like shortness of breath and fluid retention. The amyloid deposits can also infiltrate the heart’s electrical conduction system, leading to various arrhythmias and conduction blocks.
The Origin Story: Differentiating Types of Cardiac Amyloidosis
Identifying the precursor protein is paramount because treatment strategies differ entirely for each type of cardiac amyloidosis. The two most common forms affecting the heart are Light Chain (AL) amyloidosis and Transthyretin (ATTR) amyloidosis.
AL amyloidosis originates from an underlying bone marrow disorder where a clone of plasma cells produces excess abnormal immunoglobulin light chains. These light chains misfold rapidly, forming amyloid fibrils that deposit in the heart and other organs, making AL a systemic and often quickly progressive disease.
ATTR amyloidosis involves the transthyretin protein, normally produced by the liver. This type is divided into hereditary and wild-type forms. Hereditary ATTR (hATTR) results from a genetic mutation in the TTR gene, which makes the transthyretin protein unstable and prone to misfolding. This inherited form can manifest as cardiomyopathy, neuropathy, or a combination of both.
Wild-type ATTR (ATTRwt), previously known as senile systemic amyloidosis, is an age-related condition. In ATTRwt, the transthyretin protein, despite having a normal genetic sequence, becomes unstable and misfolds over time. This form predominantly affects the heart and is typically diagnosed in men over the age of 60. Determining whether the amyloid is AL or ATTR directly informs the patient’s prognosis and the selection of therapy.
Specialized Testing to Confirm the Condition
Diagnosis relies on a combination of imaging, laboratory tests, and tissue analysis, beginning with non-invasive tools. An echocardiogram often reveals the characteristic thickened heart walls and small left ventricle associated with restrictive cardiomyopathy. Cardiac Magnetic Resonance Imaging (CMR) is highly valuable, detecting a distinctive pattern of late gadolinium enhancement (LGE) that signifies the presence of amyloid within the heart tissue. The LGE pattern can offer clues to the type, with transmural enhancement often seen in ATTR and a subendocardial pattern in AL.
A crucial non-invasive test for ATTR amyloidosis is the Technetium Pyrophosphate (Tc-99m PYP) scan. This specialized nuclear imaging technique uses a radioactive tracer that preferentially binds to ATTR amyloid deposits, confirming the ATTR type and often avoiding the need for an invasive heart biopsy. However, this non-invasive diagnosis requires negative blood and urine tests for monoclonal proteins, which indicate AL amyloidosis. Definitive diagnosis and confirmation of the amyloid type often requires a biopsy, either of the heart (endomyocardial biopsy) or a less invasive site like the abdominal fat pad, with the tissue then analyzed for the precursor protein.
Current Therapeutic Approaches
Treatment for cardiac amyloidosis is highly specific to the identified protein type and focuses on two main goals: managing heart failure symptoms and stopping the production or deposition of the disease-causing protein. Supportive care involves managing fluid overload, typically using diuretics, though patients often tolerate traditional heart failure medications poorly. Pacemakers or implantable defibrillators may be needed to address arrhythmias and conduction system problems.
Disease-modifying therapies target the source of the amyloid protein. For AL amyloidosis, which stems from a bone marrow disorder, treatment involves chemotherapy regimens to destroy the abnormal plasma cells. Common agents include daratumumab, cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD). In select patients, high-dose chemotherapy followed by an autologous stem cell transplant may be used.
Conversely, ATTR amyloidosis treatment involves stabilizing the transthyretin protein or suppressing its production. The drug tafamidis is a TTR stabilizer that prevents the protein from breaking apart and forming amyloid fibrils. For patients with hereditary ATTR, gene silencers, such as antisense oligonucleotides or small interfering RNAs, are available to reduce TTR protein production by the liver.