Transthyretin Amyloid Cardiomyopathy (ATTR-CM) is a progressive heart disease resulting from the misfolding of a protein called transthyretin (TTR). This condition is a form of cardiac amyloidosis where abnormal protein deposits accumulate within the heart muscle. The accumulation of these misfolded proteins stiffens the heart walls, ultimately impairing the organ’s ability to function correctly. ATTR-CM is often underdiagnosed, but recent advancements in imaging and treatment have increased awareness of this rare condition.
The Biological Mechanism of Amyloid Formation
The Transthyretin (TTR) protein is normally produced primarily by the liver and circulates in the blood to transport thyroxine and retinol (Vitamin A). In its healthy state, TTR exists as a stable structure composed of four identical units, known as a tetramer.
The disease process begins when this stable tetramer structure becomes unstable and dissociates into individual, misfolded units. These unstable units subsequently change their shape and aggregate into insoluble clumps called amyloid fibrils.
The resulting amyloid fibrils are resistant to the body’s normal mechanisms for clearing cellular debris. They deposit themselves in the spaces between heart muscle cells, which is the hallmark of ATTR-CM.
The continuous buildup of these rigid protein deposits physically infiltrates the heart tissue, disrupting its normal architecture and function. Stopping or slowing this protein misfolding cascade is the goal of modern therapeutic interventions.
Cardiac Manifestations of ATTR-CM
The infiltration of amyloid fibrils into the heart muscle walls causes the organ to become abnormally thick and rigid. This leads to restrictive cardiomyopathy, which is the “CM” part of the acronym.
The thickened walls, particularly of the left ventricle, lose their ability to relax properly between heartbeats. This impaired relaxation means the heart struggles to fill adequately with blood.
This leads to a type of heart failure where the ejection fraction, or pumping strength, may initially be preserved. Symptoms of this filling dysfunction include shortness of breath, especially during exertion, and significant fluid retention and swelling (edema).
Patients may also experience arrhythmias or problems with the heart’s electrical conduction system. A common diagnostic clue is the presence of unexplained left ventricular wall thickening alongside an unexpectedly low electrical activity measurement on an electrocardiogram.
Hereditary Versus Wild-Type ATTR-CM
ATTR-CM is divided into two primary categories based on the origin of the misfolded transthyretin protein. The first is Hereditary ATTR-CM (hATTR-CM), caused by an inherited mutation in the TTR gene. Individuals with this genetic variant produce an unstable TTR protein from birth, leading to disease onset earlier in life.
The second type is Wild-Type ATTR-CM (wATTR-CM), which is not associated with an inherited gene mutation. This form is considered an age-related disease, where the TTR protein becomes unstable and misfolds over time. Wild-type ATTR-CM typically affects older individuals, most commonly men over the age of 65.
While both types result in the same cardiac pathology, the hereditary form can also involve other organs, such as the nerves, causing peripheral neuropathy. Differentiating between the two types is important for prognosis and treatment planning, generally achieved through genetic testing.
Modern Management and Treatment Strategies
Current management for ATTR-CM focuses on a multi-pronged approach aimed at addressing the disease’s root cause and managing symptoms. One primary strategy is TTR stabilization, which involves using medications to bind to the normal TTR tetramer structure. Stabilizers prevent the protein from dissociating and misfolding, thereby limiting the formation of new amyloid fibrils.
Another advanced strategy is TTR silencing, which aims to reduce the overall production of the problematic protein in the liver. This is achieved through novel therapies, such as small interfering RNA (siRNA) and antisense oligonucleotide (ASO) treatments. These agents significantly lower the amount of circulating TTR protein, slowing the progression of the disease.
The third component of care involves supportive treatment, managing the resulting heart failure symptoms. This often includes the use of diuretics to manage fluid retention and edema caused by the heart’s restricted filling capacity.
Patients with ATTR-CM often respond poorly to standard heart failure medications. Therefore, therapies that target the TTR protein are a central focus of modern treatment.