Catching a Heart Disease Before it Happens

By Jason Socrates Bardi

James, a 65-year-old African American man living in Mississippi, walks into his doctor's office complaining that his legs are swollen, he is overly tired, he has difficulty breathing, and he can often feel his heart beating too hard. After taking an echocardiogram, an ultrasound image of the James's heart, the doctor identifies findings consistent with protein deposits inside the heart and determines that these are indicative of cardiac amyloidosis—a common cause of heart failure in the elderly.

While the doctor's diagnosis is correct in this fictitious scenario, what he does not see is that the deposits are composed of protein fibrils made from a protein with a mutation that James has been carrying his whole life. The doctor does not know that James has been predisposed to get these plaques since the day he was born, because of the DNA he inherited from one or both parents.

Hereditary diseases are not the same as congenital ("with birth") defects. While some are manifest birth, many, like the mutation that causes James's heart disease, only become evident later in life. One of the promises of molecular medicine is to find ways to identify genetically determined disorders early in life. The discipline may also lead to new ways for such diseases to be treated and perhaps prevented.

Alzheimer's of the Heart

The amyloidoses are a collection of disorders in which proteins that are secreted from cells into the bloodstream as soluble molecules become insoluble in other tissues. There, they form microscopic fibrils that sometimes aggregate to form larger plaques made up of hundreds of misfolded proteins clustered together. Both fibrils and plaques deposit in organs, interfering with their normal function, and lead to organ failure. In the case of cardiac amyloidosis, the fibrils cause heart disease by building up deposits inside the heart, which decrease the heart's ability to pump blood with congestion of the lungs and swelling of the feet.

"We refer to this as 'Alzheimer's of the heart,'" says Professor Joel Buxbaum of the Department of Molecular and Experimental Medicine at The Scripps Research Institute (TSRI). Both cardiac amyloidosis and Alzheimer's are characterized by deposits of a particular misfolded protein. But the ß protein responsible for Alzheimer's disease does not affect the heart and the transthyretin protein that forms fibril deposits in cardiac amyloidosis are almost never found in the brain.

Cardiac amyloidosis is probably more accurately described as a group of diseases rather than a single illness, because it is strongly influenced by one's genetic makeup in more than one way. A subset of some 80 mutations in the gene that codes for the serum protein transthyretin (TTR), a 127-amino acid protein that is made in the liver and secreted into the bloodstream to carry thyroid hormone and vitamin A, can lead to cardiac amyloidosis. These mutations all cause the protein to misfold and form those characteristic waxy, starch-like deposits in the heart. Even more interesting is that the most common form of cardiac amyloidosis in the elderly occurs when transthyretin without mutations is deposited.

Buxbaum and his colleagues have characterized several of these heart disease-causing TTR mutations, including that form associated with the earliest, most aggressive clinical disease. They have also identified a mutation that is present in about four percent of African Americans (1.5 million individuals) who have ancestral ties to West Africa. The mutation gives rise to amyloid deposits and subsequent heart disease after the age of 60.

The Anatomy of a Disease

Any protein can exist in a variety of conformations, or shapes, and a realistic view of proteins in living tissue is that they regularly explore many of these conformations. However, any protein must adopt its "native" conformation to be active and carry out the biological function for which it was synthesized.

Normally, TTR circulates in the blood as an active "tetramer" made up of four separate copies, or protein subunits, that bind to each other. These subunits are encoded by the same gene on the paired chromosome 18. One of these, from either parent, can carry a mutation. TTR tetramers are composed of identical protein subunits when the genes are identical, but when one of the copies has a heritable defect, hybrid tetramers composed of mutant and normal subunits form.

The inclusion of these mutated subunits can make the tetramers less stable and cause the four subunits to dissociate under conditions in which they are usually stable. Once the misfolded subunits are free, they reassemble into the hair-like amyloid fibrils.

"These [fibrils] do not stay in solution," says Buxbaum.

Instead of remaining dissolved in the blood they form deposits either within the blood vessels or in between the cardiac muscle fibers. These fibrils can then recruit more TTR proteins and keep building until the microscopic plaques become large enough to affect the operation of the organ.

The current best therapy for the disease is a liver transplant, which replaces the mutant gene with a normal copy.


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TSRI Professor Joel Buxbaum studies a type of cardiac amyloidosis, which he describes as "Alzheimer's of the heart." Photo by Biomedical Graphics.