Catching a Heart Disease Before it Happens
By Jason Socrates
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 amyloidosisa 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
"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.
1 | 2 |