May 01, 1998
Genetic Mutation Causes Heart Failure
HHMI researchers have discovered a genetic mutation that damages heart
muscle so that it dilates to the point where the heart can no longer
The discovery may have immediate significance for millions of
people affected by dilated cardiomyopathy, says senior investigator Mark
Keating of the Howard Hughes Medical Institute at the University of
Utah. Although there is typically a poor prognosis for patients with
dilated cardiomyopathy, Keating says that his team's research suggests
that damage may be mitigated by relaxing cardiac muscle with beta
blockers, drugs commonly used for hypertension.
“It's a new way to think about heart failure.”
Mark T. Keating
"If we can help the heart to relax a bit before the damage is
really serious, we might be able to reduce the rate of cell death and slow
down the course of the disease," Keating said. Keating's team published
their research in the May 1, 1998, issue of
Most therapies for heart failure make the heart work harder to
compensate for its inefficiency. This is just the opposite of what our
data suggest should be done, Keating says. While a few cardiologists
have successfully used beta blockers to treat heart failure, most have
not tried using beta blockers because it is counter-intuitive, he notes.
"It didn't make sense to use them before, but now it does," he says. "I
hope this allows physicians to try beta blockers with conviction."
Keating and colleagues from the Mayo Clinic are the first to
show that mutations in actin molecules are associated with a human
disease. Actin is a ubiquitous structural protein found in cells in many
types of organisms from rice to yeast to mammals. Humans have six genes
that produce different forms of actin. One type of actin provides
scaffold-like support for heart muscle cells and works with the protein
myosin to generate the contractile force in muscle.
Researchers have suspected that genetic factors are responsible
for some forms of heart failure, but it took a novel method of
extracting genes from two unrelated families to identify the defect.
This missense mutation? in which one amino acid in actin is
substituted for another? reduced actin's ability to transmit
contractile force in heart cells.
Keating likens the actin mutation to a hairline fracture in
bone. "If you are just walking around with a hairline fracture of your
leg bone, there will be some discomfort, but you will be okay. If you
want to run the Boston Marathon, however, the increased stress of
running will fracture the bone." Similarly, episodic stress on the heart
can produce cracks in actin's structure that can eventually cause
heart cells to die, which leads to dilated cardiomyopathy. "This damage
is initially very subtle, but becomes important over time," Keating
Inherited and non-inherited forms of heart failure appear
similar at the molecular level, which leads Keating to speculate that
they share a common mechanism? damage to the actin scaffold. "It's a new
way to think about heart failure."