February 28, 2003
Researchers Pinpoint Genetic Cause of Heart Failure
Howard Hughes Medical Institute researchers have discovered how an
inherited disorder triggers heart failure by disrupting the flow of
calcium in heart muscle cells.
The researchers say that the finding could lead to targeted
treatment for dilated cardiomyopathy, a disorder that causes the heart
to become enlarged to the point where it can no longer pump blood
efficiently. Although the discovery was made during studies of an
inherited form of heart failure, the researchers suggest that this
molecular defect may help explain other forms of heart failure - an
emerging epidemic that affects 4.7 million Americans and costs $17.8
billion annually.
In an article published in the February 28, 2003, issue of the
journal Science, HHMI investigators Christine E. Seidman and
Jonathan G. Seidman and their colleagues showed that a defect in the
gene that encodes the protein phospholamban could cause dilated
cardiomyopathy in humans. The Seidmans collaborated with scientists
from Harvard Medical School, Brigham and Women's Hospital in Boston,
the University of Toronto and the University of Cincinnati.
There are two basic forms of cardiomyopathies — disorders that
affect the contractile ability of the heart. Hypertrophic
cardiomyopathy causes thickening of the left ventricular wall, reducing
its pumping ability. Dilated cardiomyopathy involves a stretching of
the left ventricle, which reduces the heart's pumping strength. In
either case, the inherited heart defects often cause early death. When
underlying mutations, such as those observed in cardiomyopathies, are
coupled with coronary artery disease, the results can be disastrous,
say the researchers.
“Before our work, it was thought that calcium dysregulation
might be involved in dilated cardiomyopathy, but it was uncertain
whether this was contributing to myocyte dysfunction (i.e., an inciting
event) or a secondary consequence, and that is a big difference,”
said Christine Seidman.
The heart muscle is triggered to contract and relax by a mechanism
in which calcium is released from a reservoir into the muscle cell, or
myocyte, and then rapidly pumped back into the reservoir, called the
sarcoplasmic reticulum. According to Christine Seidman, phospholamban
is a key regulatory molecule in the calcium reuptake pump.
In the process of studying the calcium regulation machinery, the
Seidmans and their colleagues discovered that a sample group of people
with inherited dilated cardiomyopathy — which often proves lethal in a
person's 20s or 30s — showed a subtle mutation in the DNA sequence of
the gene for phospholamban.
To explore whether this mutation could cause the disease Joachim
Schmitt, a fellow in the Seidman lab, created a transgenic mouse with
the corresponding phospholamban genetic defect. Analyses of the mutant
transgenic mouse was facilitated by the previous work of co-author
Evangelia G. Kranias of the University of Cincinnati. She had produced
a transgenic mouse expressing normal (wildtype) phospholamban with
normal cardiac structure and function and excellent survival.
“Substituting only one amino acid in phospholamban produced
profound changes in cardiac function, causing a premature death of the
mice with evidence of heart failure that recapitulates what we saw in
our human families,” said Christine Seidman.
Further studies using cell cultures as well as tissue from affected
people revealed in detail how the abnormal phospholamban disrupts the
calcium pump in heart muscle cells. Specifically, the scientists found
that the mutant form effectively “traps” a key enzyme
necessary for the function of the normal phospholamban protein. Normal
phospholamban is found in individuals with dilated cardiomyopathy,
since they usually possess only one abnormal copy of the phospholamban
gene.
The Seidmans and their colleagues found that affected individuals
would suffer a chronic malfunction of calcium regulation in their heart
muscle, which ultimately would lead to heart failure.
Previously known inherited defects underlying dilated cardiomyopathy
affected muscle proteins, said Christine Seidman. However, the latest
findings by the Seidmans and their colleagues suggest a second major
mechanism.
“We believe these findings point to defects in this recycling
of calcium — which do not allow the myocyte to fully relax. These can
lead to profoundly devastating consequences,” she said. More
generally, she said, the discovery hints that there may be more
mechanisms of heart failure that are yet to be discovered.
“This finding provides evidence that all heart failure is
unlikely to occur by the same pathogenic mechanism,” she said.
“Unfortunately there are many ways a heart can die.”
However, these different etiologies may trigger the same signals;
calcium dysregulation appears to be one of the important signals that
causes myocyte death. According to Christine Seidman, such findings
will likely have important implications for treatment.
“Our treatment of heart failure is, in this day and age,
relatively non-specific,” she said. “The kind of molecular
dissection of the cause of heart failure that we have done leads us to
ask whether — if we can restore normal calcium cycling in this type of
defect — can we prevent heart failure? The hope is that the answer
will be yes.
“There are pieces of this puzzle that are starting to come
together to fit a profile of a group of patients who we think would
very much benefit from modulating calcium homeostasis in heart
cells,” said Christine Seidman.
Additional research might well reveal that defects in calcium
cycling could underlie some forms of hypertrophic cardiomyopathy, which
are believed to be a very different type of failure in the contractile
apparatus, said Christine Seidman.
A major route for further research, Seidman said, will be to follow
the effects of mutant phospholamban “downstream” in the
cell machinery to discover how that defect ultimately leads to the
death of the myocyte. That type of search could lead to significant
drug targets for treating heart failure in general, she said.
“While these inherited cardiomyopathies are rare disorders, I
think they teach us so much about the biology of the system that is
relevant to a broader population,” said Seidman.
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