Releasing toxic amyloid-like oligomers from aggresomes in
cardiomyocytes leads to increased toxicity, according to studies in
mice. In contrast, reversing amyloidosis can rescue the failing
heart.

"Amyloids in the heart are very common" in heart failure patients,
senior investigator Dr. Jeffrey Robbins told Reuters Health. In
fact, he said, a recent study looking at specimens from 20 patients
with heart failure showed that 17 had very high concentrations of
amyloid.

"That's why I call cardiomyopathy 'Alzheimer's of the heart'," the
researcher added.

To investigate this phenomenon, Dr. Robbins, at Cincinnati
Children's Hospital Medical Center in Ohio, and his colleagues used
mice with desmin-related cardiomyopathy, caused by a R120G missense
mutation in the small heat-shock protein alpha-B-crystallin.

The disease is characterized in vivo by the formation of aggregates
containing alpha-B-crystallin and desmin and amyloid oligomers, the
authors explain in their report in the PNAS Early Edition published
online September 5th. The animals develop heart failure and die by 5
to 7 months of age.

In vitro experiments with cardiomyocytes of mice with the alpha-B-
crystallin mutation showed that blockade of aggresome formation led
to increased amyloid oliogomer formation in the cytoplasm, which was
associated with significantly increased cytotoxicity.

When they treated the mutant mice in vivo with doxycycline to halt
expression of the mutant alpha-B-crystallin, cardiac function was
restored and the animals survived with no visible signs of distress,
ascites fluid, or pulmonary congestion.

Microscopic examination of the cardiomyocytes showed that
doxycycline treatment did not affect aggresome levels, but it did
reduce cytoplasmic levels of the amyloid oligomer.

"It was thought that if you get rid of the aggresomes, that would be
a good thing," Dr. Robbins said. "What our paper says is, don't even
think about it, at least not in cardiomyopathy, because if you get
rid of aggresomes you're releasing this toxic material that was
sequestered from the general cytoplasm."

He suggested that blocking cardiac amyloid oligomer formation in the
cytoplasm "may be a therapeutic avenue" to treat cardiomyopathy.

He believes that a similar phenomenon may be occurring after left
ventricular assist devices are implanted in patients with heart
failure. "Our question is, if you offload the left ventricle, are
you reducing amyloid levels in the cytoplasm?" The answer, he said,
will be revealed when intracellular levels of amyloid before and
after LVAD device placement are coupled with measures of cardiac
function.

Proc Natl Acad Sci USA 2005