The genomics
revolution provides new opportunities to reduce death and disability
from cardiovascular disease. A major challenge in the coming years,
will be how to best seize these opportunities in heart failure and
ventricular hypertrophy.
Researchers have made great progress identifying mutations in genes
for cardiovascular diseases such as the Marfan syndrome and familial
hypercholesterolemia. However, this knowledge has not yet fundamentally
altered clinical practice. In addition, genes involved in more common
conditions may provide important insight into not only disease causes,
but also individual responses to environmental stresses.
Because of these observations, some say the practical promise
of the genomics revolution is overrated. However, Dr. Williams said
he hopes cardiologists will have additional confidence that genomic
approaches to disease will have true value to patients.
One current challenge is defining how different mouse models of
heart failure relate to human disease and may translate into patient
benefit.
In 1998, researchers found that cyclosporin, a calcineurin antagonist,
prevented hypertrophy and subsequent dilated cardiomyopathy in mice.
However, this finding did not translate into human benefit, due
to the drug's lack of efficacy and unacceptable cardiotoxicity.
Yet this model implicated calcineurin in signaling pathways that
lead to ventricular hypertrophy. This discovery moved researchers
toward a more sophisticated understanding of molecular signaling
pathways that regulate myocardial hypertrophy.
Human genome research has revealed a family of genes encoding proteins
structurally similar to certain transcription factors involved in
activating genes responsible for abnormal growth in cardiac hypertrophy.
These newly discovered proteins, called muscle selective calcineurin
interactive proteins, are endogenous calcineurin inhibitors. According
to Dr. Williams, they are superior to immunosuppressant drugs for
assessing the role of calcineurin in hypertrophic signaling.
Dr. Williams and colleagues generated transgenic mice overexpressing
one type of muscle selective calcineurin interactive protein. In
this mouse model, raising the level of this protein reduces or prevents
cardiac hypertrophy. The protein can also prevent ventricular hypertrophy
progressing to dilated cardiomyopathy in a rodent model.
The role of such proteins in humans remains speculative. But the
animal data at least suggests that allelic variations in human genes
could potentially modify response to myocardial stresses resulting
in heart failure.
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