Cardiac Growth and Hypertrophy-Molecules, Mice and Medicine


Robert Sanders Williams
Duke University Medical Center
Durham, NC, USA

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.


Reporter: Andrew Bowser