B is for Brian Black

It is one of cardiology's enduring mysteries. Why can one person smoke five packs of cigarettes a day, eat bacon and eggs regularly for breakfast and live to be 95, while other people can take relatively good care of themselves but then suffer heart attacks in their 50s?

Epidemiological studies point to lifestyle choices playing a significant role in cardiovascular disease, but genetic predisposition appears to play an equally significant role in the onset of heart disease; indeed, most human disease is likely a combination of both. Brian Black, part of UCSF's Cardiovascular Research Institute, has created a mouse model to help tease apart the interplay between genetic and environmental factors in heart disease.

Black's lab is looking at cardiac hypertrophy, an enlargement of the heart similar to an incurable condition in humans that can cause heart failure. When the heart is stressed from additional work required to pump blood through narrow arteries, or when there has been cardiac cell death due to lack of oxygen, the heart cells grow larger rather than divide. This initially beneficial compensation can eventually lead to dilation of the heart ventricles and heart failure.

Although no one really knows what causes this cardiac hypertrophy, recent research has shown that the heart's response to calcium is involved. It has been known for decades that calcium regulates the normal heartbeat — sharp spikes in intracellular calcium concentration trigger contraction. These spikes in calcium occur when calcium is released into the cell from the cell's internal storehouse, the sarcoplasmic reticulum. Calcium release is controlled by the multi-protein intracellular calcium release channel, which creates an opening in the sarcoplasmic reticulum membrane. It is this channel that scientists suspect is involved in hypertrophy.

Armed with the hypothesis that the intracellular calcium cycle might play a role in the hypertrophic response, Eric Jaehnig, a graduate student in Black's lab, bred mice that lack one of the sarcoplasmic reticulum's calcium-handling proteins in order to examine the causes of hypertrophy on a molecular level. "What we'd like to have is a genetic model for mice that are normal and live a full life, but when combined with an environmental stimulus get cardiac hypertrophy," says Black.

Using beta-andronergic agonists to stimulate stress, which is known to be a predisposing factor to human heart disease, Black's mice developed massive hypertrophy. "We have what we think is a model that more closely resembles human heart disease because it requires both genetic and environmental factors." The environmental signals alone are sufficient to cause heart failure in normal mice, but that effect is dramatically exacerbated in the genetically altered mice.

Black emphasizes that although the model is relatively untested, it seems to suggest that there is a molecular pathway for a genetic predisposition to cardiac hypertrophy. "We only have a few pieces of the puzzle so we don't really know what the whole picture looks like yet," says Black. "What we've found could certainly be a heart-disease, or hypertrophy, gene, but even if not, it is still helping us to understand how genetic and environmental factors cooperate to cause heart disease."

by Mitzi Baker