According to a recent research, development of heart failure can be reduced especially in those who have already experienced at attack by enhancing the levels of a protein in the heart.
S100A1 is the protein, whose level when increased above normal, helped in protecting animal hearts from added damage after simulated heart attacks. This was revealed by the study conducted by Cardiology researchers at the Center for Translational Medicine at Jefferson Medical College of Thomas Jefferson University in Philadelphia.
In some cases, the animals' heart function hardly changed at all. At the same time, other animals with heart cells lacking the gene for the protein couldn't handle the stress of a heart blockage; they went on to develop heart failure.
The findings provide more evidence that falling levels of S100A1 are critical in the loss of heart-pumping strength after a heart attack and play an important role in the progression to heart failure. Potential therapeutic strategies, the researchers say, may focus on restoring S100A1 levels to normal. The work appears September 19, 2006, in the American Heart Association journal Circulation.
The researchers, led by Walter Koch, Ph.D., director of the Center for Translational Medicine in the Department of Medicine in Jefferson Medical College of Thomas Jefferson University in Philadelphia, examined two types of mice: transgenic mice which had extremely high levels of the gene for and the protein S100A1, and knockout mice that lacked S100A1 altogether.
S100A1, part of a larger family of proteins called S100, is primarily found at high levels in muscle, particularly the heart. Previous studies by other researchers showed that the protein was reduced by as much as 50 percent in patients with heart failure. Several years ago, Dr. Koch and his co-workers put the human gene that makes S100A1 into a mouse, and found a resulting increase in contractile strength of the heart cell. The mice hearts worked better and had stronger beats. In subsequent work, he and co-workers used gene therapy to restore S100A1 levels - and heart function - to normal in failing animal hearts.
Congestive heart failure affects nearly five million Americans, many of whom have poor long-term prognoses, despite recent therapeutic advances.
In the study, the researchers caused simulated heart attacks in the two groups of animals.
"At the basal level, hearts from S100A1 knockouts don't appear to be that different," says Dr. Koch, who is W.W. Smith Professor of Medicine at Jefferson Medical College. Yet, when they caused a heart attack, "the hearts basically fell apart," he says, adding, "S100A1 appears to be a critical molecule to the adaptation of the heart to stress."
Generally, mice survive heart attacks but within a few weeks go on to develop heart failure, he notes. But without S100A1, the researchers found a more rapid onset of heart failure, which includes a higher rate of heart cell death.
The scientists compared these results to the mice with increased levels of S100A1 in the heart who also had an occluded artery and a simulated heart attack. They found the opposite effects in these mice. In fact, the hearts of these mice appeared stronger than normal mice, and did not go on to develop heart failure during the next 20 days.
"It's clear that S100A1 expression goes down after a heart attack, which is consistent with what we've seen in the past in knockouts, and the transgenic mice never lose anything," Dr. Koch says.
According to Dr. Koch, while he and his co-workers will continue to pursue new strategies using gene therapy to manipulate S100A1 levels for treating heart failure, he notes that the current study also provides insights into the potential mechanisms behind the observed S100A1 effects. They have demonstrated a newly discovered link between a certain molecular signaling pathway and changes in S100A1 levels in the heart after heart attack.
Certain cell receptors called Gq-coupled receptors, which include alpha-adrenergic and angiotensin receptors, play a role in cardiac hypertrophy and "have been implicated in being elevated in some models of heart disease," he says. "When these agents act on the heart, they stimulate pathways that lead to apoptosis and cardiac hypertrophy. It seems that they also lead to changes in S100A1 expression.
"It's clear that whenever you want to manipulate a heart molecule that doesn't have an enzymatic function, we have to use gene therapy," he notes. "We want to know as much about this as possible in case we can come up with a small molecule that can regulate its expression.
"Perhaps antagonists that act on Gq-coupled receptors, which are being used clinically for heart failure, may be part of the mechanism of action in heart failure, which is why they appear to give beneficial results. They prevent further S100A1 decreases through this mechanism."