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Researchers at the University of Chicago argue in the March 1 issue of the Journal of Clinical Investigation that vascular spasm -- a sudden, brief tightening of a blood vessel that can block blood supply to the heart -- is an under-recognized and under-treated source of damage to heart muscle.
In this study, done with mice, they show that substances released by damaged cells in the heart can trigger vascular spasm, which in turn leads to additional cardiac damage. This feedback loop can lead to reduced cardiac function, irregular heart rhythms and death.
"This is a whole new possibility for what goes wrong in degenerative heart disease," says cardiologist Elizabeth McNally, M.D., Ph.D., associate professor of medicine and genetics at the University of Chicago and director of the study. "Even though many cardiologists ignore it," she adds, "spasm happens. It plays a major role in the progression toward heart failure and it can worsen the effects of a heart attack. We think the time has come to get aggressive about treating it."
The researchers focused on mice with genetic defects that weaken the membrane of heart muscle cells. By the age of six months, these mice develop extensive cardiac lesions that resemble small heart attacks. The researchers suspected that pockets of mild, early cellular damage caused by the membrane defect actually caused nearby blood vessels to spasm, which led to localized damage and even death of heart muscle.
They found that by correcting the genetic defect in the heart muscle cells they could halt focal degeneration. Halting degeneration stopped vascular spasm. And stopping vasospasm prevented the progression of heart disease.
Curiously, correcting the genetic defect in the smooth muscle cells that lined the vessels but not in heart muscle had no effect. Those mice continued to show evidence of vascular spasm as well as progressive heart disease, demonstrating that vascular spasm arises from a process that begins in the heart muscle cells.
"Once we were convinced that even slight damage to the heart could cause vascular spasm," says McNally, "we began to look for the mechanism." One candidate was the release of chemical signals by degenerating heart cells, or by the immune system cells that infiltrate damaged tissue.
McNally's team had previously found that damaged heart cells produce more of an enzyme that helps synthesize nitric oxide, and that high concentrations of nitric oxide were present in regions of damaged heart tissue. In this paper they show that inhibiting the production of nitric oxide could reduce, but not eliminate, coronary artery spasm.
"We found one factor, but we suspect that other factors also play a role," adds McNally.
The discovery suggests new ways to prevent vasospasm in patients at risk. Drugs that block nitric oxide production are already being tested. Newer calcium channel blockers that target smooth muscle cells but do not interfere with cardiac muscle may also have a role.
"Vascular spasm is an important contributor to cardiac pathology," note the authors. Cardiomyocyte degeneration is common to many forms of cardiac pathology including heart attacks, viral infections of the heart and genetic forms of heart disease. "Inhibition of vasospasm," they conclude, "may prove useful clinically in human disease."
The National Institutes of Health, the Muscular Dystrophy Association, the Burroughs Wellcome Fund, and the American Heart Association supported this research. Additional researchers include Matthew Wheeler, Michael Allikian, Ahike Heydemann, Michele Hadhazy and Sara Zarnegar of the University of Chicago.
Journal
Journal of Clinical Investigation