“This study establishes a new paradigm for coronary artery disease, and opens a whole new set of approaches for treatment of heart disease and prevention of heart attacks,” says Noel Caplice, M.D., the Mayo Clinic cardiologist who led the study.
The plaques which cause blockage of arteries, or atherosclerosis, are composed mainly of fats, including cholesterol, inflammatory cells and smooth-muscle cells. Until now, scientists have thought the fatty portion and inflammatory cells come from the blood, while the smooth-muscle cells multiply from the vessel wall. The Mayo Clinic study points to a different source for the smooth muscle element: progenitor cells (partially developed adult stem cells) produced by the bone marrow, which become smooth-muscle cells and “home” to sites of plaque formation.
The researchers studied autopsy specimens from 13 patients who had undergone bone marrow transplants. Eight of the patients had received marrow from donors of the opposite sex, while the rest had sex-matched marrow transplants. Coronary artery samples were examined using special staining techniques to identify whether the smooth-muscle cells had male or female genetic material. The patients who had received sex-mismatched marrow had a high proportion of opposite-sex cells - many more than 10 percent - in their atherosclerotic plaques. Those with sex-matched marrow transplants had no opposite-sex smooth-muscle cells.
“This finding is significant because the survival time for these patients after transplant ranged from 41 days to 41 months,” explains Dr. Caplice. “Normally, coronary-artery blockages develop over years, or even decades, so the relatively high numbers of marrow-derived smooth muscle cells seeding over such a small time-window may be very significant. This was a short-term, snapshot study that may well underestimate the long-term importance of these progenitors in atherosclerosis. Their high concentrations in the plaques so soon after transplant suggests that the bone marrow is not just an incidental source of the smooth-muscle cells, but may be a significant mechanism contributing to the clogged arteries.”
In vessels without significant disease, the sex-mismatched smooth-muscle cells were much less plentiful. In fact, there were about 100 times as many opposite-sex cells in the plaques as there were in normal, healthy arteries. Dr. Caplice says these findings open several new possibilities for future research to prevent heart attacks.
“Apparently these progenitor cells produced by the marrow tend to stick to existing plaques,” Dr. Caplice explains. “If we can keep them from progressing to become smooth-muscle cells, or if we can affect their ‘stickiness’ so they do not congregate at the plaque site, we may be able to prevent the worsening of atherosclerosis.
“Conversely, some plaques are unstable and in danger of rupturing and being carried by the bloodstream to cause heart attacks in smaller vessels, or strokes in the brain. These so-called ‘vulnerable plaques’ are considered one of the main causes of heart attack. Circulating smooth-muscle progenitors may be able to home to these unstable plaques and seal them off to prevent ruptures.”
In a related study published earlier this month, the Mayo Clinic team proved that progenitor cells produced by the bone marrow can form new heart-muscle cells in adults, pointing the way to research that could enable the body to replace heart muscle damaged by heart attack. “Based on these two studies, learning how to guide the growth and physical properties of progenitor cells originating from the bone marrow holds exciting therapeutic potential,” Dr. Caplice concludes.
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Proceedings of the National Academy of Sciences