Aging of Progenitor Cells Contributes to Atherosclerosis
As bone marrow–derived epithelial progenitor cells that usually repair and give new life to aging arteries themselves become old, they are less likely to perform their tasks. This contributes to the progression of atherosclerosis, said researchers from Duke University School of Medicine in Durham, NC, in a report in this week’s issue of the journal Circulation (Circulation. 2003;108:457–463).
In the study led by Frederick M. Rauscher, MD, of Duke, mice treated with bone marrow–derived progenitor cells taken from mice that lacked the apolipoprotein E (ApoE) gene prevented progression of atherosclerosis in mice that also lacked the ApoE gene—even though the treated mice had persistent high cholesterol. When such mice were treated with bone marrow–derived progenitor cells from older mice that lacked the gene, the treatment was much less effective, the researchers reported. They found that cells with the potential of being vascular progenitors are less frequent in the bone marrow of aging mice that lack the ApoE gene. However, they said, the cells from the donor mice engraft in the areas at risk for atherosclerotic injury.
The researchers wrote: “In this mouse model of atherosclerosis, we have established that there is an atheroprotective property of the BM [bone marrow] that is ‘exhausted’ with aging and prolonged exposure to risk factors. Several findings indicate that this exhaustion likely involves progenitor cell–mediated vascular repair . . . Taken together, these results support a novel model of atherosclerosis in which deficient vascular repair, secondary to obsolescence of BM cells, is a critical determinant of disease initiation and progression. Whereas previous treatments for atherosclerosis have focused on eliminating multiple sources of vascular injury, we now provide evidence in support of an alternative approach, vascular repair that can attenuate atherosclerosis progression even in the continued presence of vascular injury. Once optimized, BM-derived progenitor cell restoration could have important antiatherosclerosis applications in humans.”
In an accompanying editorial (Circulation. 2003;108:378–379), Peter Libby, MD, of Harvard Medical School and The Brigham and Women’s Hospital, wrote that the “imaginative and provocative experiments by Rauscher et al show that transfer of cells propagated from the bone marrow of youthful donor mice can limit the evolution of experimental atherosclerosis in mice lacking apolipoprotein E.” Although there are many questions remaining about the studies and their application in people, Dr Libby warns that they should not deflect the medical community and researchers from the need to stem the growing burden of atherosclerosis worldwide and the task of confronting the “less glamorous” methods of prevention—lifestyle modification and use of current treatments according to stated guidelines.
Modified Metabolic Syndrome Definition Predicts Coronary Heart Disease and Type 2 Diabetes
The simplified definition of metabolic syndrome recently proposed by the National Cholesterol Education Program predicts with significant accuracy the development of coronary heart disease and type 2 diabetes, said researchers from the Glasgow Royal Infirmary in Glasgow, Scotland, in this week’s issue of the journal Circulation (Circulation. 2003;108:414–419).
The researchers used baseline assessments of body mass index (in place of waist circumference), triglycerides, high-density lipoprotein cholesterol, fasting plasma glucose concentration, and blood pressure to predict the risk of heart disease in 6447 men in the West of Scotland Coronary Prevention Study and to predict risk of developing diabetes in 5974 men in the same study. Follow-up averaged 4.9 years. The scientists found that C-reactive protein, another marker of disease, was higher in the men who had metabolic syndrome (26% of the study group) than it was in the men who did not have the syndrome.
The scientists, led by Naveed Sattar, MD, of the Department of Pathological Biochemistry of the Glasgow Royal Infirmary, found that metabolic syndrome increase the risk for a coronary heart disease event significantly, with a univariate hazard ratio of 1.76. The univariate hazard ratio for developing diabetes among the subjects with metabolic syndrome was 3.50. The risk of disease was also found in the multivariate model that incorporated usual risk factors. For example, men who had 4 or 5 features of the syndrome had a 3.7-fold increased risk of coronary heart disease and a 24.5-fold increased risk of developing diabetes when compared with men who had none of the syndrome’s features. Men with metabolic syndrome who took pravastatin saw a risk reduction for coronary heart disease that was similar to those who took the drug but did not have metabolic syndrome.
The researchers concluded: “We demonstrate that a modified version of the NCEP [National Cholesterol Education Program] definition of the metabolic syndrome prospectively
identifies risk for CHD [coronary heart disease] and even more strongly predicts new onset diabetes. The risk for each outcome increases as the characteristic components of the syndrome accumulate. Minor modifications of the current definition as achieved by adding CRP [C-reactive protein] or lowering the glucose cutoff may enhance prediction of CHD and diabetes.”
Von Willebrand Syndrome and Aortic Stenosis
Patients with severe aortic stenosis frequently exhibit type 2a von Willebrand syndrome, said researchers from a variety of medical and research institutions in Lille, France, in the July 24, 2003, issue of The New England Journal of Medicine (N Engl J Med. 2003;349:343–349).
The condition appears to cause high shear forces at the site of the stenotic valve. These forces change the shape of the von Willebrand protein, resulting in proteolysis or changes in the proteins, loss of the largest multimers, and reduction in platelet adhesion to the vascular endothelium.
In this study, the researchers led by André Vincentelli, MD, and Sophie Susen, MD, from the Equipe d’Accueil 2693, University of Lille II, Faculté de Médecine, enrolled 50 consecutive patients with aortic stenosis into their trial. Of these, 42 underwent valve replacement. The researchers assessed platelet function under high shear stress and the collagen-binding activity of von Willebrand factor, as well as antigen levels and the multimeric structure of von Willebrand factor at baseline, 1 day, 7 days, and 6 months after the operation.
They found bleeding of the skin or mucosa in 21% of the patients. In 67% to 92%, they identified malfunction of platelets under high shear stress, decreased von Willebrand factor collagen-binding activity, and the loss of the largest multimers. The extent of the symptoms correlated with the severity of the aortic stenosis.
“Primary hemostatic abnormalities were completely corrected in the first day after surgery, but tended to recur at six months, especially when there was a mismatch between patient and prosthesis,” the researchers noted. “The present study demonstrates that acquired von Willebrand syndrome is a consequence of the mechanical obstruction of blood flow and that hemostatic abnormalities and bleeding are symptoms of severe stenosis. Further prospective studies are needed to determine whether hemostatic disturbances should be taken into account in the indications for valve replacement.”
Diet First, Then Statins
Canadian researchers said that a vegetarian diet that contains known cholesterol-lowering foods is as effective as lovastatin in lowering the levels of low-density lipoprotein in the blood in the July 23, 2003, issue of The Journal of the American Medical Association (JAMA. 2003;290:502–510).
The diet combined nuts such as almonds, soy proteins, and high-fiber foods such as oats and barley, along with a special margarine product that contains plant sterols. Forty-six patients of average age 59 years and body mass index of 29 were recruited from the Clinical Nutrition and Risk Factor Modification Center at St Michael’s Hospital in Toronto. They were randomly assigned to 1 of 3 groups: one that ate a low–saturated fat diet based on milled whole-wheat cereals and low-fat dairy foods; another that took 20 mg of lovastatin daily while eating virtually the same diet; and a third that ate a diet high in plant sterols, soy protein, viscous fibers, and almonds. All three groups followed the diet for a month.
All three groups had decreases in their low-density lipoprotein levels. The decrease in the first group was 8%; the second, 30.9%; and the third, 28.6%. C-reactive protein levels were reduced 10% in the first group, 33.3% in the second, and 28.2% in the third. Although the reductions seen in the second and third groups were significantly lower than the reductions in the first group, there was no statistically significant difference between the two treatment groups.
David Jenkins, MD, lead author and a professor in the University of Toronto’s Department of Nutritional Sciences as well as Director of the St Michael’s Hospital Nutrition Center, said the success of the sterol and nut diet may be linked to human ancestry. Humans evolved eating a diet high in fiber, nuts, vegetable proteins, and plant sterols. It may also be important for the modern human population, he said.
“As we age, we tend to get raised cholesterol, which in turn increases our risk of heart disease. This study shows that people now have dietary alternative to drugs to control their cholesterol at least initially,” said Dr Jenkins in a released statement.
The special diet might include a dinner of tofu bake with eggplant, onions, sweet peppers, pearled barley, and vegetables.
“The Food and Drug Administration has approved these cholesterol-lowering foods as having legitimate health claims for heart disease risk reduction,” said Dr Jenkins. “They are also being recommended by the American Heart Association and the National Cholesterol Education Program as foods that should be incorporated into the diet. And we have now proven that these foods have an almost identical effect on lowering cholesterol as the original cholesterol-reducing drugs.”
Jenkins said many people are being put on drugs before they give diet an adequate chance to reduce their cholesterol.
In an accompanying editorial, James Anderson, MD, of the Department of Internal medicine at the University of Kentucky College of Medicine in Lexington, wrote: “Managing diet is the key to treating all common lipid disorders.”
He notes, however, that strict dietary controls such as those recommended in this study must be accompanied by extreme motivation on the part of patients, encouragement from their physicians, and counseling by dietitians and/or nutrition consultants to be successful (JAMA. 2003;290:502–510).