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UNDERSTANDING ARTEROSCLEROSIS

Saving Hearts That Grow Old

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This article promotes a

Better understanding of atherosclerosis--the inflammation and buildup
of fatty deposits in blood vessels--has triggered new approaches
to treating the nation's leading causes of death

by Delia K. Cabe



 

 

Blood vessels are built to last. Up to about 100 years, some experts say, under normal wear and tear. For that to happen, you not only have to abide by a heart-healthy lifestyle--low-fat diet, weight in check, exercise, stress management, blood pressure control, good cholesterol numbers, moderate alcohol use, no smoking--but you also should be a woman, have the right genes and age slowly.

Cut to reality: we're not perfect. Our blood vessels endure various assaults because of factors only some of which we can control. We get heart disease--some 14 million Americans have it, and 500,000 die from heart attacks annually. The older we get, the more likely it is we'll end up with it. The proof is in the numbers: heart disease affects an estimated 15 percent of adults in their late 30s to early 40s, about 50 percent of 55- to 64-year-olds, and 65 percent of those in the next decade. Obviously, many of us slept through Heart Disease Prevention 101.

Yet the heart cognoscenti say only half to three fourths of heart disease cases result from the established risk factors. The rest come about from infection and other factors that may promote atherosclerosis, the buildup of fatty deposits in blood vessels. Indeed, current research indicates that all of us are in jeopardy from the leading cause of death in the U.S. Everyone needs to maintain a healthy lifestyle, says endocrinologist Joanne Manson, chief of the division of preventive medicine at Brigham and Women's Hospital in Boston. Everyone's at risk.

Efforts to Žnd additional means of preventing heart disease have led to the unearthing of about 300 predictors, including bad relatives of the troublemaker cholesterol as well as bacteria and baldness. Yes, baldness.

Manson and her colleagues at Harvard Medical School, which is afŽliated with Brigham and Women's Hospital, published a study this year that found that hair loss, speciŽcally on the crown of the head rather than at the front, is linked to a threefold greater risk of heart disease in men. Blame it on male hormones. The connection may be elevated androgen levels, which are associated with baldness and have been linked to atherosclerosis and a higher risk of blood clotting.

Such a marker as baldness may seem an unlikely place to look for risk factors. But in 1988 Manson's group also found a correlation between height and heart disease. Let's just say that taller people are better off--perhaps because they have wider blood vessels. Such information may help identify people who are more prone to heart disease and may lead to better means for prevention and interruption of disease progression tailored to an individual's physiology. The discovery of many of these markers arose from a closer examination of the cycle of inžammation, plaque formation and injury that causes atherosclerosis, the forerunner to angina and to heart attack and stroke, the major causes of death and disability as we move into later life.

The broadened understanding of the underlying causes of heart disease has paved the way to potential therapies, including antibiotics and ACE (angiotensin converting enzyme) inhibitors. ACE inhibitors were developed to control high blood pressure, but they have recently been found to have therapeutic effects in preventing heart disease.

Read My Lipids

Atherosclerosis, which begins in our teenage years and builds up as we age, starts when the smooth muscle cells underneath the endothelium, or inner lining, of blood vessels release a signal in response to high cholesterol levels. This signal attracts monocytes--white blood cells that Žght infection and amass cholesterol, calcium and other substances. The resulting cheesy mass, or plaque, bulges like a pimple. Over time, the endothelium loses its elasticity and may rupture.

Illustration: Dusan Petricic

This injury to the lining summons clot-forming platelets, which further restrict blood žow through the already narrowed artery. An inadequate supply of oxygen-rich blood to heart muscle may cause temporary chest pain, or angina, and if blood žow is completely cut off, a heart attack--in clinical terminology, a myocardial infarction. All this from the best-known harbinger of heart trouble, the lipid cholesterol. But only to a degree.

Cholesterol has been the cause célčbre in heart disease prevention. Fifty percent of Americans have elevated cholesterol levels. And the increase occurs naturally as we age--mostly after about age 45 for men and age 55 for women. Women in their reproductive years tend to have lower levels than men of the same age. After menopause, their cholesterol levels rise. But we also should fault our lifestyles. Without a doubt, lowering dietary intake of cholesterol and saturated fats does wonders for the heart. The goal is to keep down blood levels of the bad cholesterol (low-density lipoprotein, or LDL), behavior that can produce a 25 to 35 percent reduction in what the pros term "cardiovascular events"--that is, heart attacks, strokes and the like. At the same time, don't forget about raising your levels of good cholesterol (high-density lipoprotein, or HDL), which mops up LDL.

But the picture's more complex. Some people develop heart disease in spite of attaining ideal lipoprotein levels. For them, an approach that goes beyond controlling cholesterol and other lipids may be in their future.

Six years ago researchers with the Framingham Heart Study (the decades-long study that brought us the term "risk factor") identified a relative of LDL called lipoprotein(a) as an independent risk factor for heart disease. Lp(a) fosters the deposition of cholesterol on artery walls and interferes with the body's means of dissolving clots. Lp(a) also enhances oxidation of LDL.

Oxidation is nature's way of spoiling things like food. But old food gets thrown out, whereas oxidized LDL stays in the bloodstream and penetrates the endothelium. Elevated levels of Lp(a), which are most likely genetic, place people in the "high risk" category, as would a total cholesterol level greater than 240 milligrams per deciliter of blood (mg/dl) or an HDL level less than 35 mg/dl. Blood tests to measure Lp(a) have become available, but Lp(a) is difŽcult to lower. Two therapies that show promise include the vitamin niacin at prescription doses that are 100 times higher than the recommended daily allowance and the hormone estrogen. In addition, a few studies suggest that reduction in LDLs may help.

But it now seems that some LDL particles are worse than others. In the few studies done to date, people with predominantly small LDL particles have a risk of heart disease between three and four and a half times greater than those with large LDL particles. Why does size matter? Small particles are more prone to oxidizing, damaging blood vessel walls and invading them 50 percent faster than larger particles to initiate cholesterol accumulation.

Looking for Little Stuff

Ablood test to measure LDL particles is useful in determining which drugs would be most effective in individuals with heart disease or in those who have a strong family history of it. Fortunately, current heart disease interventions cut down small-particle LDL levels. These include exercising, taking niacin (but only under a doctor's supervision) or some cholesterol-lowering drugs. Diet can also help lower triglycerides (another type of fat in the blood).


Illustration: John W. Karapelou

Even the good cholesterol, HDL, turns into a traitor in certain environments, much like a chameleon changes its colors in different surroundings, says cardiologist Alan M. Fogelman, executive chairman of the department of medicine at the University of California at Los Angeles School of Medicine.

Normally, HDL prevents LDL oxidation. But he and other researchers have observed HDL in its other guise. After surgery or during infections, atherosclerotic plaques burst more easily. These ruptures may occur because the immune system has geared up to Žght infection. In this environment, HDL changes into a molecule that promotes LDL oxidation. If studies bear out this model, researchers could develop medications to thwart HDL's metamorphosis.

The possibility that the inžammation within the blood vessel walls and the immune system's response might be triggered by an infection led investigators to two bacteria--Chlamydia pneumoniae and Helicobacter pylori (the latter was recently deemed the culprit in stomach ulcers)--and herpesvirus. Of these three, C. pneumoniae, which causes respiratory infections, has received the most attention. The burning question is whether this bacterium, which has been found in 70 to 80 percent of plaques taken from heart disease patients, is an innocent bystander or an accomplice.

Cardiologists Jeffrey L. Anderson and J. Brent Muhlestein of the University of Utah are among several researchers looking for the answer. But these two colleagues were not about to take their cue from the scientist who gave himself an ulcer by ingesting H. pylori. Instead of hardening their arteries in the name of medicine, Anderson and Muhlestein opted for studies on other animals. They set about infecting rabbits, which normally do not develop atherosclerosis, with C. pneumoniae. Plaques did indeed appear, and antibiotics reduced the number of these thickenings.

Having shown cause and effect, the researchers set their sights on humans with heart disease who had evidence of past infection with C. pneumoniae. After six months on the antibiotic azithromycin, the human subjects had a modest but signiŽcant reduction in key markers of blood vessel inflammation: C-reactive protein, tumor necrosis factor, and the interleukins IL-1 and IL-6, all of which are released by the immune system. At the end of two years, Anderson and his colleagues hope to see at least a 50 percent reduction among those treated with the antibiotic in the frequency of heart attacks, angina, stroke, and procedures such as angioplasty and bypass surgery.

Anderson is among the investigators taking part in long-term trials now under way at several medical institutions with large numbers of human subjects. If antibiotics do signiŽcantly reduce the incidence, physicians say this would be a major advance in heart disease treatment. Heart patients who show these inžammatory markers might be prescribed medication to combat the bacteria. Until that time, though, I think we shouldn't be giving antibiotics to our patients, Anderson says, because studies are still ongoing.

Meanwhile cardiologists are assessing whether taking folate and other B vitamins might lower heart disease rates. Accumulating evidence from the Physicians Health Study, the Framingham Heart Study and others seems to point to a direct relationship. And homocysteine levels in blood could be the smoking gun. Homocysteine, an amino acid that results from the body's metabolism of food, may contribute to atherosclerosis and increase clotting because it makes platelets stickier. In addition, homocysteine may lessen the žexibility of blood vessels, slowing blood žow. In people such as older adults and postmenopausal women, who typically have high levels of homocysteine in their blood, the risk of heart attack and stroke increases. Folate and other B vitamins may bring about a decrease in heart disease risk because they break down homocysteine.

Folate in Your Diet

Randomized, controlled trials are needed to determine if managing homocysteine levels, as is done with cholesterol, could join the list of heart safeguards. Nevertheless, the American Heart Association currently advocates that people who are at high risk for heart disease include more folate and other B vitamins in their diet--at least 400 micrograms' worth. That deed is accomplished simply by eating a balanced diet that includes the already recommended Žve daily servings of fruits and vegetables.

High blood pressure, or hypertension, was long ago shown to predispose people to atherosclerosis, heart attack and stroke. Hypertension is indeed an affliction of aging. The number of men and women with high blood pressure rapidly escalates in older age groups. More than 50 percent of Americans over age 65 have high blood pressure. First-line treatment to control hypertension involves a healthy diet, exercise and weight loss. If that fails, physicians prescribe antihypertensives such as ACE inhibitors. Until the 1980s, the presumed and only beneŽt of ACE inhibitors was the foiling of the body's production of angiotensin, a chemical that constricts arteries, so that blood can žow through vessels easier. But new research indicates that ACE inhibitors do more. So much more that the HOPE study evaluating the effects of the ACE inhibitor ramipril in 9,541 heart disease patients at multiple medical institutions was stopped six months early and its results released last November, before publication, so that study participants receiving a placebo could also reap the drug's beneŽts.

We got stunning results--more than we expected, says study chairman and cardiologist Salim Yusuf of McMaster University in Ontario. "It is like the discovery that cholesterol drugs lower risks of heart attacks." The data showed a 22 percent overall reduction of heart attacks, stroke or death from other cardiovascular causes. The beneŽt was independent of ramipril's small reduction in blood pressure. In fact, most of the participants did not have hypertension when they enrolled in the study. Ramipril, Yusuf adds, may have an important effect within blood vessel walls, but it is unknown if other ACE inhibitors work in a similar fashion. Now physicians can offer one more preventive approach to their patients.

But these pills and other advances are meant for those of us who have flaunted time-tested heart-saving advice or the few who have only their genes to blame for abnormal lipid levels and such. As for waiting for that quick Žx, researchers promise none. You can hope and pray. Take it from the grand pooh-bah of heart health, American Heart Association president Lynn A. Smaha: New research Žndings hold promise but no certainty of licking heart disease, so in the meantime, take care of yourself.

 

 

Better understanding of atherosclerosis--the inflammation and buildup
of fatty deposits in blood vessels--has triggered new approaches
to treating the nation's leading causes of death

by Delia K. Cabe



This article shows that reactive chemicals initiate a healing response which causes the development of plaque

 

A:\Arteriosclerosis-thrombosis-superoxides.htm

9Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1199.)
© 2000 American Heart Association, Inc.

 

 

Vascular Biology

Relationship Between Homocysteine and Superoxide Dismutase in Homocystinuria

Possible Relevance to Cardiovascular Risk

David E. L. Wilcken; Xing Li Wang; Tetsuo Adachi; Hirokazu Hara; Natalia Duarte; Kathryn Green; Bridget Wilcken

From the Department of Cardiovascular Medicine (D.E.L.W., X.L.W., N.D.), Prince of Wales Hospital, and University of New South Wales Centre for Thrombosis and Vascular Research, Sydney, Australia; the Laboratory of Clinical Pharmaceutics (T.A., H.H.), Gifu Pharmaceutical University, Gifu, Japan; and the NSW Biochemical Genetics Service (K.G., B.W.), the Royal Alexandra Hospital for Children, Sydney, Australia.

Correspondence to Professor David Wilcken, Cardiovascular Genetics Laboratory, Edmund Blacket Building, Prince of Wales Hospital, Randwick, NSW 2031, Australia. E-mail d.wilcken@unsw.edu.au

Abstract—A modest homocysteine elevation is associated with an increased cardiovascular risk. Marked circulating homocysteine elevations occur in homocystinuria due to cystathionine ß-synthase (CßS) deficiency, a disorder associated with a greatly enhanced cardiovascular risk. Lowering homocysteine levels reduces this risk significantly. Because homocysteine-induced oxidative damage may contribute to vascular changes and extracellular superoxide dismutase (EC-SOD) is an important antioxidant in vascular tissue, we assessed EC-SOD and homocysteine in patients with homocystinuria. We measured circulating EC-SOD, total homocysteine (free plus bound), and methionine levels during the treatment of 21 patients with homocystinuria, 18 due to CßS deficiency, aged 8 to 59 years, and 3 with remethylating defects. We measured total homocysteine by immunoassay, EC-SOD by ELISA, and methionine by amino acid analysis and assessed interindividual and intraindividual relationships. There was a significant, positive relationship between EC-SOD and total homocysteine. For the interindividual assessment, levels were highly correlated, r=0.746, N=21, P<0.0001. This relationship was maintained after taking into account intraindividual patient variation (r=0.607, N=62, P<0.0001). In 2 newly diagnosed CßS-deficient patients, treatment that lowered the markedly elevated pretreatment homocysteine level (from 337 to 72 and from 298 to 50 µmol/L) reduced the associated elevated EC-SOD in each by 50%. EC-SOD and methionine levels were unrelated (r=0.148, n=39, P=0.368). The positive relationship between circulating EC-SOD and homocysteine could represent a protective antioxidant response to homocysteine-induced oxidative damage and contribute to reducing cardiovascular risk in homocystinuric patients. EC-SOD levels may be relevant to the pathogenesis of vascular disease in other patient groups.


Key Words: homocysteine • superoxide dismutase • oxidative stress • vascular disease • cystathionine ß-synthase deficiency