Worse than cholesterol? Hard to believe, perhaps, but the top health concern of millions of Americans is about to be trumped by what doctors say is an even bigger trigger of heart attacks. Dr. Paul Ridker and his team of researchers have conducted studies that suggest inflammation is more important than cholesterol in triggering heart attacks. The condition is low-grade inflammation, which may originate in a variety of unlikely places throughout the body, including even excess fat. New federal recommendations are being written that will urge doctors to test millions of middle-aged Americans for it.

PERQUE note: Inflammation is an effort of the body to repair that is blocked by nutrient or buffering mineral deficits, inability to get rid of toxins, or defense burdens of the immune system that prevent repair from proceeding. The PERQUE Wellness cross-reference guide to cardiovascular health includes all the essential nutrients to overcome deficits and enhance detoxification. You can monitor results by observing declines in C-Reactive Protein (CRP) and homocysteine as well. In refractory cases, consider boosting immune system repair competence by screening for immune system burdens using the ELISA/ACT Lymphocyte Response Assay (LRA) delayed hypersensitivity tests and, for more information call: (800) 525 7372.

The discovery of its surprising ill effects is causing a top-to-bottom rethinking of the origins and prevention of heart trouble. Doctors call it a revolutionary departure from viewing the world's top killer as largely a plumbing problem blamed on cholesterol-clogged arteries, the standard theory through the modern era of cardiology.

"The implications of this are enormous," says Dr. Paul Ridker of Boston's Brigham and Women's Hospital. "It means we have an entire other way of treating, targeting and preventing heart disease that was essentially missed because of our focus solely on cholesterol." In the past year or two, experts say, the evidence has become overwhelming that inflammation hidden deep in the body is a common trigger of heart attacks, even when clogging in the arteries is minimal.

Now the main question is: How aggressively should otherwise healthy people be tested to find and treat it? The new recommendations are still being drawn up, but they will offer the first formal blueprint to answer this, probably sometime in the fall.

Doctors writing them say they will almost certainly recommend broad testing. Inflammation can be measured with a generic $10 test that looks for high levels of a chemical called C-reactive protein, one of many that increase during inflammation.

Experts expect it to quickly become a standard part of physical exams. As a result, many people ordinarily considered at low risk will probably be put on statin drugs, which lower inflammation as well as cholesterol. No one disputes the importance of cholesterol. Yet half of all heart attack victims have levels that are normal or even low. Clearly, something big was missing from the equation, and that appears to be inflammation. Ridker estimates that between 25 million and 35 million healthy middle-aged Americans have normal cholesterol but above-average inflammation, putting them at unusual risk of heart attacks and strokes.

A series of landmark studies by his team, beginning in 1997, suggest inflammation is more important than cholesterol at triggering heart attacks. They found those with high levels of C-reactive protein have twice the risk of people with elevated cholesterol. High amounts of the protein also predict increased risk of heart attacks and strokes years before they occur, even when cholesterol levels are low. Having both inflammation and high cholesterol together is especially ominous, resulting in a nine-fold increase in risk.

Everyone who reaches middle age has some degree of fatty buildup, called plaque, in the heart arteries. The new evidence suggests it becomes threatening if weakened by inflammation, which makes it squishy and fragile. Even a small lump of plaque can burst like an overripe pimple, prompting the formation of a clot that in turn chokes off blood flow and causes a heart attack.

Many people with no outward signs of anything wrong have high levels of internal inflammation. It is exactly the same sort that causes swelling, heat and redness during infections or allergic rashes. Doctors believe the internal inflammation has many possible sources. Often, the plaque itself becomes inflamed as white blood cells invade in a misguided defense attempt. But inflammation that arises elsewhere apparently can be as bad, for it bombards the plaque with damaging chemicals. For instance, fat cells churn out these inflammatory proteins, which helps explain why being overweight is so bad for the heart. Other possible triggers include high blood pressure, smoking and lingering low-level infections, such as chronic gum disease.

Although many chemicals increase during inflammation, C-reactive protein, or CRP, is particularly easy to measure. Some already test for it, including White House doctors, who checked President Bush's CRP level last summer (his was extremely low).

In March, the Centers for Disease Control and Prevention and the American Heart Association held a meeting of 50 experts in Atlanta to review the scientific evidence on inflammation and make recommendations. These are still being discussed, but some doctors involved say they are likely to urge CRP screening for people already considered at mild to moderate risk of heart attacks. These include smokers and those with a combination of other less ominous risks, such as being middle-aged and having borderline high cholesterol or blood pressure. For instance, they might recommend CRP testing for a 45-year-old man with cholesterol in the low 200s and blood pressure just below the cutoff for treatment. However, others believe CRP should measured in everyone over age 40, just like cholesterol, regardless of their other risk factors.

"It begins to look like a standard risk factor that one would evaluate at least once in middle age in most people," says Dr. Wayne Alexander of Emory University, one member of the recommendations committee. "This is a very important concept for the general public to be aware of and to think about for their own health." Doctors hope to have the recommendations ready for publication in the journal Circulation in November, followed by a campaign to teach doctors and ordinary people about it.

"Our goal is to have a broad-based consensus and use all available means to disseminate that information widely," says Dr. George Mensah, the CDC's chief of cardiovascular health. Many hospitals can already do the test. However, until the recommendations come out, most doctors are unlikely to know exactly whom to test or what to make of the results. In fact, the White House doctors who checked Bush had to call Ridker to figure out how to interpret his numbers.

CRP probably will not matter much for heart attack survivors and others who already know they have heart disease, since presumably doctors are already doing everything they can to keep their condition from getting worse. "We believe the niche for C-reactive protein -- and it is a large niche -- is the healthy population who want to do what they can to lower their risk of cardiovascular disease," says Dr. Richard Cannon of the National Heart, Lung and Blood Institute.

Screening is important because inflammation can be readily lowered in several ways. One of the most powerful is losing weight. Exercise also helps, as does moderate alcohol intake, giving up smoking and lowering blood pressure. Of course, this amounts to the same healthy living advice that doctors have long dispensed. But now they have a much better understanding of why it works so well. Furthermore, they are likely to urge these habits on people with bad CRP readings who until now would have seemed to be at no special risk of heart problems.

Many of the standard heart medicines also lower inflammation. These include aspirin, Plavix, ACE inhibitors and the statin drugs, such as Lipitor and Zocor. [These however are less safe than primary nutrient repair stimulating supplements such as PERQUE Life Guard, PERQUE MitoGuard Plus, PERQUE Potent C Guard, and PERQUE Pain Guard Forté].

The statins are now prescribed to lower cholesterol, and they do so dramatically. But studies have shown they ward off heart attacks much more powerfully than would be expected from their effects on cholesterol alone. In fact, people with moderate cholesterol seem to benefit just like those with readings off the charts. Lowering inflammation probably explains why. [The data suggests that the mild antioxidant effects of statin medications are the basis for the benefits. This is true for antioxidant deficient people. People taking sufficient, more effective nutrient antioxidants do not benefit from statins.]

Still, some important details remain to be settled. One is population-wide data on CRP levels and their connection to heart disease. Ridker is finishing a large study, to be released later this year. Ridker's study traces this relationship with CRP readings from tens of thousands of people. "Paul has got data now that slam-dunks it," says Dr. Richard Milani of the Ochsner Clinic in New Orleans.

Another gap is rock-solid evidence that lowering inflammation truly prevents heart attacks and saves lives. Ridker hopes to prove this with a study to begin this fall that will compare statin drugs and dummy pills in 15,000 middle-aged men and women with normal cholesterol and above average CRP.

The new thinking about inflammation "will change everything we do in heart disease," predicts Dr. Eric Topol, cardiology chief at the Cleveland Clinic. "In the last decade, people talked about their cholesterol levels," he says. "In the next decade, the cocktail chatter will be, 'What's your C-reactive protein?' Everyone will need to know that."

Taking high doses of vitamin E may help prevent heart attacks and strokes by preventing the progression of hardening of the arteries, according to study findings presented here at the 41st Annual Conference on Cardiovascular Disease Epidemiology and Prevention. Dr. James H. Dwyer of Keck School of Medicine, University of Southern California, said the effect is limited to doses of more than 300 milligrams a day. These high doses--sometimes as high as 1,000 milligrams a day-were associated with a slower progression of atherosclerosis, the disease commonly called hardening of the arteries. The recommended dietary allowance for vitamin E is 15 milligrams per day for adult men and women, and the tolerable upper intake level (UL) is 1,000 milligrams per day.

People who take more than the UL may increase their risk of hemorrhage, according to the Institute of Medicine. Anyone considering taking higher-than-recommended doses of the vitamin should consult their doctor first. Dwyer checked the effect of vitamin E by measuring the build-up of plaque in the carotid arteries of 573 men and women who work for a California utility company.

The carotid arteries are located in the neck, and clogging of the arteries can increase the risk of stroke. At annual check-ups, Dwyer used ultrasound to measure the thickness of the arterial walls in the volunteers who were healthy and free of diagnosed cardiovascular disease when the study began in 1994. In addition to measuring the carotid arteries, Dwyer and his colleagues used questionnaires to gather information about the use of vitamin supplements and diet.

This latest report is based on three years' of ultrasound screenings. In an interview with Reuters Health, Dwyer said the study volunteers were divided into four groups based on the use of vitamin E. The benefit was only seen in the group taking the highest level of the vitamin. He added that the benefit was limited to "vitamin E from supplements. We found no effect for dietary vitamin E."

While vitamin E was beneficial, vitamin C--another antioxidant--had no benefit and appeared to promote the progression of disease. Dwyer initially reported this negative finding for vitamin C last year based on 2 years' ultrasound data.'' Dwyer said he could not explain why one antioxidant was beneficial while the other was harmful, but said that in laboratory experiments biochemists have demonstrated that high levels of vitamin C "could induce a pro-oxidant pathway."

That would mean that vitamin C was promoting oxidation of LDL (''bad'') cholesterol. This oxidation process contributes to the build-up of plaque, the substance that narrows arteries. He said, however, that this effect has only been demonstrated in test tubes, not humans. Note: Careful studies in humans have not shown the laboratory or in vitro effect to occur in people or in vivo. Further, Dwyer's study was not designed to optimize ascorbate intake nor did it control for the form of ascorbate nor the state of the ascorbate consumed. Oxidized ascorbate or d-ascorbate (isoascorbate) are not beneficial and may be harmful. PERQUE Potent C Guard is 100% l-ascorbate, fully reduced, and fully buffered. It is recommended that intake be based on ascorbate calibration needs.

Hypercholesterolemia, a significant cardiovascular risk, is prevalent in the American population. Although many pharmaceuticals provide adequate therapeutic benefits, the majority carry significant adverse reactions, such as liver problems with the statins. Accordingly, natural means to lower cholesterol levels via safe means would be welcomed. We examined hypercholestero-lemic patients (220-300 mg/dl) in a randomized, double blind, placebo-controlled study. Three groups of 10 patients each received placebo bid, chromium (Cr as ChromeMate) 200 ug bid, or Cr 200 ug bid plus Grape Seed Extract (GSE; soluble OPC) (ActiVin) 100 mg bid. Over 2 months, the change in total cholesterol from baseline among groups was: placebo -3.5% +/-4 (SEM), Cr -10% ±5, and the combination of Cr=+ GSE - 16.5 % ±3. The decrease in the last group was significantly different from placebo (p<.01). The major change was in the LDL levels: placebo -3.0% ±4%, Cr - 14% ±4%, and the combination -20% ±6%. Again, the combination significantly decreased LDL when compared to placebo. HDL levels did not essentially change among the groups. Also, there was no significant difference for the triglyceride concentrations among the groups. In this basically normotensive population, the blood pressure changes were not significantly different. Currently, we are examining serum oxidized LDL concentrations in these patients. We conclude that a combination of natural products, specifically Cr and GSE, can decrease LDL levels significantly.

N.A. Talpur, B. Echard, S. Osman, D. Wallerstedt, M.N. Bui, V. Manohar, D. Bagchi, H.G. Preuss. Georgetown University Medical Center, Washington D.C. FASEB JOURNAL, 2000; 14: abstract 503.8

Note: These and other cardiovascular protecting nutrient are found in PERQUE2 Life Guard and PERQUE Pain Guard Forté. For a comprehensive supplement recommendation plan to reduce cardiovascular risk, click here. In various studies, chromium as citrate, picolinate, or polynicotinate have given equally beneficial results.

First the good news: Comprehensive antioxidants as found in PERQUE (e.g. Potent C Guard, Pain Guard Forte, Liva Guard and Mito Guard Plus) can eliminate the oxidized cholesterol and oxidized fats that are the cardiovascular toxins promoting heart and vascular disease. Further, healthy body chemistry usually translates into health estrogen balance at all ages.

Heart disease is the number one cause of death in both men and women. Women worry about getting breast cancer, but heart disease is much more of a threat. One out of every two women will die of heart disease, while only one in 26 will die of breast cancer. Because heart disease is such a threat to women's health, it's imperative that they be aware of things that could have an impact on it. New studies point to certain estrogen drugs as being potent culprits in the development of heart disease in women.

Premarin, a synthetic estrogen drug made from horse urine, is one of the most widely-prescribed drugs ever. If you are a woman taking this drug, take note: new data shows that Premarin may have serious adverse effects on heart health. In the largest study of its kind ever done, Premarin (combined with a synthetic progestin drug) significantly increased the risk of heart attack in women with heart disease. It also caused the risk of getting a blood clot to skyrocket. The study was published in the Journal of the American Medical Association (JAMA) in 1998. Recent studies have been published that may help explain why this occurred.

C-reactive protein

C-reactive protein is one of four proteins associated with inflammation that can be used to predict heart attack risk. Elevations in it, or the amino acid homocysteine, indicate that a person has a greater chance of having a heart attack or stroke. It's desirable to keep both-homocysteine and C-reactive protein-as low as possible. [Elevated homocysteine means a lack of one or more of B6, B12, folate, and magnesium… all found in PERQUE Life Guard, as well as PERQUE Mg Plus Guard, best absorbed with PERQUE Choline Citrate,(particularly designed to overcome magnesium uptake block). Adequate protective nutrients bring homocysteine to healthy, low levels.]

Two new studies show that Premarin drastically elevates C-reactive protein. Both studies show that within 6 to 12 months, Premarin causes C-reactive to shoot up 84% -85%. The elevation persists at three years (which is the longest the phenomenon has been studied). It makes no difference whether the drug is taken with progestins or whether it's taken on a cyclical basis. One of the studies used four different regimens, and it made no difference. These two studies are confirmed by at least two other published studies showing similar results.

Although it's clear that Premarin elevates C-reactive protein, it's not clear whether other types of synthetic estrogen also increase the protein. A study from the Netherlands finds that 2 mg. of micronised estradiol (with or without progestins) similarly increases C-reactive protein. However, a study on women with type II diabetes given transdermal estradiol with norethisterone showed significantly reduced C-reactive protein. And it's doubtful that natural estrogen itself would elevate the body's inflammatory proteins. French researchers found no elevations in C-reactive protein due to natural increases in estrogen caused by fertility drugs. So it doesn't appear that estrogen per se increases C-reactive protein, only certain types of synthetic estrogens (or their metabolites).

As part of the "acute phase response", C-reactive protein interacts with cells known as neutrophils. Neutrophils are a type of white blood cell found wherever inflammation is present. These "inflammatory cells" generate large amounts of oxidative stress as part of their role in defending the body against bacteria and viruses. C-reactive protein appears to activate neutrophils.

Documented conditions (in addition to heart disease) where C-reactive shows up are autoimmune disorders such as rheumatoid arthritis; pancreatitis; diabetes; cystic fibrosis; gastrointestinal cancer; and chronic renal failure. It is likely that most chronic diseases cause elevations in C-reactive protein.

C-reactive protein seems to cause depletion of important nutrients such as vitamins A, C, E and B6, plus carotenoids (lutein, lycopene, beta-carotene), zinc and selenium. These nutrients decline in the body when C-reactive protein goes up. It may be wise to replace these nutrients if you have a condition in which C-reactive protein may be activated.

C-reactive protein may be suppressed by taking aspirin or ibuprofen. In these cases the repair deficit repairs and the body is blocked in reacting to the repair deficit. In contrast, the cause of repair deficit and inflammation can be addressed by adequate vitamin(s) E, DHEA, nettle leaf and essential oils such as EPA, CLA, and ALA, Avoiding estrogenic hormone replacement drugs would also appear to help prevent a pathological increase in C-reactive protein levels.

References

1. Cushman M, et al. 1999. Effect of postmenopausal hormones on inflammation-sensitive proteins: the postmenopausal estrogen/progestin interventions (PEPI) study. Circulation 100:717-22.

2. de Valk-de Roo GW, et al. 1999. Both raloxifene and estrogen reduce major cardiovascular risk factors in healthy postmenopausal women: a 2-year, placebo-controlled study. Arterioscler Thromb Vasc Biol 19:2993-00.

3. Hulley S, et al. 1998. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 280(7):605-13.

4. McMillan DC, et al. 2000. Changes in micronutrient concentrations following anti-inflammatory treatment in patients with gastrointestinal cancer. Nutrition 16:425-8.

5. Ricoux R, et al. 1994. [Plasma concentration of C-reactive protein in patients with high estrogen levels]. (French). Ann Biol Clin 52:125-8.

6. Sattar N, et al. 1999. Hormone replacement therapy and sensitive C-reactive protein concentrations in women with type-2 diabetes [letter]. Lancet 354(9177):487-8.

7. van Baal WM, et al. 1999. Increased C-reactive protein levels during short-term hormone replacement therapy in healthy postmenopausal women. Thromb Haemost 81:925-8.

8. Walsh BW, et al. 2000. The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab 85:214-18.

9. Zanger D, et al. 2000. Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal women with coronary artery disease on appropriate medical management. J Am Coll Cardiol 36:1797-802

Do Statins have a Role in Primary Prevention?

Two important questions regarding statin therapy are:

• What is the overall health impact when statins are prescribed for primary prevention?
• Should the dose of statin be titrated to achieve target lipid levels?

Three new randomized controlled trials1-3, which help answer the first question and one trial providing insight into the second question have been published since our last Letter on lipid lowering therapy. This Letter addresses the first question. Estimating the overall health impact of statins in primary prevention requires balancing possible benefits and possible harms.

In this Letter benefit is estimated by combining two cardiovascular serious adverse events known to be reduced by statins in secondary prevention trials: total myocardial infarction (fatal and non-fatal)5 and total stroke (fatal and non-fatal).6 The balance between benefit and harm (overall health impact) is estimated by total mortality and total serious adverse events. Serious adverse events include any untoward medical occurrence that results in death, is life threatening, requires hospitalization or prolongation of hospitalization, or results in persistent or significant disability.

Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)

PROSPER studied the effect of pravastatin compared to placebo in two older populations of patients: 56% primary prevention (no past or symptomatic cardiovascular disease) and 44% secondary prevention (past or symptomatic cardiovascular disease) (Table 1). Pravastatin did not reduce total myocardial infarction or total stroke in the primary prevention population, RR 0.94 [0.78 - 1.14], but did so in the secondary prevention population, RR 0.80 [0.68 - 0.94], ARR 4.3%, NNT 23 for 3.2 years. Measures of overall health impact in the combined populations, total mortality and total serious adverse events, were unchanged by pravastatin as compared to placebo, RR 0.98 [0.84 - 1.14] and 1.01 [0.96 - 1.06], respectively.

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)

ALLHAT-LLT was designed to determine whether pravastatin compared with usual care reduces all-cause mortality in older, moderately hypercholesterolemic, hypertensive patients with at least 1 additional coronary heart disease risk factor. The published data is for the whole population, 86% of which was primary prevention. Pravastatin did not reduce total myocardial infarction and total stroke, RR 0.91 [0.82 - 1.01]. Pravastatin also did not reduce total mortality, RR 0.99 [0.89 - 1.09]. Total serious adverse events were not reported.

What is the overall health impact when statins are prescribed for primary prevention?

To attempt to answer this question we combined the data from the 5 mostly primary prevention trials, the 3 above plus 2 published earlier7,8 (Table 1 & Table 2). Note that these calculations reflect a population that is 84% primary prevention and 16% secondary prevention. In the pooled data the statins reduced the cardiovascular measures, total myocardial infarction and total stroke, by 1.4% as compared to control.

This value indicates that 71 mostly primary prevention patients would have to be treated for 3 to 5 years to prevent one such event. This can be compared with the same pooled outcome in 4 large secondary prevention statin trials, ARR 4.8%, NNT 21 for 5 years. (Letter #42, HPS4) In the 2 trials where serious adverse events are reported, the 1.8% absolute reduction in myocardial infarction and stroke should be reflected by a similar absolute reduction in total serious adverse events; myocardial infarction and stroke are, by definition, serious adverse events. However, this is not the case; serious adverse events are similar in the statin group, 44.2%, and the control group, 43.9% (Table 2).

This is consistent with the possibility that unrecognized serious adverse events are increased by statin therapy and that the magnitude of the increase is similar to the magnitude of the reduction in cardiovascular serious adverse events in these populations. This hypothesis needs to be tested by analysis of total serious adverse event data in both past and future statin trials. Serious adverse event data is available to trial authors, drug companies and drug regulators. The other measure of overall impact, total mortality, is available in all 5 trials and is not reduced by statin therapy. (see Table below)

CONCLUSIONS

• If cardiovascular serious adverse events are viewed in isolation, 71 primary prevention patients with cardiovascular risk factors have to be treated with a statin for 3 to 5 years to prevent one myocardial infarction or stroke.
• This cardiovascular benefit is not reflected in 2 measures of overall health impact, total mortality and total serious adverse events. (Table 2). Therefore, statins have not been shown to provide an overall health benefit in primary prevention trials.

PERQUE Cardiovascular risk reduction recommendations

1. Eat an alkaline way diet with supplementation as needed to keep the first morning urine pH in the health 6.5-7.5 range

2. Take the following cardiovascular protective supplements: