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Inflammation, Cardiovascular Disease, and Omega-3s
4/22/2005
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Research confirms damaging interaction between cholesterol and inflammation

by Craig Weatherby


Doctors’ understanding of cardiovascular disease (CVD) is undergoing a sea change, as exemplified by a recently published study from Harvard University researchers who examined predictors of cardiovascular disease (CVD) in women.


The results highlight the shifting view of CVD, from being a condition caused solely by imbalanced cholesterol levels, to one in which inflammation plays a key role.


The authors analyzed data from the Women's Health Initiative, which followed more than 72,000 women, aged 50 to 79. They found that participating women with a white blood cell count in the high normal range—more than 6.7 billion white cells per liter of blood—had twice the risk of fatal heart disease, and were 40 percent more likely to have heart attacks, 46 percent more likely to have strokes, and 50 percent more likely to die of all causes over the next six years, compared to those with a count of 4.7 billion white cells per liter.


White blood cells are part of the body's immune defense system, and their levels measure inflammation in the body.  This report adds to the growing body of evidence that inflammation play an important role in cardiovascular disease.


Studies examining links between CVD and inflammation have focused mostly on a molecule called C-reactive protein (CRP) as a marker of inflammation. This study also measured CRP levels, and found that white blood cell readings were just as good as an indicator of risk. The risk of CVD among women with elevated levels of both inflammation markers—white blood cells and CRP—was seven times higher than in women with lower levels of both markers.


The finding itself is not new, but its application to women is.  The real significance of this study is that it adds momentum to a shift in our understanding of cardiovascular disease, with implications for prevention and treatment, and the role omega-3s may play in the future.  Hang on for a ride though the world of recent CVD research.


Inflammation, and cardiovascular disease (CVD)

Doctors once viewed the risk of heart attacks as primarily a “clogged drains” plumbing problem, in which fatty deposits accumulated slowly on the inner walls of major coronary arteries, until they cut off the blood supply to key heart muscles.  (The term “atherosclerosis” refers to fat-clogged arteries.)  A cholesterol-carrying molecule called LDL—the so-called “bad” cholesterol—constitutes the bulk these arterial deposits and statistics show that people with high LDL levels have the greatest risk of developing heart disease.


However, half of all heart attacks occur in people with normal cholesterol levels. And, as imaging techniques have improved, it became clear that the arterial plaques that preceded many heart attacks weren't particularly thick.


In the 1990s, Paul Ridker, M.D.—a Harvard-affiliated cardiologist at Brigham and Women's Hospital in Boston became convinced that inflammation was destabilizing arterial plaques.


Dr. Ridker tested people for levels of C-reactive protein (CRP), a standard marker for chronic inflammation. During an acute infection, levels of CRP rise from less than 10 mg/L to 1,000 mg/L or more. By 1997, Ridker and his colleagues had shown that healthy middle-aged men with the highest CRP levels were three times as likely to suffer a heart attack in the next six years as were those with the lowest CRP levels. Further research established that a CRP reading of 3.0 mg/L or higher triples the risk of heart disease—and the danger seems even greater in women than in men. Conversely, people with extremely low CRP levels (less than 0.5 mg/L) rarely suffer heart attacks.


Dr. Ridker summarized the state of the science in a 2004 literature review: "Epidemiological and clinical studies have shown strong and consistent relationships between markers of inflammation and risk of future cardiovascular events.”


And, the results of a Mayo Clinic study indicate that inflammation is a key factor in creating arterial blockages.


The researchers employed transesophageal echocardiography (TEE) to obtain high-quality images that showed partial blockages—in the form of atherosclerotic plaques—in the aortas (major artery) of 69 percent of the 369 study subjects.  And, rather than cholesterol levels, high CRP levels were the factor most closely associated with the presence of plaques and their severity.


According Bijoy Khandheria, M.D., the cardiologist who led the study: “This new study tells us high CRP is a sign that plaques likely are being formed in the arteries, even if the person feels healthy. Our findings provide a missing link between inflammatory markers in the bloodstream and the increased risk of a cardiovascular event such as a heart attack.”


How does inflammation cause arterial plaques to burst? Researchers hypothesize that as LDL cholesterol levels increase some of it gets into the lining of coronary arteries.  This activates immune system cells (macrophages) that try to remove the cholesterol. In some cases, for reasons that remain unclear, immune-system cells release pro-inflammatory chemical “switches” called cytokines, and the plaque becomes unstable.


Despite these new findings, imbalanced cholesterol remains a prime threat.  As Dr. Ridker told Time magazine last year, "This is not about replacing cholesterol as a risk factor. Cholesterol deposits, high blood pressure, smoking—all contribute to the development of underlying plaques.  What inflammation seems to contribute is the propensity of those plaques to rupture and cause a heart attack. If there is only inflammation but no underlying heart disease, then there is no problem."


A 2000 study led by Dr. Ridker found that inflammation increases cardiovascular risk even in women with relatively low cholesterol levels: “The levels of [inflammation markers] hs-CRP and serum amyloid A were significant predictors of risk even in the subgroup of women with LDL cholesterol levels below 130 mg per deciliter, the target for primary prevention established by the National Cholesterol Education Program.”


However, the National Institutes of Health’s target level for LDL (“bad”) cholesterol has since been lowered to 100 mg per deciliter.  And, cardiologist Mark Nelson, M.D. wrote to tell us that the lowest risk for heart disease occurs at about 65 mg per deciliter.


In terms of the cholesterol part of the risk equation, these are current government guidelines for optimal cholesterol levels:

  • LDL cholesterol level should be under 100 mg/dL

  • HDL cholesterol level should be equal to or higher than 60 mg/dL

  • Total cholesterol level should be under 200 mg/dL

Inflammation is probably a less significant risk factor when LDL cholesterol levels approach or drop below 100 mg per deciliter.  But the reality is that such low levels are hard to achieve without statin drugs or truly radical diet-and-lifestyle changes—such as Dean Ornish, M.D.’s successful program featuring stress reduction measures and a super-low-fat diet.


Yet, recent research indicates that the CVD-predictive power of inflammation—as measured by CRP levels—rivals that of imbalanced cholesterol.  For example, the results of a European clinical study published in February, 2005 indicate that blood markers for systemic inflammation rival imbalanced blood lipid (i.e., cholesterol and triglyceride) levels as a predictor of heart attacks.


What causes inappropriate inflammation?

Inflammation is an essential immunological process that enables our bodies to fend off disease-causing microbes and heal wounds. Inflammation marshals a defensive assault that attacks both pathogens and any tissues they infect. Once the foe is vanquished, inflammation subsides and healing begins.


However, chronic, low-level inflammation appears to be epidemic in modern societies. What causes chronic, low-level inflammation?  Other than smoking, the evidence implicates diet as the key cause. The standard America diet is high in saturated fats, trans fats, sugars, and refined starches, all of which are known to promote inflammation.


As Nicholas Perricone M.D., points out, dietary sugars and refined starches turn on two key cellular switches called AP-1 and NF-kB, which activate pro-inflammatory genes.  Dietary sugars and refined starches also promote a process called glycation, which produces “advanced glycation end products”: protein-sugar compounds known by the all-too-appropriate acronym AGE, which generate a continuous stream of pro-inflammatory, aging-accelerating free radicals.


Americans’ love for red meats and processed foods means that we eat too many pro-inflammatory, cholesterol-raising saturated fats and trans fats.


And, the adipose tissue in the spare tire that so many Americans carry generates messenger chemicals (cytokines) that encourage inflammation and further abdominal weight gain: the perfect vicious cycle.


Last, but far from least, many of us eat too few of the strongest anti-inflammatory food factors: the omega-3 fatty acids in fish and the potent antioxidants in colorful vegetables and fruits.


Cholesterol, inflammation, or both: why do statin drugs prevent heart attacks?

With the possible exception of aspirin, statins are the most effective heart-attack prevention drugs available.  Statin drugs are simply synthetic, slightly altered versions of the statins produced by certain yeasts, like the lovastatin that occurs naturally in rice fermented by red yeast (Monascus purpureus)—which is also the active ingredient in the popular statin drug Mevacor.™


It has been thought that most of statins’ anti-CVD benefit derives from their potent cholesterol-lowering powers.  But new research suggests that their anti-inflammatory powers may play a larger role than we thought, especially in short-term versus long-term prevention of heart attacks.


Cardiologist Mark Nelson, M.D. wrote us recently to take issue with some aspects of our March 4 article about the proposal to turn statins into non-prescription drugs (“Does Statins' SuperStar Status Make Sense?”). He found special fault with the following statement in our article: “Moreover, the modest reductions in cardiac deaths and adverse events shown in most trials were neither dose-related nor fully accounted for by improvements in cholesterol levels. Instead, these benefits may stem more from statins’ substantial anti-inflammatory effects.”


Dr. Nelson wanted to make this point: “If in fact the so-called pleiotropic [i.e., anti-inflammatory] effects of statins are the most important part of their biological impact then we would expect every statin trial to show positive end points [results] with regards to reducing cardiovascular morbidity and mortality. But this is not what we find. On the contrary, the studies have consistently shown us that the statins that lower LDL the most also reduce CVD morbidity and mortality the most.”


While Dr. Nelson is absolutely correct, evidence for the importance of statins’ anti-inflammatory powers continues to accumulate at a rapid pace. In fact, the most recent research suggests that compared with cholesterol levels, inflammation may be at least a co-equal factor in both the risk of heart attack, and in explaining the CVD-preventive powers of statins.


These were the conclusions from several studies that examined the importance of statin drugs’ anti-inflammatory effects on their ability to prevent heart attacks. As we’ve said, these researchers’ findings suggest that the anti-inflammatory powers of statins are most important in preventing heart attacks in the short term, while statins’ cholesterol-lowering effects become more important over the long term:

  • “Recent advances in cardiovascular medicine demonstrate that lipid-lowering therapy by… (statins) prevents acute coronary complications, probably by limiting inflammation in atheroma [arterial plaques].

  • “CONCLUSION: The lowering of elevated CRP levels by statins may reduce the risk of coronary events independently of the effect of statins on lipid levels.”

  • “…statins also influence the atherosclerotic disease process in a lipid-independent way. This includes beneficial effects on the early pathogenetic components of atherosclerosis, such as endothelial dysfunction and inflammation. These effects are probably not visible in the large clinical trials that usually follow up cohorts of patients with late stages of atherosclerosis during a relatively short period of time.”

  • “Intensive statin therapy results in a significant early reduction in adverse cardiac events… The early benefits seen are likely to result from modulation of inflammation, endothelial function and coagulation, i.e. the pleiotropic effects, whereas the greater reduction in low-density lipoprotein cholesterol results in reduced long-term events.”

  • “Compared with patients receiving statin medication, patients without statins did not have increased cardiac mortality (even when low-density lipoprotein [LDL] levels were >125 mg/dl) when hs-CRP levels were not elevated. In contrast, patients without statins and elevated hs-CRP (top quartile) [i.e., systemic inflammation] had a 2.3-fold increase in risk for fatal coronary events, independent of LDL levels.”

  • “CONCLUSIONS: Lipid levels drawn at angiography were not predictive of survival in this population, but initiation of statin therapy [in 985 patients with severe coronary artery disease] was associated with improved survival regardless of the lipid levels. The benefit of statin therapy occurred primarily in patients with elevated CRP [i.e., systemic inflammation].”

  • “Thus, statin use in patients with high CRP [i.e., systemic inflammation] provides not only a larger but also a significantly earlier absolute survival benefit than statin use in patients with lower CRP. This provides further evidence of an anti-inflammatory effect of statins.

What’s the bottom line?  The evidence shows that seriously imbalanced blood cholesterol levels are risky, and that chronic, low-level inflammation makes matters far worse.  Statins are the most sensible therapy for most people with or at risk of CVD, since they address both causative factors, and are remarkably safe.


Omega-3s, inflammation, and CVD

Omega 3 fatty acids are helpful in preventing CVD because they inhibit plaque development, discourage harmful blood clotting, and lower blood triglyceride levels. They also reduce the risk of stroke, cardiac arrhythmia, and sudden cardiac death.


No study to date has shown that omega-3s can reduce the risk of a first heart attack.  However, several clinical trials do indicate that they can reduce the risk of a second heart attack, and there is now ample evidence that omega-3s reduce blood levels of inflammation markers associated with increased risk of heart attack, except CRP.


Last year, Harvard researchers published their analysis of blood and diet data from 727 middle-aged women who participated in the famous Nurses' Health Study:  The results indicate a key role for omega-3s in reducing CVD-related markers of inflammation:  “In conclusion, this study suggests that dietary (n-3) fatty acids [omega-3s] are associated with levels of these biomarkers reflecting lower levels of inflammation and endothelial activation, which might explain in part the effect of these fatty acids in preventing cardiovascular disease.”


While omega-3s reduce markers of inflammation, their beneficial impacts on CVD risk may not be based primarily on their antiinflammatory effects.  In a recent study, supplemental DHA restored normal artery cell function in children with high cholesterol levels, even though it increased levels of total and LDL cholesterol (it also raised HDL cholesterol levels, which reduces CVD risk) and had no effect on markers for inflammation.  As the researchers said, “FMD [flow-mediated dilation of the brachial artery] increased significantly after DHA supplementation … without affecting biomarkers for oxidative stress, inflammation or ADMA. DHA supplementation was associated with increased levels of total cholesterol, LDL- and HDL cholesterol concentrations…”


British cardiology researcher Phillip Calder of the University of Southampton summarized the evidence on omega-3s, inflammation, and CVD prevention in a 2004 review article worth quoting at length:


  • “Substantial evidence from epidemiological and case-control studies indicates that consumption of fish, fatty fish and long-chain n-3 PUFAs [omega-3s] reduces the risk of cardiovascular mortality. Secondary prevention studies using long-chain n-3 PUFAs [omega-3s] in patients post-myocardial infarction [after a heart attack] have shown a reduction in total and cardiovascular mortality, with an especially potent effect on sudden death.
  • “ Long-chain n-3 PUFAs [omega-3s] have been shown to decrease blood triacylglycerol (triglyceride) concentrations, to decrease production of chemoattractants, growth factors, adhesion molecules, inflammatory eicosanoids and inflammatory cytokines, to lower blood pressure, to increase nitric oxide production, endothelial relaxation and vascular compliance, to decrease thrombosis (blood clotting) and cardiac arrhythmias and to increase heart rate variability.

  • “These mechanisms most likely explain the primary and secondary cardiovascular protection afforded by long-chain n-3 PUFA [omega-3] consumption. A recent study suggests that long-chain n-3 PUFAs [omega-3s] might also act to stabilize advanced atherosclerotic plaques, perhaps through their anti-inflammatory effects. As a result of the robust evidence in their favour, a number of recommendations to increase intake of long-chain n-3 PUFAs [omega-3s] have been made.”

See your doctor and eat more fish, veggies, and fruit

Regardless of what research determines about the relative importance of inflammation and imbalanced blood fats, you can’t protect yourself unless you know your cholesterol and inflammation status.  So visit your doctor, get the needed blood tests, and make a plan based on the best evidence.  Statins may be indicated, and your physician will likely tell you that omega-3s and antioxidant-rich fruits and vegetables (notably berries and greens), too, can play a powerful role in prevention.


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