An inflammatory review of atherosclerosis

18 Nov

Heart disease and cardiovascular disease (CVD) are synonymously used names to describe various diseases of the heart and blood vessels. Atherosclerosis is the lesser-known name of the underlying condition and common cause of CVD that results in symptoms such as heart attack, stroke, angina and peripheral vascular disease. As a condition that hardly existed before the 20th century, complications due to atherosclerosis now account for the majority of adult illness and deaths in the industrialised world, killing more people than cancer. Due to its asymptomatic nature and frequent under-diagnosis, the first symptom of atherosclerosis can often present without warning.

Atherosclerosis has a complex aetiology and pathophysiology which is yet to be fully understood. The process of atherosclerosis is known to begin in childhood and progress uninterrupted into adulthood. However, for most people it is a preventable condition whose progression is accelerated by modifiable lifestyle risk factors such as smoking, obesity and chronic stress.

The Pathobiological Determinants of Atherosclerosis in Youth study found that the prevalence of advanced atherosclerosis in low-risk 30- to 34-year-old persons to be about the same as in high-risk 15- to 19-year-olds. Since most adolescents and young adults are more concerned about other publicised risks such as STIs, accidents, and cancer than CVD, it is essential that the right education and prevention strategies can be implemented sooner rather than later.

The lipid hypothesis doesn’t hold water

For an effective and sustainable public health response to occur we must first undo a few decades of misleading and diversionary research. First, let’s consider the evidence and arguments that falsify many of the widely-held assumptions about cholesterol and atherosclerosis.

The website of independent researcher Uffe Ravnskov and Dr Malcolm Kendrick’s 5-part presentation to a BMA Leeds meeting is a good starting point for those interested in learning more about the cholesterol controversy.

Eating saturated fat does not raise blood cholesterol

This hypothesis originates from a number of short-term studies with methodological and interpretational errors, as well as conclusions reached by mathematical formulas on pooled data from multiple trials that did not control for specific types of fats such as trans fats. We also know that traditional populations such as the Masai who consume an almost entirely animal diet have the lowest cholesterol ever measured in healthy people. Reviews of many controlled, randomised dietary trials also disprove any relationship between reduction in saturated fat intake and total cholesterol or LDL cholesterol.

Saturated fat does not cause atherosclerosis or heart disease

The 1953 study by Ancel Keys which gave rise to the lipid hypothesis (also known as the cholesterol hypothesis) selected 16 cohorts in seven countries and found a weak association between intake of saturated fat and heart disease. However, it ignored within-country differences such as a coronary mortality rate sixteen times higher on Corfu than Crete. When a greater sample of countries is included, this association disappears. To date, systematic reviews of cohort studies with strongest evidence of causation indicate only that a Mediterranean diet is beneficial for heart health.

High cholesterol does not cause atherosclerosis or heart disease

While it has been shown that rodents with high cholesterol develop atherosclerosis, there is little evidence that high cholesterol causes atherosclerosis in humans. Evidence from cholesterol-lowering trials do not support that the progress of atherosclerosis is dependent on the degree of cholesterol lowering. High cholesterol was found to be a risk factor for the first time in the Framingham Heart Study, however, at the 30-year follow up, it appeared that cholesterol was no longer a risk factor after age 47. Even more contradictory, for each 1% mg/dl drop of cholesterol there was an 11 percent increase in coronary and total mortality.

Numerous studies have since found cholesterol not to be a risk factor for populations including Canadian men, diabetics, patients with renal failure, and patients with existing CVD. Almost all studies have found cholesterol is not a risk factor for women or the elderly. In particular, old people with high cholesterol live longer than old people with low cholesterol, a finding which is especially significant since (at least in Sweden) more than 90% of cardiovascular deaths occur after age 65.

Statin side effects and familial hypercholesterolemia

If high cholesterol is the cause of atherosclerosis, then people with familial hypercholesterolemia (FH), a genetic disorder of high LDL in blood, should be at greatest risk, yet studies have shown neither the incidence nor prevalence of CVD in people with FH is associated with lipid levels. A possible cause of CVD in FH may be inborn errors of the coagulation system. In cohort studies of people with FH, plasma fibrinogen and factor VIII were significantly higher in those with CVD than in those without. Thus, the reason why statin treatment may be of benefit in FH could be explained by their antithrombotic effects and not that of cholesterol lowering. The pleiotropic effects of statins as well as their side-effects both deserve more attention.

To reiterate, no trial has found any association between the degree of cholesterol lowering and the clinical outcome. Those whose cholesterol was lowered only a little had the same small benefit as those whose cholesterol was lowered by more than 50%. There is evidence to support that high cholesterol is protective and its lowering may even counteract the pleiotropic benefits of statin treatment.

The lipoprotein immune system protects against infections

It is little known that lipoproteins (LDL and HDL are not cholesterol but transporters of fats in the blood) function as part of the innate immune system. They are able to bind and inactivate various microbial products, viruses and inhibit their biological effects such as blood clotting, red blood cell destruction, the cytokine response and viral replication. In rodents, cholesterol is mainly transported by high density lipoproteins (HDL) which has the main protective effect, whereas humans studies have found that all lipoproteins participate in the nonspecific defense system. Remnants of more than 50 different organisms have been found within human atherosclerotic plaques, with no evidence for these organisms being found in normal arteries.

Clinical and epidemiological evidence also support the hypothesis that lipoproteins protect against infectious diseases. There is evidence to suggest that subclinical infections may participate in chronic heart failure. Accordingly, patients with heart failure and low cholesterol run a greater risk of premature death than patients with high cholesterol. Low cholesterol is also a risk factor for HIV and AIDS, hepatitis B, and death due to infectious disease in patients with chemotherapy-induced neutropenia.

Cholesterol lowering may be carcinogenic

It is known that cancer mortality in people with FH is lower than in the general population. Many cohort studies have found that low cholesterol is a risk factor for cancer. Human and animal experimental evidence as well as epidemiological observations have suggested that it is low cholesterol and not statin drugs which produced this effect. In numerous statin trials, researchers have found increased numbers of patients developing non-melanoma skin cancer, breast cancer and lymphoid cancer in treatment groups. This is potentially alarming as superficial malignancies are the first types of cancers expected to be found under conditions of general carcinogenicity.

Immunity is a double-edged sword

That inflammatory cells exist in atherosclerotic plaques has been known for over 150 years, and contemporary researchers have hypothesised that the inflammatory origin of atherosclerosis is a “response to injury” to damage of the blood vessel wall by high cholesterol (hypercholesterolemia), high homocysteine (hyperhomocysteinemia), high blood pressure and some infectious organisms:

  1. Endothelial damage allows the migration of LDL cholesterol and monocytes into the arterial wall.
  2. Here, LDL becomes modified by oxidation, leading to an accumulation of T cells and LDL autoantibody production by the body’s immune response.
  3. Modified LDL is taken up by macrophages that form lipid-laden foam cells.
  4. Macrophages may become overloaded and die resulting in plaque formation.
  5. Development of an unstable plaque can result in the formation of a blood clot, the cause of a stroke or heart attack.

However, this hypothesis is contradicted by the lack of any association between blood LDL concentration and degree of endothelial damage. There is also no lipid deposition despite pronounced intimal damage in atherosclerotic plaques of children with hyperhomocysteinemia. Such studies, and that hypercholesterolemia is not a risk factor for women of any age or men over 50, cast doubt on the ability of cholesterol to cause intimal damage and initiate the inflammatory process in human atherosclerosis.

A more coherent hypothesis proposed by Ravnskov and McCully is as follows:

  1. Aggregated complexes formed by lipoproteins with microorganisms and their toxins may become trapped in the vasa vasorum (the network of small blood vessels that support the large vessels) of the major arteries.
  2. This can result in a local ischemia (blockage of blood causing tissue damage), rupture of capillaries and release of microbes into the intima initiating phagocytosis by macrophages and the formation of foam cells.
  3. This process leads to the creation of vulnerable plaques containing microbial remains, inflammatory cells, foam cells and lipid deposits.

This hypothesis explains how cholesterol enters the artery wall and accumulates in plaques, the associations between CVD and infectious diseases, the presence of bacterial remnants in plaques, and the role of lipoproteins as part of the innate immune system. The introduction of microorganisms and endotoxins into the intima explains the characteristic inflammatory response associated with atherosclerosis.

It has also been demonstrated recently that infection and inflammation causes an increase in oxidation of LDL, and that oxidised LDL promotes phagocytosis of the responsible pathogens. Thus, lipoproteins may initially serve to protect the host from infection but their prolonged presence may contribute to atherosclerosis.

Factors that aggravate endothelial damage including oxidative stress, hyperhomocysteinemia, renal failure, smoking, hypertension and diabetes all further promote the development of atherosclerosis.

Looking beyond the past

Researchers from as early as the late 19th century suspected infectious factors as the cause of atherosclerotic plaques, but they failed to produce any experimental evidence. Processed food and pharmaceutical marketing has since saturated the minds of a generation of consumers, patients, researchers and clinicians with the conveniently simple lipid hypothesis that “bad cholesterol clogs your arteries.” Examples of cholesterol fear-mongering are plentiful.

This complex of lipids, profits and politics has unfortunately overwhelmed too many of us from taking a fresh, critical look at the mounting evidence that points back to infectious and immune-mediated causes of atherosclerosis. While this review has presented just one new hypothesis which itself is open to critique, it is nonetheless evidence that falsifies the lipid hypothesis and our “assumed” understanding of atherosclerosis.

In the meantime, at least everyone can agree that atherosclerosis remains an inflammatory condition.

References

  • Vanhecke TE, Miller WM, Franklin BA, Weber JE, McCullough PA (Oct 2006). “Awareness, knowledge, and perception of heart disease among adolescents”. Eur J Cardiovasc Prev Rehabil. 13 (5): 718–23. [Fulltext]
  • Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al. Heart disease and stroke statistics–2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. Jan 27 2009;119(3):e21-181. [Fulltext]
  • Simopoulos AP, De Meester F (eds): A Balanced Omega-6/ Omega-3 Fatty Acid Ratio, Cholesterol and Coronary Heart Disease. World Rev Nutr Diet. Basel, Karger, 2009, vol 100, pp 90–109. [Book]
  • McKully KS. Chemical Pathology of homocysteine. IV. Excitotoxicity, oxidative stress, endothelial dysfunction, and inflammation. Annals of Clinical & Laboratory Science. 2009;39(3):307-320. [PDF]
  • Ravnskov U, McCully KS. Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Annals of Clinical & Laboratory Science. 2009;39(1):3-16. [PDF]