Optimal Medical Therapy

A meta-analysis of 18 studies confirms that differences in risk-factor burdens in middle age translate into significant differences in lifetime cardiovascular disease risk.  The new results from the Cardiovascular Lifetime Risk Pooling Project, published in the January 26, 2012 issue of the New England Journal of Medicine, show that risk in people in their 40s or 50s with one or two risk factors such as hypertension or high cholesterol ramps up sharply over their lifetime.

I find many “healthy” people fail to take care of their conventional cardiovascular risks because of a low short-term (10 year) risk for vascular events yet their life-time risk is very high.  There’s therefore a disconnect between the short-term risk information that we routinely calculate and long-term risks that are dramatically higher.

This isn’t necessarily news, but this is a new way to look at what you should be doing if I can tell you that, sure your 10-year risk may be low, but based on your profile right now, your lifetime risk might be 50% or more of having a major heart attack or stroke before you die. . . . I hope that’s a little more of a motivating message.

The study analyzed 18 cohort studies with 257 384 patients, including black and white men and women across a 50-year range of birth cohorts. The studies measured important cardiovascular risk factors at ages 45, 55, 65, and 75. The risk factors measured include smoking, cholesterol levels, diabetes, and blood pressure.

Calculation of lifetime risks of cardiovascular events shows that the presence of even one risk factor in middle age can dramatically increase one’s lifetime risk of cardiovascular disease compared with no risk factors, and the risk goes up with each additional risk factor.

Across the whole meta-analysis, participants with no risk factors at age 55 (total cholesterol level: < 4.5 mmol/l; blood pressure: <120 mm Hg systolic and 80 mm Hg diastolic; nonsmoking; nondiabetic) had drastically better odds of avoiding death from cardiovascular disease through the age of 80 than participants with two or more major risk factors (4.7% vs 29.6% among men and 6.4% vs 20.5% among women).

People with an optimal risk-factor profile also had lower lifetime risks of fatal coronary heart disease or nonfatal myocardial infarction (3.6% vs 37.5% among men, <1% vs 18.3% among women) and fatal or nonfatal stroke (2.3% vs 8.3% among men, 5.3% vs 10.7% among women), compared with those with two or more risk factors.

The lifetime risk of death from cardiovascular disease and coronary heart disease or of nonfatal myocardial infarction were generally about twice as high among men than among women, but the lifetime risks of fatal and nonfatal stroke were similar for men and women.

Now Is the Time to Address Risk Factors:

If we can get our young adults living healthier lifestyles and more of them into middle age with optimum [risk-factor] levels, that would be fabulous news, but if you are middle-aged and you do have a risk factor or two or more, it’s really time to address those risks.

Published in SCIENCE (2002) using a combination of balanced lifestyle intervention and modern pharmacotherapy; data suggest that world-wide we could largely eliminate the 4 major disease processes if we can enable adults to avoid risk factors in the first place. Vascular & heart disease IS a preventable disease.

Modifying the major risks for vascular disease:

For many years cardiologists have known that small reductions in BP and Cholesterol confer over many years substantial reduction in cardiovascular risk.

What is less well-known is what “aggressive multiple risk reduction” will achieve over many decades of life starting in early or mid-life.

On really meticulous lifestyle with daily moderate intensity conditioning exercise; optimal dietary intervention; good sleep hygiene – what if we could optimise BMI < 25; lower LDL < 1.8; keep BP 120/80; reduce us-CRP < 1.0; maintain normal glycaemic control (with no glucose intolerance or Insulin resistance) and maintain a resting heart rate < 70 bpm LIFELONG?

We really do understand the pathological process of cardiovascular disease:

The pathophysiology of ageing of our cardiovascular system is complicated with complex risk factor intervention.  As the previous BLOG indicated, atherosclerosis is initiated and driven by a cascade of inflammatory mediators and players with athero thrombosis (increased coagulation) featuring prominently in the progression and complication of the atherosclerotic plaque. We are BLESSED in Cardiology to have a 30 year history of evidence-based; randomised; placebo-designed; double blinded trials from ALL 4 corners of the earth which have looked at various interventions in reducing the various risk factors and what happens to objective “hard end-points” of morbidity and mortality over time.  We have extensive modern pharmacotherapy with excellent RISK verses BENEFIT to target each of the individual risks and specifically to prevent plaque formation; regress plaque and stabilise plaque.

Management of systemic hypertension:

There is irrefutable evidence-based data to support maintenance of low risk healthy BP as you age to ~ 120/80.

The goal is to prevent the sinister end-organ complications of hypertension including acceleration of atherosclerosis; hypertensive heart damage; hypertensive central nervous system damage; renal damage and ocular damage.

Any individual with hypertensive target organ damage risk stratifies into a much poorer prognosis and warrants meticulous blood pressure control with modern blood pressure agents that interfere with the neurohormonal dysfunction common to hypertension.  As indicated in the previous blog there is considerable evidence to suggest the Angiotensin Converting Enzyme Inhibitors (ACE-I) and the Angiotenisn Receptor Blockers (ARB) directly influence the progression and complication of the atherosclerosis process and treatment with these agents reduce all hard vascular end-points.

Management of dyslipidaemia:

Three decades of research and development and masses of clinical trials have contributed to the understanding that we can prevent the development of atherosclerosis; prevent the progression and complication of atherosclerosis and actually reverse atherosclerosis with plaque regression.  To achieve this it appears you do not want a LDL cholesterol too much above 1.8 mmol/l and HDL cholesterol needs to be > 1.2 mmol/l.

Cholesterol reduction in 2012:

Since the publication of the first cholesterol lowering trials in 1994, subsequent trials have confirmed the beneficial effects and safety profile of STATINS to lower cholesterol.  By pooling data from many of the many published international trials, it is possible to analyze both the positive and negative effects of the statins, based on larger numbers of observations, and begin to tackle some of the crucial issues such as: will statins be beneficial in all people including the very old, in women, in people with diabetes or in people with no cardiovascular disease (primary prevention of cardiovascular disease)? Can we be sure that statins do not cause harm, such as cancer, liver damage, muscle injury or hemorrhagic stroke?

The Cholesterol Treatment Trialists has published results from a meta-analysis of 14 randomized clinical trials.   The primary meta-analysis measured the effects on clinical outcomes (all-cause mortality, coronary heart disease [CHD] mortality and non-CHD mortality) in each trial according to the absolute low-density lipoprotein (LDL) cholesterol difference at the end of the first year of follow-up. The results were reported as effects per 1.0 mmol/l LDL reduction. Secondary analyses looked at the effects of Statins therapy on CHD death and major coronary events (MCE) in specified subgroups. Data were obtained on 90,056 individuals, 47% of whom had pre-existing CHD. Twenty four per cent of the participants were women, 21% had a history of diabetes, and 55% had hypertension. The average difference in LDL cholesterol levels at 1 year was relatively small at 1.09 mmol/l, and the mean follow-up was 4.7 years (range, 2–6 years).

Despite this small LDL reduction the primary meta-analysis revealed a 12% reduction in all-cause mortality per 1.0 mmol/l reduction in LDL cholesterol, which was largely attributable to a 19% relative reduction in CHD deaths. This reduction was similar in all subgroups including the elderly (>75 years of age), women, treated hypertensive patients with a diastolic blood pressure >90 mmHg, people with a history of diabetes (including those without vascular disease), and those with pre-treatment LDL cholesterol levels <2.60 mmol/l. There was a highly significant 23% relative reduction in the incidence of first MCE per 1.0 mmol/l reduction in LDL cholesterol, including a 26% reduction in non-fatal myocardial infarction. A significant trend toward a greater relative benefit with greater reductions in LDL cholesterol concentrations was also noted.

Coronary bypass operations were reduced by 24% per 1.0 mmol/l reduction in LDL cholesterol levels and a significant 17% relative reduction in the incidence of first stroke was noted. Once again, there was a significant trend towards greater relative reductions in stroke, associated with greater mean absolute LDL cholesterol reductions. The overall reduction in strokes largely reflected a 19% relative reduction in non-hemorrhagic strokes, with no difference in hemorrhagic strokes. The 5-year results revealed a relative reduction of major vascular events of 21% per 1.0 mmol/l reduction in LDL cholesterol concentrations. Similar reductions were seen in MCEs, coronary revascularizations, and strokes.

An analysis of safety issues showed neither an increased risk in first incident cancers nor any evidence of an excess incidence of cancer with increasing duration of treatment. The 5-year risk of muscles damage (rhabdomyolysis) was small and there was no appreciable difference in liver problems on statins as compared to Placebo.

In more recent years the advent of potent and more effective statins (these can reduce LDL by 2-5 mmol/l) have changed the landscape of preventing vascular disease further.  The results of the JUPITER (Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin) trial from November 2008 add a formidable amount of information about the beneficial effects of statins.

This study screened almost 90,000 healthy volunteers aged 50 years or more (in the case of men) or 60 years or more (women). One in five (17,802) of those screened were included in the trial. Normally, the participants would not have qualified for statin therapy; they had no history of cardiovascular disease, and their low-density lipoprotein cholesterol (LDL-cholesterol) levels were below the usual threshold for treatment of 3.33 mmol/L.  The trialists hypothesized that high-sensitivity C-reactive protein (hs-CRP) is helpful in identifying individuals at high risk, and they restricted the selection of participants to those with hs-CRP levels of 2.0 mg/dl or more. Furthermore, given that statins reduce high levels of hs-CRP, the investigators expected to see a bonus of reduced inflammation through hs-CRP-reduction.

When the trial was prematurely discontinued, after 1.9 years, Rosuvastatin (Crestor) 20 mg daily had reduced LDL-cholesterol levels by about 50% in comparison with placebo, and the results were impressive: in the rosuvastatin group, the relative risk for the primary endpoint of cardiovascular events was reduced by 44%. If this method of selecting candidates for statin therapy was to be transferred to clinical practice, we might see a substantial increase in the proportion of statin-users in the middle-aged and elderly population.

Given that the median follow-up time was only 1.9 years, the absolute reduction in risk over a longer period of, say, 5 years has to be estimated. The investigators found it plausible that the number of people needed to be treated to prevent one primary endpoint was 25. This is well in the range of other preventive medical therapies in frequent use today.

Of importance the reduction in risk was remarkably consistent across all sub groups including males; females; smokers; non-smokers etc.

Of great relevance was the data to show the reduced risk if both LDL was reduced ~ 1.8 and us-CRP was reduced < 1.0 conferring >70% risk reduction.

The results of the JUPITER trial are likely to expand the target population eligible for statin therapy, but healthcare providers face a tough question: can we afford it?  First, the analysis reinforces the findings of the individual trials showing that statins are very efficacious and safe. The results also strongly support the idea that most patients at risk of CVD benefit from treatment. This includes the elderly, women, and specified subgroups. The beneficial effect appears linked to the degree of LDL cholesterol lowering, a finding of utmost importance for the management of people at risk. If we could lower LDL cholesterol by 3.0-4.0 mmol/l, we would theoretically reduce major cardiovascular events by as much as 60-80%. If we then consider that the data presented reflect only a short period of time and were focused on first events with significant results, we must contemplate the effects we may achieve over an extended lifelong period of treatment.

The possible benefits, however, require that patients are indeed offered a Statin and then stay on their therapy for life. Unfortunately, ample evidence points to poor compliance, both regarding the number of patients treated and the unsatisfactory management of their LDL cholesterol levels.

The mechanism for improved outcome from Statins appears to be multiple including plaque stabilisation with reduced fissuring and rupture; plaque compaction and regression and interference with the entire cascade of cytokine production and inflammation.  The stability of the atherosclerotic plaque related to a much more dense fibrous capsule separating the contents of the plaque from the blood; decrease inflammatory content of the plaque primarily through lowering oxidised LDL.  Plaque compaction and plaque regression is evident on INTRAVASCULAR ULTRASOUND (IVUS) – left picture with LDL maintained at 1.6-1.8 mmol/l over 18-24 months.

The whole gambit:

Anti atherosclerosis therapy may involve multiple agents to influence the pathophysiology of the events causing atherosclerosis.

Having practised cardiology over the past 20 years; having studied intensely the evolution of vascular biology and the pathophysiology of atherosclerosis and more importantly having seen what aggressive risk reduction does in primary and secondary clinical scenarios I am absolutely convinced if we mange risk aggressively we can abrogate this sinister disease.

Say No.

Yes to healthy ageing.

Hope this helps.


Sometimes I really despair?

Sometimes I really despair.  A few days ago I heard on the radio one of the world leading, great South African medical academics  state categorically that cholesterol has no relation to cardiovascular disease.  This message was transmitted to perhaps hundreds of thousands listeners around Cape Town, South Africa and maybe the world.

Bearing in mind death and disability from cardiovascular disease is the world leader of destruction I was understandably concerned.

I had planned on moving straight ahead with “Optimal Medical Therapy” (OMT) in prevention of cardiovascular disease and in the aggressive management of those individuals who have already expressed the disease, but now I’m forced to provide a history lesson for OMT will not make sense if you are a “cholesterol sceptic”.

Actually the number of cholesterol sceptics across the world is high (just google this to be sure) and added to the “statin sceptics” we have the basis for a serious conspiracy theory. So please bear with me and take time (really take time) to read the following:

What we know about atherosclerosis – a 200 year adventure:

Atherosclerosis is a chronic disease of the arterial wall where both innate and adaptive immuno-inflammatory mechanisms are involved. Inflammation is central at all stages of atherosclerosis. It is implicated in the formation of early fatty streaks, when the endothelium is activated and expresses chemokines and adhesion molecules leading to monocyte/lymphocyte recruitment and infiltration into the subendothelium.

It also acts at the onset of adverse clinical vascular events, when activated cells within the plaque secrete matrix proteases that degrade extracellular matrix proteins and weaken the fibrous cap, leading to rupture and thrombus formation. Cells involved in the atherosclerotic process secrete and are activated by soluble factors, known as cytokines. Important recent advances in the comprehension of the mechanisms of atherosclerosis provided evidence that the immuno-inflammatory response in atherosclerosis is modulated by regulatory pathways, in which the two anti-inflammatory cytokines interleukin-10 and transforming growth factor play a critical role.

The earliest visible lesion in the development of atherosclerosis is the fatty streak. This comprises an area of intimal thickening composed of macrophages distended by lipid droplets (known as foam cells), lymphocytes, and smooth muscle cells. Plaques develop as a result of the accumulation of oxidised low-density lipoproteins (oxLDL) in the subendothelial space, followed by the diapedesis of leukocytes and formation of foam cells, proliferation of smooth muscle cells, and production of connective tissue. The landmark work of Seymour Glagov showed that the arterial wall can remodel itself in response to plaque growth by increasing its external diameter to accommodate the plaque without narrowing of the lumen. Thrombosis is the ultimate stage in the disease process that is responsible for clinically observable adverse events implicating coronary, cerebrovascular, and peripheral vascular beds. Studies indicate that in patients with atherothrombotic disease plaque formation is likely to be widespread throughout the vasculature, often affecting more than one vascular bed (systemic inflammatory disease).

More than 200 year historical perspective:

Even though atherosclerosis is reaching epidemic proportions nowadays, it is not in any way a disease specific to the modern times; it was already present in antiquity. Sir Marc Ruffer was able to identify in 1911 degenerative arterial changes suggestive of atherosclerosis in the left subclavian artery from an Egyptian mummy.

According to the historian J. O. Leibowitz, the Italian surgeon and anatomist Antonio Scarpa (1752-1832) was the first to present a pathological description of arterial wall degeneration in full detail. In his 1804 monograph on aneurysms, Scarpa opposed the view that a dilatation of the aorta was the intrinsic cause of an aneurysm leading to rupture. He emphasizes that “… especially the internal coat is subject, from slow internal cause, to an ulcerated and steatomatous (fatty) disorganization, as well as to a squamous and earthy rigidity and brittleness,” introducing the concept of an underlying metabolic disorder in the process of atherosclerosis, rather than the theory of inflammation that already prevailed at that time, the expression “heart abscess” being frequently used to describe heart pathology.

The term atheroma, derived from Greek and meaning “porridge,” was first proposed by Albrecht von Haller in 1755 to designate the degenerative process observed in the intima of arteries. London surgeon Joseph Hodgson (1788-1869) published in 1815 his Treatise on the Diseases of Arteries and Veins in which he claimed that inflammation was the underlying cause of atheromatous arteries. But thereafter, most of pathologists of the 19th century following Carl Rokitanski (1804-1878) abandoned the view that inflammation was an etiological factor and considered that atherosclerosis was a degenerative process, with intimal proliferation of connective tissue and calcification, best described by the term arteriosclerosis proposed in 1833 by French pathologist Jean Lobstein (1777-1835).

However, German pathologist Rudolf Virchow (1821-1902), a leading authority of his day in pathology and the greatest contributor to the notion of thrombosis, considered atheroma as a chronic inflammatory disease of the intima, that he called “chronic endarteritis deformans”. In his opinion, the accumulation of lipids was a late manifestation of atheroma. Finally, the Leipzig pathologist Marchand in 1904 first used the term atherosclerosis, which since has been widely adopted, instead of arteriosclerosis, to designate the degenerative process of the intimal layer of the arteries.

Until the beginning of the 20th century, the theories put forward to explain the pathogenesis of atherosclerosis remained purely descriptive and were based on the anatomical observation of human atherosclerotic vessels. A first revolution in the mechanistic assessment of atherosclerosis was initiated in 1908 when the Russian scientist Alexander Ignatowski showed that experimental atherosclerosis could be induced in rabbits by feeding them a diet of milk and egg yolk.

Nikolai N. Anichkov (1885-1964) demonstrated the role of cholesterol in the development of atherosclerosis. His classic experiments in 1913 paved the way to our current understanding of the role of cholesterol in cardiovascular disease. Anichkov’s research is often cited among the greatest discoveries of the 20th century.

Recognition of Anichkov’s Theory of Atherosclerosis:

Apparently, the only reference to Anichkov’s theory of atherosclerosis in the English-language medical literature before 1950 was a chapter written by Anichkov for the 1st edition of Cowdry’s Arteriosclerosis (1933).  A similar chapter appeared in the 2nd edition of the book, published in 1967. Anichov’s work on coronary atherosclerosis was published in Circulation in 1964. However, worldwide recognition of Anichkov’s early experiments probably came in 1950 after publication of a paper by Dr. John Gofman and his associates in Science. Gofman began by emphasizing that it was Anichkov who first discovered that feeding cholesterol to rabbits promptly led to atherosclerosis. Using Anichkov’s technique, Gofman’s group had confirmed that Anichkov was correct. Then they did something that Anichkov could not have done in 1912-they developed and used a ultracentrifuge capable of rotating its tubes 40,000 times per minute. The hypercholesteremic serum samples of their cholesterol-fed rabbits were centrifuged and then sequestered into 2 distinct compartments. The 1st fraction was designated low-density lipoprotein (LDL) cholesterol, because it floated toward the surface of the serum sample. The 2nd fraction was deposited at the bottom and was designated high-density lipoprotein (HDL)cholesterol. Gofman’s group showed further that low-density lipoprotein cholesterol is responsible for the rapid progression of atherosclerosis in animals.

The next significant leap only came during the 1970s when Brown and Goldstein showed that the LDL receptor that they had discovered, a cell surface protein that binds LDL and removes them from blood is not involved in macrophage foam-cell formation and proposed that a macrophage receptor that recognized acetylated LDL plays a key role in this process.

Subsequently, during the 1980s, the central role of oxidised LDL cholesterol (oxLDL) in the pathogenesis of atherosclerosis was exposed by Daniel Steinberg and his group, and a number of scavenger receptors mediating their uptake by macrophages were identified. The model of the Watanabe heritable hyperlipidemic (WHHL) rabbit, introduced in 1980 was particularly useful in establishing the role of oxLDL in atherogenesis. A second revolution occurred at the beginning of the 1990s when mouse models of atherosclerosis, apolipoprotein E (apoE)- and LDL receptor (LDLr)-deficient mice, were derived by homologous recombination techniques. In contrast to the previous models, mice lacking functional apoE or LDLr genes were shown to develop widely distributed arterial lesions that progress from foam cell-rich fatty streaks to fibro-proliferative plaques with lipid/necrotic cores, typical of the spectrum of human lesions.

LDL-cholesterol and cardiovascular disease:

Evidence of the causative role of LDL-cholesterol in atherosclerosis is threefold: first, genetic mutations that impair receptor-mediated removal of LDL cholesterol from plasma cause fulminant atherosclerosis; second, animals with low LDL-cholesterol levels have no atherosclerosis, whereas increasing these levels experimentally leads to disease; and third, human populations with low LDL-cholesterol levels have minimal atherosclerosis, and the process increases in proportion to the level of LDL cholesterol in the blood.

A remarkable victory for patients with coronary artery disease came when the LDL-cholesterol pathway was delineated and the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), discovered by Akira Endo, was developed to lower LDL-cholesterol levels.

Brown and Goldstein’s discovery of the LDL-receptor pathway, for which they were awarded the 1985 Nobel Prize in Physiology or Medicine, provided a genetic cause for myocardial infarction in persons with familial hypercholesterolemia and introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors.

This last concept is one of the mechanism by which statins selectively lower LDL-cholesterol levels in plasma, reducing the risk of myocardial infarction and prolonging life, as shown in multiple, definitive clinical trials.

The LDL-Receptor Pathway and Treatment with LDL Cholesterol-Lowering Drugs, which Improves Cardiovascular Outcomes:

Statin therapy does not eliminate cardiovascular risk completely. Levels of high-density lipoprotein (HDL) cholesterol correlate inversely with cardiovascular risk, but despite considerable improvements in our understanding of HDL cholesterol and its metabolism, none of the pharmacologic agents that raise HDL cholesterol that have been tested so far have had a significant effect on cardiovascular morbidity and mortality. Ongoing clinical trials of agents that raise HDL-cholesterol levels and that have other antiinflammatory and antiatherosclerotic effects are currently under way.

The oxidised LDL theory:

Atherosclerosis clearly does not develop in any animal model without a significant level of plasma cholesterol, and the dominant role of serum cholesterol is also well established in humans.

While hypertension, diabetes, and smoking are factors that dramatically increase the risk of atherosclerosis, it is not rare to have clinically significant atherosclerosis in the absence of these risk factors. In contrast, below a certain level of total cholesterol (3.5 mmol/l), atherosclerosis is practically absent in human populations (this equates perfectly with Statin trials over the past few years demonstrating plaque regression at LDL levels ~ 1.8 mmol/l).  Risk for atherosclerosis is well documented to gradually increases with increased plasma cholesterol levels.

Moreover, primary and secondary clinical trials have established the efficacy of lowering cholesterol with statins for prevention of cardiovascular disease without controversy (my next blog).

It is therefore tempting to hypothesize that the primary trigger of cytokine release in atherosclerosis has a link with cholesterol. Atherogenic cholesterol exists mainly in the form of LDL, which are the main culprit in atherosclerotic vessels. In fact, several lines of evidence support the hypothesis that oxidized lipids, including oxLDL, are the most likely triggering factors for cytokine production.

Quantitative analysis of atherosclerosis in fetal aorta showed that fatty streaks are already present at this early stage of life, lesions being more abundant in fetus from hypercholesterolemic mothers than from normocholesterolemic mothers. Interestingly, qualitative analysis of lesions depicted similar distribution of native LDL, oxLDL, and macrophages in lesions of offspring from both hypercholesterolemic and normocholesterolemic mothers. The presence of macrophages alone, without native LDL or oxLDL, or their association with native LDL, was almost never observed, and most of the lesions contained both oxLDL and macrophages. A few lesions with native LDL or oxLDL without macrophages were also present. This seminal study allows us to describe the exact chronology of events leading to fatty streak formation in humans, starting with native LDL uptake by the arterial intima, followed by LDL oxidation and, finally, monocyte recruitment after endothelial activation by oxLDL.

Oxidised LDL behaves as a potent inflammatory agent. In vivo administration of oxidised LDL to C57BL/6 mice causes rapid induction of circulating M-CSF and upregulation of genes coding for inflammatory cytokines as well as other inflammatory proteins in various tissues. OxLDL stimulates the expression of adhesion molecules. OxLDL has chemoattractant activity on monocytes, promotes their differentiation into macrophages, but inhibits their mobility. Binding of oxLDL to cells triggers the release of proinflammatory cytokines in macrophages. In addition, incubating human blood mononuclear cells with oxLDL results in T-lymphocyte activation, as assessed by increased expression of IL-2 receptors and HLA-DR antigens on T lymphocytes.

Oxidation of LDL generates many “neo-self determinants” that induce an active immune response and may challenge the regulatory pathways responsible for immune homeostasis. Both humoral and cellular immune responses can profoundly affect atherosclerotic development and progression.

The amount of lipid retained in macrophages depends on unregulated uptake of oxidised lipoproteins by scavenger receptors, as first identified by Brown and Goldstein, counterbalanced by degradation and efflux. Altogether these findings point to a role of oxLDL as a very early trigger of vascular inflammation. LDL accumulation and modification in the subendothelium trigger monocyte and lymphocyte recruitment. Thereafter, activated macrophages and lymphocytes secrete abundant amounts of cytokines that in turn can activate endothelial cells; smooth muscle cells and macrophages/lymphocytes to foster cytokine production, leading to a self-perpetuating inflammatory process that becomes less dependent on the presence of oxLDL. This might explain why oxLDL, while instrumental in triggering the early atherosclerotic events, are less critical in upholding the inflammatory environment. This might also explain in part the efficiency of antioxidant therapies in the prevention of atherosclerosis when these therapies are administered at the very beginning of the atherosclerotic process in animal models, but their failure to do so in most secondary or primary prevention clinical trials in humans, where treatment is administered at later stages of the disease when secondary inflammatory mediators become as important as the initial oxidative-related stimulus.

It is noteworthy that atherosclerotic plaques do not regress, or regress very slowly, in cholesterol-fed rabbits following short-term withdrawal of cholesterol feeding and normalization of cholesterol plasma levels. It is only after a prolonged cholesterol withdrawal period that decrease in plaque size, together with reduced vascular inflammation and plaque stabilization, is observed.  This has recently been reproduced in patients with documented coronary atherosclerosis plaque treated with high dose Rousuvastatin (CRESTOR) 40mg/d or Atorvastatin (LIPITOR) 80mg/d. Reducing serum LDL ~1.6-1.8 mmol/l caused progressive plaque regression over 2 years. There are a multitude of trials over the past decade in humans, that aggressive lipid lowering treatment using statins has been shown to be very effective in limiting plaque development and reducing plaque progression and rupture.

The cytokine network is incredibly complicated & may thus serve as a final common proinflammatory pathway regardless of the initiating event and provides a supplemental therapeutic target, especially in late stages of the disease.

Inducers of cytokine production in atherosclerosis:

According to the classical view of inflammation, cytokines are produced by cells of the innate immune system (monocytes, neutrophils, NKT cells) in response to microbial infection, toxic reagents, trauma, antibodies, or immune complexes.

An etiologic role for infectious agents in atherosclerosis, especially Chlamydia pneumoniae and cytomegalovirus (CMV), has been repeatedly evoked since the first seroepidemiologic evidence of an association of the chlamydia TWAR strain with acute myocardial infarction and chronic coronary disease was reported in 1988. However, the most recent clinical trials, including Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders (WIZARD), Azithromycin in Acute Coronary Syndrome (AZACS), Antibiotic Therapy After Acute Myocardial Infarction (ANTIBIO), Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT), and Azithromycin and Coronary Events Study (ACES), assessing the potential benefits of antibiotic therapy with the goal of targeting Chlamydia pneumoniae showed no effect of treatment in patients with CAD. Moreover, experimental studies showed that infection is not necessary for initiation or progression of atherosclerosis in apoE-deficient mice. Atherosclerosis develops identically in germ-free animals and in animals raised with ambient levels of microbial challenge.

One must therefore conclude that pathogens do not serve as etiologic agents for atherosclerosis, even though one cannot rule out a role in disease exacerbation. Several reports indicate that inoculation of atherosclerosis-prone mice with high doses of C. pneumoniae fosters atherosclerosis. Yet, the atherogenic effect of C. pneumoniae requires elevated serum cholesterol levels.

Once inflammation has been triggered and cytokine release is initiated at the onset of atherosclerotic lesion development, a number of factors that are found in the atherosclerotic plaque can participate in maintaining and amplifying cytokine production.

Immune complexes:

OxLDL is a major autoantigen involved in atherosclerosis, and both oxLDL and anti-oxLDL antibodies are present in atherosclerotic lesions. Immune complexes consisting of oxLDL and anti-oxLDL may be ingested by macrophages leading to their activation and subsequent release of inflammatory cytokines, oxygen-activated radicals, and metalloproteinase.

Defective clearance of apoptotic cells:

Intrinsic defects in the clearance of apoptotic cells are associated with spontaneous and persistent tissue inflammation and autoimmunity. This may be due to reduced production of immunoregulatory cytokines due to defective phagocytosis and/or to the immunogenic and proinflammatory potential of the unremoved apoptotic cells.

With regard to atherosclerotic plaques, it has been shown that apoptotic microparticles accumulate in the lipid core, most likely as a result of reduced capacities of clearance of apoptotic cells by foam macrophages that are in an oxidant-rich environment. Defect in the clearance of apoptotic cells/microparticles may promote and perpetuate proinflammatory cytokine production.

Cellular microparticles:

Microparticles (MPs) are plasma membrane-derived vesicles shed from the plasma membrane of stimulated or apoptotic cells. They are now acknowledged as cellular effectors involved in fundamental physiological processes including intercellular communication, hemostasis, and immunity. MPs are ideal links between inflammation, thrombosis, and atherosclerosis. MPs express a number of proinflammatory and prothrombogenic molecules and could play an important role in the dissemination of these factors to sites remote from the site of their production.

MPs are abundantly present in the lipid core of human atherosclerotic plaques where they are responsible for tissue factor activation and may contribute to plaque inflammation. MPs also circulate at high levels in the peripheral blood of patients with acute coronary syndromes and are suggested to play an important role in endothelial dysfunction in addition to their potential role as carriers of blood-borne tissue factor, involved in blood thrombogenicity.

Oxygen radicals:

Cells present in the atherosclerotic plaque can produce reactive oxygen species (ROS) such as O2-, H2O2, and ·OH in response to activation by a number of molecular actors of atherosclerosis, including cytokines (TNF, IL-1), growth factors (PDGF), vasoactive peptides (angiotensin II), platelet-derived products (thrombin, serotonin), and mechanical factors (cyclic stretch, laminar and oscillatory shear stress). Major sources of ROS include normal products of mitochondrial respiration, NADPH oxidases, NO synthases, cyclooxygenases, lipoxygenases, cytochrome P-450 monooxygenase, and xanthine oxidase. These enzymes are all expressed in the atherosclerotic plaque, but evidence suggests that NADPH oxidase-like activity appears to be the major contributing enzymatic source of ROS in the vascular wall, generating superoxide anion in endothelial and smooth muscle cells.

Angiotensin II

A large body of evidence indicates that angiotensin II (ANG II) has significant proinflammatory activity in the vascular wall, inducing the production of ROS, inflammatory cytokines, and adhesion molecules.

The proinflammatory effects of ANG II are generally considered to be Angiotensin Receptor 1 dependent and may explain why clinical studies with Angiotensin II Inhibitors (ACE-I) and Angiotensin AT1 Receptor Blocker therapy reduce the morbidity and mortality when used in patients with vascular disease.


Advanced glycation end products (AGEs), the products of nonenzymatic glycation and oxidation of proteins and lipids, accumulate in the vessel wall especially in diabetes but also in euglycemia, in the latter case driven by oxidant stress. AGEs may exert their pathogenic effects by engaging cellular binding sites/receptors. The interaction of AGEs with macrophages has been shown to activate macrophages leading to the induction of PDGF, insulin-like growth factor (IGF)-I, and proinflammatory cytokines, such as IL-1 and TNF.

Mechanical factors:

Blood flow-induced shear stress has long been recognized as critically important in atherogenesis. Atherosclerotic lesions preferentially develop in areas of disturbed or oscillatory flows, including arterial bifurcations, branch ostia, and curvatures. The vascular endothelium is extremely sensitive to changes in blood flow; in vitro experiments suggest that physiological levels of shear stress are anti-inflammatory and antiadhesive, while low or oscillatory shear stress promotes oxidative and inflammatory transformations in EC, with enhanced monocyte adhesion, VCAM-1, ICAM-1, and E-selectin expression.

This would support our myriad of clinical trials in the of treatment of HYPERTENSION with reduced target organ damage.

Epidemiological investigations clearly pointed out that hypertension is a powerful cardiovascular risk factor. Besides being associated with exaggerated atherosclerosis, elevated blood pressure levels have been found to be highly predictive of atherosclerosis-associated cardiovascular events, including ischemic coronary disease, stroke, and peripheral arterial disease. In human subjects, carotid artery intima-media thickness, measured with high-resolution B-mode ultrasound, is highly correlated with blood pressure levels and accurately reflects cardiovascular risk.

Experimental studies have demonstrated that hypertension increases the rate of atherosclerotic plaque development particularly in the setting of LDL-C > 1.8. The atherosclerotic plaques of hypertensive animals with high ANG II showed signs of instability.

Several mechanisms can account for hypertension-induced atherosclerosis. Pressure-induced stretch of the vessel wall increases endothelial permeability to LDL and accentuates LDL accumulation in the intima, which is central to the atherogenic process. In addition, hypertension may promote or aggravate vascular inflammation.


A large body of evidence links obesity with accelerated atherosclerosis. Adipose tissue is an active endocrine and paracrine organ that releases a large number of cytokines and bioactive mediators, designated adipokines. These products influence not only body weight homeostasis but also inflammation, coagulation, and fibrinolysis, which ultimately affects atherosclerosis and its clinical complications. Adipokines with proinflammatory activities include TNF, IL-6, plasminogen activator inhibitor-1 (PAI-1), angiotensinogen, leptin, and resistin. Increased production of these proteins by adipose tissue in obesity is likely to raise circulating levels of acute-phase proteins and inflammatory cytokines leading to a state of chronic low-grade inflammation that characterizes the obese.

Leptin, which shares structural and functional similarities with the IL-6 family of cytokines, enhances the production of TNF, IL-6, and IL-12 from LPS-stimulated monocytes/macrophages. Leptin also plays an important role in the regulation of adaptive immunity.

Resistin is another adipokine with potent inflammatory activities. Resistin seems to be expressed at much higher levels in mononuclear leukocytes, macrophages, and bone marrow cells than in human adipose cells.  Taken together, these data indicate that leptin and resistin may represent a novel link between metabolic signals, inflammation, and atherosclerosis.

On the contrary, adiponectin exerts potent anti-inflammatory properties. It inhibits TNF-induced expression of adhesion molecules in vascular EC blocks lipid accumulation in macrophages, and suppresses the expression of class A scavenger receptors. Adiponectin also upregulates the expression of IL-10 in human monocyte-derived macrophages and increases TIMP-1 expression through IL-10 induction. Plasma adiponectin levels are reduced in patients with CAD, and overexpression of adiponectin in apoE-/- mice inhibits the progression of atherosclerosis, an effect that appears to be mediated by adiponectin-induced IL-10 production.

Cytokines and cardiovascular risk:

Once produced, cytokines are rapidly trapped by neighboring cells via their high-affinity receptors. Accordingly, measuring the levels of circulating cytokines is not necessarily a perfect surrogate end point reflecting the actual activity of the cytokine. Nevertheless, a variety of plasma inflammatory markers have been shown to well predict future cardiovascular risk. They can be useful for risk stratification and also to identify those patients who might benefit from targeted interventional therapy. Of these markers, ultra sensitive C-Reactive Protein (us-CRP), an acute-phase protein, has been the most extensively studied, and there is now robust evidence from primary prevention cohorts and among patients presenting with an acute coronary that elevated us-CRP levels predict future cardiovascular event. The production of us-CRP occurs almost exclusively in the liver by the hepatocytes as part of the acute phase response upon stimulation by IL-6, and to a lesser degree by TNF and IL-1, originating at the site of inflammation. CRP activates the classical complement cascade and mediates phagocytosis. In the 1990s, Berk, Weintraub, and Alexander showed that plasma CRP levels are elevated in patients with “active” CAD compared with those with stable CAD. In 1994, Attilio Maseri and his group established a link between CRP elevation and cardiovascular events in patients with unstable angina (UA). In the late 1990s, several studies linked elevated ultra-sensitivity CRP (us-CRP) levels with future cardiovascular events in different populations. Of importance us-CRP is relatively cheap and easy to measure as part of a persons “risk stratification”.

It is believed that classical cardiovascular risk factors including LDL cholesterol, hypertension, smoking, and diabetes can instigate the vascular release of proinflammatory cytokines and subsequent promotion of low-grade inflammation. These proinflammatory cytokines increase serum levels of CRP, supporting the concept that CRP acts as an integrator for many inflammatory stimuli, which in association with plasma LDL-cholesterol levels can predict the cardiovascular risk. Of potential clinical interest, the combination of an inflammatory marker (CRP, SAA, sICAM-1, or IL-6) with lipid testing improved upon risk prediction based on lipid testing alone. Thus lipid and inflammatory parameters appear to be assessing different biological pathways that carry separate prognostic value. In support of this hypothesis, the PROVE-IT-TIMI 22 study recently established that the risk of recurrent myocardial infarction (MI) or death from coronary causes among patients with acute myocardial syndromes (ACS) is best predicted by the combination of LDL cholesterol and CRP levels.

Furthermore the landmark JUPITER study published in 2008 showed in HEALTHY middle age males and females identified by high us-CRP (average us-CRP 4.3 mg/L) but normal LDL (the average LDL was 2.7 mmol/l) benefit from CRESTOR 20 mg/d in reducing the time to the first vascular event (over a very short trial period average under 2 years).  Interestingly in people whose LDL was reduced to < 1.8 and us-CRP reduced to < 1.0 the risk reduction was > 70% for vascular events.


1 Timothy 2:7

“Have nothing to do with godless myths and old wives’ tales; rather, train yourself to be godly. 8 For physical training is of some value, but godliness has value for all things, holding promise for both the present life and the life to come. 9 This is a trustworthy saying that deserves full acceptance. 10 That is why we labour and strive, because we have put our hope in the living God, who is the Saviour of all people, and especially of those who believe”.

Ultimately you are allowed to choose what you believe, as we have been given God’s grace of “Spiritual Freedom” and freedom of choice.

In my next BLOG I will start the daunting task of outlining “Optimal Medical Therapy”.



Paleolithic “Cave Man” Diets

There are races of people who are all slim, who are stronger and faster than us. They all have straight teeth and perfect eyesight. Arthritis, diabetes, hypertension, heart disease, stroke, depression, schizophrenia and cancer are an absolute rarity for them. These people are the last 84 tribes of hunter-gatherers in the world. They share a secret that is over 2 million years old. Their secret is their diet, a diet that has changed little from that of the first humans 2 million years ago, and their predecessors up to 7 million years ago. Theirs is the diet that man evolved on, the diet that is coded for in our genes. It has some major differences to the diet of “civilisation”.

The diet is usually referred to as the “Paleolithic Diet” referring to the Paleolithic or Stone Age era. More romantic souls like to think of it as the diet that was eaten in the “Garden of Eden”.

The basic principles of the Paleolithic Diet are simple. At the technical level, Paleolithic Diet Theory has a depth and breadth that is unmatched by all other dietary theories. Paleolithic Diet Theory presents a fully integrated, holistic, comprehensive dietary theory combining the best features of all other dietary theories, eliminating the worst features and simplifying it all.

All major dietary components are covered (vitamins, fats, protein, fats, carbohydrates, antioxidants and phytosterols etc). This is for the simple reason that it is the only diet that is coded for in our genes, it contains only those foods that were present at the time of our early existence.

Basics of the Paleolithic Diet:

For millions of years, humans and their relatives have eaten meat, fish, fowl and the leaves, roots and fruits of many plants. One big obstacle to getting more calories from the environment is the fact that many plants are inedible. Grains, beans and potatoes are full of energy but all are inedible in the raw state as they contain many toxins.

Around 10,000 years ago, an enormous breakthrough was made, a breakthrough that was to change the course of history, and our diet, forever. This breakthrough was the discovery that cooking these foods made them edible, the heat destroyed enough toxins to render them edible. Grains include wheat, corn, barley, rice, millet and oats. Grain based foods also include products such as flour, bread, noodles and pasta. These foods entered the menu of New Stone Age (Neolithic) man, and Paleolithic diet buffs often refer to them as Neolithic foods.

The cooking of grains, beans and potatoes had an enormous effect on our food intake perhaps doubling the number of calories that we could obtain from the plant foods in our environment. Other advantages were soon obvious with these foods:

  • they could store for long periods (refrigeration unavailable in those days)
  • they were dense in calories-enabling easy transport
  • the food was also the seed of the plant later allowing ready farming of the species

These advantages made it much easier to store and transport food. We could more easily store food for winter, and for nomads and travellers to carry supplies. Food storage also enabled surpluses to be stored, and this in turn made it possible to free some people from nomadic hunter gatherers to settle into communities and become specialists in other activities, such as builders, warriors and rulers. This in turn set us on the course to modern-day civilisation.

Despite these advantages, our genes were never developed with grains, beans and potatoes and were not in tune with them, and still are not. Man soon improved further on these advances by farming plants and animals.

Instead of being able to eat only a fraction of the animal and plant life in an area, farming allows us to fill a particular area with a large number of edible plants and animals. This in turn increases the number of calories that we can obtain from an area by some 10 to 100 fold or more.

Then followed the harnessing of dairy products, which allow man to obtain far more calories from the animal over its lifetime than if it were simply slaughtered for meat. Dairy products are interesting as they combine a variety of components, some of which our genes were ready for and some not. Whist cows milk is ideal for calves, there are several very important differences between it and human milk. For example, the brain of a calf is only a tiny fraction of its body weight whereas humans have very big brains. Not surprisingly, cows milk is low in critical nutrients for brain development, particularly omega 3 fats.

Paleolithic Diet buffs refer to the new foods as Neolithic foods and the old as Paleolithic Diet foods. In simple terms we see Neolithic as bad and Paleolithic as good. Since then, some other substances have entered the diet, particularly salt and sugar, and more recently a litany of chemicals including firstly caffeine then all other additives, colouring, preservatives, pesticides etc.

Grains, Beans and Potatoes (GBP) share the following important characteristics:

  • They are all toxic when raw. These toxins include enzyme blockers, lectins and other types
  • Cooking destroys most but not all of the toxins. Insufficient cooking can lead to sickness such as acute gastroenteritis
  • They are all rich sources of carbohydrate, and once cooked this is often rapidly digestible-giving a high glycemic index (sugar spike followed by Insulin spike)
  • They are extremely poor sources of vitamins (particularly vitamins A, B-group, folic acid and C), minerals, antioxidants and phytosterols.

Therefore diets high in grains beans and potatoes (GBP):

  • Contain toxins in small amounts
  • Have a high glycemic index (ie have a similar effect to raw sugar on blood glucose levels)
  • Are low in many vitamins, minerals, antioxidants and phytosterols.

As grains, beans and potatoes form such a large proportion of the modern diet, you can now understand why it is so common for people to feel they need supplements or that they need to detox (ie that they have toxins in their system)- indeed both feelings are absolutely correct. Unfortunately, we don’t necessarily realize which supplements we need, and ironically when people go on detoxification diets they unfortunately often consume even more Neolithic foods (eg soy beans) and therefore more toxins than usual (perhaps they sometimes benefit from a change in toxins). More detail on these issues follows.

The essentials of the Paleolithic Diet are:

Eat none of the following:

  • Grains including bread, pasta, noodles
  • Beans including string beans, kidney beans, lentils, peanuts, snow-peas and peas
  • Potatoes
  • Dairy products
  • Sugar
  • Salt

Eat the following:

  • Meat, chicken and fish
  • Eggs
  • Fruit
  • Vegetables (especially root vegetables, but definitely not including potatoes or sweet potatoes)
  • Nuts, eg. walnuts, brazil nuts, macadamia, almond. Do not eat peanuts (a bean) or cashews (a family of their own)
  • Berries strawberries, blueberries, raspberries etc.

Try to increase your intake of:

  •  Root vegetables carrots, turnips, parsnips, rutabagas, Swedes
  • Organ meats liver and kidneys

Knowledge on fats has exploded over the last decade and there is a realisation in mainstream nutrition that omega 3 fats are critical to good health. It is very important to ensure that you have an adequate intake of these. The low-fat diet craze of the 90’s was well-intentioned but many people “threw out the baby with the bath-water”- most people reduced omega 3 fat intake as well as other fats, and sometimes even increased omega 6 fats. There is now a realisation that the low-fat diet theory of the 90’s doesn’t often work (it has about a 6% success rate like most other diets) and that the vast majority of the Western population need to increase their omega 3 intake and decrease their omega 6 intake. Even if you don’t end up on a Paleolithic Diet, you will benefit from a better appreciation of fats.

Technical Aspects:

The reason why grains, beans and potatoes store so well is simply because of the toxins that they contain. The enzyme blockers put them into a deep freeze, stopping them from sprouting. The lectins and other toxins are natural pesticides and can attack bacteria, insects, worms, rodents and other pests (and humans too of course).

Antinutrients – Key to bad health:

You probably already know a lot about nutrients, macronutrients (fats, protein and carbohydrates and micronutrients (vitamins, minerals, antioxidants, phytosterols etc). Now it’s time to meet the rest of the family……. We all know that foods contain a variety of nutrients. There is less awareness that many foods contain small amounts of potentially harmful substances. These are toxins, as they have toxic effects. They are normally called “antinutrients” by the scientific community as toxins sounds too alarmist. Antinutrients are very real and for over 100 years research has been done on them but it is generally only appreciated by a small group of specialised scientists. Antinutrients have an incredible range of biological effects. As you have probably already guessed, the vast majority and highest levels of antinutrients are in Neolithic foods like grains, beans and potatoes. The Paleolithic diet has incredibly low levels of antinutrients compared to the usual modern diet. I believe that this is the number one advantage of the diet.


Beans too are full of enzyme blockers and lectins. Potatoes contain enzyme blockers, lectins and another family of toxins called glycoalkaloids. Glycoalkaloids (GA) unlike lectins and enzyme blockers aren’t destroyed by cooking, even deep-frying. GA are particularly high in green or injured potatoes, which must never be eaten even if trimmed heavily and well-cooked. Many people have told me that they eat small amounts of raw potato. This is a dangerous habit and it should be discouraged very strongly.

These toxins in foods are commonly referred to as antinutrients.

  • Enzyme Blockers are abundant in all seeds including grains and beans, and also in potatoes, serving to hold them in suspended animation and also acting as pesticides. Most commonly they block the enzymes that digest protein (proteases), and are called “protease inhibitors”. They can affect the stomach protease enzyme “pepsin”, and the small intestine protease enzymes “trypsin” and “chymotrypsin”. These small intestine enzymes are made by the pancreas (it does a lot of other important things besides making insulin). Some enzyme blockers affect the enzymes that digest starch (amylase) and are called “amylase inhibitors”.

When GBP are cooked, most of the enzyme blockers are destroyed, but some are not. In human volunteers and in animal experiments high levels of protease inhibitors lead to increased secretion of digestive enzymes by the pancreas. This is because the body can sense that the enzymes have been knocked out and orders to pancreas to make more. Even if the effect of GBP based foods is only a small increase in pancreatic enzyme secretion, over many years it all adds up to a lot of extra work.

They are effective poisons, rats cannot gain weight if they have substantial amounts of enzyme blockers in the diet. As far as their preservative action is concerned, I need only to remind you that the potted grains in the tombs of the Egyptian Pharaohs were still viable and sprouted after thousands of years locked away.

Grain eating birds have evolved digestive enzymes that are resistant to grain protease inhibitors.

  • Lectins (Haemagglutins) are natural proteins that have a large variety of roles. They are amongst the most fascinating and stimulating of all biological compounds, and I have no doubt that they play a major role in many “unexplained ” diseases. I think of them as “Hannibal Lectins” as they remind of the devious criminal mastermind in the shock horror movie “Silence of the Lambs.’ Lectins are like master code-breakers. The cells of our bodies are studded with receptors which are like code pads to ensure stimulation only under the correct circumstances. Lectins have the ability to crack these codes and stimulate the receptors causing a variety of responses- covering basically the full repertoire of the cell and even tricking the cell into doing things it normally cannot do.

They also have a knack for bypassing our defences and “getting behind the lines”, and then they can travel all over the body causing harm. They can, for example:

  • strip protective mucus off tissues
  • damage the cells lining the small intestine disrupting the microscopic fingers called villi and microvilli, get swallowed whole by the small intestine cells (“pinocytosis”)
  • bind to cells including blood cells causing a clot to form (hence they were initially called “haemagglutins”)
  • make a cell act as if it has been stimulated by a hormone, or stimulate a cell to secrete an inappropriate hormone
  • promote cell division at the wrong time
  • cause growth or shrinkage of lymphatic tissue (“outposts” of white blood cells)
  • cause enlargement of the pancreas
  • cause cells to present codes (HLA’s) that they normally should not use
  • cause cell death (apoptosis)

Lectins break down the surface of the small intestine, stripping it of mucus and causing the cells to become irregular and leaky. Some lectins make cells act as if they have been stimulated by insulin. Others cause the pancreas to release insulin. Others cause immune cells to divide in the wrong way, causing growth of some white blood cells and breaking down the control of the immune system. Others cause cells to present the wrong codes (HLA’s) on their surface, tricking the immune system into thinking that intruders have been found and activating the immune system inappropriately thus leading to “autoimmune disease” where the body’s tissues are attacked by its own immune system.

Autoimmune diseases are incredibly common and increase every year that a person gets older. A disordered immune system also has a much harder job recognising and attacking the real intruders invading germs and cancer cells (you may have heard that scientists think that most people generate many cancer cells in a life time but that the immune system cleans most of them up).

It is not known whether lectins can cause cancer this is one of the most important questions in medicine today. They certainly affect colon cells in the test tube. I feel that they are likely candidates as they can stimulate abnormal cell growth and they also cause disorder in the immune system.

Lectins have many other roles besides defending seeds. For example in beans, lectins act like a glue to enable nitrogen-fixing bacteria to bind to the roots of the plant. Many important lectin families are found in animal tissues, but as we are carnivores, we have evolved to be able to deal with these just as birds that live on grains have evolved to be resistant to grain lectins.

It is ironic that the lectins were discovered more than 100 years ago and yet so many questions remain unanswered the same was true of the immune system until the 1980’s. I hope that there is more research done into lectins as they hold a whole world of disease mechanisms of which most of the medical community is blissfully unaware.

  • Exorphins are food chemicals that have morphine-like activity. They are found in dairy products and wheat. Our body has its own natural morphine like substances that are called endorphins. Endorphins work by stimulating a type of nerve cell surface receptor called endorphin receptors. Endorphins are very important in controlling pain and addictive behaviour.

Exorphins also act on endorphin receptors and may stimulate them or block them. It is logical that exorphins may therefore affect chronic pain and also affect addictive behaviour.


The Paleolithic diet makes real sense and is a “variant” of the “low carbohydrate” diets (ketogenic diets). Seemingly this style of eating is a bit more lenient on fruits and some vegetables but high is saturated animal fat and cholesterol.  Ultimately as for ALL the ketogenic diets one has to tailor them to your specific physiology; your athletic goal and your ideal “body image”.

You will need to check your lipogram; fasting glucose; HbA1c; us-CRP; renal function including electrolytes (Na+; K+ and Mg++) to assess the effect of these typical of diets on your metabolic risk.

Happy Paleo eating.