IBIS 4 – High-Dose Rosuvastatin Shrinks Coronary Plaque

Women and CVDOne year of treatment with the highest dose of the cholesterol-lowering drug Rosuvastatin can shrink plaque inside the arteries of patients who have had a certain type of heart attack known as ST-segment elevation myocardial infarction (STEMI), according to a new study presented at European Society of Cardiology Congress 2014.

BARCELONA, Spain – Tuesday 2 September 2014: One year of treatment with the highest dose of the cholesterol-lowering drug Rosuvastatin can shrink plaque inside the arteries of patients who have had a certain type of heart attack known as ST-segment elevation myocardial infarction (STEMI), according to a new study presented at ESC Congress 2014 (http://www.escardio.org/about/press/press-releases/esc14-barcelona/Pages/hotline-five-ibis-4.aspx).

Although STEMI patients often undergo a revascularization procedure (angioplasty or stent insertion) to unblock the “culprit” artery that caused their heart attack, they remain at increased risk for similar events due to plaque formation in other untreated coronary arteries.

The IBIS-4 study, which was published simultaneously in the European Heart Journal is the first to use ultrasound imaging inside coronary arteries both at the time of heart attack and after 13 months of treatment to show the benefit of high-dose statin therapy on plaque burden. The study was an investigator-initiated trial performed at five sites in Europe (University Hospitals of Bern, Copenhagen, Geneva and Zürich and Cardiocentro Lugano) without support from a pharmaceutical cholesterol-lowering manufacturer.

Previous work has shown that high-dose Rosuvastatin can reduce plaque size in patients with stable chronic atherosclerotic vascular (coronary) disease, but until now this has not been specifically investigated in arteries of patients with acute heart attacks, a setting known to harbour additional high risk plaques that can be the source for future cardiovascular events.

IVUS 3This is also the first study is the first to use intracoronary ultrasound to assess the actual plaque composition and the plaque phenotype, and to observe how both respond to high dose potent statin treatment.

IBIS-4 included 103 acute heart attack patients who were first successfully treated to unblock the culprit vessel. Subjects then underwent imaging, both at the start of the study and then after 13 months of high-intensity Rosuvastatin treatment (40 mg/d), to assess the drug’s impact on their non-culprit arteries. Rosuvastatin was given at a dose of 40 mg daily. After 13 months, ultrasonography showed that 85% of patients had regression of plaque in at least one artery, and 56% had regression in both. Overall, intracoronary plaque volume was reduced by a mean of -0.9% (p=0.007), with a mean change of the total atheroma volume of -13.7 mm3 (p=0.006). Although the reduction in plaque volume was independent from cholesterol levels at baseline, it was directly related to the extent of cholesterol reduction at 13 months. As expected, Rosuvastatin also had beneficial effects on lipoprotein levels. Low-density lipoprotein (LDL) decreased from a median of 3.29 mmol/L at baseline to 1.89 mmol/L (p<0.001), corresponding to a 43% reduction. A total of 44% of patients achieved a guideline-recommended LDL level of less than 1.8mmol/L. The beneficial effects of high-dose statin therapy on coronary plaque regression previously observed in patients with stable coronary artery disease (ASTEROID study) can be extended to those at highest risk for cardiovascular complications, namely patients with acute heart attacks. This explains at least in part the clinical benefit of high-dose statin therapy in patients with heart attacks.


Elevated ‘Lipid-Years’ in Young Adulthood Tied to Later Cardiovascular Disease

The concept of LIFETIME cardiovascular disease (CVD) risk is beautifully demonstrated in the study published online January 26, 2015 in Circulation [1].

Fifty-five-year-olds who had prolonged moderately elevated non–HDL (total atherogenic lipoproteins) levels (>160 mg/dL/ 4.0 mmol/L) when they were young adults were much more likely than their peers to have coronary heart disease by the time they were 70. In an analysis based on the Framingham Offspring Cohort the risk of cardiovascular disease (defined as myocardial infarction, angina, coronary insufficiency, or death from CVD) increased with exposure to elevated non-HDL levels in a dose-dependent way.

Specifically, during follow-up, 16.5% of the middle-aged adults who had abnormal atherogenic lipoproteins in the past 11 to 20 years developed CVD, but only 8.1% of those with elevated non-HDL in the past 1 to 10 years developed CVD. In contrast among the adults without elevation of non-HDL, only 4.4% developed CVD.

Atherogenic LP

Having decades of exposure to what many would consider to be mild to moderately elevated atherogenic lipoproteins is associated with a significantly elevated risk of cardiovascular disease. Thus, the way we think about smoking in terms of pack-years, we should be thinking about ‘atherogenic lipid-years’ [of exposure to high non-HDL].

For young adults, we really need to remember that the foundation for cardiovascular disease is being laid in our 20s, 30s, and 40s, so aggressive risk-factor modification at that age is really important. For middle-aged adults, “in the same way that a 55-year-old with a family history of cardiovascular disease [or] an increased coronary calcium score would be considered higher risk, we should take into consideration the duration of exposure to high non-HDL . . . to stratify risk.”

CVD 31

Decades of High Atherogenic Lipoproteins: A New CVD Risk Factor?

Atherosclerosis develops slowly over many years starting in childhood, and the effects of prolonged exposure to elevated atherogenic lipoproteins in young adulthood have previously not been well-defined. This research group examined data from 1478 individuals in the offspring cohort of the Framingham Heart Study who were approximately 55 years old and did not have a history of CVD when they were enrolled during 1987 to 1998.

Participants were stratified into three groups based on hyperlipidaemia (non–HDL >160 mg/dL/ 4.0 mmol/L) at enrolment. A total of 512 participants had no hyperlipidaemia; 389 participants had 1 to 10 years of hyperlipidaemia; and 577 had 11 to 20 years of hyperlipidaemia.

Only 85 participants (5.8%) were on lipid-lowering treatment at baseline.

During a median follow-up of 15 years, there were 136 cardiac events. The unadjusted risk of CVD doubled for every 10 years of exposure to hyperlipidaemia during age 35 to 55 (HR 2.0, 95% CI 1.63–2.45 per decade of hyperlipidaemia).

The association was attenuated but remained statistically significant after adjustment for sex, age, systolic blood pressure, antihypertensive therapy, smoking status, HDL, diabetes, and non–HDL cholesterol at baseline (adjusted HR 1.39, 95% CI 1.05–1.85 per decade of hyperlipidaemia). The association also remained significant after adjustment for lipid-lowering–therapy use at baseline and follow-up.

10 yr and lifetime risk

Based on the 2013 ACC/AHA Cholesterol Guidelines (using the 10-year CVD risk threshold of >7.5%), among the 55-year-old adults who had been exposed to high non-HDL for 11 to 20 years, 15.1% would have met the criteria for statin therapy at age 40 and 34.8% would have met criteria at age 50. However, this study was not designed to determine whether early statin intervention in young adults “on the hyperlipidaemia trajectory” would decrease future CVD risk.

However, it’s certainly not a stretch to say that at least adults in their 50s who have had long-term exposure to high atherogenic non-HDL (total ApoB) should be considered for statin therapy, and there are [randomized clinical trial] data to support the efficacy in that group.

This study used non–HDL cut-offs, since HDL was measured directly whereas LDL was calculated. Typically, non–HDL is 30 mg/dL/ 0.75 mmol/L higher than LDL, and the researchers found similar results using a LDL level of >130 mg/dL/ 3.2 mmol/L.

Individuals who had average non–HDL levels during the preceding 20 years that were below 125 mg/dL/ 3.1 mmol/L had a similar low risk of CVD, and those with levels above 195 mg/dL/ 4.8 mmol/L had a similar high risk of CVD. For every 10-point increase in non–HDL between 125 and 195 mg/dL, there was a 33% increased risk of CVD.

This begs the question as to what constitutes the normal range of non-HDL but in my hands I aim to keep atherogenic lipoproteins (non-HDL or total Apo B) less than 120 mg/dL/ 3.0 mmol/L or 0.8 for Apo B.

Nevertheless, this study identifies adults who may benefit from more aggressive primary prevention and again flies in the face of those sceptics who treat (atherogenic) lipoproteins with no respect.

7 things to reverse CVDThese findings suggest that adults with longstanding moderate elevations in non–HDL levels should be added to those already identified by the current guidelines as candidates for an informed patient-physician discussion about appropriate lipid-management strategies to reduce future risk of heart disease.


  1. Navar-Boggan A, Peterson E, D’Agostino R, et al. Hyperlipidaemia in young adulthood increases long-term risk of coronary heart disease. Circulation 2015

Blessings Cardiologydoc

Women Benefit from Statin Therapy

Billed as the most comprehensive of its kind, a large meta-analysis (all of the large statin trials are represented in this analysis) suggests that statin benefits in reducing “major vascular events” are about the same in women as in men when adjusted for predicted cardiovascular risk [1].


Bearing in mind that approximately 20 million will die worldwide this year from cardiovascular disease, with 55% of the epidemic expressed in women. It’s therefore unfortunate that the idea has grown up in some places that women don’t benefit as much as men from statin therapy, and I think this idea has arisen because people haven’t taken into account the fact that women in general develop vascular disease later in life than men.

It is critical to identify women who are at risk for cardiovascular disease and offer them statin therapy if they exceed a certain threshold of risk, because vascular disease is common, especially in older women, and prevention of that disease could be facilitated by wider use of statin therapy.


The study was published online on January 9, 2015 in the Lancet.

The Cholesterol Treatment Trialists’ (CTT) Collaboration performed meta-analyses on data from 22 trials of statin therapy vs controls and five trials of more intensive vs less intensive statin therapy. A total of 46 675, or 27% of 174 149 randomly assigned participants in these trials, were women. Individual participant data were available from all 27 trials.

In each group of trials, mean concentrations of total and LDL cholesterol at baseline were similar in women as they were in men.

All trials (n=27)

Group Total cholesterol, mmol/L LDL cholesterol, mmol/L HDL cholesterol, mmol/L Triglycerides, mmol/L
Women 5.6 3.4 1.3 1.5
Men 5.3 3.3 1.1 1.6

Major Vascular Events

Among all 27 trials, statins reduced the risk of major vascular events by 21% for each 1.0-mmol/L reduction in LDL cholesterol (rate ratio 0.79, 95% CI 0.77–0.81; P<0.0001), with significant reductions in both women and women.

Major vascular events included MI, stroke, the need for coronary revascularization, and cardiac death.

The proportional reductions in major vascular events for each 1.0-mmol/L reduction in LDL cholesterol seemed slightly smaller in women than in men among the 22 trials of statin vs controls, but they were still highly significant (P<0.0001) in both women, at a rate ratio (RR) of 0.85 (99% CI 0.78–0.92), and men (RR 0.78, 95% CI 0.75–0.82).

Among the five trials where more intensive therapy was compared with less intensive therapy, the proportional reductions in major vascular events among women were similar to those in men. The proportional reductions in major vascular events were also similar among individuals with a definite history of vascular disease.

Somewhat in contrast, statin effects in subjects with no known history of vascular disease seemed slightly greater in men (RR 0.72, 99% CI 0.66–0.80) than in women (RR 0.85, 95% CI 0.72–1.00).

Among all 27 trials, statin therapy reduced the risk of major coronary events by 24% for each 1.0-mmol/L reduction in LDL cholesterol, with significant reductions in both women (RR 0.83, 99% CI 0.74–0.93; P<0.0001) and men (RR 0.74, 99% CI 0.70–0.78; P<0.0001). Statin therapy also reduced coronary-revascularization procedures by the same 24% percent for each 1.0-mmol/L drop in LDL cholesterol, again with no significant sex differences evident overall.

The overall proportional reduction of 15% in any stroke for each 1.0-mmol/L reduction in LDL cholesterol (RR 0.85, 95% CI 0.80–0.89) was also similar between women and men and again broadly similar at all levels of CVD risk. Importantly, reductions in major vascular events were also broadly similar irrespective of sex at all levels of CVD risk, including among women and men whose 5-year risk of having a major vascular event was low, at <10%.

Overall, statin therapy also produced a highly significant 12% proportional reduction in vascular mortality (RR 0.88, 95% CI 0.84–0.91) for each 1.0-mmol/L reduction in LDL cholesterol and a nominally significant reduction in deaths from unknown causes.

Finally, after adjustment for non-sex differences, there were similar proportional reductions in all-cause mortality for each 1.0-mmol/L reduction in LDL cholesterol of 10% in men (RR 0.90, 99% CI 0.86–0.95) and 9% in women (RR 0.91; 99% CI 0.84–0.99).

Importantly statin treatment had no significant effect on cancer or cancer mortality, and there was no evidence of any difference in the safety of statin therapy between women and men.

This report is critical to preventative cardiology as we have powerful statins at full dose (Rosuvastatin & Atorvastatin) capable of reducing LDL by 3-4 mmol/L. With statin associated independent reduction of us-CRP (inflammatory marker) we potentially can reduce individual morbidity and mortality by 80%.

Mediterranean diet 3

Coupling statin therapy with aggressive lifestyle intervention with appropriate diet, exercise, sleep and stress reduction we can achieve excellent results, particularly in women.

Quote on life


  1. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of LDL-lowering therapy among men and women: Meta-analysis of individual data from 174,000 participants in 27 randomised trial. Lancet 2015; DOI:10.1016/S0140-6736(14)61368-4

Blessings Cardiologydoc

Cardiovascular Disease Prevention 2014

There are basically two paradigms when we’re thinking of cardiovascular disease prevention.  One is to assess risk over the next 10 years using something like the Framingham risk score or similar scoring system (SCORE system in Europe) but whist this is a perfectly valid approach, it is an incomplete way to represent risk to our patients.

The other paradigm is to assess LIFETIME risk for a cardiovascular event.  The 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 atherogenic lipoproteins ramps up sharply over their lifetime.  There is a very important disconnect between the short-term risk information that we routinely calculate and what we know, especially with this paper, are long-term risks that are dramatically higher.

10 yr and lifetime risk

Lifetime atherosclerotic vascular disease (ASCVD) risk at 50% compared to say 1.9% 10 year risk in a 42 yr man tends to grab people’s attention more.  If I can tell you that, sure your 10-year risk may be low and not too different from the “God-given” ideal, but based on your profile right now, your lifetime risk is really high and 10 times higher risk of having a major heart attack or stroke (compared to 5% risk if no risk/ optimal risk factors). . . . I hope that’s a little more of a motivating message.

The above study analysed 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 in the study included 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 (optimally managed risks to target goals), and the risk goes up exponentially with each additional risk factor.

Across the whole meta-analysis, participants with no risk factors at age 55 (total cholesterol level: < 180 mg/dL or 4.5 mmol/dL; blood pressure: <120 mm Hg systolic and 80 mm Hg diastolic; non-smoking; non-diabetic) 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.

It is Time to Address Risk Factors at an early Age

Our goal as preventative cardiologists is to get young adults living healthier lifestyles and more of them into middle age with optimum risk-factor levels which will transpose into an optimal lifetime risk of about 5% for men and 8% for women. On the flip side, if you are middle-aged and you do have a risk factor or two or more, it’s really time to address those and risk stratify to understand where your risk is coming from. It’s almost certainly going to require expert help to control those risk factors, but just as important is partnering lifestyle changes and perhaps pharmacology to get control of those risks. It’s a critically important partnership, but you can do a lot to mitigate those risks if you get serious about it.

Optimal risk reduction

Compression of morbidityIf we can enable adults to avoid conventional cardiovascular risk factors in the first place vascular disease is entirely a preventable disease. We need to be more aggressive at fostering healthy lifestyles in young people. This paper indicates targeting young people should pay off in the long run, not just in less cardiovascular disease, but, by extrapolation, also in reduced overall health costs.


  1. Berry J, Dyer A, Cai X, et al. Lifetime risks of cardiovascular disease. N Engl J Med 2012 366:321-329.


Primary Prevention with Statin Therapy

JAMA logo

I have reproduced this article EXACTLY from the Journal of the American Medical Association (JAMA) in response to the AHA 2013 NEW lipid guidelines.

JAMA Weighs In on CVD Guidance, Statins in Primary Prevention Shelley Wood November 25, 2013

CHICAGO, IL – Another week and another flurry of insights and opinions on the new CVD prevention guidelines, this time in the journal that once cornered the market on cholesterol guidance.

Back in 2001, when the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults released their third report (ATP III), it was the Journal of the American Medical Association (JAMA) that published the report. Ditto the previous edition, ATP II, in 1993.

This time around, in the wake of the partnership struck between the American Heart Association (AHA), American College of Cardiology (ACC), and the original guidelines developer, the National Heart, Lung, and Blood Institute (NHLBI), the new guidelines and accompanying risk calculator were simultaneously published in the flagship journals of the two cardiology organisations.

Seemingly keen to get in on a piece of the action, JAMA has today published online a Clinical Evidence Synopsis[1], accompanied by a commentary by Dr Jennifer Robinson, vice chair for the new cholesterol guidelines and a co-author of the guidelines for assessing CV risk[2]. Both the clinical evidence synopsis and Robinson’s commentary zero in on what has emerged as the most controversial aspect of the new four-part CVD guideline packet: the use of statins in primary prevention. Specifically, experts have raised concerns that too many patients will be swept into drug therapy by the new CV risk calculator.

The clinical evidence synopsis, by Dr Fiona Taylor (London School of Hygiene and Tropical Medicine) and colleagues, sums up their 2013 Cochrane meta-analysis that updated a 2011 meta-analysis reviewing the evidence on statin use in primary prevention[3]. Taylor et al’s analysis included 18 trials conducted between 1994 and 2008 and published between 2011 and 2013, enrolling almost 57 000 patients. Compared with placebo, statins reduced LDL by 39 mg/dL, all-cause mortality by 14%, fatal and non-fatal CVD by 22%, coronary heart disease by 27%, stroke by 22%, and coronary revascularisation by 38%. Risk of cancer, myalgia, rhabdomyolysis, liver-enzyme elevations, renal dysfunction, or arthritis were no different between the patients taking statins and those on placebo, nor was drug discontinuation. An increased risk of diabetes with statins was seen “in one of the two trials reporting this outcome.”

Dr Rita Redberg (University of California, San Francisco), who recently co authored a New York Times Op-Ed expressing concern that the new cholesterol guidelines would lead to statin over treatment, commented on the JAMA articles for heartwire .

Redberg pointed out that this latest Cochrane analysis comes to starkly different conclusions than the 2011 Cochrane review, despite having many of the same authors. That may be in part due to the “elimination of major trials,” something also at odds with a 2009 meta-analysis by Ray et al that found no benefit of statins in reducing all-cause mortality.

In her commentary, Robinson notes that the 2013 Cochrane meta-analysis was one of the pieces of evidence reviewed by the ACC/AHA guideline writers, along with other “high-quality randomized trials and systematic reviews and meta-analysis of randomized trials.” These included the 2010 and 2012 Cholesterol Treatment Trialists meta-analysis, as well as the AFCAPS/TexCAPS, MEGA , and JUPITER trials. It was from these studies, she notes, that the cut points of a 5% and 7.5% or greater 10-year risk of atherosclerotic cardiovascular disease were derived, and not plucked from thin air, as some critics have alleged.

The recent studies, writes Robinson, “provide evidence that largely refutes the major criticisms against statins used for primary prevention. Statins are well tolerated in properly selected individuals. Statins reduce total mortality as well as atherosclerotic cardiovascular disease events in lower-risk individuals. Concerns about cost are no longer relevant with five of the currently available statins available as generic drugs. . . . The accumulated evidence should convince those with a philosophical aversion to statin therapy for primary prevention to reconsider their stance.”

To heartwire , Robinson pointed out that much of the criticism of the new guidelines and risk calculator has centred on the idea that millions more Americans will be encouraged to take statins. In fact, she points out, “in 2005, 35 million Americans were already on a statin, so if you apply our CV risk calculator, you’d see 32 million on a statin. There are [still] a lot of people being treated, but [with these new guidelines] you are not going to see more people being treated, it may just not be the same people.”

She also addressed the controversial Ridker and Cook analysis, which came out with much fanfare during last week’s AHA meeting, as well as its call to treat only subjects who are similar to those enrolled in the major clinical trials rather than use an untested global risk-prediction score.

“We tried that,” Robinson said, “and what you get when you apply clinical-trial inclusion criteria is that you fail to identify about 40% of high-risk people [who would benefit from statin therapy] and you overtreat about 35% of people who have less than a 5% 10-year risk of CVD.”

The four major criticisms of the guidelines as they pertain to statin therapy are concerns about adverse effects, lack of a total mortality benefit, cost, and a “philosophical aversion to drug therapy,” Robinson writes.

“None of these really stand up under the light of evidence anymore,” she told heartwire . “It’s fine to have a philosophical aversion to statins, but when all the evidence flies in the face of that, it seems like that’s an attitude that should fall by the wayside.”

Asked if she’s concerned that all the focus on statins in the cholesterol guidelines has eclipsed important information in the lifestyle and obesity guidelines, released the same day, Robinson maintained that statins deserve the attention they’ve been basking in over the last few weeks.

“Only 10% of Americans have optimal CV health: that’s why we need statins. We’ve been telling people to diet and exercise for at least 50 years; this is not a new thing. I think the problem with this approach is that if we wait until people do what we tell them to do for diet and exercise and smoking cessation, we are going to be withholding a lifesaving therapy from exactly the people who will benefit. Of course, keep telling people to diet, exercise, and quit smoking, but when people can’t or won’t do that, we can’t withhold therapy.”

Redberg for her part, remains adamant that the focus of primary-prevention efforts should be on promoting healthy lifestyle, not prescribing drugs. “Healthy-lifestyle measures such as healthy diet, regular physical activity, and smoking cessation . . . have been shown to reduce heart disease and cancer and are associated with living longer as well as better. The multiple adverse effects-fatigue, weakness, muscle problems, memory loss, and diabetes risk-and concern for underreporting of adverse events in current trials noted in the current and previous Cochrane meta-analysis (all industry-sponsored [based on] data that are not publicly available) all mean that the chance of benefit from statins in primary prevention is still dwarfed by the chance of harms. ”

Robinson, however, pointed to the fact that one of the most vocal critics of specific high-profile drugs and their expanded use was also invited by JAMA to respond to the new cholesterol guidance. The Viewpoint by Dr Bruce Psaty with Dr Noel S Weiss (University of Washington, Seattle) was published online in JAMA last week on a day many cardiologists were travelling home from the AHA meeting[4]. 

In it, notes Robinson, Psaty was “highly supportive” of the new guidelines. He writes: “Overall, the revised 2013 ACC/AHA guidelines represent a strong fit with the clinical-trial evidence: treatment thresholds resemble eligibility criteria of the trials; statins are clearly identified as the first-line drug therapy; and treatment targets are abandoned.”

“We were pretty pleased,” Robinson told heartwire .

That’s not enough to reassure Redberg, who insists all research into statins in primary prevention should be reviewed “by groups that do not have conflicts of interest and that make their data freely available to the research community and clinicians for independent analysis.”


Grain Intake – and Cardiovascular Disease

Epidemiological studies have suggested that whole-grain intake is protectivefood_0320 against cancer, cardiovascular disease, diabetes and obesity. Just about every health care system worldwide recommends consuming three servings of whole grains daily.

Whole grains are rich in nutrients and phytochemicals; have high concentrations of dietary fibre, resistant starch, and oligosaccharides. Whole grains are rich in antioxidants including trace minerals and phenolic compounds and these compounds have been linked to disease prevention. Other protective compounds in whole grains include phytate, phyto-oestrogens such as lignan, plant stanols and sterols, and vitamins and minerals. t1larg.gluten.foods.giAlthough it is difficult to separate the protective properties of whole grains from dietary fibre and other components, the disease protection seen from whole grains in prospective epidemiological studies far exceeds the protection from isolated nutrients and phytochemicals in whole grains.

So what is going wrong with the failure to prevent atherosclerotic cardiovascular disease (ASCVD)?

Despite all the preventative lifestyle and nutritional guidelines, ASCVD remains the biggest killer worldwide with the epidemic of vascular disease closely associated with diets predominantly carbohydrate based, including high intake of grains.  Confirming my personal experience as a non invasive preventative cardiologist for the past 20 years, I find it extremely hard to find truly healthy 50+ men or women. Published in Circulation 2011 it seems “ideal cardiovascular health” in healthy American 50+ men and women is equally impossibly hard to achieve despite the prevailing lifestyle wisdom and nutritional information available to all.  

Ideal CV Health  Circulation

In this study only 1/1000 “healthy individuals” (average age 57) achieved all 7 of the health behaviors and health factors.

  1. Non-smoking
  2. Body Mass Index < 25 m2/kg
  3. Moderate physical activity 150 minutes/ week
  4. 4-5 key components of the AHA Dietary guidelines
  5. Total Cholesterol < 5.0 mmol/l (<200 mg/dL)
  6. BP ~ < 120/80
  7. Fasting Glucose < 6.0 mmol/l (< 100 mg/dL)

Ideal CV Health  Circulation results

Also confirming what I see every day is a high prevalence of “sub clinical” atherosclerosis and cardiovascular disease in “so-called” healthy 50+ individuals.  Note the high background prevalence of sub clinical disease even in normal BMI and normal waist measurement in American men and women (average age 57).

Burden of sub clinical CVD

Prev sub clinical CVD

A very famous paper by Boyd Eaton in The New England Journal of Medicine in 1985 suggested that humans, before agricultural times (>10 000 years ago), basically, did not consume cereal grains. 

Since then a number of toxic components that affect many people beyond celiac disease have been identified.  Cereal grains, particularly gluten-containing grains, have a variety of elements or compounds that are toxic, not just to humans, but to other mammals, birds, and insects. This is precisely why cereal grains have evolved, as these antinutrients protect them from predation. Grains are basically grass seeds and are the reproductive material of a plant responsible for the survival of the species.

Grass family

Plants have taken a number of evolutionary strategies to prevent predation by birds and insects and even pathogens, fungus, and bacteria and perhaps humans. One is that they evolve structures like thorns and hard shells and physical barriers making it very difficult for the predator to get to the seed. To avoid being eaten, cereal grains and legumes have taken on another strategy in which they have evolved toxic compounds (anti-nutrients), essentially to make them unpalatable. PicofWheatThe effect of some of these anti-nutrients is to increase intestinal permeability so that the toxic compound can get past the gastrointestinal barrier and into the bloodstream to interact with our physiology to produce pathological effects.

These toxic compounds in the seeds are more concentrated in the finished product that humans eat in terms of flour-produced products or flour-containing foods and in susceptible individuals cause increased gastrointestinal permeability and multi system pathologies.

There are three compounds in wheat which we know cause intestinal permeability. The best studied of which gluten or, actually, a protein is called gliadin (and related proteins derived from grass seeds). All seem to increase intestinal permeability by a mechanisms elucidated by Alessio Fasano’s group at the University of Maryland. gluten-sensitivityPublished in 2009 these scientists linked a human protein (zonulin) to inflammatory and autoimmune disorders like celiac disease; multiple sclerosis; Thyroiditis; arthritis and diabetes. Alessio Fasano identified zonulin as a molecule in the human body called “haptoglobin 2 precursor”.

Haptoglobin is a molecule that has been known to scientists for many years, identified as a marker of inflammation in the body. Haptoglobin 1 is the original form of the haptoglobin molecule, and scientists believe it evolved 800 million years ago. Haptoglobin 2 is a permutation found only in humans. It’s believed the mutation occurred in India about 2 million years ago, spreading gradually among increasing numbers of people throughout the world.

Dr. Fasano’s study revealed that zonulin is the precursor molecule for haptoglobin 2 – that is, it is an immature molecule that matures into haptoglobin 2. It was previously believed that such precursor molecules served no purpose in the body other than to mature into the molecules they were destined to become. But Dr. Fasano’s study identifies precursor haptoglobin 2 as the first precursor molecule that serves another function entirely – opening a gateway in the gut, or intestines, to let gluten in. 

Apes, monkeys and chimpanzees do not have haptoglobin 2 but 80 percent of humans have it. Apes, monkeys and chimpanzees rarely develop autoimmune disorders whilst humans suffer from more than 70 different kinds of such autoimmune conditions. 

This molecule could be a critical piece of the puzzle in celiac disease, non-celiac gluten sensitivity, other autoimmune disorders and allergies and even cancer, all of which are related to an exaggerated production of zonulin/pre-haptoglobin 2 in response to gluten and other grain proteins, leading to the loss of the protective barrier of cells lining the gut and other areas of the body, like the blood brain barrier.


People who suffer from celiac disease and non-celiac gluten sensitivity (NCGS) have sensitivity to gluten and therefore suffer gastrointestinal symptoms and other systemic symptoms when they eat it.

Seemingly in sensitive people, gluten generates an exaggerated release of zonulin that makes the gut more permeable to large molecules, including gluten itself. The permeable gut allows these macromolecules access to the rest of the body triggering an autoimmune response in which a celiac patient’s immune system identifies gluten as an intruder and responds with an attack targeting the intestine instead of the intruder producing the typical small intestine villous atrophy. An inappropriately high level of production of zonulin also seems responsible for the passage through the intestine of other intruders (other antigens) linking other conditions such as type 2 diabetes, metabolic syndrome, multiple sclerosis and many allergies and autoimmune disease.

Whilst celiac disease is relatively uncommon (~1%) the prevalence of non-celiac gluten sensitivity (NCGS) seems much higher and may be grossly underestimated in the general population.

There are other compounds in wheat that increase intestinal permeability. Extensively studied is wheat germ agglutinin or WGA (a lectin). WGA seems to increase intestinal permeability through two pathways: paracellular and transcellular pathways. In other words the WGA or the lectin can go between cells or it can go through cells through receptor-mediated pathways.


The third component in wheat that increases intestinal permeability is an obscure protein called thaumatin-like proteins. This has been studied in other plant products, but not so much so in wheat. So, we suspect that wheat actually has three compounds: gliadin, WGA, and thaumatin-like proteins that seem to act synergistically to increase intestinal permeability in some people to some degree leading to activation of our immune systems leading to autoimmunity and chronic inflammation with pathological effects on cardiovascular disease, cancers, and other diseases.

WGA is a powerful lectin which seemingly binds to everything including interfering (amongst others) with Vitamin D metabolism. One of the animal models back in the 1980s to study rickets was to feed puppy’s whole grains (wheat).  When the diets comprised 45 to 50% of total energy from grains, they could induce rickets.  Relevant to the development of cardiovascular disease is the association outlined nicely by David S.H. Bell, MD (South Med J. 2011;104 (5):340-344) that Vitamin D deficiency is associated with the risk factors of inflammation, insulin resistance and endothelial dysfunction, and left ventricular hypertrophy. As a result there is an increase in cardiovascular events (CVEs) associated with vitamin D deficiency. Deficiency of vitamin D results in an increased expression of genes that are associated with activation of the renin-angiotensin system and genes that are associated with malfunction of calcium channels.  Therefore, activation of these genes is likely to lead to hypertension, left ventricular hypertrophy and congestive heart failure.

Vitamin D replacement has also been shown to increase high-density lipoprotein levels mainly due to an increase in the size of the high-density lipoprotein particle.  The increase in high-density lipoprotein particle size improves reverse cholesterol transportation (protective to the arterial wall) which has also been shown to improve with vitamin D replacement. 

Epithelial cells contain on their outer surface a glycocalyx.  When you look at a cross-section of flow in an artery, the red blood cells and white blood cells that flow through the artery never touch the endothelial cells because of the surface glycocalyx. The gut is lined with similar epithelial cells preventing macromolecule absorption due in part to the glycocalyx barrier. It prevents large macromolecules (and other antigens) from being absorbed inappropriately. So, we only absorb fatty acids; sugar molecules and amino acids.

WGA like many lectins, bind the glycocalyx causing it to be shed exposing the bare epithelial cells to the gut contents, or in the case of the artery, the contents of the bloodstream. Whenever the glycocalyx is shed in epithelial cells, it causes pro-inflammatory cytokines (TNF alpha, interleukin-2; interleukin-6) that also increases intestinal permeability and compromise vascular integrity (endothelial dysfunction) increasing permeability of the arteries to atherosclerotic lipoproteins causing atherosclerotic cardiovascular disease (ASCVD).

Conventional diets with 60% of daily calories from carbohydrates including a large proportion of grains, may therefore compound (paradoxically) some of the risk for ASCVD with leaky-gut syndrome; dyslipidaemia and high systemic inflammatory burden and autoimmune disease.  h_LDLpathwayThere is a tendency towards lower HDL and to small dense LDL particles size in people consuming high carbohydrate diets including high (often refined) grain intake.  The increased systemic inflammation (high us-CRP) promoting oxidation of the small dense LDL molecules is the typical atherogenic environment to potentiate ASCVD.What-is-Paleolithic-Diet

Perhaps some very good reasons to re-visit a Paleolithic low carbohydrate style diet.