Atherogenic Lipoproteins and Cardiovascular Disease

The lay press has again questioned the role of “cholesterol” in the pathophysiology of atherosclerotic cardiovascular disease and the relative benefit of Statin therapy especially in healthy people with no heart disease.  Chris Kresser writes an impressive blog:

The Diet-Heart Myth: Cholesterol and Saturated Fat Are Not the Enemy

By Chris Kresser on April 19, 2013

Professor Tim Noakes has supported this ethos with both authors slating the benefit of Statin for “primary prevention of cardiovascular disease” in so-called heathy people (I will address this in my next blog).

Both authors are spot on with their understanding that cardiovascular disease is a disease of lipoproteins and not cholesterol.  Both authors are correct that 2/3 of people who eat diets low in carbohydrate but rich in cholesterol and saturated fat may actually improved their HDL and LDL particle size.  One needs to point out though that 1/3 of people will severely deteriorate their lipogram and seriously increase atherogenic lipoproteins probably due to LDL-receptor defects and in these individuals their vascular risk is very high.

I agree therefore that we need to stop talking about cholesterol and cardiovascular risk but rather talk of the “atherogenic lipoproteins” and  “total atherogenic risk”.

LDL-C or apoB as the Best Target for Reducing Cardiovascular Disease:

For more than 20 years, LDL-C has been considered to be a major lipid risk factor, and in most national guidelines, LDL-C is considered to be the main target of lipid-lowering therapy. Large meta-analyses (see later) of interventional studies with statins have shown that reduction of LDL-C leads to reduction of the risk of coronary heart disease (CHD) and CVD in people with established vascular disease (secondary prevention) and in healthy people (at risk) but with no vascular disease (primary prevention).

However, even persons subjected to an active therapy in these trials display a high residual risk. One of the reasons for such a high residual risk may be the fact that LDL-C is not necessarily the best risk marker in all individuals.

At present, obesity and obesity-related insulin resistance, metabolic syndrome and Type 2 diabetes mellitus (T2D) is a worldwide phenomenon. Even in patients with metabolic syndrome and diabetes, lipoproteins play the major role in the development of atherosclerotic macrovascular complications. However, LDL-C is not the major characteristic of lipid changes associated with the aforementioned states. These states are associated with atherogenic dyslipidemia, characterized especially by increased levels of triglycerides (TGs), reduced HDL-C and an increased prevalence of small dense LDL (sdLDL) at relatively normal levels of LDL-C. Low HDL-C and high plasma TGs are considered to represent an important residual risk besides LDL-C.

Nevertheless, normal LDL-C does not mean that the atherogenic particle number is normal, and this fact is often underestimated. The increased number of sdLDL associated with atherogenic dyslipidemia is reflected in increased concentrations of apoB, which is a better marker of atherogenic lipoprotein numbers than concentrations of LDL-C. In fact, apoB is a key component of atherogenic dyslipidemia, as will be discussed later.

Pathophysiology:

Atherogenic lipoprotein particles can vary considerably in their cholesterol content, but each particle contains only one molecule of apoB-100 (or simply apoB). As a result, serum concentration of apoB is a better marker of atherogenic lipoprotein particle numbers than both LDL-C and non-HDL-C (total cholesterol minus HDL). Especially in subjects with a large number of cholesterol-depleted sdLDL, LDL-C underestimates the number of LDL particles the most (see Figure below). Subjects with obesity, insulin resistance, metabolic syndrome, hypothyroidism; leaky gut syndrome and diabetes tend to have high levels of sdLDL and also have a multiplication of other potentially atherogenic lipoprotein particles rich in TGs, namely VLDL and their remnants IDL, which are not contained within the LDL-C parameter.

In the figure above the LDL-C level in specimen “A” and “B” may be equal but in “A” the lipoproteins are large non-dense fluffy with only 5 Apo-B (the red circles)  compared to “B” where there are small dense LDL with other atherogenic lipoproteins with 9 Apo-B molecules.

The concentration of apoB is better marker of the number of all potentially atherogenic particles because all these lipoprotein particles (VLDL, IDL, LDL [including sdLDL] and Lp[a]) contain only one molecule of apoB-100 and various amounts of cholesterol (see Figure below).

All apoB-containing lipoprotein species appear to be atherogenic to a greater or lesser extent, but larger apoB-carrying particles, such as VLDL, may be less atherogenic than the smaller LDL particles.

Small dense LDL particles are probably more atherogenic than large buoyant (fluffy) LDL as they enter the artery wall much more easily and are not well-recognized by LDL receptors and thus remain longer in the subendothelial space, where they undergo modification and induce inflammation. Modification affects the structure of apoB-100 so that it becomes a ligand for the scavenger receptors of monocytes or macrophages. Cholesterol then accumulates in the cytoplasm of macrophages to form foam cells, which is the characteristic feature of all stages of atherosclerosis.

Experimental studies demonstrated that apoB, by highly specific interaction with proteoglycans, leads to entrapment and retention of lipoprotein particles in the artery wall, where they become oxidized or otherwise modified. Thus, it is apoB and not the cholesterol content of the lipoprotein particle that leads to the initiation of atherosclerotic processes and subsequent deposition of cholesterol in the artery wall.

The greater atherogenicity of small dense (sd) LDL particles in comparison with large buoyant LDL is supported by findings from the Quebec Cardiovascular Study that confirmed that a greater proportion of sdLDL at baseline was a strong and independent predictor of CHD in the first 7 years of follow-up. By contrast, an elevated concentration of large LDL was a poor predictor of CHD in this study and seemed to be paradoxically associated with a low CVD.

Review of Prospective Studies Comparing apoB & LDL-C as Predictors of Cardiovascular Risk:

Numerous prospective studies have shown that apoB predicts CHD in both genders, and is better than LDL-C in this respect.The largest from these studies was the AMORIS, which observed 98,722 men and 76,831 women over the age of 60 years for approximately 5 years. In this study, by use of different multivariate analyses, apoB proved to be more significant than LDL-C and added predictive power to that of LDL-C for prediction of the risk of fatal heart attack. 

Another major finding of the AMORIS was that in individuals with concentrations of LDL-C below the median, apoB was a better predictor of risk than LDL-C. This is a very important finding as almost 50% of coronary patients may have plasma cholesterol concentrations of less than 5.2 mmol/l and a large proportion of coronary patients with normal cholesterol levels have elevated apoB concentrations.

This finding can be explained by the presence of sdLDL and is in agreement with the results from the Québec Cardiovascular study,^[ which showed that the risk of MI is higher in individuals who have high LDL-C and a high concentration of apoB than in those with high concentrations of LDL-C and low apoB.

A further important finding of the AMORIS is that apoB and apoA-I (the lipoprotein in HDL) added power to predict fatal MI not only in men and women under 70 years of age but also for those aged 70 years or more. Total cholesterol loses its predictive power in people aged 70 years or older, while apoB, apoA-I and the apoB:apoA-I ratio remain important risk predictors of MI in this age category.

Numerically, the steepest increase in risk of MI was obtained in the AMORIS for the apoB:apoA-I ratio, which increased approximately 3.8-fold in men and just below threefold in women when the risk for those in the highest quartile was compared with those in the lowest quartile.

Prospective studies support the concept that the number of atherogenic particles is a more important indicator of risk than the amount of cholesterol transported in these particles.

In which Populations does LDL-C most Underestimate the Number of Atherogenic Particles?

LDL-C most underestimates the number of atherogenic lipoprotein particles in conditions with a large prevalence of sdLDL. It was proved that sdLDL starts to increase with TG levels of 1.5 mmol/l. The increased number of sdLDL is particularly common in subjects with visceral obesity, metabolic syndrome and diabetes mellitus.

It is well-known that diabetes increases the risk of CVD more in women than in men. In particular, women who become diabetic differ from nondiabetic women in their markedly increased concentrations of apoB, while their LDL-C and non-HDL-C remain comparable with nondiabetic women.

Familial combined hyperlipidemia (FCH) also belongs to clinical entities associated with insulin resistance, an increased number of sdLDL and disproportionately increased concentration of apoB compared with LDL-C. Diagnosis of this most common familial dyslipidemia is based on measuring apoB and not just lipid. FCH is found in approximately 0.5–2% of the general population and in 10–20% of patients with premature vascular disease. In some cohorts of patients with a history of  heart attack FCH was found in up to 40% of cases.

Small dense LDL is also frequently found in patients with established CVD especially in those with relatively low total cholesterol and LDL-C. In elderly people, LDL-C loses its predictive power while apoB still predicts the CHD risk. Approximately 45% of the population over 60 years of age have metabolic syndrome, which is characterized by an increased number of LDL particles at a relatively normal LDL-C concentration.

Thus, apoB measurement in order to assess CHD risk is especially important in the rapidly growing subset of the population with obesity, characteristics of metabolic syndrome, diabetes and in a growing subset of the older population.

Conclusion & Future Perspective:

It is usually argued that the introduction of apoB as a marker of risk and target of therapy would lead to confusion of both physicians and patients. For more than two decades, a great effort was devoted to education on the issue of the role of ‘bad cholesterol’ (LDL-C) in the development of atherosclerosis and the necessity of cholesterol-lowering therapy in the prevention of CVD. Thus, most authorities in this field think that it is necessary, at least for an interim period of time, to introduce apoB assessment to the routine lipid profile.

ApoB is a marker of the risk of atherogenic particles, especially LDL risk, and cannot substitute the whole lipid profile, especially at baseline examination. Thus, as this article suggests, apoB should be a part of the routine lipid panel at baseline. However, when apoB is the target, total cholesterol, LDL-C and non-HDL-C need not be measured on routine follow-up visits. Thus, apoB could unify all lipid targets representing the proatherogenic lipoprotein particle risk into one parameter.

Estimation of baseline TGs is useful, as a mild-to-moderate increase in TGs is a good marker of insulin resistance and its associated risk factors and also as a marker of increased risk of CVD.Even in patients treated with statins to achieve very low levels of LDL-C of less than 1.8 mmol/l, high TG levels represent a considerable residual risk. 

Nevertheless, especially in hypertriglyceridemia, CVD risk is influenced by concomitant apoB levels. High apoB levels in hypertriglyceridemia indicate an increase in potentially atherogenic particles such as sdLDL and smaller TG-rich particles, such as IDL and smaller VLDL, while low apoB levels instead indicate an increase in larger TG-rich lipoprotein species such as chylomicrons and large VLDLs, which are less atherogenic (owing to their volume, they do not easily enter the artery wall). Thus, increased TG levels of ≥1.7 mmol/l are markers of increased cardiovascular risk.

Estimation of HDL-C is also important for the evaluation of CVD risk, as it is an independent risk factor for CVD. Even in patients treated with statins to achieve very low levels of LDL-C of less than 1.8 mmol/l, low HDL-C significantly contributed to macrovascular risk.

The research in recent years has shown that the functionality of HDL and its specific subpopulations may be even more important than HDL-C levels. Nevertheless, at present, we do not have a useful method for measuring HDL functionality in clinical practice. Various drugs can influence different HDL species and various HDL functions. Thus, the results of clinical end point trials and not HDL-C levels should be decisive in this respect. However, as most drugs used for the treatment of lipid disorders usually influence more than one lipoprotein class, it will be very difficult to decide which part of the outcome is an HDL-related effect.

Several observations have shown that for many antiatherogenic roles of HDL, apoA-I is more important than HDL particle cholesterol content. Thus, in future, HDL-C assessment could probably be substituted with apoA-I assessment until better methods for the evaluation of HDL functionality are developed.

At present, the apoB:apoA-I ratio seems to be the best marker of cholesterol balance. It was shown to be the best marker of cardiovascular risk for MI and CVD in the AMORIS (see figure) and INTERHEART studies.  I personally use the apoB:apoA-I ratio as a promising marker of both risk and treatment effect.

I keep my personal ApoB/ ApoA1 at 0.26 which as you can see from the figure above gives me an extremely low risk for AMI.

Summary:

• Recent data demonstrate that apoB is a better marker of risk than LDL-C and a more appropriate target of lipid-lowering therapy, especially in the growing subset of the population with established vascular disease, obesity, metabolic syndrome and/or diabetes.

Pathophysiology:

• As all potentially atherogenic lipoprotein particles contain only one molecule of apoB and various amounts of cholesterol, the concentration of apoB is a better marker of atherogenic particle numbers than LDL-C and non-HDL-C. LDL-C most underestimates the risk in subjects with an increased number of cholesterol-depleted small dense LDL. The number of atherogenic particles that are able to enter the artery wall is more important than the cholesterol transported in these particles.

Prospective epidemiological studies:

• In most of the available prospective studies comparing apoB with LDL-C and/or non-HDL-C, apoB is a better marker of vascular disease risk.

Interventional studies:

• Statins lower LDL-C and non-HDL-C more than apoB (in terms of percentage decrease from baseline and lower population percentile levels). Many patients reaching their LDL-C and non-HDL-C goals remain at high risk owing to high levels of atherogenic particles as judged by apoB assessment, especially those with elevated triglycerides such as those with metabolic syndrome and Type 2 diabetes. Owing to this fact, apoB provides a more consistent goal for lipid-lowering treatment and a better assessment of on-treatment residual risk than LDL-C and non-HDL-C.

Availability of apoB measurement & standardization

• The measurement of apoB is standardized, automated, inexpensive and does not require fasting samples.

Conclusion & future perspective

• ApoB should be measured in all subjects with abnormal lipid profiles and with a moderate or high risk of cardiovascular disease to evaluate their lipid-associated risk. ApoB should be the primary target of lipid-altering therapy. For the interim period of time, apoB should be measured as an additional and equivalent part of the lipid profile, at least in patients with a high cardiometabolic risk.
• The apoB:apoA-I ratio is a promising future parameter for evaluating both risk and treatment effects. ApoB and apoA-I should be measured in all prospective and interventional studies to obtain further evidence on this topic and to help to set appropriate targets.
• The ‘apoB paradigm’ should be explored in more detail as it offers new strategies for LDL-C lowering.

Cardiologydoc

Oral contraceptive use and atherosclerosis

Being International Women’s Day I raise a topic that has bothered me for years.  As a preventative non-invasive cardiologist I have had the privilege of seeing many women age 35-65 years who look particularly gorgeous on the “outside” but have advanced sub-clinical atherosclerosis on the “inside”. A common feature in these women is prolonged use of oral contraception (OC) during their lives. 

To introduce discussion on OC use and “premature” atherosclerosis I show you a carotid ultrasound of a healthy 60 year woman free of sub-clinical atherosclerosis.

This is a longitudinal view of the carotid artery with “edge-detection” software tracking the intima-media (IM) interface.  In this woman  the IM is pristine reflecting no thickening, no irregularity and no plaque (free of sub-clinical disease).

By contrast this 45-year-old woman has a very large 0.24 cm “soft” atherosclerotic plaque at the origination of the internal carotid artery.

This plaque has filled 50% of the diameter of the proximal internal carotid artery and thus reflects quite severe (advanced)  sub-clinical atherosclerosis in a “well woman” who has had prolonged exposure to oral contraceptive therapy (OC) and was at the time of this examination still taking a low dose mixed estrogen/ progestogen containing OC .

So what data is available to suggest an association of OC to atherosclerosis?

Jamil and Siddiq write a compelling article:

“Comparison of CVD risk associated with the long term use of contraceptives in young females” J App Pharm Sci. 2012; 2 (11): 062-066.

They correctly point out abnormal lipid profiles have been associated with major risk factors for cardiovascular disease (CVD) which is one of the most dominant causes of death in the world and is mainly due to vascular atherosclerosis.

I have previously indicated that cardiovascular disease is the leading cause of adult mortality, with women comprising 55% of the epidemic.

Extensive use of hormonal contraception by females through their reproductive life has led to the concern about the effects of oral contraceptives on the risk factors for coronary heart disease. OC-induced changes in both carbohydrate and lipoprotein risk factors may contribute to the increased risk of vascular disease as orally administered estrogens increase hepatic triglyceride synthesis and VLDL secretion. Estrogens increase the rates of elimination of LDL, VLDL and chylomicrons; suppress the synthesis of key enzymes of lipoprotein metabolism, hepatic and lipoprotein lipase, and increase synthesis of the principal apo-protein of HDL, Apo-A1. Interestingly though, although estrogens have been shown to elevate HDL, the subtype of HDL has been shown to be “non-functional” in reverse transporation of atherogenic LDL from the plaque back to the liver. So the high HDL in women taking estrogen based hormone therapy may be misleading and lead the individual (and the doctor) into a false sense of security.

So oral contraception usage has been found to be associated with adverse findings in several metabolic, cardiovascular and inflammatory parameters, which is consistent with an increased future risk of cardiovascular and metabolic disease. These findings should invite more criticism of recent trends that encourage the prescription of oral contraceptives for years during reproductive life and especially in pre-menopausal women.

In general, progestogens oppose estrogen effects on lipoproteins according to type and dose leading to a range of different lipoprotein profiles including abnormally low HDL level; abnormally high LDL level and an increase in the LDL: HDL cholesterol ratio. The decline in HDL is associated more with androgenic progestins.

This study compared the extent of cardiovascular atherosclerotic risk associated with the lipid metabolism in women using hormonal contraceptives in an urban population of low socio-economic group. The conclusion was that the use of OC’s was associated with the highest atherogenic index and the authors suggested that hormonal contraception should be used under close monitoring until further studies conducted to completely eradicate the risk associated with hormonal preparations.

Perhaps more compelling research comes from a team of Belgian researchers who made the surprise discovery that women who have used oral contraceptives (OC’s) for some time appear to be at increased risk of atherosclerosis in the carotid and femoral arteries. They also found that those taking the pill had three times higher C-reactive protein (CRP) levels than those not using it.  

This data was presented by Dr Ernest Rietzschel (Ghent University, Belgium) at the American Heart Association (AHA) 2007 Scientific Sessions. This was the first documentation of the large elevations in CRP seen in women taking the pill. 

It’s staggering that for a drug that is being used by 80% of women at some point in their lives, there is so little information about the long-term safety. This study is important and provocative, because it raises new questions about the long-term safety of a widely used class of drugs.

CRP increased threefold in those taking OC’s:

Rietzschel and colleagues started out by assessing novel risk factors for atherosclerosis in women participating in the Asklepios study, a blinded sample of women volunteers aged 35 to 55 years in the Belgian population who were free from overt cardiovascular disease.

Of 1301 women (mean age 45.7 years) in Asklepios, 27.4% were taking OC’s and 10.0% were taking hormone replacement therapy (HRT). Past OC use was much higher, however, with 81% of women having taken it for at least one year, with a median exposure of 13 years.

After multivariate adjustment, women who were not taking OC’s or HRT had high-sensitivity CRP of 1.0 mg/L compared with 1.2 for those currently taking HRT and 3.3 for women currently taking OC’s. 

OC’s an important factor in global atherosclerotic burden:

The researchers found an increase in the prevalence of carotid and femoral atherosclerosis in this group of otherwise young, apparently healthy women. Their data suggest a 20% to 30% increased prevalence of plaque in the carotid and femoral arteries per 10 years of OC exposure. In the light of widespread and usually prolonged OC use, these results suggested OC use could be an important factor in the global atherosclerotic burden.

Perhaps the article which raises the most concern is this very recent paper in NEJM June 2012. A massive number of women taking OC were followed (1,626,158) contributing 14,251,063 person-years of observation during which 3311 thrombotic strokes (21.4 per 100,000 person-years) and 1725 myocardial infarctions (10.1 per 100,000 person-years) occurred. 

The table taken from the paper shows the STAGGERING increase in incidence in stroke and coronary deaths with increasing age and exposure to the OC’s.

So my concern:

For a drug that is used widely amongst young women there seems to be some data suggesting increased lifetime risk of atherosclerosis predisposing to increased morbidity and mortality in the woman’s lifetime.

Women seeking oral contraception present a unique opportunity for doctors to give advice on the prevention of cardiovascular disease at an early age. “Young women have an idea that they won’t succumb to cardiovascular disease, which is entirely wrong, because more women die of cardiovascular disease than men. Maybe this is a good time to start talking to young women. Okay, you want to take the pill, but think about the long-term implications. You should stop smoking, check your weight, and be more physically active. Also, we know the pill has effects on blood pressure and lipid profiles, so these should be checked and managed.”

Blessings to all the women of the world - take care of yourselves.

Cardiologydoc

Diabetes Mellitus and Statins – the whole deal

This topic is very close to my heart as a “preventative, non-invasive” cardiologist.  I have 20 years practical experience in both primary prevention (in heathy individuals) and aggressive secondary risk modification (in those with established vascular disease) and have a database of ~ 10 000 individuals treated with both weak and potent Statin therapy, in high and low doses over many years.

The association of statin use and new onset diabetes mellitus has been known since 2010 but only hit the headline with 2 major publications in 2012 and the FDA announcement that clinicians should be aware of this association (February 2012). 

The debate has centred on the following:

1. Is this a real effect of statins?
2. Is there “cause and effect” or is the association driven by confounding factors?
3. What is the clinical relevance?
4. Should we in any way change our practice of prescribing (high dose potent) statins?

  Ultimately anything we do in life shares this very important paradigm of RISK versus BENEFIT and the costs involved.  Driving an incredibly dangerous weapon (your motor car) at slow or high-speed carries profound risk-benefit. Investing in your future economic well-being and preventing the commonest disease process on planet earth has exactly the same implications.  Investing in your cardiovascular health through prevention of atherosclerosis of your arteries requires dedicated attention to detail life-long.  The one thing we do know is that attainment of “ideal cardiovascular health” is extremely difficult to achieve just with lifestyle and diet.

Only 1/1000 healthy individuals (age ~ 50) achieved all 7 of the health behaviors and factors.

The prevalence of “sub clinical” atherosclerosis and cardiovascular disease is equally VERY high in “so-called” healthy 50 year individuals.

So what are the risks of diabetes with statin therapy?

Statins have been available since the 1980s but their risk of inducing diabetes did not surface for nearly 20 years. When all the data available from multiple studies was pooled in 2010 for more than 91,000 patients randomly assigned to be treated with a statin or a sugar pill (placebo), the risk of developing diabetes with any statin was one in every 255 patients treated.

The weaker statins like pravastatn introduced in the early 1990′s seemingly do not carry any clear-cut risk. It is only with the more potent statins like Zocor (simvastatin), Lipitor (atorvastatin) and Crestor (rosuvastatin), particularly at higher doses, that the risk of diabetes shows up. The cause-and-effect is unequivocal, because the multiple large trials of the more potent statins had a consistent excess of diabetes.

Overall the incidence of new onset diabetes mellitus is 9-12% over 5 years of statin therapy with high dose more potent statins offering the higher risk.  This has to be balanced by the benefit in cardiovascular reduction over the same period of 5 years ~25-50% or with potent high dose Statins 20% risk reduction per 1 mmol/l reduction LDL. 

Essentially a nice way of looking at risk verses benefit  is to look at the number of people needed to treat (NNT) to prevent ONE MAJOR cardiovascular event (CVE) verses the number needed to treat to HARM (NNH) one patient (in this case a new onset of diabetes).

With statin therapy in primary prevention the NNT is 90 people over 2 years & 65 over 5 years.  With secondary prevention the NNT is 150 over one year and only 10-40 over 5 years to save one major CVE.  The NNH is 250 over a 5 year; 300 over 2 year & 500 over 1 year. In other words we will generally see one new case of diabetes in 500 treated with generally a high potency high dose statin.  

With potent statins like rosuvastatin (Crestor) and high dose atorvastatin (Lipitor) the benefit in reducing MCE is very impressive due to plaque reduction and plaque stabilisation.

For every 1 mmol of LDL reduced (with statins) there is approximately 20% risk reduction independent of the risk of the person (<5%  to high risk > 30%).

Of importance is the typical phenotype predicting which patients develop diabetes on statin therapy.  Those individuals with “metabolic syndrome” with elevated fasting blood sugar, increase visceral adiposity, high normal blood pressure or hypertension, and elevated triglycerides are those at risk for developing diabetes on statins.  If patients had  four of these risk factors, they have a 25% risk of developing diabetes. If they have none of these risks factors, their risk was just 2%. That is not surprising, as we know these are just the factors that predict new onset diabetes.

The possible confounding factors relating statins to new onset diabetes are also relevant.  Many people who take statins to lower atherogenic lipoproteins (LDL) rely on the “pill approach” rather than a holistic approach with correct lifestyle, exercise and nutrition and as I see every day the risks for progressive metabolic syndrome are exacerbated despite statin therapy. In my practice we focus on all 10 of the parameters that drive cardiovascular disease and consequently I see extremely few cases of diabetes on statin therapy:

1. ApoB/ ApoA1 (total atherogenic/ non atherogenic lipoproteins)
2. Ultrasensitive CRP < 1.0
3. Non smoking of all tobacco products
4. BMI < 25%
5. Optimal nutrition tailor prescribed for the individual phenotype
6. Moderate intensity exercise on most daily/ week
7. BP ~ 120/80
8. GLucose < 6.0
9. Alcohol in moderation
10. Stress reduction

Remember the cumulative effect of statin therapy on our arteries over many decades is profound and forms the basis of the philosophy of “optimal medical management.”  This accounts for the incredible outcome in trials like STENO-2; BARI-2D and COURAGE where major cardiac event rate was impressively reduced compared to conventional management and even invasive (coronary stents) or surgical intervention (coronary bypass surgery).

So in summary:

The consistency of the statin clinical-trial findings, the temporal association and the dose-dependency of the effect all provide a strong argument for causality for statins and diabetes.

Whilst the precise mechanism for cause-and-effect is NOT known further work is needed to elucidate the mechanisms of action at hepatic, skeletal-muscle, adipocyte, beta-cell, and mitochondrial levels that could impair insulin action and glucose homeostasis. There is certainly no evidence to support statin worsening insulin resistance nor evidence to suggest increasing risk via accelerated oxidised LDL due to statin.

The bottom line is a fairly simple, straightforward clinical message. Even in a lower-risk primary-prevention population, the cardiovascular benefits of statin therapy outweigh the diabetes hazard, even among those with highest risks for diabetes (metabolic syndrome).

With the incredible benefit and low NNT in secondary prevention the risk-benefit ratio greatly favors benefit in treating patients to goal (generally LDL < 1.8 and ApoB/ ApoA1 0.3- 0.5) with high potency high dose statin therapy.

In other words the clinical RELEVANCE of new onset of diabetes mellitus with statin therapy is minimal as the benefit of major cardiac event reduction outweighs any proposed negative effect of the diabetes.

Blessings

Cardiologydoc

Vitamin K2 and Vascular Disease

I have been asked to talk about the role of Vitamin K (K2 specifically) in the pathogenesis of vascular disease.  This is a controversial topic as “mainline cardiology” has not yet embraced the data and the “jury” is not yet out as to the importance of vitamin K2 in preventing and treating cardiovascular disease.  The data I will summarise is extremely interesting and I believe we will be incorporating this knowledge into prevention and management of atherosclerotic vascular disease soon.

Introduction:

We have been conventionally taught that the role of vitamin K was solely ascribed to coagulation and coagulation was thought to be involved only in the venous system.

This view has dramatically changed with the recent (last decade) discovery of vitamin K-dependent proteins outside the coagulation cascade and the role of coagulation factors in the pathogenesis of atherosclerosis on the arterial side. Vitamin K-dependent proteins are involved in the regulation of vascular smooth muscle cell migration, apoptosis (programmed cell death), and vascular calcification.

Vascular calcification is a well recognised important independent predictor of cardiovascular disease and closely correlates cardiac morbidity and mortality. The involvement of vitamin K-dependent proteins such as matrix Gla-protein (MGP) in vascular calcification makes that calcification amendable for intervention with high intake of vitamin K2. 

Nutritional vitamin K consists of two forms:

• vitamin K1 (a phylloquinone also known as phytonadione)
• vitamin K2 (a menaquinone)

Vitamin K1 is found in leafy green vegetables (lettuce, spinach and broccoli)where it is tightly bound to the chloroplast membrane resulting in a poor absorption (poor bio-availability) of vitamin K1 from vegetables but it is still the dominant form making up about 90% of the vitamin K in a typical Western diet.

Vitamin K2 is found in fermented foods such as cheese, sauerkraut and the Japanese Natto (a foul-smelling sticky web of fermented soybeans typically served with a Japanese breakfast.derived from the bacterium Bacillus subtilis). The absorption of vitamin K2 is apparently much better as compared to vitamin K1 comprising 10% of our vitamin K consumption.  Vitamin K2 importantly can be synthesised in the colon by microflora. There are apparently 4 isoforms of vitamin K2 determined by the number of prenyl side chains (MK-4; MK-7; MK-8 & MK-9). MK-4 is found in meat whereas the MK-7 to 9 tend to come from the fermented foods.

Importantly the bioavailability of the isoforms differ with MK-4 demonstrating very poor bioavailability at a nutritional level dose compared to excellent bioavailability with MK-7.

After being absorbed in the intestine, vitamin K, as a fat soluble vitamin is transported by lipoproteins, as it has no specific carrier protein. The different lipophilicity (fat solubility) of K1 and K2 may result in substantial differences in plasma transport, half-life and delivery to target tissues (t1/2 for K1 ~ 3 hours; 1.5 hours for MK-4 and > 70 hours for MK-7; MK-8 & MK-9).

Vitamin K-dependent proteins:

Vitamin K-dependent proteins constitute a family of 16 known proteins with diverse functions, not only involved in the haemostatic coagulation pathway. The vitamin K dependent coagulation proteins (clotting factors II, VII, IX and X) are essential for the coagulation cascade and are γ-carboxylated in the liver to be functionally active. They are well-balanced by the anticoagulant factors protein C and protein S.

All these vitamin K-dependent proteins are mainly synthesized and γ-glutamylcarboxylated in the liver, with the exception of proteins S which is synthesized in part by endothelial cells.

Over the past decade an enormous amount of evidence has suggested that coagulation factors play an important role in (chronic) inflammation. Phagocytosis of apoptotic cells by macrophages is thought to limit the inflammatory response and Protein S has been identified as a factor responsible for stimulation of this phagocytosis. Additionally protein S regulates the expression and function of scavenger receptor A (SR-A) on macrophages resulting in diminished uptake of acetylated low density lipoprotein.

Protein C deficiency is associated with severe coagulation response to endotoxin and this Protein C also plays a significant role in the inflammatory response with activate Protein C inhibiting endotoxin-induced production of important cytokines like TNF-alpha, IL-1, IL-6 and Il-8 by momocytes/macrophages.

Extrahepatic vitamin K-dependent proteins:

Within the arterial vessel wall vitamin K-dependent proteins are synthesized with functions not related to blood coagulation.

Growth arrest specific gene 6 protein (Gas-6) is a vitamin K-dependent protein produced by vascular smooth muscle cells (VSMCs). Gas-6 seems to protects VSMCs from calcification by inhibiting apoptosis as the cell death may act as a nidus for calcification.

The vitamin K-dependent matrix Gla-protein (MGP) is regarded as the strongest inhibitor of vascular calcification (VC) and produced by many cells, including VSMCs. Rescue experiments in MGP null mice demonstrated that MGP acts locally in the vascular tissue as restoration of MGP expression in arteries completely rescued the arterial mineralization phenotype, whereas hepatic MGP expression, resulting in high systemic MGP levels, did not.

Vascular calcification as a marker of atherosclerosis risk stratifies into high risk outcome:

Vascular calcification (VC) is associated with increased cardiovascular mortality and morbidity, and is recognised as a strong and independent risk factor for cardiovascular death. The amount of VC, as measured and quantified by multidetector computed tomography (CT-coronary angiography) is an important predictor of:

• all-cause mortality
• vascular complications
• myocardial infarction and stroke

Patients with higher coronary artery calcification scores have approximately ten times more chance to have a cardiac event in the next 3–5 years. Patients with a calcification-progression over 15% per year had a 17.2 fold increased risk of myocardial infarction compared to patients without significant progression.

Vascular calcification is an even stronger predictor than the Framingham Risk Score (FRS) which is currently used to score 10-year risk prediction for cardiovascular events.

Clinically,VC causes stiffening of the vascular arteries via elastic fiber and VSMC calcification resulting in:

• decreased arterial compliance with the development of chronic systemic hypertension
• development of left ventricular hypertrophy leading to diastolic heart failure
• decreased coronary perfusion 

In spite of this data, calcification of arteries has been generally neglected and considered to be clinically unmodifiable, often regarded as an end stage passive process not amenable to therapeutic intervention.  Recent data however suggests that punctated and spotty calcification in the atherosclerotic plaque influence stability negatively and render the plaque vulnerable to rupture thus potentiating the progression of atherosclerosis and vascular events.

As VC is a complex and actively regulated process involving cells and vitamin K dependent proteins acting as catalysts and inhibitors. Recruitment of macrophages in the atherosclerotic plaque and consequently their secretion of inflammatory cytokines may serve as a signal for intimal calcification.  When VSMCs phagocytose calcium crystals it seemingly destabilize atherosclerotic plaques by initiating inflammation and by causing SMC death. 

Circulating biomarkers (MGP) for detecting vascular calcification:

This is an attractive concept to screen for and perhaps regulate mechanisms of VC.  Vitamin K-dependent proteins have been associated with the earliest calcification areas in the plaque. Uncarboxylated MGP seemingly strongly correlates with both medial and intimal calcification. By measuring circulating MGP isoforms it has been shown that the majority of the healthy population have sub-optimal levels of vascular vitamin K. Preliminary data suggest that some MGP conformations are associated with aspects of cardiovascular disease for instance patients with high VC scores display high levels of inactive MGP, especially dialysis patients.

This creates possibilities for targeting VC with vitamin K therapy. Indeed high intake of vitamin K has been shown to regress preformed medial calcification in a rat model and the first data is available in dialysis patients showing that vitamin K supplementation markedly reduced the level of plasma uncarboxylated prothrombin, uncarboxylated osteocalcin and inactive MGP.

Conclusion:

Effort must be directed towards retarding or reversing the development of calcification in the vasculature, especially in those patients prone to vascular calcification (chronic kidney disease, diabetes, atherosclerotic cardiovascular disease). In these patients the treatment with vitamin K antagonists should be reconsidered perhaps with a view to used specific Thrombin inhibitors in cases where anticoagulation is required.

Therefore, it is of importance to identify patients with vascular disease and to evaluate different strategies that are more effective in the prevention of hypercoagulability as well as vascular calcification.

Here lies the real interest in high dose vitamin K2 replacement to minimise and reverse vascular calcification as part of general prevention and management of atherosclerotic vascular disease.

This is consistent with separate research also showing superior health benefits from vitamin K2, including:

• The Rotterdam Study the first study demonstrating the beneficial effect of vitamin K2, showed that people who consume 45 μg/d of K2 daily live seven years longer than people getting 12 μg/d
• Data from the Prospect EPIC Cohort published in
  Nutrition, Metabolism & Cardiovascular Diseases
  Gast et.al. Volume 18, Issue 7 Pages 504-510, September 2009
  suggested a high menaquinone intake reduces the incidence of coronary heart disease (CHD). 16,057 women, enrolled between 1993 and 1997 and aged 49–70 years, who were free of cardiovascular diseases at baseline. Intake of vitamin K and other nutrients was estimated with a food frequency questionnaire. After a mean follow-up of 8.1±1.6 years, with 480 incident cases of CHD. Mean vitamin K1 intake was 211.7±100.3 μg/d and vitamin K2 intake was 29.1±12.8 μg/d.After adjustment for traditional risk factors and dietary factors, the authors observed an inverse association between vitamin K2 and risk of CHD with a Hazard Ratio (HR) of 0.91 [95% CI 0.85–1.00] per 10 μg/d vitamin K2 intake. This association was mainly due to vitamin K2 subtypes MK-7, MK-8 and MK-9. Vitamin K1 intake was not significantly related to CHD

Um food for thought….

Blessings Cardiologydoc

Atherosclerosis hope in 2013

The prevalence of coronary atherosclerosis among deployed USA service members who died during the past decade is 8.5%, which is markedly lower than rates observed in soldiers who served in the Korean and Vietnam wars. 

This prevalence demonstrates a steep decline from the rates of 77% noted in the Korean War and 45% in the Vietnam War — researchers wrote in the Journal of the American Medical Association in December 2012.

JAMA 2012; 308:2624-2625.

Bryant J. Webber, MD, of the Uniformed Services University of the Health Sciences in Bethesda, Md., and colleagues conducted a study of 3,832 (mean age, 25.9 years; 98.3% men) members of the armed forces with available autopsy reports who died from combat-related or unintentional injuries in support of Operation Enduring Freedom and Operation Iraqi Freedom/New Dawn between 2001 and 2011.

Coronary atherosclerosis was classified as minimal (fatty streaking only), moderate (10% to 49% luminal narrowing of ≥1 vessel) and severe (≥50% narrowing of ≥1 vessel).

Prevalence of any coronary atherosclerosis was 8.5% (95% CI, 7.6-9.4); severe coronary atherosclerosis, 2.3% (95% CI, 1.8-2.7); moderate, 4.7% (95% CI, 4-5.3); and minimal, 1.5% (95% CI, 1.1-1.9). The researchers found that age was most strongly associated with prevalence of atherosclerosis. Service members with atherosclerosis were older than those without (30.5 years vs. 25.3 years; P<.001). Further, prevalence of atherosclerosis appeared to be approximately seven times higher in those aged at least 40 years vs. those aged 24 years or younger (45.9% vs. 6.6%).

Data also indicated that, compared with service members without conventional cardiovascular risk factors (11.1%), prevalence of atherosclerosis was greater among those with a diagnosis of dyslipidemia (50%), hypertension (43.6%) or obesity (22.3%). 

In an accompanying editorial from the National Heart, Lung, and Blood Institute, highlighted these issues but also indicated these autopsy studies again show that coronary disease begins at a young age and even in a better risk controlled population group almost 1 in 2 soldiers over 40 have significant coronary atherosclerosis.  Once again aggressive primary prevention is key.

Declines in cardiovascular disease risk factors in these military personnel have almost certainly contributed to the observed reductions in prevalence of subclinical atherosclerosis, incidence of clinical atherosclerotic disease, and deaths from heart disease. Although age-adjusted heart disease death rates have declined by 72% since their peak during the Vietnam War years, cardiovascular disease still remains the leading cause of death in the United States. The national battle against heart disease is not over; increasing rates of obesity and diabetes signal a need to engage earlier and with greater intensity in a campaign of pre-emption and prevention.

It is important to note that rates of obesity, smoking, hypertension, dyslipidemia, and impaired fasting glucose are markedly lower in USA military service members than in men and women of the same age in the civilian US population–making it possible to understand the high rate of poor general health in USA and high degree of sub clinical disease in “healthy” US individuals. While primary and secondary prevention have likely contributed equally to national declines in heart disease deaths, advances in primary, but not secondary, prevention most likely explain the declines in coronary atherosclerosis across the three autopsy studies.

Some great advances in primordial and primary prevention of atherosclerotic vascular disease have taken place over the past decade.  In my next blog I will highlight some of the novel new approaches to prevent and minimise the clinical effects of atherosclerosis.

Blessings Cardiologydoc

 

2012 in review

The WordPress.com stats helper monkeys prepared a 2012 annual report for this blog.

Here’s an excerpt:

4,329 films were submitted to the 2012 Cannes Film Festival. This blog had 19,000 views in 2012. If each view were a film, this blog would power 4 Film Festivals

Click here to see the complete report.

South African Dyslipidaemia Guideline Concensus Statement 2012

Published recently in the South African Medical Journal 2012; 102: 177-188 are the consensus guidelines for the management of dyslipidaemia. I have taken extracts directly from this paper to highlight the 2012 guidelines.

Introduction:

South Africa is a multi-ethnic society, with a large range of cultures and lifestyles at different stages of epidemiological transition. In all sub-populations, cardiovascular disease is a major cause of morbidity and mortality. Every day, approximately 80 people die of myocardial infarction or heart failure, while another 60 die due to stroke.

The INTERHEART Africa study indicated that more premature acute myocardial infarctions occur in sub-Saharan Africa than in any other of the 52 countries participating in the INTERHEART study.

This statistic reflects a lack of prevention, early detection and effective management of cardiovascular risk factors in the countries of this region.In particular in the black population increasing urbanisation and adoption of an unhealthy lifestyle, the prevalence of cardiovascular disease (CVD) and the incidence of premature death are likely to continue to increase.

Consequently, the timely institution of lifestyle modification, early diagnosis and effective management of CVD risk factors are essential to curb the epidemic of cardiac disease that has been seen in other countries.

In 2003, the South African Heart Association (SA Heart) and the Lipid and Atherosclerosis Society of Southern Africa (LASSA) officially adopted the European Guidelines for the Prevention of Cardiovascular Disease to replace the SA Lipid guidelines published in 2000.

The European document has recently been updated with the publication of the European Society of Cardiology (ESC)/European Society of Atherosclerosis (EAS) Guideline for the Management of Dyslipidaemias in 2011.

This Consensus Statement promotes current best management of dyslipidaemia and should be adopted by all health care professionals in South Africa.

Using a cardiovascular risk stratification score:

Individuals who are considered to be at very high risk of cardiovascular events (>30% risk of a suffering a cardiovascular event over next 10 years) are listed in Table 1. Patients in this group DO NOT require cardiovascular risk scoring, because the risk score will be an underestimate in these settings.

Risk scoring using well-documented key risk factors is appropriate to estimate the total cardiovascular risk in asymptomatic adults. This risk scoring is especially important in individuals with the following:

• Those with hypertension and or on antihypertensive medication
• Those who smoke any form of tobacco product
• BMI ≥30 kg/m2 or waist circumference > 94 cm for men, >80 cm for women
• People with “metabolic syndrome”
• Family history for premature cardiovascular disease (in males < 55 years and female before 60 years)
• Auto-immune chronic inflammatory disease such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis

When to start screening for CVD (when to risk stratify):

In South Africa, because the prevalence of familial hypercholesterolaemia is as high as 1 in 100 in some communities, each individual should be tested, preferably with a full lipogram or at least TC/LDL-C, at least once in young adulthood (from 20 years of age). Particular attention should be paid to individuals with other risk factors for CVD (list above).

How to use the risk scoring system:

The European guidelines use the Systematic Coronary Risk Estimation(SCORE) system to estimate cardiovascular risk. Because this scoring system is based on an exclusively European population, it may not accurately reflect coronary risk in South Africa. While it is recognised that it would be impossible to accurately estimate risk in all South African subpopulations with a single data set, the Adult Treatment Panel (ATP) III Framingham risk tables provide and estimate of the 10-year risk of any cardiac event have been validated in white and black populations in the USA and are transportable to other culturally diverse populations. Consequently, we considered this approach to be more appropriate for South Africa. Nevertheless, these risk tables are likely to underestimate risk in South African black and Indian patients. The Framingham CHD tables may also underestimate total CVD risk in middle-aged and older women, whose risk of stroke and heart failure is typically higher than that of CHD. 

Consequently, more recent Framingham equations predict 10-year total CVD risk (including CHD, stroke, transient ischaemic attack and heart failure).The updated Framingham CVD risk tables for men and women and an algorithm for management and cholesterol goals have been incorporated into these recommendations (Appendix 1).

The points are added to calculate the 10 year risk for men and women.

The risk is defined as the following:

The goals of treatment follow the risk:

In all cases of dyslipidaemia it is important to exclude and manage any secondary cause of abnormal lipids:

The use of Statins:

Statins have demonstrated effectiveness in both primary and secondary prevention. The effect is dependent on the extent to which LDL-C is lowered and not on the type of statin used. At their maximum doses, the various statins differ in their capacity to lower LDL-C.

For every mmol/l reduction in LDL-C there is a:

• 10% reduction in total mortality
• 20% reduction in all-cause mortality
• 23% recudtion in major cardiac events
• 17% reduction in stroke

The effect of statin therapy is similar in all patient subgroups and becomes significant after 1 year, increasing progressively thereafter.

The scheme for introducing Statin therapy:

• First evaluate the risk
• Involve the patient in CV risk management and decisions
• Identify the LDL-C target based on the risk
• Calculate the % reduction in LDL-C required to reach target
• Choose the Statin (and dose) most appropriate to achieve the desired reduction

Other Cholesterol lowering agents:

The cholesterol absorption inhibitor ezetimibe (Ezetrol) in combination with simvastatin (Inegy) was shown to reduce major atherosclerotic events in patients with advanced chronic kidney disease. Although no other outcome studies have been completed, ezetimibe is recommended:

• As second-line treatment in combination with a statin when the LDL-C target is not reached at the highest tolerated statin dose.
• When there is intolerance to statins (or high dose statin).
• Bile acid sequestrants and nicotinic acid have cholesterol lowering properties. They may occasionally be useful alone or in combination with statin therapy. However, their side-effects limit wider application.

Finally the South African Heart Association/LASSA guidelines for lifestyle modification for patients with dyslipidaemia are summarized in Appendix 2:

In summary:

Additional tests:

The Consensus Statement also discusses the use of novel biomarkers of CVD (e.g. hs or us-CRP) and imaging technologies (e.g. coronary calcium scoring, carotid intima-media thickness) whilst is not recommended routinely these should be reserved to refine risk assessment in patients considered to be at moderate risk where there is uncertainty about whether to initiate drug therapy.

Measuring Lipoprotein – a (Lp-a) is appropriate in defining HIGH CVD risk subjects and/or when there is a family history of premature cardiovascular disease. 

Blessings for 2013

Cardiolodydoc