28 Feb 2011

HDL & Heart Disease

High Density Lipoprotein & Heart Disease 

It is very well documented that high concentrations of the so-called "good cholesterol" - high density lipoprotein (HDL) - has protective value against cardiovascular diseases such as ischemic stroke and myocardial infarction. Low concentrations of HDL correlate with an increased risk for atherosclerotic diseases.

Similar to some of the other bio markers of cardiac risk, without wanting to willingly state the obvious, it is important to recognise that low-HDL levels are merely one of the symptoms of the cause of heart disease.

Guidelines suggest that men are at risk with HDL levels of 40 mg/dL (1.0 mmol/L) or less, whereas levels of 60 mg/dL (1.6 mmol/L) or above are described as desirable.  Women are considered to be at risk if HDL levels are 50 mg/dL (1.3 mmol/L) or less, while levels of 60 mg/dL (1.6 mmol/L) or above are described as desirable.
HDL is the smallest of the lipoprotein particles, it is also the densest lipoprotein as it contains the highest proportion of protein.

HDL carries many different types of lipid and proteins, several of which have very low concentrations but are biologically very active.  For example, HDL and their protein and lipid constituents have very important anti-inflammatory, antioxidant and anti-thrombotic properties, which act in concert to improve endothelial function and inhibit atherosclerosis, thereby reducing cardiovascular risk.
Men tend to have noticeably lower HDL levels, with smaller size and lower cholesterol content than women. This is coincidental with an increased incidence of atherosclerotic heart disease in men.
The importance of normal to high levels of HDL is reflected in the observation that people with very low LDL levels remain exposed to increased cardiac risk if their HDL levels are not high enough.
Anecdotally, I have encountered reports of individuals increasing HDL values from normal levels to over 80mg/dl, whilst decreasing triglycerides from over 150 down to 50mg/dl when adopting a very-low-carb, high saturated-fat diet.

HDL as an indirect forward transporter
The metabolism of HDL is very complex, and there are many different types of HDL. 
In a nutshell, HDL is an apoA lipoprotein which is made either by the small intestine or the liver, and in contrast to the apoB lipoproteins (Chylomicrons, VLDL, IDL, LDL) which primarily forward transport cholesterol and lipids to peripheral tissues, HDL is considered mainly as a reverse transporter of cholesterol from peripheral tissue to the liver, or to steroid producing organs such as the adrenals, ovary, and testes.
It is important not to view HDL purely as a reverse transporter.  It also plays an important role in enabling the other lipoproteins to deliver their cargos quickly and effectively.  It achieves this by sharing out key protein identification molecules to other lipoproteins in circulation; in effect HDL also functions as a lending library of identification proteins.
For example, HDL donates proteins (apoE and apoC2) to chylomicrons which are only equipped with apoB48 when they are made in the intestines. These donated proteins are essential for the chylomicrons to deliver their lipid and cholesterol cargo to peripheral tissues. 
Once the chylomicron has delivered 80% of its triglyceride contents it discards its apoC2 protein and becomes a chylomicron remnant.  This chylomicron remnant now needs to be recycled by the liver. The chylomicron still has its apoE molecule which it got from HDL earlier, which it needs to bind with the LDL receptors at the liver, where it is absorbed and recycled. 
When VLDL is released from the liver it is equipped with the apoB100 protein, it then picks up apoE and apoC2 in circulation from HDL, enabling VLDL to dock at peripheral tissues and release its cargo (apoC2 is used to dock at peripheral tissues, apoE is used to dock at the liver when it returns as a VLDL remnant). When delivering to peripheral tissues, after 50% of its triglyceride contents are deposited, VLDL discards its apoC2 protein, becoming a VLDL remnant. 
About 50% of the VLDL remnant particles then return to the liver to be absorbed and recycled, the remainder are transformed into new LDL particles.  This occurs via the interaction of the VLDL remnant and an enzyme called hepatic lipase, which virtually empties the VLDL remnant of its triglyceride contents into the liver.  In the process the apoE identification protein is lost and returned to HDL in the circulation, creating a new LDL particle consisting of an apoB100 protein and next to zero triglycerides.
If you have high levels of apoB lipoproteins and low levels of apoA lipoproteins, in other words high triglycerides and low HDL (Triglyceride levels and HDL levels tend to be inversely proportional), the rate of HDL’s protein lending capacity is going to be inferior to the high demand from the large number of apoB lipoproteins needing those apoE and apoC2 proteins in order to make their deliveries.  This all contributes to increased duration of lipoprotein exposure to unfavorable modification in circulation. 
High HDL is therefore necessary for optimal forward delivery of triglycerides, which may partly explain the increased expression of HDL in response to high-fat nutrition.  This increased HDL expression may be a parallel to increased chylomicron production in the intestines in response to increased dietary fat absorption.
Hopefully, from the above description, it can be appreciated how important high HDL levels are not only as reverse cholesterol transport from tissues, but also as an essential indirect element in the forward process of triglyceride and cholesterol delivery to peripheral tissues via their protein lending capacity.

HDL’s other positive roles.
HDL’s key identification protein is apoA.  The apoA identification protein is important as it allows HDL to dock at peripheral tissue cells which need to off-load cholesterol. 
From an anti-atherogenic perspective, apoA is also very important because it enables HDL to dock at scavenger receptor sites on macrophages which have been consuming oxidised and damaged lipoproteins, facilitating the removal of their waste for return to the liver for healthy excretion, rather than being left to contribute to plaque formation. 
HDL also has an important anti-oxidant role and is responsible for delivering vitamin E to cells.   As demonstrated here, it is 3-5 times more effective than LDL at delivering vitamin E to endothelial cells. LDL appears to deliver vitamin E to these cells simply by being taken up as a whole particle, whereas HDL interacts with what could be called the "HDL receptor" and delivers vitamin E to the endothelial cell at a much faster rate than it would if it were completely consumed by the cell.

When HDL breaks down
Similar to the other lipoproteins, HDL particles can become modified by over exposure to an undesirable environment.  When serum triglyceride levels are continually elevated due to excessive carbohydrate consumption, HDL particles become enriched with triglycerides, making them better targets for hepatic lipase.  As hepatic lipase acts upon the over-fat HDL they become more and more unstable, eventually resulting in the release of their apoA identification protein, rendering them unable to carry out their vital roles.

Dietary influences upon HDL
Diets high in saturated fats and cholesterol have been shown to increase HDL levels both by increasing the transport rates and decreasing catabolic rates of HDL.  It is suggested in this study that this is perhaps as an adaptation to the metabolic load of a high fat diet.

Low-fat diets have repeatedly been
found to have the opposite effect by actually decreasing healthy levels of HDL.
As with LDL particles, we also need to look at lipoprotein sub-types when looking at HDL.  Studies have found that the largest and most buoyant HDL particles (HDL2) correlate significantly with HDL's most protective effects. That is, the more HDL2 particles you have, the less your chances of having a heart attack.  Increased levels of the denser HDL3, is reportedly unrelated to reduced coronary disease.
A diet low in fat, compared to one high in total fat and saturated fat, has been demonstrated to significantly reduce levels of these large HDL lipoproteins.  This is not a short-term effect, with studies showing persistent results after 12 months.
This study found that “A reduction in dietary total and saturated fat decreased both large (HDL2 and HDL2b) and small, dense HDL sub-populations, although decreases in HDL2 and HDL2b were most pronounced.” - Berglund et al (1999).  It has also been shown that saturated and omega-3 fats selectively increase desirable large HDL.

Allow naturally healthy HDL levels to florish
In the vast majority of cases, good health is largely about you and what environment you force your body to exist in.  High and healthy HDL levels are a prime example of this.

I was going to discuss how you can elevate HDL levels, but it would be more accurate to say that the following suggestions will allow HDL levels to elevate to their natural levels.

With a healthy diet and lifestyle it is not unrealistic for your HDL levels to exceed 60+ mg/dl.

1)   Firstly and most importantly, gravitate as close as possible towards the very-low-carb, high-fat nutritional model:
  • In a study of the effects of “6-month adherence to a very low carbohydrate (<25g/day) diet program”, triglyceride levels decreased 56 ± 45 mg/dL , and HDL cholesterol levels increased 10 ± 8 mg/dL.
  • This low-carbohydrate, ketogenic diet study over 6 months observed many beneficial changes in serum lipid subclasses, including a 5% increase HDL particle size, and a 21% increase in large HDL.
2)   Avoid low-fat, high-carbohydrate diets:
  • In controlled trials, low-fat, high-carbohydrate diets decrease HDL concentrations. The effect is strongest when carbohydrates replace saturated fatty acids, but is also seen when carbohydrates replace mono- and polyunsaturated fatty acids.  The effect is seen in both short- and long-term trials and therefore appears to be permanent. This finding is supported by epidemiological studies in which populations eating low-fat, high- carbohydrate diets were shown to have low HDL concentrations.
  • It has been demonstrated that a low cholesterol, but high polyunsaturated fat diet reduced HDL by 17.4%, highlighting the importance of saturated fat in this respect; and a low cholesterol, very low-fat diet has more dramatic effects upon HDL reducing its levels by 28%.
3)   Perform regular aerobic exercise:
  • Perform aerobic exercise regularly at moderate intensity (Sustained walking or light jogging is sufficient)(Ref, Ref). 
  • Minimal weekly exercise volume for a modest increase in HDL levels has been estimated to be 900 kcal of energy expenditure per week or 120 minutes of low-intensity exercise per week. 
  • In a study comparing runners with sedentary men, the mean HDL cholesterol level was 65 mg mg/dL in the runners and 41 mg /dL in the controls. The lipid-rich HDL2 species accounted for a much higher proportion of the HDL in runners (49% v 29%). Part of the positive adaptation here appears to be related to increased mean biologic half-life of HDL proteins, which was 6.2 days in the runners compared with 3.8 days in the sedentary men.
  • In a study of “Miles Run per Week and High-Density Lipoprotein Cholesterol Levels in Healthy, Middle-aged Men” results indicate a dose-response relationship between miles run per week and increased levels of HDL. Most changes were noted in those who ran 7 to 14 miles per week at mild to moderate intensities. The HDL increase was valued at 0.3mg/dl per mile.
  • In many studies changes in HDL levels are not large and it is suggested that the potential for exercise-related changes in HDL may be modest in many subjects.  However, in studies where insignificant to low exercise induced rises in total HDL are reported, results can be misleading without an accurate assessment of the HDL subfractions.  Heart healthy HDL2 can rise in line with proportional decreases in HDL3, resulting in an insignificant change in total HDL, but with an underlying very desirable upswing in HDL2 levels (Sample).
4)   Consider supplementing your diet with omega-3 fish oil:-
(Note: Due to its highly unstable nature I wouldn’t touch flax seed oil with a barge-pole! Also, the following benefits appear to be exclusive to marine derived n-3 PUFA.  If following a genuinely low-carbohydrate diet with plenty of pasture raised animal food sources supplementation is likely to be unnecessary.)
  • After 8 weeks a 40% increase in HDL2 cholesterol was reported in response to supplementation of 1.88 g of eicosapentaenoic acid [EPA] and 1.48 g of docosahexaenoic acid [DHA] per day. 
  • This study of 6 weeks supplementation of 2.8g/d of eicosapentaenoic acid (EPA) and 1.7g/d of docosahexaenoic acid (DHA) the levels of total HDL-cholesterol did not change, however  HDL2 increased by a whopping 74%, with a concomitant 19% decrease of HDL3.
If not following low-carb, high-sat-fat nutrition you could consider a niacin supplement (Vitamin B3):-
  • Niacin has a well-documented history in the treatment of heart disease.  For an easily available and modest vitamin it has relatively powerful lipoprotein regulating ability, including a down-regulation of triglyceride, VLDL, and LDL production; whilst increasing HDL levels.
  • This trial used between 1,000 and 2,000 mg/day over 12 weeks, and reported dose-proportional benefits using an extended release formula.  It is worth noting that continuous daily 24 hour exposure to niacin over an extended period can be toxic to the liver, therefore self-prescription of very-slow-release niacin should be avoided.
  • However, taking niacin may be considered to be a mere biochemical shortcut.  Niacin acts through the beta-hydroxybutyrate (ketone body) receptor.  In effect by taking these large doses of niacin you are simply mimicking ketones and fooling the body into thinking that its primary fuel source is fats, creating the positive metabolic processes which ketogenic nutrition triggers – down-regulation of VLDL, decrease in TAG, increase in HDL-C, and redistribution of LDL to a larger particle size.
NOTE:   If you are eating a high-saturated fat intake with very low carbs you will have all the positive lipoprotein benefits nature intended, without touching a niacin supplement.

NOTE2:  Moderate to low alcohol consumption has inconclusive effects upon HDL levels:
  • Whilst alcohol consumption correlates with both reduced coronary heart disease and increased plasma HDL cholesterol concentrations, the HDL mediated cardio-protective effects of moderate alcohol consumption appear inconclusive.  Previously reported rises in total HDL appear to be more associated with increases in the inert HDL3 with insignificant changes in the cardio-protective HDL2. [Ref1 , Ref2].
  • The beneficial effects associated with the consumption of red wine with meals, appears to be more related to its capacity to reduce the susceptibility of human plasma and LDL to lipid peroxidation, rather than via possible influences upon HDL.)