Reference Section

High-density Lipoprotein Cholesterol The Next Battle Front in the Fight Against Hear t Disease
a report by

D r R a i f Taw a ko l
Director, Evergreen Lipid Center Medical

Dr Raif Tawakol MD is Director of the Evergreen Medical Lipid Center, Director of Evergreen Medical Diabetes Center and Director of Circadian Sleep Center. His primary interest in lipids has been focused on high-density lipoprotein (HDL) metabolism for the last 10 years, with clinical work in raising HDL more than 50% for the last five years. Dr Tawakol has been published in Diabetes Care this year, and presented a Poster presentation at the American Diabetes Association (ADA) in June, entitled Marked HDL Cholesterol Benefit in Patients with Low HDL-C and Type 2 Diabetes or Impaired Glucose Tolerance with Combined Treatment of Pioglitazone and Low Dose Nicotinic Acid. His clinical research is in raising HDL using combination therapy with an emphasis on inflammatory markers, free fatty acid (FFA), C-reactive protein (CRP) and lipoproteinassociated phospholipase A2 (LPPLA2) in the metabolic syndrome, and diabetes and the relationship to heart failure.

Many patients on statin therapy understandably develop a false sense of security. They enjoy a lowered level of low-desity lipoprotein (LDL) and a risk reduction of some 35%. However, two out of three patients develop a myocardial infarction (MI) while on a statin therapy. Statins often do not increase HDL levels to any substantial degree (except for Rosuvastatin, which increases high-density lipoprotein (HDL) by 8% to 14%), nor do they alter the LDL particle size, from small dense LDL to a larger, less dangerous LDL particle size.3 These patients with low (or even normal) HDL levels do not avoid the attendant myocardial damage.4 Low HDL levels are linked to an increased risk of coronary heart disease (CHD)1 in the Framingham Study, and even in patients with relatively normal LDL and HDL levels, a small LDL particle size5 (pattern type B) can cause significant events in 50% of patients,2 as in the Quebec Cardiovascular Study6,7(which also showed that HDL2 particles contributed to the cardioprotective effects of high HDL-C levels more than HDL3 particles). Thus, to provide more protection against unwarranted myocardial events thrombosis and occlusion more attention should be devoted to increasing HDL levels and to modification of LDL particle size. Although atherosclerosis occurs due to abnormal lipids, the entire damaging process has three components: dyslipoproteinemia; the inflammatory component, or endothelial inflammation caused by endothelial dysfunction; and the thrombotic event. It is as a result of the high triglycerides and low HDL, along with a large lipid load, that the inflammatory reaction occurs.
Atherosclerosis

bioavailability, and reduces the lipid load in the vascular wall. This may in part explain the protective effect of HDL9,10 from CHD and illustrates the potential therapeutic benefit of increasing HDL in patients at risk from atherosclerosis.12
Inflammation and HDL

The inflammatory response in cardiovascular disease and the participation of the inflammatory mediators TNFa in the atherosclerotic process ending in plaque rupture,17 is well established. The vascular cytokines18 along with the selectins, the interleukin family, recruiting matrix metalloproteinase (MMP) family of cytokines with growth and transforming factors is also well established. This ultimately leads to an increase in C-reactive protein (CRP) and LP-PLA215, both important markers of cardiovascular risk and events. CRP, lipoprotein-associated phospholipase A2 (A2LPPLA2) added to HDL2b in patients with insulin resistance (IR) may refine the predictive value for cardiovascular risk and events. There are several aspects to the mechanisms of inflammation pertaining to HDL: Surface endothelial vascular inflammation that promote the initial phases of local vascular inflammation that become subendothelial occur more frequently with low HDL even when LDL is relatively normal,21 excluding the presence of small dense (SD)-LDL. Cellular changes that promote the efflux of cholesterol from macrophages,19 aided by Scavenger receptor (SR) B1, prevent or reduce the macrophage content of cholesterol, are hindered during MMP reactions.24 Its consequent effects that later result in the familiar high-sensitivity (hs) CRP are increased when HDL is low.20 Platelet activation often associated with high triglycerides and low HDL are a cause for global platelet activation,25 with rapid translocation of P-selectin platelet alpha-granules. Intracellular cyclic adenosine monophosphate (cAMP) is a potent
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34

It is well documented that reduced HDL-C levels are associated with an increased risk of coronary artery disease (CAD),8 while those patients whose HDL is increased after an event32 are afforded a partial protection against a second event. Intravenous infusion of HDL rapidly normalizes endothelium-dependent vasodilation by increasing nitric oxide (NO)

HDL Cholesterol The Next Battle Front in the Fight Against Hear t Disease
inhibitory pathway that results in global downregulation of platelet activation. cAMP promotes the formation of apolipoprotein (Apo) A1 through ATPbinding cassette, sub-family (ABCA1), and is reduced in the absence of an adequate level of HDL often due to the excessive formation of phosphodiesterases (PDE) 3, 4, and 5s. The upregulation of inflammatory adhesion molecules which induce CRP is completely prevented by in vitro treatment that HDL. HDL-C with a high Apo A1 can exert anti-inflammatory effects on the vasculature.22 HDLs ability to return the process to normal in the presence of adequate or normalized HDL.23 Lastly, there is the oxidative-based inflammation incited by formation oxLDL-C with macrophage oxidative foam cell formation in such instances an adequate HDL acts as an inhibiting factor.24
Thrombosis and HDL
Figure 1: Framingham Study
Relative CHD risk over 4 years
3

High LDL-C and Low HDL-C: Increased Risk of CHD

HDL-C (mg/dL)
1

85 65 45

25 100 150 LDL-C (mg/dL) 200

Framingham Study, (see below) the yellow bars in the back show a much higher CHD risk if HDL is low (2535) regardless of LDL levels, while the blue short bars show a relatively low CHD risk when HDL is high (7585) less influenced by LDL level.

Triglyceride-rich lipoproteins and oxLDL are associated with a procoagulant profile and contribute to a prothrombotic risk via enhanced platelet reactivity25,30 and an associated increased plasminogen activator inhibitor-1 (PAI-1). Fibrinolysis is also significantly reduced.31 High HDL has an anticoagulant effect through polymorphisms of paraoxonase (PON1) that inhibits the oxidation of LDL by reducing platelet thrombus formation30 and increasing pro-fibrinolytic properties. High levels of D-dimer commonly present in patients with low HDL, low levels of ApoA-I and high ApoB were independently associated with recurrent coronary events.31 The resulting inflammatory instability, causing a thinning of the cap over the plaque with its subsequent rupture,17 combined with an increase in thrombogenicity that creates most of the eventual risk of thrombosis and occlusion. Inflammation is one of the most prominent single factors that eventually trigger the occurrence of an occlusive coronary, carotid, or peripheral vascular event. The resulting tissue damage ultimately leads to loss of organ function.
R e v e r s e C h o l e s t e r o l Tr a n s p o r t

transfer protein (CETP) pathway. Approximately 50% of the HDL is involved in reverse cholesterol transport (RCT), while the rest is involved in reducing inflammation, thrombosis, influencing cellular cardiac and vascular remodeling, and improving endothelial function, as well as vasodilatation and the production of NO. Free Apo A1 potentiates these effects, preserving the presence of prostacyclin and cAMP levels, which are important resident vasodilators.39 Apo A1, the anti-atherogenic apolipoprotein, provides 70% of the protein content of HDL, forming the majority of the attachments to the outer shell, which serve as acceptors for cholesterol released from the cells. Its synthesis is required for HDL production and is involved in the esterification (binding) of free cholesterol on HDL42 and later the maturation of HDL by lecithin:cholesterol acyltransferase (LCAT).70 Apo A1 activates the important transfer protein LCAT, which is vital to the endothelial surface. ApoA-I, synthesized by the liver hepatocyte, interacts with cellular ATP-binding cassette transporter (ABCA1),40 which mediates the first step of reverse cholesterol transport, which is then secreted into the plasma as a lipid-poor particle, forming HDL2b particles, a cholesterol acceptor similar to prebeta-HDL. Removal of excess cholesterol from macrophages and the vascular wall occurs in a similar manner.41 ABCA1 is also a key regulator of the plasma Apo A1 and HDL pool size Through transfer by CETP, a cholesteryl ester core is added, and those including cholesterol from ApoB are returned to the liver mediated by SR-BI, thus controlling the selective transfer of cholesteryl ester from HDL to hepatocyte and other cells.

Free cholesterol is normally distributed to all cells since it is involved in the formation of various important components of the cell structure and function, including the formation of steroids and hormones. HDL is responsible for the process of bringing either the excess cholesterol (redistribution of cholesterol) or the unused cholesterol from the various parts of the body back to the liver, 50% of the cholesterol is recycled via reverse cholesterol transport, and the remaining 50% is recycled through the cholesteryl ester
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Reference Section

Cholesterol is taken up selectively to be excreted through two possible pathways: through the liver and then to bile promoted by phospholipid transfer protein (PLTP), and through the transfer of cholesteryl esters from HDL to apoB-containing lipoproteins in exchange for triglycerides, mediated by CETP. SR B144 controls the cholesterol and CE between cells, while CETP controls CE transfer and triglyceride exchange with triglyceride-rich lipoproteins enrichment, resulting in a smaller, denser LDL. High CETP and free fatty acid (FFA) tend to be detrimental to maintaining a high level of HDL and a larger HDL2b pool. There is an inverse correlation between plasma adiponectin and tumor necrosis factor (TNF)-, C-reactive protein, and visceral adipose tissue. Adiponectin decreases, with increasing IR or weight gain, increasing CETP early in the metabolic syndrome even prior to adiposity in young hypertensives, thus HDL decreases, which in turn decreases the lipolysis directed toward LPL69 and the Apo C II donation by HDL, resulting in an increase in endothelial lipase,71 an important factor in the causation of instability at the endothelial surface and degradation of HDL. The lipase system is mainly LPL,69 endothelial71 and hepatic lipase, the latter significantly enhances HDL and CE uptake, ultimately raising triglycerides and reducing HDL, producing a smaller denser HDL3b and c subclass.
HDL Par ticle Size and FFA

proliferation, and cellular cholesterol homeostasis. Adiponectin shares in these functions by raising HDLC through its receptor T-cadherin, which resides on the endothelium as well as the muscle. The independent association between low HDL-C and subclinical left ventricular (LV) systolic dysfunction, and a lower cardiac index, which unfavorably modifies LV structure and diastolic function75, is often a higher left ventricular mass and index, and a lower pulse pressure/stroke index. Hypertensive metabolic syndrome patients often have early diastolic LV abnormalities. A frequent association with obstructive sleep apnea (OSA) with a higher incidence of microvoltage T wave alterans (M-TWA) and QT and QTc dispersion during periods of oxygen desaturation is not uncommon. Ischemic heart disease with unstable angina and acute coronary syndrome (ACS) risk are more closely associated with the low HDL-C/high triglyceride syndrome than with increased LDL or total cholesterol levels. Rupture of a lipid-laden unstable endothelial plaque that is 50% occlusive appears to be a key event.
C a rd i ova s c u l a r R i s k a t Va r i o u s H D L Levels

The typical dyslipidemia associated with insulin reisitance (IR) and type 2 diabetes commonly increases the efflux of FFA from adipose tissue with impaired muscle utilization of FFA, which causes an elevated FFA in these individuals.65 It has been postulated to be the cause behind pancreatic lipotoxicity, with loss of first phase insulin secretion in the metabolic syndrome and diabetes and later pancreatic beta cell failure. It is the elevated FFA in the presence of high triglycerides and low HDL that compound the LDL and SDLDL66 oxidative potential.
C a rd i ova s c u l a r E f f e c t s o f H D L

ATP III guidelines set a low HDL level below 40mg/dl to be a much higher risk of cardiovascular events.They also suggest that higher HDL is better without establishing a treatment goal for HDL. IR HDL levels below 31.5mg/dl increase that risk by an added 32%, while HDL <31.5mg/dl without IR increases the relative risk by only 5%.This added risk with IR is due to the common association of low absolute level of HDL-C with a smaller HDL3 particle size, or a greater proportion of HDL3 to HDL2b (the latter contains a larger proportion of Apo A1).
Management and Therapy for Low HDL

38

Elevated HDL-C or ApoA-I, are protective to the endothelial surface against endothelial dysfunction and CAD. The interaction between the lipoproteins endothelial surface46 and cardiovascular tissues involves activation of cellular NO signaling pathways, endothelialen NO-Synthase endothelial nitric oxide synthase (eNOS),47 protacycline with regulation of genes or the modification of proteins involved in vasomotor function, platelet activation, thrombosis and thrombolysis, cell adhesion, apoptosis and cell

Reducing risk factors is vital and can produce dramatic results as shown by numerous investigators in many trials, some conferring 68% morbidity and mortality reductions when there is a concomitant HDL-C increase with reduction in both LDL and triglycerides, and improvement in particle size. Raising HDL-C to 5060mg/dl from a level of <35mg/dl usually reduces the non HDL-C by at least 4080 points, if the triglycerides are concomitantly elevated at baseline. Recent clinical trials such as the veterans affairs high density lipoprotein cholesterol intervention trial (VAHIT)8 and the Quebec Cardiovascular Trial in patients with CAD indicate that increasing previously low levels of HDL-C significantly reduces the cumulative
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HDL Cholesterol The Next Battle Front in the Fight Against Hear t Disease
occurrence of cardiovascular and cerebrovascular events in patients whose only lipid abnormality was low HDL. These data provide a compelling scientific basis for a more targeted and segmental approach to managing patients with dyslipidemia, where decreasing elevated levels of LDL-C and increasing low levels of HDL-C should comprise dual targets of pharmacotherapy.
N i a c i n , Fe n o f i b r at e s a n d Pe rox i s o m e Proliferator Receptors

novel approach that has been very successful, which has been tried clinically in several hundred patients, is a combination of niacin, fenofibrate and a PPARy agonist. These can increase HDL by 81%89 or more by combining all three drugs in lower than the usual upper limit therapeutic doses, in patients with a baseline HDL below 40mg/dl.90 Combination statin and niacin88 or statin and fenofibrate87 have been used clinically with success and advantages over monotherapy. With statin combination therapy, first consideration should be given to less hepatotoxic and hydrophilic statins used as at lower dosage. In order to meet additional therapy goals, added colesevelam and ezitimibe can raise HDL-C by an additional 10%, and can reduce inflammation by an additional 20% to 35%, representing a substantial risk reduction. The new battle ground against myocardial damage is through modulation of HDL-C and Apo A1 metabolism. By reduction in cholesterol content, change in LDL and HDL particle size, (modified by the Apo A1 pool), reduction in CE content and triglyceride transfer eventually modify the lipid profile. The key factor is overall reduction in FFA accumulation eight hours after meals, so as to reduce endothelial lipase,71 a key factor in the catabolic destruction of HDL-C.
Conclusion
HDLs are the Multifunctional Va n g u a r d s o f t h e C a r d i o v a s c u l a r S y s t e m

Current therapeutic strategies to raise HDL-C and improve the particle distribution is through combination therapy, which improves the HDL increase beyond the 30% limit for monotherapy. This may be achieved by use of nicotinic acid that predominantly stimulates LPL80 through the adipocyte receptor HM 74, a specific G-protein-coupled receptor, where it reduces triglycerides and Apo-B containing lipoproteins mainly through: decreasing fatty acid mobilization from adipose tissue triglyceride stores; and inhibiting hepatocyte diacylglycerol acyltransferase (DAG2) and triglyceride81 synthesis with reduction in VLDL,Apo B and triglyceride production in the liver and increased catabolism, leading to increased intracellular Apo B degradation and subsequent decreased secretion of VLDL and LDL particles. It raises HDL by decreasing the fractional catabolic rate of Apo AI without affecting the synthetic rates, while selectively increasing the plasma levels of Apo-AI subfraction HDL2b (HDL subfraction without apo AII), a cardioprotective subfraction of HDL in patients with low HDL.82 Fenofibrates have a major function of peroxisome proliferator receptors (PPAR)y agonist effect,83 which reduces the triglyceride-rich lipoproteins.84 They also increase Apo AI production and lipoprotein lipase activity, and reduce Apo CIII, thus increasing HDL. PPARy increase Adiponectin,86 thus raise HDL, in addition to improving glucose transport and utilization, and reducing FFA.All three classes of drugs improve the particle size from small dense to the larger type A. A

A cluster of interrelated plasma lipid and lipoprotein abnormalities associated with alterations in HDL and HDL subfraction metabolism contributes to the risk of atherosclerosis and cardiovascular events in patients with IR and type 2 diabetes. HDL levels control atherogenesis, vascular inflammation, endothelial function, and thrombogenicity. Features of the HDL dyslipidemia can be improved by a variety of therapeutic combinations and lifestyle changes including weight loss, and or exercise.The alteration in particle size of both HDL and LDL contribute to events and progression of disease, therefore therapy that ameliorates particle size enhances the effectiveness of the therapeutic modality.

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