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Dyslipidemia and cardiovascular diseases

Mahdavi, Homa; Kim, Juyong Brian; Safarpour, Scheila; Tien, Duc A; Navab, Mohamad

Current Opinion in Lipidology: April 2009 - Volume 20 - Issue 2 - p 157–158
doi: 10.1097/MOL.0b013e32832956ed
Bimonthly update: Edited by Alan Rees
Free

David Geffen School of Medicine, University of California, Los Angeles, California, USA

Correspondence to Mohamad Navab, BH-307 CHS, Cardiology-Medicine, 10833 Le Conte Avenue, Los Angeles, CA, USA Tel: +1 310 206 2678; e-mail: mnavab@mednet.ucla.edu

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Introduction

Despite the progress made in the management of hypercholesterolemia with statins, events are reduced by only 30% [1••]. Protecting the other 70% requires, additionally, interventions including adjunctive use of anti-inflammatory or immunologic treatments. The results of the statin trials seriously underestimate the ultimate potential of cholesterol-lowering therapy. Experts suggest continuing and more extensive use of lipid-improving regimens and intervention at an earlier stage [1••].

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HDL therapy

HDL, which is a major target for therapy in CAD, is highly heterogeneous, has a variety of functions that may contribute to its cardiovascular protective effects, including promotion of reverse cholesterol transport (RCT), anti-inflammatory and nitric oxide-promoting effects [2]. Under the inflammatory pressure, however, HDL can become dysfunctional [3]. Normal HDL has high levels of antioxidants and active antioxidant proteins/enzymes and is anti-inflammatory (aiHDL). Proinflammatory HDL (piHDL) has high levels of prooxidant molecules, which interfere with HDL removal of cellular toxic waste and HDL delivery of this metabolic waste for elimination.

HDL from individuals with coronary artery disease (CAD) was not able to prevent LDL lipid oxidation [4] and HDL from obese individuals was unable to maintain vascular relaxation [5]. In renal patients, the survival rate for those with aiHDL was four-fold than for those with piHDL [6•]. Women with systemic lupus erythematosus (SLE) have increased risk of coronary artery disease (CAD). McMahon et al. [7] showed that SLE patients had high levels of piHDL, which correlated with the levels of oxidized LDL. SLE patients with CAD had higher piHDL scores than those without CAD. Patients with Crohn's disease had piHDL, which improved upon standard therapy [8].

Among other factors, the failure of torcetrapib has fuelled speculation that in addition to raising HDL-cholesterol, the quality and function of HDL needs to be improved [9]. Statins were shown to improve HDL quality and function in patients with CAD [10]. Patients with rheumatoid arthritis (RA) have increased risk of myocardial infarction. Charles-Schoeman et al. [11•] showed that in a group of patients with active RA, unlike HDL from healthy individuals, HDL from patients with RA was proinflammatory. This piHDL was rendered anti-inflammatory by high-dose atorvastatin [11•].

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Novel compounds and approaches

Several compounds are being tested in clinical trials including an extended-release niacin, which does not produce flushing and increases HDL–apoA1 and decreases triglycerides and VLDL/LDL [12]; a PPAR-α agonist LY518674, affecting the production and clearance of apoA-I and HDL [13]; the apoA-I mimetic peptide 4F, which was shown to be safe and well tolerated and improved the HDL anti-inflammatory index [4]; and a microsomal triglyceride transfer protein inhibitor (AEGR-733) [14]. In addition, it is recommended [15,16] that efforts be directed toward promotion of RCT and its robust measures.

As obesity and metabolic syndrome have become a serious global health issue [17], therapeutic strategies are needed that directly target adipose tissue to optimally reduce cardiometabolic risk.

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Conclusion

Certain lipoproteins and the renin–angiotensin–aldosterone system are important in the pathogenesis of atherosclerotic cardiovascular disease.

Understanding how risk factors such as high blood pressure, dysregulated blood lipids and diabetes contribute to atherosclerotic disease, as well as elucidation of the molecular pathogenesis of atherosclerotic plaques, are leading to new targets for therapy [18••].

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

1•• Steinberg D, Glass CK, Witztum JL. Evidence mandating earlier and more aggressive treatment of hypercholesterolemia. Circulation 2008; 118:672–677. A thorough review on the therapy of hypercholesterolemia emphasizing on the benefits of maximal lowering of LDL and early preventive care.
2 Navab M, Gharavi N, Watson AD. Inflammation and metabolic disorders. Curr Opin Clin Nutr Metab Care 2008; 11:459–464.
3 Navab M, Reddy S, Van Lenten BJ, et al. Role of dysfunctional HDL in atherosclerosis. J Lipid Res 2008. [Epub ahead of print]
4 Bloedon LT, Dunbar R, Duffy D, et al. Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients. J Lipid Res 2008; 49:1344–1352.
5 Perségol L, Vergès B, Gambert P, et al. Inability of HDL from abdominally obese subjects to counteract the inhibitory effect of oxidized LDL on vasorelaxation. J Lipid Res 2007; 48:1396–1401.
6• Kalantar-Zadeh K, Kopple JD, Kamranpour N, et al. HDL-inflammatory index correlates with poor outcome in hemodialysis patients. Kidney Int 2007; 72:1149–1156. A powerful study on a large cohort for an extended period demonstrating the advantage of having anti-inflammatory HDL.
7 McMahon M, Grossman J, FitzGerald J, et al. Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 2006; 54:2541–2549.
8 van Leuven SI, Hezemans R, Levels JH, et al. Enhanced atherogenesis and altered high density lipoprotein in patients with Crohn's disease. J Lipid Res 2007; 48:2640–2646.
9 Nicholls SJ. HDL: still a target for new therapies? Curr Opin Invest Drugs 2008; 9:945–949.
10 Ansell BJ, Navab M, Hama S, et al. Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation 2003; 108:2751–2756.
11• Charles-Schoeman C, Khanna D, Furst DE, et al. Effects of high-dose atorvastatin on antiinflammatory properties of high density lipoprotein in patients with rheumatoid arthritis: a pilot study. J Rheumatol 2007; 34:1459–1464. This study suggests that statin therapy might have a beneficial role in reducing inflammation in rheumatoid arthritis.
12 Kamanna VS, Ganji SH, Kashyap ML. Niacin: an old drug rejuvenated. Curr Atheroscler Rep 2009; 11:45–51.
13 Millar JS, Duffy D, Gadi R, et al. Potent and selective PPAR-{alpha} agonist LY518674 upregulates both ApoA-I production and catabolism in human subjects with the metabolic syndrome. Arterioscler Thromb Vasc Biol 2009; 29:140–146.
14 Samaha FF, McKenney J, Bloedon LT, et al. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat Clin Pract Cardiovasc Med 2008; 5:497–505.
15 Rader DJ, Alexander ET, Weibel GL, et al. Role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis. J Lipid Res 2008. [Epub ahead of print]
16 deGoma EM, deGoma RL, Rader DJ. Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches. J Am Coll Cardiol 2008; 51:2199–2211.
17 Toh SA, Rader DJ. Dyslipidemia in insulin resistance: clinical challenges and adipocentric therapeutic frontiers. Expert Rev Cardiovasc Ther 2008; 6:1007–1022.
18•• Rader DJ, Daugherty A. Translating molecular discoveries into new therapies for atherosclerosis. Nature 2008; 451:904–913. This review skillfully analyzes the role of dyslipidemia, hypertension and diabetes in the molecular pathogenesis of atherosclerotic plaques and discusses approaches towards understanding targets for therapy.
© 2009 Lippincott Williams & Wilkins, Inc.