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Communications to the Editor |

Lipid-Lowering Agents and Artery Endothelial Function Lipid-Lowering Agents and Artery Endothelial Function FREE TO VIEW

Ken-ichiro Inoue, MD; Yutaka Kawahito, MD, PhD; Toshikazu Yoshikawa, MD, PhD; Hajime Sano, MD, PhD
Author and Funding Information

Affiliations: Kyoto Prefectural University of Medicine Kyoto, Japan,  Albany Medical College Albany, NY

Correspondence to: Ken-ichiro Inoue, MD, First Department of Internal Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto-city, 602-8858, Kyoto, Japan; e-mail: keni@kk.ii4u.or.jp



Chest. 2001;119(6):1979-1980. doi:10.1378/chest.119.6.1979
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We read with interest the recent article by Houghton and colleagues (September 2000),1which indicated an improvement in coronary resistance artery function in hypercholesterolemic patients after treatment with pravastatin. After reading the article, we would like to know whether such endothelial function is improved by treatment with other types of lipid-lowering agents, such as bezafibrate and clofibrate. Bezafibrate and clofibrate are recognized not only as hypolipidemic drugs, but as pharmacologic ligands of peroxisome proliferator-activated receptor α (PPAR-α), one of the ligand-activated nuclear receptor transcriptional factors.2Inoue et al3 demonstrated the expression of PPAR-α in human vascular endothelial cells by reverse transcriptase-polymerase chain reaction. They also demonstrated the increased expression of PPAR-α in these cells after exposure to bezafibrate, suggesting that PPAR-α in endothelial cells plays a regulatory role in the pathogenesis of hyperlipidemia and atherosclerosis, and also in the processes of inflammation and coagulation. Another study4reported that inflammatory activation of aortic smooth muscle cells, which is a hallmark of atherosclerosis, is inhibited by the activation of PPAR-α by these fibrates. In addition, the activation of PPAR-α by these fibrates leads to the induction of apolipoprotein (apo)-AI and apo-AII expression in hepatocytes, resulting in an increase in circulating high-density lipoprotein cholesterol.5 Therefore, further study of resistance artery endothelial function in relation to such fibrates might result in more interesting data.

Houghton, JL, Pearson, TA, Reed, RG, et al (2000) Cholesterol lowering with pravastatin improves resistance artery endothelial function.Chest118,756-760. [CrossRef] [PubMed]
 
Auboeuf, D, Rieusset, J, Fajas, L, et al Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-α in humans.Diabetes1997;46,1319-1327. [CrossRef] [PubMed]
 
Inoue, I, Shino, K, Noji, S, et al Expression of peroxisome proliferator-activated receptor α (PPAR α) in primary cultures of human vascular endothelial cells.Biochem Biophys Res Commun1998;246,370-374. [CrossRef] [PubMed]
 
Staels, B, Koenig, W, Habib, A, et al Activation of human aortic smooth-muscles is inhibited by PPARα but not PPARγ activators.Nature1998;393,790-793. [CrossRef] [PubMed]
 
Vamecq, J, Latruffe, N Medical significance of peroxisome proliferator-activated receptors.Lancet1999;354,141-148. [CrossRef] [PubMed]
 

Lipid-Lowering Agents and Artery Endothelial Function

To the Editor:

Inoue and colleagues are correct in bringing to attention the possible role of fibrate drugs, a different class of lipid-lowering agent than that employed in our study (September 2000),1for use in treatment of endothelial dysfunction. Seiler et al2 showed that cholesterol-lowering therapy with benzafibrate, over a 7-month period, resulted in improved exercise-induced vasomotion of angiographically normal and previously dilated stenotic coronary arteries.

Evans et al3recently reported that after 3 months of treatment with ciprofibrate, improvement was demonstrated in fasting and postprandial brachial artery endothelial function among subjects with type 2 diabetes mellitus. The comments of Inoue et al regarding the vascular biology of fibrate drugs are topical. Evidence mounts that not only cholesterol-lowering but nonlipid effects of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor drugs are important elements in the ultimate clinical benefit. For example, one important collateral effect of these agents, which was initially unexpected, is the apparent reduction of endothelial inflammation. Ridker et al4found, in the Air Force/Texas Coronary Atherosclerosis Prevention Study, that treatment with lovastatin among subjects with average low-density lipoprotein (LDL) cholesterol levels independently lowered levels of C-reactive protein (CRP), the prototypic marker of vascular inflammation. Retrospective analysis showed that this translated into an improved cardiovascular event rate in subjects with elevated CRP levels even among those with low LDL cholesterol levels. A number of large randomized clinical trials56 have shown clinical benefits in patients after treatment with HMG-CoA reductase inhibitors resulting in significant reductions in myocardial infarction, stroke, and death during follow-up. The benefits have been conjectured to be out of proportion to the observed LDL reduction.7 This further supports the notion that lipid-lowering agents have other actions that independently lead to the repair of endothelial dysfunction. Ultimately, expanded indications for the use of lipid-lowering agents are likely in both the primary and secondary prevention of clinically significant coronary artery disease. In the future, the selection of lipid-lowering agents may be complexly dictated by factors such as the degree of vascular inflammation and the presence of postprandial lipemia in addition to the classical quantitative assessment of high-density and LDL cholesterol and triglyceride levels.

References
Houghton, JL, Pearson, TA, Reed, RG, et al Cholesterol lowering with pravastatin improves resistance artery endothelial function: report of six subjects with normal coronary arteriograms.Chest2000;118,756-760. [CrossRef] [PubMed]
 
Seiler, C, Suter, TM, Hess, OM Exercise-induced vasomotion of angiographically normal and stenotic coronary arteries improves after cholesterol-lowering drug therapy with benzafibrate.J Am Coll Cardiol1995;26,1615-1622. [CrossRef] [PubMed]
 
Evans, M, Anderson, RA, Graham, J, et al Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus.Circulation2000;101,1773-1779. [CrossRef] [PubMed]
 
Ridker, PM, Rifai, N, Miles, JS, et al Lovastatin 20–40 mg/day lowers high sensitivity C-reactive protein levels in AFCAPS/TexCAPS [abstract]. Circulation. 2000;;102 ,.:II833
 
Shepherd, J, Cobbe, SM, Ford, I, et al Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Prevention Study Group.N Engl J Med1995;333,1301-1307. [CrossRef] [PubMed]
 
Sacks, FM, Pfeffer, MA, Moye, LA, et al The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.N Engl J Med1996;335,1001-1009. [CrossRef] [PubMed]
 
Rosenson, RS, Tangney, CC Antiatherothrombotic properties of statins: implications for cardiovascular event reduction.JAMA1998;279,1643-1650. [CrossRef] [PubMed]
 

Figures

Tables

References

Houghton, JL, Pearson, TA, Reed, RG, et al (2000) Cholesterol lowering with pravastatin improves resistance artery endothelial function.Chest118,756-760. [CrossRef] [PubMed]
 
Auboeuf, D, Rieusset, J, Fajas, L, et al Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-α in humans.Diabetes1997;46,1319-1327. [CrossRef] [PubMed]
 
Inoue, I, Shino, K, Noji, S, et al Expression of peroxisome proliferator-activated receptor α (PPAR α) in primary cultures of human vascular endothelial cells.Biochem Biophys Res Commun1998;246,370-374. [CrossRef] [PubMed]
 
Staels, B, Koenig, W, Habib, A, et al Activation of human aortic smooth-muscles is inhibited by PPARα but not PPARγ activators.Nature1998;393,790-793. [CrossRef] [PubMed]
 
Vamecq, J, Latruffe, N Medical significance of peroxisome proliferator-activated receptors.Lancet1999;354,141-148. [CrossRef] [PubMed]
 
Houghton, JL, Pearson, TA, Reed, RG, et al Cholesterol lowering with pravastatin improves resistance artery endothelial function: report of six subjects with normal coronary arteriograms.Chest2000;118,756-760. [CrossRef] [PubMed]
 
Seiler, C, Suter, TM, Hess, OM Exercise-induced vasomotion of angiographically normal and stenotic coronary arteries improves after cholesterol-lowering drug therapy with benzafibrate.J Am Coll Cardiol1995;26,1615-1622. [CrossRef] [PubMed]
 
Evans, M, Anderson, RA, Graham, J, et al Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus.Circulation2000;101,1773-1779. [CrossRef] [PubMed]
 
Ridker, PM, Rifai, N, Miles, JS, et al Lovastatin 20–40 mg/day lowers high sensitivity C-reactive protein levels in AFCAPS/TexCAPS [abstract]. Circulation. 2000;;102 ,.:II833
 
Shepherd, J, Cobbe, SM, Ford, I, et al Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Prevention Study Group.N Engl J Med1995;333,1301-1307. [CrossRef] [PubMed]
 
Sacks, FM, Pfeffer, MA, Moye, LA, et al The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.N Engl J Med1996;335,1001-1009. [CrossRef] [PubMed]
 
Rosenson, RS, Tangney, CC Antiatherothrombotic properties of statins: implications for cardiovascular event reduction.JAMA1998;279,1643-1650. [CrossRef] [PubMed]
 
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