Medical Hypotheses 75 (2010) 397400

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Niacin in the prevention of atherosclerosis: Signicance of vasodilatation

P. Tuohimaa a,*, M. Jrvilehto b
a b

Medical School, University of Tampere and Department of Clinical Chemistry, Tampere University Hospital, 33014 Tampere, Finland Department of Biology, University of Oulu, 90014 Oulu, Finland

a r t i c l e

i n f o

s u m m a r y
There is a rising interest towards the old drug, nicotinic acid (niacin, vitamin B3), because at pharmacological concentrations it has a benecial effect on HDL cholesterol. Its use, however, was limited due to its adverse effect, ushing. When the mechanism of ushing was solved, a combination of niacin and DP1 receptor antagonist or prostaglandin inhibitor is used, there has been a comeback of niacin with extensive clinical trials. This paper argues that the new strategy with niacin for the prevention of atherosclerosis should be re-evaluated, because vasodilatation of the peripheral vessels might be crucially important in the early primary prevention according to our vasa vasorum hypoxia hypothesis. 2010 Elsevier Ltd. All rights reserved.

Article history: Received 31 March 2010 Accepted 1 April 2010

Vasa vasorum hypoxia as an initial cause of atherosclerosis Atherosclerotic cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Atherosclerosis is a disease of the coronary and large arteries. Typically, the rst signs of atherosclerosis are observed deep in the intimal layer or between the media and intima. There are several theories about the development of atherosclerotic plaques. If an endothelial dysfunction would initiate the accumulation of cholesterol via scavenger receptors [13], the cholesterol accumulation and inammation would rst occur supercially beneath the endothelium. Only our recent hypothesis on vasa vasorum hypoxia provides a logical explanation for the early development of atherosclerosis deep in the arterial wall, between the media and intima at the branching sites of arteries [4]. We postulated that a functional hypoxia of the most peripheral vasa vasorum (vv) develops gradually in response to a constriction of the peripheral small arteries and hypertension compressing intramural small arteries and capillaries of the wall of large arteries (Fig. 1A). The external vv originate from the branches of the main artery and they run longitudinally along the media-adventitia border [5]. The branches of vv run circumferentially or retrograde towards the branch point. Vasa vasorum are functional endarteries. The oxygen perfusion of the wall of the main artery comes into the intimal layer directly from the lumen (outward diffusion) and into the adventitia and media from the vasa vasorum (inward diffusion). The putative sequential events of atherosclerosis are depicted schematically in Fig. 1B and C. Fig. 1 shows only the external vasa vasorum. Our vasa vasorum hypoxia hypothesis includes that not cholesterol or microbes are the initial cause of
* Corresponding author. Tel.: +358 50 3610643. E-mail address: pentti.tuohimaa@uta. (P. Tuohimaa). 0306-9877/$ - see front matter 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2010.04.007

the atherosclerosis but vasoconstriction (and consequent hypertension) begins the fatal process. Accumulation of cholesterol, microbes and inammatory cells are consequences of damages of capillaries in the arterial wall allowing free efux of the macromolecules. The recurrent branch of the external vv ends to the concave angle of the arterial bifurcation. This is the most vulnerable part of vv to vasoconstriction and hypertension from two sides compressing the intramural artery (Fig. 1B, white arrows). According to Lames law the oxygen perfusion from the vv is limited leading to hypoxia in the oxygen demanding smooth muscle layer. Since the muscle contraction is prolonged in hypoxia, the situation is progressive, unless peripheral vasodilatation increases the perfusion of the most distant vv. Since their introduction in the 1980s, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have emerged as the one of the best-selling medication classes to date, with numerous trials demonstrating powerful efcacy in preventing cardiovascular outcomes [6,7]. Because of wide use also harmful side effects are evident. Non-cholesterol effects are known as pleiotropic effects such as vasodilatation and decrease of blood pressure (wanted side effects) or unwanted side effects such as myopathy and rhabdomyolysis [8]. Recently, much attention has been paid to the old drug, nicotinic acid (niacin), which was found being effective in the prevention of atherosclerosis, but because of its unpleasant side effect, peripheral vasodilatation or ush its use was limited [913]. Today, niacin is experiencing a reappraisal, because it is exceptionally benecial in increasing HDL cholesterol. On the other hand, the ush can be prevented with a specic medication, since its mechanism is known. However, it is possible that this side effect, vasodilatation, could be an important factor in the prevention of atherosclerosis. This article points out that two important factors in the early development of atherosclerosis have

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Fig. 1. A schematic presentation of the initial development of atherosclerosis (vasa vasorum hypoxia hypothesis). (A) Normal, (B) vasoconstriction and functional hypoxia and (C) plaque formation. (1) A vasoconstriction of the vasa vasorum (B) causes a functional hypoxia (blue spot). The most vulnerable site is the muscle layer with a high oxygen consumption at the branching site, where hypertension from both sides (white arrows) compresses vasa vasorum. (2) Hypoxia in turn leads to a damage of the endothelium. Inammatory cells including macrophages invade the damaged area. (3) Different macromolecules (lipoproteins etc.) and microbes (viruses and bacteria) extravasate through the damaged endothelium and the macrophages begin phagocytosis forming foam cells (C) (white spot). (4) Plagues grow in size and nally extrude into the lumen of the main artery. After neovascularization, a hemorrhagic rupture may occur leading to an obstruction. Dotted line in Fig 1A stands for media-intima border, where the outward oxygen diffusion from lumen and the inward diffusion from the vasa vasorum meet.

been forgotten: vasoconstriction of vv and inuence of the consequent hypertension on the oxygen supply of arterial walls (Lames law).

Table 1 Risk and protective factors in atherosclerosis and their effects on cholesterol, vasoconstriction and blood pressure. LDL HDL 0 ; 0 0 0 " 0 0 0 " " Vasoconstriction + + + + + + + + + + + Reference Rahman and Laher [20] Reaven [21] Rozanski et al. [22] Touyz and Schiffrin [23] Drager et al. [24] Cruz et al. [26] Zittermann and Koerfer [27] Roberts et al. [28] Veillard and Mach [29] Gille et al. [11] Deng and Deitrich [31]

Association of vasodilatation/vasoconstriction with atherosclerosis There are several risk factors associated with atherosclerosis including sedentary lifestyle, hyperlipidemia, elevated serum cholesterol and triglycerides, obesity, smoking, hypertension, stress, male gender, sleep apnea, infections and diabetes mellitus [14 18]. Protective factors include active sports, female gender (estrogen), vitamin D3, a high HDL cholesterol, caloric restriction, low body weight, a moderate use of alcohol. Table 1 shows a summary of the risk and protective factors and their effects on lipid balance and vasoconstriction/vasodilatation. Nicotine is known as high risk factor for atherosclerosis. However it does not affect serum lipid composition [19]. Nicotine is strongly vasoconstrictive for the peripheral vessels [20]. It reduces production and bioavailability of nitric oxide (NO), increases production and release of endothelin. Obesity and metabolic syndrome are well known risk factors of atherosclerosis. Typical lipid prole and hypertension belong to the denition of the metabolic syndrome [21]. Eventhough stress is a clear risk factor for atherosclerosis [22] and it is often associated with changes in serum lipid prole, the mechanism is not known and it is unlikely that stress could directly regulate cholesterol metabolism. In vascular stress, endothelin-1 is released from the endothelium leading to a peripheral vasoconstriction [23]. Endothelin-1 plays an important role in

Risk factor Nicotine Obesity Stress Hypertension Sleep apnea Protective factor Estrogen Vitamin D Physical exercise Statins Niasin Alcohol

0 " 0 0 0 ; 0 ; ; 0 0

hypertension by increasing peripheral resistance via vasoconstriction [23], but it does not affect serum lipids. Sleep apnea can directly cause hypoxia in vasa vasorum, but it is a high risk factor when it is combined with hypertension [24]. All the protective factors in atherosclerosis seem to be vasodilators. Estrogens may explain the sex difference in serum lipid prole [25], they are also known to dilate peripheral arteries [26]. Vitamin D is proven to be effective in prevention of atherosclerosis [27], it has weak or no effect on serum lipids. Physical exercise seems to lower LDL cholesterol, but it does not affect HDL cholesterol [28],

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its vasodilatating effects are obvious. Statins were developed to lower serum cholesterol, but their pleiotropic effects include vasodilation [29]. Beside its benecial effect on HDL, niacin can dilate peripheral vessels causing ush [11]. The effect of alcohol on atherosclerosis is controversial, although its benecial effects of a moderate alcohol use are well documented [30]. It is clear that acute low doses of EtOH increase both the release of NO and endothelial NOS (eNOS) expression, and augment endothelium-mediated vasodilatation, whereas higher doses impair endothelial functions [31]. It can be concluded from the Table 1 that all risk factors are vasoconstrictive and hypertensive and all protective factors are vasodilatative, but not all of them inuence cholesterol levels suggesting that cholesterol cannot explain all the development of atherosclerosis, but vasoconstriction and blood pressure might be more crucial. According to our vasa vasorum hypoxia hypothesis the vasodilatation would be benecial in the prevention of the atherosclerosis, which ts well with the clinical experience. NO is a critical endothelium-derived vasodilatatory factor anti-atherosclerotic properties [32]. It is interesting that the pleiotropic effects of statins include vasodilation and decrease of blood pressure [3336]. Although the pleiotropic effects of statins have been widely analysed, their signicance in the prevention of atherosclerosis has been neglected. The ability of nicotinic acid to strongly increase the plasma concentration of high-density lipoprotein (HDL) cholesterol has in recent years led to an increased interest in the pharmacological potential of nicotinic acid [10,11]. Flushing is regarded as an adverse effect of niacin, results from GPR109A-mediated production of prostaglandin D2 and E2 in Langerhans cells which act on DP1 and EP2/4 receptors in dermal capillaries causing their vasodilatation [37]. DP1 receptor antagonist (laropiprant) attenuates the niacin ush in animals and humans. A reformulated preparation of extended-release niacin lowers ushing compared with the extended-release niacin. Aspirin pretreatment seems to attenuate ushing from this preparation. However, these combination drugs prevent most of the peripheral vasodilatation and may, thus, be less effective in decreasing blood pressure, which might be also a benecial effect of niacin. We propose that it is reasonable to re-evaluate the goals in the primary prevention of atherosclerosis. It seems that vasodilatation might be the most important, whereas lipid-lowering drugs may delay the progression atherosclerosis in the secondary prevention, when combined with vasodilatation. Therefore, statins are optimal in the secondary prevention, but also niacin by increasing HDL should be useful, if its capacity for peripheral vasodilatation is maintained. Conict of interest statement None declared. Acknowledgement The paper is funded by the EVO grant of the Tampere University Hospital. References
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