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Niacin in the prevention of atherosclerosis: Significance of vasodilatation

P. Tuohimaa a,*, M. Jrvilehto b

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

a r t i c l e i n f o

Article history:

Received 31 March 2010

Accepted 1 April 2010

s u m m a r y

There is a rising interest towards the old drug, nicotinic acid (niacin, vitamin B3), because at pharmaco-

logical concentrations it has a beneficial effect on HDL cholesterol. Its use, however, was limited due to itsadverse effect, flushing. When the mechanism of flushing was solved, a combination of niacin and DP1

receptor antagonist or prostaglandin inhibitor is used, there has been a comeback of niacin with exten-

sive clinical trials. This paper argues that the new strategy with niacin for the prevention of atheroscle-

rosis 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.

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 first signs

of atherosclerosis are observed deep in the intimal layer or be-

tween the media and intima. There are several theories about the

development of atherosclerotic plaques. If an endothelial dysfunc-

tion would initiate the accumulation of cholesterol via scavenger

receptors [13], the cholesterol accumulation and inflammation

would first occur superficially 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 bor-

der [5]. The branches of vv run circumferentially or retrograde to-

wards 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 dif-

fusion). The putative sequential events of atherosclerosis are de-

picted schematically in Fig. 1B and C. Fig. 1 shows only the

external vasa vasorum. Our vasa vasorum hypoxia hypothesis in-

cludes that not cholesterol or microbes are the initial cause of

the atherosclerosis but vasoconstriction (and consequent hyper-

tension) begins the fatal process. Accumulation of cholesterol,

microbes and inflammatory cells are consequences of damages of

capillaries in the arterial wall allowing free efflux of the

macromolecules.

The recurrent branch of the external vv ends to the concave an-

gle 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-methylglut-

aryl 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 efficacy in prevent-

ing cardiovascular outcomes [6,7]. Because of wide use also harm-

ful 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 flush its use

was limited [913]. Today, niacin is experiencing a reappraisal, be-

cause it is exceptionally beneficial in increasing HDL cholesterol.

On the other hand, the flush can be prevented with a specific med-

ication, 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

0306-9877/$ - see front matter 2010 Elsevier Ltd. All rights reserved.doi:10.1016/j.mehy.2010.04.007

* Corresponding author. Tel.: +358 50 3610643.

E-mail address: [email protected] (P. Tuohimaa).

Medical Hypotheses 75 (2010) 397400

Contents lists available at ScienceDirect

Medical Hypotheses

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m e h y
http://dx.doi.org/10.1016/j.mehy.2010.04.007mailto:[email protected]://www.sciencedirect.com/science/journal/03069877http://www.elsevier.com/locate/mehyhttp://www.elsevier.com/locate/mehyhttp://www.sciencedirect.com/science/journal/03069877mailto:[email protected]://dx.doi.org/10.1016/j.mehy.2010.04.007


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been forgotten: vasoconstriction of vv and influence of the conse-

quent hypertension on the oxygen supply of arterial walls (Lames

law).

Association of vasodilatation/vasoconstriction with

atherosclerosis

There are several risk factors associated with atherosclerosis

including sedentary lifestyle, hyperlipidemia, elevated serum cho-

lesterol and triglycerides, obesity, smoking, hypertension, stress,

male gender, sleep apnea, infections and diabetes mellitus [14

18]. Protective factors include active sports, female gender (estro-

gen), 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 produc-

tion 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 profile

and hypertension belong to the definition of the metabolic syn-

drome [21]. Eventhough stress is a clear risk factor for atheroscle-

rosis [22] and it is often associated with changes in serum lipid

profile, 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 periph-eral vasoconstriction [23]. Endothelin-1 plays an important role in

hypertension by increasing peripheral resistance via vasoconstric-

tion [23], but it does not affect serum lipids. Sleep apnea can di-

rectly 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 vasodila-

tors. Estrogens may explain the sex difference in serum lipid profile

[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 tolower LDL cholesterol, but it does not affect HDL cholesterol [28],

Fig. 1. A schematic presentation of the initial development of atherosclerosis (vasavasorum 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.

Inflammatory cells including macrophages invade the damaged area. (3) Different macromolecules (lipoproteins etc.) and microbes (viruses and bacteria) extravasate

through thedamaged endothelium andthe macrophages begin phagocytosis forming foam cells (C)(white spot). (4)Plagues grow in size andfinally extrude into thelumenof

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.

Table 1

Risk and protective factors in atherosclerosis and their effects on cholesterol,

vasoconstriction and blood pressure.

LDL HDL Vasoconstriction Reference

Risk factor

Nicotine 0 0 + Rahman and Laher [20]

Obesity " ; + Reaven [21]

Stress 0 0 + Rozanski et al. [22]

Hypertension 0 0 + Touyz and Schiffrin [23]

Sleep apnea 0 0 + Drager et al. [24]

Protective factor

Estrogen ; " + Cruz et al. [26]

Vitamin D 0 0 + Zittermann and Koerfer

[27]

Physical

exercise

; 0 + Roberts et al. [28]

Statins ; 0 + Veillard and Mach [29]

Niasin 0 " + Gille et al. [11]

Alcohol 0 " + Deng and Deitrich [31]

398 P. Tuohimaa, M. Jrvilehto/ Medical Hypotheses 75 (2010) 397400


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its vasodilatating effects are obvious. Statins were developed to

lower serum cholesterol, but their pleiotropic effects include vaso-

dilation [29]. Beside its beneficial effect on HDL, niacin can dilate

peripheral vessels causing flush [11]. The effect of alcohol on ath-

erosclerosis is controversial, although its beneficial 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 endo-

thelial NOS (eNOS) expression, and augment endothelium-medi-

ated 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 influence cholesterol levels sug-

gesting that cholesterol cannot explain all the development of ath-

erosclerosis, but vasoconstriction and blood pressure might be

more crucial. According to our vasa vasorum hypoxia hypothesis

the vasodilatation would be beneficial in the prevention of the ath-

erosclerosis, which fits well with the clinical experience. NO is a

critical endothelium-derived vasodilatatory factor anti-atheroscle-

rotic 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

significance in the prevention of atherosclerosis has been ne-

glected. 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 po-

tential 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 antago-

nist (laropiprant) attenuates the niacin flush in animals and hu-

mans. A reformulated preparation of extended-release niacin

lowers flushing compared with the extended-release niacin. Aspi-

rin pretreatment seems to attenuate flushing from this prepara-

tion. However, these combination drugs prevent most of theperipheral vasodilatation and may, thus, be less effective in

decreasing blood pressure, which might be also a beneficial 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-lower-

ing drugs may delay the progression atherosclerosis in the sec-

ondary 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.

Conflict of interest statement

None declared.

Acknowledgement

The paper is funded by the EVO grant of the Tampere University

Hospital.

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