Journal Reading

Pleiotropic Effects of Statins

Daniel Pella, Rafael Rybar and Viola Mechivora

*dr. Mohamad Ananto C.

** dr. Wursito, SpJP (K)

*RESIDENT OF INTERNAL MEDICINE, FACULTY OF MEDICINE, BRAWIJAYA UNIVERSITY, SAIFUL

ANWAR HOSPITAL
** SUPERVISOR CARDIOLOGY DEPARTMENT , BRAWIJAYA UNIVERSITY, SAIFUL ANWAR HOSPITAL

Introduction
Cardiovascular disease, which includes coronary heart disease, stroke,

and peripheral arterial disease is the leading cause of death worldwide (1).
According to WHO statistics

-more than 16 million people die because CVD in 2001, and 25 million
approximately death annually are expected from CVD (2).
Statins were discovered in 1976 when endo et al, found that a product of

mould penicillium sitrium was able to inhibit acivity of one of the enzym
of cholesterol synthesis, 3-hydroxy-3 methyl-glutaryl coenzyme A
reductase
(
HMG
CoA
reductase
).(3)
REF
1. World Health Organization. The World Health report 2002: Reducing risks, promoting healty life. Geneva: WHO 2002.
2. American Heart Association, Statistical fact sheet-populations. International Disease Statistics. Dallasm T : American Heart
Association 2003.
3. Endo A, Kuroda M, Competitive inhibition of 3-HMG-CoA reductase by ML 236 A and ML 236 B. 1976;72:323-6

Introduction(2)
basic pillars in the secondary and primary prevention of
atherosclerosis. (5-7)
Statins preventing progression of atherosclerosis, even able to cause
regression of the disease
Decrease of CV endpoints, but also mortality found in clinical studies
could not be explained only by the decrease of atherogenic lipids
Speculation about pleiotropic effects appeared and was confirmed by
further research activity.
Statins

REF

5. Simvastatin study group. Randomized trial of cholesterol lwering in 4444 patients.Lancet 1994;334:1383-9
6. Sacks FM, Pfeffer MA, the effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol
levels N Eng J med 1996
7. The Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study group. N Eng J Med 1998;339: 1349-57

Characteristics of Statins
Statins Inhibit Hydroxymethylglutaryl coenzym A reductase ( HMG

CoA reductase ), the enzym that controls rate limiting step of

cholesterol synthesis.

Characteristic statins
Some studies stated about additional beneficial effect of statin

because mevalonate, is the precursor not only of cholesterol but

also of many nonsteroidal isoprenoid compounds, inhibition of
HMG-CoA reductase may produce pleiotropic effects.(12)
Statins may effect a variety process, several recent in vitro and in

vivo experiments HMG coA reductase inhibitors have anti

atherosclerotic effects that are not related to lipid lowering
seen as the new aspirin.(12)

REF
12. Veilard NR, Mach F. Statins : The new aspirin? Cell mol life Sci 2002;59:1771-86

Characteristic of statins

Characteristic of statins

Pleiotropic Effects
Definition :

From Greek pleion meaning more, tropos meaning

direction or turn, producing or having multiple effects from a
single gene.
Antiatherogenic pleiotropic effects of statins :
- Improvement of endothelial dysfunction
- Antioxidative
- Antiinflammatory
- Antiproliferative
- Antitrombotic effects
- Neoangiogenesis

AntiInflammatory Effects

Elevated markers for inflammation such as CRP, interleukin-6,

ICAM-1, and serum amyloid A associated with increase risk for
reccurent cardiovascular events.(31)
Recent study decrease of hs CRP achieved 89% in the atorvastatin
group and 85% in pravastatin group.(32)
REF
32. Cannon CP, Braunwald E. Comparison of intensive and moderate lipid lowering statins following acute coronary
syndromes. Neng J Med 2004;350:1495-504

Statins and Endothelial dysfunction

Abnormal endothelium-dependent vasomotor responses predict the

long-term progression of atherosclesosis. (27,38)
Increase nitric oxide synthesis and improve blood flow dependent
upon endotheliumm

REF
27.Schachinger V. Britten MB, Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary
heart disease. Circulation 2002;101: 1899-906
38. Nissen SE, Tuxcu. Effect of intensive? Compared with moderate lipid lowering therapy on progression of oronary
atherosclerosis: JAMA 2004;291:1071-80

Immunomodulatory

Chronic administration of statins can also inhibit PPAR and ,

which are known inflammatory mediators.
Pleiotropic actions may help in reducing vascular inflammation
and in antirejection regimens following graft arterial disease
(GAD)

Statin and plaque stability

Statins may foster plaque stability through a reduction in macrophage and

cholesterol ester contents and by incrreasing the volume of collagen
contents
The most important finding for plaque stability is the combination of lipidlowering effects with pleiotropic ones ( especially decrease of plaque lipid
core size and inhibition of inflammatory reaction ).(43)

Antioxidant actions of Statin

Statins and coagulation

Statins support fibrinolysis and maintain balance between prothrombotic

and fibrinolytic mechanisms (15,77)

REF
15.Efthimiodis AP, Pirropoulos Action of statins upon thrombogenesis, fibrinolysis and inflammation in coronary syndrome. Clin
Chem 2006:186-92
77. Rosenson RS. Non lipid lowering effects of statins on atherosclerosis. Curr cardiol Rep 1999;1-255-32.

Normalization of sympathetic outflow

Chronic administration of statins lower sympathetic outflow

Statins have been shown to produce beneficial effects in HT, MI , CHF
and cerebral ischemia.(82,83)
REF
82. Glorisos N, Troffa C, Soro A. Effect of the HMG CoA reductase inhibitors. Cardiology 2001;95;9-13.
85. Pontrelli L, Parris W, Cheung RC. Atorvastatin treatment beneficially alters the lipoprotein profile and iscreases low density
lipoprotein particle diameter in patients with combined dyslipidemia and impaired fasting glucose . Metabolism 2002;51:33442.

Statins in peripheral arterial disease

Statins improve lower extremity functioning in PAD by retarding the

deleterious effects of atherosclerosis on leg arteries

REF
81. Hernandez-Perera o, Ferez-Sala, Hernandez G, Diaz et al. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase
inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in
vascular endothelial cells. J Clin invest 2002;101:2711-9.

Pleiotropic effects of statins in Nonatherosclerotic disease

Possible negative pleiotropic effects of statins

Statins inhibition of geranyl pyrophosphate synthesis and subsequently

dekaprenyl-4-benzoate, which is precursor of coenzyme Q10

Coenzyme Q10 very important subtance in myocardial energetic
metabolism and stability of cell membrane
When deficient, myocites prone to damage in the form of myopathy or
myositis, or even rhabdomyolisis.(44)
Hypothesis by moosman and behl identified a possible role of
deficiency of selenium and association with adverse effect of statin,
myopathy and polyneuropathy.(47)
Silver
et al evaluated LV diastolic function with doppler
echocardiography , coenzym Q10 improved parameters of diastolic
function.(48)
REF

44. Singh, RB, Pella D, Chopra et al. Overview of ubiquinone, in memory of champion. Dr. Emile . Bliznakov. J of Nutr and Environment
Med 2003;13:211-4
47. Moosmann B, Behl. Seleprotein synthesis and side effects of statin. Lancet 2004;363:892-4.

Conclusion
Statins have same mode of action via inhibition of HMG CoA

reductase, but differ between each other in the extent of this inhibition
Pleiotropic effects of statins numerous and varied, it may add to

desireable effect of a drug and interfere the treatment

Further study of pleiotropic functions of statins may provide insights

into the biology of atherosclerosis ( and other disease like osteoporosis,

rheumatoid arthritis, connective tissue disease ) even those individuals
who achieved current lipid goals.

THANK YOU

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