Why the overstated beneficial effects of statins do not resolve the cholesterol controversy

Mascitelli, Luca; Pezzetta, Francesca; Goldstein, M. R.

doi:10.1093/qjmed/hcp028

Cited by 4 publications

(2 citation statements)

References 4 publications

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“…The lack of association between total or LDL cholesterol and degree of atherosclerosis in unselected individuals was demonstrated by a study during the 1930s [47] and has since been noted by many others, notably by W. E. Stehbens [48-54] and U. Ravnskov [55-59], and others, e.g. [60]. Therefore, the hypothesis that elevated blood cholesterol constitutes a major cause of coronary arteriosclerosis is questionable.…”

Section: Analysis Of Main Assumptions Of the Currently Endorsed Hypotmentioning

confidence: 99%

Neovascularization of coronary tunica intima (DIT) is the cause of coronary atherosclerosis. Lipoproteins invade coronary intima via neovascularization from adventitial vasa vasorum, but not from the arterial lumen: a hypothesis

Субботин

2012

Theor Biol Med Model

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Background An accepted hypothesis states that coronary atherosclerosis (CA) is initiated by endothelial dysfunction due to inflammation and high levels of LDL-C, followed by deposition of lipids and macrophages from the luminal blood into the arterial intima, resulting in plaque formation. The success of statins in preventing CA promised much for extended protection and effective therapeutics. However, stalled progress in pharmaceutical treatment gives a good reason to review logical properties of the hypothesis underlining our efforts, and to reconsider whether our perception of CA is consistent with facts about the normal and diseased coronary artery. Analysis To begin with, it must be noted that the normal coronary intima is not a single-layer endothelium covering a thin acellular compartment, as claimed in most publications, but always appears as a multi-layer cellular compartment, or diffuse intimal thickening (DIT), in which cells are arranged in many layers. If low density lipoprotein cholesterol (LDL-C) invades the DIT from the coronary lumen, the initial depositions ought to be most proximal to blood, i.e. in the inner DIT. The facts show that the opposite is true, and lipids are initially deposited in the outer DIT. This contradiction is resolved by observing that the normal DIT is always avascular, receiving nutrients by diffusion from the lumen, whereas in CA the outer DIT is always neovascularized from adventitial vasa vasorum . The proteoglycan biglycan, confined to the outer DIT in both normal and diseased coronary arteries, has high binding capacity for LDL-C. However, the normal DIT is avascular and biglycan-LDL-C interactions are prevented by diffusion distance and LDL-C size (20 nm), whereas in CA, biglycan in the outer DIT can extract lipoproteins by direct contact with the blood. These facts lead to the single simplest explanation of all observations: (1) lipid deposition is initially localized in the outer DIT; (2) CA often develops at high blood LDL-C levels; (3) apparent CA can develop at lowered blood LDL-C levels. This mechanism is not unique to the coronary artery: for instance, the normally avascular cornea accumulates lipoproteins after neovascularization, resulting in lipid keratopathy. Hypothesis Neovascularization of the normally avascular coronary DIT by permeable vasculature from the adventitial vasa vasorum is the cause of LDL deposition and CA. DIT enlargement, seen in early CA and aging, causes hypoxia of the outer DIT and induces neovascularization. According to this alternative proposal, coronary atherosclerosis is not related to inflammation and can occur in individuals with normal circulating levels of LDL, consistent with research findings.

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Section: Analysis Of Main Assumptions Of the Currently Endorsed Hypotmentioning

confidence: 99%

Neovascularization of coronary tunica intima (DIT) is the cause of coronary atherosclerosis. Lipoproteins invade coronary intima via neovascularization from adventitial vasa vasorum, but not from the arterial lumen: a hypothesis

Субботин

2012

Theor Biol Med Model

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“…Is it not ironic that β‐blockers and digoxin, drugs that have been used almost exclusively in the cardiovascular arena, might someday prove useful in the treatment of prostate cancer? On the other hand, is it not worrisome that statins, whose beneficial cardiovascular action is thought to be mediated by pleiotropic effects unrelated to their cholesterol‐lowering effects [31], might actually promote cancer by these pleiotropic effects?…”

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confidence: 99%

Effect of Statin Use on Biochemical Outcome Following Radical Prostatectomy

Goldstein¹,

Mascitelli²

2011

BJU International

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Might the beneficial effects of statin drugs be related to their action on iron metabolism?

Mascitelli¹,

Goldstein²

2012

QJM

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Although the cholesterol-heart hypothesis is often regarded as a dogmatic belief, controversy continues to surround the aetiology and pathogenesis of atherosclerosis. In fact, lowering cholesterol with statin drugs has been shown to reduce cardiovascular risk. However, statins have pleiotropic effects independent of their capacity to lower cholesterol. We highlight that statin drugs exert an important action on iron metabolism, which in turn may prevent progression and destabilization of atherosclerotic plaque. If it is found that the effect of statins on iron metabolism is a mechanism of their beneficial action, this consequence of statin use can be clinically replicated by other methods, such as controlled reduction of body iron stores. This might allow the use of lower doses or even obviate the use of statins in primary cardiovascular prevention, and therefore avoid the side effects and expense of these drugs.

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Why the overstated beneficial effects of statins do not resolve the cholesterol controversy

Cited by 4 publications

References 4 publications

Neovascularization of coronary tunica intima (DIT) is the cause of coronary atherosclerosis. Lipoproteins invade coronary intima via neovascularization from adventitial vasa vasorum, but not from the arterial lumen: a hypothesis

Neovascularization of coronary tunica intima (DIT) is the cause of coronary atherosclerosis. Lipoproteins invade coronary intima via neovascularization from adventitial vasa vasorum, but not from the arterial lumen: a hypothesis

Effect of Statin Use on Biochemical Outcome Following Radical Prostatectomy

Might the beneficial effects of statin drugs be related to their action on iron metabolism?

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