Sunday, September 2, 2012


Cardiovascular Diseases and Atherosclerosis 

Coronary heart disease (CHD), also called coronary artery disease (CAD) is the narrowing of the coronary artery (the artery that supplies the heart muscle with oxygenated blood), which is often caused by atherosclerosis.  CHD may progress to ischaemic heart disease (IHD), which is a disease that involves ischemia (reduced blood supply) of the heart.  Angina is a symptom of IHD at times when the heart has insufficient blood supply. 

Rupture of unstable atherosclerotic plaque in the coronary arteries can form a blood clot (thrombus), whichs blocks blood flow to heart.  This causes a myocardial infarction (MI) (heart attack), where the heart receives an inadequate amount of oxygen to generate sufficient energy to maintain cellular homeostasis, and often some heart cells die as a result.

Atherosclerosis can also occur in the carotid artery (the artery that supplies the brain with oxygenated blood).  Then rupture of unstable atherosclerotic plaque or a blood clot may result in an ischemic stroke. 

Peripheral vascular disease (PVD), also called peripheral artery disease (PAD) can also be caused by atherosclerosis in the arteries leading to the legs, arms, etc* 

So atherosclerosis is the main cause of angina, heart attacks and ischaemic strokes.  Angina and especially heart attacks can lead to cardiomyopathy and further heart problems.  And atherosclerosis is a cause of hypertension.  While blood clots can trigger heart attacks and strokes, blood clots can be caused by ruptured atherosclerotic plaque and blood clots without any atherosclerosis is unlikely to block arteries.  I think it’s fair to say that in almost all cases: angina, heart attacks and ischaemic strokes are dependent on atherosclerosis. 

* This is probably the main reason why erectile dysfunction is so prevalent in those with CHD and may precede other signs/symptoms of CHD. 

Hypotheses of Atherosclerosis

There are a few different hypotheses as to what the initiating event in atherosclerosis is

The response-to-injury hypothesis has a few different variations.  (1) Endothelial cells wear away over time. (the cells that line the innermost part of the arteries).  But endothelial cells remain intacts in atherosclerosis and plaque build-up occurs beneath the endothelium [1].  (2) High blood pressure and inflammation cause endothelial damage, then cholesterol levels increase and the endothelial cells take up more cholesterol, where sustained injury results in a pathological accumulation of cholesterol.  Endothelial damage would increase cholesterol and cholesterol by endothelial cells [2], but only oxidised cholesterol causes atherosclerosis and cells regulate their cholesterol levels (see below).  (3) Endothelial dysfunction increases endothelial permeability, which increases the penetration and retention of lipoproteins (see response-to-retention).  Endothelial dysfunction is not sufficient to cause atherosclerosis [1], but is a contributing factor which I discuss here.

The response-to-retention hypothesis suggests the retention of lipoproteins, particularly LDL, is the initiating event in atherosclerosis.  The more LDL particles (LDL-P) the more likely they are to penetrate the endothelium.  The lipoproteins get stuck behind the endothelium by sticky proteins called proteoglycans.  This triggers an inflammatory response that oxidises the LDL particle and then macrophages engulf the stuck lipoproteins and form foam cells [1]

The oxidative modification hypothesis suggests LDL needs to be modified to initiate atherosclerosis (see below) 

Modified LDL and Atherosclerosis

Despite the labelling of LDL as ‘bad cholesterol’, regular LDL particles don’t cause the cholesterol-rich foam cells (plaques) that occur in atherosclerosis.  Even very high levels of LDL don’t lead to foam cells in vitro.  The foam cells only develop when the LDL particle is modified and there are many possible modifications (including many types of oxidative modification) [3]. 

Serum contains many antioxidants to protect against oxidative modification of LDL.  For example a 10% concentration of fetal calf serum almost completely protects against it.  It’s suggested that if LDL particles penetrate the endothelial layer they have more exposure to oxidants from smooth muscle cells and less exposure to antioxidants in the serum, which may result in LDL oxidation [3].  The problem is that LDL is the major transporter of vitamin E and atherosclerotic plaque contains a surprisingly high concentration of antioxidants, which in the case of some antioxidants (vitamin C, uric acid, vitamin E) is only slightly lower than plasma levels [1]. 

Not all oxidants are the same, there are two kinds of oxidants: 1e-oxidants and 2e-oxidants.  1e-oxidants include superoxide (O2-), nitric oxide (NO) and hydroxyl radicals (OH-), and are generally quenched by antioxidants such as vitamin C and E.  2e-oxidants include hypochlorous acid (HOCl) and peroxynitrite (ONOO-)* and antioxidants such as vitamin C and E are generally ineffective against them** [1]. 

The 1e, 2e distinction is supported by the type of LDL oxidation: 

Minimally oxidised LDL refers to LDL that is still recognised by the LDL receptor but not by macrophage scavenger receptors, and also promotes macrophage differentiation and chemoattraction.  Minimally oxidised LDL seems to be the result of vitamin E depletion and contains mostly lipid oxidation products and no protein oxidation [1]. 

Oxidised LDL (oxLDL) is where the ApoB protein is oxidised, which enables it to be recognised by macrophage scavenger receptors.  2e-oxidants preferentially react with proteins rather than lipids [1].  oxLDL has a number of additional effects such as promoting smooth muscle cell proliferation, monocyte adhesion, the production of autoantibodies, pro-inflammatory cytokines, platelet aggregation (blood clotting).  oxLDL is also toxic to endothelial cells, upregulates angiotensin receptors and production and inhibits endothelial nitric oxide synthase (eNOS) [1] [4] [5] 

oxLDL is bad stuff.  Macrophages protect endothelial cells from the toxic effects of oxLDL, and HDL particles transport oxidised lipids back to the liver.  Macrophages have a receptor for modified LDL called scavenger receptor A (SRA).  Unlike the LDL receptor, SRA doesn’t become downregulated as the cholesterol content of the cell increases [5].  What this means is that macrophages can continue to accumulate cholesterol from oxLDL but not regular LDL (or minimally oxidised LDL).

From here, macrophages that have engulfed oxLDLs become foam cells and form atherosclerotic plaque. 

* I’ll be mentioning hypochlorous acid and peroxynitrite in later posts 

** The 1e, 2e distinction may explain how pharmaceutical doses of vitamin E have pretty much failed in RCTs [1] 

Further Reading:
(1) High Cholesterol And Heart Disease — Myth or Truth?
(2) The Diet-Heart Hypothesis: Oxidized LDL, Part I
(3) The straight dope on cholesterol - Part IV
(4) Role of Oxidative Modifications in Atherosclerosis (note: it's a great paper, but only if you have time, as it's ~50,000 words long)

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