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Atherosclerosis and greasy sewer lines

Cory Mermer
Thought the analogy to the clogged arteries and the greasy foods was interesting.  Perhaps it is this mindset that has caused much of the misconceptions to date.
(See article in Savannah Morning Star on  http://savannahnow.com/stories/102903/LOC_greasypipes.shtml )

Here is a story about one small town having to spend a quarter of a million dollars a year clearing household grease from sewer lines. I bet it is true everywhere. And with the holiday cooking season about to begin, cities know the grease problem is heaviest this time of year.
In Savannah, Ga., city officials say last year the city unclogged 800 sewer lines. Seventy
percent of these blockages were cooking grease-related. Al's Morning Meeting reader Jennifer Smith Richards, a reporter for the Savannah Morning News writes, "A reporter here ... just wrote about the high cost of removing fat and grease from sewer pipes in the south. She found it costs $500 a pop to clear a blockage, and the City of Savannah has to
flush the fat some 500 times a year. This happens all because people dump their grease down the sink rather than trashing it."

Lots of sewer departments now have little cameras they can send down the pipes - so now you can really visualize this story. And just in time for the start of the November TV ratings book!
The Savannah Morning News story said:

Photos taken inside clogged city sewer pipes look nearly identical to medical photos of the blood vessels of patients who have spent a lifetime gorging on fried chicken, sausage, and bacon. "It's like your arteries," said John Parker, environmental compliance inspector with the city's Water and Sewer Department. "Grease builds up in there. It's gory."
And just like in the body, clogs can form little by little, the accumulation of lots of neighbors each sending a little grease down the drain.

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Kilmer McCully
This story is illustrative of a common misconception of the pathogenesis of arteriosclerosis.  In fact, the pathological changes in arteriosclerotic arteries consist mainly of connective tissue changes.  These changes start as deposition of glycosaminoglycans, destruction of elastic laminae, hyperplasia of smooth muscle cells, and production of collagen.  These changes produce a thickened, tough, inelastic artery wall containing calcification.  As these connective tissue changes progress, the lumen becomes narrowed.  Only later in the process do the deposits of lipids convert the fibrous plaques to atheromas containing cholesterol, cholesterol esters, triglycerides, organized thrombi, and neovascularization. 

A better analogy is that arteriosclerosis is more nearly like the deterioration of sewer pipes from accumulation of rusty deposits that narrow the lumen.  This process produces a thickened  wall of altered composition that narrows the passage of water.  If grease is added to the effluent of sewer pipes, some grease can become trapped in the altered wall of the pipe, accounting for the deposits given in the example.

As Cory points out, this analogy indicates the pervasiveness of the misconceptions about the role of fats in the pathogenesis of arteriosclerosis.

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Malcolm Kendrick
I agree with much of what you say. However, I would suggest that the initiating event in plaque formation (I am not interested in thickened artery walls much) is endothelial damage, followed by thrombus formation. The changes you mention are the after effects of 'healing' following incorporation of the thrombus in the arterial wall.

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Karl Arfors
I am tired of the MANTRA discussion of FAT deposit that goes on all the time even if "WE" don't believe in fat and cholesterol. Along the line as Kilmer wrote:"some grease can become trapped in the altered wall of the pipe, accounting for the deposits given in the example."

I am a specialist in microcirculation, inflammation, white cell rolling and sticking, thrombosis and hemostasis. It wasn't long time ago when endothelial cells were looked upon as wallpapers of the vasculature and today they are communicating and helping to orchestrate the behaviour of all our circulating cells.

I support all the statements made by Kilmer “illustrative of the common misconception of the pathogenesis of the atherosclerosis” and I can also support your statement of early endothelial damage - but not always followed by thrombus formation – sometimes of course there can be overstimulation and a thrombus formed.

The general response to an endothelial damage is activation of platelets but also of all the inflammatory cells (that are called upon to come and repair – and for the repair mainly the monocytes).

The “rusty deposits” that Kilmer mentions are also triggering monocytes,  like oxidized cholesterol and LDL and products from Homocysteine that Kilmer can describe better!

When the leukocytes arrive and the monocytes, the inflammation starts and when monocytes are activated they stimulate smooth muscle proliferation by all the growth factors (among them basic Fibroblast Growth Factor - bFGF) which are the basic events in atherosclerosis and the thickening of the wall.

Did you know, what Kilmer told me that if you remove the cholesterol oxides from the cholesterol (you by from Sigma) you can inject any amount into animals without any deposits forming in the aorta. Right Kilmer?   - So the oxidized stuff is the culprit –  stimulating and activating the inflammatory cells. You may also know that activated “white cells” generate a lot of free radicals that make further damage and release myeloperoxidase and carry on the inflammation. 

When activated inflammatory cells are present and generating and releasing free radicals they also release MPO (myeloperoxidase). This can be seen as a sign of low grade inflammation 

In the October 23 issue of New England J of Med (2003;349:1595-1604) there was an interesting article:  

Prognostic Value of Myeloperoxidase in Patients with Chest Pain  
Background Inflammation is linked to adverse outcomes in acute coronary syndromes. Myeloperoxidase, an abundant leukocyte enzyme, is elevated in culprit lesions that have fissured or ruptured in patients with sudden death from cardiac causes. Numerous lines of evidence suggest mechanistic links between myeloperoxidase and both inflammation and cardiovascular disease.  
Conclusions A single initial measurement of plasma myeloperoxidase independently predicts the early risk of myocardial infarction, as well as the risk of major adverse cardiac events in the ensuing 30-day and 6-month periods.

 I am pretty sure Kilmer will support this from his experience in pathophysiology.

Some other time I could tell you more about why smoking is so damaging and creating atherosclerosis and from experiments  why scavenging the radicals with Vitamin C would be so helpful when free radicals are inhaled with the smoke.

Have you seen the interesting study  in New England J Med Nov. 29, 2001? Decreased Rate of Coronary Restenosis after Lowering of Plasma Homocysteine Levels  (this paper is attached). It is not easy to make a study where you in a time period of one year can document that taking three vitamins B6, B12 and Folic acid will decrease restenosis most likely because of diminished Homocysteine levels. 

And please don’t forget that most antioxidants are there to prevent different fats and cholesterol and LDL to become oxidized. When they are, they will trigger the inflammatory cells to try and remove it and the cascades are running. Most of your E-vitamin are associated with your LDL molecules. 

An additional point. The statins, which block the Q10 synthesis, (Q10 is a necessary anti-oxidant in heart mitochondria) are in fact working also as antiinflammatory (decreased binding of white cells to the endothelial lining) this is described in the litterature. Statins should not be used because of all side effects of course  - but this is complicated biology indeed because the different white cells are doing a lot of other things  including also hunting down your tumor cells.

There are 209 items listed when you search for statins and inflammation  and I take the freedom to take one sentence out of context: 

These findings support the idea of non-lipid effects of statins in atherosclerosis. Further, recent observations using in vivo and in vitro models of atherosclerosis have shed light on their potential role for manipulation of various cellular functions via inhibition of the mevalonate pathway. Among them, recently identified inhibitory effects of statins on monocyte-endothelial interaction suggest their effect on inflammation. Herein, we discuss recent progress in this area of study, with special focus on the biological function of statins.

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Malcolm Kendrick
Thanks for that. We agree on much, but where we diverge, if not greatly, is on the basic
process plaque formation.

I believe that there are two basic, interrelated process happening:

Endothelial dysfunction/damage (Which can be caused by: raised blood sugar, increased free radicals, homocysteine, smoking, turbulant blood flow, raised cortisol/adrenaline, raised insulin levels etc.)

Increased blood coagulability (which can be caused by: raised blood sugar, raised cortisol/adrenline, raised fibrinogern/lipoprotein(a) - secondary to insulin resistance, smoking etc.)

If both process are happening at the same time, endothelial damage occurs, then a thrombus forms over the area of endothelial damage. The endothelium then re-grows over the top of the thrombus 'drawing' it into the arterial wall. After this, other repair processes take over to 'heal' the damaged area and remove the remnants of the thrombus. These healing processes are what we are looking at with inflammation/migration of monocytes, growth of smooth muscle cells.

If the area of damage and thrombus formation is imperfectly healed this will act as an focus for repeated endothelial damage/thrombus formation, and a plaque will grow at the point as the result of repeated thrombotic episodes.

The reason why cholesterol is found in plaques is primarily because LDL and VLDL are both incorporated into blood clots as they form (they are integral to the clotting process). In addition Lp(a) plays a key role in 'plugging' areas of damage an artery. And Lp(a) is LDL with a different apolipoprotein attached to it, so it will bring a lot of cholesterol into the area.

I would agree that endothelial damage is the primary event in plaque formation, and without this nothing would happen, but I think that raised blood coagulability and the resultant thrombus formation is key to the growth of the plaque.

I believe that most true risk factors for CHD cause both processes e.g. smoking, homocysteine, raised blood sugar levels, raised levels of stress hormones.

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Kilmer McCully
I totally agree with Malcolm that intimal injury is the initial phase in development of plaques.  I also agree that increased blood coagulability is an important factor in initiation of plaques.  I might point out that homocysteine is a potent procoagulant that affects many phases of the clotting cascades.  Some examples are effects of homocysteine on tissue factor, thromboxane, protein S and protein C, thrombomodulin, fibrin binding of lp(a), tissue plasminogen activator by affecting Annexin II, and activation of platelets.  Malcolm is correct that cholesterol deposits and cholesterol crystals are seen in organizing thrombi.  Some prominent examples are organizing hematomas in various organs, hemorrhages into multinodular goiters, cellular degeneration in renal cell carcinomas, and organizing mural thrombi in aorta and arteries.  The cholesterol crystals and lipid deposits in organizing hematomas are derived in part from the cellular membranes of platelets and other cells that are involved in thrombosis and cellular degeneration. 

The cholesterol deposits in atheromas are also derived by the process of plasma filtration through the wall of the artery, as first pointed out by Rudolf Virchow in 1852.  Filtration of plasma through the wall of arteries is facilitated by increased permeability by intimal injury and by turbulence
and increased blood pressure within arteries.  More recent studies in the 1950s and 1960s have shown that LDL and VLDL bind to the glycosaminoglycans of plasma and the sulfated glycosaminoglycan deposits in early atheromas. Finally, homocysteine facilitates deposition of lipids and cholesterol in atheromas by reacting with LDL to form aggregates that are phagocytosed by vascular macrophages, as my colleagues M Narszewicz, E Mirkiewicz, A
Olszewski and I showed in Nutr Metab Cardiovas Dis 1994;4:70-77 "Thiolation of low-density lipoprotein by homocysteine thiolactone causes increased aggregation and altered interaction with cultured macrophages."

Karl is correct that highly purified cholesterol is totally without effect on arterial intima when injected into monkeys, as shown by Bruce Taylor's group at Albany in the 1970s.  Taylor used Fieser's method for purifying cholesterol by reaction with bromine water to form crystalline dibromocholesterol.  After recrystallization, the bromine is released by acetic acid, forming highly pure cholesterol that is free of cholesterol oxides.  Ordinary crystalline cholesterol rapidly forms cholesterol oxides when exposed to atmospheric oxygen.  This means that the many feeding
experiments with "pure" cholesterol in animals must be reinterpreted, since cholesterol preparations inevitably contain cholesterol oxides, unles they are carefully protected from oxygen during feeding or injection experiments. Taylor's group showed that a variety of cholesterol oxides, such as 7-hydroxy-, 25-hydroxy-cholesterols, cholestanone, and cholestane triol are highly atherogenic in monkeys, forming early intimal lesions within 24 hours of intravenous administration.

The recent finding that myeloperoxidase is a predictor of coronary heart disease fits well with the concept of oxidant stress induced by hyperhomocysteinemia.  Like C-reactive protein and other inflammatory mediators and cytokines, as pointed out by Karl, myeloperoxidase is activated by pro-inflammatory and pro-oxidant substances, most importantly homocysteine.  The histopathological changes of inflammation, including tissue necrosis, granulation tissue, infiltration by inflammatory cells, thromobosis, angiogenesis, and proliferation of stromal and epithelial tissues are well demonstrated by administration of the free base of homocysteine thiolactone to mice, as reported in McCully KS, Vezeridis MP, "Histopathological effects of homocysteine thiolactone on epithelial and stromal tissues," Exp Molec Pathol 1989;51:159-170.  In addition the vascular lesions observed in homocystinuric patients are characterized by intimal injury and thrombosis, as reported in McCully KS, "Vascular pathology of homocysteinemia:  implications for the pathogenesis of arteriosclerosis" Am J Pathol 1969;56:111-128.

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Uffe Ravnskov
None of the participants in this discussion has mentioned anything about the role of microorganisms. There is a huge number of observations suggesting that infectious processes take part in the pathologic vascular processes. Research within this area has exploded during the last decade. According to Medline there are at least 200 reviews of this issue. What strikes me most are the following: 

According to Osler atherosclerotic changes of the arteries are seen in syphilis and typhoid fever, even in children, and focal arterial degeneration are found in great frequency in children who have died from scarlet fever, measles, diphtheria, smallpox and influenza (J Pathol. 12, 426, 1907) 

Bacteria and virus, or their DNA have been found by various techniques in the atherosclerotic lesions in a large proportion of patients, in particular Chlamydia pneumonia (the TWAR bacteria) and cytomegalovirus (too many papers to quote). 

Bacterial toxins and cytokines are seen more often in the blood from patients with recent heart disease and stroke, in particular during and after an acute cardiovascular event, and some of them are strong predictors of cardiovascular disease (again, too many papers to quote)

Acute infections, most often in the upper respiratory tract have been noted in a large proportion of patients 2-4 weeks before they are struck by a myocardial infarction or a stroke (Neurology 50, 196-203, 1998; J Intern Med 225, 293-296, 1989; Stroke 27, 1999-2004, 1996; BMJ 296, 1156-60, 1988). The frequency of infections in these patients is significantly higher than in appropriate control individuals.

There is a strong association between infectious burden, expressed as number of seropositive reactions against various microorganisms, and degree of atherosclerosis and also risk of CV mortality (Circulation 1054, 15-21, 2002). 

In five trials treatment of patients with coronary heart disease with antibiotics that are effective against Chlamydia pneumonia, was successful; a total of 104 cardiovascular events were noted among the 412 non-treated patien ts, but only 61 events among the 410 patients in the treatment groups. (Lancet 350, 404-407, 1997. Circulation 96, 404-407, 1997. Circulation 102, 1755-1760, 2000. Circulation 106, 1219-1223, 2002. Circulation 105, 2646-2652, 2002).  In one further trial a significant decreased progression of atherosclerosis in the carotid arteries was seen (Circulation 106, 2428-2433, 2002).  

However, in four other trials, one of which included more than 7000 patients, no significant effect was seen (Circulation 99, 1540-1547, 1999.  J. Med. Ass. Thailand 84 (Suppl 3), S669-S675, 2001.  Lancet 361, 809-813, 2003. JAMA 290, 1459-1466, 2003).

The reason for these inconsistent results may be that the treatment was too short (in one of the trials treatment was only given for five days). Also, Chlamydia pneumoniae, the TWAR bacteria, can only propagate inside human cells and when located in white blood cells they are resistant to antibiotics. Treatment may also have been ineffective because the mentioned antibiotics have no effect on virus. In this connection it is interesting to mention that vaccination against influenza  a viral disease prevented heart mortality; after six months 8 % of the control patients had died, but only 2 % of the vaccinated patients (Circulation 105, 2143-2147, 2002). It is worth mentioning that this effect was much better than that achieved by any statin trial, and in a much shorter time. 

It is difficult, at least for me, to dispel these findings with the idea that the infections are secondary, that the microorganisms are innocent bystanders. On the other side, to class atherosclerosis as an infectious disease does not exclude important roles of other factors. Any compound toxic to the arterial intima may predispose to attacks from microorganisms.

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Morley Sutter
I have long been impressed by the evidence of involvement of microorganisms in atherosclerosis and have published my views some years ago. One of our problems is our general naïve thinking about microbes:  although the term is not used routinely, almost all microbes are “opportunistic” in that they cause disease only when conditions are propitious, otherwise, we would have colds constantly.  They also theoretically could initiate a series of events leading to disease but not be present at the time the disease is manifest. 

This creates considerable difficulty in demonstrating that a particular organism is the necessary, but insufficient cause of a disease.  It seems to me that the presence of antibodies is a crude measure of whether a microbe is involved in a disease, yet so often this is what is measured.  The best evidence is to attempt to eradicate the microbe or interfere with its pathogenic action, but any agent used for this purpose would have to be effective and selective for the purpose it was intended.  Nevertheless, on current evidence, microbes are at least as attractive putative “causers” of atherosclerosis as any nutritional or psychological excess or lack.

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Eddie Vos
May I add 2 things to the discussion:

 1. re Kilmer's description of the arterio/athero sclerotic process. His first words are "connective tissue changes" and NOT: white cells,endothelium, inflammation, cell proliferation et al.  The causa causans may well lie in the "ground substance" that cell containing fibrous sponge like structure that determines what reaches and leaves the cells they surround.  The superb book by Morrison and Schjeide "Coronary Heart Disease and the Mucopolysaccharides (Glycosaminoglycans)" [ISBN 0398029032; 1974] is a primer as to the role of connective tissue and its sulfation [think homocysteine]. Once the ground substance deteriorates or what it does, so do the cells, be they endothelium or muscle or white cells.  Ground substance i.e. connective tissue is closely related / made of: cartilage /chondroitinS / glucosamine / sulfate / keratin / hyaluronic acid /heparinS et al.  

2. re Morley's viral or bacterial microorganisms in atherosclerosis, I believe his key word is "opportunistic".  I believe that the opportunity for inflammation and damage manifests itself to a large degree due to suboptimal micronutrient intake, i.e. low E, C, the B's, D, omega-3 and the carotenoids that weaken the system and allow opportunity for microorganisms getting out of hand.  For example, the role of low selenium status in cardiomyopathy and in viruses getting the opportunity of doing damage is well established.  

Ergo: optimizing micronutrients will lower microorganism "opportunity", strengthen the host, decrease Kilmer's homocysteine thiolactone and maintain a happy ground substance, the very foundation of cell health and function.  Micronutrients are the great confounder and we can beat ourselves silly over inflammation, cholesterol, carbs and stress if we don't first account for their role and status, with homocysteine our best marker to date.