The research into the pathogenesis of atherosclerosis has been hindered by several misconceptions.
Firstly, the wrong choice of experimental animal is often made. The human ground substance with its dependency upon ascorbic acid, is the substrate in which cholesterol plaques occur, and thus a species such as the guinea pig, which shares the human need for extrinsic ascorbic acid, is one of the few animals with this feature. Rabbits, rats, mice, chickens etc, indeed any species independently capable of synthesizing ascorbic acid, overlook this vital point.
The argument has been made that very few humans suffer from scurvy and therefore ascorbic acid is not important. After all, many people drink a glass of orange juice daily and yet have a myocardial infarction. This thinking is wrong. Ascorbic acid is rapidly lost from human tissue under all forms of stress (1), and this is the cause of their depletion rather than malnutrition. About 150 days is needed for humans to develop scurvy on a purely nutritional basis (2). Stress-induced scurvy can occur abruptly. There is latent scurvy in the tissues of 20 % of autopsies (3). Moreover, though not widely appreciated, ascorbic acid varies locally throughout the body, even in the same type of tissue. In arterial tissue, at sites where there is local mechanical stress, there is depletion and often total loss of ascorbic acid, while adjacent non-stressed segments of the same artery remain normal (1).
While cholesterol is an inherent constituent of atheromatous plaques, cholesterol feeding of herbivorous animals does not operate within the boundaries of physiological circumstances. Such cholesterol feeding introduces a lipid storage disease with loading of the reticulo-endothelial system, and hypercholesterolemia. It is equally foreign to the human with atherosclerosis, except perhaps the rare case of human lipid storage disease. Treatment of experimental ‘atherosclerosis’ induced by cholesterol loading is hard to interpret because of the association of large artificially-induced accumulation of lipid in non- arterial tissues. This is not a problem in scurvy-induced experimental atherosclerosis without cholesterol feeding.
Blood cholesterol levels, though valuable in the diagnosis of lipid storage disease, are inappropriate as criteria of success or failure in the therapy of atherosclerosis. Cholesterol in plaques in the intima of arteries is atherosclerosis; blood cholesterol is not.
Criteria of success or failure of therapy of atherosclerosis, to be meaningful, must be based upon visualized morphological changes in size of atherosclerotic plaques. The plaque is the hall-mark of atherosclerosis. Changes in plaque size do not have to be accompanied by clinical improvement or deterioration to show there has been a change for better or for worse. In a given case, serial arteriography may show decrease in size of a plaque, while an adjacent plaque, under the same treatment, is unchanged. This is a reflection of the state of the plaque, whether scar, hyalinization, or mainly cholesterol. Ultrasound is not the entire answer. Echogenic plaques are the advanced stage of scar and hyalinised plaque. The earlier and reversible cholesterol plaques are echolucent (4), and may be overlooked by ultrasound. Arteriography, combined with ultrasound, allows the distinction. Any morphological difference, under therapeutic influence, may be taken as change in the right or the wrong direction and is the sign that the underlying process is or is not being addressed.
Even seemingly minor improvement demonstrated by arteriography may be highly significant in increasing perfusion; this will depend upon the site of the plaque, whether threatening arterial obstruction, or not. Flow is directly proportional to R4 where ‘R’ is the radius of the vessel. For example, a femoral artery narrowed to 2 mms by atherosclerosis, would have a flow of 24 or 16 units. If therapy increased this radius by only 0.2 mms, the flow would be increased to 2.24 which is just over 23 units, an increase of over 43 %.
Serial femoral arteriograms of 16 patients with atherosclerosis were followed for various periods of time (5). Of the six controls not receiving ascorbic acid supplement, none had spontaneous improvement; three showed enlargement of plaques, the other three remained unchanged. The time intervals varied from 70 to 192 days. Of the ten treated with ascorbic acid 500 mgs. t.i.d., six had a decrease in some, but not all, of their plaques*. Of the other four, one remained unchanged; the other three developed some plaque enlargement despite therapy. The duration of treatment ranged from 62 to 172 days.
The demonstration that ascorbic acid reverses all guinea pig (6) and some human atherosclerosis (5), indicates ascorbic acid is effective treatment. To improve all plaques in a given patient, a trial would have to be started prior to the onset of scar or hyalinization. Such patients would have purely cholesterol-ladened lesions. This is the situation in the guinea pig model, where reversal is total. Meanwhile for the advanced human case, prophylactic ascorbic acid is well worth while. Six out of ten treated patients had some shrinkage of some of their plaques, indicating the underlying process was at least arrested, though there may not always be clinical evidence to support this. Clinical improvement will be limited to those whose symptoms are from cholesterol plaques, not from critically situated atherosclerosis comprised of scar or hyaline plaques.
These considerations must be taken into account in the assessment of the value of ascorbic acid therapy, not forgetting that cholesterol plaques are responsive both in man and the experimental animal. In xanthoma tuberosum, where there is a cholesterol deposit in skin and arteries, the disappearance of the xanthomata in the skin is obvious to the naked eye ** and strongly suggests the same is happening in the arteries.
The dose of ascorbic acid required is established by finding how much is needed to restore the ascorbic acid content of human arterial tissue to normal levels at autopsy (1), or by the dose that arteriography has shown yields improvement in plaque size (5). Ascorbic acid is cheap and safe, and a delayed release form of 1000 mgs b.i.d. meets the requirement. This dose is also effective in xanthomatosis.
Of the mechanical factors that influence atherosclerosis, hypertension is the commonest and most amenable to treatment. The desirable blood pressure should provide adequate perfusion of vital organs without causing orthostatic dizziness. Perfusion of vital organs is fundamental and must be provided even at the expense of a degree of hypertension.
The elastic tissue of arteries requires attention. The vital role of elastic tissue is well demonstrated in the case of the internal mammary artery *** which is well endowed with elastic tissue and embryologically is the ventral aorta. This artery almost never develops atherosclerosis. Threatened or damaged elastic tissue may be amenable to treatment. In the case of homocysteinuria (7), with its strong influence to destroy elastic tissue, the acquired form may present with low vitamine B12 levels going on to megaloblastic anemia; at an early stage the underlying homocysteineuria is detectable. Treatment should be with folic acid, at least 1 mg daily, Vit B12, and Vit B6 and the dose adjusted until the level of homocystinuria is below 15 micromoles per litre.
Syphilitic aortitis damages arterial elastic tissue and is complicated by atherosclerosis (9). This needs attention.
*See paper entitled ‘Ground Substance’, Fig 5 (a) and (b). Here are serial arteriograms showing decrease in plaque size related to ascorbic acid therapy.
** In Fig 2 of ‘Ground Substance’ the hands of a patient with xanthoma tuberosum.
*** See Fig 4 in the paper ‘Questions Raised by Coarctation of the Aorta.’
BIBLIOGRAPHY
1. Willis, G.C., Fishman, S., C.M.A.J., 72: 500, 1955.
2. Peters, R.A., et al. Lancet, 1: 853, 1948
3. Yavorsky, M., Almaden, P., and King, C. G. J. Biol Chem. 106: 525, 1934
4. Gray-Weale, A.C., et al, J. Cardiovasc Surg (Torino) 29: 676, 1988.
5. Willis, G.C., Light, A.W., Gow, W.S., C.M.A.J., 71: 562, 1954.
6. Willis, G.C. C.M.A.J., 77: 106, 1957.
7. Verhoef, P., et al, Arteriosclerosis, Thrombosis, and Vasc Biol. 17: 989, 1997.
8. Duff, G.L., Arch of Path. 20: 371, 1935.
9. Willis, G.C. C.M.A.J., 70(1): 1-9, 1954.