Matthias Rath M.D. and Linus Pauling Ph.D

Part 2 of 2 (previous)

Other Lipoprotein Disorders Associated with CVD

In a large population study Goldstein et al. discussed three frequent lipid disorders, familial hypercholesterolemia, familial hypertriglyceridemia, and familial combined hyperlipidemia. Ascorbate deficiency unmasks these underlying genetic defects and leads to an increased plasma concentration of lipids (e.g. cholesterol, triglycerides) and lipoproteins (e.g. LDL, VLDL) as well as to their deposition in the impaired vascular wall.

As with LP(a), this deposition is a defense measure counteracting the increased permeability. It should, however, be noted that the deposition of lipoproteins other than LP(a) is a less specific defense mechanism and frequently follows LP(a) deposition. Again, these mechanisms function as a defense only for a limited time. With sustained ascorbate deficiency the continued deposition of lipids and lipoproteins leads to atherosclerotic plaque development and CVD. Some mechanisms will now be described in more detail.

Hypercholesterolemia, LDL-receptor Defect

A multitude of genetic defects lead to an increased synthesis and/or a decreased catabolism of cholesterol or LDL. A well characterized although rare defect is the LDL receptor defect. Ascorbate deficiency unmasks these inherited metabolic defects and leads to an increased plasma concentration of cholesterol-rich lipoproteins, e.g. LDL, and their deposition in the vascular wall. Hypercholesterolemia increases the risk for premature CVD primarily when combined with elevated plasma levels of LP(a) or triglycerides.

The mechanisms by which ascorbate supplementation prevents the exacerbation of hypercholesterolemia and related CVD include an increased catabolism of cholesterol. In particular, ascorbate is known to stimulate 7-a-hydroxylase, a key enzyme in the conversion of cholesterol to bile acids and to increase the expression of LDL receptors on the cell surface. Moreover, ascorbate is known to inhibit endogenous cholesterol synthesis as well as oxidative modification of LDL.

Hypertriglyceridemia, Type III Hyperlipidemia

A variety of genetic disorders lead to the accumulation of triglycerides in the form of chylomicron remnants, VLDL, and intermediate density lipoproteins (IDL) in plasma.

Ascorbate deficiency unmasks these underlying genetic defects and the continued deposition of triglyceride-rich lipoproteins in the vascular wall leads to CVD development. These triglyceride-rich lipoproteins are particularly subject to oxidative modification, cellular lipoprotein uptake, and foam cell formation. In hypertriglyceridemia nonspecific foam-cell formation has been observed in a variety of organs."

Ascorbate-deficient foam cell formation, although a less specific repair mechanism than the extracellular deposition of LP(a), may have also conferred stability .
Ascorbate supplementation prevents the exacerbation of CVD associated with hypertriglyceridemia, Type III hyperlipidemia, and related disorders by stimulating lipoprotein lipases and thereby enabling a normal catabolism of triglyceride-rich lipoproteins.

Ascorbate prevents the oxidative modification of these lipoproteins, their uptake by scavenger cells and foam cell formation.

Moreover, we propose here that, analogous to the LDL receptor, ascorbate also increases the expression of the receptors involved in the metabolic clearance of triglyceride-rich lipoproteins, such as the chylomicron remnant receptor.

The degree of build-up of atherosclerotic plaques in patients with lipoprotein disorders is determined by the rate of deposition of lipoproteins and by the rate of the removal of deposited lipids from the vascular wall. It is therefore not surprising that ascorbate is also closely connected with this reverse pathway.

Hypoalphalipoproteinemia

Hypoalphalipoproteinemia is a frequent lipoprotein disorder characterized by a decreased synthesis of HDL particles. HDL is part of the 'reverse-cholesterol-transport' pathway and is critical for the transport of cholesterol and also other lipids from the body periphery to the liver.

In ascorbate deficiency this genetic defect is unmasked, resulting in decreased HDL levels and a decreased reverse transport of lipids from the vascular wall to the liver. This mechanism is highly effective and the genetic disorder hypoalphalipoproteinemia was greatly favored during evolution.

With ascorbate supplementation HDL production increases, leading to an increased uptake of lipids deposited in the vascular wall and to a decrease of the atherosclerotic lesion. A look back in evolution underlines the importance of this mechanism. During the winter seasons, with low ascorbate intake, our ancestors became dependent on protecting their vascular wall by the deposition of lipoproteins and other constituents.

During spring and summer seasons the ascorbate content in the diet increased significantly and mechanisms were favored that decreased the vascular deposits under the protection of increased ascorbate concentration in the vascular tissue.

It is not unreasonable for us to propose that ascorbate can reduce fatty deposits in the vascular wall within a relatively short time.

In an earlier clinical study it was shown that 500 mg of dietary ascorbate per day can lead to a reduction of atherosclerotic deposits within 2 to 6 months."

This concept, of course, also explains why heart attack and stroke occur today with a much higher frequency in winter than during spring and summer, the seasons with increased ascorbate intake.

Other Inherited Metabolic Disorders Associated with CVD

Beside lipoprotein disorders many other inherited metabolic diseases are associated with CVD. Generally these disorders lead to an increased concentration of plasma constituents that directly or indirectly damage the integrity of the vascular wall. Consequently these diseases lead to peripheral angiopathies as observed in diabetes, homocystinuria, sickle-cell anemia (the first molecular disease described," and many other genetic disorders.

Similar to lipoproteins the deposition of various plasma constituents as well as proliferative thickening provided a certain stability for the ascorbatedeficient vascular wall. We illustrate this principle for diabetic and homocystinuric angiopathy.

Diabetic Angiopathy

The pathomechanism in this case involves the structural similarity between glucose and ascorbate and the competition of these two molecules for specific cell surface receptors."

Elevated glucose levels prevent many cellular systems in the human body, including endothelial cells, from optimum ascorbate uptake- Ascorbate deficiency unmasks the underlying genetic disease, aggravates the imbalance between glucose and ascorbate, decreases vascular ascorbate concentration, and thereby triggers diabetic angiopathy.

Ascorbate supplementation prevents diabetic angiopathy by optimizing the ascorbate concentration in the vascular wall and also by lowering insulin requirement-"

Homocystinuric Angiopathy

Homocystinuria is characterized by the accumulation of homocyst(e)ine and a variety of its metabolic derivatives in the plasma, the tissues and the urine as the result of decreased homocysteine catabolism."

Elevated plasma concentrations of homocyst(e)ine and its derivatives damage the endothelial cells throughout the arterial and venous system. Thus homocystinuria is characterized by peripheral vascular disease and thromboembolism. These clinical manifestations have been estimated to occur in 30 per cent of the patients before the age of 20 and in 60 per cent of the patients before the age of 40.

Ascorbate supplementation prevents homocystinuric angiopathy and other clinical complications of this disease by increasing the rate of homocysteine catabolism.

Thus, ascorbate deficiency unmasks a variety of individual genetic predispositions that lead to CVD in different ways. These genetic disorders were conserved during evolution largely because of their association with mechanisms that lead to the thickening of the vascular wall. Moreover, since ascorbate deficiency is the underlying cause of these diseases, ascorbate supplementation is the universal therapy.

The Determining Principles of This Theory

The determining principles of this comprehensive theory are schematically summarized.

1. CVD is the direct consequence of the inability for endogenous ascorbate production in man in combination with low dietary ascorbate intake.

2. Ascorbate deficiency leads to increased permeability of the vascular wall by the loss of the endothelial barrier function and the loosening of the vascular connective tissue.

3. After the loss of endogenous ascorbate production scurvy and fatal blood loss through the scorbutic vascular wall rendered our ancestors in danger of extinction. Under this evolutionary pressure over millions of years genetic and metabolic countermeasures were favored that counteract the increased permeability of the vascular wall.

4. The genetic level is characterized by the fact that inherited disorders associated with CVD became the most frequent among all genetic predispositions. Among those predispositions lipid and lipoprotein disorders occur particularly often.

5. The metabolic level is characterized by the direct relation between ascorbate and virtually all risk factors of clinical cardiology today. Ascorbate deficiency leads to vasoconstriction and hemostasis and affects the vascular wall metabolism in favor of atherosclerogenesis.

6. The genetic level can be further characterized. The more effective and specific a certain genetic feature counteracted the increasing vascular permeability in scurvy, the more advantageous it became during evolution and, generally, the more frequently this genetic feature occurs today

7. The deposition of LP(a) is the most effective, most specific, and therefore most frequent of these mechanisms. LP(a) is preferentially deposited at predisposition sites. In chronic ascorbate deficiency the accumulation of LP(a) leads to the localized development of atherosclerotic plaques and to myocardial infarction and stroke.

8. Another frequent inherited lipoprotein disorder is hypoalphalipoproteinemia. The frequency of this disorder again reflects its usefulness during evolution. The metabolic upregulation of HDL synthesis by ascorbate became an important mechanism to reverse and decrease existing lipid deposits in the vascular wall.

9. The vascular defense mechanisms associated with most genetic disorders are nonspecific. These mechanisms can aggravate the development of atherosclerotic plaques at predisposition sites.

Other nonspecific mechanisms lead to peripheral forms of atherosclerosis by causing a thickening of the vascular wall throughout the arterial system. This peripheral form of vascular disease is characteristic for angiopathics associated with Type III hyperlipidemia, diabetes, and many other inherited metabolic diseases.

10. Of particular advantage during evolution and therefore particularly frequent today are those genetic features that protect the ascorbate-deficient vascular wall until the end of the reproduction age. By favoring these disorders nature decided for the lesser of two evils: the death from CVD after the reproduction age rather than death from scurvy at a much earlier age. This also explains the rapid increase of the CVD mortality today from the 4th decade onwards.

11. After the loss of endogenous ascorbate production the genetic mutation rate in our ancestors increased significantly- This was an additional precondition favoring the advantage not only of APO(a) and LP(a) but also of many other genetic countermeasures associated with CVD.

12. Genetic predispositions are characterized by the rate of ascorbate depiction in a multitude of metabolic reactions specific for the genetic disorder." The overall rate of ascorbate depletion in an individual is largely determined by the polygenic pattern of disorders. The earlier the ascorbate reserves in the body are depleted without being resupplemented, the earlier CVD develops.

13. The genetic predispositions with the highest probability for early clinical manifestation require the highest amount of ascorbate supplementation in the diet to prevent CVD development. The amount of ascorbate for patients at high risk should be comparable to the amount of ascorbate our ancestors synthesized in their body before they lost this ability: between 10,000 and 20,000 milligrams per day.

14. Optimum ascorbate supplementation prevents the development of CVD independently of the individual predisposition or pathomechanism. Ascorbate reduces existing atherosclerotic deposits and thereby decreases the risk for myocardial infarction and stroke. Moreover, ascorbate can prevent blindness and organ failure in diabetic patients, thromboembolism in homocystinuric patients, and many other manifestations of CVD.

Conclusion

In this paper we present a unified theory of human CVD. This disease is the direct consequence of the inability of man to synthesize ascorbate in combination with insufficient intake of ascorbate in the modem diet. Since ascorbate deficiency is the common cause of human CVD, ascorbate supplementation is the universal treatment for this disease.

The available epidemiological and clinical evidence is reasonably convincing.

Further clinical confirmation of this theory should lead to the abolition of CVD as a cause of human mortality for the present generation and future generations of mankind.

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