"An important scientific innovation rarely, makes its way by gradually winning over and converting its opponents. What does happen is that its opponents gradually die out and that the growing generation is familiar with the idea from the beginning."
-Max Planck

This paper is dedicated to the young physicians and the medical students of this world

Abstract

Until now therapeutic concepts for human cardiovascular disease (CVD) were targeting individual pathomechanisms or specific risk factor,. On the basis of genetic, metabolic, evolutionary, and clinical evidence we present here a unified pathogenetic and therapeutic approach.

Ascorbate deficiency is the precondition and common denominator of human CVD. Ascorbate deficiency is the result of the inability of man to synthesize ascorbate endogenously in combination with insufficient dietary intake. The invariable morphological consequences of chronic ascorbate deficiency in the vascular wall are the loosening of the connective tissue and the loss of the endothelial barrier function.

Thus human CVD is a form of pre-scurvy. The multitude of pathomechanisms that lead to the clinical manifestation of CVD are primarily defense mechanisms aiming at the stabilization of the vascular wall. After the loss of endogenous ascorbate production during the evolution of man these defense mechanisms became life-saving.

They counteracted the fatal consequences of scurvy and particularly of blood loss through the scorbutic vascular wall. These countermeasures constitute a genetic and a metabolic level. The genetic level is characterized by the evolutionary advantage of inherited features that lead to a thickening of the vascular wall, including a multitude of inherited diseases.

The metabolic level is characterized by the close connection of ascorbate with metabolic regulatory systems that determine the risk profile for CVD in clinical cardiology today. The most frequent mechanism is the deposition of lipoproteins, particularly lipoprotein (a) [Lp(a)], in the vascular wall.

With sustained ascorbate deficiency, the result of insufficient ascorbate uptake, these defense mechanisms overshoot and lead to the development of CVD. Premature CVD is essentially unknown in all animal species that produce high amounts of ascorbate endogenously. In humans, unable to produce endogenous ascorbate, CVD became one of the most frequent diseases.

The genetic mutation that rendered all human beings today dependent on dietary ascorbate is the universal underlying cause of CVD- Optimum dietary ascorbate intake will correct this common genetic defect and prevent its deleterious consequences.

Clinical confirmation of this theory should largely abolish CVD as a cause for mortality in this generation and future generations of mankind.

Introduction

We have recently presented ascorbate deficiency as the primary cause of human CVD. We proposed that the most frequent pathomechanism leading to the development of atherosclerotic plaques is the deposition of LP(a) and fibrinogen/fibrin in the ascorbate-deficient vascular wall.

In the course of this work we discovered that virtually every pathomechanism for human CVD known today can be induced by ascorbate deficiency. Beside the deposition of LP(a) this includes such seemingly unrelated processes as foam cell formation and decreased reverse-cholesterol transfer, and also peripheral angiopathies in diabetic or homocystinuric patients.

We did not accept this observation as a coincidence. Consequently we proposed that ascorbate deficiency is the precondition as well as a common denominator of human CVD. This farreaching conclusion deserves an explanation; it is presented in this paper.

We suggest that the direct connection of ascorbate deficiency with the development of CVD is the result of extraordinary pressure during the evolution of man.

After the loss of the endogenous ascorbate production in our ancestors, severe bloodloss through the scorbutic vascular wall became a life-threatening condition. The resulting evolutionary pressure favored genetic and metabolic mechanisms predisposing to CVD.

The Loss of Endogenous Ascorbate Production in the Ancestor of Man

With few exceptions all animals synthesize their own ascorbate by conversion from glucose. In this way they manufacture a daily amount of ascorbate that varies between about 1 gram and 20 grams, when compared to the human body weight.

About 40 million years ago the ancestor of man lost the ability for endogenous ascorbate production. This was the result of a mutation of the gene encoding for the enzyme L-gulono-g-lactone oxidase (GLO), a key enzyme in the conversion of glucose to ascorbate. As a result of this mutation all descendants became dependent on dietary ascorbate intake.

The precondition for the mutation of the GLO gene was a sufficient supply of dietary ascorbate. Our ancestors at that time lived in tropical regions. Their diet consisted primarily of fruits and other forms of plant nutrition that provided a daily dietary ascorbate supply in the range of several hundred milligrams to several grams per day. When our ancestors left this habitat to settle in other regions of the world the availability of dietary ascorbate dropped considerably and they became prone to scurvy.

Fatal Blood Loss Through the Scorbutic Vascular Wall - An Extraordinary Challenge to the Evolutionary Survival of Man

Scurvy is a fatal disease. It is characterized by structural and metabolic impairment of the human body, particularly by the destabilization of the connective tissue. Ascorbate is essential for an optimum production and hydroxylation of collagen and elastin, key constituents of the extracellular matrix. Ascorbate depletion thus leads to a destabilization of the connective tissue throughout the body.

One of the first clinical signs of scurvy is perivascular bleeding.

The explanation is obvious: Nowhere in the body does there exist a higher pressure difference than in the circulatory system, particularly across the vascular wall. The vascular system is the first site where the underlying destabilization of the connective tissue induced by ascorbate deficiency is unmasked, leading to the penetration of blood through the permeable vascular wall.

The most vulnerable sites are the proximal arteries, where the systolic blood pressure is particularly high. The increasing permeability of the vascular wall in scurvy leads to petechiae and ultimately hemorrhagic blood loss.

Scurvy and scorbutic blood loss decimated the ship crews in earlier centuries within months. It is thus conceivable that during the evolution of man periods of prolonged ascorbate deficiency led to a great death toll. The mortality from scurvy must have been particularly high during the thousands of years the ice ages lasted and in other extreme conditions, when the dietary ascorbate supply approximated zero.

We therefore propose that after the loss of endogenous ascorbate production in our ancestors, scurvy became one of the greatest threats to the evolutionary survival of man.

By hemorrhagic blood loss through the scorbutic vascular wall our ancestors in many regions may have virtually been brought close to extinction.

The morphologic changes in the vascular wall induced by ascorbate deficiency are well characterized: the loosening of the connective tissue and the loss of the endothelial barrier function. The extraordinary pressure by fatal blood loss through the scorbutic vascular wall favored genetic and metabolic countermeasures attenuating increased vascular permeability.

Ascorbate Deficiency and Genetic Countermeasures

The genetic countermeasures are characterized by an evolutionary advantage of genetic features and include inherited disorders that are associated with atherosclerosis and CVD. With sufficient ascorbate supply these disorders stay latent. In ascorbate deficiency, however, they become unmasked, leading to an increased deposition of plasma constituents in the vascular wall and other mechanisms that thicken the vascular wall.

This thickening of the vascular wall is a defense measure compensating for the impaired vascular wall that had become destabilized by ascorbate deficiency. With prolonged insufficient ascorbate intake in the diet these defense mechanisms overshoot and CVD develops.

The most frequent mechanism to counteract the increased permeability of the ascorbate-deficient vascular wall became the deposition of lipoproteins and lipids in the vessel wall. Another group of proteins that generally accumulate at sites of tissue transformation and repair are adhesive proteins such as fibronectin, fibrinogen, and particularly apo(a). It is therefore no surprise that LP(a), a combination of the adhesive protein APO(a) with a low density lipoprotein (LDL) particle, became the most frequent genetic feature counteracting ascorbate deficiency.'

Beside lipoproteins, certain metabolic disorders, such as diabetes and homocystinuria, are also associated with the development of CVD. Despite differences in the underlying pathomechanism, all these mechanisms share a common feature: they lead to a thickening of the vascular wall and thereby can counteract the increased permeability in ascorbate deficiency. In addition to these genetic disorders, the evolutionary pressure from scurvy also favored certain metabolic countermeasures.

Ascorbate Deficiency and Metabolic Countermeasures

The metabolic countermeasures are characterized by the regulatory role of ascorbate for metabolic systems determining the clinical risk profile for CVD. The common aim of these metabolic regulations is to decrease the vascular permeability in ascorbate deficiency. Low ascorbate concentrations therefore induce vasoconstriction and hemostasis and affect vascular wall metabolism in favor of atherosclerogenesis.

Towards this end ascorbate interacts with lipoproteins. coagulation factors, prostaglandins, nitric oxide, and second messenger systems such as cyclic monophosphates. It should be noted that ascorbate can affect these regulatory levels in a multiple way- In lipoprotein metabolism low density lipoproteins (LDL), LP(a), and very low density lipoproteins (VLDL) are inversely correlated with ascorbate concentrations, whereas ascorbate and HDL levels are positively correlated.

Similarly, in prostaglandin metabolism ascorbate increases prostacyclin and prostaglandin E levels and decreases the thromboxane level. In general, ascorbate deficiency induces vascular constriction and hemostatis, as well as cellular and extracellular defense measures in the vascular wall.

In the following sections we shall discuss the role of ascorbate for frequent and well established pathomechanisms of human CVD. In general, the inherited disorders described below are polygenic. Their separate description, however, will allow the characterization of the role of ascorbate on the different genetic and metabolic levels.

APO(a) and LP(a), the Most Effective and Most Frequent Countermeasure

After the loss of endogenous ascorbate production, APO(a) and LP(a) were greatly favored by evolution. The frequency of occurrence of elevated LP(a) plasma levels in species that had lost the ability to synthesize ascorbate is so great that we formulated the theory that APO(a) functions as a surrogate for ascorbate.'

There are several genetically determined isoforms of APO(a). They differ in the number of kringle repeats and in their molecular size. An inverse relation between the molecular size of APO(a) and the synthesis rate of LP(a) particles has been established. Individuals with the high molecular weight APO(a) isoform produce fewer LP(a) particles than those with the low APO(a) isoform.

In most population studies the genetic pattern of high APO(a) isoform/low LP(a) plasma level was found to be the most advantageous and therefore most frequent pattern. In ascorbate deficiency LP(a) is selectively retained in the vascular wall. APO(a) counteracts increased permeability by compensating for collagen, by its binding to fibrin, as a proteinthiol antioxidant, and as an inhibitor of plasmin-induced proteolysis. Moreover, as an adhesive protein APO(a) is effective in tissue-repair processes (8).

Chronic ascorbate deficiency leads to a sustained accumulation of LP(a) in the vascular wall. This leads to the development of atherosclerotic plaques and premature CVD, particularly in individuals with genetically determined high plasma LP(a) levels. Because of its association with APO(a), Lp(a) is the most specific repair particle among all lipoproteins. LP(a) is predominantly deposited at predisposition sites and it is therefore found to be significantly correlated with coronary, cervical, and cerebral atherosclerosis but not with peripheral vascular disease.

The mechanism by which ascorbate resupplementation prevents CVD in any condition is by maintaining the integrity and stability of the vascular wall.

In addition, ascorbate exerts in the individual a multitude of metabolic effects that prevent the exacerbation of a possible genetic predisposition and the development of CVD. If the predisposition is a genetic elevation of LP(a) plasma levels the specific regulatory role of ascorbate is the decrease of APO(a) synthesis in the liver and thereby the decrease of LP(a) plasma levels.

Moreover, ascorbate decreases the retention of LP(a) in the vascular wall by lowering fibrinogen synthesis and by increasing the hydroxylation of lysine residues in vascular wall constituents, thereby reducing the affinity for LP(a) binding.

In about half of the CVD patients the mechanism of LP(a) deposition contributes significantly to the development of atherosclerotic plaques. Other lipoprotein disorders are also frequently part of the polygenic pattern predisposing the individual patient to CVD in the individual.

Be Sure to Read Part 2 of this article

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