A Unified Theory of Human Cardiovascular Disease Leading the Way to the Abolition of This Disease as a Cause for Human Mortality Matthias Rath M.D. and Linus Pauling Ph.D.1 "An important scientific innovation rarely The metabolic level is characterized by the close makes its way by gradually winning over and connection of ascorbate with metabolic regulatory converting its opponents. What does happen systems that determine the risk profile for CVD in is that its opponents gradually die out and that clinical cardiology today. The most frequent the growing generation is familiar with the mechanism is the deposition of lipoproteins, idea from the beginning. " Max Planck particularly lipoprotein(a) [Lp(a)], in the vascular wall. With sustained ascorbate deficiency, the This paper is dedicated to the young physicians result of insufficient ascorbate uptake, these and the medical students of this world. defense mechanisms overshoot and lead to the development of CVD. Premature CVD is Abstract essentially unknown in all animal species that Until now therapeutic concepts for human produce high amounts of ascorbate endogenously. cardiovascular disease (CVD) were targeting In humans, unable to produce endogenous individual pathomechanisms or specific risk ascorbate, CVD became one of the most frequent factors. On the basis of genetic, metabolic, diseases. The genetic mutation that rendered all evolutionary, and clinical evidence we present human beings today dependent on dietary here a unified pathogenetic and therapeutic ascorbate is the universal underlying cause of approach. Ascorbate deficiency is the precon- CVD. Optimum dietary ascorbate intake will dition and common denominator of human CVD. correct this common genetic defect and prevent its Ascorbate deficiency is the result of the inability deleterious consequences. Clinical confirmation of man to synthesize ascorbate endogenously in of this theory should largely abolish CVD as a combination with insufficient dietary intake. The cause for mortality in this generation and future invariable morphological consequences of chronic generations of mankind. ascorbate deficiency in the vascular wall are the loosening of the connective tissue and the loss of Key words the endothelial barrier function. Thus human Ascorbate, vitamin C, cardiovascular disease, CVD is a form of pre-scurvy. The multitude of lipoprotein(a),hypercholesterolemia, pathomechanisms that lead to the clinical hypertriglyceridemia, hypoalphalipoprotein-emia, manifestation of CVD are primarily defense diabetes, homocystinuria. mechanisms aiming at the stabilization of the vascular wall. After the loss of endogenous ascor- Introduction bate production during the evolution of man these We have recently presented ascorbate defi- defense mechanisms became life-saving. They ciency as the primary cause of human CVD. We counteracted the fatal consequences of scurvy and proposed that the most frequent pathome-chanism particularly of blood loss through the scorbutic leading to the development of atherosclerotic vascular wall. These countermeasures constitute a plaques is the deposition of Lp(a) and genetic and a metabolic level. The genetic level is fibrinogen/fibrin in the ascorbate-deficient characterized by the evolutionary advantage of vascular wall.1.2 In the course of this work we inherited features that lead to a thickening of the discovered that virtually every patho-mechanism vascular wall, including a multitude of inherited for human CVD known today can be induced by diseases. ascorbate deficiency. Beside the deposition of Lp(a) this includes such seemingly unrelated 1. Linus Pauling Institute of Science and Medicine, 440 Page Mill processes as foam cell formation and decreased Road, Palo Alto. CA 94306. reverse-cholesterol 5 Journal of Orthomolecular Medicine Vol. 7, No. 1, 1992 transfer, and also peripheral angiopathies in of the connective tissue. Ascorbate is essential for diabetic or homocystinuric patients. We did not an optimum production and hydroxy-lation of accept this observation as a coincidence. collagen and elastin, key constituents of the Consequently we proposed that ascorbate de- extracellular matrix. Ascorbate depletion thus ficiency is the precondition as well as a common leads to a destabilization of the connective tissue denominator of human CVD. This far-reaching throughout the body. One of the first clinical conclusion deserves an explanation; it is signs of scurvy is perivascular bleeding. The presented in this paper. We suggest that the direct explanation is obvious: Nowhere in the body does connection of ascorbate deficiency with the there exist a higher pressure difference than in the development of CVD is the result of circulatory system, particularly across the extraordinary pressure during the evolution of vascular wall. The vascular system is the first site man. After the loss of the endogenous ascorbate where the underlying destabilization of the production in our ancestors, severe blood-loss connective tissue induced by ascorbate deficiency through the scorbutic vascular wall became a life- is unmasked, leading to the penetration of blood threatening condition. The resulting evolutionary through the permeable vascular wall. The most pressure favored genetic and metabolic vulnerable sites are the proximal arteries, where mechanisms predisposing to CVD. the systolic blood pressure is particularly high. The increasing permeability of the vascular wall The Loss of Endogenous Ascorbate Production in scurvy leads to petechiae and ultimately in the Ancestor of Man hemorrhagic blood loss. With few exceptions all animals synthesize Scurvy and scorbutic blood loss decimated the their own ascorbate by conversion from glucose. ship crews in earlier centuries within months. It is In this way they manufacture a daily amount of thus conceivable that during the evolution of man ascorbate that varies between about 1 gram and periods of prolonged ascorbate deficiency led to a 20 grams, when compared to the human body great death toll. The mortality from scurvy must weight. About 40 million years ago the ancestor have been particularly high during the thousands of man lost the ability for endogenous ascorbate of years the ice ages lasted and in other extreme production. This was the result of a mutation of conditions, when the dietary ascorbate supply ap- the gene encoding for the enzyme L-gulono-g- proximated zero. We therefore propose that after lactone oxidase (GLO), a key enzyme in the the loss of endogenous ascorbate production in conversion of glucose to ascorbate. As a result of our ancestors, scurvy became one of the greatest this mutation all descendants became dependent threats to the evolutionary survival of man. By on dietary ascorbate intake. hemorrhagic blood loss through the scorbutic The precondition for the mutation of the GLO vascular wall our ancestors in many regions may gene was a sufficient supply of dietary ascorbate. have virtually been brought close to extinction. Our ancestors at that time lived in tropical The morphologic changes in the vascular wall regions. Their diet consisted primarily of fruits induced by ascorbate deficiency are well and other forms of plant nutrition that provided a characterized: the loosening of the connective daily dietary ascorbate supply in the range of tissue and the loss of the endothelial barrier several hundred milligrams to several grams per function. The extraordinary pressure by fatal day. When our ancestors left this habitat to settle blood loss through the scorbutic vascular wall in other regions of the world the availability of favored genetic and metabolic countermeasures dietary ascorbate dropped considerably and they attenuating increased vascular permeability. became prone to scurvy. Ascorbate Deficiency and Genetic Fatal Blood Loss Through the Scorbutic Countermeasures Vascular Wall - An Extraordinary Challenge The genetic countermeasures are characterized to the Evolutionary Survival of Man by an evolutionary advantage of genetic features Scurvy is a fatal disease. It is characterized by and include inherited disorders that structural and metabolic impairment of the human body, particularly by the destabilization 6 A Unified Theory of Human Cardiovascular Disease are associated with atherosclerosis and CVD. should be noted that ascorbate can affect these With sufficient ascorbate supply these disorders regulatory levels in a multiple way. In lipoprotein stay latent. In ascorbate deficiency, however, they metabolism low density lipoproteins (LDL), become unmasked, leading to an increased Lp(a), and very low density lipoproteins (VLDL) deposition of plasma constituents in the vascular are inversely correlated with ascorbate wall and other mechanisms that thicken the concentrations, whereas ascorbate and HDL levels vascular wall. This thickening of the vascular wall are positively correlated. Similarly, in is a defense measure compensating for the prostaglandin metabolism ascorbate increases impaired vascular wall that had become prostacyclin and prostaglandin E levels and destabilized by ascorbate deficiency. With decreases the thromboxane level. In general, prolonged insufficient ascorbate intake in the diet ascorbate deficiency induces vascular constriction these defense mechanisms overshoot and CVD and hemostatis, as well as cellular and develops. extracellular defense measures in the vascular The most frequent mechanism to counteract the wall. increased permeability of the ascorbate-deficient In the following sections we shall