M. Rath, L. Pauling
Journal of Orthomolecular Medicine 1991, 6:125-134

Summary

Human cardiovascular disease (CVD) is the result of the accumulation of lipoprotein(a), Lp(a), rather than of low density lipoprotein (LDL), in the vascular wall. It is generally not the consequence of plasma LDL levels, but rather of the level of Lp(a), which is formed in the liver in amounts largely determined by the rate of synthesis of apo(a). This rate is increased by low ascorbate concentrations. Human CVD is primarily a degenerative disease caused by ascorbate deficiency. This deficiency is the result of the inability of humans to synthesize endogenous ascorbate combined with an insufficient dietary ascorbate intake. The deficiency is aggravated by genetic defects such as the LDL receptor defect and by exogenous risk factors for CVD leading to additional ascorbate depletion. Ascorbate deficiency results in morphologic changes of the vascular wall.

In order to avoid the fatal consequences of extreme ascorbate depletion, such as hemorrhagic bleeding in scurvy, ascorbate deficiency simultaneously increases the plasma concentration of vasoconstrictive and hemostatic risk factors, including Lp(a) and fibrinogen. Chronic ascorbate deficiency leads to the extracellular accumulation of Lp(a) and fibrinogen/fibrin, the hallmarks of the atherosclerotic lesion. The underlying impairment of the vessel wall is unmasked mainly at sites of altered hemodynamic conditions, leading to myocardial infarction and stroke as the predominant manifestations of human CVD. Thus for patients with coronary or cerebrovascular disease the instability of the vessel wall due to ascorbate deficiency is the leading risk factor, rather than plasma constituents. In contrast, risk factors in plasma trigger the manifestation of peripheral vascular disease (PVD). In this condition plasma constituent such as oxygen free radicals from cigarette smoke or oxidatively modified triglyceride-rich lipoproteins exert a noxious effect on the vascular wall in the periphery and PVD develops. Ascorbate depletion of the vascular tissue is also a precondition for the manifestation of PVD. Human CVD is multifactorial. Ascorbate deficiency, however, is the common denominator of this disease. The comprehensive pathogenetic and therapeutic concept presented in this paper represents the solution to the puzzle of human cardiovascular disease and should lead to the improvement of human health.…

Read more: Solution to the Puzzle of Human Cardiovascular Disease: Its Primary Cause Is Ascorbate Deficiency, Leading to the Deposition of Lipoprotein(a) and Fibrinogen/Fibrin in the Vascular Wall

M. Rath, L. Pauling
Journal of Orthomolecular Medicine 1992, 7: 5-15

Summary

Until now therapeutic concepts for human cardiovascular disease (CVD) were targeting individual pathomechanisms or specific risk factors. 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.

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Read more: Unified Theory of Human Cardiovascular Disease Leading the Way to the Abolition of This Disease as a Cause for Human Mortality

M. Rath, L. Pauling
Journal of Orthomolecular Medicine 1992, 7: 17-23

Summary

Most human diseases, independent of their individual genetic or exogenous origin, proliferate via similar pathomechanisms. One of these universal pathways is propagated by oxygen free radicals. Here we present another universal pathomechanism: the degradation of the connective tissue by the protease plasmin. This mechanism had been described for some diseases but its universal character has still been insufficiently understood. We propose now that the proliferation of cancer, cardiovascular disease (CVD), and also inflammatory and many other diseases depends to a varying degree on this pathomechanism.

Activated macrophages, but also cancer cells, virally transformed cells, and other pathogenic cells secrete considerable amounts of plasminogen activators, which lead to an activation of plasminogen to the protease plasmin which activates procollagenase to collagenase. The resulting degradation of the extracellular matrix is a precondition for the proliferation and the clinical manifestation of any disease. Most acute and chronic diseases make use of this pathomechanism. This pathomechanism is the exacerbation of a mechanism used under physiological conditions by a variety of cellular systems of the human body. The exacerbation under pathological conditions is the result of a chronic imbalance between activators and inhibitors of this pathway. Apoprotein (a), apo(a), by virtue of its homology to plasminogen is proposed to be a competitive endogenous inhibitor of plasmin induced proteolysis and tissue degradation. The essential amino acid L-lysine functions as an exogenous inhibitor of this pathway. Therapeutic administration of L-lysine and synthetic lysine analogs, such as tranexamic acid, should lead to an effective control of plasmin- induced tissue degradation. Comprehensive clinical confirmation of this work will particularly improve the therapeutic options for advanced forms of CVD, cancer, and inflammatory and infectious diseases, including AIDS.…

Read more: Plasmin-Induced Proteolysis and the Role of Apoprotein(a), Lysine, and Synthetic Lysine Analogs

M. Rath
Journal of Orthomolecular Medicine 1992, 7: 73-80

Summary

It is gratifying to report the discovery of decisive missing pieces in the greatest scientific puzzle: the evolution of man. The evolution of homo sapiens is the result of a unique combination of genetic, metabolic, environmental, and dietary conditions. The underlying genetic precondition for the evolution of man was the loss of endogenous ascorbate production in his ancestor, about 40 million years ago. This genetic mutation set the metabolism of all descendants fundamentally apart from other species. Millions of years later, during the Ice Ages, this genetic mutation became the basis for the dramatic acceleration of human evolution and a quadruplication of the brain size in the recent 2.5 million years. During the Ice Ages dietary ascorbate intake approximated zero and billions of our ancestors died from scurvy. Scurvy was the greatest threat to the evolutionary survival of man and genetic features that counteracted the fatal consequences of scurvy were greatly favored. The vascular wall became the focus of this adaptation and genetic features that counteract increased vascular permeability had a selective evolutionary advantage.

The more effective a genetic feature was in stabilizing the ascorbate deficient vascular wall, the greater was its contribution to the development and differentiation of the human body during evolution. The most effective feature stabilizing the vascular wall in ascorbate deficiency was lipoprotein(a)(Lp(a)); the most important feature for the increase of brain size and intelligence as well as improved fertility was the adhesive protein apoprotein(a) (apo(a)). In general, promoters of evolution were those metabolic features that became available at an increased concentration during ascorbate deficiency, including most lipids and lipoproteins. These discoveries suggest that the final picture of human evolution will largely be completed by a new scientific field: metabolic anthropology. Most importantly, this new scientific discipline may contribute to a significant improvement of human health in this generation and in future generations of mankind.…

Read more: Solution to the Puzzle of Human Evolution