skip page navigationOregon State University

Research Newsletter-Fall/Winter 2012

Stephen Lawson


Stephen Lawson
LPI Administrative Officer


Although lipoprotein(a) [Lp(a)] was discovered about 50 years ago, surprisingly little is known about its cellular and biochemical functions. Lp(a) consists of a low-density lipoprotein (LDL) particle containing an apolipoprotein B-100 molecule linked to another apoprotein molecule called apo(a), which determines the functional characteristics of Lp(a) and largely accounts for its heart disease risk. Blood concentrations of Lp(a) are genetically determined and generally highest in blacks and lowest in whites. While concentrations of Lp(a) are stable in individuals over time, they can vary among people by 1,000-fold. There are many genetic variations in the size of the apo(a) particle in Lp(a), which accounts for the variable association with cardiovasc ular pathologies and events.

Many large-scale studies have explored the relationship between Lp(a) and cardiovascular diseases, consistently finding an association between high Lp(a) levels and atherosclerosis, heart attacks, or stroke; Lp(a) has been validated as a significant, independent risk factor for heart disease. Despite these significant correlations, the precise role of Lp(a) in elevating the risk for heart disease and stroke remains speculative. Lp(a) seems to be proinflammatory; it activates NF-κB, a transcription factor that binds to DNA and stimulates inflammatory processes. As a consequence, Lp(a) promotes the recruitment of immune cells called monocytes to the intima, the innermost layer of blood vessels and arteries facing the blood stream. Once monocytes have migrated to the intima, they can become engorged with oxidized LDL—becoming “foam” cells—and initiate atherosclerotic lesion formation.

Lp(a) also has been found to impair fibrinolysis, the process by which fibrin in blood clots is broken down by plasmin, the active form of plasminogen. By interfering with this process, Lp(a) contributes to thrombosis (blood clot formation) that could result in a heart attack or stroke. Clot formation in the arterial wall, called “mural thrombosis,” contributes to the growth of atherosclerotic lesions; “occlusive thrombosis,” on the other hand, blocks an artery and triggers a heart attack or stroke. Lp(a) may also enhance coagulation, which could further contribute to thrombotic events.

The Hypothesis

In 1990, Linus Pauling and a cardiologist colleague published a paper entitled “Hypothesis: Lipoprotein(a) is a surrogate for ascorbate” in the Proceedings of the National Academy of Sciences (PNAS) on the putative relationship between vitamin C and Lp(a). They hypothesized that Lp(a) serves as an evolutionary surrogate or substitute for vitamin C in animals that do not endogenously synthesize vitamin C, such as humans and monkeys. Indeed, Lp(a) is found in few species, mainly those that do not synthesize vitamin C. Since the absence of detectable Lp(a) in most species—almost all of which synthesize vitamin C—does not seem to be biologically disadvantageous, it was also proposed that vitamin C serves as a surrogate for Lp(a). In a subsequent paper, Pauling noted that our ancestors’ loss of the ability to synthesize vitamin C and the acquisition of Lp(a) synthesis both occurred about 40 million years ago.

As a surrogate for vitamin C and owing to its pro-clotting functions, Pauling and his colleague suggested that Lp(a) might help repair lesions in the arterial wall caused by mechanical stress, free radicals, and/or sub-optimum collagen synthesis when vitamin C concentrations are insufficient. However, atherosclerosis results from the chronic, pathological deposition of Lp(a). A corollary is that adequate vitamin C status in humans, such as that achieved by sufficient intake, may help prevent arterial damage and reduce the need for the deposition of Lp(a) and/or lower its levels, thus preventing the development of atherosclerotic plaque. Scurvy caused by vitamin C deficiency results in capillary fragility and hemorrhage. Lp(a) may help by inhibiting fibrinolysis, thus preventing hemorrhage. Pauling and his colleague also suggested that the apo(a) part of Lp(a), rich in disulfide groups, may function as an antioxidant, thereby inhibiting LDL lipid oxidation associated with plaque formation. In this way, Lp(a) also would serve as a surrogate for the premier water soluble antioxidant—vitamin C—when its levels are low.

In their first PNAS paper, Pauling and his colleague proposed that Lp(a) would be present in guinea pigs, a species unable to synthesize vitamin C. In a subsequent paper in PNAS in 1990, they showed that, indeed, Lp(a) is present in guinea pigs. They further found that vitamin C deficiency in these animals promoted the development of atherosclerotic plaque and that supplemental vitamin C prevented its development and the accumulation of Lp(a) in the arterial wall. They also suggested that depletion of vitamin C increases the permeability of the vascular wall, thereby contributing to the infiltration of Lp(a) and leading to plaque formation and mural thrombosis. In chronic vitamin C insufficiency, the prolonged action and accumulation of Lp(a) may result in the development of plaque (mural thrombosis) and adverse events like heart attacks and strokes related to occlusive thrombosis.

The PNAS papers were followed up with a series of papers published in the Journal of Orthomolecular Medicine (JOM) further outlining the putative relationship between vitamin C, Lp(a), heart disease, cancer, diabetes, and other diseases, emphasizing, especially, the role of chronic vitamin C deficiency in their etiology.

Lowering Lp(a)

Unfortunately, neither diet nor exercise has been found to lower Lp(a) levels. There have been at least three randomized, controlled trials to evaluate the effect of supplemental vitamin C on Lp(a) levels. A 1994 study with 124 healthy men and women aged 17 to 74 detected no significant effect of 1 or 2 grams per day of vitamin C for one month on Lp(a) levels. Published in 1995, another study enrolled 44 patients with coronary heart disease who received either placebo or 4.5 grams per day of vitamin C for 12 weeks. The authors reported no statistically significant effect of vitamin C on Lp(a) levels. The last study, published in 2000, enrolled 101 healthy men and women who received either placebo or 1 gram per day of vitamin C for eight months. Again, the authors reported no significant effect of vitamin C on Lp(a) levels. These results conflict with an earlier uncontrolled, small study published in 1992 with 11 heart disease patients given 9 grams per day of vitamin C for 14 weeks. In that study, vitamin C lowered Lp(a) levels by an average of 27%. Overall, these studies suggest that supplemental vitamin C does not lower Lp(a) levels in humans.

However, a few strategies to lower Lp(a) levels have been suggested by some small studies. One study of 37 heart disease patients in 2002 found that daily doses of 81 mg of aspirin for six months lowered Lp(a) levels by an average of 82% in those subjects with high baseline levels of Lp(a) (>30 mg/dl). Another study in 1998 with 73 hypercholesterolemic patients reported that a daily dose of 2,000 mg of niacin for 96 weeks lowered Lp(a) levels by an average of 39%. This dose of niacin is almost 60 times higher than the tolerable upper intake level—the highest daily intake likely to pose no risk of adverse effects—of 35 mg/day for adults. The time-release niacin used in the 1998 study was generally well tolerated; common side effects included skin flushing and slightly elevated liver enzymes.

Other studies have reported that L-carnitine, a nonprotein amino acid, lowers Lp(a) levels. One study in 2000 found that 2 grams per day of L-carnitine lowered Lp(a) levels by nearly 8% in 36 subjects with high baseline levels of Lp(a) (40-80 mg/dl). In 2003, a randomized, placebo-controlled study in 94 diabetic patients found that Lp(a) levels were lowered by 21% in patients taking 2 grams per day of L-carnitine for six months.

Lysine, Lp(a), and Angina

The amino acids lysine and proline are chemically converted to other forms (hydroxylysine and hydroxyproline, respectively) by vitamin C for collagen synthesis. In the case of chronic vitamin C deficiency, these conversions cannot take place effectively, and collagen synthesis is impaired, leading to the loss of the structural integrity of vascular and other tissues and subsequent hemorrhage, as previously mentioned. In this situation, fibrin, by promoting clot formation, may be valuable in protecting against blood loss. Pauling and his colleague speculated that Lp(a) binds excessively to fibrin in clots, impairing fibrin breakdown by plasmin. They also speculated that lysine may bind to Lp(a). In this case, lysine might help remove chronically deposited Lp(a) or interfere with its deposition. Thus, lysine may have therapeutic benefit in atherosclerosis and angina, which is caused by poor blood flow in arteries compromised by atherosclerosis.

Pauling published three case reports in the early 1990s in the JOM on the rapid relief from severe, exercise-induced angina in heart disease patients taking 3-6 grams/day each of lysine and vitamin C. There are some plausible explanations as to why vitamin C may have that effect, mainly related to its beneficial effect on endothelial function, i.e., its ability to relax blood vessels and improve blood flow via stabilization or increase of tetrahydrobiopterin—an enzyme cofactor that controls nitric oxide synthesis—but the role of lysine remains obscure. In two of the three case reports by Pauling, the patients had been taking large doses of vitamin C, but relief was only observed after the implementation of lysine. Because the relief from angina was so rapid in the reported cases, Pauling suggested, as previously mentioned, that lysine—by binding to Lp(a)—may quickly remove Lp(a) from plaque and also prevent its deposition in developing plaque. Unfortunately, no controlled clinical trials have yet been published to validate or refute this strategy to control angina, and the molecular interactions between lysine and Lp(a) aren’t known.

Lysine is found in the diet, and it can be used in the body as a precursor to synthesize carnitine, an amino acid critical for mitochondrial energy production in cells. In his first case report on the amelioration of angina with vitamin C and lysine, Pauling noted that vitamin C is important in the hydroxylation reactions that synthesize carnitine from lysine. A number of studies have found that carnitine supplementation, as an adjunct to conventional therapy, is useful in treating heart disease, including heart attacks, heart failure, angina, and peripheral arterial disease.

patent certificate


Several relevant patent applications were filed by Pauling and his collaborator, and three were awarded: “Use of ascorbate and tranexamic acid solution for organ and blood vessel treatment prior to transplantation” (1993), “Prevention and treatment of occlusive cardiovascular disease with ascorbate and substances that inhibit the binding of lipoprotein (A)” (1994), and “Therapeutic lysine salt composition and method of use” (1997).

The first of these described the treatment of organs or arteries used in transplantation with a solution containing vitamin C and tranexamic acid, both of which were postulated to inhibit the binding of Lp(a) to blood vessel walls, in order to prevent subsequent atherosclerotic complications. The inventors proposed that this method would have general applications for the prevention and treatment of heart disease, especially atherosclerosis, and utility for coronary bypass patients, diabetics, and patients undergoing hemodialysis or organ transplants. The patent awarded in 1994 explained the putative use of vitamin C, tranexamic acid, lysine, and nicotinic acid (niacin) to reduce plasma levels of Lp(a) and prevent its binding to the arterial wall, thereby inhibiting atherosclerosis. The final patent addressed the use of lysine, vitamin C, beta-carotene, N-acetyl cysteine (a precursor for the synthesis of glutathione, an important endogenous antioxidant), vitamin E, and nicotinic acid to prevent and treat heart disease. The evidence provided in support of the patent applications was based on experiments with guinea pigs and human aortas obtained postmortem. While animal models of human disease are frequently useful, they do not always predict human outcomes. No data from human clinical trials were presented, so the patent provisions remained largely speculative. It’s not unusual for patents to be awarded in order for the inventor to establish priority in advance of actual proof.


We know that vitamin C has value in promoting cardiovascular health. It not only reduces the risk for heart disease and stroke but also lowers blood pressure and promotes vasodilation in patients with atherosclerosis, thus improving blood flow that may also attenuate angina. To date, the hypothesized relationship between vitamin C and Lp(a) has been neither proven nor refuted. It’s also not yet known if lysine itself, rather than serving simply as a precursor for carnitine synthesis, plays an important role in preventing or treating heart disease or angina. And neither the dose-response relationships nor various combinations of micronutrients have been adequately addressed experimentally. Controlled clinical trials are needed to answer these provocative questions. Lastly, there is no compelling evidence from controlled trials that any micronutrient or combination of micronutrients reverses atherosclerosis in humans, although some may inhibit its development or retard its progression.

Last updated November 2012