Asymmetric dimethylarginine (ADMA) proved to be a key factor in the question of why some people produce enough nitric oxide, while others do not. In 1992, Drs. Salvador Moncada and Patrick Vallance helped solve this puzzling question. They discovered that another amino acid, ADMA, plays a significant role in cardiovascular disease. They discovered that this modified amino acid can block the production of nitric oxide.
Biochemists had known for many years that ADMA was in urine, but Drs. Moncada and Vallance were the first ones to realize how significant this was. They observed that patients with kidney failure, who are known to have accelerated atherosclerosis, along with higher risk of heart attack and stroke, were not able to excrete ADMA, and therefore had high blood levels. They thought the possible reason for this was that this arginine-like molecule blocked the effect of L-arginine. This hypothesis proved to be correct.
Asymmetric dimethylarginine is identical to L-arginine, except that it has two extra methyl groups attached to it. Both ADMA and L-arginine are able to attach to the enzyme NO synthase (NOS). When L-arginine attaches, it converts to nitric oxide, however, when ADMA attaches, it can not be converted, thereby blocking the production of nitric oxide.
After the findings of Drs. Moncada and Vallance, research teams around the world wanted to find out if ADMA was the reason for low levels of nitric oxide in people who were at risk for, or already had, cardiovascular disease.
Drs. Rainer Boger and Stephanie Bode-Boger from the University of Hannover in Germany found this to be true in patients with peripheral arterial disease (PAD). Their findings showed that the worse the PAD, the higher the blood level of ADMA. Not long after that, Dr. Imaizumi and coworkers in Japan had similar findings with regards to brain arteries. Dr. Imaizumi’s team used ultrasound to observe blood vessels in the neck of 120 Japanese patients. They found that the thickest amount of plaque was found in the people with the highest level of ADMA. Dr. Azuma’s group in Tokyo found blood level of ADMA to be an independent marker for vessel thickening in women.
Dr. John Cooke of Stanford Medical School collaborated with many different scientists from around the world and found that high levels of blood asymmetric dimethylarginine were present in people with all types of cardiovascular disease risk factors, including high cholesterol, high triglycerides, high blood pressure, high blood sugar, insulin resistance, high homocysteine, and tobacco use.
Triglycerides are a common type of fat found in your blood and in fatty foods. They are one of our main sources of energy and our body’s most common type of fat. Our body uses whatever calories it needs from the food we eat for quick energy. Any additional calories are converted into triglycerides and stored in fat cells for later use. Regardless of what type of food from which you get your calories, if you consume excess calories, it will be stored as fat. If you consume excess calories on a regular basis, you may have high triglyceride levels.
At normal levels, triglycerides are important for optimal health. Research has not clearly shown whether high triglyceride levels directly increase your risk for heart disease, however, it is part of a group of conditions known as metabolic syndrome. The other factors of metabolic syndrome are high blood pressure, high blood sugar, excess fat in your abdominal area, and low HDL (good) cholesterol levels. Metabolic syndrome definitely increases your risk for heart disease, diabetes, and stroke.
A study performed in collaboration between Dr. Cooke of Stanford, and Dr. Pia Lundman and coworkers at the Karolinska Institute in Stockholm, found a strong correlation between triglyceride and ADMA levels in the blood. Along with these findings, Dr. Ali Fard at Columbia University found that after eating a high-fat or high-carbohydrate meal, ADMA levels in the blood increased. He found that the level of fat in the blood was the highest about two hours after the meal and this increased level remained for about four to six hours. This causes poor endothelial function and is possibly one of the main reasons people with heart disease often complain of angina (chest pain) after this type of meal.
Another study between Dr. John Cooke and Dr. Gerald Reaven, also of Stanford, found that when someone was insulin resistant, they also had high levels of asymmetric dimethylarginine. This correlation between asymmetric dimethylarginine levels and insulin resistance is stronger than with any other marker.
Dr. John Cooke further collaborated with Dr. Rene Malinow at Oregon Health Sciences and found that homocysteine will increase the level of ADMA in people with vascular disease. They gave these patients methionine (which converts to homocysteine in the body), and measured the function of their endothelium both before the methionine and after. After receiving methionine, their homocysteine levels rose, along with ADMA, and their endothelial function decreased. They were able to determine that the homocysteine was directly responsible for the increase in ADMA. However, they found that people with a healthy endothelium were resistant to methionine, and their ADMA levels did not increase, nor did their endothelial function deteriorate. They came to the conclusion that if you have a healthy endothelium, you have some natural resistance to some of these damaging factors.
Dr. John Cooke concluded that asymmetric dimethylarginine levels are high in people with cardiovascular disease risk factors or who already have heart disease. He believes that ADMA is a common pathway by which all risk factors manifest their negative effects on the blood vessel wall. An accumulation of ADMA occurs in people with risk factors and this blocks the production of nitric oxide. This in turn causes poor blood flow and the progression of atherosclerosis.
There are two ways of getting rid of ADMA in the body, excretion in the urine, or being broken down by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). At Stanford, they found that ADMA levels were balanced by the breakdown action of DDAH. If DDAH was reduced or impaired, then ADMA levels gradually increase. All of the major cardiovascular disease risk factors contribute to the diminished ability of DDAH to breakdown ADMA. This is because of the effects of oxygen radicals. They found that DDAH is extremely sensitive to these free radicals. Therefore, increasing antioxidant activity is vital in reducing oxygen radicals, which in turn helps DDAH to reduce levels of asymmetric dimethylarginine. This causes an increase in the production of nitric oxide and improves the health and function of the endothelium.