Study shows long-term use of arginine doesn't help PAD

John Cooke

When atherosclerosis strikes the legs, hardening the arteries, it can cause severe pain and weakness, eventually growing so severe that patients may struggle to walk around the house.

In his ongoing 20-year quest to find some relief for patients with peripheral arterial disease, or PAD, John Cooke, MD, discovered early on that arginine, an amino acid that can be given as a supplement, helped ease pain by relaxing arteries and increasing blood flow. He became hopeful he'd struck on something that could really help.

Now, he's taken a second look, and his most recent batch of research results published July 10 in the journal Circulation have changed his mind about arginine as a treatment for heart disease.

"To our surprise, arginine did not produce a sustained benefit," said Cooke, a professor of cardiovascular medicine who directs the medical school's Program in Vascular Medicine and Biology. "In fact, all the measurements tended to go the wrong way."

Cooke's earlier, short-term studies of the supplement had shown arginine reduced symptoms in people with heart and vessel disease. But in his long-term study of arginine, which involved 133 patients, Cooke found there is no benefit and may be some possible harm in the long-term use of arginine in patients with PAD.

"It's very curious," he said. "Long-term use of arginine causes a form of tolerance to its short-term effects."

The history of arginine as a treatment for heart disease began in the early 1990s, when Cooke's lab and other scientists found a benefit for heart patients in small, short-term studies. In these studies, arginine increased the body's production of a blood vessel relaxant called nitric oxide. The increased production of nitric oxide improved blood flow and reduced symptoms of pain and discomfort, he said.

He formed a company, Cooke Pharma, with the intent of developing arginine into a therapy in 1997. The company sold the HeartBar, a nutritional bar enriched with arginine.

The hope was that by reducing painful symptoms in PAD patients, they could increase their level of activity, which helps control the disease.

Cooke Pharma was acquired by United Therapeutics in 2000 and the HeartBar was discontinued in 2006, primarily due to lack of sales. Arginine isn't very tasty, Cooke said.

The National Institutes of Health funded Cooke's subsequent $5 million, long-term study of arginine in 2002. Patients with PAD were divided into two groups, given either arginine supplements or a placebo over a six-month period. All patients underwent extensive medical testing including blood, urine, treadmill and other vascular testing.

The results surprised researchers by completely reversing earlier findings. Measures of nitric oxide in the patients who took arginine were found to be not improved or reduced compared with the placebo group.

Other medical professionals are still recommending arginine as a supplement to their heart patients, but Cooke no longer does.

"We feel we have seen a benefit," said Amir Lerman, MD, another researcher studying arginine and professor of medicine at the Mayo Clinic College of Medicine. He conducted his own long-term study of arginine in 1998 which showed that large doses of arginine increased blood flow in coronary arteries by 150 percent and reduced the severity of angina by 70 percent.

"We have never seen any major side effects in any of our patients. I cannot explain the difference," Lerman said.

Current treatment for PAD, which affects 12 million people, is directed toward preventing adverse events, such as heart attack, stroke and gangrene. Medication, diet, tobacco cessation and exercise have been shown to prevent progression of the disease and death. However, treatment of the symptoms (aching of the legs caused by walking) is limited.

Cooke's co-authors include cardiovascular fellows Andrew Wilson, PhD, Randall Harada, MD, and Nandini Nair, MD, PhD; and Naras Balasubramanian, PhD, a senior research associate in biostatistics.