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Stanford Report, November 19, 2003

New pathway provides insight into heart disease

By MITZI BAKER

A new signaling pathway appears to play a critical role in the development of heart disease, according to researchers at the School of Medicine.

Now that this marker of cardiac dysfunction, known as the APJ-apelin pathway, has been identified, it could lead to better diagnosis of heart problems, perhaps even allowing doctors to intervene in heart disease by blocking or boosting levels of critical proteins.

Euan Ashley (left) and Mary Chen were lead authors of a study that revealed a new signaling pathway that plays a critical role in heart disease. The finding may pave the way to improved diagnosis and treatment. Photo: Mitzi Baker

"The thing that’s clear is that apelin is increased in heart failure," said Euan Ashley, MD, PhD, a clinical fellow in cardiovascular medicine and one of the lead authors of the study presented Nov. 12 at the annual American Heart Association meeting in Orlando.

"The idea of a blood test to help make a diagnosis of heart disease is very appealing," Ashley said. "But my bigger hope is for therapeutic potential, and given what we know about apelin levels changing a lot during heart failure, either blocking or enhancing this system may provide a treatment for heart failure."

The APJ-apelin signaling pathway’s role in cardiac health was discovered by straightforward techniques combined so that previously unnoticed connections emerged.

Researchers united Stanford’s experience with cardiac-assist devices with the ability of microarrays to scan for activity of thousands of genes at once. In the study, researchers looked at two heart tissue samples from each patient. One sample came from patients suffering end-stage heart disease before any type of surgical intervention, and the second sample was taken after the same patients’ hearts had recovered with the help of artificial pumps known as left-ventricular assist devices, or LVADs.

The patients in this study relied upon LVADs to pump their blood as they waited for an appropriate donor heart to become available for transplant. When the device was implanted, a small section of heart tissue had to be removed, which provided the "before" sample for the study. Once a donor heart arrived, the patient’s old heart became the "after" sample.

"By comparing the two states, the genes we are seeing show the differences between the patients at their worst and when their hearts have had a chance to recover," said Mary Chen, life science research assistant in cardiovascular medicine and the study’s other lead author. In other words, the things that get worse during heart failure improve with the aid of an LVAD.

Genes that change during the recovery process could provide valuable insight into the progression of heart disease because heart tissue after LVAD use approximates the patient’s healthy heart. The researchers screened matched samples from 11 male patients before and after their heart transplants using microarrays to test for the activity of more than 12,000 genes. Among the genes that changed greatly between the two states was one called BNP, already known to be the first marker of heart disease to date. While this provided some confirmation of their technique, far more intriguing was the discovery of a new pathway.

"Right at the top of our list was a gene that nobody had paid any attention to," said Ashley. "That was our first light bulb." He explained that the gene they found to be most active in the recovering heart was related to angiotensin — shown 20 years ago to be important in heart failure, leading to the class of drugs known as ACE inhibitors.

The gene they found produces a receptor called APJ. The protein that combines with this receptor is apelin, which had been shown recently to be perhaps the most potent stimulator of heart contractions ever discovered. Nobody had connected apelin and APJ to cardiac failure until now, the researchers said.

To provide further evidence that apelin played a role in heart disease, the Stanford team detected the protein in human blood. Once they determined what a normal range was, they looked at patients with various stages of heart disease and found that the level of apelin in a person’s blood reflected the condition of their heart determined by standard methods. They further showed that apelin is located in the lining of the blood vessels, but it signals to the receptor APJ in the heart.

Other Stanford researchers who contributed to this presentation are Alicia Deng, life science research assistant in cardiovascular medicine; Philip Tsao, PhD, assistant professor of research in cardiovascular medicine; and Thomas Quertermous, MD, the William G. Irwin Professor in Cardiovascular Medicine. This work was supported by the Donald W. Reynolds Cardiovascular Clinical Research Center at Stanford.



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