Dietary inorganic nitrate may reduce heart dysfunction caused by powerful anti-cancer drug

Since the 1960s, the anti-cancer drug doxorubicin has remained a top choice for chemotherapy because of its superior efficacy to fight cancer. However, the drug is known to lead to permanent heart damage. Currently, there is no Food and Drug Administration-approved therapy for prevention or treatment of heart damage caused by doxorubicin.

In a study, published online ahead of print on May 16 in the Journal of the American College of Cardiology, using a mouse model the team demonstrated that mice treated with dietary inorganic nitrate had a reduced rate of heart dysfunction caused by doxorubicin. On a molecular level, the dietary nitrate stabilized the mitochondria and protected against free-radical damage to the heart.

“These results may have significant impact in reducing the risk and degree of heart damage in patients who depend on doxorubicin for treatment of cancers. This is because inorganic nitrate is a water-soluble and very inexpensive chemical that could be ideal for long-term oral administration during the course of cancer treatment with doxorubicin,” said Rakesh C. Kukreja, Ph.D., principal investigator for the project at VCU, and the Eric Lipman professor in cardiology in the VCU School of Medicine and the scientific director of the VCU Pauley Heart Center.

According to Kukreja, the nitrate dose used in this study is 400 percent of the World Health Organization Acceptable Daily Intake (WHO-ADI). He said that nitrate can easily be obtained from foods including leafy green vegetables, spinach and lettuces, which have high levels of nitrate, or beverages such as beet juice that are commercially available and safely used in humans.

Mitochondria are cellular organelles critical for converting oxygen and nutrients into ATP, the key fuel for cellular function. The free radicals generated in the mitochondria of cardiac cells by doxorubicin lead to the breakdown of regular cellular function, resulting in programmed cardiac cell death. Over time, cell death has been linked to decreased heart function or heart failure.

Kukreja collaborated with VCU Pauley Heart Center Division researchers Shu-Guang Zhu, M.D., Ph.D., Anindita Das, Ph.D, Qun Chen, M.D., Ph.D., and Lei Xi, M.D., and Edward J. Lesnefsky, M.D., McGuire Veterans Affairs Medical Center.

The study was funded by the National Institutes of Health, the American Heart Association, and the U.S. Department of Veterans Affairs.

EDITOR'S NOTE: A copy of the study is available for reporters by email request by contacting Amanda Jekowsky, ajekowsk@acc.org.

About VCU and the VCU Medical Center: Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located on two downtown campuses in Richmond, VCU enrolls more than 32,000 students in 211 certificate and degree programs in the arts, sciences and humanities. Sixty-nine of the programs are unique in Virginia, many of them crossing the disciplines of VCU's 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation's leading academic medical centers. For more, see www.vcu.edu.

About the VCU Pauley Heart Center: The VCU Pauley Heart Center is recognized nationally for its heart failure and heart transplantation programs, and was among the first in the United States to implant the CardioWest temporary Total Artificial Heart, or TAH-t – the only total artificial heart approved by the U.S. Food and Drug Administration. The heart center is comprised of the Divisions of Cardiology, Cardiothoracic Surgery and Pediatric Cardiology. There is close collaboration between the divisions to provide advanced, patient-centered care to patients of all ages, with every type of heart disease, with the best possible outcomes. Pauley Heart Center's superior performance resulted in VCU Medical Center being recognized as one of the top 100 U.S. hospitals for cardiovascular care, according to a Thomson Reuters study.