As if cancers affecting the blood are not bad enough, they sometimes cause heart damage, too. But, scientists have not fully understood how and why this cardiac injury occurs.
Researchers at The University of Texas Health Science Center at Houston (UTHealth) and Baylor College of Medicine now have discovered that the cancer metabolite D-2-hydroxyglutarate (D2-HG) weakens the heart. Normally D2-HG is produced at low levels but because of an error in the metabolism of cancer cells, large amounts of D2-HG escape into the circulation.
These new findings could help explain the link between cancer and heart disease.
“We showed how a metabolite produced by blood cancers impairs the heart’s pumping ability in mathematical and animal models,” said Heinrich Taegtmeyer, M.D., D.Phil., the study’s senior author and a professor of cardiovascular medicine at McGovern Medical School at UTHealth.
Findings appear in the Proceedings of the National Academy of Sciences of the United States of America (PNAS).
If scientists can figure out how to block the activity of the metabolite D2-HG, they could conceivably treat cancer and heart disease in a “single go,” said Taegtmeyer, who is also on the faculty of The University of Texas Graduate School of Biomedical Sciences at Houston.
Anja Karlstaedt, M.D., Ph.D., the study’s first author and a postdoctoral research fellow in the Department of Internal Medicine, said, “Elevated blood levels of D2-HG in acute myeloid leukemia (AML) predispose the heart to weakness. We now have discovered the molecular mechanisms involved in the process.”
AML, cancer of the blood and bone marrow, will claim more than 10,000 lives in the United States by year-end, according to the American Cancer Society.
“Collectively, our results highlight the impact of cancer cell metabolism on function and metabolism of the heart,” the researchers wrote in the paper.
“Further studies on the mechanisms leading to metabolic and epigenetic dysregulation may offer new opportunities to treat cancer and prevent (rather than cause) heart failure at the same time,” they added.
These heart problems were initially thought to be a side effect of cancer drugs, Taegtmeyer said. It was subsequently determined that certain cancers were to blame.
As the next step, Karlstaedt is using mathematical models to identify compounds that may be able to reverse the detrimental effects of D2-HG.
Study coauthors include Heidi Vitrac, Ph.D., and Hernan Vasquez, Ph.D., of McGovern Medical School; Xiaotian Zhang, Ph.D., and Margaret A. Goodell, Ph.D., of Baylor College of Medicine; Jing Han Wang of Zhejiang University School of Medicine, Hangzhou, China; and Romain Harmancey, Ph.D., of the University of Mississippi Medical Center, Jackson.
The paper, titled “Oncometabolite D-2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart,” was supported by the Roderick D. MacDonald Research Fund, The Friede Springer Herz Stiftung, National Institutes of Health grants (R01-HL-61483 and K99/R00-HL-112952) and the Adrienne Helis Malvin Medical Research Foundation.