Heart failure after chemotherapy: New insights light the way for possible therapeutic

If you or a loved one has ever been treated for cancer with chemotherapy, you are likely aware of the common side effects of these widely used treatments, including fatigue, hair loss and anemia. An additional and poorly understood side effect of chemotherapy is cardiotoxicity—damage to the heart that can cause life-threatening heart failure years after treatment. However, the link between chemotherapy and heart failure is not fully understood, and it remains impossible to predict which patients will experience cardiotoxicity.

In a study recently published in Cell, a team from the Texas A&M University School of Medicine showed that the chemotherapeutic agent, Doxorubicin (Doxo), induces cancer therapy-related heart failure by causing damage to cellular mitochondria, which in turn trigger a cardiotoxic immune response. Led by the laboratory of A. Phillip West, PhD, an assistant professor in the Department of Microbial Pathogenesis and Immunology, this research sheds light on the link between heart failure and chemotherapy and provides insight into a novel immune sensing paradigm that detects mitochondrial damage.

Mitochondria are best known as the cellular components that generate cellular energy. Mitochondria contain their own DNA (mtDNA), which codes for many of the proteins mitochondria use to produce energy. Prior work from the West lab has shown that mtDNA is released into the cytoplasm, outside of the cell, or into circulation when mitochondria are damaged. This release of mtDNA can trigger immune responses, including production of a protein mediator called type I interferon (IFN-I). IFN-I is important in fighting viral infections, but persistent IFN-I production is linked to autoimmune diseases, cancer, aging-related disorders, and inflammatory responses in heart failure.

Yuanjiu Lei, PhD, the first author of the study and a recent graduate of the Texas A&M School of Medicine, sought to explore the relationship between chemotherapy, mitochondrial damage and IFN-I signaling. She performed experiments in which heart cells called cardiomyocytes were treated with Doxo and demonstrated elevated IFN-I signaling in these cells. Lei also showed that damaged mitochondria within Doxo-treated cardiomyocytes accumulate and release Z-form mtDNA, an altered DNA structure that strongly activates the immune system. Moreover, she observed that Doxo-treated cardiomyocytes express high levels of the Z-DNA stabilizing immune sensor ZBP1.

Based on these data, the research team hypothesized that ZBP1 might play a role in connecting Doxo-induced mitochondrial damage, IFN-I responses, and cardiotoxicity. To further explore this hypothesis, they performed collaborative experiments with the laboratories of Pingwei Li, PhD, from the Department of Biochemistry and Biophysics at the Texas A&M College of Agriculture and Life Sciences, and Jason Upton, PhD, from the Department of Biological Sciences at Auburn University. These studies demonstrated that ZBP1 binds to Z-form mtDNA released from damaged mitochondria, stabilizing it and facilitating its interaction with another DNA sensor cyclic GMP-AMP synthase (cGAS). The novel complex of ZBP1 and cGAS then recruits additional immune signaling factors to sustain IFN-I responses in the heart after Doxo chemotherapy.

To determine whether these findings were relevant to heart failure, the team then utilized a preclinical experimental animal model of Doxo-induced cardiotoxicity. Models exposed to Doxo for several weeks (a timeline analogous to a cancer treatment regimen) exhibited high levels of IFN-I, immune cell infiltration into the heart, and cardiac injury. Working with Carl Tong, MD, PhD, FACC, from the Department of Medical Physiology at the Texas A&M School of Medicine, the team measured heart function in animal models during and after chemotherapy using echocardiography. Strikingly, models deficient in ZBP1 or IFN-I were protected from Doxo-induced cardiotoxicity and exhibited less cardiac dysfunction and heart failure after chemotherapy treatment.

Overall, this study shows that ZBP1 sustains IFN-I responses to mitochondrial damage and Z-form mtDNA release, and it reveals that ZBP1 is a key factor in chemotherapy-related cardiac dysfunction and perhaps other cardiovascular disorders.

“Given that cancer therapy-associated heart failure is a significant and growing public health concern, we believe that targeting this novel mtDNA-innate immune axis may provide a therapeutic path for cancer patients and survivors experiencing this devastating health issue,” West said.

Other authors included Jordyn J. VanPortfliet, Yi-Fan Chen, Joshua D. Bryant, Sylvia Torres-Odio, Ying Li, Bing Wang, and Laura Ciaccia West of Texas A&M University; Danielle Fails and Michael Spencer of Fortis Life Sciences; Katherine B. Ragan of the University of Texas at Austin; Jingti Deng, Armaan Mohan, and Timothy E. Shutt of the University of Calgary Alberta, Canada; Olivia N. Brahms and Shawn D. Yates of Auburn University; Marcus W. Bosenberg of Yale School of Medicine; and Gerald S. Shadel of the Salk Institute.

This work was supported by the National Institutes of Health (R01HL148153, R01AI155621, R01CA193522, R01HL145534, R01AI145287, R01AR069876, R01CA216101, R21AI135709, F31HL160141, and P30ES029067) the Natural Sciences and Engineering Research Council of Canada (NSERC—RGPIN-2016-04083), and the American Heart Association (825908). Additional support was provided by an X-Grant from the Texas A&M University Office of the Vice President for Research.