UAB MEDICINE CARDIOVASCULAR SERVICES UPDATE 2019 FEATURES To read the full stories, please visit uabmedicine.org/refercv ‘RESETTING’ DYSFUNCTIONAL T-CELLS COULD REVERSE CHRONIC HEART FAILURE A heart attack triggers an acute inflammatory response, followed by resolution of inflammation and wound healing. A severe heart attack, however, can cause chronic and sustained inflammation that leads to heart failure and death. role in chronic ischemic heart failure.” Restoring the proper function of T-regs in humans, Dr. Prabhu adds, is “an appealing therapeutic target for the resolution of chronic inflammation in ischemic cardiomyopathy.” In mouse experiments, University of Alabama at Birmingham scientists have found a way to hit an immunological “reset button” that stops this inappropriately sustained inflammation. It reverses the pathologic enlargement and pumping failure of the heart, and it suggests a therapeutic approach to treating human heart failure. Published in the journal Circulation, the research is being led by UAB Medicine cardiovascular disease physician Sumanth Prabhu, MD. Furthermore, the UAB researchers showed that the dysfunctional T-reg cells were essential for adverse left- ventricular remodeling. Essentiality was demonstrated by selectively ablating the dysfunctional T-reg cells at four weeks after inducing heart failure. Ablation was done by giving diphtheria toxin to genetically engineered mice that have the diphtheria toxin receptor inserted into T cells at the Foxp3 gene site, or by giving the mice anti-CD25 antibodies. The research found that a group of immune cells called regulatory T-lymphocyte cells, or T-regs, appear to go rogue in heart failure. Instead of their normal job to resolve inflammation, the dysfunctional T-reg cells become pro- inflammatory and prevent the growth of new capillaries. Experimental removal of those dysfunctional T-reg cells from heart-failure mice acted as a reset button to reverse heart failure, and the replacement T-regs that the mice produced resolved inflammation. This shows, Dr. Prabhu says, that dysfunctional T-reg cells play “an essential pathogenetic T-reg ablation reversed left-ventricular remodeling over the next four weeks. Also, ablation with antibody halted further increase in left-ventricular remodeling, while remodeling in the heart failure mice given a non-specific antibody continued to worsen. Ablation alleviated fibrosis and systemic inflammation in the heart, and it enhanced growth of new capillaries. Importantly, the new T-reg cells produced by the mice after an ablation pulse were no longer pro- inflammatory; instead, they showed restoration of normal T-reg immunosuppressive capacity. RANKED IN TOP 20 NATIONALLY BY U.S. News & World Report NEONATAL PIG HEARTS CAN HEAL FROM HEART ATTACK Researchers at the University of Alabama at Birmingham and at several institutions in Singapore have discovered that the hearts of newborn piglets can almost completely heal themselves after experimental heart attacks. This regenerative capacity is short-lived, disappearing by day three after birth. Still, this study marks the first time the ability to regrow heart muscle has been shown in large mammals. Published in the journal Circulation, this research has significant clinical implications, says lead UAB researchers Jianyi “Jay” Zhang, MD, PhD, and Wuqiang Zhu, MD, PhD. Although no study has ever assessed neonatal heart regeneration in humans (except a case study of one patient), there is evidence that surgical correction of anomalous coronary arteries in the first three months of life is associated with significant improvement of systolic function. Therefore, identifying a regenerative window in larger mammals is a crucial step toward understanding the human heart regenerative window, and it may serve as a platform for future clinical studies in human infants afflicted by devastating heart conditions. This could establish new guidelines for timing of pediatric heart surgeries that benefit from the regenerative potential of the newborn human heart, help to design novel surgical techniques for pediatric heart surgery, and assist in developing new therapeutic modalities to enhance or prolong this regenerative window. Most importantly, understanding the mechanisms that underlie the drastic changes in neonatal cardiac cardiomyocyte proliferation during the first week of life may lead to the ability to manipulate these mechanisms to promote myocardial regeneration in injured hearts, not only in children but also in adult patients. The research found that one-day-old piglets were able to functionally and structurally recover from experimental heart attacks, as measured by heart pumping ability, thickness of the heart muscle in the left ventricle, and a near absence of fibrotic scar tissue. In contrast, three-day-old piglets had significant functional and structural impairments, and two- day-old piglets showed only partial recovery.