Accelerated adverse cardiac remodeling in a model of TET2 mutation-driven clonal hematopoiesis is ameliorated by IFNa treatment by modulating the monocyte response

Background - Clonal hematopoiesis of indeterminate potential (CHIP) is the selection and expansion of a genetically distinct subpopulation of blood cells. While a natural age-related process, it is known to cause cancer, and interestingly, it is also associated with an increased risk of developing cardiovascular disease. Blood cancers caused by CHIP are successfully treated with specific cancer treatment without cardiotoxic effects. Therefore, we investigated the effect of the immunotherapy agent interferon-α (IFNα, a pleiotropic cytokine known to modulate hematopoietic stem cell proliferation) on cardiac function in a novel murine CHIP model with a myocardial infarction (MI). Methods - Competitive bone marrow transplantation of either wild type (WT) or TET2-/- CD45.2+ bone marrow cells into CD45.1+ PepBoy C56Bl/6J mice was performed to produce a WT group and a hematopoietic TET2-deficient (TET2def) group, which mimics TET2 mutation-driven clonal hematopoiesis. Subsequently, MI was induced in all mice through permanent ligation of the left anterior descending artery. Mice were divided in vehicle or IFNα (20.000 U/day) groups and treated 5x/week for 4 weeks after which they were sacrificed. Cardiac echocardiography was performed at baseline and sacrifice to determine cardiac function. Peripheral blood was collected to determine the effect of treatment on blood cell composition using flow cytometry, and immunohistochemical (IHC) stainings were performed on cardiac sections to assess myocardial inflammation. Results - After 4 weeks of treatment post-MI, cardiac function was significantly worse in TET2def vehicle mice compared to WT vehicle mice, based on left ventricular ejection fraction (LVEF) (p=0.04). IFNα treatment in TET2def mice prevented LVEF decline significantly (p=0.02), which was not observed in IFNα vehicle mice (p=0.02), suggesting TET2-specific effects of IFNα. In the circulation, expansion of TET2-/- lymphocytes (p=0.02) and neutrophils (p=0.03) was significantly inhibited by IFNα treatment, whereas anti-inflammatory Ly6Clow monocytes were significantly increased (p=0.03). Furthermore, immunofluorescence staining from TET2def mice revealed increased myocardial inflammation as assessed by IL-1β expression compared to WT mice, which was reduced in the TET2def hearts treated with IFNα. Conclusions - The presence of TET2 mutation-driven clonal hematopoiesis results in adverse LV remodeling in a mouse post MI heart failure mode. This decline of LVEF is ameliorated by IFNα treatment. IFNα also prevents lymphocyte and neutrophil expansion and increases Ly6C monocytes. These findings alongside reduced cardiac IL-1β expression in TET2def mice suggest a shift in the monocyte response as an underlying mechanism in the cardioprotective effect of IFNα-mediated effects in TET2 mutation-driven clonal hematopoiesis.