Aggressive Cholesterol Lowering Normalizes Atherosclerosis Regression in Jak2(V617F) Clonal Hematopoiesis.

BACKGROUND -: Clonal hematopoiesis (CH) has emerged as an important risk factor for atherosclerotic cardiovascular disease (ACVD). Mouse studies have established a causal role of CH in atherosclerosis progression and have defined macrophage inflammatory responses as a key underlying mechanism. We undertook the present study to assess the hypothesis that ongoing inflammation would impede atherosclerosis regression in Jak2(V617F) (Jak2(VF) ) CH mice. METHODS AND RESULTS -: Chimeric Jak2 (VF/WT) or control WT/WT bone marrow was transplanted into Ldlr (-/-) mice and, following 13-16 weeks of Western diet-induced atherosclerosis progression, cholesterol was lowered either moderately (to 200-300 mg/dl) or markedly (to 100 mg/dl). With moderate cholesterol lowering there was impaired regression in Jak2(VF) CH mice compared to controls. However, with marked cholesterol lowering, regression was similar in Jak2(VF) CH and control mice.Two mechanisms of low-density lipoprotein (LDL) lowering-induced suppression of inflammation in plaques were implicated: 1) reversal of increased proliferation, DNA damage and Absent in Melanoma 2 (AIM2) inflammasome activation specifically in Jak2(VF) macrophages and 2) markedly increased macrophage triggering receptor expressed on myeloid cells 2 (TREM2), c-myc expressing macrophages in both Jak2(VF) and control mice. CONCLUSIONS -: Aggressive LDL lowering reverses inflammasome activation and induces pro-resolving changes in macrophages in Jak2(VF) CH, halting atherosclerosis progression and promoting features of plaque stabilization. These findings suggest that aggressive LDL cholesterol lowering could effectively reverse ACVD risk in individuals with JAK2(VF) clonal hematopoiesis.