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.

Translational Perspective

Clonal hematopoiesis increases the risk of atherosclerotic cardiovascular disease. Amongst mutations associated with clonal hematopoiesis, Jak2 ^V617F confers the greatest increased risk of atherosclerotic cardiovascular disease. Our findings demonstrate that aggressive LDL lowering normalizes atherosclerosis regression in Jak2 ^V617F clonal hematopoiesis by reversing inflammasome activation and inducing pro-resolving changes in macrophages. These changes lead to increased features of plaque stability, including decreased macrophage burden, increased collagen, and improved efferocytosis. These results suggest that aggressive LDL-C lowering in Jak2 ^V617F clonal hematopoiesis patients would mitigate the increased atherosclerotic cardiovascular disease risk.