Ischemic-Trained Monocytes Improve Arteriogenesis in a Mouse Model of Hindlimb Ischemia

Objective: Monocytes, which play an important role in arteriogenesis, can build immunologic memory by a functional reprogramming that modifies their response to a second challenge. This process, called trained immunity, is evoked by insults that shift monocyte metabolism, increasing HIF (hypoxia-inducible factor)-1α levels. Since ischemia enhances HIF-1α, we evaluate whether ischemia can lead to a functional reprogramming of monocytes, which would contribute to arteriogenesis after hindlimb ischemia. Methods and Results: Mice exposed to ischemia by 24 hours of femoral artery occlusion (24 hours trained) or sham were subjected to hindlimb ischemia one week later; the 24-hour trained mice showed significant improvement in blood flow recovery and arteriogenesis after hindlimb ischemia. Adoptive transfer using bone marrow-derived monocytes (BM-Mono) from 24-hour trained or sham donor mice, demonstrated that recipients subjected to hindlimb ischemia who received 24 hours ischemic-trained monocytes had remarkable blood flow recovery and arteriogenesis. Further, ischemic-trained BM-Mono had increased HIF-1α and GLUT-1 gene expression during femoral artery occlusion. Circulating cytokines and GLUT-1 were also upregulated during femoral artery occlusion.Transcriptomic analysis and confirmatory qPCR performed in 24 hours trained and sham BM-Mono revealed that among the 15 top differentially expressed genes, 4 were involved in lipid metabolism in the ischemic-trained monocytes. Lipidomic analysis confirmed that ischemia training altered the cholesterol metabolism of these monocytes. Further, several histone-modifying epigenetic enzymes measured by qPCR were altered in mouse BM-Mono exposed to 24 hours hypoxia. Conclusions: Ischemia training in BM-Mono leads to a unique gene profile and improves blood flow and arteriogenesis after hindlimb ischemia.

Alternative Combined Retrograde–Antegrade Use of a Re-entry Device in the Revascularization of a Surgically Ligated Superficial Femoral Artery Occlusion

We report a case of a diabetic patient with critical limb ischemia, who previously underwent thromboendarterectomy at the right lower extremity, resulting in surgical ligation at the proximal third of the right superficial femoral artery (SFA). Twenty months later, the patient developed foot ulcers; endovascular treatment was therefore performed. After obtaining a retrograde right SFA subintimal access, directly puncturing the occluded segment of the artery, a re-entry intravascular ultrasound-guided catheter was used to gain proximal re-entry. Then, the same device was used again, in antegrade fashion, to obtain re-entry into the patent popliteal artery. A covered stent was deployed in the site of the surgical closure. In the following 3 months, foot ulcers healed.