**4. Conclusions**

This review addresses a new field of LEAD therapy. Thus, at first glance, therapeutic use of blood flow restriction and peripheral artery disease and LEAD are of a contradictory nature, but both induce physiological vessel growth by hemodynamic forces and hemodynamic adaptions. We want to emphasize overlaps in e ffects on vessel physiology and function and the need for new clinical trials that would focus on the e ffects of BFR in cardiovascular patients.

There is a lack of evidence regarding studies focused on BFR with resistance exercise, particular in seniors [73]. Promising results are presented by Shimizu et al. They showed that BFR training improved endothelial function and blood circulation in active elderly people [74].

A long-term effect of structured exercise training is a decrease in blood flow-associated hypoxia, which is also mediated by effects of fluid shear. Similar physiological changes occur as a consequence. Additionally, BFR could serve as a model for how exercise leads to adaptations in LEAD, and further beneficial effects of BFR could also work when implemented in exercise training for LEAD patients.

However, many mechanisms are not ye<sup>t</sup> proven by high quality evidence. As further considerable differences between the mechanism of the two comparators in this review exist; a final statement (or even recommendation) regarding whether BFR can act as a model for the mechanism of how exercise affects LEAD cannot be given. Considering the differences and (of course) contraindications for exercising, BFR can, nevertheless, be used as a model for certain outcomes of LEAD exercise intervention effects modeling or, from a practical point of view, sample size calculation. As future clinical applications of BFR training in LEAD patients should be evaluated, the most beneficial effect is expected in patients with stable lower grade LEAD. Patients with previous vascular interventions (stent or bypass surgery) might not be suitable for BFR due to the risk of occlusion of the vascular reconstruction by external mechanical forces. By simulating hypoxic metabolism in BFR intervals, the physiological activation of autogenious pro-arteriogenetic changes could be triggered. Due to the reduction in mechanical forces during BFR and low-load training, the method could be suitable in particular for patients with limited physical resilience. A known problem, when mobility is ye<sup>t</sup> limited by LEAD to lower than 100 m, is that effective exercise is difficult to conduct. Regarding this problem, BFR training could be useful for the preconditioning of a structured exercise program for patients with advanced Fontaine IIb LEAD.

#### **Funding:** This research received no external funding

**Acknowledgments:** The Goethe Research Academy for Early Career Researchers (GRADE) provided editorial assistance during preparation of this manuscript.

**Conflicts of Interest:** The authors declare no conflict of interest.
