**6. Conclusions**

Based on the growing problem of patients with coronary artery disease and incomplete revascularization, several promising therapeutic alternatives for myocardial revascularization have been examined. Because of the known survival benefit of patients with a functional coronary collateral circulation, its promotion is a promising concept. However, until now, none of the evaluated concept could be implemented in daily clinical practice despite appealing results in clinical trials.

Biochemical concepts of angio- or arteriogenesis by growth factors seem to be prone to potentially harmful effects, since arteriogenesis shares many common mechanisms with inflammatory diseases, such as atherosclerosis. Thus, the risk benefit ratio is inappropriate and further research using growth factors was discontinued.

Biophysical concepts are based on increasing arteriogenesis via elevated tangential vascular fluid shear stress. Physical exercise training or external counterpulsation have been documented to positively affect clinical symptoms as well as coronary blood flow. The effect of both physical arteriogenic procedures is, however, transient (i.e., vanishes after its termination) and the time-consuming procedure of several hours per week limits the use to selected, highly motivated patients.

Alternative techniques such as coronary sinus reduction or promotion of extracardiac coronary supply by permanent occlusion of the distal internal mammary artery are promising approaches, since they have a permanent effect and ought to be efficacious in reducing myocardial ischemia to the effect that it is clinically relevant. Both approaches are being currently studied in ongoing clinical trials (NCT0271043 respectively NCT03710070) and the results of these investigations will clarify the clinical potential of those new therapeutic methods.

**Author Contributions:** Conceptualization, B.MR. and S.C.; Writing—Original Draft Preparation, B.MR. and S.C.; Writing—Review & Editing, B.MR. and S.C.; Visualization, B.MR.; Supervision, C.S.; Project Administration, C.S.; Funding Acquisition, C.S.

**Funding:** This research was funded by the Swiss National Science Foundation for Research (Grant #32003B\_163256/1 to CS).

**Acknowledgments:** We thank Romy Sweda, MD, for her contribution to the revision of this manuscript.

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