*3.2. Arteriogenesis*

"Although capillary sprouting may deliver some relief to the underperfused territory, only true collateral arteries are principally capable of providing large enough amounts of blood flow to the ischemic area at risk for necrosis or loss of function." [41] Hence, arteriogenesis is the process of outward remodelling [44] (i.e., growth in diameter and length) of pre-existing anastomoses [45], resulting in an increased flow capacity of the artery.

Fluid shear stress, "the product of spatial flow velocity changes during the cardiac cycle and blood viscosity" [46] "is the primary and strongest arteriogenic stimulus" [47]. It leads to the expression of nitric oxide (NO), VEGF and monocyte chemoattractant protein-1 (MCP-1), resulting in the attraction and activation of monocytes [41,44,48–51]. Those inflammatory cells conduct the process of arteriogenesis with induction of cell proliferation as well as preparation of the extracellular matrix to enable cell migration [48].

Arteriogenesis is a common phenomenon that interventional cardiologists encounter on a daily basis as it appears (e.g., in the course of hypertensive heart disease with concentric left ventricular hypertrophy and augmented myocardial mass). Due to the direct and curvilinear relationship between myocardial mass and coronary arterial cross-sectional area [52], structural remodelling (i.e., arteriogenesis of the epicardial coronary arteries) occurs, resulting in large vascular calibres and, because of undirected growth, also affecting vascular length. Thus, this leads to the typical corkscrew pattern that is seen in this condition (Figure 4A).

**Figure 4.** Angiographic presentation of two different pathophysiological etiologies of arteriogenesis. (**A**) Arteriogenesis in the course of hypertensive heart disease with concentric left ventricular hypertrophy. Enlarged myocardial mass is the driving force behind this arterial growth. (**B**) Arteriogenesis solely initiated by constant elevation of fluid shear stress. Iatrogenic drainage of the left anterior descending artery (LAD) into the right ventricular cavity after myocardial biopsy significantly increased coronary blood flow and consequently vascular size.

Importantly and in contrast to the previously outlined process of angiogenesis, myocardial ischemia is unrelated to this process [53,54]. Arteriogenesis depends solely on physical pressure gradients across pre-formed anastomoses between different arterial territories with consequent augmentation of endothelial fluid shear stress [47,53,55]. Figure 4B illustrates this concept: After myocardial biopsy with perforation of the LAD and consecutive drainage into the (low resistance) right ventricular cavity, blood flow in the LAD increased due to the abrupt decrease in "vascular" resistance. As a consequence, abundant growth of the LAD, both in cross-sectional area and length, could be observed [56].

### **4. Therapeutic Promotion of the Coronary Collateral Circulation**

The following chapter summarizes the most promising therapeutic approaches of coronary collateral promotion divided according to the basic concept of biochemical or biophysical methods.
