Abstract
Collateral arteries are a vessel subtype that bridges two artery branches, forming a natural bypass that can deliver blood flow downstream of an occlusion. These bridges in the human heart are associated with better outcomes during coronary artery disease. We recently found that their rapid development in neonates supports heart regeneration, while the non-regenerative adult heart displays slow and minimal collateralization. Thus, inducing robust collateral artery networks could serve as viable treatment for cardiac ischemia, but reaching this goal requires more knowledge on their developmental mechanisms and functional capabilities. Here, we use whole-organ imaging and 3D computational fluid dynamics (CFD) modeling to identify the spatial architecture of and predict blood flow through collaterals in neonate and adult hearts. We found that neonate collaterals are more numerous, larger in diameter, and, even when similar in size/number, are predicted to more effectively re-perfuse an occluded coronary network when compared to adults. CFD analysis revealed that collaterals perform better in neonates because of decreased differential pressures along their coronary artery tree. Furthermore, testing of various collateral configurations indicated that larger, more proximal collaterals are more beneficial than many smaller ones, identifying a target architecture for therapeutic interventions. Morphometric analysis revealed how the coronary artery network expands during postnatal growth. Vessel diameters do not scale with cardiac muscle growth. Instead, the coronary tree expands solely by adding additional branches of a set length, a burst of which occurs during murine puberty. Finally, we compared mouse structural and functional data to human hearts. Surprisingly, fetal human hearts possessed a very large number of small, but mature, smooth muscle cell covered collaterals while angiogram data indicated adult patients with chronic coronary occlusions contained at least two. Comparing size ratios with modeled mouse data suggested low re-perfusion capabilities of the embryonic collaterals but higher functional benefits of those in diseased adults. Our unique interdisciplinary approach allowed us to quantify the functional significance of collateral arteries during heart regeneration and repair–a critical step towards realizing their therapeutic potential.
Competing Interest Statement
The authors have declared no competing interest.
