Complex hemodynamics at the apex of an arterial bifurcation induces vascular remodeling resembling cerebral aneurysm initiation

Abstract

Background and purpose: Arterial bifurcation apices are common sites for cerebral aneurysms, raising the possibility that the unique hemodynamic conditions associated with flow dividers predispose the apical vessel wall to aneurysm formation. This study sought to identify the specific hemodynamic insults that lead to maladaptive vascular remodeling associated with aneurysm development and to identify early remodeling events at the tissue and cellular levels.

Methods: We surgically created new branch points in the carotid vasculature of 6 female adult dogs. In vivo angiographic imaging and computational fluid dynamics simulations revealed the detailed hemodynamic microenvironment for each bifurcation, which were then spatially correlated with histologic features showing specific tissue responses.

Results: We observed 2 distinct patterns of vessel wall remodeling: (1) hyperplasia that formed an intimal pad at the bifurcation apex and (2) destructive remodeling in the adjacent region of flow acceleration that resembled the initiation of an intracranial aneurysm, characterized by disruption of the internal elastic lamina, loss of medial smooth muscle cells, reduced proliferation of smooth muscle cells, and loss of fibronectin.

Conclusions: Strong localization of aneurysm-type remodeling to the region of accelerating flow suggests that a combination of high wall shear stress and a high gradient in wall shear stress represents a "dangerous" hemodynamic condition that predisposes the apical vessel wall to aneurysm formation.

Figure 1

A, Schematic of bifurcation creation. L (R)-CCA indicates left (right) common carotid artery. B, A created bifurcation. C, Over-lay of CFD-calculated velocity vectors (color indicates magnitude) on a histologic section of a bifurcation (from dog No. 4) 2 months after creation (van Gieson’s staining). D, WSS and WSSG along the median wall of the bifurcation apex (left branch) reveal 3 regions with distinct flow characteristics: I, the impingement region; II, acceleration region; and III, recovery region. The range of normal physiologic WSS values for a straight vessel segment is indicated by the gray band.

Figure 2

Morphology (hematoxylin and eosin stain, ×50) of bifurcations (A) 2 weeks (dog No. 1, left branch) and (B) 2 months (dog No. 4, left branch) after creation, (C) in a natural carotid bifurcation, and (D) at the suture site (dog No. 3, R2–L2). The blue arrow indicates the apex. 1, 2 and 3, 4 are magnified views (×400) of regions II and I in the corresponding bifurcation, stained with trichrome (1, 3) and van Gieson (2, 4). Hyperplastic remodeling is demonstrated in region I (3, 4): hyperplasia in the intimal layer to the luminal side of the IEL is indicated by yellow arrows. In the 2-month created bifurcation, the media was thicker (B), and additional layers of elastin were present in the subendothelial layer (arrowhead; B4). Destructive remodeling is demonstrated in region II (1, 2): In the 2-month created bifurcation, a “groove” was formed with thinned media (B). The IEL was disrupted and endothelium lost (B2). Anastomosis did not affect the remodeling described (D). R2–L2 anastomosis in dog No. 3, trichrome staining. Note the elevated collagen content immediately adjacent to the suture site but normal vessel wall a short distance (≈1 mm) from the suture.

Figure 3

Medial SMC proliferation in a natural carotid bifurcation and 2 created bifurcations (dogs No. 1 and 4). A, Proliferation index (PCNA-positive nuclei/total medial SMCs) is shown from the impingement region into the left branch of the bifurcations. B–D, PCNA staining of representative sections from regions I, II, and III of the 2-month bifurcation.

Figure 4

Fibronectin staining in regions I, II, and III (A–C) of the left branch of dog No. 4 and an unmanipulated left common carotid artery (D). Arrow indicates the apex. Note diminished staining of the media in region II (B).

Figure 5

Hemodynamic environments (as defined in Figure 1D) and localization of remodeling events in (A) dog No. 2 (right branch), (B) No. 4 (left branch), and (C) No. 6 (left branch). Hyperplastic responses were observed in region I, whereas all destructive events were in region II. Bifurcation lumen (reconstructed from in vivo imaging) with WSS distribution.