Temporal evolution of mechanical stimuli from vascular remodeling in response to the severity and duration of aortic coarctation in a preclinical model

Abstract

Coarctation of the aorta (CoA) is one of the most common congenital cardiovascular diseases. CoA patients frequently undergo surgical repair, but hypertension (HTN) is still common. The current treatment guideline has revealed irreversible changes in structure and function, yet revised severity guidelines have not been proposed. Our objective was to quantify temporal alterations in mechanical stimuli and changes in arterial geometry in response to the range of CoA severities and durations (i.e. age of treatment) seen clinically. Rabbits were exposed to CoA resulting in peak-to-peak blood pressure gradient (BPGpp) severities of ≤ 10, 10–20, and ≥ 20 mmHg for a duration of ~ 1, 3, or 20 weeks using permanent, dissolvable, and rapidly dissolvable sutures. Elastic moduli and thickness were estimated from imaging and longitudinal fluid–structure interaction (FSI) simulations were conducted at different ages using geometries and boundary conditions from experimentally measured data. Mechanical stimuli were characterized including blood flow velocity patterns, wall tension, and radial strain. Experimental results show vascular alternations including thickening and stiffening proximal to the coarctation with increasing severity and/or duration of CoA. FSI simulations indicate wall tension in the proximal region increases markedly with coarctation severity. Importantly, even mild CoA induced stimuli for remodeling that exceeds values seen in adulthood if not treated early and using a BPGpp lower than the current clinical threshold. The findings are aligned with observations from other species and provide some guidance for the values of mechanical stimuli that could be used to predict the likelihood of HTN in human patients with CoA.

Coarctation duration and severity predict risk of hypertension precursors in a preclinical model and hypertensive status among patients

“…; strain, wall tension). Recent work 8,9 characterized the temporal evolution of these stimuli that ultimately resulted in permanent changes to proximal aortic structure and function 8 for the groups of rabbits in the current study.…”

“…Area under the dose response curves (AUD) was then quantified as an aggregate measure of dysfunction. Detailed results of each index are noted elsewhere 8,9 with aggregate alterations and multiple linear regression fits presented below.…”

“…The >20 mmHg BPGpp seems to date back to surgical outcomes from several decades ago 7 , but persists despite notable advances. Experimental results implementing BPGpp below the current guideline in rabbits has revealed HTN precursors within the proximal region exposed to high blood pressure (BP) 8,9 . These include medial thickening and stiffening, and endothelial dysfunction, which all persisted after treatment.…”

Coarctation Duration and Severity Predict Risk of Hypertension Precursors in a Preclinical Model and Hypertensive Status Among Patients

“…Although CoA may be a combination of these issues, the current results show that the duration a coarctation with severity below the current putative treatment threshold is present, in the absence of these other possible contributors, can lead to consequences of proximal aortic stiffening and endothelial dysfunction rooted in pronounced mechanical stimuli. 9 Association of traditional hypertension biomarkers with predictors in the current study has yet to be determined in future work. However, arterial thickening, stiffening, and active arterial response are all determinants of aortic biomechanical behavior previously related to hypertension.…”

“…The main findings from the current study are, therefore, likely a result of adverse mechanical stimuli imposed on the proximal aorta as a result of the coarctation, with changes in BP and deformation primarily implicated (eg, strain, wall tension). Recent work 8,9 characterized the temporal evolution of these stimuli that ultimately resulted in permanent changes to proximal aortic structure and function 8 for the groups of rabbits in the current study.…”