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

BACKGROUND: Coarctation of the aorta (CoA) often leads to hypertension posttreatment. Evidence is lacking for the current >20 mm Hg peak-to-peak blood pressure (BP) gradient (BPGpp) guideline, which can cause aortic thickening, stiffening, and dysfunction. This study sought to find the BPGpp severity and duration that avoid persistent dysfunction in a preclinical model and test if predictors translate to hypertension status in patients with CoA. METHODS: Rabbits (n=75; 5-12/group) were exposed to mild, intermediate, or severe CoA (≤12, 13-19, ≥20 mm Hg BPGpp) for ≈1, 3, or 22 weeks using dissolvable and permanent sutures with thickening, stiffening, contraction, and endothelial function evaluated via multivariate regression. Relevance to patients with CoA (n=239; age, 0.01-46 years; median 3.7 months) was tested by retrospective review of predictors (preoperative BPGpp, surgical age, etc.) versus follow-up hypertension status. RESULTS: CoA duration and severity were predictive of aortic remodeling and active dysfunction in rabbits, and hypertension in patients with CoA. Interaction between patient age and BPGpp at surgery contributed significantly to hypertension, similar to rabbits, suggesting preclinical findings translate to patients. Machine learning decision tree analysis uncovered that preoperative BPGpp and surgical age predict risk of hypertension along with residual postoperative BPGpp. CONCLUSIONS: These findings suggest the current BPGpp threshold determined decades ago is likely too high to prevent adverse coarctation-induced aortic remodeling. The results and decision tree analysis provide a foundation for revising CoA treatment guidelines considering the interaction between CoA severity and duration to limit the risk of hypertension.

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

Background: Coarctation of the aorta (CoA) often leads to hypertension (HTN) post-treatment. Evidence is lacking for the current >20 mmHg peak-to-peak blood pressure gradient (BPGpp) guideline, which can cause aortic thickening, stiffening and dysfunction. This study sought to find the BPGpp severity and duration that avoid persistent dysfunction in a preclinical model, and test if predictors translate to HTN status in CoA patients. Methods: Rabbits (N=75; 5-12/group) were exposed to mild, intermediate or severe CoA (≤12, 13-19, ≥20 mmHg BPGpp) for ~1, 3 or 22 weeks using dissolvable and permanent sutures with thickening, stiffening, contraction and endothelial function evaluated via multivariate regression. Relevance to CoA patients (N=239; age=0.01-46 years; median 3.7 months) was tested by retrospective review of predictors (preoperative BPGpp, surgical age, etc.) vs follow-up HTN status. Results: CoA duration and severity were predictive of aortic remodeling and active dysfunction in rabbits, and HTN in CoA patients. Interaction between patient age and BPGpp at surgery contributed significantly to HTN, similar to rabbits, suggesting preclinical findings translate to patients. Machine learning decision tree analysis uncovered that pre-operative BPGpp and surgical age predict risk of HTN along with residual post-operative BPGpp. Conclusions: These findings suggest the current BPGpp threshold determined decades ago is likely too high to prevent adverse coarctation-induced aortic remodeling. The results and decision tree analysis provide a foundation for revising CoA treatment guidelines considering the interaction between CoA severity and duration to limit the risk of HTN.

Consistency of the continuous flow pressure gradient despite aortic arch anomalies co-existing with coarctation.

Aims: Severity assessment for coarctation of the aorta (CoA) is challenging due to concomitant morphological anomalies (complex CoA) and inaccurate Doppler-based indices. Promising diagnostic performance has been reported for the continuous flow pressure gradient (CFPG), but it has not been studied in complex CoA. Our objective was to characterize the effect of complex CoA and associated hemodynamics on CFPG in a clinical cohort. Methods and Results: Retrospective analysis identified discrete juxtaductal (n=25) and complex CoA (n=43; transverse arch and/or isthmus hypoplasia) patients with arm-leg systolic blood pressure gradients (BPG) within 24 hours of echocardiography for comparison to BPG by conventional Doppler indices (simplified Bernoulli equation and modified forms correcting for proximal kinetic energy and/or recovered pressure). Results were interpreted using the current CoA guideline (BPG ≥20 mmHg) to compare diagnostic performance indicators including receiver operating characteristic curves, sensitivity, specificity, and diagnostic accuracy, among others. Echocardiography Z-scored aortic diameters were applied with computational stimulations from a preclinical CoA model to understand aspects of the CFPG driving performance differences.Diagnostic performance was substantially reduced from discrete to complex CoA for conventional Doppler indices calculated from patient data, and by hypoplasia and/or long segment stenosis in simulations. In contrast, diagnostic indicators for the CFPG only modestly dropped for complex vs discrete CoA. Simulations revealed differences in performance due to inclusion of the Doppler velocity index and diastolic pressure half-time in the CFPG calculation. Conclusion: CFPG is less affected by aortic arch anomalies co-existing with CoA when compared to conventional Doppler indices.

Aortic Remodeling Kinetics in Response to Coarctation-Induced Mechanical Perturbations.

Background: Coarctation of the aorta (CoA; constriction of the proximal descending thoracic aorta) is among the most common congenital cardiovascular defects. Coarctation-induced mechanical perturbations trigger a cycle of mechano-transduction events leading to irreversible precursors of hypertension including arterial thickening, stiffening, and vasoactive dysfunction in proximal conduit arteries. This study sought to identify kinetics of the stress-mediated compensatory response leading to these alterations using a preclinical rabbit model of CoA. Methods: A prior growth and remodeling (G&R) framework was reformulated and fit to empirical measurements from CoA rabbits classified into one control and nine CoA groups of various severities and durations (n = 63, 5-11/group). Empirical measurements included Doppler ultrasound imaging, uniaxial extension testing, catheter-based blood pressure, and wire myography, yielding the time evolution of arterial thickening, stiffening, and vasoactive dysfunction required to fit G&R constitutive parameters. Results: Excellent agreement was observed between model predictions and observed patterns of arterial thickening, stiffening, and dysfunction among all CoA groups. For example, predicted vascular impairment was not significantly different from empirical observations via wire myography (p-value > 0.13). Specifically, 48% and 45% impairment was observed in smooth muscle contraction and endothelial-dependent relaxation, respectively, which were accurately predicted using the G&R model. Conclusions: The resulting G&R model, for the first time, allows for prediction of hypertension precursors at neonatal ages that is currently challenging to examine in preclinical models. These findings provide a validated computational tool for prediction of persistent arterial dysfunction and identification of revised severity-duration thresholds that may ultimately avoid hypertension from CoA.

Intravascular imaging of angioplasty balloon under-expansion during pre-dilation predicts hyperelastic behavior of coronary artery lesions.

Introduction: Stent-induced mechanical stimuli cause pathophysiological responses in the coronary artery post-treatment. These stimuli can be minimized through choice of stent, size, and deployment strategy. However, the lack of target lesion material characterization is a barrier to further personalizing treatment. A novel ex-vivo angioplasty-based intravascular imaging technique using optical coherence tomography (OCT) was developed to characterize local stiffness of the target lesion. Methods: After proper institutional oversight, atherosclerotic coronary arteries (n = 9) were dissected from human donor hearts for ex vivo material characterization <48 h post-mortem. Morphology was imaged at the diastolic blood pressure using common intravascular OCT protocols and at subsequent pressures using a specially fabricated perfusion balloon that accommodates the OCT imaging wire. Balloon under-expansion was quantified relative to the nominal balloon size at 8 ATM. Correlation to a constitutive hyperelastic model was empirically investigated (n = 13 plaques) using biaxial extension results fit to a mixed Neo-Hookean and Exponential constitutive model. Results and discussion: The average circumferential Cauchy stress was 66.5, 130.2, and 300.4 kPa for regions with <15, 15-30, and >30% balloon under-expansion at a 1.15 stretch ratio. Similarly, the average longitudinal Cauchy stress was 68.1, 172.6, and 412.7 kPa, respectively. Consequently, strong correlation coefficients >0.89 were observed between balloon under-expansion and stress-like constitutive parameters. These parameters allowed for visualization of stiffness and material heterogeneity for a range of atherosclerotic plaques. Balloon under-expansion is a strong predictor of target lesion stiffness. These findings are promising as stent deployment could now be further personalized via target lesion material characterization obtained pre-operatively.

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

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.

Clinical, Experimental, and Computational Validation of a New Doppler-Based Index for Coarctation Severity Assessment.

BACKGROUND: Long-term morbidity including hypertension often persists in coarctation patients despite current guidelines. Coarctation severity can be invasively assessed via peak-to-peak catheter pressure gradient (PPCG), which is estimated noninvasively via simplified Bernoulli equation and conventionally reported as peak instantaneous Doppler gradient (PIDG). However, underlying simplifications of the equation limit diagnostic accuracy. We studied the diagnostic performance of a new Doppler-based diastolic index called the continuous flow pressure gradient (CFPG) versus conventional indices in assessing coarctation severity. METHODS: In a rabbit model mimicking human aortic coarctation, temporal blood pressure waveforms revealed the diastolic instantaneous pressure gradients and spectral Doppler features impacted by coarctation severity. We therefore hypothesized that CFPG provides superior correlation with coarctation gradients measured invasively. PIDG and CFPG were quantified using color flow echocardiography in humans and rabbits with discrete coarctations. Results were compared with PPCG in rabbits (n = 34) and arm-leg systolic gradients (n = 25) in humans via 1-way analysis of variance, Pearson's correlation, linear regression, and Bland-Altman analysis. RESULTS: A threshold of CFPG ≥ 4.6 mm Hg was identified via the Youden index as representative of PPCG ≥ 20 mm Hg (the current guideline value for coarctation intervention) in rabbits, while a CFPG ≥1.0 mm Hg represented an arm-leg systolic gradient ≥20 mm Hg in humans. Accuracy measures revealed superior correlation of CFPG (R2 > 0.80) and mild receiver operating characteristic improvement (area under the receiver operating characteristic curve, 0.94-0.95) compared with PIDG (R2 < 0.63; area under the receiver operating characteristic curve, 0.89-0.95). Inter-/intraobserver variability tested by intraclass correlation coefficient revealed measurement reliability with differences ≤8.2% and 10.7%, respectively. Computational simulations of anesthetized versus conscious hemodynamics showed parameters were minimally impacted by isoflurane inherent in the data used to derive CFPG. These results confirm the potential diagnostic accuracy of CFPG in echocardiography-based coarctation severity assessment. We are optimistic that CFPG will be useful for translation of results from preclinical studies that revisit current guidelines to limit morbidity in humans with aortic coarctation.