Effect of muscle activation scheme in human head-neck model on estimating cervical spine ligament strain from military volunteer frontal impact data.

Cervical spine (c-spine) injuries are a common injury during automobile crashes. The objective of this study is to verify an existing head-neck (HN) finite element model with military volunteer frontal impact kinematics by varying the muscle activation scheme from previous literature. Proper muscle activation will allow for accurate percent elongation (strain) of the c-spine ligaments and will serve to establish ligamentous response during non-injury frontal impacts. Previous human research volunteer (HRV) frontal impact sled tests reported kinematic data that served as the input for HN model simulation. Peak sled acceleration (PSA) was varied between 10G and 30G for HRVs. Muscle activation was shifted to begin at 0 ms at start of impact to allow for proper muscle contraction in the HN model. Then, extensor muscle activation magnitude was varied between 20 and 100% to determine the proper activation necessary to match kinematic outputs from the model with experimental results. The model was validated against 10G test recorded response. Ligament strain was measured from multiple ligaments along the c-spine once the model was verified. The 40% activated extensor muscle scheme was deemed the most biofidelic, with CORA scores of 0.743 and 0.686 for head X linear acceleration and angular Y acceleration for 10G pulse. All PSA groups scored well with this muscle activation. Most ligaments were buffered well by the active simulation, with only the interspinous ligament nearing physiologic injury. With the HN model verified against additional kinematic data, simulations with higher accelerations to predict areas of injury in real life crash scenarios are possible.

Human genotyping and an experimental model reveal NPR-C as a possible contributor to morbidity in coarctation of the aorta.

Coarctation of the aorta (CoA) is a common congenital cardiovascular (CV) defect characterized by a stenosis of the descending thoracic aorta. Treatment exists, but many patients develop hypertension (HTN). Identifying the cause of HTN is challenging because of patient variability (e.g., age, follow-up duration, severity) and concurrent CV abnormalities. Our objective was to conduct RNA sequencing of aortic tissue from humans with CoA to identify a candidate gene for mechanistic studies of arterial dysfunction in a rabbit model of CoA devoid of the variability seen with humans. We present the first known evidence of natriuretic peptide receptor C (NPR-C; aka NPR3) downregulation in human aortic sections subjected to high blood pressure (BP) from CoA versus normal BP regions (validated to PCR). These changes in NPR-C, a gene associated with BP and proliferation, were replicated in the rabbit model of CoA. Artery segments from this model were used with human aortic endothelial cells to reveal the functional relevance of altered NPR-C activity. Results showed decreased intracellular calcium ([Ca2+]i) activity to C-type natriuretic peptide (CNP). Normal relaxation induced by CNP and atrial natriuretic peptide was impaired for aortic segments exposed to elevated BP from CoA. Inhibition of NPR-C (M372049) also impaired aortic relaxation and [Ca2+]i activity. Genotyping of NPR-C variants predicted to be damaging revealed that rs146301345 was enriched in our CoA patients, but sample size limited association with HTN. These results may ultimately be used to tailor treatment for CoA based on mechanical stimuli, genotyping, and/or changes in arterial function.

Compensated right ventricular function of the onset of pulmonary hypertension in a rat model depends on chamber remodeling and contractile augmentation.

Right-ventricular function is a good indicator of pulmonary arterial hypertension (PAH) prognosis; however, how the right ventricle (RV) adapts to the pressure overload is not well understood. Here, we aimed at characterizing the time course of RV early remodeling and discriminate the contribution of ventricular geometric remodeling and intrinsic changes in myocardial mechanical properties in a monocrotaline (MCT) animal model. In a longitudinal study of PAH, ventricular morphology and function were assessed weekly during the first four weeks after MCT exposure. Using invasive measurements of RV pressure and volume, heart performance was evaluated at end of systole and diastole to quantify contractility (end-systolic elastance) and chamber stiffness (end-diastolic elastance). To distinguish between morphological and intrinsic mechanisms, a computational model of the RV was developed and used to determine the level of prediction when accounting for wall masses and unloaded volume measurements changes. By four weeks, mean pulmonary arterial pressure and elastance rose significantly. RV pressures rose significantly after the second week accompanied by significant RV hypertrophy, but RV stroke volume and cardiac output were maintained. The model analysis suggested that, after two weeks, this compensation was only possible due to a significant increase in the intrinsic inotropy of RV myocardium. We conclude that this MCT-PAH rat is a model of RV compensation during the first month after treatment, where geometric remodeling on EDPVR and increased myocardial contractility on ESPVR are the major mechanisms by which stroke volume is preserved in the setting of elevated pulmonary arterial pressure. The mediators of this compensation might themselves promote longer-term adverse remodeling and decompensation in this animal model.

Lumped-parameter models of the pulmonary vasculature during the progression of pulmonary arterial hypertension.

A longitudinal study of monocrotaline-induced pulmonary arterial hypertension (PAH) was carried out in Sprague-Dawley rats to investigate the changes in impedance (comprising resistance and compliance) produced by elevated blood pressure. Using invasively measured blood flow as an input, blood pressure was predicted using 3- and 4-element Windkessel (3WK, 4WK) type lumped-parameter models. Resistance, compliance, and inductance model parameters were obtained for the five different treatment groups via least-squares errors. The treated animals reached levels of hypertension, where blood pressure increased two folds from control to chronic stage of PAH (mean pressure went from 24 ± 5 to 44 ± 6 mmHg, P < 0.0001) but blood flow remained overall unaffected. Like blood pressure, the wave-reflection coefficient significantly increased at the advanced stage of PAH (0.26 ± 0.09 to 0.52 ± 0.09, P < 0.0002). Our modeling efforts revealed that resistances and compliance changed during the disease progression, where changes in compliance occur before the changes in resistance. However, resistance and compliance are not directly inversely related. As PAH develops, resistances increase nonlinearly (Rd exponentially and R at a slower rate) while compliance linearly decreases. And while 3WK and 4WK models capture the pressure-flow relation in the pulmonary vasculature during PAH, results from Akaike Information Criterion and sensitivity analysis allow us to conclude that the 3WK is the most robust and accurate model for this system. Ninety-five percent confidence intervals of the predicted model parameters are included for the population studied. This work establishes insight into the complex remodeling process occurring in PAH.