Current Understanding of the Right Ventricle Structure and Function in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a disease resulting in increased right ventricular (RV) afterload and RV remodeling. PAH results in altered RV structure and function at different scales from organ-level hemodynamics to tissue-level biomechanical properties, fiber-level architecture, and cardiomyocyte-level contractility. Biomechanical analysis of RV pathophysiology has drawn significant attention over the past years and recent work has found a close link between RV biomechanics and physiological function. Building upon previously developed techniques, biomechanical studies have employed multi-scale analysis frameworks to investigate the underlying mechanisms of RV remodeling in PAH and effects of potential therapeutic interventions on these mechanisms. In this review, we discuss the current understanding of RV structure and function in PAH, highlighting the findings from recent studies on the biomechanics of RV remodeling at organ, tissue, fiber, and cellular levels. Recent progress in understanding the underlying mechanisms of RV remodeling in PAH, and effects of potential therapeutics, will be highlighted from a biomechanical perspective. The clinical relevance of RV biomechanics in PAH will be discussed, followed by addressing the current knowledge gaps and providing suggested directions for future research.

An exploratory assessment of stretch-induced transmural myocardial fiber kinematics in right ventricular pressure overload.

Right ventricular (RV) remodeling and longitudinal fiber reorientation in the setting of pulmonary hypertension (PH) affects ventricular structure and function, eventually leading to RV failure. Characterizing the kinematics of myocardial fibers helps better understanding the underlying mechanisms of fiber realignment in PH. In the current work, high-frequency ultrasound imaging and structurally-informed finite element (FE) models were employed for an exploratory evaluation of the stretch-induced kinematics of RV fibers. Image-based experimental evaluation of fiber kinematics in porcine myocardium revealed the capability of affine assumptions to effectively approximate myofiber realignment in the RV free wall. The developed imaging framework provides a noninvasive modality to quantify transmural RV myofiber kinematics in large animal models. FE modeling results demonstrated that chronic pressure overload, but not solely an acute rise in pressures, results in kinematic shift of RV fibers towards the longitudinal direction. Additionally, FE simulations suggest a potential protective role for concentric hypertrophy (increased wall thickness) against fiber reorientation, while eccentric hypertrophy (RV dilation) resulted in longitudinal fiber realignment. Our study improves the current understanding of the role of different remodeling events involved in transmural myofiber reorientation in PH. Future experimentations are warranted to test the model-generated hypotheses.

The Effects of Healthy Aging on Right Ventricular Structure and Biomechanical Properties: A Pilot Study.

Healthy aging has been associated with alterations in pulmonary vascular and right ventricular (RV) hemodynamics, potentially leading to RV remodeling. Despite the current evidence suggesting an association between aging and alterations in RV function and higher prevalence of pulmonary hypertension in the elderly, limited data exist on age-related differences in RV structure and biomechanics. In this work, we report our preliminary findings on the effects of healthy aging on RV structure, function, and biomechanical properties. Hemodynamic measurements, biaxial mechanical testing, constitutive modeling, and quantitative transmural histological analysis were employed to study two groups of male Sprague-Dawley rats: control (11 weeks) and aging (80 weeks). Aging was associated with increases in RV peak pressures (+17%, p = 0.017), RV contractility (+52%, p = 0.004), and RV wall thickness (+38%, p = 0.001). Longitudinal realignment of RV collagen (16.4°, p = 0.013) and myofibers (14.6°, p = 0.017) were observed with aging, accompanied by transmural cardiomyocyte loss and fibrosis. Aging led to increased RV myofiber stiffness (+141%, p = 0.003), in addition to a bimodal alteration in the biaxial biomechanical properties of the RV free wall, resulting in increased tissue-level stiffness in the low-strain region, while progressing into decreased stiffness at higher strains. Our results demonstrate that healthy aging may modulate RV remodeling via increased peak pressures, cardiomyocyte loss, fibrosis, fiber reorientation, and altered mechanical properties in male Sprague-Dawley rats. Similarities were observed between aging-induced remodeling patterns and those of RV remodeling in pressure overload. These findings may help our understanding of age-related changes in the cardiovascular fitness and response to disease.

Angiotensin Receptor-Neprilysin Inhibition Attenuates Right Ventricular Remodeling in Pulmonary Hypertension.

BackgroundPulmonary hypertension (PH) results in increased right ventricular (RV) afterload and ventricular remodeling. Sacubitril/valsartan (sac/val) is a dual acting drug, composed of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan, that has shown promising outcomes in reducing the risk of death and hospitalization for chronic systolic left ventricular heart failure. In this study, we aimed to examine if angiotensin receptor-neprilysin inhibition using sac/val attenuates RV remodeling in PH.Methods and ResultsRV pressure overload was induced in Sprague-Dawley rats via banding the main pulmonary artery. Three different cohorts of controls, placebo-treated PH, and sac/val-treated PH were studied in a 21-day treatment window. Terminal invasive hemodynamic measurements, quantitative histological analysis, biaxial mechanical testing, and constitutive modeling were employed to conduct a multiscale analysis on the effects of sac/val on RV remodeling in PH. Sac/val treatment decreased RV maximum pressures (29% improvement, P=0.002), improved RV contractile (30%, P=0.012) and relaxation (29%, P=0.043) functions, reduced RV afterload (35% improvement, P=0.016), and prevented RV-pulmonary artery uncoupling. Furthermore, sac/val attenuated RV hypertrophy (16% improvement, P=0.006) and prevented transmural reorientation of RV collagen and myofibers (P=0.011). The combined natriuresis and vasodilation resulting from sac/val led to improved RV biomechanical properties and prevented increased myofiber stiffness in PH (61% improvement, P=0.032).ConclusionsSac/val may prevent maladaptive RV remodeling in a pressure overload model via amelioration of RV pressure rise, hypertrophy, collagen, and myofiber reorientation as well as tissue stiffening both at the tissue and myofiber level.

Physiologic Medium Maintains the Homeostasis of Immature Bovine Articular Cartilage Explants in Long-Term Culture.

The ability to maintain living articular cartilage tissue in long-term culture can serve as a valuable analytical research tool, allowing for direct examination of mechanical or chemical perturbations on tissue behavior. A fundamental challenge for this technique is the recreation of the salient environmental conditions of the synovial joint in culture that are required to maintain native cartilage homeostasis. Interestingly, conventional media formulations used in explanted cartilage tissue culture investigations often consist of levels of metabolic mediators that deviate greatly from their concentrations in synovial fluid (SF). Here, we hypothesize that the utilization of a culture medium consisting of near-physiologic levels of several highly influential metabolic mediators (glucose, amino acids, cortisol, insulin, and ascorbic acid) will maintain the homeostasis of cartilage explants as assessed by their mechanical properties and extracellular matrix (ECM) contents. Results demonstrate that the aforementioned mediators have a strong effect on the mechanical and biochemical stability of skeletally immature bovine cartilage explants. Most notably, (1) in the absence of cortisol, explants exhibit extensive swelling and tissue softening and (2) in the presence of supraphysiologic levels of anabolic mediators (glucose, amino acids, insulin), explants exhibit increased matrix accumulation and tissue stiffening. In contrast, the administration of physiologic levels of these mediators (as present in native SF) greatly improves the stability of live cartilage explants over one month of culture. These results may have broad applicability for articular cartilage and other musculoskeletal tissue research, setting the foundation for important culture formulations required for examinations into tissue behavior.

Applying a Hybrid Experimental-Computational Technique to Study Elbow Joint Ligamentous Stabilizers.

Much of our understanding of the role of elbow ligaments to overall joint biomechanics has been developed through in vitro cadaver studies using joint motion simulators. The principle of superposition can be used to indirectly compute the force contributions of ligaments during prescribed motions. Previous studies have analyzed the contribution of different soft tissue structures to the stability of human elbow joints, but have limitations in evaluating the loads sustained by those tissues. This paper introduces a unique, hybrid experimental-computational technique for measuring and simulating the biomechanical contributions of ligaments to elbow joint kinematics and stability. in vitro testing of cadaveric joints is enhanced by the incorporation of fully parametric virtual ligaments, which are used in place of the native joint stabilizers to characterize the contribution of elbow ligaments during simple flexion-extension (FE) motions using the principle of superposition. Our results support previously reported findings that the anterior medial collateral ligament (AMCL) and the radial collateral ligament (RCL) are the primary soft tissue stabilizers for the elbow joint. Tuned virtual ligaments employed in this study were able to restore the kinematics and laxity of elbows to within 2 deg of native joint behavior. The hybrid framework presented in this study demonstrates promising capabilities in measuring the biomechanical contribution of ligamentous structures to joint stability.

Development of a hybrid computational/experimental framework for evaluation of damage mechanisms of a linked semiconstrained total elbow system.

BACKGROUND: Long-term durability of total elbow arthroplasty (TEA) is a concern, and bearing wear or excessive deformations may necessitate early revision. The current study used experimental wear testing and computational finite element modeling to develop a hybrid computational and experimental framework for the evaluation of TEA damage mechanisms. METHODS: Three Coonrad-Morrey (Zimmer-Biomet Inc., Warsaw, IN, USA) TEA implants were used for experimental wear testing for 200,000 cycles. Gravimetric measurements were performed before and after the tests to assess the weight change caused by wear. A finite element model of the implant was also developed to analyze ultrahigh-molecular-weight polyethylene (UHMWPE) damage. RESULTS: High localized contact pressures caused visible creep and plastic flow, deforming bushings and creating unintended UHMWPE-on-UHMWPE contact surfaces where considerably high wear rates were observed. Average experimentally measured vs. model-predicted wear was 9.5 ± 1.0 vs. 14.1 mg for the of the medial bushing, 8.5 ± 1.0 vs. 13.9 mg for the lateral humeral bushing, and 34.1 ± 0.7 vs. 36.9 mg for the ulnar bushings, respectively. Model predicted contact stresses on the surfaces of bushings were substantially higher than the yield limit of conventional UHMWPE (87 MPa for the humeral bushings and 83 MPa for the ulnar bushing). CONCLUSIONS: Our study discovered that unintended wear at UHMWPE-UHMWPE contact surfaces, "fed" by excessive plastic flow may, in fact, be of more concern than wear that occurs at the intended metal-UHMWPE contact interfaces. Furthermore, formation of high localized contact stresses much above the yield limit of UHMWPE is another likely contributor to bushing failure for this implant.