Biology subjects

Hutcheson, J. D.

Publications and source records attributed to Hutcheson, J. D..

5 recordsLinked to original sources

bioRxiv2025

Intrinsic Phenotypic Differences, Not Hemodynamic Shear, Associate with Cusp-Specific Remodeling in Aortic Valve Disease

Aortic valve disease (AVD) is asymmetric. Various clinical reports indicate that the non- coronary cusp (NCC) is disproportionally burdened by pathological remodeling like inflammation, fibrosis, and calcification. This has long been attributed to the resulting differences in hemodynamic load that arise from the presence, or lack thereof, of coronary ostia in respective sinuses. However, there is little to no empirical evidence to suggest that these differences in hemodynamic shear alone are enough to drive the difference in pathological remodeling that is observed. C57BL/6J mice exhibit a high variance in right coronary ostium (RCO) positioning with respect to the right coronary cusp (RCC). Through computational fluid dynamics (CFD) simulations of a mouse aortic valve (AoV) during end diastolic loading, we show negligible differences in wall shear stress (WSS) between a high RCO on the RCC and no ostium on the NCC. Also, though CFD analyses depict at least an order of magnitude difference in WSS through physiologically relevant ostia positions within the sinuses, ostium position does not correlate with calcification burden in a CKD mouse model of calcific AVD. Cusp dependent extracellular matrix (ECM) abundance analysis reveals asymmetric collagen and elastin content in healthy adult mice, but this does not follow the same trend as pathological remodeling. Instead, asymmetric abundance of elastin (P=0.034) and collagen (P=0.018) was mainly driven by an increase of these ECM proteins in the left coronary cusp (LCC) with no differences in leaflet thickness. Cusp dependent transcriptomic (spatial and bulk RNA sequencing) analyses reveal asymmetric phenotypic profiles between the three cusps in healthy adult mice. Of note, genes associated with vascular smooth muscle cell contraction and known modulators of AoV remodeling were upregulated in the NCC and downregulated in both the RCC and LCC. Together, these data suggest that the differences in shear resulting from the coronary ostia are not sufficient to explain the asymmetric onset of calcific AVD.

physiology↗

bioRxiv2024

Sex-Specific Changes in Cardiac Function and Electrophysiology During Progression of Adenine-Induced Chronic Kidney Disease in Mice

BACKGROUNDChronic kidney disease (CKD) and cardiovascular disease (CVD) often co-exist and interact; however, notable sex-dependent differences are observed in how these conditions manifest and progress in parallel, despite men and women sharing similar risk factors. Identifying sex-specific diagnostic markers of cardiac structure and function throughout CKD progression could elucidate why the development and progression of these diseases differ by sex. METHODS AND RESULTSAdult, C57BL/6J male and female mice were subjected to a high-adenine (0.2%) diet throughout 12-weeks to induce CKD. Control mice were fed a normal chow diet. Every three weeks, electrocardiogram (ECG) and echocardiogram-based markers of cardiac physiology were evaluated. Adenine-induced CKD showed markers of left ventricular (LV) hypertrophy in male mice only. CKD males had markers indicative of LV systolic and diastolic dysfunction throughout regimen duration, worsening as disease progressed. Adenine males had a prolonged QTc and STc intervals when compared to Adenine females and Control males. Sex-dependent differences in the duration of the Speak-J marker, measured via ECG, was identified, with Adenine males showing increases in duration earlier than Adenine females compared to their Control counterparts. CONCLUSIONSIn this study, we identified sex-dependent differences in cardiac structure, function, and electrophysiology in a mouse model of CKD-induced CVD throughout disease progression. We found that male mice are more prone to developing LV hypertrophy, systolic dysfunction, and diastolic dysfunction, with significant increases in ECG markers indicative of ventricular dysfunction observed in adenine-treated males at late stages of the disease. Additionally, we identified a new ECG parameter, Speak-J duration, that highlights sex-specific cardiac electrophysiological changes, demonstrating the models utility in studying sex-dependent cardiac differences.

pathology↗

bioRxiv2022

Time-dependent Role of Bisphosphonates on Atherosclerotic Plaque Calcification

Atherosclerotic plaque calcification directly contributes to the leading cause of morbidity and mortality by affecting the plaque vulnerability and rupture risk. Small microcalcifications can increase plaque stress and promote rupture, whereas large calcifications can stabilize plaques. Drugs that target bone mineralization may lead to unintended consequences on ectopic plaque calcification and cardiovascular outcomes. Bisphosphonates, common anti-osteoporotic agents, elicited unexpected cardiovascular events in clinical trials. Here, we investigated the role of bisphosphonates treatment and timing on the disruption or promotion of vascular calcification and bone mineral in a mouse model of atherosclerosis. We started the bisphosphonate treatment either before plaque formation, at early plaque formation times associated with the onset of calcification, or at late stages of plaque development. Our data indicate that long term bisphosphonate treatment (beginning prior to plaque development) leads to higher levels of plaque calcification, with a narrower mineral size distribution. When given later in plaque development, we measured a wider distribution of mineral size. These morphological alterations may associate with higher risk of plaque rupture by creating stress foci. Yet, bone mineral density positively correlated with the duration of bisphosphonate treatment.

bioengineering↗

bioRxiv2021

Epidermal Growth Factor Receptor Inhibition Prevents Caveolin-1-dependent Calcifying Extracellular Vesicle Biogenesis

Chronic kidney disease (CKD) increases the risk of cardiovascular disease, including vascular calcification, leading to higher mortality. Release of calcifying extracellular vesicles (EVs) by vascular smooth muscle cells (VSMCs) promotes the ectopic mineralization of vessel walls. Caveolin-1 (CAV1) protein plays a key role in genesis of calcifying EVs in VSMCs. Epidermal growth factor receptor (EGFR) co-localizes with and influences the intracellular trafficking of CAV1. Using a diet-induced mouse model of CKD, we measured serum EGFR and assessed the potential of EGFR inhibition to prevent vascular calcification. Mice with CKD developed widespread vascular calcification, which associated with increased serum levels of EGFR. We computationally analyzed 7651 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) and Framingham cohorts to assess potential correlations between coronary artery calcium and single nucleotide polymorphisms (SNPs) associated with elevated serum levels of EGFR. Individuals in the MESA and Framingham cohorts with SNPs associated with increased serum EGFR exhibit elevated coronary artery calcium. In both the CKD mice and human VSMC culture, EGFR inhibition significantly reduced vascular calcification by mitigating the release of CAV1-positive calcifying EVs. EGFR inhibition also increased bone mineral density in CKD mice. Given that EGFR inhibitors exhibit clinical safety and efficacy in other pathologies, the current data suggest that EGFR may be an ideal target to prevent pathological vascular calcification.

pathology↗

bioRxiv2020

Synthetic Photoplethysmography (PPG) of the radial artery through parallelized Monte Carlo and its correlation to Body Mass Index (BMI)

Cardiovascular disease is one of the leading causes of death in the United States and obesity significantly increases the risk of cardiovascular disease. The measurement of blood pressure (BP) is critical in monitoring and managing cardiovascular disease hence new wearable devices are being developed to make the BP metric mode accessible to physicians and patients. Several wearables utilize photoplethysmography from the wrist vasculature to derive BP assessment although many of these devices are still at the experimental stage. With the ultimate goal of supporting instrument development, we have developed a model the photoplethysmographic waveform derived from the radial artery at the volar surface of the wrist. To do so we have utilized the relation between vessel biomechanics through Finite Element Method and Monte Carlo light transport model. The model shows similar features to that seen in PPG waveform captured using an off the shelf device. We observe the influence of body mass index (BMI) on the PPG signal. A degradation the PPG signal of up to 40% in AC to DC signal ratio was thus observed.

bioengineering↗