Driving Habits, Cognition, and Health-Related Quality of Life in Middle-Aged and Older Adults with HIV

Cognitive impairment is known to increase with aging in people living with HIV (PLWH). Impairment in cognitive domains required for safe driving may put PLWH at risk for poor driving outcomes, decreased mobility, and health-related quality of life (HRQoL). This study described the driving behaviors of middle-aged and older PLWH and examined correlations between driving behaviors and cognitive functioning (Aim 1), and driving behaviors and HRQoL domains (Aim 2). A sample of 260 PLWH ages 40 and older completed a comprehensive assessment including a battery of cognitive tests, an HRQoL measure, and a measure of self-reported driving habits. Associations between driving habits, cognitive function, and HRQoL domains were examined. While 212 (81.54%) participants reported currently driving, only 166 (63.85%) possessed a driver\u27s license. Several significant correlations emerged between driving habits and both cognitive and HRQoL variables, with a general pattern suggesting that current greater driving exposure was associated with better cognitive functioning and HRQoL. Given consistent associations that emerged between the social functioning HRQoL domain and several driving habits, multivariable regression was conducted to examine the unique association between an index of greater driving exposure (i.e., days driven per week) and social functioning, adjusting for potential confounders (race, income, education, depression, and global cognition). Results showed that more days driven per week was a significant, independent correlate of higher social functioning. Understanding the factors underlying driving behaviors in PLWH may contribute to interventions to promote better mobility and improved access to care

Cover Image Defining the Cardiac Fibroblast Secretome in a Fibrotic Microenvironment

Background Cardiac fibroblasts (CFs) have the ability to sense stiffness changes and respond to biochemical cues to modulate their states as either quiescent or activated myofibroblasts. Given the potential for secretion of bioactive molecules to modulate the cardiac microenvironment, we sought to determine how the CF secretome changes with matrix stiffness and biochemical cues and how this affects cardiac myocytes via paracrine signaling. Methods and Results Myofibroblast activation was modulated in vitro by combining stiffness cues with TGF&beta;1 (transforming growth factor &beta; 1) treatment using engineered poly (ethylene glycol) hydrogels, and in vivo with isoproterenol treatment. Stiffness, TGF&beta;1, and isoproterenol treatment increased AKT (protein kinase B) phosphorylation, indicating that this pathway may be central to myofibroblast activation regardless of the treatment. Although activation of AKT was shared, different activating cues had distinct effects on downstream cytokine secretion, indicating that not all activated myofibroblasts share the same secretome. To test the effect of cytokines present in the CF secretome on paracrine signaling, neonatal rat ventricular cardiomyocytes were treated with CF conditioned media. Conditioned media from myofibroblasts cultured on stiff substrates and activated by TGF&beta;1 caused hypertrophy, and one of the cytokines in that media was insulin growth factor 1, which is a known mediator of cardiac myocyte hypertrophy. Conclusions Culturing CFs on stiff substrates, treating with TGF&beta;1, and in vivo treatment with isoproterenol all caused myofibroblast activation. Each cue had distinct effects on the secretome or genes encoding the secretome, but only the secretome of activated myofibroblasts on stiff substrates treated with TGF&beta;1 caused myocyte hypertrophy, most likely through insulin growth factor 1.</p

Cardiac Fibroblasts Mediate a Sexually Dimorphic Fibrotic Response to beta-Adrenergic Stimulation

Background Biological sex is an important modifier of cardiovascular disease and women generally have better outcomes compared with men. However, the contribution of cardiac fibroblasts (CFs) to this sexual dimorphism is relatively unexplored. Methods and Results Isoproterenol (ISO) was administered to rats as a model for chronic &beta;‐adrenergic receptor (&beta;‐AR)‐mediated cardiovascular disease. ISO‐treated males had higher mortality than females and also developed fibrosis whereas females did not. Gonadectomy did not abrogate this sex difference. To determine the cellular contribution to this phenotype, CFs were studied. CFs from both sexes had increased proliferation in vivo in response to ISO, but CFs from female hearts proliferated more than male cells. In addition, male CFs were significantly more activated to myofibroblasts by ISO. To investigate potential regulatory mechanisms for the sexually dimorphic fibrotic response, &beta;‐AR mRNA and PKA (protein kinase A) activity were measured. In response to ISO treatment, male CFs increased expression of &beta;1‐ and &beta;2‐ARs, whereas expression of both receptors decreased in female CFs. Moreover, ISO‐treated male CFs had higher PKA activity relative to vehicle controls, whereas ISO did not activate PKA in female CFs. Conclusions Chronic in vivo &beta;‐AR stimulation causes fibrosis in male but not female rat hearts. Male CFs are more activated than female CFs, consistent with elevated fibrosis in male rat hearts and may be caused by higher &beta;‐AR expression and PKA activation in male CFs. Taken together, our data suggest that CFs play a substantial role in mediating sex differences observed after cardiac injury. </div

FGF-2 inhibits contractile properties of valvular interstitial cell myofibroblasts encapsulated in 3D MMP-degradable hydrogels

Valvular interstitial cells (VICs) are responsible for the maintenance of the extracellular matrix in heart valve leaflets and, in response to injury, activate from a quiescent fibroblast to a wound healing myofibroblast phenotype. Under normal conditions, myofibroblast activation is transient, but the chronic presence of activated VICs can lead to valve diseases, such as fibrotic aortic valve stenosis, for which non-surgical treatments remain elusive. We monitored the porcine VIC response to exogenously delivered fibroblast growth factor 2 (FGF-2; 100 ng/ml), transforming growth factor beta 1 (TGF-β1; 5 ng/ml), or a combination of the two while cultured within 3D matrix metalloproteinase (MMP)-degradable 8-arm 40 kDa poly(ethylene glycol) hydrogels that mimic aspects of the aortic valve. Here, we aimed to investigate VIC myofibroblast activation and subsequent contraction or the reparative wound healing response. To this end, VIC morphology, proliferation, gene expression related to the myofibroblast phenotype [alpha smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF)] and matrix remodeling [collagens (COL1A1 and COL3) and MMP1], and contraction assays were used to quantify the cell response. Treatment with FGF-2 resulted in increased cellular proliferation while reducing the myofibroblast phenotype, as seen by decreased expression of CTGF and α-SMA, and reduced contraction relative to untreated control, suggesting that FGF-2 encourages a reparative phenotype, even in the presence of TGF-β1. TGF-β1 treatment predictably led to an increased proportion of VICs exhibiting the myofibroblast phenotype, indicated by the presence of α-SMA, increased gene expression indicative of matrix remodeling, and bulk contraction of the hydrogels. Functional contraction assays and biomechanical analyses were performed on VIC encapsulated hydrogels and porcine aortic valve tissue explants to validate these findings

Osteopontin activity modulates sex‐specific calcification in engineered valve tissue mimics

Abstract Patients with aortic valve stenosis (AVS) have sexually dimorphic phenotypes in their valve tissue, where male valvular tissue adopts a calcified phenotype and female tissue becomes more fibrotic. The molecular mechanisms that regulate sex‐specific calcification in valvular tissue remain poorly understood. Here, we explored the role of osteopontin (OPN), a pro‐fibrotic but anti‐calcific bone sialoprotein, in regulating the calcification of female aortic valve tissue. Recognizing that OPN mediates calcification processes, we hypothesized that aortic valvular interstitial cells (VICs) in female tissue have reduced expression of osteogenic markers in the presence of elevated OPN relative to male VICs. Human female valve leaflets displayed reduced and smaller microcalcifications, but increased OPN expression relative to male leaflets. To understand how OPN expression contributes to observed sex dimorphisms in valve tissue, we employed enzymatically degradable hydrogels as a 3D cell culture platform to recapitulate male or female VIC interactions with the extracellular matrix. Using this system, we recapitulated sex differences observed in human tissue, specifically demonstrating that female VICs exposed to calcifying medium have smaller mineral deposits within the hydrogel relative to male VICs. We identified a change in OPN dynamics in female VICs in the presence of calcification stimuli, where OPN deposition localized from the extracellular matrix to perinuclear regions. Additionally, exogenously delivered endothelin‐1 to encapsulated VICs increased OPN gene expression in male cells, which resulted in reduced calcification. Collectively, our results suggest that increased OPN in female valve tissue may play a sex‐specific role in mitigating mineralization during AVS progression