R2 - Cardiovascular and Renal Impact of Coincident Osteoarthritis and Chronic Stress

Introduction: : Osteoarthritis (OA), the most common chronic joint disease, is a major drain on healthcare spending and a leading cause of disability across the world [1]. Individuals with OA who are of lower socioeconomic status (SES) tend to have increased self-reported pain and physical disability [2]. Environmental factors contributing to low SES such as housing and food insecurity, unpredictable changes in social status, and abnormal working hours are associated with increased incidence of cardiovascular and renal diseases [3], [4], [5], [6], which are often comorbid with OA [7], [8]. Chronic kidney disease is exerting an increasingly heavy burden on global health while cardiovascular disease remains the primary cause of mortality globally. Thus, it is important to quantify the currently unknown interactive effects of OA and chronic environmental stress on the cardiovascular and renal systems. We aimed to investigate differences in cardiac and renal performance in a murine model of OA and chronic variable stress. We hypothesized that combining presence of OA and chronic, unpredictable variable stress (CVS) would worsen cardiovascular and renal function.

Materials and

Methods: : We modeled OA in each animal (n=44 female, n=47 male; C57BL6/J mice, Jackson Labs) by surgical destabilization of the medial meniscus(DMM) on the left knee at 16 weeks of age; in sham surgeries(SHAM), the medial meniscus was exposed but left intact[9]. Long term application of CVS (cage tilt, cage rock, temporary food deprivation, reverse light cycle, damp, dirty, predator, or no bedding, and abnormal light and fear-conditioned ultrasonic vocalization exposure) simulated environmental stress; control animals (Control) had standard housing and food conditions throughout the study[10]. Each animal underwent ultrasound imaging of the heart and both kidneys (25-55 MHz transducer, Vevo 3100, VisualSonics) at 32 weeks. After acquiring longitudinal and transverse views of each kidney, we used color and pulsed-wave Doppler imaging to quantify flow velocity in the renal arterioles. Cardiac images include a parasternal (PS) long-axis view of the left ventricle (LV) to assess systolic function and a motion (M)-mode image of the PS short-axis view to assess morphology; mitral inflow velocity from PW Doppler in the apical 4-chamber view characterized diastolic function. We then performed a dobutamine stress test via intraperitoneal administration[11] and acquired post-dobutamine PS long-axis and short-axis M-Mode images, analyzing all ultrasound images to assess function and morphology (Vevo LAB v5.8.2, VisualSonics). Statistical analysis (p < 0.05; R) used factorial ANOVA with OA status, presence of stressors, and sex as between-subjects factors for all metrics; for metrics also collected after dobutamine injection, we added timepoint as a within-subjects factor. Trends to significance were reported at p< 0.1.

Results, Conclusions, and Discussions:: DMM mice had a significantly lower renal resistivity index (p=0.042, transformed as inverse square) in the left kidney only, suggesting some effect of OA on renal function. Iso-volumetric relaxation time (IVRT) trended longer for DMM animals (p=0.071) but was not significantly different by sex, even though E/A wave ratio was (p=0.031). The CVS-sex (p=0.087) and OA-sex (p=0.099) interaction terms trended to significance for E/A, suggesting sex-specific changes in diastolic function due to CVS and OA. For DMM mice, LV posterior wall (PW) thickness was significantly lower at peak systole (p=0.004) and higher at end diastole (p=0.0136, transformed as inverse), revealing a change in cardiac wall strain due to OA. More interestingly, while diastolic LV diameter increased in SHAM CVS mice, it stayed constant or decreased in DMM CVS mice (p=0.028). The converse observation was significant in systolic LV anterior wall (AW) thickness (p=0.044). For systolic LV diameter, the normal, DMM-attributed increase in Control mice decreases in magnitude or becomes a decrease in CVS mice with dobutamine injection (p=0.026). The observed decrease in wall thickness for DMM Control mice compared to their SHAM counterparts becomes smaller in magnitude or even increases post-dobutamine; DMM CVS mice do not exhibit this recovery in wall thickness (AW: p=0.027, PW: p=0.036). Therefore, dobutamine stress test exposed changes in systolic cardiac function where the addition of OA seems to attenuate or reverse the morphological LV changes seen with CVS. Overall, the combination of OA and CVS impacts cardiac morphology differently than OA or CVS alone, and future research should further characterize these impacts and the mechanisms behind them.

Acknowledgements and/or References (Optional):: Acknowledgements: I would like to acknowledge Joslyn Ferguson and Aasish Karuturi for their assistance in ultrasound image acquisition.

References
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