Abstract
Clinical trials evaluating the efficacy of chronic electrical stimulation of the carotid baroreflex for the treatment of hypertension (HTN) are ongoing. However, the mechanisms by which this device lowers blood pressure (BP) are unclear, and it is uncertain which patients are most likely to receive clinical benefit. Mathematical modeling provides the ability to analyze complicated interrelated effects across multiple physiological systems. Our current model HumMod is a large physiological simulator that has been used previously to investigate mechanisms responsible for BP lowering during baroreflex activation therapy (BAT). First, we used HumMod to create a virtual population in which model parameters (n = 335) were randomly varied, resulting in unique models (n = 6092) that we define as a virtual population. This population was calibrated using data from hypertensive obese dogs (n = 6) subjected to BAT. The resultant calibrated virtual population (n = 60) was based on tuning model parameters to match the experimental population in 3 key variables: BP, glomerular filtration rate, and plasma renin activity, both before and after BAT. In the calibrated population, responses of these 3 key variables to chronic BAT were statistically similar to experimental findings. Moreover, blocking suppression of renal sympathetic nerve activity (RSNA) and/or increased secretion of atrial natriuretic peptide (ANP) during BAT markedly blunted the antihypertensive response in the virtual population. These data suggest that in obesity-mediated HTN, RSNA and ANP responses are key factors that contribute to BP lowering during BAT. This modeling approach may be of value in predicting BAT responses in future clinical studies.
Highlights
More than a billion people have hypertension (HTN), which is currently the world’s leading preventable risk factor for cardiovascular morbidity and all-cause mortality [1]
Calibration resulted in a virtual population (n = 60, shown in green) with similar baseline mean arterial pressure (MAP), glomerular filtration rate (GFR), and plasma renin activity (PRA) as experimental data (n = 6, shown in black, Fig 1)
The results of this study: 1) provide further validation that HumMod accurately reproduces responses to physiological interventions and support the utility of using the virtual population approach to elucidate mechanistic insight into HTN therapy, 2) suggest several baseline physiological factors of importance that predict the antihypertensive response to baroreflex activation therapy (BAT), 3) suggest that suppression of renal sympathetic nerve activity (RSNA) and increases in atrial natriuretic peptide (ANP) secretion contribute but, independently, are not obligatory factors for blood pressure (BP) lowering with BAT, unless both are blocked simultaneously
Summary
More than a billion people have hypertension (HTN), which is currently the world’s leading preventable risk factor for cardiovascular morbidity and all-cause mortality [1]. Many patients still have uncontrolled blood pressure (BP) and are at increased risk of cardiovascular morbidity and mortality [2]. Most of these patients have primary HTN, which is associated with increased sympathetic nerve activity (SNA) [3, 4]. Modeling population responses to baroreflex activation therapy adherence to all the PLOS ONE policies on sharing data and materials. In a randomized controlled Phase III clinical trial, the wellstudied Rheos device (CVRx, Minneapolis) was used to stimulate the carotid baroreflex and substantially reduced BP in patients with uncontrolled hypertension [8, 9]. While cleared for use in Europe, neither this device nor the second generation Barostim Neo system has been approved by the Food and Drug Administration for HTN therapy in the US
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