In silico trial of baroreflex activation therapy for the treatment of obesity-induced hypertension

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.

Fig 1. Baseline variables in the experimental (n = 6, shown in black from [22]) and virtual populations (both uncalibrated [n = 6,092 in red] and calibrated [n = 60, in green]) in three dimensions: Mean arterial pressure, plasma renin activity, and glomerular filtration rate.

Fig 2. Responses to BAT in experimental [22] (Exp) and virtual populations.

Mean arterial pressure, glomerular filtration rate, and plasma renin activity were not significantly different between the two groups at baseline or after BAT.

Fig 3. Cardiovascular responses to BAT among control (BAT Control), RSNA Clamp, ANP Clamp, and ANP+RSNA Clamp simulations.

*p<0.05; #p<0.05 vs. baseline.

Fig 4. Atrial natriuretic peptide (ANP), renal sympathetic nerve activity (RSNA), cardiac sympathetic nerve activity, and peripheral sympathetic nerve activity during 1 month of BAT in the control, RSNA Clamp, ANP Clamp, and ANP+RSNA Clamp simulations.

*p<0.05; #p<0.05 vs. baseline.

Fig 5. Renin secretion and its determinants before and during BAT in the control, RSNA Clamp, ANP Clamp, and ANP+RSNA Clamp simulations.

*p<0.05; #p<0.05 vs. baseline.

Fig 6. Changes in renal function during BAT in the control, RSNA Clamp, ANP Clamp, and ANP+RSNA Clamp simulations.

*p<0.05; #p<0.05 vs. baseline.