Key result
In an in silico model of resistant hypertension, simulated creation of a small AV fistula reduced blood pressure by 14 mmHg at 8 weeks, an effect primarily driven by increased ANP secretion.
Why the study?
The mechanisms contributing to the antihypertensive effects of a small central arteriovenous fistula are unclear.
Does the creation of a small arteriovenous fistula reduce blood pressure via increased ANP secretion in a mathematical model of resistant hypertension?
Does the creation of a small arteriovenous fistula reduce blood pressure via increased ANP secretion in a mathematical model of resistant hypertension?
In silico modeling suggests that increased ANP secretion, rather than reduced total peripheral resistance, is the primary driver of long-term blood pressure reduction following AV fistula creation for resistant hypertension.
In silico AVF effects via ANP are hypothesis-generating; leaves open clinical translation in hypertension.
Percutaneous creation of a small central arteriovenous (AV) fistula is currently being evaluated for the treatment of uncontrolled hypertension (HT). Although the mechanisms that contribute to the antihypertensive effects of the fistula are unclear, investigators have speculated that chronic blood pressure (BP) lowering may be due to 1) reduced total peripheral resistance (TPR), 2) increased secretion of atrial natriuretic peptide (ANP), and/or 3) suppression of renal sympathetic nerve activity (RSNA). We used an established integrative mathematical model of human physiology to investigate these possibilities from baseline conditions that mimic sympathetic overactivity and impaired renal function in patients with resistant HT. After a small fistula was stimulated, there were sustained increases in cardiac output, atrial pressures, and plasma ANP concentration (3-fold), without suppression of RSNA; at 8 wk, BP was reduced 14 mmHg along with a 32% fall in TPR. In contrast, when this simulation was repeated while clamping ANP at baseline BP decreased only 4 mmHg, despite a comparable fall in TPR. Furthermore, when chronic resetting of atrial mechanoreceptors was prevented during the fistula, RSNA decreased 7%, and along with the same threefold increase in ANP, BP fell 19 mmHg. This exaggerated fall in BP occurred with a similar decrease in TPR when compared with the above simulations. These findings suggest that ANP, but not TPR, is a key determinant of long-term BP lowering after the creation of an AV fistula and support a contribution of suppressed RSNA if resetting of the atrial-renal reflex is truly incomplete. NEW & NOTEWORTHY The mechanisms that contribute to the antihypertensive effects of a small arteriovenous (AV) fistula comparable to the size used by the ROX coupler currently in clinical trials are unclear and not readily testable in clinical or experimental studies. The integrative mathematical model of human physiology used in the current study provides a tool for understanding key causal relationships that account for blood pressure (BP) lowering and for testing competing hypotheses. The findings from the simulations suggest that after creation of a small AV fistula increased ANP secretion plays a critical role in mediating long-term reductions in BP. Measurement of natriuretic peptide levels in hypertensive patients implanted with the ROX coupler would provide one critical test of this hypothesis.
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Clemmer et al. (2019) studied Resistant hypertension. Simulated small central arteriovenous (AV) fistula vs. Simulations with clamped ANP or prevented mechanoreceptor resetting was evaluated on Blood pressure (BP) reduction. In an in silico model of resistant hypertension, simulated creation of a small AV fistula reduced blood pressure by 14 mmHg at 8 weeks, an effect primarily driven by increased ANP secretion.
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