Testing Computer Models Predicting Human Responses to a High-Salt Diet

Abstract

Recently, mathematical models of human integrative physiology, derived from Guyton’s classic 1972 model of the circulation, have been used to investigate potential mechanistic abnormalities mediating salt-sensitivity and salt-induced hypertension. We performed validation testing of two of the most evolved derivatives of Guyton’s 1972 model, QCP-2005 and HumMod-3.0.4, to determine if the models accurately predict sodium balance and hemodynamic responses of normal subjects to increases in salt intake within the real-life range of salt intake in humans. Neither model, nor the 1972 Guyton model, accurately predicts the usual changes in sodium balance, cardiac output, and systemic vascular resistance that normally occur in response to clinically realistic increases in salt intake. Furthermore, although both contemporary models are extensions of the 1972 Guyton model, testing revealed major inconsistencies between model predictions with respect to sodium balance and hemodynamic responses of normal subjects to short-term and long-term salt loading. These results demonstrate significant limitations with the hypotheses inherent in Guyton models regarding the usual regulation of sodium balance, cardiac output and vascular resistance in response to increased salt intake in normal salt-resistant humans. Accurate understanding of the normal responses to salt loading is a prerequisite for accurately establishing abnormal responses to salt loading. Accordingly, the present results raise concerns about the interpretation of studies of salt sensitivity with the various Guyton models. These findings indicate a need for continuing development of alternative models that incorporate mechanistic concepts of blood pressure regulation fundamentally different from those in the 1972 Guyton model and its contemporary derivatives.

Effect of high-salt diet on blood pressure and body fluid composition in patients with type 1 diabetes: randomized controlled intervention trial

“…Moreover, importantly, there is an increasing body of literature that questions the validity of the classical volume theory. [13][14][15][16] Therefore, a careful assessment of responses in patients with type 1 diabetes to dietary high salt is warranted.…”

Low-dose L-NAME induces salt sensitivity associated with sustained increased blood volume and sodium-chloride cotransporter activity in rodents

“…In contrast, the without-L-NAME treatment group may have responded to the same degree of salt-induced volume expansion by vasodilating and reducing systemic vascular resistance, which prevents the salt-induced increases in blood volume from increasing BP, which is consistent with previous studies. [5][6][7][8][13][14][15][16][17] The decrease in blood volume was associated with an increase in urinary sodium excretion. This finding suggests that to maintain salt-sensitive hypertension, sodium retention and increases in blood volume are necessary.…”

“…1,2 Salt sensitivity is especially common in normotensive individuals from subpopulations known to have a higher frequency of hypertension, such as black people, older subjects, and first-degree relatives of hypertensive patients, suggesting that salt sensitivity is a predictor of hypertension. 3,4 With respect to the pathophysiology of salt sensitivity, the relative roles of abnormal vascular resistance responses to salt loading [5][6][7][8] versus abnormal sodium-volume responses to salt loading [9][10][11][12] are controversial. Most studies in normotensive subjects have indicated that the initiation of salt-induced hypertension usually involves abnormal vascular resistance responses to increased salt intake and not higher renal retention of a salt load in salt-sensitive normotensive subjects than in salt-resistant normotensive controls.…”

Mathematical models for kidney function focusing on clinical interest

“…Developed as part of the classic Guyton model of cardiovascular function [16,17], these were not stand-alone kidney models and they gave a rather simple input-output description of kidney function with scant internal detail, but they were developed with the clinic in mind by Guyton and his colleagues and established their conviction that the kidney plays a central role in blood pressure regulation. This work was of central importance for research into the mechanisms of blood pressure regulation, though a recent paper [29] has cast doubt on the validity of the predictions of both the classic Guyton model and its more recent descendants [1,24] under conditions of salt loading. Hallow and colleagues [18][19][20] have updated and improved on the Guyton "platform", taking advantage of Karaaslan's improved version [26,27] of the Guyton kidney.…”