HumMod Projects

A listing of projects and publications that use specific versions of Hummod.

Modeling the physiological role of the heart and kidney in heart failure with preserved ejection fraction during baroreflex activation therapy

John S Clemmer et al. Am J Physiol Heart Circ Physiol. 2022.
Pub Med 35984764

Heart failure (HF) is a leading cause of death and is increasing in prevalence. Unfortunately, therapies that have been efficacious in HF patients with reduced ejection fraction (HFrEF) have not convincingly shown a reduction in cardiovascular mortality in patients with HF with preserved ejection fraction (HFpEF). It is thought that high sympathetic nerve activity (SNA) in the heart plays a role in HF progression. Clinical trials demonstrate that baroreflex activation therapy reduces left ventricular (LV) mass and blood pressure (BP) in hypertensive HFpEF patients; however, the mechanisms are unclear. In the present study, we used HumMod, a large physiology model to simulate HFpEF and predict the time-dependent changes in systemic and cardiac hemodynamics, SNA, and cardiac stresses during baroreflex activation. The baseline HFpEF model was associated with elevations in systolic BP, diastolic dysfunction, and LV hypertrophy and stiffness similar to clinical HFpEF. Simulating 12 months of baroreflex activation resulted in reduced systolic BP (-25 mmHg) and LV mass (-15%) similar to clinical evidence. Baroreflex activation also resulted in sustained decreases in cardiac and renal SNA (-22%) and improvement in LV β1 adrenergic function. However, the baroreflex induced reductions in BP and improvements in cardiac stresses, mass, and function were mostly attenuated when renal SNA was clamped at baseline levels. These simulations suggest that the suppression of renal SNA could be a primary determinant of the cardioprotective effects from baroreflex activation in HFpEF.

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

John S Clemmer , W Andrew Pruett, Robert L Hester
Pub Med 34793497

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.

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Questioning the renoprotective role of L-type calcium channel blockers in chronic kidney disease using physiological modeling

Kyle H. Moore and John S. Clemmer
Pub Med 34486399

Chronic kidney disease (CKD) is characterized by the progressive functional loss of nephrons and hypertension (HTN). Some antihypertensive regimens attenuate the progression of CKD (blockers of the renin-angiotensin system). Although studies have suggested that calcium channel blocker (CCB) therapy mitigates the decline in renal function in humans with essential HTN, there are few long-term clinical studies that have determined the impact of CCBs in patients with hypertensive CKD. Dihydropyridine (DHP) or L-type CCBs preferentially vasodilate the afferent arteriole and have been associated with glomerular HTN and increases in proteinuria in animal models with low renal function. Small clinical studies in vulnerable populations with renal disease such as African Americans, children, and diabetics have also suggested that DHP CCBs exacerbate glomerular injury, which questions the renoprotective effect of this class of antihypertensive drug. We used an established integrative mathematical model of human physiology, HumMod, to test the hypothesis that DHP CCB therapy exacerbates pressure-induced glomerular injury in hypertensive CKD. Over a simulation of 3 yr, CCB therapy reduced mean blood pressure by 14-16 mmHg in HTN both with and without CKD. Both impaired tubuloglomerular feedback and low baseline renal function exacerbated glomerular pressure, glomerulosclerosis, and the decline in renal function during L-type CCB treatment. However, simulating CCB therapy that inhibited both L- and T-type calcium channels increased efferent arteriolar vasodilation and alleviated glomerular damage. These simulations support the evidence that DHP (L-type) CCBs potentiate glomerular HTN during CKD and suggest that T/L-type CCBs are valuable in proteinuric renal disease treatment.

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Preeminent Role of the Cardiorenal Axis in the Antihypertensive Response to an Arteriovenous Fistula: An In Silico Analysis

John S. Clemmer, W. Andrew Pruett, Robert L. Hester, Thomas E. Lohmeier
Pub Med 31469293

Initial clinical studies extending up to 1 year after creation of an arteriovenous fistula with the ROX coupler have demonstrated impressive blood pressure lowering in patients with resistant hypertension. Although the mechanisms that contribute to the antihypertensive effects of the fistula are unclear, investigators have speculated that chronic blood pressure lowering may be due to: 1) reduced total peripheral resistance, 2) increased secretion of atrial natriuretic peptide, and/or 3) suppression of renal sympathetic nerve activity. The lack of mechanistic understanding for blood pressure lowering with the fistula limits the interpretation and impact of clinical trials and adds to the uncertainty as to which hypertensive patients are most likely to respond favorably to this device-based treatment. We used HumMod to mimic essential hypertension and predict 8 week responses to an arteriovenous fistula. The findings from the simulations suggest that after the fistula, increased atrial natriuretic peptide secretion plays a critical role in mediating long-term reductions in blood pressure. 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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Role of the Heart in Blood Pressure Lowering During Chronic Baroreflex Activation: Insight from an in Silico Analysis

John S. Clemmer, W. Andrew Pruett, Robert L. Hester, Radu Iliescu, Thomas E. Lohmeier
Pub Med 30004810

Electrical stimulation of the baroreflex chronically suppresses sympathetic activity and arterial pressure and is currently being evaluated for the treatment of resistant hypertension. Both experimental and clinical studies have shown that the presence of renal nerves is not an obligate requirement for sustained reductions in blood pressure during chronic electrical stimulation of the carotid baroreflex. Simulations using our model indicated that both increased secretion of atrial natriuretic peptide and suppressed renal sympathetic nerve activity play key roles in mediating long-term reductions in blood pressure during chronic baroreflex activation. However, when suppression of renal sympathetic nerve activity was blocked, the blood pressure response to baroreflex activation was not appreciably impaired due to inordinate fluid accumulation and further increases in atrial pressure and atrial natriuretic peptide secretion. These simulations provide a mechanistic understanding of experimental and clinical observations showing that baroreflex activation effectively lowers blood pressure in subjects with previous renal denervation.

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Simulating a virtual population’s sensitivity to salt and uninephrectomy

John S. Clemmer, Robert L. Hester, and W. Andrew Pruett
Pub Med 29285341

Reduced functional renal mass plays an important role in causing salt sensitive hypertension for many individuals. Factors that are important during decreased renal mass and how they affect blood pressure or salt sensitivity are unclear. We used HumMod to create a heterogeneous population of 1000 virtual patients by randomly varying physiological parameters. After simulating uninephrectomy in the virtual population, topological data analysis identified three salt sensitive clusters associated with a blunted increase in renal blood flow and higher increases in distal sodium reabsorption as compared to the salt resistant population. These methodologies could potentially be used to discover patterns in patient’s sensitivity to dietary change or intervention and could be a revolutionary tool in personalizing medicine.

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Validating the physiologic model HumMod as a substitute for clinical trials involving acute normovolemic hemodilution

Charles R. Sims III, MD; Luis R. Delima, MD; Arthur Calimaran, MD; Robert Hester, PhD; W. Andrew Pruett, PhD
Pub Med 28863020

Blood conservation strategies and transfusion guidelines remain a heavily debated clinical topic. Previous investigational trials have shown that acute isovolemic hemodilution does not limit adequate oxygen delivery; however, a true critical hemoglobin level has never been investigated or defined due to safety concerns for human volunteers. This model was developed to replicate the cardiovascular and metabolic findings of previous clinical studies of acute isovolemic hemodilution and use coronary blood flow and coronary oxygen delivery in extreme hemodilution to predict a safety threshold.

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Physiological mechanisms of water and electrolyte disturbances following transsphenoidal pituitary surgery

Evan T. Blair, John S. Clemmer, H. Louis Harkey, Robert L. Hester, and W. Andrew Pruett
Pub Med 28797976

Disturbances in water and electrolyte homeostasis are common following transsphenoidal surgery. Clinically, it is generally accepted that damage to the pituitary is the source of these disturbances, but the mechanisms behind the response variability and underlying pathophysiology remains unknown. In this model, we simulate pituitary stalk damage. The damaged neurons were modeled to undergo a 5-day countdown to degeneration, and then release stored ADH as they die. This tests the hypothesis that simply changing the degree of damage to the pituitary stalk produces a spectrum of water and electrolyte disturbance along which the full variety of presentations of postsurgical water and electrolyte disturbances can be identified. This simulation shows that merely modifying the level of damage does not produce every presentation of water and electrolyte imbalance. This suggests that other mechanisms, which are still unclear and not a part of this model, may be responsible for postoperative hyponatremia and require further investigation.

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Mechanisms of Blood Pressure Salt Sensitivity: New Insights from Mathematical Modeling

Clemmer JS, Pruett WA, Coleman TG, Hall JE, Hester RL.
Pub Med 27974315

Excess salt intake increases blood pressure and the risk for cardiovascular disease. Chronic experimental studies investigating the mechanisms of salt sensitivity are rare and, in most cases, devoid of the hormonal, neural, renal and hemodynamics changes that take place under more chronic conditions. In HumMod, certain types of kidney dysfunction, such as low kidney mass or impaired regulation of angiotensin II, were associated with salt sensitivity. However, increased preglomerular resistance, increased renal sympathetic nerve activity, or inability to decrease peripheral resistance does not appear to influence salt sensitivity. This model provides a platform for testing competing concepts of long-term blood pressure control during changes in salt intake.

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Validation of an integrative mathematical model of dehydration and rehydration in virtual humans

Pruett WA, Clemmer JS, Hester RL.
Pub Med 27899683

The body utilizes multiple interacting systems to maintain water homeostasis, reflecting this task’s overall importance in preserving life. Vasopressin is an acutely acting hormone that contributes to short-term water homeostasis. In this study, we validated HumMod against six challenges to water homeostasis, emphasizing changes in vasopressin, electrolytes, and water balance. The chief perturbations were dehydration via water restriction (Lifestyle/Diet/Control) or by hypertonic saline infusion (Intervention/Fluids/IVDrip). The main observations were ADH (Hormones/ADH/Pool), serum sodium (Electrolytes/Na), and the components of urine (Organs/Kidney/Excretion/Urine).

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