HumMod Projects

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

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

Kyle H. Moore and John S. Clemer

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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 ID

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 ID

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 ID

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 ID

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 ID

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 ID

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 ID

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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