Introducing the renin-angiotensin-aldosterone (RAAS) hypertension platform: an in-silico approach to evaluating efficacy of RAAS modulating drugs on blood-pressure control and end-organ protection
Ramesh Sarangapani(1), Anna Georgieva(1), Ramprasad (Prasad) Ramakrishna(1), Gabriel Helmlinger(1), Donald Stanski(1), Arthur Lo(2), Manoj Rodrigo(2), Jennifer Beh(2) , Stuart Friedman(2) , Kortney Leabourne(2), Hector De Leon(2), Jeff Trimmer(2)
(1) M&S, Novartis Pharmaceuticals, NJ, USA; (2) Entelos Inc., CA, USA
Objective: We present a systems-biology approach to modeling blood-pressure (BP) regulation and end-organ protection offered by RAAS modulation therapy.
Background: Data from the National Health and Nutrition Examination Survey (NHANES) indicate that more than 50 million Americans suffer from elevated BP; worldwide, these figures are close to one billion. Suboptimal BP control is recognized as the leading risk factor for morbidity and mortality throughout the world, and in particular in the elderly population (JNC7). Data from observational and outcomes studies have confirmed a clear and consistent relationship between BP elevation and increases in cardiovascular and renal events from end-organ damage.
Methods: The focus of the present work is to capture the pathophysiological mechanisms of hypertension and its impact on end-organ status using a deterministic modeling approach. The resulting RAAS hypertension model features a modular design with four key modules, namely, systemic, renal, cardiovascular and nervous systems. The first two modules are explicitly represented in the first generation RAAS platform. The systemic module captures a systems-level representation of the RAAS pathway and its interactions with sodium and water regulation to achieve long-term BP control. The renal module includes a representation of the kidney as an assembly of single nephrons and associated fluid dynamics processes that influence glomerular filtration rate.
Results: Here, we present the key features of the first generation RAAS hypertension platform and the model parameterization using literature data. Model based simulations of systemic and renal biomarkers in select patient phenotypes following treatment with angiotensin-converting-enzyme inhibitors, angiotensin-receptor-blockers and direct renin-inhibitors and their comparison to observed data is reported.
Conclusion: These results demonstrate the RAAS hypertension platform as a valuable tool in elucidating multi-faceted disease progression patterns in various hypertensive patient phenotypes, and the benefits and limitations of different treatment options.
Key words: Renin-angiotensin-aldosterone-system (RAAS), Mechanistic modeling, Hypertension, Biomarkers, Renal disease progression