1. Treatment-Resistant Hypertension: Pathophysiology Power Over Pressure www.poweroverpressure.com

2. Perceptions of hypertension have changed over time 1. Page IH. J Clin Invest. 1934;13:909-915. 2. Chobanian AV. N Engl J Med. 2009;361:878-887. 3. Veterans Administration Cooperative Study Group. JAMA. 1967;202:1028-1034. 4. Calhoun DA, et al. Circulation. 2008;117(25):e510-e526. Efficiency of the kidney is not altered by marked fall in BP, occurring spontaneously or induced. 1 (Page) In patients with chronic kidney disease, a fall in BP occurring spontaneously or as a result of surgical renal denervation caused no change in renal efficiency. 1 Arterial pressure is elevated to overcome mechanical resistance against blood flow in renal disease. 1 ( Traube) (Theory generalized to include hypertension due to various etiologies). 1 Landmark study demonstrated a 96% reduction in CV events over 18 months with the use of a triple antihypertensive regimen compared with placebo in patients with severe hypertension (P<0.001). 3,4 Is High BP Good? High BP Is Good! The widespread opinion in the 1950s was that lowering BP could be harmful. 2 Lowering BP would impair perfusion of vital organs, increasing CV risk and renal disease. 2 Low BP Is Bad! High BP Is Bad! Power Over Pressure www.poweroverpressure.com BP = blood pressure; CV = cardiovascular.

3. The kidney is a central regulator of the electrical, chemical, and mechanical, forces that control BP SNS = sympathetic nervous system. RAAS = renin-angiotensin-aldosterone/system. Campbell W. The Autonomic and Peripheral Nervous Systems. In: Campbell, WW, editor. DeJong's The Neurologic Examination. 6th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2005 p. 535-547. Cowley A. Nat Rev Genetics. 2006;7:829-840. Kaplan NM, Victor R. Kaplan's Clinical Hypertension. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010. Schlaich M, et al. Hypertension. 2009;54:1195-1201. Guyton AC. Science. 1991;252:1813-1816. Electrical Chemical Mechanical SNS Kidney: BP Regulation Brain RAAS Cytokines Neurohormones Heart rate Vasodilation/ Vasoconstriction Volume control Power Over Pressure www.poweroverpressure.com

4. The SNS is part of the body’s autonomic nervous system –Operates without conscious control The SNS connects the brain, heart, blood vessels, and kidneys, each of which plays an important role in the regulation of BP Primary electrical component of BP control is the sympathetic nervous system (SNS) Epinephrine—adrenal glands Norepinephrine—kidney Inhibits digestive activity Stimulates glucose release by liver Dilates pupils Inhibits salivation Relaxes bronchi Accelerates heart Relaxes bladder Contracts rectum Cervical Thoracic Lumbar Campbell W. The Autonomic and Peripheral Nervous Systems. In: Campbell, WW, editor. DeJong's The Neurologic Examination. 6th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2005 p. 535-547. Power Over Pressure www.poweroverpressure.com

5. The kidneys are the most central contributors to BP, playing electrical, mechanical, and hormonal roles Ang II = Angiotensin II. Aldo = Aldosterone. RBF = Renal blood flow. GFR = Glomerular filtration rate. Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201. Hall JE, Guyton AC. Textbook of Medical Physiology. 12th ed. Philadelphia, PA: Saunders Elsevier, 2011.  Vasoconstriction  Contractility/Rate  Renin  Na+/Volume  RBF/GFR Ang II Aldo  Blood Pressure  Neurohormones Power Over Pressure www.poweroverpressure.com

6. The kidneys are the most central contributors to BP, playing electrical, mechanical, and hormonal roles RBF = Renal blood flow. GFR = Glomerular filtration rate. Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201. Hall JE, Guyton AC. Textbook of Medical Physiology. 12th ed. Philadelphia, PA: Saunders Elsevier, 2011.  Vasoconstriction  Contractility/Rate  Renin  Na+/Volume  RBF/GFR Ang II Aldo  Blood Pressure  Neurohormones Power Over Pressure www.poweroverpressure.com Ang II = Angiotensin II. Aldo = Aldosterone. RBF = Renal blood flow. GFR = Glomerular filtration rate. Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201. Hall JE, Guyton AC. Textbook of Medical Physiology. 12th ed. Philadelphia, PA: Saunders Elsevier, 2011.

7. Kidneys are the most central contributors to BP, playing electrical, mechanical, and hormonal roles Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201. Hall JE, Guyton AC. Textbook of Medical Physiology. 12th ed. Philadelphia, PA: Saunders Elsevier, 2011.  Vasoconstriction  Contractility/Rate  Renin  Na+/Volume  RBF/GFR Ang II Aldo  Blood Pressure  Neurohormones Kidney impairment or dysfunction =  afferent activity Power Over Pressure www.poweroverpressure.com

8. Kidneys are the most central contributors to BP, playing electrical, mechanical, and hormonal roles Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201. Hall JE, Guyton AC. Textbook of Medical Physiology. 12th ed. Philadelphia, PA: Saunders Elsevier, 2011.  Vasoconstriction  Contractility/Rate  Renin  Na+/Volume  RBF/GFR Ang II Aldo  Blood Pressure  Neurohormones Kidney impairment or dysfunction =  afferent activity Amplifies central, or systemic, sympathetic outflow Power Over Pressure www.poweroverpressure.com

9. Kidneys are the most central contributors to BP, playing electrical, mechanical, and hormonal roles Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201. Hall JE, Guyton AC. Textbook of Medical Physiology. 12th ed. Philadelphia, PA: Saunders Elsevier, 2011.  Vasoconstriction  Contractility/Rate  Renin  Na+/Volume  RBF/GFR Ang II Aldo  Blood Pressure  Neurohormones Kidney impairment or dysfunction =  afferent activity Amplifies central, or systemic, sympathetic outflow Power Over Pressure www.poweroverpressure.com

10. Renin-angiotensin-aldosterone system (RAAS) is central to the pathogenesis of hypertension Schrier RW, ed. Renal and Electrolyte Disorders 5th ed.1997. Water and salt retention. Effective circulating volume increases. Perfusion of the juxtaglomerular apparatus increases AngiotensinogenAngiotensin IAngiotensin II Renin ACE Pulmonary and renal epithelium: Decrease in renal perfusion Increased sympathetic activity Tubular Na + reabsorption, K + excretion and water retention Aldosterone secretion Vasoconstriction and increased BP Antidiuretic hormone secreted from pituitary, leading to water absorption Power Over Pressure www.poweroverpressure.com

11. Sympathetic drive plays a critical role in hypertension Afferent Renal Sympathetics The kidney is a source of central sympathetic activity, sending signals to the CNS Efferent Renal Sympathetics Sympathetic signals from the CNS modulate the physiology of the kidneys CNS = central nervous system. Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201. Power Over Pressure www.poweroverpressure.com

12. Sympathetic drive is elevated in multiple types of hypertension LVH=left ventricular hypertrophy. *P<0.05 Compared with borderline hypertension. / † P<0.05 Compared with white-coat hypertension. / ‡ P<0.05 Compared with normal pressure. § P<0.05 Compared with high-normal pressure. / ¶ P<0.05 Compared with essential hypertension–stage 1. / # P<0.05 Compared with essential hypertension–stages 2 and 3. Adapted from Smith P, et al. Am J Hypertens. 2004; 217-222. Baseline activity (normotensives) *†*† Normotensives High Normals White-coat Borderline Hypertension Essential Hypertension – Stage 1 Essential Hypertension – Stages 2 and 3 Essential Hypertension With LVH Sympathetic Activity per Minute 80 60 40 20 0 *†‡*†‡ * †‡§†‡§ *‡§¶*‡§¶ †‡§#†‡§# Single-unit efferent sympathetic nerve activity (s-MSNA) Power Over Pressure www.poweroverpressure.com

13. Summary: pathophysiology of treatment-resistant hypertension While treatment-resistant hypertension is a well-recognized phenomenon, perceptions of hypertension have changed over time BP is controlled by the complex interaction of several forces –Electrical: SNS, brain –Hormonal: RAAS, cytokines, neurohormones –Mechanical: heart rate, vasodilation/vasoconstriction, volume control The kidneys play a major role in BP control due to their intrinsic SNS connection Salt and water homeostasis along with BP regulation are controlled by RAAS Efferent and afferent signaling between the CNS and kidneys play a critical role in hypertension Elevated SNS activity is found in patients with multiple types of hypertension Power Over Pressure www.poweroverpressure.com