Treatment-Resistant Hypertension: Pathophysiology

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

2. Perceptions of hypertension have changed over time High BP Is Bad! High BP Is Good! • 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 • 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 • 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 • 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! Is High BP Good? BP = blood pressure; CV = cardiovascular. 1. Page IH. J Clin Invest. 1934;13:909-915. 2. Chobanian AV. N Engl J Med. 2009;361:878-887. 3. Veterans AdministrationCooperative Study Group. JAMA. 1967;202:1028-1034. 4. Calhoun DA, et al. Circulation. 2008;117(25):e510-e526. Power Over Pressure www.poweroverpressure.com

3. The kidney is a central regulator of the electrical, chemical, and mechanical, forces that control BP SNS Electrical Brain RAAS Kidney: BP Regulation Cytokines Chemical Neurohormones Heart rate Vasodilation/ Vasoconstriction Mechanical Volume control 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. Power Over Pressure www.poweroverpressure.com

4. Primary electrical component of BP control is the sympathetic nervous system (SNS) • 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 Dilates pupils Inhibits salivation Cervical Relaxes bronchi Accelerates heart Thoracic Inhibits digestive activity Stimulates glucose release by liver Lumbar Epinephrine—adrenal glandsNorepinephrine—kidney Relaxes bladder Contracts rectum 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  Neurohormones  Blood Pressure  Vasoconstriction  Contractility/Rate  RBF/GFR  Na+/Volume  Renin Ang II 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. Aldo Power Over Pressure www.poweroverpressure.com

6. Kidneys are the most central contributors to BP, playing electrical, mechanical, and hormonal roles  Neurohormones  Blood Pressure  Vasoconstriction  Contractility/Rate Kidney impairment or dysfunction =  afferent activity  RBF/GFR  Na+/Volume  Renin Ang II Aldo 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. Power Over Pressure www.poweroverpressure.com

7. Kidneys are the most central contributors to BP, playing electrical, mechanical, and hormonal roles  Neurohormones  Blood Pressure  Vasoconstriction  Contractility/Rate Kidney impairment or dysfunction =  afferent activity Amplifies central, or systemic, sympathetic outflow  RBF/GFR  Na+/Volume  Renin Ang II Aldo 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. Power Over Pressure www.poweroverpressure.com

8. Kidneys are the most central contributors to BP, playing electrical, mechanical, and hormonal roles  Neurohormones  Blood Pressure  Vasoconstriction  Contractility/Rate Kidney impairment or dysfunction =  afferent activity Amplifies central, or systemic, sympathetic outflow  RBF/GFR  Na+/Volume  Renin Ang II Aldo 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. Power Over Pressure www.poweroverpressure.com

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

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

11. Sympathetic drive is elevated in multiple types of hypertension 80 Single-unit efferent sympathetic nerve activity (s-MSNA) †‡§# †‡§ 60 *‡§¶ *† ‡ * Sympathetic Activity per Minute 40 *† Baseline activity (normotensives) 20 0 White-coat High Normals Normotensives Borderline Hypertension Essential Hypertension With LVH Essential Hypertension – Stage 1 Essential Hypertension – Stages 2 and 3 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. Power Over Pressure www.poweroverpressure.com

12. 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