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Treatment-Resistant Hypertension: Pathophysiology. Power Over Pressure www.poweroverpressure.com. Perceptions of hypertension have changed over time. High BP Is Bad!. High BP Is Good!. - PowerPoint PPT Presentation
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Treatment-Resistant Hypertension:Pathophysiology
Power Over Pressurewww.poweroverpressure.com
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 AdministrationCooperative 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 Pressurewww.poweroverpressure.com
BP = blood pressure; CV = cardiovascular.
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 Pressurewww.poweroverpressure.com
• 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 glandsNorepinephrine—kidney
Inhibits digestive activity
Stimulates glucose release by liver
Dilates pupils
Inhibits salivation
Relaxes bronchi
Accelerates heart
Relaxes bladder
Contracts rectum
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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 Pressurewww.poweroverpressure.com
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 Pressurewww.poweroverpressure.com
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 Pressurewww.poweroverpressure.com
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 Pressurewww.poweroverpressure.com
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 Pressurewww.poweroverpressure.com
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
Angiotensinogen Angiotensin I Angiotensin 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 Pressurewww.poweroverpressure.com
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 Pressurewww.poweroverpressure.com
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)
*†
Normote
nsive
sHigh
Nor
mals
Whit
e-co
at
Borde
rline H
yper
tensio
n
Essen
tial H
yper
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tage 1
Essen
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yper
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tages
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yper
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ute
80
60
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20
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*†‡
*
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Single-unit efferent sympathetic nerve activity (s-MSNA)
Power Over Pressurewww.poweroverpressure.com
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 Pressurewww.poweroverpressure.com