treatment-resistant hypertension: pathophysiology

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!


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


• 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

Cer

vica

lTh

orac

icLu

mba

r

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.


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


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.



Ang II

Aldo


Kidney impairment or dysfunction = afferent activity


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.



Ang II

Aldo


Kidney impairment or dysfunction = afferent activity

Amplifies central, or systemic, sympathetic outflow


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


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.


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

tensio

n – S

tage 1

Essen

tial H

yper

tensio

n – S

tages

2 an

d 3

Essen

tial H

yper

tensio

n With

LVH

Sym

path

etic

Act

ivity

per

Min

ute

80

60

40

20

0

*†‡

*

†‡§ *

‡§¶

†‡§#

Single-unit efferent sympathetic nerve activity (s-MSNA)


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


treatment-resistant hypertension: pathophysiology

Documents

renal disease

renal efficiency

severe hypertension

chronic kidney disease

pagein patients

landmark study

j clin

n engl j