Effects of AcuteBP Elevation onthe Vessel Wall

Pathophysiology overview

Sustained neurohormonal activation and vasoconstriction leads to • Endothelial decompensation • Altered vascular structure

Vicious cycle of homeostatic failure begins, leading to • Loss of cerebral and local autoregulation• Organ system ischemia and dysfunction• Myocardial infarction

Pathophysiology of hypertension

INAPPROPRIATELY HIGH SYMPATHETIC OUTFLOW

Increased large arterial stiffness

Inappropriately high

cardiac output

Abnormal venoconstriction

and high venous return

INAPPROPRIATELY HIGH RENIN RELEASE

ABNORMAL RENAL

SALT/WATER HANDLING

Increased systemic

resistance

Courtesy of JL Izzo Jr, MD.

NO

PGI2

CatecholaminesAT-II

ADH (vasopressin)Aldosterone

TxA2

ET1

Endogenous vasoconstrictors

The endothelium modulates vascular tone

Courtesy of JJ Ferguson III, MD.

Endogenous vasodilators

Proposed vascular pathophysiology of hypertensive urgency

Vaughan CJ, Delanty N. Lancet. 2000;356:411-7.Courtesy of JJ Ferguson III, MD.

Acute ↑ BP triggers ↑ cellular adhesion molecular expression

NO

PGI2

CatecholaminesAT-II

ADH (vasopressin)Aldosterone

TxA2

ET1( - ) ( + )

CAMs

Endogenous vasodilators

Endogenous vasoconstrictors

• Overwhelmed control of vascular tone leads to coagulation cascade activation• Loss of endothelial activity coupled with coagulation and platelets promotes DIC

Proposed vascular pathophysiology of hypertensive emergency

Vaughan CJ, Delanty N. Lancet. 2000;356:411-7. Courtesy of JJ Ferguson III, MD.

TxA2

Endothelial shear stress

Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.ESS = endothelial shear stress

Proportional to the product of blood viscosity (μ) and spatial gradient of

blood velocity at the wall (dv/dy).

Endothelial mechanoreceptors sense changes in shear stress

Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.ESS = endothelial shear stress

Shear stress rapidly activates endothelial signal transduction and gene expression

Chien S et al. Hypertension. 1998;31[part 2]:162-9.

Maximum activation

Signal Transduction

Basal activityRas

ERKJNK

0 30 60min

Ac

tiv

ati

on

Maximum activation

Gene Expression

Basal activity

C-fos mRNAMCP-1 mRNA

0 60 120min

Ac

tiv

ati

on

180 240

Definition and example of pulsatile, low, and oscillatory ESS

Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.ESS = endothelial shear stress

Cross-section

Bloodflow

Pulsatile ESS(15-70 dyne/cm2)- Direction: Unidirectional- Magnitude: Physiologic time-average

Low and oscillatory ESS(<10-12 dyne/cm2)- Direction: Bidirectional (oscillatory)- Magnitude: Low time-average

Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.

Implications of low and high shear stress

Effects of high shear stress

Endothelial dysfunction

Vascular injury

Thrombosis

Neurohumoral activation

Atherosclerosis

Plaque rupture

Effects of low shear stress

Perioperative triggers of adverse physiologic states

• Surgical trauma

• Anesthesia/analgesia

• Intubation/extubation

• Pain

• Hypothermia

• Bleeding/anemia

• Fasting

• Transfusion

Devereaux PJ et al. CMAJ. 2005;173:627-34.

Inflammatory

Hypercoagulable

Stress

Hypoxia

Physiologic state

Proposed mechanisms of perioperative MI

Devereaux PJ et al. CMAJ. 2005;173:627-34.

InflammationHypercoagulable

stateStress Hypoxia

↑TNF-α↑IL-1↑IL-6↑CRP

↑PAI-1↑Factor VIII↑Platelet reactivity↑Antithrombin III

↑Catecholamine and cortisol levels

↓Oxygen delivery

Plaque fissuring

Coronary artery shear stress

Plaque fissuring

↑BP↑HR↑FFAs↑Relative insulin

deficiency

↑Oxygen demand

Myocardial ischemia

Acute coronary thrombosis

Perioperative myocardial infarction

Summary: The pathophysiology of acute hypertensive syndromes

Mechanical stress on the vessel wall

↑BPRelease of humoral

vasoconstrictors

↑BP

Endothelial damage

Activation of the clotting cascade

Further release of humoral

vasoconstrictors

Fibrinoid necrosis of small blood

vessels

Pressure natriuresis

Volume depletion

RAAS activation

Vasopressinendothelin

catecholaminesMajor physiologic

derangements Courtesy of JJ Ferguson III, MD.

Pathophysiology of acute hypertensive syndromes: A vicious cycle

Courtesy of JJ Ferguson III, MD.

Vascular injury

Tissue ischemia

Vasoconstrictor release

Summary: Acute hypertension

Nonsurgical patients

• Little studied in past decade

• Multiple knowledge gaps– Patient characteristics– Treatment patterns– Outcomes

Perioperative patients

• Frequent finding

• Emerging data demonstrate importance of tighter BP control than currently recommended

Acute hypertension: Conclusions

• New options are needed

• Need for long-term patient follow-up in hypertensive urgencies/emergencies