1. Effects of Acute BP Elevation on the Vessel Wall

2. 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

3. 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.

4. NO PGI 2 Catecholamines AT-II ADH (vasopressin) Aldosterone TxA 2 ET 1 Endogenous vasoconstrictors The endothelium modulates vascular tone Courtesy of JJ Ferguson III, MD. Endogenous vasodilators

5. 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 PGI 2 Catecholamines AT-II ADH (vasopressin) Aldosterone TxA 2 ET 1 ( - )( + ) CAMs Endogenous vasodilators Endogenous vasoconstrictors

6. 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. TxA 2

7. 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).

8. Endothelial mechanoreceptors sense changes in shear stress Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93. ESS = endothelial shear stress

9. 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 activity Ras ERK JNK 03060 min Activation Maximum activation Gene Expression Basal activity C-fos mRNA MCP-1 mRNA 060120 min Activation 180240

10. 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 Blood flow Pulsatile ESS (15-70 dyne/cm 2 ) - Direction: Unidirectional - Magnitude: Physiologic time-average Low and oscillatory ESS (<10-12 dyne/cm 2 ) - Direction: Bidirectional (oscillatory) - Magnitude: Low time-average

11. 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

12. 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

13. Proposed mechanisms of perioperative MI Devereaux PJ et al. CMAJ. 2005;173:627-34. Inflammation Hypercoagulable state StressHypoxia ↑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

14. Summary: The pathophysiology of acute hypertensive syndromes Mechanical stress on the vessel wall ↑BP Release 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 Vasopressin endothelin catecholamines Major physiologic derangements Courtesy of JJ Ferguson III, MD.

15. Pathophysiology of acute hypertensive syndromes: A vicious cycle Courtesy of JJ Ferguson III, MD. Vascular injury Tissue ischemia Vasoconstrictor release

16. 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

17. Acute hypertension: Conclusions New options are needed Need for long-term patient follow-up in hypertensive urgencies/emergencies