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Houston Gr Jan 20.Pdf The following potential conflict of interest relationships are germane to my presentation. The Role of Vascular Biology, Equipment: None Nutrition and Nutraceuticals in the Speakers Bureau: Takeda, Novartis, Boehringer Ingelheim, Forest, Bristol-Meyers, Squibb, Daiichi Sanko, Sanofi-Aventis ,Biotics, Prevention and Treatment Designs for Health and Spectracell of Hypertension and Stock Shareholder: None Grant/Research Support: Biotics Cardiovascular Disease Consultant: Takeda, Biotics, Designs for Health, Spectracell Other: Biotics Research Corporation, Designs for Health and Spectracell Mark C. Houston, M.D. MSc, ABAARM, FACP, FAHA,FASH Associate Clinical Professor of Medicine Vanderbilt University School of Medicine Status of FDA devices used for the material being Director, Hypertension Institute and Vascular Biology Section Chief Nutrition Division, HI presented Medical Director of Clinical Research and CME , HI NA/Non-Clinical Medical Director of Life Extension Institute American Society of Hypertension (ASH) Specialist and Fellow in Clinical Hypertension (FASH) Status of off-label use of devices, drugs or other materials Saint Thomas Medical Group Saint Thomas Hospital and Health Services that constitute the subject of this presentation NA/non- Nashville, Tennessee HYPERTENSIONINSTITUTE.COM clinical Vascular Disease is a Balance “The blood vessel has a finite Vascular Injury number of responses to an infinite number of insults.” vs Vascular Repair Mark Houston MD,MS 2002 Hypertension is not a disease, it is the “correct” but chronic dysregulated response with an exaggerated outcome of the infinite insults to the blood vessel with the subsequent environmental- gene expression patterns in which the vascular system is the innocent bystander. This Environment-Gene Interaction is a combination of the infinite biomechanical and biohumoral (biochemical, metabolic and nutritional insults) Modulation of the environmental insults as well as the downstream disturbances of gene expression patterns is the key to the prevention and treatment of hypertension and cardiovascular disease. Role of vascular “Neo-antigens” secondary to damaged proteins Houston 2011 Hypertension, Vascular Biology and the Blood Vessel Eftekhari A et al. J of Hypertension 2011;29:896-905 Hypertension is not a disease but is a marker for vascular dysfunction. An elevated blood pressure is one of many responses of the blood vessel to endothelial dysfunction, vascular smooth muscle dysfunction and impaired microvascular function and structure. Endothelial dysfunction and microvascular smooth muscle dysfunction precede the development of hypertension by decades. Houston MC.Vascular Biology in Clinical Practice. Hanley and Belfus 2000 38 Houston MC Handbook of Hypertension Wiley Blackwell Oxford UK 2009 Vascular Endothelium : Strategic Anatomical Position The Endothelium Maintains Vascular Health Houston MC Vascular Biology in Clinical Practice. Hanley and Belfus. Philadelphia 2000 Houston MC Vascular Biology in Clinical Practice. Hanley and Belfus, Philadelphia. 2000 Houston MC, Handbook of Hypertension. Wiley Blackwell, Oxford UK 2009 Houston MC. Handbook of Hypertension. Wiley-Blackwell Oxford UK. 2009 CIRCULATING BLOOD Platelet Function Coagulation Dilatation Modulates Monocyte and Leukocyte Adhesion Growth Inhibition Inflammation Antithrombotic Anti-inflammatory ENDOTHELIUM Strategic Location Antioxidant Constriction Permeability Growth promotion Contractile State Modulates Prothrombotic Proliferative Response (Growth) Proinflammatory Migratory Response Pro-oxidant Redox State VASCULAR SMOOTH MUSCLE CELLS (VSMC) 41 BALANCE OF NITRIC OXIDE VS Endothelium-Dependent Responses ANGIOTENSIN II (not present in all blood vessels) Houston MC. Handbook of Hypertension. Wiley-Blackwell, Oxford Short term regulation Long term regulation UK 2009 Blood Blood ET ACh VP P 5-HT TBk AT-II VP T ANGIOTENSIN II IS VASOCONSTRICTIVE X AA AA + mRNA L-arginine COX HYPERTENSIVE, INFLAMMATORY, COX NOS Big ET Endoperoxides ECE O2 INCREASES OXIDATIVE STRESS, VASCULAR EDHF PGI2 NO TXA ET-1 IMMUNE DYSFUNCTION, THROMBOSIS, 2 Endothelium EDHF Endoperoxides PGI2 NO O2 + GROWTH AND IS PROATHEROGENIC. K TXA2 +EDHF GC ET-1 hyperpolarization cGMP NITRIC OXIDE IS VASODILATORY, ANTI- IP TX/Endo Relaxation + ET Relaxation + HYPERTENSIVE,ANTI-INFLAMMATORY, AC Contraction REDUCES OXIDATIVE STRESS, REDUCES Smooth muscle cAMP cells Relaxation Ca2+ VASCULAR IMMUNE DYSFUNCTION AND Ca2+ THROMBOSIS AND IS ANTI-ATHEROGENIC Houston MC.Vascular Biology in Clinical Practice. Hanley and Belfus. Philadelphia 200046 Houston MC Handbook of Hypertension. Wiley-Blackwell, Oxford UK 2009 Endothelial Dysfunction (ED) Two Paradigms of Endothelial Activation: 149 Expert Review in Cardiovascular Therapeutics. 2010;8 821 Biochemical and Biomechanical Houston MC. Handbook of Hypertension. Wiley Blackwell Oxford UK 2009 10? Characterized by decreased release of relaxing factors (vasodilators) and propensity to secrete contracting factors Biochemical Biomechanical (vasoconstrictors). Reduced EDV: endothelial vasodilation Activation or Fluid shear stress dysfunction = Hydrostatic Blood-borne pressure Key, initial and earliest event in vascular disease. Present Phenotypic mediators with only risk factors but no atherosclerosis. Modulation of Structure and Precedes intimal thickening and clinical atherosclerosis by a Function of decades. Autocrine Cyclic strain Resting mediators Paracrine Endothelial Cell mediators Correlation with future CV events (MI, PCTA, CABG, sudden death). Diverse pathophysiologic stimuli are capable of inducing The term endothelial activation is used to connote the modulation of endothelial functional phenotype, in response to physiologic and pathophysiologic stimuli, which can have both adaptive and nonadaptive consequences. By virtue of its position at the interface between flowing blood and tissues, endothelium is exposed to a vast array of both biochemical and biomechanical stimuli that can induce endothelial activation. The biochemical stimuli (hormones, growth factors, similar nonadaptive changes in endothelial function. cytokines and bacterial products) can be delivered via the blood and also in an autocrine (acting on the cell of origin) or paracrine (acting on adjacent cells) 105,107 manner. The biomechanical stimuli consist of wall shear stresses (tractive forces generated at the luminal endothelial interface by blood flow), pressures “Syndrome of Endothelial Dysfunction.” (hydrostatic forces that act perpendicular to the endothelial interface), and cyclic strains (circumferential stretching of endothelium and other cells within the vessel wall, as a consequence of pulsatile blood flow). Hypertension (1 and 2) has reduced EDV in both peripheral 146 and coronary arteries.107 150 151 105 Endothelial Dysfunction: Endothelial Dysfunction Pathophysiologic Stimuli and Consequences Disturbed Flow Inflammatory Cytokines ED Oxidized Lipoproteins Advanced Glycosylation End Products Function Structure Homocysteine Increased Prothrombotic Activity Leukocyte adhesion Altered junctions molecules & Small Large Arteries & transport chemoattractants Arteries Remodeling Cell surface procoagulant EDRF activity PGI2 Expression of C2 SVR C1 PP Plaques Impaired Vasorelaxation Increased growth factors & (Vasospasm) mitogens Permeability & Increased Trapping of LDL Leukocyte Clots Recruitment BP Small Artery Remodeling SMC Migration, Proliferation & Flow Organ Cohn, J ECM Production C 2 Reserve Dysfunction ISH, August 2000 VASCULAR REPAIR:ENDOTHELIAL PROGENITOR CELLS VASCULAR REPAIR:ENDOTHELIAL PROGENITOR CELLS Disproportionally impaired microvascular structure in (EPC’S) Disproportionally impaired microvascular structure in NEJM 2003: 348:593 essential hypertension. Therapeutic Advances in Cardiovascular Disease 2010;4:55-69 Eftekhari A et al. J of Hypertension 2011; 29:896-905 J Clin Nutr 2010;92:161 The level of BP elevation does not give an accurate Marker of neovascularization and vascular endothelial repair indication of the microvascular involvement and Most predictive of all known cardiovascular risk factors impairment in hypertension. Correlates with hypertension and other CHD risk factors High risk patients have a lower number and early senescence of EPC’s with a higher risk of CHD, CVA and CVD Hypertensive patients have abnormal Telomere length in leukocytes determine hematopoeitic stem cell reserve and EPC production. Telomere length genes. microvasculature in the form of inward eutrophic Released from bone marrow remodeling of the small resistance arteries leading to High content of MnSOD and GPx-1 impaired vasodilatory capacity, increased vascular Increase with exercise, E2, resveratrol, red wine, ACEI, ARB, resistance, increased media to lumen ratio, and statins. decreased maximal organ perfusion and reduced flow Decrease with oxidative stress, inflammation, A-II, obesity, low E2 and low testosterone. reserve. In the heart, this is CFR ( coronary flow reserve). Hypertension is a disease of the blood vessel. Microvascular impairment precedes the development of hypertension Eftekhari A. et al. J of Hypetension 2011;29:896-905 Which occurs first: The hypertension or the Giannattasio C. et al. J Hypertension 1995;13:259 Giannattasio C. et al. J Hypertension 1995;13:259 diseased blood vessel, or is it both? It is bidirectional. Significant structural microvascular impairment occurs long before the BP begins to rise in normotensive offspring of Hypertension is part of vascular
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