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DR JULIAN JOHNY THOTTIAN DM CARDIO RESIDENT CMC KOZHIKODE

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Introduction Relatively modern disorder Prevalence Increases with age Environmental factors play role Genetic variation is possible

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Highly prevalent in the industrialized world with readily available food Industrialization, environmentalisation & genetic factors play a role

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Definition Essential, primary, or idiopathic hypertension is defined as high BP in which secondary causes such as renovascular disease, renal failure, pheochromocytoma, aldosteronism, or other causes of secondary hypertension or mendelian forms (monogenic) are not present.

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Risk factors (1) Obesity (2) Insulin resistance (3) High alcohol intake (4) High salt intake (in salt-sensitive patients) (5) Aging (6) Sedentary lifestyle (7) Stress (8) Low Potassium intake (9) Low Calcium intake Furthermore, many of these factors are additive, such as obesity and alcohol intake Most commonly related to PH are overweight & obesity accounting for 65%

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Interaction among genetic and environmental factors in the development of hypertension. Carretero O A, and Oparil S Circulation 2000;101:329-335 Copyright American Heart Association

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Blood pressure equation BP = cardiac output (CO) x total peripheral resistance (TPR) Cardiac Output = stroke volume (SV) x heart (HR) TPR depends on the tone of the resistance vessels = Mean BP Total Peripheral Resistance X Cardiac Output

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Homeostatic control cycles MAPCOSV venous return aldosterone Blood volume baroreceptors Vasomotor centre HR Contractile force renin venous tone Peripheral resistance sympathetic nervous system angiotensin Renal blood pressure parasympathetic nervous system Neural RAAS Vasomotor Endocrine

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10 Causes of hypertension = Increased Cardiac Output Intravascular Volume Glomerular filtration Sodium excretion Extracellular Fluid Renal Nerve Activity Myocardial Performance Adrenergic Activity Increased Vasoconstriction Adrenergic Stimuli Angiotensin II Endothelin Endothelium-derived Contracting Factors Thromboxane Decreased Vasodilation Prostacyclin Nitric oxide EDHF* Textor SC. Atlas of Diseases of the Kidney, 2001. *Endothelium-derived Hyperpolarizing Factors www.hypertensiononline.org Mean BP Total Systemic Vascular Resistance X Cardiac Output

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11 Mechanisms of essential hypertension Renal/Hormonal: Sodium & volume regulation Intrinsic renal pressure/naturesis system RAAS (renin angiotensin aldosterone system) Atrial/Brain naturetic peptides Vascular: tone of resistance vessel Abnormal cellular ion pumps Vascular remodelling Neural: Central Sympathetic Nervous system

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12 Renal regulation of BP Intrinsic GFR --------------------> PT-Na+------------> BP RAAS Angiotensin II-------------> Constriction-----> BP DT-Na+ Naturetic factors BV --------> ANF----------> Dilation ---------> BP DT-Na+ Aldosterone BP regulation by 3 renal mechanisms:

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Intrinsic pressure naturiesis Sodium load Volume expansion Cardiac Output Excretion of sodium load Tissue overperfusion BP Tissue vasoconstriction Pressure naturiesis BP Simple loop, keeping BP stable

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Renin-angiotensin-aldosterone system (RAAS) Renin Substrate AIAII AT1 Receptor ACERenin Converting enzyme receptors AT2 Receptor (Angiotensinogen) Kidney Liver Circulation Lung Circulation Aldosterone

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AT1 receptor drives hypertension Direct vasoconstriction. Central sympathetic Peripheral sympathetic release Sodium reabsorption. Aldosterone release. Renal blood flow AT-1receptors Smooth muscle cell proliferation Blood volumeVasoconstriction Cardiac & vascular remodelling Blood pressure Angiotensin II Vasoconstrictor, renally & peripherally Aldosterone release (volume expansion ) Muscle hypertrophy (vessel, heart) Fibrosis (especially in heart & mesangium)

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Vascular mechanisms

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Resistance vessels Concept: Resistance vessels (arterioles) set peripheral resistance and blood pressure Microcirculation protects target organ from systemic blood pressure (damaging) autoregulation Systemic pressure microcirculation Resistance vessels Target organ

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Cell ionic fluxes Implicated channels Na channel Na/H exchange channel Na+/K+/Cl- co-transport Na/Ca exchange Na/Li countertransport Unclear significance, may be epiphenomena, contributory or causal Target more likely in vascular smooth muscle Could increase Ca influx, increasing tone in wall

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Ion fluxes trigger cell growth Modulated by Angiotensin II Stimulates cell growth, leading to hypertrophy

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Sympathetic nervous system Sympathetic outflow Higher centres External environment Baroreceptors Angiotensin II Diet Insulin Glucose Leptins Vasculature LVH Kidneys Thrombogenesis Glucose Metabolism Renin

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Abnormal autonomic NS in hypertension Concept of increased pressor responsiveness on resistance vessels

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Hypertension a reset problem? Renal blood flow reduced in response to sodium in hypertensives (reset through RAAS? Or abnormal renal prostaglandins) Less flow allows more tubular sodium resorption Leads to higher blood volume and pressure Homeostasis in effect reset at a higher level RAAS should be suppressed at hypertensive levels, but rarely is, possibly further driving BP In predisposed individuals, other mechanisms maintain hypertension and leads to tissue damage

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Genes and essential hypertension Jeunemaitre et al first reported a polymorphism in the angiotensinogen gene linked with essential hypertension in hypertensive siblings from Utah and France Substitution of methionine for threonine at position 235 (M235T) and is associated with increased concentrations of plasma angiotensinogen Corvol P, Jeunemaitre X. Molecular genetics of human hypertension: role of angiotensinogen. Endocr Rev. 1997;18:662677

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25 Rat models have had their genetic diversity pruned by selection, mostly major (homozygous) genes left Most human populations are outbred (exceptions) Polygenes are more important Pima African Americans Outbred populations Major genes Polygenes

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26 Interaction genes & environment

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27 Interactions in essential hypertension Environment Fetal Genetics Modifiable Na intake K intake Obesity Exercise Small effect Environment overwhelms genetics (migration studies) Large effect Modifiers & Magnifiers

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Other potential genes Angiotensin-converting enzyme 2 -adrenergic receptor -adducin Angiotensinase C Renin-binding protein G-protein 3 -subunit Atrial natriuretic factor Insulin receptor

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CONCEPT OF SALT SENSITIVITY Concept of heterogeneity of blood pressure responsiveness to alterations in dietary sodium intake was first suggested by studies in 19 hypertensive subjects who were observed after a normal (109 mmol/d), low (9 mmol/d), and then high (249 mmol/d) sodium intake Kawasaki T, Delea CS, Bartter FC, Smith H. The effect of high-sodium and low-sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension. Am J Med. 1978;64:193-198

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73% of black hypertensive patients were salt sensitive compared with 56% of a white hypertensive group; but in the normotensive population, the frequency of salt sensitivity among blacks (36%) was similar to that seen among whites (29%) In the large epidemiological INTERSALT study, the relationship between sodium excretion and blood pressure was most notable when examined on the basis of age. Rodriquez BL, Labarthe DR, Huang B, Lopez-Gomez J. Rise of blood pressure with age. Hypertension. 1994;24:779-785

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Salt-sensitive individuals had a rise in blood pressure over time that was significantly (P