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
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
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