Transcript ESSENTIAL HYPERTENSION ETIOPATHOGENESIS

DR JULIAN JOHNY THOTTIAN
DM CARDIO RESIDENT
CMC KOZHIKODE
Introduction
 Relatively modern disorder
 Prevalence Increases with age
 Environmental factors play role
 Genetic variation is possible
 Highly prevalent in the industrialized world with
readily available food
 Industrialization , environmentalisation & genetic
factors play a role
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.
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%
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
Blood pressure equation
Mean BP =
Cardiac
Output
X
Total Peripheral
Resistance
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
Homeostatic control cycles
Vasomotor centre
Neural
baroreceptors
parasympathetic
nervous system
sympathetic
nervous system
Endocrine
Vasomotor
Peripheral
resistance
MAP
CO
HR
Contractile
force
venous
return
SV
venous
tone
Blood
volume
aldosterone
Renal blood
pressure
renin
angiotensin
RAAS
Causes of hypertension
Mean BP =
Cardiac
Output
Increased Cardiac Output
Intravascular Volume




Glomerular filtration
Sodium excretion
Extracellular Fluid
Renal Nerve Activity
Myocardial Performance
 Adrenergic Activity
X
Total Systemic
Vascular Resistance
Increased
Vasoconstriction
 Adrenergic Stimuli
 Angiotensin II
 Endothelin
 Endothelium-derived
Contracting Factors
 Thromboxane
Decreased
Vasodilation
 Prostacyclin
 Nitric oxide
 EDHF*
*Endothelium-derived
Hyperpolarizing Factors
Textor SC. Atlas of Diseases of the Kidney, 2001.
www.hypertensiononline.org
10
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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Renal regulation of BP
BP regulation by 3 renal mechanisms:
Intrinsic
GFR
--------------------> PT-Na+------------>
BP
RAAS
Angiotensin II------------->  Constriction---->
 DT-Na+
Aldosterone
Naturetic factors
BV --------> ANF---------->  Dilation --------->
 DT-Na+
BP
BP
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Intrinsic pressure naturiesis
Excretion of
sodium load
Sodium load
BP
Volume
expansion
Pressure naturiesis
Simple loop,
keeping BP
stable
BP
 Cardiac Output
Tissue
overperfusion
Tissue vasoconstriction
Renin-angiotensin-aldosterone
system (RAAS)
Renin
ACE
AT1
Receptor
Kidney
Renin
Substrate
Liver
AI
Circulation
(Angiotensinogen)
AII
Circulation
Lung
Converting
enzyme
Aldosterone
AT2
Receptor
receptors
AT1 receptor drives hypertension
Angiotensin II
•Vasoconstrictor, renally & peripherally
•Aldosterone release (volume expansion)
•Muscle hypertrophy (vessel, heart)
•Fibrosis (especially in heart & mesangium)
AT-1receptors
Direct
vasoconstriction.
Central sympathetic
Peripheral
sympathetic
release
Vasoconstriction
Sodium reabsorption.
Aldosterone release.
Smooth muscle
cell
proliferation
Renal blood flow
Blood volume
Blood pressure
Cardiac & vascular
remodelling
Vascular mechanisms
Resistance vessels
• Concept:
Systemic pressure
Resistance
vessels
autoregulation
microcirculation
Target
organ
• Resistance vessels (arterioles) set peripheral resistance and
blood pressure
• Microcirculation protects target organ from systemic
blood pressure (damaging)
Cell ionic fluxes
Implicated channels
 Unclear significance,
 may be epiphenomena,
contributory or causal
 Na channel
 Na/H exchange channel
 Na+/K+/Cl- co-transport
 Na/Ca exchange
 Na/Li countertransport
 Target more likely in vascular
smooth muscle
 Could increase Ca influx,
increasing tone in wall
Ion fluxes trigger cell growth
•Modulated by Angiotensin II
•Stimulates cell growth, leading to hypertrophy
Sympathetic nervous system
External
environment
Angiotensin II
Higher
centres
Sympathetic
outflow
Baroreceptors
Diet
Insulin
Glucose
Leptins
Vasculature
Kidneys
LVH
Renin
Glucose
Metabolism
Thrombogenesis
Abnormal autonomic NS in hypertension
Concept of increased pressor responsiveness on resistance vessels
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
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;18:662–677
Polygenes are more important
 Rat models have had their
genetic diversity pruned by
selection, mostly major
(homozygous) genes left
 Most human populations are
outbred (exceptions)
Polygenes
Major genes
Pima
African
Americans
Outbred populations
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Interaction genes & environment
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Interactions in essential hypertension
Environment overwhelms
genetics (migration studies)
Modifiable
•Na intake
Environment
•K intake
•Obesity
•Exercise
Large
effect
Genetics
Modifiers
&
Magnifiers
Fetal
Small
effect
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Other potential genes
Angiotensin-converting enzyme
β2-adrenergic receptor
α-adducin
Angiotensinase C
Renin-binding protein
G-protein β3-subunit
Atrial natriuretic factor
Insulin receptor
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
 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
 Salt-sensitive individuals had a rise in blood pressure over
time that was significantly (P<.001) greater than in those
who were salt resistant.
 A more consistent finding has been the alteration in salt
sensitivity of blood pressure after weight loss in obese
subjects
 Genetic- greater frequency of salt sensitivity among
Japanese with the haptoglobin 1-2 genotype than among
those who were homozygous for 2-2
 Investigators were unable to identify differences in salt
sensitivity based on the three different patterns (II, ID, and
DD)
 Salt-sensitive subjects were all blacks who demonstrated a
decrease in renal blood flow in response to the high salt
diet, whereas the salt-resistant group, which included all of
the white subjects as well as some blacks, showed an
increase in renal blood flow
 Observations in both experimental animals and humans
have been cited that provide substantial indirect evidence
that salt sensitivity is associated with a reduction in
nephron number or glomerular surface area
Myron H. Weinberger
Other hormones
 ANF -Salt-sensitive hypertensive men have lower levels
of ANF after a high salt intake than subjects whose
blood pressure is not salt sensitive. Gerdts E, Myking OL, Omvik
P. Salt sensitive essential hypertension evaluated by 24 hour ambulatory blood
pressure. Blood Pressure. 1994;3:375-380
 KALLIKREIN KININ SYSTEM -Salt-sensitive
hypertensive patients have lower levels of urinary
kallikrein than those who are salt resistant Ferri C,
Bellini C, Carlomagno A, Perrone A, Santucci A. Urinary kallikrein and salt
sensitivity in essential hypertensive males Kidney Int. 1994;46:780-788.
ALDOSTERONE
VEGF
INCREASED RENAL OXIDATIVE
STRESS
ENDOTHELIN
OUTCOMES
 Kimura and Brenner have suggested that salt
sensitivity is associated with an increased
intraglomerular pressure and hence a higher risk of
developing glomerulosclerosis and CRF.
Furthermore, salt sensitivity is associated with several
features known to confer a greater renal and
cardiovascular risk such as microalbuminuria , high
levels of LDL and Lp(a) , insulin resistance , a lack of
nocturnal decrease in blood pressure and an
increased left ventricular mass .
Morimoto et al. have followed a group of salt‐sensitive
and salt‐resistant hypertensive patients for 17 years
and could demonstrate that salt sensitivity is indeed
an independent cardiovascular risk factor
Excessive weight gain
Current estimates indicate that more than 1 billion
people in the world are overweight or obese
Framingham Heart Study, for example, suggest that
approximately 78% of primary hypertension in men
and 65% in women can be ascribed to excess weight
gain
Each 10% weight gain is associated with a 6.5 mm Hg
increase in systolic BP
 A BMI of <25 is considered normal or healthy, whereas
a BMI of 26 to 28 (as compared with BMI <23)
increases the risk of high BP by 180% and the risk of
insulin resistance by >1000%.
 BP in obese adolescents is sodium-sensitive, and
fasting insulin is the best predictor of this sensitivity.
Rocchini AP, Key J, Bondie D, Chico R, Moorehead C, Katch V, Martin M. The effect of
weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J
Med. 1989;321:580–585
Effect of Obesity on Tissue Blood
Flow and Cardiac Output
 Expansion of extracellular fluid volume, as well as
increased tissue blood flow and cardiac output
 Increased flow leads to tissue growth due to increased
workload and metabolic demands
 Despite higher resting blood flows in many tissues,
there appears to be reduced blood flow "reserve"
during exercise in obese, compared with lean,
individuals.
Cardiac reserve is also reduced
Mechanisms of Impaired Renal Pressure
Natriuresis in Obesity Hypertension
Sympathetic Nervous System Activation in
Obesity Hypertension
 Evidence of increased SNS activity in obesity-
(1) SNS activation, especially renal sympathetic
activity, is increased in obese subjects
(2) Pharmacologic blockade of adrenergic activity
lowers blood pressure to a greater extent in obese,
compared with lean, individuals
(3) Renal denervation markedly attenuates sodium
retention and hypertension associated with a high-fat
diet
 SNS activity is highly differentiated
 Cardiac sympathetic activation is not so much elevated
when compared to kidney and skeletal muscles
 But SNS activity in kidney is not so much activated to
cause vasoconstriction but surely increases renin and
increased tubular absorption
Genetic factors and SNS activity
 In Pima Indians who have a high prevalence of obesity but
a relatively low prevalence of hypertension.
In black men, SNS activity is higher, and hypertension is
more prevalent than in white men despite comparable
levels of obesity.
In young, overweight, black women, adiposity is associated
with sympathetic hyperactivity.
Factors such as differences in fat mass distribution may
contribute to some of the racial variation in SNS responses
to increasing adiposity.
Abdominal obesity elicits a much greater sympathetic
activation than does subcutaneous or lower body obesity.207
Several potential mediators of SNS
activation
(1) Hyperinsulinemia
(2) Ang II
(3) Increased levels of free fatty acids
(4) Impaired baroreceptor reflexes
(5) Activation of chemoreceptor-mediated reflexes
associated with sleep apnea
(6) Cytokines released from adipocytes (ie,
"adipokines") such as leptin, TNF-, and IL-6
Hyperleptinemia
 Leptin released from adipocytes
 It increases SNS activity and decreases appetite
 It acts on the hypothalamus
 The hypertensive effects of leptin are enhanced when
NO synthesis is inhibited as often occurs in obese
subjects with endothelial dysfunction.
How leptin acts….
RAAS
 Obese subjects- visceral obesity, often have mild to
moderate increases in plasma renin activity,
angiotensinogen, ACE activity, Ang II, and aldosterone
levels.
Activation of the RAS in obese subject occurs despite
sodium retention, volume expansion, and
hypertension, all of which would normally tend to
suppress renin secretion and Ang II formation.
There have been no large-scale clinical studies
comparing the effectiveness of RAS blockers in obese
and lean hypertensive patients, although smaller
clinical trials have shown that both ARBs and ACE
inhibitors are effective in lowering blood pressure in
obese hypertensive patients.
 Increased aldosterone and MR activation also appear to
contribute to obesity-induced hypertension
 Combined blockade of MR and Ang II might be especially
effective in treating patients with obesity hypertension.
The observation that MR antagonism attenuated
glomerular hyperfiltration may also have important
implications for renal protection in obesity.
Administration of the MR antagonists also provides
significant antihypertensive benefit in resistant obese
patients.
The reductions in blood pressure caused by MR
antagonism in obese patients with resistant hypertension
occurred despite concurrent therapy with ACE inhibitor or
ARB, calcium channel blocker, and thiazide diuretic,
suggesting that MR activation in obesity may occur
independently of Ang II–mediated stimulation of
aldosterone secretion
RENIN HYPERTENSION
 Renin-sodium profiling in patients with essential (primary)

1.
2.
3.
hypertension reveals that the plasma renin activity (PRA) is increased
in 15 percent, normal in 60 percent, and reduced in approximately 25
percent .
Low renin levels are found more frequently in blacks and in the elderly
Although it is likely that patients with low-renin essential hypertension
(LREH) represent part of a continuum of hypertensives, this subgroup
may have some relatively unique characteristics:
The elevation in blood pressure is more likely to be salt-sensitive .
The response to nonpharmacologic therapy, particularly weight
reduction, may be less pronounced .
The antihypertensive response may be greatest with a diuretic or
calcium channel blocker .
Non modulators
 A subgroup of hypertensive patients has been
described in whom the “normal” alterations in renal
blood flow associated with a high dietary sodium
intake and a “normal” response of plasma aldosterone
to administered angiotensin II are not seen. This
subgroup has been defined as non-modulators, and
many but not all of the subjects in this subgroup have
been characterized as salt sensitive in terms of their
blood pressure response to alterations in dietary
sodium intake
RENAL COMPRESSION IN OBESITY
 Compression of the kidneys---- increased intrarenal
pressures------ impaired renal pressure natriuresis and
hypertension.
Increased intrarenal hydrostatic pressure may, in turn,
cause compression of the loops of Henle and vasa
recta, thereby increasing tubular sodium and water
reabsorption.
 Renal medullary histology shows increased
extracellular matrix that exacerbates intrarenal
compression.
Glomerular injury and nephron loss
 Proteinuria in the nephrotic range folowed by
progressive loss of kidney function is seen
 Glomerulomegaly and focal/segmental glomerular
sclerosis is seen
 Increased expression of TGF-beta and inreased
mesangial matrix
 Praga and coworkers reported that of patients with a
BMI greater than 30 who had undergone unilateral
nephrectomy, 92% developed proteinuria or renal
insufficiency, but only 12% of patients with a BMI less
than 30 developed these disorders.
Role of insulin resistance or
metabolic syndrome
Supporting a role for hyperinsulinemia in hypertension
comes mainly from epidemiologic studies showing
correlations between insulin resistance,
hyperinsulinemia, and blood pressure and from shortterm studies indicating that insulin has sympathetic
effects that, if sustained, could theoretically increase
blood pressure.
However, chronic hyperinsulinemia, in the absence of
obesity, does not raise blood pressure in either dogs or
humans - Hall et al
 Chronic infusion of insulin reduced BP in humans
even in patients with renal dysfunction due to
peripheral vasodilator effects.
 It did not enhance the hypertensive effects of other
pressor substances such as norepinephrine or Ang II.
 These observations suggest that hyperinsulinemia per
se is insufficient to cause chronic hypertension.
Insulin Resistance - Hypertension
Independent of Hyperinsulinemia?
Insulin resistance has also been suggested to cause
hypertension by increasing TPR through mechanisms that
are independent of hyperinsulinemia.
Antihyperglycemic agents that increase insulin sensitivity, thiazolidinediones, also lower BP as they influence the
expression of multiple genes by binding to the peroxisome
proliferator-activated receptor- (PPAR), a nuclear receptor.
Thiazolidinediones may also inhibit L-type calcium
channels, and they reduce blood pressure in renovascular
hypertension that is not associated with insulin resistance
or hyperinsulinemia.
 Direct causal relationship between insulin resistance
and hypertension has not been established.
Abnormalities of glucose and lipid metabolism
associated with insulin resistance may, over a period of
many years, lead to vascular and renal injury and in
this way contribute indirectly to increased blood
pressure.
 Insulin causes decreased mobilization of fatty acids
 When adipocyte become resistant to insulin -
decreasing lipid storage and increasing plasma
concentration of fatty acids. These changes, if
prolonged, could contribute to atherosclerosis and
increased blood pressure, especially if the renal blood
vessels and glomeruli are damaged
 Glucotoxicity- could cause glycosylation of glomerular
proteins, increased production of extracellular matrix,
and loss of nephron function.
 The metabolic disturbances associated with severe
insulin resistance could exacerbate hypertension by
causing renal injury, although the importance of these
effects in the absence of diabetes is still unclear
Hypertension and insulin
resistance
 Insulin resistance is secondary to vascular changes that
occur in hypertension
 Insulin resistance may occur as a result of increased
peripheral vascular resistance, decreased tissue blood
flow, and vascular rarefaction, which decrease the
delivery of insulin and glucose and therefore impair
glucose uptake
 Although peripheral vascular resistance is elevated in
hypertension, most tissues, including skeletal muscles,
do not appear to be underperfused.
Also, multiple studies indicate that underperfusion of
peripheral tissues cannot explain, quantitatively,
chronic hyperinsulinemia
Hall et al
INFLAMMATORY CYTOKINES
 The RAS and SNS, interact with the proinflammatory
cytokines, such as interleukin (IL)-6 and tumor
necrosis factor- (TNF- alpha).
The SNS stimulates the release of proinflammatory
cytokines, and sympathetic nerves may also serve as a
source of cytokines.
Experimental evidence also suggests that
proinflammatory cytokines may activate the SNS.
EICOSANOIDS
 The largest production of PGE2 occurs in the renal
medulla with decreasing synthesis in the cortex.
PGE2 is synthesized and rapidly inactivated, and after
it is synthesized, it is released, not stored.
After it has been released, PGE2 inhibits sodium
reabsorption by several mechanisms, including direct
effects on the renal tubules
Vitamin D deficiency
Associated with cardiovascular risk factors.
It has been observed that individuals with a vitamin D
deficiency have higher systolic and diastolic blood
pressures than average.
Vitamin D inhibits renin secretion and its activity, it
therefore acts as a "negative endocrine regulator of the
renin-angiotensin system".
Hence a deficiency in vitamin D leads to an increase in
renin secretion. This is one possible mechanism of
explaining the observed link between hypertension and
vitamin D levels in the blood.
Forman JP, Giovannucci E, Holmes MD, et al. (May 2007). "Plasma 25-hydroxyvitamin D
levels and risk of incident hypertension". Hypertension 49 (5): 1063–9
THANK YOU
Quiz
1.
a.
b.
c.
d.
All are acute BP control mechanisms except?
CNS ischaemic response
Chemoreceptors
Baroreceptors
Renal
2. False about salt sensitivity
a. More common in blacks
b. Associated with reduced nephrons and glomerular
surface area
c. Salt sensitivity decreases with age
d. Salt sensitivity varies with weight loss
3. Which condition causes parallel shift of pressure
natriuresis curve
a. Increased preglomerular resistance
b. Decreased renal mass
c. Decreased renal glomerular capillary filtration
coefficient
d. Increased distal collecting tubule reabsorption
 4. Obesity causes all except
a. Increase SNS activation
b. Increase RAAS activity
c. Decrease in PAI-1
d. Causes insulin resistance
 5.False about leptin
a. It synthesized from liver
b. It acts on the hypothalamus
c. It increases SNS activity
d. It suppresses hunger
 6. Renin hypertension – which is false
a. The elevation in blood pressure is more likely to be
salt-sensitive.
b. The response to nonpharmacologic therapy,
particularly weight reduction, may be less pronounced
c. The antihypertensive response may be greatest with
a diuretic or calcium channel blocker.
d. Low renin in EHT is seen in 60% of subjects.
 7.Salt sensitivity in hypertension. False statement
a. Increased intraglomerular pressure and hence a
higher risk of developing glomerulosclerosis and
CRF
b. Increase LDL
c. Increased urinary kallikrein
d. Increases Lp(a)
 8 In obesity which is false
a) Increase in HR
b) Increase in sympathetic activity
c) Increase in cardiac output
d) Increase in cardiac reserve
 9) False regarding insulin resistance
a)Insulin infusion causes fall in BP
b) Thiazolidinediones causes fall in BP by increasing
insulin sensitivity
c) Insulin resistance has role in pathogenesis of EHT
d) Hypertension causes insulin resistance and vice versa.
 10) All are seen in EHT except
a) Haptoglobin mutation
b) Angiotensinogen gene mutation
c) Polygenic inheritance
d) IP3/DAG cascade