Endothelial dysfunction in Hypertension.

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Endothelial dysfunction in Hypertension.

• Dr.K.S.Ravindranath MD.DM.DNB
• Professor of Cardiology
• Sri Jayadeva Institutue of Cardiology
• Bangalore

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EndotheliumThe Largest Living Organ
Tunica adventitia Tunica media Tunica intima
Endothelium Subendothelial connective
tissue Internal elastic membrane Smooth muscle
cells Elastic/collagen fibers External elastic
membrane
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The normal endothelium
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EndotheliumThe Largest Living Organ
1 ½ kg. 6 tennis courts Semi-permeable
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Endothelial nitric oxide production and action
Acetyl choline, bradykinin etc
High Shear
Receptors
EC
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Control of Vascular Tone
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Endothelial Dysfunction- Risk Factors
Dyslipedemia
Oxidative stress CHF
Insulin resistance
Hypertension
Diabetes
Endothelial dysfunction
? Vasoconstriction
Inflammation
Atherosclerosis
ISCHEMIC
Thrombosis
Plaque rupture
ACS
Coronary events
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Pathophysiologic Effectsof Angiotensin II
Cardiac myocyte
Fibroblast
Peripheral artery
Coronary artery
Hypertrophy
Hyperplasia
Vasoconstriction
Vasoconstriction
Apoptosis
Collagen synthesis
Endothelial dysfunction
Endothelial dysfunction
Hypertrophy
Atherosclerosis
Cell sliding
Fibrosis
Restenosis
Increased wall stress
Decreased compliance
Increased O2 consumption
Thrombosis
Impaired relaxation
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Effects of Aldosterone
Fibroblast
Cardiac myocyte
Peripheral artery
Kidney
Vasoconstriction
Hypertrophy
Hyperplasia
Potassium loss
Collagen synthesis
Endothelial dysfunction
Norepinephrine release
Sodium retention
Fibrosis
Hypertrophy
Decreased compliance
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Dysfunctional Endothelium
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• Hypertension
• Oxidative stress plays determining role in ?
  EDNO
• ? Tetrahydrobiopterin
• ? generation of O2
• Arginine deficiency
• ? ADMA

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Reactive oxygen species and endothelial
dysfunction
Ang II
Reduced NO bioactivity
NO
ROS
Macrophages
Integrins
Chemotaxis factors (MCP-1)
Endothelium
ICAMs
Selectins
NO
NO
Vasodilation
NO
VSMC
Werner N, Nickenig G. Eur Heart J. 2003 5(suppl
A) A9-A13
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Endothelial dysfunction and HT

• NO inactivation ? of reactive oxygen species,
• ? ?production of AT II and endothelin,
• ? availability of NO precursor L-arginine,
• Defect in G-protein dependent intracellular
  signalling pathway.

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ED - Hypertension

• Primary or secondary not clear
• ED Normotensive offsprings of HTN patients
  Could be primary
• ED Reversed by ACEI , Ca antagonists could be
  consequence

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• Normotensive offspring of individuals with
  essential HT have impaired vasodilator response
  to Ach, suggests a primary abnormality and
  genetic basis .
• Cirulation 1996,941298-1303

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ED - HTN

• Endothelium dependent vasodilation not only
  operates in large conductace vessels, but
• Is also controls dilation in small ( resistance)
  vessels,
• ED - resistant vessels Micro vascular
  Dysfunction Nephropathy Microalbuminuria
• ED - Peripheral arteries
• - Coronary Macro Micro
  circulation
• - Renal circulation

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How to Assess ED

• Endothelium-dependent vasodilation
• Acetyl choline or post-ischaemic FMD
• Coronary or forearm arteries
• Intima-media thickness (IMT)
• Microalbuminuria
• Plasma markers
• ADMA, CRP, adhesion molecules
• Clinical diagnosis

• flow-mediated dilatation (FMD)
• asymmetric dimethylarginine (ADMA)

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Serum Markers

• Endothelin - I, Angiotensin- II, CRP
• VWF / Ros / Cytokines
• t-PA
• PAI-I
• ICAM
• VCAM
• E-Selectin P Selectin
• ADMA
• Endothelial progenitor cells (EPCs)

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Brachial Artery Flow-Mediated
Vasodilation Baseline 5
Minutes Post-Occlusion Blood Pressure
Cuff Occlusion 1 Minute
Release
3.6 mm
3.1 mm
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Impaired EDNO bioactivity in HT.
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Murakami T et al. J Am Coll Cardiol
200137294ACVEs over 4 Years in 480 Patients
with Suspected CAD According to Brachial Artery
FMD
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Predictors of MACE in symptomatic population
with coronary risk factors ( Park et al )
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Yonsei Med J vol 44 no 6 ,2003
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• Negative correlation between the rise of SBP and
  endothelium dependent vasodilation due to NO/cGMP
  pathway
• Rather than a benign process, exercise induced HT
  may predict possible CVS morbidity due to
  evolving endothelial dysfunction.
• Also seen in white coat hypertension

Yonsei Med J vol 44 no 6
,2003
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Correcting Endothelial Dysfunction

• Risk factor modification ( BP, DM, Smoking)
• Exercise and weight loss
• Blockade of the RAS- ACE T / ARB
• LDL reduction, HDL augmentation.
• PPAR-? agonists
• Antioxidants
• Reducing homocysteine levels
• Improving insulin sensitivity
• Lowering CRP
• L-arginine.

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Statins- Myocardial neovascularization
Hypertension / Dyslipidemia
1
Mobilization (VEGF-R)
EPC
EPC
EPC
EPC
EPC
Bone Marrow
2
Peripheral blood
Endothelial dysfunction
? eNO
Migration
Ischemia
3
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Vascular protection

• ACEI vs placebo
• HOPE
• EUROPA

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Reduction in oxidative stress with ACE inhibition
ACE inhibition
Tissue ACE activity
Ang II ?
p22phox
O2 degradation ?
rac-1
p47 phox
ecSOD ?
NADPH oxidase ?
NO availability ?
O2 production ?
Landmesser U, Drexler H. Eur Heart J. 2003
5(suppl A) A3-A7.
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Endothelial dysfunction and HT

• Hypertensive patients with DM have endothelial
  dysfunction that can be related to
  microalbuminuria ,as well as modified by
  antihypertensive therapy.
• J. Hum. Hyperten 2005

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HOPE Primary outcomes

• Effects beyond baseline therapy
• Aspirin
• Beta-blockers
• Lipid-lowering agents
• Diuretics
• Other antiplatelets
• Calcium channel blockers

RR
Ramipril 10 mg

• p 0 0001
• p 0.005

The Heart Outcomes Prevention Evaluation Study
Investigators. N Engl J Med. 2000342 145-153
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HOPE Impact of ramipril on stroke based on
baseline BP
BMJ 20023241-5
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Angiotensin Receptor Blockers Mechanism of Action
RENIN
Angiotensin IANGIOTENSIN II

Angiotensinogen
ACE
Other paths
AT1 Receptor Blocker
RECEPTORS
AT1
AT2
Vasoconstriction
Proliferative Action
Vasodilatation
Antiproliferative Action
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Improved endothelial function with Losartan but
not with atenolol
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LIFE study
BP during Follow -up
mmHg
Time ( Months )
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ARB in hypertension LIFE Study
Endpoint Losartan (n4605) Atenolol (n4588) Adjusted RR () p
Primary composite 11 13 -13 0.021
CV mortality 4 5 -11 0.206
Stroke 5 7 -25 0.001
MI 4 4 7 0.628
Total mortality 8 9 -10 0.128
New-onset DM 6 8 -15 0.001
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How Could Losartan Reduce the Risk of Stroke
Beyond Blood Pressure? Potential Sites of Action
Cardiac remodeling/enlargement
Vascular remodeling
Endothelial dysfunction
Prothrombotic state
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Cardiovascular diseases in men according to BP
Lancet 2006367168-176
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TROPHY Trial

• 30 to 65 (inclusive) years of age
• Not treated for hypertension
• First visit BP not exceeding 155/99 mm Hg
• Average BP 139/85-89 or 130-139/89 mm Hg (3
  visits) as determined by an automatedBP
  measurement device

Julius et al. N Engl J Med 2006
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Development of clinicalhypertension
Cumulative incidence
1.0
Placebo
0.9
Candesartan
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
1
2
3
4
Years in study
Numbers of hypertension-free individuals Candesart
an 391 356 309 191 128 Placebo 381 269 184 118
85
Julius et al. N Engl J Med 2006
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Risk reduction in development ofclinical
hypertension, candesartan versus placebo
0-2 years
0-4 years
0
Relative risk reduction
9.6
-10
15.6
Absolute risk reduction
-20
26.8
-30
-40
66.3
-50
-60
-70

Julius et al. N Engl J Med 2006
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Clinical implications

1. Continuous pharmacological treatment of
   prehypertension not recommended long-term
   safety of this approach has not been demonstrated
2. In TROPHY, the rate of transition from
   prehypertension to stage 1 hypertension in the
   placebo group was 15 per year
3. To facilitate early detection of stage 1
   hypertension, subjects with prehypertension
   should be followed closely, preferably at three
   months intervals

Julius et al. N Engl J Med 2006
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B-blockers and endothelial function.

• Carvedilol which has antioxidant properties may
  improve endothelial function,
• Nebivolol endothelium dependent dilation of
  blood vessels via L-ariginine / NO pathway.

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Ca channel blockers

• Amlodipine appears to ? ? production of NO,
• ? NO response to amlodipine ( 79) was
  similar in magnitude to that of ramiprilat.
• 
  Am J Cardiol. 1999
• Nifedepine GITS, Lacidipine

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Thank You
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Thank you
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• Indeed ,simple drugs like aspirin may influence
  endothelial function in HT,
• Recent data- relationship of endothelium to
  angiogenesis,
• Hypertensive patients with DM have endothelial
  dysfunction that can be related to
  microalbuminuria ,as well as modified by
  antihypertensive therapy.
• J. Hum. Hyperten 2005

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• Aldosterone- cardiovascular inflammation,
  Endothelial dysfunction, fibrosis,
• Aldosterone promotes endothelial dysfunction
  independent of blood pressure,
• Most likely mediated by ? cyclooygenase 2
  derived prostacyclin mediated vasoconstriction,
• Cyclooxygenase -2 inhibitor could be used to
  restore endothelial dysfunction ?
• Needs further studies in view of other serious
  side effects of COX-2 T

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RECENT TRIALS OF ACE(-)/ARBs..

• ALBUMINURIA RENNAL,AASK
• NEW AF LIFE, TRACE
• LV MASS LIFE
• NEW ONSET DIABETES,
• INTIMA MEDIAL THICKNESS,
• SYSTEMIC INFLAMMATORY MARKERS

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Angiotensin Receptor Blockers Mechanism of Action
RENIN
Angiotensin IANGIOTENSIN II

Angiotensinogen
ACE
Other paths
AT1 Receptor Blocker
RECEPTORS
AT1
AT2
Vasoconstriction
Proliferative Action
Vasodilatation
Antiproliferative Action
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Normal Arterial Wall
Tunica adventitia Tunica media Tunica intima
Endothelium Subendothelial connective
tissue Internal elastic membrane Smooth muscle
cells Elastic/collagen fibers External elastic
membrane
Astra Zeneca
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Regulatory Functions of the EndotheliumNormal D
ysfunction
Vasodilation
Vasoconstriction
NO, PGI2, EDHF, BK, C-NP
ROS, ET-1, TxA2, A-II, PGH2
Thrombolysis
Thrombosis
PAI-1, TF, Tx-A2
tPA, Protein C, TF-I, vonWF
Platelet Disaggregation NO, PGI2
Adhesion Molecules CAMs, Selectins
Antiproliferation NO, PGI2, TGF-?, Hep
Growth Factors ET-1, A-II, PDGF, bFGF, ILGF,
Interleukins
Lipolysis
Inflammation ROS, NF-?B
LPL
Vogel R
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Endothelium

• Stimulants of endothelium dependent relaxation
• Shear stress (exercise)
• Hormones (acetylcholine, estrogen, insulin,
  vasopressin)
• Bradykinin, histamine
• Platelet derived factors (ADP, serotonin)
• Thrombin

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Steps inhibited by NO
LUMEN
T
LDL
F C
MCP-1
ox-LDL
INTIMA
MEDIA
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Oxidative stress plays an imp role in ED

• ? in oxidative stress
• ?
• Endothelial cells are exposed to ROS
• ?
• combine with NO to form peroynitrates
• ?
• Endothelial cells loose their protective
  phenotype and express vasoconstrictive ,
  proinflammatory factors

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HOPE

• Benefits of ramipril were observed among pts
  who were already taking a number of effective
  treatments, such as aspirin, beta-blockers, and
  lipid lowering agents, indicating that the ACE
  inhibition offers an additional approach to the
  prevention of atherothrombotic complications

N Engl J Med 2000342145-153
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Correcting Endothelial Dysfunction

• Risk factor modification ( BP, DM, Smoking)
• Exercise and weight loss
• Blockade of the RAS- ACE T / ARB
• LDL reduction, HDL augmentation.
• PPAR-? agonists
• Antioxidants
• Reducing homocysteine levels
• Improving insulin sensitivity
• Lowering CRP
• L-arginine.

73
EndotheliumThe Largest Living Organ

• 1 ½ kg.
• 6 tennis courts
• Semi-permeable

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Endothelial dysfunction and HT

• HT
• ?
• Oxidation of tetrahydrobiopterin- a critical
  factor for NO synthase
• ?
• ? NO production
• ?
• ? endothelial superoxide production.
• ( J Clin Invest 2003 )

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Proposed pro-atherogenic mechanisms of reactive
oxygen species
Angiotensin II
? Vascular ROS production
Endothelial dysfunction (Reduced NO availability)
LDL oxidation
Pro-inflammatory gene expression (VCAM-1, MCP-1)
Vascular inflammation
Progression and clinical complications of
atherosclerosis
Landmesser U, Drexler H. Eur Heart J. 2003
5(suppl A) A3-A7.