www,heartsense.in. Endothelial dysfunction is the root pathology in the pathogenesis of hypertension, diabetes and IHD. This technical article is aimed towards health care professionals. For patient information on health and heart disease, visit www.heartsense.in.
2. Topics
• Why Indian Scenario?
• Describing endothelial dysfunction
• Measures of endothelial dysfunction
• Clinical relevance
• What the future holds...
3. Why Indian Scenario?
• South Asian population groups have a 50 – 60%
higher incidence of cardiovascular disease when
compared to white Caucasians.
• Higher incidence of type 2 DM in Indians
• Higher prevalence of triad of glucose intolerance,
hyperinsulinemia and intra-abdominal fat
distribution.
• High carbohydrate diet induces hyperinsulinemia
• Low level of physical activity
4. Why Indian Scenario?
• High levels of insulin resistance
• Low HDL (and high levels of small HDL
particles), high small dense LDL.
• Higher levels of obesity – ‘foetal origin of adult
disease (FOAD)’
• High incidence of other risk factors – smoking,
hypertension, family history
• Higher level of inflammation - atherosclerosis
5. • ‘Cellular monolayer’ - Inner lining of our
bloods vessels is the Endothelium
• It plays a central role in regulating the
vasomotor tone & local homeostasis &
control of the coagulation process
• Endothelial cells have ‘Sensors’ and release
‘Mediators’
• ‘Mediators’ are the functional molecules on
the cell surface
The Vascular Endothelium
6.
7. (S)
The vascular endothelium serves multiple functions:
1) It regulates fluid and molecule traffic between blood and tissues
2) It is an anti-coagulant surface
3) It contributes to vascular homeostasis and repair
4) It plays a vital role in vascular tone and blood flow regulation ***
Endothelial cells serve multiple functions.
Assessing this function is the most practical way of measuring
endothelial function.
8.
9. Molecular mechanisms of Endothelial Functions
In Health Dysfunction
Vasodilation Vasoconstriction
NO, PGI2, EDHF, BK,
C-NP
ROS, ET-1, TxA2, A-II
Thrombolysis Thrombosis
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
PAI-1, TF, Tx-A2
tPA, Protein C, TF-I,
vonWF
LPL Vogel R
13. Endothelial and Vascular Dysfunction:
A “Barometer of Cardiovascular Risk”
• Marker of the inherent atherosclerotic risk
• An integrated index of both the overall CV risk
factor burden and the sum of all vasculo-
protective factors in an individual.
Aging Diet
Smoking Inactivity
Diabetes ↑ Cholesterol
↑ Blood Pressure Oxidative Stress
Genetics Medications
14.
15.
16.
17. Clinical Methods for Assessing
Endothelium-Dependent Dilation
Coronary Arteries
• Epicardial Artery Diameter
with ACh
• CBF with ACh
• Epicardial Artery Diameter
with Adenosine
Forearm
• Brachial Artery Diameter
with Arterial Occlusion
• Forearm Blood Flow with
ACh
19. http://www.cvphysiology.com/Blood%20Flow/BF006.htm
Reactive Hyperemia
Reactive hyperemia is the transient increase in organ blood flow that occurs following a
brief period of ischemia (e.g., arterial occlusion).
The left panel shows the effects of a 2 min arterial occlusion on blood flow. In this example, blood flow goes to zero
during arterial occlusion. When the occlusion is released, blood flow rapidly increases (i.e., hyperemia occurs) that lasts
for several minutes. The hyperemia occurs because during the period of occlusion, tissue hypoxia and a build up of
vasodilator metabolites (e.g., adenosine) dilate arterioles and decrease vascular resistance. Then when perfusion
pressure is restored (i.e., occlusion released), flow becomes elevated because of the reduced vascular resistance. During
the hyperemia, the tissue becomes reoxygenated and vasodilator metabolites are washed out of the tissue. This causes
the resistance vessels to regain their normal vascular tone, thereby returning flow to control.
22. Takese B, Am J Cardiol 1998:82:1535
Comparison of Brachial and Coronary
Flow-Mediated Vasodilation
Brachial artery FMD represents the
endothelial function of coronary artery
23. Effect of ACh-Induced Forearm Vasodilation* on 32-
Month CVE’s (%) in 225 Never Treated Hypertensive
Subjects
(* Relative Flow Increase)
0
1
2
3
4
5
6
7
8
Tertile 1 Tertile 2 Tertile 3
ACh FBF
%CVE's
Lower Ach induced vasodilatation is
associated with higher CV events
Perticone F et al, Circulation 2001;104:191
24. Murakami T et al. J Am Coll Cardiol 2001;37:294A
CVE’s over 4 Years in 480 Patients with Suspected
CAD According to Brachial Artery FMD
0%
5%
10%
15%
20%
25%
<4% 4%-8% >8%
CHD Events
CV Events
25.
26.
27.
28.
29. Endothelial dysfunction: Indian Scenario
• India has high prevalence of diseases associated with
endothelial dysfunction: CAD, DM, Hypertension, etc.
• Risk factors of endothelial dysfunction like smoking,
dyslipidemia are also very common in Indian
population.
• There are relatively less studies in Indian population
for direct assessment of endothelial function
30. Endothelial Dysfunction in T2DM patients in
India
• In a study in Baroda, 40 T2DM patients were taken as cases
and 40 matched healthy persons were taken as controls.
• Endothelial function was studied in both groups by ultrasound
assessment of endothelial dependent flow-mediated dilation
(FMD) of the brachial artery and endothelial independent
flow using sublingual nitrate (GTN%).
• Comparisons were made and analyzed statistically between
the diabetics and non-diabetic matched controls
Journal Indian Academy of Clinical Medicine l 2012; 13(3): 206-9
31. Diabetics have lower vasodilatation than non-
diabetic persons
Journal Indian Academy of Clinical Medicine l 2012; 13(3): 206-9
32. Endothelial function as per BMI
Obese persons have lower vasodilatation than
non-obese persons
Journal Indian Academy of Clinical Medicine l 2012; 13(3): 206-9
33. Endothelial function as per lipid levels
Journal Indian Academy of Clinical Medicine l 2012; 13(3): 206-9
34. Conclusion
• Diabetics have worse endothelial functions than
non diabetics
• Endothelial function was related to dyslipidemia
and obesity
Journal Indian Academy of Clinical Medicine l 2012; 13(3): 206-9
35. Endothelial function in patients with
microvascular disease
• Cardiac syndrome X (Csx) : presence of angina-like
chest pain, a positive stress test and angiographically
normal coronaries, considered as a microvascular
CAD
• In a study in Hyderabad, the brachial artery FMD was
measure in both endothelium dependent/
independent vasodilatation by high resolution
ultrasound in 30 cardiac syndrome X patients and
matched with 30 healthy control subjects
Cardiovascular Ultrasound 2011, 9:40
36. Endothelial function in patients with
microvascular disease
Results:
• Significantly decreased flow mediated dilatation was
observed in patients when compared to control (9.42
vs 21.11, p < 0.01)
• Total, 46% of subjects had endothelial dysfunction
and of them, Csx subjects had higher prevalence
(76% vs 16% p < 0.01) than control subjects.
Cardiovascular Ultrasound 2011, 9:40
37. Endothelial function in patients with
microvascular disease
Factors associated with endothelial dysfunction
Cardiovascular Ultrasound 2011, 9:40
Higher BMI, SBP and DBP are associated with
endothelial dysfunction in microvascular diseases`
38. Endothelial Senescence in premature
CAD patients in India
• Objective: To evaluate role of vascular senescence in
premature CAD (PCAD) by comparing numerical status and
senescence of circulating endothelial progenitor cells (EPCs) in
PCAD patients to controls.
• EPCs were measured by flow cytometry in 57 patients with
CAD, and 57 controls without evidence of CAD, recruited from
random patients ≤ 50 years at AIIMS, New Delhi.
• EPC senescence as determined by telomere length (EPC-TL)
and telomerase activity (EPC-TA) was studied by real time
polymerase chain reaction (PCR) and PCR– ELISA respectively.
Vemparala et al. BMC Cardiovascular Disorders 2013,
13:104
39. Endothelial Senescence in premature
CAD patients in India
Vemparala et al. BMC Cardiovascular Disorders 2013, 13:104
*Adjusted for age, sex, BMI, smoking and medication
40. Endothelial Senescence in premature
CAD patients in India
Conclusion
• There is an association between increased
endothelial cell senescence with PCAD in young
patients from India.
• This suggests that early accelerated vascular cell
senescence may play an important mechanistic role
in CAD epidemic in developing countries like India
Vemparala et al. BMC Cardiovascular Disorders 2013, 13:104
41. What does all this mean?
• Endothelial dysfunction is a precursor to most
cardiovascular risk factors and CVD.
• Methods to alter endothelial dysfunction can
help modify incidence of risk factors
• In vitro EPC modification and injection of
‘potent’ EPCs into coronary arteries is the way
forward.
