Endothelial dysfunction in indian scenario

ENDOTHELIAL DYSFUNCTION IN THE INDIAN SCENARIO

HeartSense Teamwww.heartsense.in

Topics

• Why Indian Scenario?• Describing endothelial dysfunction• Measures of endothelial dysfunction• Clinical relevance• What the future holds...

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

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

• ‘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

(S)

The vascular endothelium serves multiple functions:1) It regulates fluid and molecule traffic between blood and tissues2) It is an anti-coagulant surface3) It contributes to vascular homeostasis and repair4) 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.

Molecular mechanisms of Endothelial Functions

In Health DysfunctionVasodilation 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 FactorsET-1, A-II, PDGF, bFGF, ILGF,

Interleukins

Lipolysis InflammationROS, NF-B

PAI-1, TF, Tx-A2tPA, Protein C, TF-I,

vonWF

LPLVogel R

Coronary Heart

Disease

Endothelial Dysfunction

NO ↑Inflammation ↑Thrombosis

“Response-to-Injury” Hypothesis

GenesCoronary

Risk Factors

O2 Endothelial Cells and

H2O2 Vascular Smooth Muscle

Oxidative Stress: Endothelial Dysfunction and CAD/Renal Risk

Factors

Endothelial Dysfunction

Apoptosis

VasoconstrictionLeukocyteadhesion

Lipiddeposition

ThrombosisVSMCgrowth

HypertensionSmokingDiabetes LDL Homocysteine Estrogen

deficiency

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 DietSmoking InactivityDiabetes ↑ Cholesterol↑ Blood Pressure Oxidative StressGenetics Medications

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

BASELINE POST OCCLUSION

Brachial Artery Ultrasound with FMD

http://www.cvphysiology.com/Blood%20Flow/BF006.htm

Reactive HyperemiaReactive 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.

Brachial Artery Flow-Mediated Vasodilation

Baseline 5 Minutes Post-OcclusionBlood Pressure CuffOcclusion – 1 Minute Release

3.1 mm 3.6 mm

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

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

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 EventsCV Events

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

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

Diabetics have lower vasodilatation than non-diabetic persons


Endothelial function as per BMI

Obese persons have lower vasodilatation than non-obese persons


Endothelial function as per lipid levels


Conclusion

• Diabetics have worse endothelial functions than non diabetics

• Endothelial function was related to dyslipidemia and obesity


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


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.



Factors associated with endothelial dysfunction


Higher BMI, SBP and DBP are associated with endothelial dysfunction in microvascular diseases`

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



*Adjusted for age, sex, BMI, smoking and medication


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


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.

Available research

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Endothelial dysfunction in indian scenario