Correlation of IL-6, IL-10, IL-18 and TNF-α Levels with ......Correlation of IL-6, IL-10, IL-18 and...
Transcript of Correlation of IL-6, IL-10, IL-18 and TNF-α Levels with ......Correlation of IL-6, IL-10, IL-18 and...
Correlation of IL-6, IL-10, IL-18 and TNF-α Levels with Severity of Rheumatic Mitral Stenosis and Secondary Pulmonary Hypertension
Vimal Mehta, Pratishtha Mehra, Gaurav Tripathi, Jamal Yusuf, Bhawna Mahajan, Sanjay Tyagi
G. B. Pant Institute of Postgraduate Medical Education and Research, New Delhi, India
o Rheumatic heart disease (RHD) remains a major public health problem in
many parts of the world with an estimated world-wide prevalence of 33
million patients, of which about one-third cases (13.2 million) occur in India.
o The pathogenesis of acute rheumatic fever involves a complex network of
genetic, environmental and immunological interactions.
o The inflammatory response in acute rheumatic fever, on cardiac tissues is
induced by antigenic mimicry of the streptococcal protein M leading to an
abundant infiltration of CD4+ T cells.
o This leads to production of inflammatory cytokines (e.g., TNF-α, IL-2, and
IL-10), which potentiate the immune response in rheumatic fever.
Introduction
o Any evidence of clinical infection
o Moderate to severe mitral regurgitation/aortic stenosis or regurgitation
o ARF in last 6 months/any other CV disease or pulmonary disease
o Pregnancy and lactating mothers
o Any autoimmune or inflammatory condition/other significant illness
Exclusion Criteria
Conclusions o Chronic rheumatic mitral stenosis patients have increased IL-6, IL-10,
IL-18, TNF-α and hs-CRP levels suggesting a continuous ongoing
inflammatory activity even in clinically silent chronic phase.
o Further subjects having severe mitral stenosis had increased TNF-α levels
in comparison to subjects with mild to moderate mitral stenosis suggesting
its possible role in acceleration of rheumatic process.
A B
Hypothesis
o The severity of mitral stenosis in many RHD patients continues to progress
despite absence of recurrent rheumatic fever
o To determine the role of inflammatory cytokines in progression of rheumatic
valvular injury and its hemodynamic sequelae- pulmonary hypertension
Aims and Objectives
o To determine the serum levels of cytokines IL-6, IL-10, IL-18, TNF-α and
hs-CRP in peripheral blood of patients with chronic isolated rheumatic mitral
stenosis and compare it with controls
o To determine association of serum levels of IL-6, IL-10, IL-18, TNF-α and
hs-CRP with severity of rheumatic mitral stenosis & pulmonary hypertension
Inclusion and Exclusion Criteria
o Age >18 years
o Subjects with chronic rheumatic heart disease with mitral stenosis
diagnosed on echocardiography
Inclusion Criteria
Methodology Total subjects screened: 184
Screen failure: 12
Screen failure: 9
Rheumatic heart disease with isolated
mitral stenosis: 84 (Group A)
Age and gender matched controls: 79
(Group B)
Investigations done
ECG
ECHOCARDIOGRAPHY
Routine blood investigations
Serum IL-6, IL-10, IL-18, TNF-α, hs-CRP levels
Investigations done
ECG
ECHOCARDIOGRAPHY
Routine blood investigations
Serum IL-6, IL-10, IL-18, TNF-α, hs-CRP levels
Echocardiography Images of Study Subjects
Fig A: Normal mitral valve: short-axis
view showing thin mitral leaflets
Fig B: Normal mitral valve: M-mode
showing movement of AML and PML
Fig C: Mitral stenosis: short-axis view
showing thickened mitral leaflets
Fig D: Mitral stenosis: M-mode showing
PML excursion in anterior direction
Fig E: Mitral stenosis: AML doming and
spontaneous echo contrast
Fig F: Mitral stenosis: Diastolic
transmitral gradient of 43/26 mm Hg
A B C
D E F
Parameters Group A Group B P value
Number 84 79
Gender: Male
Female
22
62
31
48
NS
Age (years) 34.6 ± 10.6 30.0 ± 4.9 NS
Hb (gm/dL) 12.8 ± 1.8 13.1 ± 1.6 NS
TLC (per mm3) 4424 ± 1202 4892 ± 1486 NS
ESR 14.6 ± 2.9 12.4 ± 1.9 NS
Results o The presence or absence of atrial fibrillation did not have any impact on
cytokine levels.
o There was strong linear correlation between various cytokine levels.
Baseline Characteristics of Study Subjects
Rheumatic heart disease with mitral stenosis, n=84 (Group A)
Severity of mitral stenosis Presence or absence of pulmonary hypertension
Subgroup Aa
MVA ≤ 1 cm2
n= 59 (70%)
Subgroup Ab
MVA > 1 cm2
n= 25 (30%)
Subgroup Ac
RVSP ≥36 mm Hg
n= 47 (56%)
Subgroup Ad
RVSP <36 mm Hg
n= 37 (44%)
53 (63%) patients were in sinus rhythm and 31 (37%) patients had atrial fibrillation
IL-6 (pg/ml) IL-10 (pg/ml) hs-CRP (mg/l)
Group A 6.6 8.1 4.7
Group B 2.7 3.5 2.6
0
1
2
3
4
5
6
7
8
9
Group A
Group B P <0.001
P <0.001
P <0.001
P <0.001
Graph 1: Serum levels of IL-6, IL-10 and hs-CRP in Group A and B Graph 2: Serum levels of IL-18 and TNF-α in Group A and B
Echo Parameter (Gp A) Subgroup No. Mean SD
LA size (cm) Subgroup Aa
Subgroup Ab
59
25
4.5
4.3
0.52
0.30
MVA (cm2) Subgroup Aa
Subgroup Ab
59
25
0.8
1.3
0.18
0.17
Mean Gradient
(mm Hg)
Subgroup Aa
Subgroup Ab
59
25
18.6
7.9
6.5
1.9
Peak Gradient
(mm Hg)
Subgroup Aa
Subgroup Ab
59
25
28.4
12.4
7.5
2.1
RVSP (mm Hg) Subgroup Ac
Subgroup Ad
47
37
55.3
26.3
20.0
4.5
0
5
10
15
20
25
Subgroup Aa Subgroup Ab Subgroup Ac Subgroup Ad
5.6
6.9 6.8 6.2
8.3 7.7
8.7
7.4
20.7
7.5
20.2
22.9
3.7 4.3 4.8 4.7
IL-6 IL-10 TNF-α hs-CRP
Graph 3: IL-6, IL-10, TNF-α, hs-CRP levels
IL-18 (pg/ml) TNF-α (pg/ml)
Group A 136.3 21.2
Group B 47.9 5.3
0
20
40
60
80
100
120
140
160
Group A
Group B
P <0.001
P <0.001
Left atrial diameter 4.47 ± 0.52 cm
Mitral valve area 0.95 ± 0.28 cm2
Peak transmitral gradient 20.18 ± 7.56 mm Hg
Mean transmitral gradient 13.08 ± 6.57 mm Hg
Right ventricular systolic pressure 42.58 ± 20.88 mm Hg
Echocardiography Parameters of RHD Mitral Stenosis Group A
Subgroups of Rheumatic Heart Disease Patients
0
20
40
60
80
100
120
140
160
Subgroup Aa Subgroup Ab Subgroup Ac Subgroup Ad
146.3
112.3
145.3
124.7
IL-18
Graph 4: IL-18 levels in various subgroups
• CD4+ T cells are the major effectors of autoimmune
reactions in the heart tissue in RHD patients.
• IL-6 is a pro-inflammatory cytokine with role in ARF.
• IL-10 is produced by activated immune cells, esp.
monocytes/ macrophages and T cell subsets, and
regulates the functions of many different immune cells.
• IL-18 is a proinflammatory cytokine which belongs to
the IL-1 superfamily and produced mainly by
macrophages and stimulates various immune cell types.
• TNF-α is a proinflammatory cytokine that has been
associated with severity of different autoimmune and
inflammatory diseases.
#TNF-α:
P <0.0001 *IL-10:
P =0.02
P =NS
* *
#
#