710 901
( Cytomegalovirus; CMV )
( Coronary artery disease; CAD ) CMV
60 93 153
CMV CMV 1.
2. CMV
3.CMV PCR
( p<0.05 ) CMV CMV nested PCR
CMV PCR CMV
( Cytomegalovirus; CMV ) ( Coronary artery disease; CAD ) -6 ( Interleukin-6; IL-6 )
C ( High sensitivity C-reactive protein; Hs-CRP )
( coro- nary artery disease; CAD )
1-34-6
C-reactive protein: CRP IL-6 homocysteine..
7 - 1 0
( cytomegalovirus; CMV )
11-14
( cytomegalovirus; CMV )
15-18
CMV
( immuno-compromised ) AIDS CMV
CMV
19-23
CMV
CAD
24, 25LDL ( low density lipoprotein )
26-29
30-32
CMV CAD
C M V 1 9 9 9
D o u g l a s 6 0 %
33-35
pp65 antigenemia assay C M V
36-38
CMV PCR
39-42
P C R
40, 43, 44
CMV CMV DNA
45-48
PCR CMV DNA
49-53( real-time PCR )
CAD CMV-DNA
real-time PCR
54-56
6 0
45 15
C A D 9 3 6 4 2 9
persantin thalli- um heart scan
( )
IL-6 ELISA
( R D system ) 100 l 100 l well ( R D system ELISA )
Control ( n=60 ) CAD ( n=93 ) p value
Age mean ( range ) 62.1 ( 41-83 ) 64.6 ( 40-85 ) NS
sex male/female 45/15 64/29 NS
Risk factor n (%)
Smoke 12 ( 21.4 ) 32 ( 39.5 ) <0.05
Diabetes 10 ( 16.7 ) 29 ( 31.2 ) <0.05
Hypertension 21 ( 35.0 ) 50 ( 53.8 ) <0.05
Cholesterol mg/dL 219.8 37.5
a213.0 48.6 NS
LDL mg/dL 143.3 79.3 125.5 36.8 NS
TG mg/dL 117.8 82.7 196.9 126.6 <0.001
HDL mg/dL 56.9 19.1 44.6 11.8 <0.001
Bilirubin mg/dL 0.95 0.36 0.48 0.21 <0.001
NS not significant. p>0.05
a
mean SD
Wash Buffer
IL-6 200 l ( con- jugated with Horseradish peroxidase )
Wash Buffer
200 l Substrate Solution [ H
2O
2+tetram- ethylbenzidine mixture ( 1:1 ) ] well
20 50 l Stop solu-
tion ( 2N sulfuric acid ) ( OD450nm )
10%
High sensitivity C-reactive protein ( hs-CRP ) Particle-enhanced technology scattered light ( Behring BN nephelometer )
hs-CRP
Bilirubin uric acid HDL-C TG cholesterol BUN
( Wake Pure Chemical Industries, Ltd ) HITACHI 7070
DNA Puregene DNA purification Kit ( Gentra, Minnesota, USA ) ( 0.3ml )
D N A 0 . 1 m l - 8 0
Nested PCR UL122
MIE-4 ( 5'-CCAAGCGGCCTCTGATAAC- CAAGCC-3' ), MIE-5 ( 5'-CAGCACCATCC- TCCTCTTCCTCTGG-3' ) 435bps
57
( ABI )
Primer express
N S 1 ( 5 ' - T G A A G G T C T T - T G C C C A G TA C AT- 3 ' ) , N A S 1 ( 5 ' - T G G C - C A A A G T G TA G G C TA C A AT- 3 ' )
129bps 1
st-PCR 50 l
30pmol 5 l
DNA 1.5U Taq polymerase ( Promega, Madison,
WI ) 2
nd-PCR 50 l
30pmol 1 l 1
st-PCR 1.5U Taq polymerase PCR
95 10 40 ( 95
1 55 1 72 1 )
72 10 Nested PCR 7
PAGE ethidium bromide
UV
Real time PCR ABI PRISM
7000 UL83
pp549s ( 5'-GTCAGCGTTCGTGTTTCCCA-3' ) pp812as ( 5'-GGGACACAACACCGTAAAGC- 3 ' ) p p 7 7 0 s ( 5 ' F A M - C C C G - CAACCCGCAACCCTTCATG-3'TAMRA )
pp549s, pp812as PCR
( TOPO TA Cloning Kit,
Invitrogen ) DNA
260nm Real time PCR
25 l
12.5pmol 5 pmol 5 l DNA
1U platinum taq 95 10
45 ( 95 15 65 1
)
54Spearman's rank
test Chi-Square test
multiple logistic regres- sion models CAD
( odds ratio, OR ) 95%
( confidence interval, CI ) p<0.05
C A D
6 0 4 5
15 CAD 93
6 4 2 9
L D L
TG HDL
( )
multiple logistic re- gression models
CMV PCR
CAD IL-6 hs-CRP
anti CMV IgG
CMV 97
CMV DNA PCR
25 31.2 CAD ( )
CMV
CMV 4 ( level
1~4 ) ( relative risk )
CAD CMV IgG level 2~4 level
1 1.58 ( p=0.395 )
2.17 ( p=0.187 ) 5.06 ( p=0.078 )
( ) CMV
IL-6 hs-CRP PCR
C M V I L - 6
( r=0.249, p=0.055 ) CAD IL-6 hs- CRP ( r=0.634, p<0.001 )
IL-6 CMV hs-CRP
( r=0.178, p=0.028 r=0.503, p<0.001 ) ( )
CMV
C M V nested PCR
( Data not shown ) nested PCR
1 5
nested PCR CMV
CAD 29 nested PCR 14 CMV ( p<0.05 )
( )
1 .
C M V C A D
2 . C M V P C R 3.CAD CMV
CMV CMV CMV
IgM IgG
CAD CMV
Control n ( % ) CAD n ( % ) p value
Hs-CRP mg/dL 2.51 0.63
a11.81 2.23 <0.001
IL-6 pg/ml 1.09 0.40 13.69 4.82 0.002
CMV IgG EU/ml 49.2 2.4 56.0 2.3 0.097
Positive>15 EU/ml 59(98.3) 91(97.8) 0.703
Nested PCR 15(25) 29(31.2) 0.409
NS not significant. p>0.05
a
mean SEM CMV
Control ( n=60 ) CAD (n=93) relative risk (95% CI) p value CMV IgG ( EU/ml )
mean ( range ) 49.2 ( 2.8~98.7 ) 56.0 ( 9.18~135.4 ) Quartiles distribution n ( % )
1 ( 15~30 EU/ml ) 8 ( 13.6% ) 6 ( 7.7% )
2 ( 30~60 EU/ml ) 35 ( 59.3% ) 49 ( 53.8% ) 1.58 ( 0.55~4.49 ) 0.395
3 ( 60~90 EU/ml ) 14 ( 23.7% ) 27 ( 29.7% ) 2.17 ( 0.69~6.86 ) 0.187
4 ( 90 EU/ml ) 2 ( 3.4% ) 9 ( 9.9% ) 5.06 ( 0.83~30.75 ) 0.078
p values were calculated by logistic regression analysis.
CI denotes confidence interval.
CMV CAD CMV
a n t i - C M V I g G CMV
58-61
CMV 90%
62, 63
CAD CMV
9 7 %
CAD
( )
CAD CMV
CMV CMV
nested PCR CMV
25% ( ) 31.2% ( CAD )
C M V P C R
CMV
CMV P C R
C M V
DNA PCR
15, 64-67IL-6 hs-CRP CAD
CMV CMV PCR
IL-6 hs-CRP CAD ( r=0.634,
p<0.001 ) CMV IL-
6 ( r=0.249, p=0.055 )
CMV IL-6
( r=0.178, p=0.028 ) CMV
hs-CRP
IL-6
CMV CAD
5 2 , 6 8 - 7 2
CMV
C M V C M V
CMV IgG hs-CRP IL-6
Item
Group CMV IgG CMV IgG CMV IgG IL-6
and IL-6 and hs-CRP and PCR and hs-CRP
Control
r value 0.249 0.045 0.044 0.119
p value 0.055 0.737 0.737 0.370
CAD
r value 0.102 0.077 -0.128 0.634
p value 0.335 0.467 0.222 <0.001
Total
r value 0.178 0.127 -0.047 0.503
p value 0.028 0.119 0.561 <0.001
CMV nested PCR CMV
pp65 antigenemia
real time PCR (
) NASBA
p p 6 7 m R N A
U L 8 3 r e a l t i m e
PCR CMV UL83 pp65
pp65 antigenemia test nested PCR nested PCR
25 nested PCR ( + ) CMV
29 nested PCR ( + ) CAD 1 4
CAD CMV
( ) nested PCR ( - ) ( Data not shown )
CMV CAD
CAD CMV
CMV
CAD CAD
CMV CMV
CMV CAD
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The Correlation Between Cytomegalovirus Infection and Coronary Artery Disease
Yung-Liang Liao
1, Yi-Chueh Yang
1, Ting-Chun Hung
1, Hui-Yi Yap
2, Chia-Fong Chen
3, Tung-Nan Liao
3, and Ching-Nan Lin
1Primary CMV infection is usually asymptomatic and results in latent, lifelong persistence of the viral genome.
Periodically, the virus might reactivate from latency and regain its ability to multiply. CMV is a major cause of life- threatening illness in immunocompromised patients. Various lines of evidence suggest that chronic inflammation is involved in the initiation and progression of atherosclerosis and its complications including coronary artery di- sease ( CAD ). Several infectious agents, particularly CMV, have been suggested to play a role in the develop- ment of atherosclerosis. In this study, we measured serum levels of IL-6, anti-CMV IgG ( CMV IgG ), high sen- sitivity C-reactive protein ( hs-CRP ) by ELISA or nephelometry, CMV qualitative analysis by nested PCR, and CMV viral load quantitative analysis by real time PCR in 93 CAD patients and 60 normal healthy controls. Our study showed that the levels of IL-6, and hs-CRP were significantly increased in patients with CAD ( p=0.002 and p<0.001, respectively ). There was no statistical significance in CMV IgG positive rate in both groups, howe- ver, there was a trend for higher antibody titers in the CAD group according to the quartile levels of analysis ( p=0.078 ). In nested PCR positive cases, the CMV viral loads were significantly elevated in CAD patients than in normal controls ( p<0.05 ); meanwhile, there was no difference in CMV positive rates between the two groups using nested PCR qualitative assay. Conclusion: In CMV nested PCR positive cases, CMV viral loads were sig- nificantly elevated in CAD patients than in normal controls. However, there were no differences in CMV nested PCR and CMV IgG positive rates between the two groups. ( J Intern Med Taiwan 2007; 18: 88-96 )
1
Department of Pathology, Chi-Mei Foundation Hospital, Tainan, Taiwan,
2
Department of Internal Medicine, Chi-Mei Foundation Hospital.
3
