Angiotensin converting enzyme inhibitor therapy reduces the vascular oxidative state in normotensive patients with newly diagnosed type 2 diabetes mellitus

JACC

March 19.2003

ABSTRACTS

- Vascular Disease, Hypertension,

to 10 FM ADP. Glycation

< 0.02

those with HbAlc < 6.5% (no diabetes). Results The capacity of platelets to bind fibrinogen either tirofiban

1.05 * 0.6

Macrophages

(n=lZ)

14.6 * 9.8

35.1 * 9.1

< 0.0001

SMC (%I?.-actin)

19.9 * 15.2

8.7 f 10.6

< 0.001

MMP-1 (% area)

41.2 + 23.4

26.5 t 9.4

0.01

Conclusion:

In

decreased Increased

this

atherosclerotic

rabbit

smooth muscle cell density, plaque burden. Metalloprotease

model,

radiation

was

associated

with

increased infiltration of macrophages and 1 was also over-expressed in the radiated

arteries. Thus, special care should be taken in hypercholesterolemic

patients treated with

(50 @ml)

pared

with 38 without

blood

from patients

0.002).

Eptifibatide

Enzyme

Vascular

Patients

With

Newly

Diagnosed

Stamatios

Lerakis,

Inhibitor

Oxidative

State

Therapy

2 Diabetes

Mellitus BobbvV.

Khan,

minutes

to 60 minutes

Medicine,

Atlanta,

Background:

Emory

University

an the vascular

gen species are significant

&dative

in the pathogenesis

state and production

of atherosclerosis.

after addition

of reactive oxy-

The therapeutic

use of

outcome

Background:Apoptosls-inducing

pressure male:15)

These patients

that these agents may have vascular

reduction. Methods: with newly diagnosed

were under fair metabolic

benefits

independent

We followed 33 normotensive (less than one year) type II diabetes control

(glycosylated

hemoglobin

subjects mellitus.

< 7.5%) and

with normal renal function and no evidence of overt proteinuria. The subjects started on the ACE inhibitor quinapril 20 mglday for 4 weeks. Serum samples drawn.

The elythrocyte

superoxide

dation were measured. Results: Treatment with quinaprfl post: 812+98

U/gHb,

dismutase

(E-SOD)

significantly

p
were were

activity and lag time for LDL oxi-

increased

quinapril

E-SOD

therapy

activity

significantly

blood

pressure

(pre:

11&l

1; post:

11&8

mm

Hg.

NS).

LDL

(p =

by 64 * 21% in blood from patients

with

after 5 minutes,

platelets

from

from patients with diabetes.

of cell

Little Rock, AR

death,

caspase

initially

inhibitors

factor (AIF) is a potent caspase-independent

characterized

in HeLa

do not completely

lial cells (HCAECs).

we hypothesized

8 Resu/ls:

Cultured

(Nature

block apoptosis

1999;

in human

to examine

HCAECs

the presence

were pre-treated

pathway

397:441-6).

coronary

that AIF may be another

these cells. This study was designed regulation by ox-LDL. Methods

cells

Since

artery endothe-

pathway

of apoptosis

of AIF in HCAECs

with ox-LDL

in

and its

in different

con-

(pre: 543+70;

centrations (0-BOwg/ml) and for different time points (l-24 h). Western blot analysis was used to determine AIF expression using anti-human AIF goat anttbody. Reverse tran-

enhanced

scription-polymerase

lag

time for LDL oxidation in these subjects (pre: 63_+11; post: SF&l0 sec. pcO.O5), suggesting an increased resistance of LDL modification in the vasculature. No changes in systolic

17 % in

diabetes

Wenauana Zhanq Madhu Shokeen, Dayuan Li, Jawahar L. Mehta, University of Arkansas for Medical Sciences, Little Rock, AR, Central Arkansas Veterans Healthcare System,

studies demonstrate

from those without

of ADP. By contrast,

was seen with samples

renin-angiotensin system (RAS) antagonists, including ACE inhibitors, results in a significant reduction of cardiovascular events in patients with coronary artery disease. Recent of blood (female:l8,

wtth corn-

by 67 f

Identification of Apoptosis-Inducing Factor Expression in Human Coronary Artery Endothelial Cells and Its Upregulation by Ox-Low-Density Lipoprotein

School of

GA

The increase

binding

binding

Greater clinical benefits associated with GP Ilb-llla antagonists in patients appear to reflect augmented inhibitory effects in those with diabetes. The

1152-129

Rekha G. Menon.

fibrmogen

augmentationis mediated,at least in part, by glycatlonof membraneproteinsthat slows the rate of bindingof fibrinogen.

in Normotensive

Type

in blood from 34 patients

inhibited

and

to a greater extent by

patients with diabetes bound 39% less /‘s-fibrinogen (% bound 1”s-fibrinogen, diabetes = 0.44 t 0.22, n=ll; no diabetes = 0.72 f 0.31, 1~10; p = 0.03). Increased platelet mem-

1152-126

Converting

fibrinogen

with the fruc-

r 6.5% (diabetes),

was inhibited

(1.5 pg/ml)

Tirofiban

was determined

with HbAlc

285A

and by 52 + 23% in blood from those without diabetes (p = 0.024). Total stimulated binding of fibrinogen assessed with the use of flow cytometry or I ‘ss-fibrinogen was similar 10

Conclusions with diabetes

the

or eptifibatide

diabetes.

inhibited

brane protein glycation

Reduces

in patients

with and by 53 + 19 % in blood

VBT. Angiotensin

were compared

proteins

1.6*0.5

Plaque Area (mm2) (% RAM 11)

membrane

tosamine

Radiated

assay. Results

of platelet

p Value

Sham (n=lO)

and Prevention

cholesterol,

or

chain

reaction

with

pactin

as internal

standard

(primers: sense-S-GGATCCTGGGGCCAGGGTACTGAT-3 CTCGGGGAAGAGlTGAATCACTTC-3’). We also sequenced DNA Sequencer.

In the resting

cells, faint but distinct

was performed

and antisenseAIF gene by ABI

AIF bands

were detected

5’377 in all

metabolic control were noted with quinapril therapy. Conclusions: Administration of ACE inhibitor therapy Improves the vascular oxidative state in patients with newly diagnosed

HCAEC preparations. The gene sequence had 99% homology with neuronal and HeLa cell AIF gene. Ox-LDL treatment of HCAECs cells significantly induced the expression of

Type II diabetes

AIF (mRNA

pressure

mellitus.

reduction

1152-127

Furthermore,

or changes Roxithromycin

to be independent

control of diabetes

Inhibits

Recurrent Markus G. Enqelmann, Grosshadern, Munich,

these effects appear

in the metabolic

Plaque

Formation

Lipopolysaccharide

of blood

Induced

Inflammation

AIF expression.

by

Constanze V. Redl, Sigrid Nikol, University of Munich, Klinikum Germany, University Hospital, University of Muenster, Muenster,

expression

we demonstrated

increased

plaque

formation

occurred

study we assessed

induced

atherogenesis

Methods

and results:

were treated

the effect of macrolide

in the absence Rabbits

with a single

(n=14)

of a bacterial

treatment

on prevention

perivascular

injection

of LPS-

infection.

were fed a cholesterol-enriched of bacterial

diet. All animals

lipopolysaccharide

(LPS)

placed next to auncular, carotid and femoral arteries and sodium chloride placed next to the contralateral arteries with repeated perivascular injectlons over 90 days. 5 days after initial LPS or sodium Group A animals control. Vascular histology,

chloride

treatment

the animals

were randomized

to two groups.

were treated with roxithromycin 40 mg/kg/d, gioup B animals served as tissues (n=41 treated segments) were analyzed using morphomehy at

and using lmmunohistochemistry

to detect macrophages.

lymphocytes,

vascu-

lar smooth muscle cells. Repeated LPS application resulted in significant plaque formation compared with control (Group B, plaque-area index 0.122+0.05 vs 0.029t0.02, p=O.OZ). The plaque treatment (Group trol, p=O.O49). Conclusion:

induction

effect of LPS was inhibited

A, plaque-area

index 0.045*0.02.

by long term

LPS treatment,

Increase I” plaque

formation

roxithromycin

con-

vs 0.017+0.01,

after repeated

perivascular

LPS

application in cholesterol-fed animals can be inhibited by long term treatment using roxithromycin. The anti-inflammatory effect of macrolides may contribute to reduced atherogenesis

through

1152-128

specific bacterial

Enhancement llla

of Inhibitory

Antagonists

Glycation

products

in Patients

on the

Kinetics

such as LPS. Effects With

Atul Aqqarwal,

Burlington,

K. Keatinq,

of Fibrinogen

Effects

effects of GP Ilb-llla

of platelets

Kinetics of binding

to bind fibrinogen of I “s -labeled

was determlned

fibrinogen

to platelets

did not affect the expression

express

AIF. and ox-LDL

of AIF

upregulates

the

of cell death.

David J. Schneider,

Edward

F. Terrien,

associated

Burlington.

A. Whitaker,

Burton E.

lnflammat!on portends adverse outcomes after percutaneous (PCI). Interleukin-I receptor antagonist (IL-l Ra) accompanies by macrophages

of Vermont,

Deborah

Background: interventions interleukin-I

University

with atherosclerotic

VT

plaques.

coronary release of

Interleukin-1

stim-

ulates release of interleukin-6 (IL-6) and C-reactive protein (CRP). To determine whether local inflammation could be detected in coronary blood, the concentrations of IL-1Ra. IL6, and CRP were measured ies. Methods:

Concentrations

in blood simultaneously of CRP (@ml),

mined by ELISA in blood obtained

from the coronary

IL-6 (pgiml),

in 75 patients

and IL-1Ra (pg/ml)

majority

(68%)

of the patients

studied

= 595*388.

peripheral=545*378;

artery and

artery. Results were com-

had acute

coronary

(ACS), and 36% had elevation of cardiac markers. Despite substantial variability, IL-1Ra was consistently greater (by 50) in coronary compared blood (coronary

alter-

were deter-

before PCI from the femoral

from a guide catheter after engagement of the culprit coronary pared with the use of paired Student’s t-tests. The

and femoral

syndromes

inter-individual with peripheral

p=O.O03). IL-1Ra was greater

in core-

in coronary and peripheral blood. The concentration of IL-1Ra was greater in patients with diabetes (n=Zl), both in coronary blood (diabetes = 748+492, no diabetes =

of Vermont,

in response

Concentrations

artery and in samples

= 6.4k9.9.

blood (diabetes

of IL-1Ra

penpheral=6.9+10;

= 709*510.

are greater

from patients

in blood

with diabetes

p=O.l)

no diabetes obtained

mellitus.

were seen

= 482*294;

betes.

inflammatory

state that may contribute

to accelerated

p

from the culprit

IL-1 Ra may be use-

ful for detecting and assessing the magnitude of local inflammation associated prit lesions. Greater concentrations of IL-1 Ra in patients with diabetes mellitus a heightened

The

with the use of flow cytometry. were characterized

coronary

p=O.4) and IL-6 (coronary

p =O.OZ) and peripheral

=0.02). Conclusions:

and the kinetics of fibrin-

ogen bindmg to platelets from patients with and without diabetes. Methods Blood was incubated with tlrofiban or eptlfibatide in vitro for 15 minutes. capacity

of caspase

eral=9.5+14:

Binding

University

antagonists

the inhlbitor

at m

Ilb/

Background: Glycoprotem (GP) Ilb-llla antagonists reduce subsequent cardiac events to a greater extent I” patients with diabetes. To identify mechanisms potentially responsiinhibitory

resulted

of

of Glycoprotein

VT

ble, we characterized

ox-LDL

nary blood from those with marker positive ACS (by 47), marker negative ACS (by 48), and stable symptoms (by 44). Similar concentrations of CRP (coronary = 9.0515, periph-

Diabetes:

Burton E. Sobel. David J. Schneider,

protein/ml

L. Dauerman.

538+325; Fnedetike

cells to 50pg

Sobel, Harold

Ftesulte:

The significant

of HCAECs

Increased Concentrations of Interleukin-1 Receptor Antagonist Associated With Diabetes Mellitus and in the Vicinity of Coronary Plaques: A Sensitive Marker of Inflammation

after repetitive

LPS application in cholesterol-fed animals. Thus, repeated local infection by microorgan~sms may contribute to atherogenesis through specific bacterial products such as LPS. In the current

Z-VAD.fmk,

of this novel pathway

1152-130

Recently

Exposure

induced by ox-LDL. Conclusions:This study shows that HCAECs

In Vivo

Germany Alms:

and protein).

in maximal increase. Induction of expression was evident at 1 h, and became maximal 24 h. Treatment of HCAECs with actinomycin-D blocked ox-LDL-mediated increase

mellitus.

atherogenesis

with culsuggests in dia-