Anker, Stefan D.

Bolger, Aidan P.

Doehner, Wolfram

Pavitt, Darrell V.

Reaveley, David A.

Tarpey, Margaret M.

von Haehling, Stephan

Wensel, Roland

Elsevier - Publisher Connector 

JACC March 19,2003 ABSTRACTS - Cardiac Function and Heart Failure 207A 
NYHA classes in patients with left ventricular dysfunction after MI. Trandolapril resulted 
in significantly lower furosemide consumption. 
expression of TlMPs is unchanged while expression of MMPP and 9 is increased. Ther- 
apy with ER-MET does not influence TlMPs but reduces expression of MMPP and 9, a 
finding consistent with reduced RIF following chronic therapy with the ER-MET. 
NL HF-Untreated HF + E&MET I.0 Average NYHA class I 
1.2 
1.4 
1 .B 
1.8 
2.0 months 
0 10 20 30 40 50 B( 
80 
70 
60 
50 
40 
30 
20 
10 
il Dose offurosrmidr- mglday I 
I 184-81 Elevated Plasma Xanthine Oxidase Activity in Chronic 
Heart Failure: Source of Increased Oxygen Radical 
Load and Effect of Allopurinol in a Placebo Controlled, 
Double Blinded Treatment Study 
Wolfram Ooehner, Margaret M. Tarpey, Darrell V. Pavitt, Aidan P. Bolger. Roland 
Wensel, Stephan van Haehling, David A. Reaveley, Stefan D. Anker, National Heart & 
Lung Institute, London, United Kingdom, University of Alabama, Birmingham, AL 
Background: Elevated xanthine oxidase (X0) activity contributes to production of reac- 
tive oxygen species. Hyperuicemia is common in chronic heart failure (CHF), however, 
enzyme activity of circulating plasma X0 has not been studied in CHF. We hypothesised, 
that plasma X0 activity is elevated in CHF compared to healthy controls, paralleled by 
increased free radical load, and that X0 inhibition with allopurinol decreased both. As a 
marker of free radical load serum allantoin was measured, which is generated in the 
humans exclusively via non-enzymatic oxygen radical dependent “rate oxidation. 
Methods: In 67 CHF patients (mean age 65+1Oy, NYHA 2.4+0.7. peak VQ 16.6+6.6 
ml/kg/min) and 15 controls (age 33+1Oy) we measured plasma X0 activity (HPLC), uric 
acid (UA), and allantoin (gas chromatography-mass spectrometfy). In 17 CHF patients 
with known hyperuricemia (UA 517+95Fmol/L), the effect of allopurinol (300mg od for 1 
week) was tested in a placebo controlled double-blinded, cross-over study. 
Results: CHF patients were hyperuricemic (UA 461*14~mol/L; normal range 210440 
pmol/L) and had increased plasma X0 activity (7.01*0.60 vs 0.69e1.23 vs wU/ml; 
pcO.001). The upper limit of normal was defined as 3.35 fiU/ml X0 (normal mean value 
+2SD). All but one control and 11 patients (16%) had normal plasma X0 activity, but 56 
patients (64%) had elevated X0 activity (Chi* p<O.OOOl). Allantoin was elevated in CHF 
compared to reference control values (4l.Ot26.2 vs 13.4k1.6 pmol/L). In the double- 
blinded allopurinol treatment study, plasma X0 activity was reduced in all 17 patients by 
49% (from 4.35i 2.7* to 2.2&l .3, p<O.OOl). Allopurinol also reduced allantoin levels by 
16% (from 25.7i4.1 to 21 .l+l.O. ~~0.02). 
Conclusion: The activity of circulating plasma X0 is elevated in patients with CHF. 
Treatment with allopurinol results in reduction of X0 activity that is paralleled by lower 
allantoln indicating reduced oxygen radical load. Thus, a potentially new therapeutic 
option emerges to reduce oxygen radical load in CHF. 
1184-82 Chronic Monotherapy With Extended Release 
Metoprolol Succinate Attenuates mRNA Gene 
Expression for MMPP and MMPS in Dogs With Heart 
Failure 
Sharad Rastoa, Ramesh C. Gupta, Sudhish Mishra, Hideaki Morita, George Suzuki, 
Sidney Goldstein, Hani N. Sabbah, Henry Ford Health System, Detroit, Ml 
Background: Accumulation of collagen in the cardiac interstitium or “reactive interstitial 
fibrosis” (RIF) occurs in heart failure (HF) and contributes to LV dysfunction and remodel- 
ing. Matrix metalloproteinases (MMPs) are upregulated in HF and contribute to RIF. We 
previously showed that therapy with extended release metoprolol succinate (ER-MET) 
sianificantlv reduces RIF in doas with HF. In this studv. we examined the effects of 
I .  
chronic therapy with ER-MET on gene expression of MMPP and MMP9 (gelatinases) and 
on tissue inhibitors of MMPs (TlMPsl in LV of doos with microembolization-induced HF. 
Methods: Total RNA was isolated from LV tissue of 14 dogs with HF randomized to 3 
months therapy with ER-MET (50 mg, once daily, n=7) or to no therapy at all (n=7) and 
from LV of 6 normal (NL) dogs. mRNA expression for MMPP and 9 and TlMPt and 2 was 
measured using reverse transcriptase polymerase chain reaction and bands quantified in 
densitometric units. Results: Results are shown in the table. There were no differences 
in expression of TlMPl and 2 among the 3 study groups. Expression of MMPP and 9 was 
increased in untreated-HF dogs compared to NL. ER-MET significantly reduced this 
increase in expression of MMPP and 9. Conclusions: In dogs with HF, mRNA gene 
TIMPl 
TIMPP 
MMPP 
MMP9 
2.33 0.35 + 2.93 + 0.46 1.90+0.38 
1.31 0.04 + 1.39 + 0.02 1.35 0.06 + 
1.30+0.16 2.04 + 0.11’ 1.39 + o..ow 
1.2220.14 2.50 + 0.04’ 1.15+0.1w 
*=P<O.O5 vs. NL; A=P<O.O5 vs. HF-Untreated 
1184-83 Dietary Fish Oil Supplementation Improves Endothelial 
Function in Patients With Congestive Heart Failure 
David R. Moraan, Lana J. Dixon, Colm G. Hanratty. Sinead M. Hughes, William J. 
Leahey, Naglaa A. El-Sherbeeny, G. Dennis Johnston, Gary E. McVeigh. Queen’s 
University Belfast, Belfast, United Kingdom 
Background 
Systemic vasoconstriction and reduced peripheral perfusion are hallmarks of congestive 
heart failure (CHF). Endothelial dysfunction is a frequent finding in CHF and is associ- 
ated with reduced bioavailability of the vasodilator auto&d nitric oxide (NO). Omega-3. 
fatty acids (fish oils) have been shown to have beneficial effects on endothelial function 
and vascular responses in a number of vascular diseases which may be secondary to 
increased NO bioavailability. We conducted a study to establish whether addition of 
omega9- fatty acids to background therapy in patients with CHF would improve endot- 
helial dysfunction. 
Methods 
20 patients with grade II and Ill CHF (15 male) mean age 73 were recruited. Sodium 
nitropmsside (SNP) (6. 9, 12nmolImin) and acetylcholine (ACH) (120,160, 240nmollmin) 
were infused into the non-dominant brachial artery. Forearm blood flow (FABF) 
responses assessed by venous occlusion plethysmography. Patients received fish oil or 
olive oil drink for 6 weeks in a double blinded randomised cross over trial with assess- 
ment of FABF at baseline and after each treatment. 
Results 
See table 
Conclusion 
Dietary fish oil significantly improved endothelial function as assessed by FABF 
responses to ACH. There are several possible mechanisms by which fish oils could 
potentially improve endothelial function in CCF. Further studies are required to attempt to 
elucidate the mechanism for this improvement and to establish whether will be associ- 
ated with improved outcomes. 
Forearm Blood Flow responses to infusion of SNP and ACH (values are arbitary units) 
(*=p<o.ol) 
SNP ACH 
Baseline 1 14.22 (10.93,17.51) 7.95(4.81,11.60) 
Fish oil 11.66 (6.17,15.15 11.27 (7.31.15.23) 
Baseline 2 13.55 (10.74,16.36) 7.66 (4.95,10.41) 
Olive oil 14.36 (11.67,17.09) 7.27 (4.66,9.66) 
POSTER SESSION 
1185 Cardiac Transplantation: Cellular 
Mechanisms and Rejection 
Tuesday, April 01, 2003, NoonQ:OO p.m. 
McCormick Place, Hall A 
Presentation Hour: 1:OO p.m.-2:OO p.m. 
1185-59 Acute Rejection in Human Heart Transplantation: 
Identification and Characterization of Two Important 
Markers (MIP-1 p and VE-Cadherin) 
Ana L. S. Roussoulieres Olivier Raisky, Lara Chalabreysse. George Dureau, Catherine 
Cerutti. Pascale Boissonnat, Laurent Sebbag, Jean-Paul Gare. Jean-Franpois Obadia, 
Jean Ninet, Olivier Bastien, FranCoise Thivolet-Bejui. John L. McGregor, H6pital 
Cardiologique Louis Pradel, Lyon, France, INSERM, Lyon, France 
Background: An extensive number of molecules are involved in acute rejection (AR) fol- 
lowing heart transplantation. We have previously identified by DNA arrays, in a murine 
model of heterotopic heart transplantation, a number of genes implicated in allograft AR. 
The expression of 2 of these genes, MIP-lp and VE-Cadherin, was investigated in the 
present study as potential new markers of AR in cardiac tissue following human heart 
transplantation. 
Methods: We have previously studied the expression profile of genes involved in AR 


Elevated plasma xanthine oxidase activity in chronic heart failure: Source of increased oxygen radical load and effect of allopurinol in a placebo controlled, double blinded treatment study 

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Elevated plasma xanthine oxidase activity in chronic heart failure: Source of increased oxygen radical load and effect of allopurinol in a placebo controlled, double blinded treatment study

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