Role of adenosine monophosphate deaminase-1 gene polymorphism in patients with congestive heart failure (influence on tumor necrosis factor-α level and outcome)

Gastmann, Anja; Sigusch, Holger H.; Henke, Andreas; Reinhardt, Dirk; Surber, Ralf; Gastmann, Oliver; Figulla, Hans R

doi:10.1016/j.amjcard.2004.02.011

Cited by 23 publications

(18 citation statements)

References 20 publications

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“…The reason for performing this study was previous reports suggesting a survival benefit associated with the mutant AMPD1 allele in patient groups with heart failure [7][8][9] and coronary artery disease [10] . The pathophysiological explanation of this observation is not completely clear.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have suggested a survival benefit associated with the mutant AMPD1 allele in patient groups with heart failure [7][8][9] and coronary artery disease [10] . This benefit may be linked to the enhanced production of adenosine since adenosine has cardioprotective actions, including augmentation of coronary blood flow and ischaemic preconditioning [11,12] .…”

Section: Introductionmentioning

confidence: 99%

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Association between AMPD1 Gene Polymorphism and Coagulation Factors in Patients with Coronary Heart Disease

Agewall¹,

Norman²

2006

Pathophysiol Haemos Thromb

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The aim of this study was to investigate whether the C34T and G468T variations in the adenosine monophosphate deaminase-1 (AMPD1) gene were associated with intima-media thickness of the carotid and brachial artery, endothelial function of the brachial artery, glucose metabolism, haemostatic variables and cardiac hypertrophy in patients (n = 109) with coronary heart disease. The plasminogen activator inhibitor-1 activity and the von Willebrand factor were higher in the CC homozygote group compared to the CT/TT group (p < 0.05). There were no differences between the groups regarding intima-media complex of the carotid and brachial artery, presence of plaque in the carotid region, flow-mediated dilatation, ejection fraction or dimensions of the heart. In conclusion, there were no differences between the mutant AMPD1 allele carriers and CC homozygotes regarding surrogate values for atherosclerosis, endothelial function, dimensions and ejection fraction of the heart, glucose tolerance and other well-known cardiovascular risk factors, whereas plasminogen activator inhibitor-1 activity and von Willebrand levels were lower in the mutant AMPD1 allele carriers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association between AMPD1 Gene Polymorphism and Coagulation Factors in Patients with Coronary Heart Disease

Agewall¹,

Norman²

2006

Pathophysiol Haemos Thromb

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“…11 In addition, patients with increased muscle adenosine levels due to mutation in at least 1 allele of the adenosine monophosphate deaminase 1 (AMPD1) gene had a longer survival than patients with the wild-type genoptype. [12][13][14] Furthermore, in patients with heart failure, increased levels of adenosine were associated with severity of disease. 15 These initial studies led investigators to identify the specific adenosine receptor (AR) subtypes that mediated the salutary benefits of adenosine.…”

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confidence: 99%

Regulated Overexpression of the A ₁ -Adenosine Receptor in Mice Results in Adverse but Reversible Changes in Cardiac Morphology and Function

Funakoshi¹,

Chan²,

Good³

et al. 2006

Circulation

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Background-Both the A 1 -and A 3 -adenosine receptors (ARs) have been implicated in mediating the cardioprotective effects of adenosine. Paradoxically, overexpression of both A 1 -AR and A 3 -AR is associated with changes in the cardiac phenotype.To evaluate the temporal relationship between AR signaling and cardiac remodeling, we studied the effects of controlled overexpression of the A 1 -AR using a cardiac-specific and tetracycline-transactivating factor-regulated promoter. Methods and Results-Constitutive A 1 -AR overexpression caused the development of cardiac dilatation and death within 6 to 12 weeks. These mice developed diminished ventricular function and decreased heart rate. In contrast, when A 1 -AR expression was delayed until 3 weeks of age, mice remained phenotypically normal at 6 weeks, and Ͼ90% of the mice survived at 30 weeks. However, late induction of A 1 -AR still caused mild cardiomyopathy at older ages (20 weeks) and accelerated cardiac hypertrophy and the development of dilatation after pressure overload. These changes were accompanied by gene expression changes associated with cardiomyopathy and fibrosis and by decreased Akt phosphorylation. Discontinuation of A 1 -AR induction mitigated cardiac dysfunction and significantly improved survival rate. Conclusions-These data suggest that robust constitutive myocardial A 1 -AR overexpression induces a dilated cardiomyopathy, whereas delaying A 1 -AR expression until adulthood ameliorated but did not eliminate the development of cardiac pathology. Thus, the inducible A 1 -AR transgenic mouse model provides novel insights into the role of adenosine signaling in heart failure and illustrates the potentially deleterious consequences of selective versus nonselective activation of adenosine-signaling pathways in the heart. (Circulation. 2006;114:2240-2250.)

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“…The scarce evidence indicates that the T allele probably increases adenosine: during exercise (not during rest), venous adenosine levels increase in carriers of 34TT (4). Furthermore, the AMPD1 34CϾT variant improves survival of patients with established congestive heart failure (7,8) or patients with established coronary artery disease (9,10), probably by promoting release of adenosine, a well-known cardioprotective substance (11). How AMPD1 34CϾT interacts with MTX in RA (factors that influence purine enzyme kinetics) is purely speculative.…”

Section: To the Editormentioning

confidence: 99%

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Wessels¹,

Huizinga²,

Guchelaar³

et al. 2007

Arthritis & Rheumatism

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Effect of the 34C>T variant in the AMPD1 gene on the clinical response to methotrexate in patients with rheumatoid arthritis: comment on the article by Wessels et al To the Editor:We read with interest the pharmacogenetics study by Wessels et al, in which they explored the effect of polymorphisms in genes involved in the metabolism of adenosine on the clinical response to methotrexate (MTX) in patients with rheumatoid arthritis (1). Patients carrying at least 1 allele with the 34CϾT variant in AMPD1 were more likely to have a good clinical response. This finding is relevant, because it offers the possibility to tailor antiinflammatory therapy in individual patients. Unfortunately, the authors do not speculate about the possible underlying mechanism of action.AMPD1 encodes the muscle isoform of adenosine monophospate deaminase (AMPD), which catalyzes the intracellular conversion of AMP to IMP. The 34CϾT variant encodes a truncated protein with loss of function (2). As a consequence, AMP is preferentially converted into adenosine. Endogenous adenosine has potent antiinflammatory properties. Evidence is accumulating that the antiinflammatory effects of MTX are mediated by increased adenosine receptor stimulation (3). Polyglutamated MTX inhibits the enzyme 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, which will increase the intracellular AICAR concentration. Subsequently, AICAR itself inhibits AMPD and adenosine deaminase, which will increase the AMP and adenosine concentrations (3). As such, it is expected that in patients with the 34CϾT variant, the antiinflammatory potential of MTX is reduced rather than increased, because the deficient AMPD enzyme prevents further inhibition by MTX.Moreover, we would like to comment on the use of the European League Against Rheumatism (EULAR) response criteria in the study by Wessels et al, because this may have contributed to a suboptimal interpretation of the data. The authors' primary cutoff point is a Disease Activity Score (DAS) of Յ2.4 at 6 months: they considered patients with a DAS of Յ2.4 to be responders and the rest to be nonresponders. One of the secondary end points is good or moderate improvement, which they define as a decrease of Ͼ1.2 or Ͼ0.6, respectively, in the DAS. The EULAR response criteria, however, define good response as an end DAS of Յ2.4 and a decrease in the DAS of Ͼ1.2. A bad response is defined as a decrease in the DAS of Յ0.6 regardless of the end DAS or a decrease in the DAS of Ͼ0.6 to Յ1.2 if the end DAS remains Ͼ3.7 (4). The use of the EULAR criteria as postulated in the Wessels study leads to pooling of good responders, moderate responders, and nonresponders in the so-called responder group and of moderate responders and nonresponders in the so-called nonresponder group. This can lead to serious confounding.In conclusion, the association between the 34CϾT variant of AMPD1 and the increased likelihood of a good response to MTX cannot be explained with the current paradigm of the mechanism of action of MTX and may be conf...

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Role of adenosine monophosphate deaminase-1 gene polymorphism in patients with congestive heart failure (influence on tumor necrosis factor-α level and outcome)

Cited by 23 publications

References 20 publications

Association between AMPD1 Gene Polymorphism and Coagulation Factors in Patients with Coronary Heart Disease

Association between AMPD1 Gene Polymorphism and Coagulation Factors in Patients with Coronary Heart Disease

Regulated Overexpression of the A ₁ -Adenosine Receptor in Mice Results in Adverse but Reversible Changes in Cardiac Morphology and Function

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Role of adenosine monophosphate deaminase-1 gene polymorphism in patients with congestive heart failure (influence on tumor necrosis factor-α level and outcome)

Cited by 23 publications

References 20 publications

Association between AMPD1 Gene Polymorphism and Coagulation Factors in Patients with Coronary Heart Disease

Association between AMPD1 Gene Polymorphism and Coagulation Factors in Patients with Coronary Heart Disease

Regulated Overexpression of the A 1 -Adenosine Receptor in Mice Results in Adverse but Reversible Changes in Cardiac Morphology and Function

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Regulated Overexpression of the A ₁ -Adenosine Receptor in Mice Results in Adverse but Reversible Changes in Cardiac Morphology and Function