Myocardial Expression of the Arginine:Glycine Amidinotransferase Gene Is Elevated in Heart Failure and Normalized After Recovery

Cullen, Martin E.; Yuen, Ada H. Y.; Felkin, Leanne E.; Smolenski, Ryszard T.; Hall, Jennifer L.; Grindle, Suzanne; Miller, Leslie W.; Birks, Emma J.; Yacoub, Magdi H.; Barton, Paul J.R.

doi:10.1161/circulationaha.105.000448

Cited by 94 publications

(98 citation statements)

References 26 publications

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“…30 GATM mRNA expression is highest in the kidney, which is thought to be the major site of homoarginine synthesis. 31 In addition, GATM is also expressed in other tissues, such as liver and brain, skeletal muscle, heart, lung, and salivary glands. 31 The lead SNP identified in our GWAS, rs1153858, is located ≈600 bp downstream of the GATM gene.…”

Section: Discussionmentioning

confidence: 99%

“…31 In addition, GATM is also expressed in other tissues, such as liver and brain, skeletal muscle, heart, lung, and salivary glands. 31 The lead SNP identified in our GWAS, rs1153858, is located ≈600 bp downstream of the GATM gene. It is in high linkage disequilibrium (r in meta-analysis), which codes the exchange of glutamine against histidine at position 110.…”

Section: Discussionmentioning

confidence: 99%

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Genome-Wide Association Study Identifies 3 Genomic Loci Significantly Associated With Serum Levels of Homoarginine

Kleber¹,

Seppälä²,

Pilz³

et al. 2013

Circ Cardiovasc Genet

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Background-Low serum levels of the amino acid derivative, homoarginine, have been associated with increased risk of total and cardiovascular mortality. Homoarginine deficiency may be related to renal and heart diseases, but the pathophysiologic role of homoarginine and the genetic regulation of its serum levels are largely unknown. Methods and Results-In 3041 patients of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study referred for coronary angiography and 2102 participants of the Young Finns Study (YFS), we performed a genome-wide association study to identify genomic loci associated with homoarginine serum levels and tested for associations of identified singlenucleotide polymorphisms with mortality in LURIC. We found genome-wide significant associations with homoarginine serum levels on chromosome 2 at the carbamoyl phosphate synthetase I locus, on chromosome 5 at the alanine-glyoxylate aminotransferase 2 locus, and on chromosome 15 at the glycine amidinotransferase locus, as well as a suggestive association on chromosome 6 at the Homo sapiens mediator complex subunit 23 gene/arginase I locus. All loci harbor enzymes located in the mitochondrium are involved in arginine metabolism. The strongest association was observed for rs1153858 at the glycine amidinotransferase locus with a P value of 1.25E-45 in the combined analysis and has been replicated in both the Die Deutsche Diabetes Dialyse Studie (4D study) and the Graz Endocrine Causes of Hypertension (GECOH) study. Conclusions-In our genome-wide association study, we identified 3 chromosomal regions significantly associated with serum homoarginine and another region with suggestive association, providing novel insights into the genetic regulation of homoarginine. (Circ Cardiovasc Genet. 2013;6:505-513.)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study Identifies 3 Genomic Loci Significantly Associated With Serum Levels of Homoarginine

Kleber¹,

Seppälä²,

Pilz³

et al. 2013

Circ Cardiovasc Genet

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“…[3][4][5][6] Interestingly, the key enzyme for homoarginine synthesis, arginine: glycine amidinotransferase, is upregulated in the failing heart and is highly expressed in the brain. 1,10 Inborn errors of this enzyme lead to disturbances in energy metabolism, so-called creatine deficiency syndromes, which are associated with mental disorders. 11 Our data are limited by the relatively low number of events, which preclude adequately powered analyses of specific causes of stroke deaths.…”

Section: Discussionmentioning

confidence: 99%

Low Serum Homoarginine Is a Novel Risk Factor for Fatal Strokes in Patients Undergoing Coronary Angiography

Pilz

Tomaschitz

Meinitzer

et al. 2011

Stroke

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Background and Purpose-Low serum concentrations of the amino acid homoarginine have been associated with endothelial dysfunction and an increased risk of all-cause and cardiovascular mortality. We aimed to investigate whether homoarginine levels are also associated with fatal strokes and a history of nonfatal cerebrovascular disease. Methods-Serum homoarginine was measured in 3305 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study who were referred to coronary angiography at baseline (1997 to 2000) and were followed up with respect to mortality. Results-During a median follow-up time of 9.9 years, 991 patients died including 61 fatal (ischemic and hemorrhagic) strokes. In a binary logistic regression analysis, the odds ratio (with 95% CI) for fatal stroke per SD of homoarginine was 0.52 (0.37 to 0.73; PϽ0.001) and remained significant after multivariable adjustments (0.62 [0.42 to 0.91]; Pϭ0.014). For previous cerebrovascular disease events, the multivariable adjusted OR per SD of homoarginine was 0.82 (0.70 to 0.96; Pϭ0.014). Conclusions-Low homoarginine levels are a novel risk factor for fatal strokes and are reduced in patients with a history of cerebrovascular disease. Further studies are needed to explore the significance of homoarginine to risk stratification and therapeutic approaches in the prevention of strokes.

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“…Elevated myocardial arginine:glycine amidinotransferase levels have been reported in failing hearts requiring LVAD support, and these normalized after myocardial recovery sufficient to allow device explantation. 64 This change was specific to patients who recovered and was not seen in patients who had LVAD unloading but no myocardial recovery. Arginine:glycine amidinotransferase is a rate-limiting enzyme that catalyzes the formation of guanidinoacetate, the immediate precursor of creatinine, and hence is a rate-limiting enzyme in the creatine synthesis pathway.…”

Section: Metabolic Enzymesmentioning

confidence: 97%

Molecular Changes After Left Ventricular Assist Device Support for Heart Failure

Birks

2013

Circulation Research

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102

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Abstract-Heart failure is associated with remodeling that consists of adverse cellular, structural, and functional changes in the myocardium. Until recently, this was thought to be unidirectional, progressive, and irreversible. However, irreversibility has been shown to be incorrect because complete or partial reversal can occur that can be marked after myocardial unloading with a left ventricular assist device (LVAD). Patients with chronic advanced heart failure can show near-normalization of nearly all structural abnormalities of the myocardium or reverse remodeling after LVAD support. However, reverse remodeling does not always equate with clinical recovery. The molecular changes occurring after LVAD support are reviewed, both those demonstrated with LVAD unloading alone in patients bridged to transplantation and those occurring in the myocardium of patients who have recovered enough myocardial function to have the device removed. Reverse remodeling may be attributable to a reversal of the pathological mechanisms that occur in remodeling or the generation of new pathways. A reduction in cell size occurs after LVAD unloading, which does not necessarily correlate with improved cardiac function. However, some of the changes in both the cardiac myocyte and the matrix after LVAD support are specific to myocardial recovery. In the myocyte, increases in the cytoskeletal proteins and improvements in the Ca 2+ handling pathway seem to be specifically associated with myocardial recovery. Changes in the matrix are complex, but excessive scarring appears to limit the ability for recovery, and the degree of fibrosis in the myocardium at the time of implantation may predict the ability to recover. (Circ Res. 2013;113:777-791.)

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Myocardial Expression of the Arginine:Glycine Amidinotransferase Gene Is Elevated in Heart Failure and Normalized After Recovery

Cited by 94 publications

References 26 publications

Genome-Wide Association Study Identifies 3 Genomic Loci Significantly Associated With Serum Levels of Homoarginine

Genome-Wide Association Study Identifies 3 Genomic Loci Significantly Associated With Serum Levels of Homoarginine

Low Serum Homoarginine Is a Novel Risk Factor for Fatal Strokes in Patients Undergoing Coronary Angiography

Molecular Changes After Left Ventricular Assist Device Support for Heart Failure

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