Rationale Creatine is an intrinsic component of cardiac energy metabolism. We therefore hypothesised that genetic deletion of the creatine biosynthetic enzyme, arginine:glycine amidinotransferase (AGAT KO), would result in impaired cardiac function secondary to chronic creatine deficiency.
Methods & Results Creatine levels were undetectable in KO hearts using magnetic resonance spectroscopy, while ATP levels remained unchanged. In vivo cardiac haemodynamics via a 1F Millar mikro-tip catheter revealed that KO mice had low LV systolic pressure and heart rate, with impaired contractility (dP/dtmax), relaxation (dP/dtmin) and inotropic reserve compared to wild-type. This was confirmed by ex vivo perfusion in Langendorff mode, with LV systolic pressure and rate pressure product lower in KO mice, suggesting intrinsic myocardial dysfunction. Dietary creatine supplementation (0.5% for 7 days or 7 weeks) rescued in vivo LV systolic pressure but no other haemodynamic parameter, despite normalisation of myocardial creatine levels. In contrast, KO mice also had low plasma homoarginine (HA) levels (14% of WT) and supplementation with HA (14 mg/L in drinking water for 10 days) completely rescued all remaining haemodynamic parameters. The mechanism for this was not secondary to gross differences in NO bioavailability since nitrate and nitrite levels were unchanged, however, global S-nitrosylation was reduced in KO hearts, and corrected by HA supplementation but not by creatine.
Conclusions AGAT knockout mice exhibit inotropic and luscitropic dysfunction rescuable by homoarginine but not creatine supplementation, indicating that homoarginine deficiency is the main driver of this phenotype. These findings may explain why low plasma HA is associated with cardiovascular mortality in at-risk patients.
- CARDIAC PROCEDURES AND THERAPY
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