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Homoarginine and creatine deficiency do not exacerbate murine ischaemic heart failure
Debra J McAndrew1,2,3, Hannah A Lake1,2,3, Sevasti Zervou1,2,3
1Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Insights
Low homoarginine and creatine levels do not worsen chronic heart failure in mice. This suggests these deficiencies may not play a major causative role in heart failure progression.
Area of Science:
- Biochemistry
- Cardiovascular Physiology
- Genetics
Background:
- Low homoarginine and creatine levels correlate with heart failure severity in humans.
- L-arginine:glycine amidinotransferase (AGAT) synthesizes both creatine and homoarginine.
- AGAT knockout (AGAT-/-) mice exhibit combined deficiencies.
Purpose of the Study:
- To investigate the impact of combined creatine and homoarginine deficiency on chronic heart failure pathophysiology.
- To determine if AGAT deficiency exacerbates heart failure in a mouse model.
Main Methods:
- Two studies utilized AGAT-/- mice and wild-type controls.
- Study 1: Induced myocardial infarction (MI) in mice with homoarginine deficiency but normal creatine.
- Study 2: Induced MI and manipulated creatine levels post-MI in AGAT-/- mice.
Main Results:
- All groups developed chronic heart failure with left ventricular (LV) remodeling and dysfunction.
- Neither homoarginine deficiency alone nor combined with creatine deficiency significantly affected mortality.
- No significant impact on LV remodeling or contractile/lusitropic function was observed.
Conclusions:
- Low homoarginine and creatine levels do not appear to worsen established chronic heart failure.
- These findings argue against a major causative role for these deficiencies in heart failure progression.
- Correcting homoarginine deficiency may not be necessary in heart failure patients, though high levels could still be beneficial.
Aims:
Low levels of homoarginine and creatine are associated with heart failure severity in humans, but it is unclear to what extent they contribute to pathophysiology. Both are synthesized via L-arginine:glycine amidinotransferase (AGAT), such that AGAT-/- mice have a combined creatine and homoarginine deficiency. We hypothesized that this would be detrimental in the setting of chronic heart failure.
Methods And Results:
Study 1: homoarginine deficiency-female AGAT-/- and wild-type mice were given creatine-supplemented diet so that both had normal myocardial creatine levels, but only AGAT-/- had low plasma homoarginine. Myocardial infarction (MI) was surgically induced and left ventricular (LV) structure and function assessed at 6-7 weeks by in vivo imaging and haemodynamics. Study 2: homoarginine and creatine-deficiency-as before, but AGAT-/- mice were given creatine-supplemented diet until 1 week post-MI, when 50% were changed to a creatine-free diet. Both groups therefore had low homoarginine levels, but one group also developed lower myocardial creatine levels. In both studies, all groups had LV remodelling and dysfunction commensurate with the development of chronic heart failure, for example, LV dilatation and mean ejection fraction <20%. However, neither homoarginine deficiency alone or in combination with creatine deficiency had a significant effect on mortality, LV remodelling, or on any indices of contractile and lusitropic function.
Conclusions:
Low levels of homoarginine and creatine do not worsen chronic heart failure arguing against a major causative role in disease progression. This suggests that it is unnecessary to correct hArg deficiency in patients with heart failure, although supra-physiological levels may still be beneficial.
