Abstract P217: Cardiac Involvement In Creatine Deficiency Syndrome: From Transgenic Model To Humans

Abstract

Background: Electrocardiographic/echocardiographic abnormalities consistent with early-stage cardiomyopathy were previously reported in creatine transporter (CrT) deficiency. Nevertheless, cardiac involvement has never been accurately characterized. Aim: widen the current knowledge of the cardiac phenotype associated with creatine deficiency in a murine transgenic model and in patients with creatine deficiency syndrome (CDS). Methods: Wild type and transgenic CrT -/y mice (n=20) were serially evaluated in vivo by electrocardiogram (EKG) and echocardiography for 6 months, and ex vivo by histological/biochemical analyses. Nine patients with CDS (n=4 with L-arginine:glycine amidinotransferase - AGAT- deficiency, n=5 with CrT deficiency) underwent blood samples, including cardiac biomarkers, EKG, Holter monitoring, echocardiography and cardiac magnetic resonance (CMR). Results: Compared to wild type, CrT -/y mice showed a prolongation of QT interval (p=0.008) associated with a lower expression of ATPase sarcoplasmic/endoplasmic reticulum Ca 2+ transporting 2, involved in turn in intracellular Ca 2+ homeostasis. The significant reduction in mitochondrial ATP rate production (p<0.001) was attributed to a limited availability of ketone bodies, whereas ATP synthase F1 subunit alpha was not affected. No differences were detected in the left ventricular systolic function, neither by 2D-echo nor by speckle tracking. A prolonged QTc interval, detected in 7 patients at Holter monitoring, was mainly detected in case of CrT deficiency, without evidence of tachyarrhythmias. Although no impairment of cardiac function was detected at CMR, only subjects with AGAT deficiency showed an increase level of plasmatic norepinephrine and of native T1 value - 1 with an increase of extracellular volume, matching with the detection of late gadolinium enhancement. Conclusion: Prolonged QT interval is observed in murine model - even with a slightly impaired metabolism - and in subjects with CrT deficiency. Biohumoral signs of neurohormonal activation and an initial replacement fibrosis - the latter suggested by the increase of native T1 - are identified in subjects with AGAT deficiency, but their clinical significance remains to be determined.