The CML/esRAGE ratio as a potential biomarker of early diastolic impairment in asymptomatic type 1 diabetic patients without overt heart disease

Heart failure is a prevalent complication of diabetic microangiopathy, and early identification of myocardial dysfuntion is crucial. Advanced glycation end products (AGEs) bind to their receptor RAGE and further promote diabetic late complications as well as heart failure. Two soluble RAGE isoforms, endogenous secretory RAGE (esRAGE) and the cleaved extracellular fragment of membrane RAGE (collectively termed sRAGE), are believed to exert cardioprotective effects by acting as RAGE decoy receptors. This pilot study aimed to investigate the associations of AGEs, sRAGE and esRAGE with early cardiac dysfunction identified via advanced echocardiography. We enrolled 29 type 1 diabetic patients without known heart disease(EF ≥ 50%) and 31 healthy controls. Plasma levels of two major AGEs, carboxymethyllysine(CML) and methylglyoxal-derived hydroimidazolone 1(MG-H1), as well as sRAGE and esRAGE were measured using immunoassay. Conventional, tissue Doppler, and speckle-tracking echocardiography were performed. In the diabetic group, global longitudinal strain (GLS) and peak early diastolic velocity at the lateral mitral annulus [e(lat)] were significantly lower, while E/e(lat) was higher. CML levels and CML/esRAGE ratio were increased, and esRAGE was decreased in the diabetic group. Pearson correlation analysis showed GLS was significantly associated with disease duration, total cholesterol (TC), HbA1c, esRAGE, and CML/esRAGE ratio; Univariate linear regression confirmed that higher CML/esRAGE ratio was associated with lower e(lat) (β = -0.006, P = 0.047).Variables with P < 0.1 in univariate regression together with pre-specified clinical covariates including age, gender, HbA1c, disease duration, and heart rate were incorporated into stepwise multiple regression; the model demonstrated that CML/esRAGE was independently associated with e(lat) (β = -0.006, 95%CI: [-0.012, -0.001], P = 0.049). Elevated CML/esRAGE ratio is associated with impaired left ventricular diastolic function, and may represent a candidate biomarker for early diastolic dysfunction. Our study also suggest that CML/esRAGE ratio may not associated with GLS abnormalities reflecting subclinical systolic dysfunction. All observations from this pilot study require further validation in large independent prospective cohorts.