Background
Carnosine dipeptidase II (CNDP2) converts lactate and phenylalanine into Lac-Phe, an exercise-induced metabolite which may be cardioprotective. Although lactate is an essential cardiac energy source, elevated blood lactate is associated with worse outcomes while rapid lactate clearance appears to predict favourable outcomes; however, the mechanisms underlying these observations are unclear. To investigate the role and regulation of CNDP2 in the heart, we investigated associations between CNDP2 genotype, CNDP2 gene expression, and circulating CNDP2 concentration.
Methods
Cardiac CNDP2 gene expression and six genetic variants were assessed in left ventricular tissue from 108 heart donors and 110 patients with end-stage heart failure (HF) using Taqman assays. Circulating CNDP2 protein was measured in 37 patients with acute chest pain, 36 patients with acute decompensated heart failure (ADHF) and 10 heart-healthy volunteers using an ELISA (Abcam).
Results
Cardiac CNDP2 gene expression was 1.3-fold lower in end-stage HF patients compared to controls (p<0.001 adjusted for age and sex). The major alleles for two genetic variants, rs17088884 and rs7235253, were associated with higher CNDP2 expression (p<0.001). Genotype frequencies for rs8088885 differed between patients (TT=73.1%, CT=18.5%, CC=8.33%) and donors (TT=69.1%, CT=29.1%, CC=1.80%, p=0.026). Circulating CNDP2 was highest in ADHF patients (median 29.5 ng/mL) compared to acute chest pain patients (6.36 ng/mL) and controls (11.1 ng/mL) (p<0.001). ADHF patients who died within 90 days showed markedly higher circulating CNDP2 (100 ng/mL, n=12) than survivors (26.4 ng/mL, n=24) (p=0.100). Circulating CNDP2 was correlated positively with cardiac biomarkers NT-proBNP (r=0.4, p<0.001) and troponin T (r=0.3, p=0.023) in all patients.
Conclusion
CNDP2 gene expression in human heart may be modulated by common genetic variation. Circulating CNDP2 was highest in patients with ADHF and was associated with markers of HF severity and heart damage. Our findings suggest a potential role for CNDP2 and highlight the importance of lactate metabolism in HF.