RNA Sequencing Analysis and Atrial Natriuretic Peptide Production in Patients with Dilated and Ischemic Cardiomyopathy

BACKGROUND: The atrium is the major site of ANP synthesis, which has been said to increase in heart failure as a result of increased production in the left ventricular (LV) myocardium. This is a key issue related to its diagnostic and prognostic capabilities. We aimed to evaluate protein levels of proANP and ANP and the enzymes that cleave the natriuretic peptides, corin and furin, in the LV tissue of heart transplant patients with dilated (DCM) and ischemic (ICM) cardiomyopathy compared with control donors (CNT). We also evaluate mRNA levels of ANP gene (NPPA) by RNA sequencing in the same tissue. METHODS AND RESULTS: Seventy-three human LV tissue samples from ICM (n = 30) and DCM (n = 33) patients and CNT (n = 10) were analyzed by Western blot and RNA sequencing. Comparing protein levels according to etiology, neither DCM nor ICM showed levels of proANP or ANP different from those of CNT. However, NPPA was increased in both groups compared to CNT (DCM 32 fold, p<0.0001; ICM 10 fold, p<0.0001). Corin (but not furin) was elevated in the ICM group compared to CNT (112±24 vs. 100±7, p<0.05), and its level was inversely related with LV ejection fraction (LVEF) (r = −0.399, p<0.05). CONCLUSIONS: Patients present with elevated levels of NPPA but not of proANP or ANP proteins in LV tissue, which may be due to posttranscripcional regulation of NPPA or different pathways for ANP secretion between the atrium and ventricle. Moreover, there are differences between DCM and ICM in corin levels, indicating that a different molecular mechanism may exist that converge in this syndrome. Further, LV concentration of corin is inversely related to LVEF in ICM.