Epigenetics, inflammation and metabolism in right heart failure associated with pulmonary hypertension

Abstract

Right ventricular failure (RVF) is the most important prognostic factor for both morbidity and mortality in pulmonary arterial hypertension (PAH), but also occurs in numerous other common diseases and conditions, including left ventricle dysfunction. RVF remains understudied compared with left ventricular failure (LVF). However, right and left ventricles have many differences at the morphological level or the embryologic origin, and respond differently to pressure overload. Therefore, knowledge from the left ventricle cannot be extrapolated to the right ventricle. Few studies have focused on the right ventricle and have permitted to increase our knowledge on the right ventricular-specific mechanisms driving decompensation. Here we review basic principles such as mechanisms accounting for right ventricle hypertrophy, dysfunction, and transition toward failure, with a focus on epigenetics, inflammatory, and metabolic processes.

Keywords: cytokines; mitochondrial switch; right ventricle hypertrophy.

Fig. 1.

Human heart development. The determination and differentiation patterns are mentioned at each concerned stage. (a) Formation of the cardiac crescent at day 15, showing the first and second heart field (also known as anterior and posterior heart field, respectively). (b) At days 18–19, endocardial tubes appear. RV progenitors are located in the anterior heart field, whereas LV progenitors are positioned in the posterior mesoderm. (c) Fusion to form the heart tube. (d) At day 21, identification of heart future regions is morphologically possible. (e) Reorientation of heart’s anterior portion (looping) along the left/right axis of the embryo. (f) The four-chamber heart is now entirely formed. LA, left atrium; LV, left ventricle; OFT, outflow tract; RA, right atrium; RV, right ventricle.

Fig. 2.

Differential miRNA expression between right ventricular hypertrophy and right ventricular failure.

Fig. 3.

MiRNAs and methylation patterns involved in right ventricular hypertrophy. Increase in miR-93 inhibits Sirt1 activity, which usually repress p53 known to induce apoptosis through the mitochondria. Mir-148 upregulation obstructs DNMT3b activity, and miR-1298 can both inhibit FAK and LAMB3 (Laminin subunit beta 3). Also, a diminution of miR-208 is responsible of Mef2c upregulation and inhibition of α-MHC expression. DNMT3b, DNA Methyltransferase 3 Beta; LAMB3, Laminin subunit beta 3; Sirt1, Sirtuin 1.

Fig. 4.

Metabolic mitochondrial switch. In right ventricular hypertrophy, the primary energy source becomes glycolysis, as opposed to the fatty acid oxidation. Some miRNAs interact with metabolism enzymes: an increase of miR-34 a can repress the activity of the LDH, miR-93 can block Mgst1 activity, and miR-28 prevent mitochondrial aldehyde dehydrogenase activity. ALDH2, mitochondrial aldehyde dehydrogenase; LDH, lactate dehydrogenase; Mgst1, microsomal glutathione S-transferase 1.