Cellular and molecular basis of RV hypertrophy in congenital heart disease

Abstract

RV hypertrophy (RVH) is one of the triggers of RV failure in congenital heart disease (CHD). Therefore, improving our understanding of the cellular and molecular basis of this pathology will help in developing strategic therapeutic interventions to enhance patient benefit in the future. This review describes the potential mechanisms that underlie the transition from RVH to RV failure. In particular, it addresses structural and functional remodelling that encompass contractile dysfunction, metabolic changes, shifts in gene expression and extracellular matrix remodelling. Both ischaemic stress and reactive oxygen species production are implicated in triggering these changes and will be discussed. Finally, RV remodelling in response to various CHDs as well as the potential role of biomarkers will be addressed.

Figure 1

(A) An overview of changes associated with RV pressure overload. Key triggers of RV pressure overload include pulmonary hypertension, RV outflow tract obstruction or RV being the systemic ventricle. RV pressure overload induces RVH that, through remodelling, leads to RV failure. It is of note, however, that RV failure is a continuous process and may begin as the time of hypertrophy and remodelling rather than being seen as a sequential process. (B) Effect of RVH-induced ischaemia. RVH is characterised by tissue hypoxia arising from ischaemia and microcirculatory insufficiency. Ischaemia-derived ROS, through the activation of transcription factors, drive the metabolic remodelling, contractile dysfunction and fibrosis that occur in RV failure. RVH, RV hypertrophy; PA, pulmonary artery; ROS, reactive oxygen species; MMPs, matrix metalloproteinases.

Figure 2

ROS-induced intracellular changes in cardiomyocyte. The increased intracellular ROS levels occurring in RV pressure overload affect several cardiomyocytes functions. ROS can stimulate pro-hypertrophic pathways by targeting key molecules in this process, such as MAPK, PKC and Src proteins. The redox-mediated activation of target transcription factors (HIF-1α, cMyc and FOXO1) might be responsible for the abnormal PKD activation, which inhibits mitochondrial oxidative metabolism, leading to mitochondrial dysfunction. Sustained ROS levels cause mPTP opening and mitochondrial membrane depolarisation. As a consequence, more ROS are produced and cytochrome c is release from mitochondria causing cell apoptosis. HIF-1α activation also decreases the activity of the O₂-sensitive Kv channel (Kv1.5), resulting into membrane depolarisation and elevation of cytosolic Ca²⁺. The surplus of cytosolic Ca²⁺, in addition to the excessive Ca²⁺ released from the sarcoplasmic reticulum, as a consequence ROS-mediated RyR2 channel activation and SERCA inhibition, contributes to myocytes contractile dysfunction. ROS are also responsible for the MMPs/TIMPs imbalance that drives ECM remodelling and fibrosis. Antioxidant compounds, like Folic acid or EUK-134, by scavenging the ROS in excess, can help restore the impaired cardiomyocyte function. Furthermore, DCA can restore ROS production and mitochondrial membrane potential by inhibiting PDK and thereby improving glucose oxidation. ↑ indicates increase in levels; ↓ indicates decrease in level. ROS, reactive oxygen species; PCK, protein kinase C; MAPK, mitogen-activated protein kinase; mPTP, mitochondrial permeability transition pore; PDK, pyruvate dehydrogenase kinase; HIF, hypoxia-inducible factor; FOXO1, Forkhead box protein O1; cMyc, v-myc avin myelocytomastosis viral oncogene homologue; RyR2, ryanodine receptor 2; Kv 1.5, potassium voltage channel; SR, sarcoplasmic reticulum; SERCA, sarcoplasmic reticulum Ca²⁺-ATPase; MMP, matrix metalloproteinases; TIMP, tissue inhibitor metalloproteinases; ECM, extracellular matrix; DCA, dichloroacetate; PKD, protein kinase D. See text for more details.

Figure 3

Dysregulated miRNAs in congenital heart diseases (CHDs). A figure showing the link between CHD and miRNAs in cardiomyocytes. Small number of miRNAs are upregulated in cardiomyocyte during CHD. These miRNAs can be released from the cell in microvesicles, by incorporation into exosomes, by linkage to high-density lipoproteins or bound to RNA-binding proteins. Dysregulated levels of miRNAs, crucial in RV development, are found in the bloodstream of children with VSD. The differentially expressed has-miR-222-3p, has-let-7e-5p and has-miR-433 bind with specific transcription factors (NOTCH1, GATA4, HAND1 and ZFPM) associated with RV morphogenesis. See text for more details.