Molecular Mechanisms of Right Ventricle Remodeling due to Tricuspid Regurgitation

Tricuspid regurgitation (TR) is a disorder in which the heart`s tricuspid valve does not close properly. Based on its etiology, it is divided into two subgroups:

primary TR with intrinsic disease of the tricuspid valve apparatus; and secondary TR, the result of tricuspid valve annular dilatation and/or right ventricular maladaptive remodeling, due to right ventricular (RV) pressure and/or volume overload. Secondary TR accounts for 70–85% of all cases. Because the RV tolerates volume overload well, patients are operated on at a late stage in the disease. Frequently, RV function shows very little improvement, despite successful tricuspid valve repair or replacement, leading to irreversible right ventricle dysfunction. To date, little is known about the mechanisms underlying right heart remodelling that results from TR. Our hypothesis is that RV remodeling is regulated by distinct pathways, different from those implicated in left ventricular remodeling.

The monocrotaline (MCT) rat model is a frequent model of pulmonary hypertension (PH). We ran a preliminary experiment to establish the MCT rat model and to identify the changes in gene pathway activation in our model.

Nine adult Sprague‑Dawley rats were divided into a control group (and MCT-injected group (n = 3 for both groups), PH was induced by a single intraperitoneal injection of MCT (60 mg/kg). The Control rats were injected with saline. The rats were examined by echo and then sacrificed; the right ventricles, right atrium and the tricuspid valve were isolated for RNA preparation and gene array analysis.

Bioinformatics analyses using the Gene Ontology (GO) and KEGG databases were carried out to identify the genes and pathways specifically associated with PH and TR. In our present work, complex connections among remodeling, proliferation, inflammation and extracellular remodeling pathways in the etiology of TR were revealed. The key genes, thus identified, in tricuspid valve encode Top2a (7-fold upregulated), MKi67(7-fold upregulated) involved in proliferation, in ventricle BMP10(3-fold upregulated), Pik3r5 (2.8-fold upregulated) involved in ventricle remodeling and in atrium OLR1584 (573-fold down regulated), OLR1301 (56-fold down regulated) involved in proliferation and apoptosis. These gene products are predicted to play critical roles in TR development and progression.

Echocardiography revealed moderate TR at MCT group as compared with no TR in controls.

The present study provides valuable information on targets for future research in this under-studied field. The identified molecular pathways and their influence on remodeling will be further assessed in a larger study which is underway.