Molecular and physiological characterization of RV remodeling in a murine model of pulmonary stenosis

Abstract

physiological characterization of RV remodeling in a murine model of pulmonary stenosis. Am J Physiol Heart Circ Physiol 295: H1351-H1368, 2008. First published June 27, 2008 doi:10.1152/ajpheart.91526.2007 dysfunction is a common long-term complication in patients after the repair of congenital heart disease. Previous investigators have examined the cellular and molecular mechanisms of left ventricular (LV) remodeling, but little is known about the stressed RV. Our purpose was to provide a detailed physiological characterization of a model of RV hypertrophy and failure, including RV-LV interaction, and to compare gene alterations between afterloaded RV versus LV. Pulmonary artery constriction was performed in 86 mice. Mice with mild and moderate pulmonary stenosis (PS) developed stable hypertrophy without decompensation. Mice with severe PS developed edema, decreased RV function, and high mortality. Tissue Doppler imaging demonstrated septal dyssynchrony and deleterious RV-LV interaction in the severe PS group. Microarray analysis showed 196 genes with increased expression and 1,114 with decreased expression. Several transcripts were differentially increased in the afterloaded RV but not in the afterloaded LV, including clusterin, neuroblastoma suppression of tumorigenicity 1, Dkk3, Sfrp2, formin binding protein, annexin A7, and lysyl oxidase. We have characterized a murine model of RV hypertrophy and failure, providing a platform for studying the physiological and molecular events of RV remodeling. Although the molecular responses of the RV and LV to afterload stress are mostly concordant, there are several key differences, which may represent targets for RV failure-specific therapy. gene expression; right ventricle; tetralogy of Fallot THE RIGHT VENTRICLE IS UNIQUELY at risk in patients with complex congenital heart disease involving right-sided obstructive lesions (e.g., tetralogy of Fallot, tetralogy/pulmonary atresia) and in patients with systemic right ventricles (1,40,46). Increased stress on the right ventricle in the form of increased hemodynamic loading (pressure and/or volume) may result in abnormalities in cardiac structure, function, metabolism, coronary perfusion, neurohormonal activation, and molecular signaling. These stresses lead to both adaptive and maladaptive structural and molecular remodeling of the right ventricle and deleterious effects on the left ventricle through ventricular-ventricular interaction and may limit long-term survival (3,7,29,42). For many of these patients, detrimental conditions for the right ventricle exist throughout life, even after successful repair or palliation. As surgical techniques for the primary repair of complex forms of congenital heart disease improve, long-term survival and quality of life will depend on our ability to preserve long-term right ventricular (RV) function. Decisions regarding the ideal time for surgical reintervention will need to be based on more quantitative rather than qualitative measures.Developing a better understanding of the molecu...

Pressure-overload hypertrophy of the developing heart reveals activation of divergent gene and protein pathways in the left and right ventricular myocardium

“…In contrast in RV-PAB there was downregulation of transcripts for actin and cytoskeleton protein binding, intracellular transport, and the sarcomere and myofibril. This would agree with previous reports that have suggested that in RV hypertrophy, mitochondrial and metabolic remodeling are the predominant changes in growing animals as well as in adult hypertrophy models (1,6,27,32). The downregulation of these mechanoskeletal processes occurring in the RV but not in the LV would account for the more rapid progression to contractile failure in RV-PAB compared with LV-AOB.…”

“…Total tissue RNA was isolated and quality and purity was assessed by spectrophotometric analysis and agarose gel electrophoresis as described previously (32). Total tissue ventricular myocardial protein was isolated, and quality and purity was assessed by SDS-PAGE as described previously (23).…”

Mechanism of Pressure-Overload Right Ventricular Hypertrophy in Infant Rabbits

“…11,22) Clinically, long-term RV hypertension causes various complications in some congenital diseases such as surgically repaired tetralogy of Fallot. 5,6) The increased stress on the RV limits long-term survival. 23) As surgical techniques for the primary repair of complex forms of congenital heart disease improve, long-term survival and quality of life will depend on right ventricular function.…”

“…23) As surgical techniques for the primary repair of complex forms of congenital heart disease improve, long-term survival and quality of life will depend on right ventricular function. 6) In contrast to the many studies on LV hypertrophy, there are very few investigations related to the RV, especially in infants.…”

“…6) Although there are many studies concerning left heart failure, only a few reports have considered the mechanisms of right heart failure, especially in congenital heart disease.…”