Anne-Marie Koop

7 271 response to the sudden cardiac stress. As previously observed by us, 19 one would expect that correcting the expression levels of Hand2, which is elevated in disease, would reduce maladaptation and confer protection. Nevertheless, a loss of functionmutation in the Hand2 gene results in increased RV volumes at both end-diastole and end-systole, as well as decreased ejection fraction and cardiac output in mice subjected to RV pressure overload, compared to controls, indicating an inability of the RV to adapt to pressure overload. Impaired cardiac function was associated with increased hypertrophic growth of the RV, reflected by increased heart weight to bodyweight ratios, increased Fulton index as well as elevated cardiomyocyte CSA. While collagen deposition reached similar levels in both control and Hand2 -knockout mice subjected to RV stress, absence of Hand2 inhibits expression of fibrosis-related genes markers early in the disease process. TGF β signaling is involved in tissue repair and scar formation 28 and not only it is an important regulator of vascular remodelling and inflammation of the lung 29 and kidney, 30 it also regulates hypertrophy and fibrosis in the heart. 31-33 While endoglin is an established regulator of vascular remodelling, 34,35 it also plays a critical role in the development of fibrosis by serving as a coreceptor for TGFb signaling. 36,37 Their expression profiles confirm the similar collagen deposition observed in the banded animals, independently of the genotype and the fact that the Hand2 knockout hearts display more severe hypertrophic phenotypes. These results, together with the observed increase in some of the hypertrophic gene markers, strongly suggest that absence of Hand2 expression, under pressure overload of the RV, drives cardiac remodelling towards a more hypertrophic phenotype, without exaggerated fibrosis. Nevertheless, such a phenotype is characterized by a stronger impairment of cardiac function as reflected by the altered functional parameters measured by MRI. Due to the pericardium and the common ventricular septum (ventricular interdependence), alterations in loading conditions of the RV are known to influence septal reconfiguration and motion towards the LV 38,39 and, in this way, affect left ventricular performance by altering the LV pressure-volume curve. 40,41 Assessing the eccentricity index of the LV shape reflects the abnormal motion of the intraventricular septum depending on the type of right ventricular overload, whether systolic or diastolic. 42 In our study, animals that were subjected to PAB revealed an index significantly greater than 1.0 at both systole and diastole which confirms right pressure overload 42 and subsequent abnormal leftward septal motion and configuration. But was the LV affected? In control mice, RV pressure overload did affect the LV as cardiomyocyte hypertrophy and mRNA expression of hypertrophic markers and pro-fibrotic genes were increased. In the absence of Hand2 expression, the hypertrophic response was lost, with decreased cardiomyocyte CSA and associated gene expression. Whereas these results indicate some degree of