Anne-Marie Koop

312 The effect of interventricular interdependence on LV molecular mechanisms As has been recognized since the early twentieth century, the LV and RV are inextricably linked by the various mechanisms as part of ventricular interdependence. Both systolic and diastolic function of the ventricles are affected by the other ventricle. 57-59 Not only the presence of asynchronicity or regional inhomogeneity will influence cardiac output, 60,61 but also the interplay of end systolic and diastolic volumes with the end systolic and diastolic pressures in both ventricles will affect cardiac elastance. 62,63 Furthermore, LV atrophy has been described as result of reduced RV stroke volume in conditions of RV pressure overload. 64 In the presence of these hemodynamic and morphologic findings, it is not surprising that underlying LV molecular mechanisms are affected by RV pressure overload as well. In chapter 6 we found that in the LV the calcineurin- NFAT signaling was affected in conditions of RV pressure overload. In addition, the miR-199b-Dyrk1a feedback loop seemed identical to what has previously been found in the pressure loaded LV. 51 Also chapter 7 demonstrates activation of molecular mechanisms of LV remodelling. Again, the reaction of Hand2 on calcineurin-NFAT signaling in the LV exposed to conditions of RV pressure load is comparable to changes in the LV in conditions of LV pressure load. These findings address that the activation of pathologic remodelling of the LV already occurs in early stages of RV disease. This contributes to the relevance for early interventions in patients with a pressure overloaded RV. Models of right ventricular pressure load To measure the effect of increased pressure load on the RV, several models have been used. These models include models of pulmonary arterial hypertension in rats subjected to hypoxia 30,32,37,65,66 , SUGEN and hypoxia 26,26,33,67 or monocrotoline 34-36, 38, 40, 68-71 , and fawn hooded rats 39 . Other models concern rats or (transgenic) mice subjected to increased fixed afterload by PAB. 28, 33, 35, 72-75 However, the stimulus used to induce increased RV pressure will have substantial effects on the etiology and severity of disease. The differences between the models are driven by the level of endothelial damage, inflammation, cytokine migration, and vasoconstriction. 76 In the current thesis, we choose to specifically characterize models of PAB. This model represents a condition of fixed afterload, including both compensated RVdysfunction and clinical RV failure. Since it concerns a mechanical stimulus, other organs will not directly be affected by the stimulus, enabling the evaluation of the net effect of increased RV pressure load. Of course different PAB-models may represent different tightness of bandings, with subsequent differences of functional status and mortality. Activationof pathologic left ventricular remodelling already occurs in early stage of RV disease.