Background Right ventricular hypertrophy (RVH) and RV failure contribute to morbidity and mortality in pulmonary arterial hypertension (PAH). The cause of RV dysfunction and the feasibility of therapeutically targeting the RV are uncertain. We hypothesized that RV dysfunction and electrical remodeling in RVH result, in part, from a glycolytic-shift in the myocyte, caused by activation of pyruvate dehydrogenase kinase (PDK). Methods and Results We studied 2 complementary rat models: RVH+PAH (induced by monocrotaline) and RVH+without PAH (induced by pulmonary artery banding, PAB). Monocrotaline-RVH reduced RV O2-consumption and enhanced glycolysis. RV 2-fluoro-2-deoxy-glucose uptake, Glut-1 expression and pyruvate dehydrogenase phosphorylation increased in monocrotaline-RVH. The RV monophasic action potential duration and QTc-interval were prolonged due to decreased expression of repolarizing voltage-gated K+ channels (Kv1.5, Kv4.2). In the RV working-heart model, the PDK inhibitor, dichloroacetate, acutely increased glucose oxidation and cardiac work in monocrotaline-RVH. Chronic dichloroacetate therapy improved RV repolarization and RV function in vivo and in the RV Langendorff model. In PAB-induced RVH, a similar reduction in cardiac output and glycolytic shift occurred and it too improved with dichloroacetate. In PAB-RVH the benefit of dichloroacetate on cardiac output was ~1/3 that in monocrotaline-RVH. The larger effects in monocrotaline-RVH likely reflect dichloroacetate’s dual metabolic benefits in that model: regression of vascular disease and direct effects on the RV. Conclusion Reduction in RV function and electrical remodeling in 2 models of RVH relevant to human disease (PAH and pulmonic stenosis) result, in part, from a PDK-mediated glycolytic shift in the RV. PDK inhibition partially restores RV function and regresses RVH by restoring RV repolarization and enhancing glucose oxidation. Recognition that a PDK-mediated metabolic shift contributes to contractile and ionic dysfunction in RVH offers insight into the pathophysiology and treatment of RVH.

High-frequency echocardiography and high-field-strength magnetic resonance imaging (MRI) are new noninvasive methods for quantifying pulmonary arterial hypertension (PAH) and right ventricular (RV) hypertrophy (RVH). We compared these noninvasive methods of assessing the pulmonary circulation to the gold standard, cardiac catheterization (micromanometer-tipped catheters), in rats with monocrotaline-induced PAH and normal controls. Closed-chest, Sprague-Dawley rats were anesthetized with inhaled isoflurane (25 monocrotaline, 6 age-matched controls). Noninvasive studies used 37.5-MHz ultrasound (Vevo 770; VisualSonics) or a 9.4-T MRI (Bruker BioSpin). Catheterization used a 1.4-F micromanometer-tipped Millar catheter and a thermodilution catheter to measure cardiac output (CO). We compared noninvasive measures of pulmonary artery (PA) pressure (PAP) using PA acceleration time (PAAT) and CO, using the geometric PA flow method and RV free wall (RVFW) thickness/mass with cardiac catheterization and/or autopsy. Blinded operators performed comparisons using each method within 2 days of another. In a subset of rats with monocrotaline PAH, weekly echocardiograms, catheterization, and autopsy data assessed disease progression. Heart rate was similar during all studies (>323 beats/min). PAAT shortened, and the PA flow envelope displayed systolic "notching," reflective of downstream vascular remodeling/stiffening, within 3 wk of monocrotaline. MRI and echocardiography measures of PAAT were highly correlated (r(2) = 0.87) and were inversely proportional to invasive mean PAP (r(2) = 0.72). Mean PAP by echocardiography was estimated as 58.7 - (1.21 x PAAT). Invasive and noninvasive CO measurement correlated well (r(2) >or= 0.75). Noninvasive measures of RVFW thickness/mass correlated well with postmortem measurements. We conclude that high-resolution echocardiography and MRI accurately determine CO, PAP, and RV thickness/mass, offering similar results as high-fidelity right heart catheterization and autopsy, and that PAAT accurately estimates PAP and permits serial monitoring of experimental PAH. These tools are useful for assessment of the rodent pulmonary circulation and RVH.

Background-The underlying mechanisms that contribute to global right ventricular (RV) dysfunction in patients with repaired tetralogy of Fallot are incompletely understood. We therefore sought to quantify regional RV abnormalities and to determine the relationship of these to global RV function and exercise capacity. Methods and Results-Clinical and cardiac magnetic resonance data from 62 consecutive patients with repaired tetralogy of Fallot were analyzed (median age at follow-up 23 years [limits 9 to 67 years]). Using cardiac magnetic resonance data, 3D RV endocardial surface models were reconstructed from segmented contours, and a correspondence between end diastole and end systole was computed with a novel algorithm. Regional RV abnormalities were quantified and expressed as segmental ejection fraction, spatial extent of dyskinetic area, displacement of dyskinetic area, and score of extent of late gadolinium enhancement. Regional abnormalities of function and hyperenhancement were greatest in the RV outflow tract (RVOT).

Right ventricular (RV) dysfunction can serve as an indicator of heart and lung disease and can adversely affect the left ventricle (LV). However, normal RV function must be characterized before abnormal states can be detected. We can describe a method for reconstructing the 3D motion of the RV images by fitting of a deformable model to extracted tag and contour data from multiview tagged magnetic resonance images(MRI). The deformable model is a biventricular finite element mesh built directly from the contours. Our approach accommodates the geometrically complex RV by using the entire lengths of the tags, localized degrees of freedom (DOFs), and finite elements for geometric modeling. We convert the results of the reconstruction into potentially useful motion variables, such as strains and displacements. The fitting technique is applied to synthetic data, two normal hearts, and a heart with right ventricular hypertrophy (RVH). The results in this paper are limited to the RV free wall and septum. We find noticeable differences between the motion variables calculated for the normal volunteers and the RVH patient. AbstractRight ventricular (RV) dysfunction can serve as an indicator of heart and lung disease and can adversely affect the left ventricle (LV). However, normal RV function must be characterized before abnormal states can be detected. We describe a method for reconstructing the 3D motion of the RV images by fitting of a deformable model to extracted tag and contour data from multiview tagged magnetic resonance images (MRI). The deformable model is a biventricular finite element mesh built directly from the contours. Our approach accommodates the geometrically complex RV by using the entire lengths of the tags, localized degrees of freedom (DOFs), and finite elements for geometric modeling. We convert the results of the reconstruction into potentially useful motion variables, such as strains and displacements. The fitting technique is applied to synthetic data, two normal hearts, and a heart with right ventricular hypertrophy (RVH). The results in this paper are limited to the RV free wall and septum. We find noticeable differences between the motion variables calculated for the normal volunteers and the RVH patient.