A non-invasive method for estimating regional myocardial contractility in vivo would be of great value in the design and evaluation of new surgical and medical strategies to treat and/or prevent infarction-induced heart failure. As a first step towards developing such a method, an explicit finite element (FE) model-based formal optimization of regional myocardial contractility in a sheep with left ventricular (LV) aneurysm was performed using tagged magnetic resonance (MR) images and cardiac catheterization pressures. From the tagged MR images, 3-dimensional (3D) myocardial strains, LV volumes and geometry for the animal-specific 3D FE model of the LV were calculated, while the LV pressures provided physiological loading conditions. Active material parameters (T max_B and T max_R ) in the non-infarcted myocardium adjacent to the aneurysm (borderzone) and in myocardium remote from the aneurysm were estimated by minimizing the errors between FE model-predicted and measured systolic strains and LV volumes using the successive response surface method for optimization. The significant depression in optimized T max_B relative to T max_R was confirmed by direct ex vivo force measurements from skinned fiber preparations. The optimized values of T max_B and T max_R were not overly sensitive to the passive material parameters specified. The computation time of less than 5 hours associated with our proposed method for estimating regional myocardial contractility in vivo makes it a potentially very useful clinical tool.

Right ventricular (RV) failure is a serious common clinical problem that is poorly understood. Therefore, for failing and nonfailing hearts, we examined the distinctive inotropic responses induced in the RV myocardium after the stimulation of ␣ 1-adrenergic receptors (ARs). In RV trabeculae from nonfailing mouse hearts, ␣ 1-ARs induced a negative inotropic response, consistent with our previous study. In marked contrast, in RV trabeculae from failing hearts, 12 wk after coronary artery ligation, ␣1-ARs induced a positive inotropic response. Mechanistically, experiments with skinned trabeculae showed that ␣1-ARs decreased myofilament Ca 2ϩ sensitivity in the nonfailing RV myocardium, whereas ␣1-ARs increased Ca 2ϩ sensitivity in heart failure. This suggests that a switch in the Ca 2ϩ sensitivity response to ␣1-AR stimulation explained the switch in the RV ␣1-AR inotropic response in heart failure. Myosin light chain kinase (MLCK) can increase myofilament Ca 2ϩ sensitivity, and the smooth muscle isoform (smMLCK), which is also present in cardiomyocytes, was more abundant in the RV myocardium from failing versus nonfailing hearts. Moreover, the MLCK inhibitor ML-9 prevented the switch of the RV myocardium to a positive ␣1-AR inotropic response in heart failure. In the left ventricular myocardium, in contrast, ␣1-AR inotropic responses were not different in failing versus nonfailing hearts, and smMLCK abundance was not increased in heart failure. In relation to human disease, we found that smMLCK mRNA and protein levels were increased in RVs from failing human hearts. We conclude that the RV inotropic response to ␣1-ARs is switched from negative to positive in heart failure, through a pathway involving increased myofilament Ca 2ϩ sensitivity. Since ␣1-AR agonist catecholamines are elevated in heart failure, increased ␣1-AR inotropic responses in the RV myocardium may be adaptive in heart failure by helping the failing RV respond to increased pulmonary pressures. right ventricle; myosin light chain kinase; myofilament calcium sensitivy RIGHT VENTRICULAR (RV) failure is a prevalent cause of cardiovascular collapse and a major public health problem (14,20). RV failure frequently arises in patients with left ventricular (LV) failure and causes markedly worse symptoms and prognosis compared with patients with LV failure without RV dysfunction (9,11,13). Moreover, the prognosis of heart failure patients with pulmonary hypertension is strongly related to RV dysfunction (13).Despite its clinical significance, RV failure is relatively understudied and poorly understood (31). The RV has been viewed merely as a weak LV (14). Conversely, we (33) reported that the RV and LV have fundamentally different inotropic responses to stimulation of ␣ 1 -adrenergic receptors (ARs), which caused negative inotropic responses in the RV myocardium but positive inotropic responses in the LV myocardium. This and another study (31) have indicated that the RV and LV are categorically different and that RV failure cannot be understood by extrapola...