Multiscale Contrasts Between the Right and Left Ventricle Biomechanics in Healthy Adult Sheep and Translational Implications.

Cardiac biomechanics play a significant role in the progression of structural heart diseases (SHDs). SHDs alter baseline myocardial biomechanics leading to single or bi-ventricular dysfunction. But therapies for left ventricle (LV) failure patients do not always work well for right ventricle (RV) failure patients. This is partly because the basic knowledge of baseline contrasts between the RV and LV biomechanics remains elusive with limited discrepant findings. The aim of the study was to investigate the multiscale contrasts between LV and RV biomechanics in large animal species. We hypothesize that the adult healthy LV and RV have distinct passive anisotropic biomechanical properties. Ex vivo biaxial tests were performed in fresh sheep hearts. Histology and immunohistochemistry were performed to measure tissue collagen. The experimental data were then fitted to a Fung type model and a structurally informed model, separately. We found that the LV was stiffer in the longitudinal (outflow tract) than circumferential direction, whereas the RV showed the opposite anisotropic behavior. The anisotropic parameter K from the Fung type model accurately captured contrasting anisotropic behaviors in the LV and RV. When comparing the elasticity in the same direction, the LV was stiffer than the RV longitudinally and the RV was stiffer than the LV circumferentially, suggesting different filling patterns of these ventricles during diastole. Results from the structurally informed model suggest potentially stiffer collagen fibers in the LV than RV, demanding further investigation. Finally, type III collagen content was correlated with the low-strain elastic moduli in both ventricles. In summary, our findings provide fundamental biomechanical differences between the chambers. These results provide valuable insights for guiding cardiac tissue engineering and regenerative studies to implement chamber-specific matrix mechanics, which is particularly critical for identifying biomechanical mechanisms of diseases or mechanical regulation of therapeutic responses. In addition, our results serve as a benchmark for image-based inverse modeling technologies to non-invasively estimate myocardial properties in the RV and LV.

Panobinostat Plus Bortezomib Versus Lenalidomide in Patients with Relapsed and/or Refractory Multiple Myeloma: A Matching-Adjusted Indirect Treatment Comparison of Survival Outcomes using Patient-level Data.

BACKGROUND: In the UK, the standard of care for patients with multiple myeloma who received ≥2 prior treatments is lenalidomide plus dexamethasone (LEN + DEX) and pomalidomide plus DEX (POM + DEX) (in Wales only). Recently, panobinostat plus bortezomib and DEX (PAN + BTZ + DEX) was licensed in this setting. The current study assessed the progression-free survival (PFS) and overall survival (OS) outcomes with PAN + BTZ + DEX versus LEN + DEX (primary comparator) and POM + DEX (exploratory comparator). METHODS: Since an anchor-based indirect treatment comparison was not feasible, the matching-adjusted indirect treatment comparison approach was used. To compare the survival outcomes, patient-level data were generated for the comparators utilizing published Kaplan-Meier survival estimates. The use of approximated patient-level data and matched data for PAN + BTZ + DEX allowed the use of Cox proportional hazards models and the assessment of the proportional hazards assumption. In cases where there was evidence that the proportional hazards assumption was violated, time-dependent hazard ratios (HRs) were estimated. Median and mean values for PFS and OS were predicted. RESULTS: For both PFS and OS, the proportional hazards assumption was not satisfied, therefore time-dependent HRs were estimated. Using time-dependent HRs, the mean PFS was estimated to be 11.83 months for PAN + BTZ + DEX and 10.96 months for LEN + DEX. The corresponding mean OS estimates were 30.73 and 27.76 months, respectively. Comparisons with POM + DEX were affected by large uncertainty and did not allow making robust inferences. CONCLUSIONS: To our knowledge, this is the first study that combined matching-adjusted indirect treatment comparison with time-dependent HRs to address changing patterns in the HR. The results suggest that treatment with PAN + BTZ + DEX and LEN + DEX are associated with similar mean PFS and OS in the third-line treatment setting of multiple myeloma.