Right ventricular function evaluated by volumetric analysis during left heart bypass in a canine model of postischemic cardiac dysfunction

AbstractRight ventricular function during left heart bypass was evaluated by volumetric analysis with a conductance catheter in 12 dogs with postischemic cardiac dysfunction. The conductance catheter was used to assess the volumetric status of the right ventricle and thereby allowed a right ventricular pressure-volume curve to be obtained, in which transient volume loading on the right ventricle was applied. The following right ventricular properties during left heart bypass were assessed and compared with properties measured without left heart bypass, by means of load-independent parameters: maximum elastance, stroke work/end-diastolic volume relation, end-diastolic pressure/volume relation, and stroke work/end-diastolic pressure relation. The stroke volume derived from the conductance catheter and the electromagnetic flow probe showed good linear correlation (r2 = 0.733 to 0.975). After initiation of left heart bypass, maximum elastance did not change significantly, although volume intercept significantly increased, from 1.2 ± 7.3 to 3.6 ± 7.9 ml ( p < 0.05). End-diastolic pressure/volume relation was well fitted to the exponential curve (EDP = e (k1 · EDV+k2) ) and was shifted to the right and downward during left heart bypass; the slope k1 significantly decreased, from 0.12 ± 0.06 to 0.10 ± 0.07 ( p < 0.01). Stroke work/end-diastolic volume relation and stroke work/end-diastolic pressure relation were closely fitted to the linear regression, and their slopes were significantly increased during left heart bypass, from 0.14 ± 0.08 to 0.18 ± 0.08 ( p < 0.05) and from 0.22 ± 0.15 to 0.34 ± 0.19 ( p < 0.01), respectively. These results suggest that the decompression of the left ventricle and septal shifting by left heart bypass provide good diastolic compliance and good systolic performance because of afterload unloading of the right ventricle. Thus the left heart bypass improved the overall right ventricular performance, particularly at higher end-diastolic pressures, in dogs with postischemic cardiac dysfunction. (J THORAC CARDIOVASC SURG 1995;109:796-803

ANGPTL4 Expression Is Increased in Epicardial Adipose Tissue of Patients with Coronary Artery Disease

Epicardial adipose tissue (EAT) is known to affect atherosclerosis and coronary artery disease (CAD) pathogenesis, persistently releasing pro-inflammatory adipokines that affect the myocardium and coronary arteries. Angiopoietin-like 4 (ANGPTL4) is a protein secreted from adipose tissue and plays a critical role in the progression of atherosclerosis. Here, the expression of ANGPTL4 in EAT was investigated in CAD subjects. Thirty-four consecutive patients (13 patients with significant CAD; 21 patients without CAD) undergoing elective open-heart surgery were recruited. EAT and pericardial fluid were obtained at the time of surgery. mRNA expression and ANGPTL4 and IL-1β levels were evaluated by qRT-PCR and ELISA. The expression of ANGPTL4 (p = 0.0180) and IL-1β (p < 0.0001) in EAT significantly increased in the CAD group compared to that in the non-CAD group and positively correlated (p = 0.004). Multiple regression analysis indicated that CAD is a contributing factor for ANGPTL4 expression in EAT. IL-1β level in the pericardial fluid was significantly increased in patients with CAD (p = 0.020). Moreover, the expression of ANGPTL4 (p = 0.004) and IL-1β (p < 0.001) in EAT was significantly increased in non-obese patients with CAD. In summary, ANGPTL4 expression in EAT was increased in CAD patients

Bortezomib-cyclophosphamide-dexamethasone induction/consolidation and bortezomib maintenance for transplant-eligible newly diagnosed multiple myeloma: phase 2 multicenter trial

[Objectives:] We conducted a phase II trial to prospectively evaluate the efficacy and safety of bortezomib-cyclophosphamide-dexamethasone (VCD) induction, autologous stem cell transplantation (ASCT), VCD consolidation, and bortezomib maintenance in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients in Japan (UMIN000010542). [Methods:] From 2013 to 2016, 42 patients with a median age of 58 (range 42–65) years with NDMM were enrolled in 15 centers. The primary endpoint was the complete response (CR) /stringent CR (sCR) rate after transplantation, and overall/progression-free survival rates were also evaluated. [Results:] Following induction therapy, the overall response rate was obtained in 71% of patients, including a CR/sCR of 10% and a very good partial response (VGPR) of 26%. Twenty-six of the 42 patients completed ASCT following the protocol and CR/sCR and VGPR rate 100 days after ASCT was 26% and 17%, respectively. During consolidation therapy, 3 of the 24 patients achieved deeper responses. Eight of the 18 patients completed 2-year bortezomib maintenance without disease progression and grade 3/4 toxicities. Five patients were VGPR or partial response after ASCT but maintained response with 2-year bortezomib maintenance. Two-year overall and progression-free survival rates were 92.5% (95% confidence interval [CI]: 78.5%−97.5%) and 62.6% (95% CI: 45.8%−75.5%), respectively. Grade 3/4 toxicities (≥ 10%) included neutropenia (19%) and anemia (17%) in induction, and thrombocytopenia (29%) in consolidation. [Conclusion:] VCD induction/consolidation and bortezomib maintenance with ASCT for NDMM resulted in a high CR/sCR rate and provided good overall/progression-free survival in Japan

Modeling of Rifampicin-Induced CYP3A4 Activation Dynamics for the Prediction of Clinical Drug-Drug Interactions from In Vitro Data.

Induction of cytochrome P450 3A4 (CYP3A4) expression is often implicated in clinically relevant drug-drug interactions (DDI), as metabolism catalyzed by this enzyme is the dominant route of elimination for many drugs. Although several DDI models have been proposed, none have comprehensively considered the effects of enzyme transcription/translation dynamics on induction-based DDI. Rifampicin is a well-known CYP3A4 inducer, and is commonly used as a positive control for evaluating the CYP3A4 induction potential of test compounds. Herein, we report the compilation of in vitro induction data for CYP3A4 by rifampicin in human hepatocytes, and the transcription/translation model developed for this enzyme using an extended least squares method that can account for inherent inter-individual variability. We also developed physiologically based pharmacokinetic (PBPK) models for the CYP3A4 inducer and CYP3A4 substrates. Finally, we demonstrated that rifampicin-induced DDI can be predicted with reasonable accuracy, and that a static model can be used to simulate DDI once the blood concentration of the inducer reaches a steady state following repeated dosing. This dynamic PBPK-based DDI model was implemented on a new multi-hierarchical physiology simulation platform named PhysioDesigner