Left ventricular mass regression following implantation of MIRA bileaflet valves in patients with severe aortic stenosis

The aim of this study was to evaluate the factors that determine the course of left ventricular mass regression in a homogeneous group of patients following aortic valve replacement by use of the mechanical Edwards MIRA bileaflet prosthesis. Furthermore, we examined if the 19-mm valve leads to an equally good outcome when compared with larger 21- and 23-mm valves. We included 79 patients (49 men) with a mean age of 65 ± 9 years operated on for isolated aortic valve replacement with the MIRA valve prosthesis. The analyses included preoperative and postoperative echocardiograms during a follow-up of at least 18 months (995 ± 439 days) after valve surgery. Indication for valve replacement was aortic stenosis in 59 and combined disease (aortic stenosis and regurgitation) in 20 patients. Concomitant coronary artery bypass grafting was performed in 28 patients. Left ventricular mass index declined from 155.6 ± 47 g/m² to 128.8 ± 35 g/m² (P < 0.001) at final visit and normalized in 49% of the patients. Female sex and a preoperatively highly elevated left ventricular mass index were identified as risk factors for residual hypertrophy. However, age and valve size did not have a predictive value for completeness of left ventricular mass regression. This study supports the evidence that an extensive preoperative left ventricular hypertrophy results in an incomplete postoperative mass regression in patients with aortic bileaflet valves. It shows that the slightly elevated pressure gradient in MIRA 19-mm valves does not affect left ventricular mass regression.     

Small molecule MIRA-1 induces in vitro and in vivo anti-myeloma activity and synergizes with current anti-myeloma agents

Background:

Small molecule MIRA-1 induced mutant p53-dependent apoptosis in several types of solid tumours. However, anti-tumour activity of MIRA-1 in haematological malignancies including multiple myeloma (MM) is unknown. In this study, we evaluated the effect of MIRA-1 in MM.

Methods:

We examined the anti-tumour activity of MIRA-1 alone or in combination with current anti-myeloma agents in a panel of MM cell lines, primary MM samples, and in a mouse xenograft model of MM.

Results:

MIRA-1 treatment resulted in the inhibition of viability, colony formation, and migration and increase in apoptosis of MM cells irrespective of p53 status accompanied by upregulation of Puma and Bax and downregulation of Mcl-1 and c-Myc. Genetic knockdown of p53 did not abrogate apoptotic response of MIRA-1. MIRA-1 triggered activation of PERK and IRE-α leading to splicing of XBP1 indicating an association of endoplasmic reticulum stress response. Furthermore, combined treatment of MIRA-1 with dexamethasone, doxorubicin or velcade displayed synergistic response in MM cells. Importantly, MIRA-1 alone or in combination with dexamethasone retarded tumour growth and prolonged survival without showing any untoward toxicity in the mice bearing MM tumour.

Conclusions:

Our data provide the preclinical framework for clinical evaluation of MIRA-1 as a novel therapeutic agent to improve patient outcome in MM.