delivery-cardioactive-therapeutics-porcine-myocardial-infarction

Delivery of Cardioactive Therapeutics in a Porcine Myocardial Infarction Model

Myocardial infarction is one of the leading causes of death and disability worldwide, and there is an urgent need for novel cardioprotective or ...

The University of Sydney

Westmead hospital

We review the history of cardiac cell therapy, highlighting lessons learned from initial adult stem cell (ASC) clinical trials. We present pluripotent stem cell-derived cardiomyocytes (PSC-CMs) as a leading candidate for robust regeneration of infarcted myocardium but identify several issues that must be addressed before successful clinical translation.

Robust Cardiac Regeneration: Fulfilling the Promise of Cardiac Cell Therapy.

In the last decade, interest in gene therapy as a therapeutic technology has increased, largely driven by an exciting yet modest number of successful applications for monogenic diseases. Setbacks in the use of gene therapy for cardiac disease have motivated efforts to develop vectors with enhanced tropism for the heart and more efficient delivery methods. Although monogenic diseases are the logical target, cardiac arrhythmias represent a group of conditions amenable to gene therapy because of focal targets (biological pacemakers, nodal conduction, or stem cell-related arrhythmias) or bystander effects on cells not directly transduced because of electrical coupling.

Gene and Cell Therapy for Cardiac Arrhythmias.

A 52-year-old man presented with palpitations and dyspnea. Extensive bilateral pulmonary emboli (PEs) were identified on computed tomography pulmonary angiogram. Transthoracic echocardiography demonstrated a mobile bi-atrial thrombus straddling the interatrial septum. Consensus decision of a multidisciplinary pulmonary embolus response team was made for emergency thrombectomy of the pulmonary and intra-cardiac clot. Intraoperatively, a patent foramen ovale was identified and repaired. He had an excellent outcome and was discharged home on oral anticoagulation. In this unique case of a bi-atrial thrombus and sub-massive PEs, we demonstrate the utility of dedicated pulmonary embolus response teams in providing rapid and individualized management decisions for complex PE patients.

"PERT-inent" Management: The Role of the Pulmonary Embolus Response Team in Managing Paradoxical Embolus in Transit.

Breath-held (BH) cardiac magnetic resonance imaging (CMR) is the gold standard for volumetric quantification. However, large animals for pre-clinical research are unable to voluntarily breath-hold, necessitating general anaesthesia and mechanical ventilation, increasing research costs and affecting cardiovascular physiology. Conducting CMR in lightly sedated, free-breathing (FB) animal subjects is an alternative strategy which can overcome these constraints, however, may result in poorer image quality due to breathing motion artefact. We sought to assess the reproducibility of CMR metrics between FB and BH CMR in a porcine model of ischaemic cardiomyopathy. FB or BH CMR was performed in 38 porcine subjects following percutaneous induction of myocardial infarction. Analysis was performed by two independent, blinded observers according to standard reporting guidelines. Subjective and objective image quality was significantly improved in the BH cohort (image quality score: 3.9/5 vs. 2.4/5; p < 0.0001 and myocardium:blood pool intensity ratio: 2.6-3.3 vs. 1.9-2.3; p < 0.001), along with scan acquisition time (4 min 06 s ± 1 min 55 s vs. 8 min 53 s ± 2 min 39 s; p < 0.000). Intra- and inter-observer reproducibility of volumetric analysis was substantially improved in BH scans (correlation coefficients: 0.94-0.99 vs. 0.76-0.91; coefficients of variation: < 5% in BH and > 5% in FB; Bland-Altman limits of agreement: < 10 in BH and > 10 in FB). Interstudy variation between approaches was used to calculate sample sizes, with BH CMR resulting in greater than 85% reduction in animal numbers required to show clinically significant treatment effects. In summary, BH porcine CMR produces superior image quality, shorter scan acquisition, greater reproducibility, and requires smaller sample sizes for pre-clinical trials as compared to FB acquisition.

Comparative assessment of motion averaged free-breathing or breath-held cardiac magnetic resonance imaging protocols in a porcine myocardial infarction model.

Exciting pre-clinical data presents pluripotent stem cell-derived cardiomyocytes (PSC-CM) as a novel therapeutic prospect following myocardial infarction, and worldwide clinical trials are imminent. However, despite notable advances, several challenges remain. Here, we review PSC-CM pre-clinical studies, identifying key translational hurdles. We further discuss cell production and characterization strategies, identifying markers that may help generate cells which overcome these barriers.

Dinesh Selvakumar

Centre for Heart Research,
The Westmead Institute for Medical Research,
Centre for Heart Research, The Westmead Institute for Medical Research

The University of Sydney

Delivery of Cardioactive Therapeutics in a Porcine Myocardial Infarction Model

Dinesh Selvakumar

Centre for Heart Research,The Westmead Institute for Medical Research,Centre for Heart Research, The Westmead Institute for Medical Research

The University of Sydney

Delivery of Cardioactive Therapeutics in a Porcine Myocardial Infarction Model

Centre for Heart Research,
The Westmead Institute for Medical Research,
Centre for Heart Research, The Westmead Institute for Medical Research