Recirculating cardiac delivery of AAV2/1SERCA2a improves myocardial function in an experimental model of heart failure in large animals.

Abnormal excitation-contraction coupling is a key pathophysiologic component of heart failure (HF), and at a molecular level reduced expression of the sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA2a) is a major contributor. Previous studies in small animals have suggested that restoration of SERCA function is beneficial in HF. Despite this promise, the means by which this information might be translated into potential clinical application remains uncertain. Using a recently established cardiac-directed recirculating method of gene delivery, we administered adeno-associated virus 2 (AAV2)/1SERCA2a to sheep with pacing-induced HF. We explored the effects of differing doses of AAV2/1SERCA2a (low 1 x 10(10) d.r.p.; medium 1 x 10(12) d.r.p. and high 1 x 10(13) d.r.p.) in conjunction with an intra-coronary delivery group (2.5 x 10(13) d.r.p.). At the end of the study, haemodynamic, echocardiographic, histopathologic and molecular biologic assessments were performed. Cardiac recirculation delivery of AAV2/1SERCA2a elicited a dose-dependent improvement in cardiac performance determined by left ventricular pressure analysis, (+d P/d t(max); low dose -220+/-70, P>0.05; medium dose 125+/-53, P<0.05; high dose 287+/-104, P<0.05) and echocardiographically (fractional shortening: low dose -3+/-2, P>0.05; medium dose 1+/-2, P>0.05; high dose 6.5+/-3.9, P<0.05). In addition to favourable haemodynamic effects, brain natriuretic peptide expression was reduced consistent with reversal of the HF molecular phenotype. In contrast, direct intra-coronary infusion did not elicit any effect on ventricular function. As such, AAV2/1SERCA2a elicits favourable functional and molecular actions when delivered in a mechanically targeted manner in an experimental model of HF. These observations lay a platform for potential clinical translation.

Mitral valve replacement via a right mini-thoracotomy in the dog: use of carbon dioxide to reduce intracardiac air.

OBJECTIVE: To develop a clinically applicable method of minimally invasive mitral valve replacement (MVR) with cardioplegia, and examine the ability of carbon dioxide (CO2) to improve de-airing. METHODS: MVR was performed via a 5 x 3-cm right lateral minithoracotomy in eight greyhounds. Peripheral cardiopulmonary bypass and an ascending aortic balloon catheter (endoaortic clamp) were used for cardioplegia and aortic root venting. The endoaortic clamp was inflated in the ascending aorta under fluoroscopy and cardioplegic solution was infused. In four dogs, CO2 at 2 l/min was used to displace air in the chest. A left atriotomy was made, the valve exposed and a mechanical valve implanted. After left atrial closure, retained intracardiac gas was aspirated from the aortic root and collected in a bubble-trap. The endoclamp was deflated and the animal weaned from bypass. RESULTS: A satisfactory MVR was performed in all cases. The clamp time was 64 +/- 13 min and all dogs were stable post-bypass. In the CO2 group, intrathoracic CO2 was maintained above 86% and 0.1 +/- 0.1 ml of gas was collected, compared to 1.3 +/- 0.8 ml in the non-CO2 group (P < 0.05). CONCLUSIONS: Femoro-femoral bypass and use of the endoaortic clamp allow a safe and efficacious MVR via a right minithoracotomy in the dog. A high intrathoracic CO2 concentration reduces the amount of retained intracardiac gas.

Treatment of polypharmacy overdose with multimodality extracorporeal life support.

A 45-year-old woman presented to the emergency department of a tertiary referral hospital after taking an overdose of verapamil, doxepin, quetiapine, diazepam, temazepam, and clonazepam. She rapidly developed shock refractory to pharmacological support and was placed on percutaneous venoarterial extracorporeal membrane oxygenation (ECMO). She had a severe metabolic acidosis from a combination of shock and drug intoxication that improved with continuous venovenous haemodialysis. Forty-eight hours after presentation, while still on ECMO, the patient had complete cardiac standstill for three and a half hours, attributable to slow-release verapamil, that resolved after the commencement of plasmapheresis. The role of plasmapheresis in verapamil overdose requires further study.

Successful use of ECMO in adults with life-threatening infections.

Two cases of critically ill patients who received extracorporeal membrane oxygenation (ECMO) using different forms of circuitry and for different indications are presented. Both patients had life-threatening infections with septic shock and were not able to be supported by conventional means. The first patient had staphylococcal septicaemia and received venoarterial ECMO for circulatory failure. The second patient had psittacosis and received venovenous ECMO for respiratory failure. We discuss the expanding indications for this technology and the role it has to play in adult intensive care.