A total closed chest sheep model of cardiogenic shock by percutaneous intracoronary ethanol injection

Abstract

To develop a reproducible and stable closed chest model of ischemic cardiogenic shock in sheep, with high survival rate and potential insight into human pathology. We established a protocol for multi-step myocardial alcoholisation of the left anterior descending coronary artery by percutaneous ethanol injection. A thorough hemodynamic assessment was obtained by invasive and non-invasive monitoring devices. Repeated blood samples were obtained to determine haemoglobin and alcohol concentration, electrolytes, blood gas parameters and cardiac troponin I. After sacrifice, tissue was excised for quantification of infarction and histology. Cardiogenic shock was characterized by a significant decrease in mean arterial pressure (− 33%), cardiac output (− 29%), dP/dt max (− 28%), carotid blood flow (− 22%), left ventricular fractional shortening (− 28%), and left ventricle end-systolic pressure-volume relationship (− 51%). Lactate and cardiac troponin I levels increased from 1.4 ± 0.2 to 4.9 ± 0.7 mmol/L (p = 0.001) and from 0.05 ± 0.02 to 14.74 ± 2.59 µg/L (p = 0.001), respectively. All haemodynamic changes were stable over a three-hour period with a 71% survival rate. The necrotic volume (n = 5) represented 24.0 ± 1.9% of total ventricular mass. No sham exhibited any variation under general anaesthesia. We described and characterized, for the first time, a stable, reproducible sheep model of cardiogenic shock obtained by percutaneous intracoronary ethanol administration. Five to 10% of patients presenting with acute myocardial infarction (AMI) develop cardiogenic shock (CS). This population has a high mortality rate (40%-50%) 1 , despite the improvement in survival due to primary reperfusion therapy, optimal pharmacological treatment, intra-aortic balloon pumping and the use of short-term mechanical circulatory support (STMCS) 1. Insights into the pathophysiology of CS remain crucial to the development of new approaches, either pharmacological or mechanical, to reduce local and systemic effects of CS, and to appraise safety and efficacy of novel procedures prior to clinical translation. In this context, large animal models may provide a heuristic methodology to test pathophysiological hypotheses and new therapeutic procedures. These models should mimic human pathology, be reproducible, allow for control of the extent of ischemia, rely on minimally invasive techniques, require short preparation time and easy animal management, lead to impaired cardiac function and be cost-effective. Several models of myocardial infarction exist and are based on coronary artery ligation, coronary artery occlusion (by angiography balloon catheter or embolization), or intra-coronary alcoholisation. However, the current large animal models are suboptimal for several reasons, e.g. high mortality

Effectiveness and Safety of a Prolonged Hemodynamic Support by the IVAC2L System in Healthy and Cardiogenic Shock Pigs

“…Second, the initial period of 48 h of support was not achieved for all healthy pigs, but it is the first description of prolonged general anesthesia in pigs (maximum 54 h in our study) and the first IVACL2L support >2 h to our knowledge (median support of 34 and 12 h in healthy and CS pigs, respectively). Third, contrary to the previous publication of MCS in CS situation, we did not use the pressure volume loop to define CS and approach hemodynamic effects of our MCS ( 19 , 20 ), but we use TTE and Swan Ganz catheter monitoring as it is used in clinical practice. Fourth, we used surgical ligation of the LAD artery to create our ischemic CS model.…”

“…Our invasive open chest model was associated with bleeding and a systemic inflammatory response syndrome that may explain the relative instability of our hemodynamic results over time. Recently, a model of total percutaneous ischemic CS has been described based on an intracoronary ethanol injection titration under the fluoroscopic guidance ( 20 , 21 ). It is possible that this model initially made it possible to visualize a more stable hemodynamic effect over time, by limiting the hypovolemia and vasoplegia secondary to bleeding.…”

The sheep as a pre-clinical model for testing intra-aortic percutaneous mechanical circulatory support devices

“…However, traditional heart failure models, such as models of ischaemia, volume- or pressure overload or rapid pacing models, are known to lack reproducibility due to high mortality rates and inconsistent manifestations of heart failure. A novel refined closed chest sheep model of cardiogenic shock recently described by Rienzo et al 37 not only attenuates the shortcomings of previously described large animal heart failure models but reducing the invasiveness of intervention over all. We are convinced that, by complementing our model with a reliable heart failure model in the future will allow us to use the adult sheep not only for device safety testing but also for pre-clinical efficacy and effectiveness studies of novel pMCS devices.…”

An innovative ovine model of severe cardiopulmonary failure supported by veno-arterial extracorporeal membrane oxygenation

“…To date, only one study by Marques and collaborators has reported the use of intramural left ventricle ethanol injections, unfortunately with limited and inconclusive description of outcomes and no use of VA-ECMO to achieve considerable levels of cardiac failure [29]. Several experimental heart failure models have been published with intracoronary ethanol injections [30,31]. However, the pathogenesis of these models is essentially distinct from an intramural injection model as the former achieves LV injury by promoting a persistent and extensive constitution of thrombi distally to the injection site, while the latter induces myocardial necrosis without intraluminal thrombi [32,33].…”