Microembolization of the coronary arteries : an ovine model of acute myocardial infarction

Abstract

Left ventricular dysfunction due to acute myocardial infarction is a common clinical problem which often progresses to chronic heart failure. Several neuroendocrine inhibitors have been shown to attenuate this progression. Much of the original work has been done on the rat coronary ligation model. More recently, a model of coronary microembolization was developed in the dog. There is a need for an animal model which is more relevant to human disease. The sheep has a coronary circulation which is similar to humans and is of a suitable size to permit repeated haemodynamic and hormonal measurements. The purpose of this study was to develop and characterize the haemodynamic and neuroendocrine features of an ovine model of myocardial infarction and left ventricular dysfunction.

Fifteen instrumented sheep underwent selective microembolization of either the left anterior descending or left circumflex coronary artery with 0.5 ml 90 micron polystyrene beads. Haemodynamic and plasma hormones were measured pre-embolization (baseline) and then at 2, 4, 6, 12 h and 1, 2, 3, 5 and 7 days post-embolization.

Of the 15 sheep studied, 2 (13%) died on the day of embolization from arrhythmias. In the remaining sheep, left ventricular systolic pressure (nadir 83.1 ± 7.0 at 6 h vs. 103.2 ± 7.5 mmHg baseline; p<0.001) was reduced and remained below basal levels for the duration of the 7 day study period. Systolic arterial pressure decreased (nadir 66.1 ± 4.5 at 6 h vs. 78.3 ± 3.2 mmHg baseline; p<0.001), returning to basal levels by day 2. Diastolic arterial pressure (peak 63.9 ± 5.2 at 2 h vs. 52.5 ± 3.4 mmHg baseline; p<0.001) and mean arterial pressure (peak 69.6 ± 5.3 at 2 h vs. 61.1 ± 3.3 mmHg baseline; p<0.001) increased initially, then decreased to basal levels by 4 h. Cardiac output decreased (nadir 4.2 ± 0.8 at 12 h vs. 5.4 ± 0.9 L/min baseline; p<0.05) returning to basal levels by day 2. Left ventricular end-diastolic pressure tended to decline (p>0.05) during the first 6 h following embolization. Heart rate increased within 2 h of embolization (peak 111.8 ± 8.0 at 12 h vs. 69.9 ± 4 bpm baseline; p < 0.001) remaining elevated until day 5. Left atrial pressure increased (peak 6.8 ± 0.9 at 24 h vs. 4.4 ± 0.7 mmHg baseline; p<0.05), returning to basal levels by day 2. Following embolization the left ventricular ejection fraction at day 7 was reduced (38.8 ± 3.5 day 7 vs. 46.0 ± 3.9 % pre-embolization; p<0.05).

The cardiac enzymes creatine kinase (peak 1960 ± 238 at 6 h vs. 99.2 ± 12.8 units baseline; p < 0.001) and troponin-T (peak 12.0 ± 2.6 at day 2 vs. 0.03 ± 0.01 µg/L baseline; p<0.001) were both increased following microembolization and then returned to basal levels by days 2 and 5 respectively. Plasma brain natriuretic peptide (peak 11.5 ± 1.3 at 12 h vs. 3.8 ± 0.4 pmol/L baseline; p<0.001) and plasma renin activity (peak 1.31 ± 0.22 at day 3 vs. 0.56 ± 0.05 nmol/L/min baseline; p<0.005) were both increased remaining above basal levels at day 7. Plasma atrial natriuretic peptide (peak 24.9 ± 2.6 at 6 h vs. 13.6 ± 0.8 pmol/L baseline; p<0.001) increased returning to basal levels by day 1. The hypothalamic-pituitary-adrenal axis hormones corticotrophin releasing hormone (p>0.05), arginine vasopressin (p<0.001), adrenocorticotrophin (p<0.001) and cortisol (p<0.001) were all elevated following microembolization. Peak levels were obtained at 40 minutes following embolization. In conclusion, this model clearly mimics the haemodynamic, hormonal and enzymatic features of acute myocardial infarction and left ventricular dysfunction. It is a suitable model for evaluating the efficacy of therapeutic interventions in cardiovascular disease.