Key result
Total LAD devascularization induces chronic ischemic heart failure in ~100% of models with high survival.
Why the study?
Canine ischemic cardiomyopathy models are limited by the competing needs to induce sufficient myocardial injury to cause severe LV dysfunction while minimizing early mortality.
Does Total LAD Devascularization improve survival and the attainment of chronic ischemic heart failure in a canine model compared to standard LAD ligation?
Does Total LAD Devascularization improve survival and the attainment of chronic ischemic heart failure in a canine model compared to standard LAD ligation?
The total left anterior descending devascularization technique provides a highly reproducible canine model of chronic ischemic heart failure with optimized survival.
Supports optimized canine chronic HF modeling for preclinical testing; leaves open translation to human therapies.
Background There is a paucity of novel therapeutics for chronic heart failure (HF). Preclinical large animal models of chronic HF are crucial to translating fundamental discoveries. Canine models of ischemic cardiomyopathy are frequently utilized but are severely limited by competing needs to both induce sufficient muscle injury which results in an appropriately severe degree of left ventricular dysfunction yet to also minimize early mortality. Methods Twenty-eight healthy adult dogs (30±4 kg, 15/28 male) underwent thoracotomy procedures followed by one of three types of left anterior descending (LAD) coronary artery ligations: Simple LAD (proximal and distal LAD ligation), LAD and Lateral (proximal and distal LAD, distal first diagonal, and proximal first obtuse marginal), and Total LAD Devascularization (TLD including the proximal and distal LAD, proximal aspects of the first, second, and third diagonals, and proximal aspects of first and second epicardial right ventricular branches of the LAD). Invasive and non-invasive hemodynamics were followed until attainment of chronic severe HF, which was achieved when left ventricular ejection fraction (LVEF) was <40% and N-terminal prohormone B-type Natriuretic peptide (NT-proBNP) >900 pmol/L, both for two consecutive measurements. Results Overall post-ligation early mortality (within 48 h of coronary ligation) was 18% (n=5/28), and the overall survival rate at 5 weeks post-ligation was 68% (n=19/28). At post-ligation week 1, LVEF was acutely reduced in all animals, from 54±4 to 38±1%, p<0.001. Beyond week 1, systolic function recovered over 3-4 weeks and then slowly declined as the left ventricle dilated and both systolic and diastolic function worsened. The magnitude of the initial decline in LVEF predicted ultimate HF development. Dogs with Simple LAD and LAD plus Lateral had excellent and limited survival at 48 hours (100% and 47%, respectively), yet the second group more likely developed chronic HF at 9 – 14 weeks (50% versus 57%, respectively). Dogs with TLD had both improved survival at 48 hours (90%) and excellent development of chronic HF (100%). Conclusions By focusing on the LAD only and limiting collateral flow to it by ligating all side branches, optimal survival and attainment of chronic ischemic HF can be achieved in the canine heart.
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Khan et al. (2022) studied Healthy canines (Preclinical model for chronic ischemic heart failure) (n=28). Total LAD Devascularization (TLD) vs. Simple LAD ligation or LAD and Lateral ligation was evaluated on Attainment of chronic severe heart failure (LVEF <40% and NT-proBNP >900 pmol/L for two consecutive measurements). Total left anterior descending devascularization achieved a 90% survival rate at 48 hours and a 100% success rate in developing chronic ischemic heart failure.
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