Distinct Phenotypes Induced by Three Degrees of Transverse Aortic Constriction in Mice

Abstract

Introduction Experimental models of left ventricular (LV) remodeling provide important preclinical methods for identifying novel therapeutic targets and evaluating experimental therapies for heart failure. Transverse aortic constriction (TAC) is a well-established model of pressure overload-induced cardiac hypertrophy and failure in mice. The degree of constriction “tightness” dictates the TAC severity and is determined by the gauge (G) of needle used. Though many reports use the TAC model, few studies have directly compared the range of resulting phenotypes. Hypothesis We hypothesize that different gauges of TAC will induce distinct phenotypes, which may be suitable for use in different preclinical studies. Methods Mice were randomized to receive TAC surgery with varying degrees of tightness: mild (25G), moderate (26G) or severe (27G) for 4 weeks, alongside sham-operated controls. Weekly echocardiography and terminal hemodynamic analysis determined cardiac remodeling and functional changes. Results All TAC models induced significant, severity-dependent trans-TAC pressure gradients, LV hypertrophy and diastolic dysfunction compared to sham mice. Mice subjected to 26G TAC additionally exhibited cardiac fibrosis and mild systolic dysfunction, in terms of left ventricular strain rate and preload-recruitable stroke work, whereas mice in the 27G TAC group had even more severe cardiac fibrosis, global systolic and diastolic dysfunction in terms of ejection fraction and LV filling indices, and were more likely to display features of heart failure, such as elevated plasma BNP (903.6±59.2 pmol/mL in 27G TAC vs. 676.0±33.8 pmol/mL in 26G TAC; P Conclusions 25G, 26G and 27G TAC produced different responses in terms of cardiac structure and function. 25G TAC led to a mild hypertrophic phenotype characterized by diastolic dysfunction, similar to hypertensive heart disease. 26G TAC led to a moderate hypertrophic phenotype with mixed systolic and diastolic dysfunction, comparable to early decompensation. Lastly, 27G TAC led to a severe hypertrophic phenotype with severely reduced systolic function, similar to clinical heart failure with reduced ejection fraction. These distinct phenotypes may be applicable to specific preclinical settings.