Induction of Cardiac Hypertrophy by a Controlled Reproducible Sutureless Aortocaval Shunt in the Mouse

Abstract

Much of the understanding about the pathophysiological responses to chronic cardiac overload has been gained by the use of rat and dog models of aortocaval fistula (ACF). The use of a similar model in genetically manipulated mice may further elucidate the molecular mechanisms in these responses. The only reports about ACF in mice to date have applied a needle puncture to create the ACF, which may result in an uncontrolled and irreproducible size of the shunt, and require several weeks to induce the characteristic cardiac changes. In order to obtain a more consistent approach to characterize this mode of cardiac hyperfunction, we present a surgical murine model of ACF that results in rapid progression of the typical systemic and cardiac changes. A sutureless side-to-side infrarenal surgical anastomosis of 0.6–0.8 mm in diameter was created between the abdominal aorta and inferior vena cava in ICR (Institute of Cancer Research) mice. Six to 7 days later, significant cardiac hypertrophy developed. The heart/body weight ratio increased from 0.45 ± 0.02% in control mice to 0.77 ± 0.03% in mice with ACF (p <. 003). The dry heart weight ratio increased from 0.099 ± 0.0033% to 0.13 ± 0.008% (p <. 006). The ACF dramatically induced the atrial and ventricular expression of atrial natriuretic factor mRNA, and increased the total cardiac content of endothelin-1 (162.5 ± 50.6 vs. 83.9 ± 9.0 pg). Mean arterial pressure in anesthetized mice with ACF decreased from 69.8 ± 4.9 to 54.8 ± 5.5 mm Hg (p <. 025). Urinary sodium excretion returned to preoperative levels several days following surgery. These results demonstrate that cardiac hypertrophy could be rapidly and reproducibly achieved in mice by the placement of a surgical ACF. This model, when applied in genetically manipulated mice, may be a valuable tool for functional genomic studies about the pathogenesis of cardiac hypertrophy and heart failure.

KEYWORDS:

• atrial natriuretic peptide
• cardiac hypertrophy
• endothelin
• mouse surgical arteriovenous fistula