Large animal models of heart failure: a critical link in the translation of basic science to clinical practice

Abstract

Congestive heart failure (HF) is a clinical syndrome, with hallmarks of fatigue and dyspnea, that continues to be highly prevalent and morbid. Because of the growing burden of HF as the population ages, the need to develop new pharmacological treatments and therapeutic interventions is of paramount importance. Common pathophysiologic features of HF include changes in left ventricle structure, function, and neurohormonal activation. The recapitulation of the HF phenotype in large animal models can allow for the translation of basic science discoveries into clinical therapies. Models of myocardial infarction/ischemia, ischemic cardiomyopathy, ventricular pressure and volume overload, and pacing-induced dilated cardiomyopathy have been created in dogs, pigs, and sheep for the investigation of HF and potential therapies. Large animal models recapitulating the clinical HF phenotype and translating basic science to clinical applications have successfully traveled the journey from bench to bedside. Undoubtedly, large animal models of HF will continue to play a crucial role in the elucidation of biological pathways involved in HF and the development and refinement of HF therapies.

Figure 1

Top: changes in regional myocardial geometry after induction of MI in pigs by selective coronary ligation performed using radio-opaque markers placed within the MI region. Bottom: rate of change in regional MI size up to 8 weeks post-MI computed relative to week 2 values. Rapid acceleration of infarct expansion was quantified in this model. Reproduced from reference #16.

Figure 2

Sheep MI Model: (A) Sheep heart as exposed through a left thoracotomy. (B) The LV is measured from apex to base. The left anterior descending (LAD) coronary artery and any of its diagonal branches that pass below an imaginary line drawn parallel to the base of the heart at a level 40% of the distance from apex to base are ligated. (C) The anteroapical ischemic zone is immediately apparent. The resulting infarct typically involves 21–24% of the LV mass and leads to progressive LV dilatation and loss of global function. (D) A photograph of a sheep anteroapical infarct 1 hour after coronary ligation. Courtesy of R.C. Gorman, M.D., Cardiothoracic Surgery, University of Pennsylvania.

Figure 3

Left: Shaded surface display of RV and LV of endo- and epicardial surfaces at end-diastole in a dog before (normal, top left) and after mitral regurgitation (bottom left) using magnetic resonance imaging in the dog. Note the nonuniform dilatation of the LV cavity and the reduction in volume of the RV as well as expansion of the LV into the RV cavity. Adapted from reference #28. Right: End-diastolic volume calculated angiographically is shown at base line (B), at acute mitral regurgitation (AMR), and after mitral regurgitation had been present for 3 months (MR3) in canines. End-diastolic volume was significantly increased at 3 months in comparison with base line and acute mitral regurgitation. Reproduced from reference #26. Figures used with permission from American Journal of Physiology.

Figure 4

Serial changes in plasma norepinephrine, atrial natriuertic factor (ANF), and cGMP in control dogs (▼), dogs with long-term rapid pacing (▲), and dogs with long-term pacing and concomitant ACE inhibition (•). Top: In pacing groups, norepinephrine significantly increased from baseline values after 1 week and appeared to plateau with long-term tachycardia. Plasma norepinephrine was significantly lower with ACE inhibition compared to pacing only group. Middle: ANF levels were significantly increased after 1 week of rapid pacing, remaining elevated through the 4 week protocol. Bottom: ACE inhibition was found to attenuate cGMP elevation with long-term rapid pacing. Reproduced from reference #43.