Large animal models of right heart failure due to pulmonary hypertension: a bridge to translational success

Right heart failure drives morbidity and mortality in pulmonary arterial hypertension (PAH). At present, there are no chronic pharmaceutical interventions that directly augment right heart function in humans despite many promising results in rodent studies. The lack of translational success may be due to the relative scarcity of studies examining large animal models of right heart failure. However, in recent years, a rapid expansion of large animal investigations worldwide is generating new important physiological and mechanistic data. Large animal models provide more human-relevant biology, which can be paired with physiological assessments and multi-omic profiling to expand our knowledge of right heart failure. Here, we highlight findings obtained from pigs, sheep, cows and dogs, and define some potential limitations of each large animal model. In addition, we outline important questions that could be addressed in future research. Although imperfect, large animals will likely serve important roles in the development of right heart-directed therapies ranging from mechanical interventions to pharmaceutical approaches as they move up the translational pipeline. Hopefully, the field will continue these critical lines of research to promote the discovery of novel therapeutics for our patients who are in desperate need of new options.