A report on the use of animal models and phenotyping methods in pulmonary hypertension research

Abstract

The failure to translate positive results from preclinical studies into new clinical therapies is a major problem throughout medical research. Specifically, in pulmonary hypertension, numerous research studies have shown beneficial effects of new therapies in experimental models, but these have largely failed to translate into clinical benefit in human trials. This is undoubtedly due, at least in part, to inadequacies of the models, but while monogenic animal models will never fully recapitulate human disease, they do still provide the best platform on which to test novel therapeutic agents. In the postgenomic era, there is emphasis on a greater understanding of disease pathogenesis, which has subsequently led to the development of both new targets and new models in which to test them. The evolution of new technologies means that we are now better equipped to phenotype these models, but the level of detail provided varies dramatically throughout the literature. However, subtle variances in experimental methods can make comparing data/findings between research laboratories difficult and are a possible contributing factor to variance between preclinical and clinical data. The aim of this report was to capture information on current practice for use of the growing array of animal models, to help movement toward developing guidelines and standards for the "best" use of animal models of pulmonary hypertension.

Keywords: animal models; phenotyping; pulmonary hypertension.

Figure 1

Percentage breakdown of countries represented in the poll (A), in comparison to the breakdown of corresponding authors from the first 3 volumes of Pulmonary Circulation (B).

Figure 2

Percentage of responders who use specific models routinely in the laboratory for target identification or basic studies on disease process. Hx: hypoxia; Mct: monocrotaline; SuHx: Sugen5416 + hypoxia; PAB: pulmonary artery banding; schisto: schistosomiasis; Tg: transgenic; FH Rat: fawn-hooded rat; ApoE: apolipoprotein E; Pyrol: pyrrole.

Figure 3

Models used to identify novel targets or study basic disease mechanisms: A, percentage breakdown of responders by the number of different models used; B, percentage breakdown of models where only 1 model is used. Hx: hypoxia; Mct: monocrotaline; tg: transgenic.

Figure 4

Models to test the efficacy of novel preclinical interventions: A, percentage breakdown of responders by the number of different models used; B, percentage breakdown of models where only 1 model is used. SuHx: Sugen5416 + hypoxia; Hx: hypoxia; schisto: schistosomiasis.

Figure 5

Percentage of poll responders who use each of the listed models in their preclinical tests. Abbreviations are as in Figure 2.

Figure 6

Percentage of responders to the poll who are blinded while doing preclinical intervention studies (A), would be willing to submit study design to a central registry (B), and would be willing to submit data to a central repository (C).

Figure 7

Percentage of responders who have access to the various equipment used to phenotype animals for pulmonary hypertension. Pressure cath: pressure catheter; PV-Cath: pressure-volume catheter; MRI: magnetic resonance imaging; CT: computed tomography; PET-CT: positron emission tomography–computed tomography; FMT: fluorescence-mediated tomography; Resp function: respiratory function.

Figure 8

Percentage breakdown of responses from poll participants as to the reason for the current large percentage of failures to translate preclinical results into clinical benefits.