Regenerative cell therapy for pulmonary arterial hypertension in animal models: a systematic review

Abstract

Background: Pulmonary arterial hypertension (PAH) is a rare disease characterized by widespread loss of the pulmonary microcirculation and elevated pulmonary arterial pressures leading to pathological right ventricular remodeling and ultimately right heart failure. Regenerative cell therapies could potentially restore the effective lung microcirculation and provide a curative therapy for PAH. The objective of this systematic review was to compare the efficacy of regenerative cell therapies in preclinical models of PAH.

Methods: A systematic search strategy was developed and executed. We included preclinical animal studies using regenerative cell therapy in experimental models of PAH. Primary outcomes were right ventricular systolic pressure (RVSP) and mean pulmonary arterial pressure (mPAP). The secondary outcome was right ventricle/left ventricle + septum weight ratio (RV/LV+S). Pooled effect sizes were undertaken using random effects inverse variance models. Risk of bias and publication bias were assessed.

Results: The systematic search yielded 1285 studies, of which 44 met eligibility criteria. Treatment with regenerative cell therapy was associated with decreased RVSP (SMD - 2.10; 95% CI - 2.59 to - 1.60), mPAP (SMD - 2.16; 95% CI - 2.97 to - 1.35), and RV/LV+S (SMD - 1.31, 95% CI - 1.64 to - 0.97). Subgroup analysis demonstrated that cell modification resulted in greater reduction in RVSP. The effects on RVSP and mPAP remained statistically significant even after adjustment for publication bias. The majority of studies had an unclear risk of bias.

Conclusions: Preclinical studies of regenerative cell therapy demonstrated efficacy in animal models of PAH; however, future studies should consider incorporating design elements to reduce the risk of bias.

Systematic review registration: Suen CM, Zhai A, Lalu MM, Welsh C, Levac BM, Fergusson D, McIntyre L and Stewart DJ. Efficacy and safety of regenerative cell therapy for pulmonary arterial hypertension in animal models: a preclinical systematic review protocol. Syst Rev. 2016;5:89.

Trial registration: CAMARADES-NC3Rs Preclinical Systematic Review & Meta-analysis Facility (SyRF). http://syrf.org.uk/protocols/ . Syst Rev 5:89, 2016.

Keywords: Animal models of human disease; Cell therapy; Meta-analysis; Pulmonary hypertension.

Fig. 1

PRISMA flow diagram

Fig. 2

Forest plot of effect of regenerative cell therapy on RVSP in preclinical models of PAH (a). Reported in standardized mean difference and 95% confidence intervals. Subgroup analysis of RVSP and b cell enhancement, c cell type, and d timing of administration. Letters indicate two separate experiments within the same publication. Asterisk denotes cell enhancement within the same experiment, right single quotation mark indicates different cell subtype within the same experiment, and subscript number denotes a separate study/publication within the same year

Fig. 3

Forest plot of mean pulmonary arterial pressure in preclinical models of PAH. a mPAP for all studies. Subgroup analysis of mPAP by b enhancement, c cell type, and d timing of intervention. Reported in standardized mean difference and 95% confidence intervals. IV intravenous, IT intratracheal. Letters indicate two separate experiments within the same publication. Asterisk denotes cell enhancement within the same experiment

Fig. 4

Forest plot of Fulton’s index (RV/LV+S ratio). Reported in standardized mean difference and 95% confidence intervals. Letters indicate two separate experiments within the same publication

Fig. 5

Risk of bias assessment using the SYRCLE tool