Therapies to limit myocardial injury in animal models of myocarditis: a systematic review and meta-analysis

Abstract

Current myocarditis guidelines do not advocate treatment to prevent myocardial injury and scar deposition in patients with myocarditis and normal left ventricular ejection fraction. We aimed to ascertain the utility of beta blockers, calcium channel blockers and antagonists of the renin-angiotensin system in ameliorating myocardial injury, scar formation and calcification in animal in vivo models of myocarditis. The project was prospectively registered with the PROSPERO database of systematic reviews (CRD42018089336). Primary outcomes (necrosis, fibrosis and calcification) were meta-analysed with random-effects modelling. 52 studies were systematically reviewed. Meta-analysis was performed compared with untreated controls. In each study, we identified all independent comparisons of treatment versus control groups. The pooled weighted mean difference (WMD) indicated treatment reduced necrosis by 16.9% (71 controlled analyses, 95% CI 13.2-20.7%; P < 0.001), however there was less evidence of an effect after accounting for publication bias. Treatment led to a 12.8% reduction in fibrosis (73 controlled analyses, 95% CI 7.6-18.0%; P < 0.001). After accounting for publication bias this was attenuated to 7.8% but remained significant. Treatment reduced calcification by 4.1% (28 controlled analyses, 95% CI 0.2-8.0%; P < 0.0395). We observed significant heterogeneity in effect size in all primary endpoints, which was predominantly driven by differences between drug categories. Beta blockers and angiotensin-converting enzyme (ACE) inhibitors were the only agents that were effective for both necrosis and fibrosis, while only ACE inhibitors had a significant effect on calcification. This study provides evidence for a role for ACE inhibitors and beta blockers to prevent myocardial injury and scar deposition in in vivo models of myocarditis. There is a need for further well-designed studies to assess the translational application of these treatments.

Keywords: Calcification; Drug treatment; Fibrosis; Meta-analysis; Myocarditis; Necrosis; Remodelling; Systematic review.

Fig. 1

Flow chart of the study selection process. A systematic review yielded 347 reports. After removal of duplicates and the application of inclusion and exclusion criteria, 52 studies were included in the meta-analysis

Fig. 2

Reporting of study quality indicators. Study quality was assessed using the CAMRADES checklist (a) and SYRCLE risk of bias tool (b). Values are expressed as the percentage of studies reporting each quality indicator

Fig. 3

Summary plot of meta-analysis of drug efficacy for primary outcomes. Forest plots of the effect of eligible treatments on primary outcomes, pooled using random-effects meta-analysis. Overall, 172 controlled comparisons were included. The diamonds represent the pooled difference using a random-effects model. I² is the percentage of total variation across studies due to heterogeneity. CI Confidence interval, WMD weighted mean difference

Fig. 4

Summary plot of meta-analysis of drug efficacy for secondary outcomes. Forest plots of the effect of eligible treatments on secondary outcomes, pooled using random-effects meta-analysis. Overall, 263 controlled comparisons were included. The diamonds represent the pooled difference using a random-effects model. I² is the percentage of total variation across studies due to heterogeneity. CI Confidence interval, WMD weighted mean difference, RR relative risk