A randomized pilot trial of remote ischemic preconditioning in heart failure with reduced ejection fraction

Abstract

Background: Remote ischemic preconditioning (RIPC) induced by transient limb ischemia confers multi-organ protection and improves exercise performance in the setting of tissue hypoxia. We aimed to evaluate the effect of RIPC on exercise capacity in heart failure patients.

Methods: We performed a randomized crossover trial of RIPC (4×5-minutes limb ischemia) compared to sham control in heart failure patients undergoing exercise testing. Patients were randomly allocated to either RIPC or sham prior to exercise, then crossed over and completed the alternate intervention with repeat testing. The primary outcome was peak VO2, RIPC versus sham. A mechanistic substudy was performed using dialysate from study patient blood samples obtained after sham and RIPC. This dialysate was used to test for a protective effect of RIPC in a mouse heart Langendorff model of infarction. Mouse heart infarct size with RIPC or sham dialysate exposure was also compared with historical control data.

Results: Twenty patients completed the study. RIPC was not associated with improvements in peak VO2 (15.6+/-4.2 vs 15.3+/-4.6 mL/kg/min; p = 0.53, sham and RIPC, respectively). In our Langendorff sub-study, infarct size was similar between RIPC and sham dialysate groups from our study patients, but was smaller than expected compared to healthy controls (29.0%, 27.9% [sham, RIPC] vs 51.2% [controls]. We observed less preconditioning among the subgroup of patients with increased exercise performance following RIPC (p<0.04).

Conclusion: In this pilot study of RIPC in heart failure patients, RIPC was not associated with improvements in exercise capacity overall. However, the degree of effect of RIPC may be inversely related to the degree of baseline preconditioning. These data provide the basis for a larger randomized trial to test the potential benefits of RIPC in patients with heart failure.

Trial registration: ClinicalTrials.gov +++++NCT01128790.

Conflict of interest statement

Competing Interests: Andrew Redington is co-holder of a patent and shareholder in a company developing an automated remote preconditioning device. There was no commercial funding or other involvement for this project and an automated device was not used in this study. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Patient flow through the study.

22 patients consented to participate in the study. Two patients declined repeat testing and were excluded from the analysis; 20 patients complete the study protocol with paired testing.

Figure 2. Individual exercise test results for sham versus RIPC intervention.

Peak VO2 is shown for all study subjects undergoing exercise stress testing immediately following sham and RIPC interventions.

Figure 3. Langendorff mouse heart infarct size after perfusion with dialysate from heart failure patients versus healthy controls.

Heart failure patient dialysate, irrespective of RIPC or sham treatment, reduced infarct to the same extent as the dialysate from RIPC-treated healthy controls, as compared to sham treated healthy controls.

Figure 4. Infarct size stratified by the effect of RIPC on exercise performance.

In the Langendorff model, mean infarct size was significantly smaller after perfusion with dialysate from the subgroup of patients who had no improvement in exercise performance following RIPC treatment. Data are presented as mean +/− SD % of infarcted myocardium.