Remote Ischemic Preconditioning Acutely Improves Coronary Microcirculatory Function

Jerrett K Lau, Probal Roy, Ashkan Javadzadegan, Abouzar Moshfegh, William F Fearon, Martin Ng, Harry Lowe, David Brieger, Leonard Kritharides, Andy S Yong, Jerrett K Lau, Probal Roy, Ashkan Javadzadegan, Abouzar Moshfegh, William F Fearon, Martin Ng, Harry Lowe, David Brieger, Leonard Kritharides, Andy S Yong

Abstract

Background Remote ischemic preconditioning (RIPC) attenuates myocardial damage during elective and primary percutaneous coronary intervention. Recent studies suggest that coronary microcirculatory function is an important determinant of clinical outcome. The aim of this study was to assess the effect of RIPC on markers of microcirculatory function. Methods and Results Patients referred for cardiac catheterization and fractional flow reserve measurement were randomized to RIPC or sham. Operators and patients were blinded to treatment allocation. Comprehensive physiological assessments were performed before and after RIPC/sham including the index of microcirculatory resistance and coronary flow reserve after intracoronary glyceryl trinitrate and during the infusion of intravenous adenosine. Thirty patients were included (87% male; mean age: 63.1±10.0 years). RIPC and sham groups were similar with respect to baseline characteristics. RIPC decreased the calculated index of microcirculatory resistance (median, before RIPC: 22.6 [interquartile range [IQR]: 17.9-25.6]; after RIPC: 17.5 [IQR: 14.5-21.3]; P=0.007) and increased coronary flow reserve (2.6±0.9 versus 3.8±1.7, P=0.001). These RIPC-mediated changes were associated with a reduction in hyperemic transit time (median: 0.33 [IQR: 0.26-0.40] versus 0.25 [IQR: 0.20-0.30]; P=0.010). RIPC resulted in a significant decrease in the calculated index of microcirculatory resistance compared with sham (relative change with treatment [mean±SD] was -18.1±24.8% versus +6.1±37.5; P=0.047) and a significant increase in coronary flow reserve (+41.2% [IQR: 20.0-61.7] versus -7.8% [IQR: -19.1 to 10.3]; P<0.001). Conclusions The index of microcirculatory resistance and coronary flow reserve are acutely improved by remote ischemic preconditioning. This raises the possibility that RIPC confers cardioprotection during percutaneous coronary intervention as a result of an improvement in coronary microcirculatory function. Clinical Trial Registration URL: www.anzctr.org.au/ . Unique identifier: CTRN12616000486426.

Keywords: coronary flow reserve; coronary physiology; microcirculation; microcirculatory resistance; remote ischemic preconditioning.

Figures

Figure 1
Figure 1
Patient recruitment and randomization. Patients were randomized to RIPC or sham treatment after coronary angiogram, and the need for FFR measurement was established. A coronary physiology study was performed before and after the allocated treatment. FFR indicates fractional flow reserve; RIPC, remote ischemic preconditioning.
Figure 2
Figure 2
Coronary physiology measurements obtained from 1 patient who was randomized to RIPC. Data were obtained before (A) and after (B) RIPC. There was a reduction in IMR and TmnH with RIPC, whereas the CFR increased. IMR=Pd×TmnH. CFR indicates coronary flow reserve; FFR, fractional flow reserve; IMR, index of microcirculatory resistance; Pa, mean proximal pressure; Pd, mean distal pressure; RIPC, remote ischemic preconditioning; TmnH, mean transit time during hyperemia.
Figure 3
Figure 3
Remote ischemic preconditioning reduces the IMR and increases the CFR through an increase in hyperemic coronary flow. There was a significant reduction in IMRcalc (A) and the IMR (B) with RIPC, whereas the CFR (C) increased significantly. There was a significant reduction in TmnH (D) with RIPC, suggesting an increase in hyperemic coronary flow. IMRcalc, CFR and TmnH: n=15; IMR: n=12; Individual filled symbols represent measurements before or after RIPC in each patient joined with a line, and open symbols and bars represent mean±SD. Bas indicates baseline; CFR, coronary flow reserve; Hyp, hyperemic; IMR, index of microcirculatory resistance; IMRcalc, calculated index of microcirculatory resistance; RIPC, remote ischemic preconditioning; TmnH, mean transit time during hyperemia.
Figure 4
Figure 4
Sham had no effect on IMR, CFR, or hyperemic coronary flow. There was no effect of sham on IMRcalc (A), IMR (B), CFR (C), or TmnH (D). IMRcalc, CFR, and TmnH: n=15; IMR: n=9. Individual filled symbols represent measurements before or after sham in each patient joined with a line, and open symbols and bars represent mean±SD. CFR indicates coronary flow reserve; IMR, index of microcirculatory resistance; IMRcalc, calculated index of microcirculatory resistance; RIPC, remote ischemic preconditioning; TmnH, mean transit time during hyperemia.
Figure 5
Figure 5
Comparison of change in markers of coronary microcirculatory function with remote ischemic preconditioning and sham. The relative change in IMRcalc (A) and CFR (B) induced by RIPC was significantly different to the change due to sham treatment. Individual filled symbols represent relative change in measurement with RIPC/sham in each patient, with negative and positive values indicative of reductions and increases with treatment, respectively. Open symbols and bars represent mean±SD. CFR indicates coronary flow reserve; IMRcalc, calculated index of microcirculatory resistance; RIPC, remote ischemic preconditioning.

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