Mild hypothermia attenuates ischaemia/reperfusion injury: insights from serial non-invasive pressure-volume loops

Abstract

Aims: Mild hypothermia, 32-35°C, reduces infarct size in experimental studies, potentially mediating reperfusion injuries, but human trials have been ambiguous. To elucidate the cardioprotective mechanisms of mild hypothermia, we analysed cardiac performance in a porcine model of ischaemia/reperfusion, with serial cardiovascular magnetic resonance (CMR) imaging throughout 1 week using non-invasive pressure-volume (PV) loops.

Methods and results: Normothermia and Hypothermia group sessions (n = 7 + 7 pigs, non-random allocation) were imaged with Cardiovascular magnetic resonance (CMR) at baseline and subjected to 40 min of normothermic ischaemia by catheter intervention. Thereafter, the Hypothermia group was rapidly cooled (mean 34.5°C) for 5 min before reperfusion. Additional CMR sessions at 2 h, 24 h, and 7 days acquired ventricular volumes and ischaemic injuries (unblinded analysis). Stroke volume (SV: -24%; P = 0.029; Friedmans test) and ejection fraction (EF: -20%; P = 0.068) were notably reduced at 24 h in the Normothermia group compared with baseline. In contrast, the decreases were ameliorated in the Hypothermia group (SV: -6%; P = 0.77; EF: -6%; P = 0.13). Mean arterial pressure remained stable in Normothermic animals (-3%, P = 0.77) but dropped 2 h post-reperfusion in hypothermic animals (-18%, P = 0.007). Both groups experienced a decrease and partial recovery pattern for PV loop-derived variables over 1 week, but the adverse effects tended to attenuate in the Hypothermia group. Infarct sizes were 10 ± 8% in Hypothermic and 15 ± 8% in Normothermic animals (P = 0.32). Analysis of covariance at 24 h indicated that hypothermia has cardioprotective properties incremental to reducing infarct size, such as higher external power (P = 0.061) and lower arterial elastance (P = 0.015).

Conclusion: Using non-invasive PV loops by CMR, we observed that mild hypothermia at reperfusion alleviates the heart's work after ischaemia/reperfusion injuries during the first week and preserves short-term cardiac performance. This hypothesis-generating study suggests hypothermia to have cardioprotective properties, incremental to reducing infarct size. The primary cardioprotective mechanism was likely an afterload reduction acutely unloading the left ventricle.

Keywords: Acute myocardial infarction; Hypothermia; Ischaemia; Pressure–volume loops; Reperfusion injury; induced.

Graphical Abstract

Figure 1

Illustration of the study design, including the ischaemia/reperfusion protocol (A) and timing of the CMR sessions (B).

Figure 2

A typical example from the Normothermia group. The basis for the non-invasive PV loops is ventricular volumes plotted against ventricular pressure. Short-axis cine images covering the LV were delineated over the cardiac cycle (A). The resulting left ventricular volume curves at each time point (B) and the estimated intraventricular pressure curves (C) are used in conjunction to calculate the non-invasive PV loops (D). SV, stroke volume; MAP, mean arterial pressure; SW, stroke work.

Figure 3

Left ventricular volume curves ‘V(t),’ systolic and diastolic blood pressures (BP), together with an elastance model ‘E(t)’ scaled in amplitude and time, yield estimations of left intraventricular pressure curves ‘P(t)’ (A). The subsequent PV loop can be used to estimate information about cardiac energy mechanics (B), such as PE, SW, maximal elastance (E_MAX), arterial elastance (E_A), and VA coupling. Elastance is calculated as the pressure change (ΔP) over the volume change (ΔV). Panels C and D portray a typical example from each of the two groups, Normothermia and Hypothermia, at 24 h after ischaemia/reperfusion injury with larger VA decoupling in the Normothermia group compared with Hypothermia.

Figure 4

(A) The Hypothermia protocol acutely reduced the internal temperature before reperfusion in the Hypothermia group (n = 7; rightmost; blue) compared with the Normothermia group (n = 7; leftmost; red). Consequently, end-tidal CO₂ was reduced, which was not fully restored at the 2 h imaging session. (B) Box plots showing the infarct size and myocardial oedema for the Normothermia and Hypothermia groups on Day 7. (C) Typical examples of T1-weighted ex vivo images used for quantification and corresponding in vivo LGE images used for the Hypothermia and Normothermia groups. White arrows demarcate hyperintense regions indicating infarct. CE-SSFP: contrast-enhanced steady-state free precession; LVM: left ventricular mass.

Figure 5

Error bar plots showing mean ± standard error of the mean for SV, EF, CO, MAP, heart rate, end-diastolic volume (EDV), and end-systolic volume (ESV). The reductions in volumetric variables seen in the Normothermia group (n = 7) were generally ameliorated in the Hypothermia group (n = 7). MAP fell significantly in the Hypothermia group after the intervention of mild hypothermia. P-values from Friedman’s test compare results over four time points within each group.

Figure 6

Error bar plots showing mean ± standard error for SW, external power, efficiency, contractility (E_MAX), arterial elastance (E_A), and VA coupling. The adverse effects of ischaemia/reperfusion injuries on PV loop-derived variables seen in the Normothermia group (n = 7) were generally attenuated in the Hypothermia group (n = 7). P-values from Friedman’s test compare results over four time points within each group.

Figure 7

Regression analyses of the relative changes from baseline to 24 h after ischaemia/reperfusion with six PV loop-derived measurements. If the regression lines differ in slope or offset between the Hypothermia group (n = 7; bottom equation; blue) and Normothermia group (n = 7; top equation; red) that means that hypothermia itself, in addition to the infarct size, modulates the observed results. There are slight trends in external power, efficiency, E_MAX, and VA coupling. This means that the intervention of mild hypothermia offsets and attenuates the adverse effects caused by ischaemia/reperfusion. P-values by the ANCOVA tests if the relative reductions in PV loop variables between Hypothermia and Normothermia groups differ while adjusting for infarct size.