2218
Cardioprotective Effects of Mild Therapeutic Hypothermia in Hemorrhagic Myocardial Infarctions: Early Findings in a Swine Model of Acute Reperfused Myocardial Infarction1Cedars Sinai, Los Angeles, CA, United States, 2UCLA, Los Angeles, CA, United States, 3Northern Ontario School of Medicine, Thunder Bay, ON, Canada
Synopsis
Patients who experience hemorrhagic myocardial infarctions (hMIs) have increased risk of adverse outcomes, yet a protective therapy remains to be developed. We hypothesized that mild hypothermia to the heart can reduce the effects of hemorrhage and improve left ventricular functional recovery in the setting of reperfused infarctions. This was studied using a swine model of hemorrhagic infarction exposed to cooled pericardial saline infusion to confer hypothermia. Results show a significant decrease in hemorrhagic remnants and increase in LVEF for the hypothermia group relative to controls at 1 month post-MI. Therapeutic cooling has the potential to offer cardioprotective benefits for hMI.
Introduction
There is increasing evidence that patients experiencing hemorrhagic myocardial infarctions (hMIs) have significantly worse prognoses than those experiencing non-hMIs. Yet, it remains unknown whether there is a causal relationship between hemorrhage and the observed adverse outcomes and if so, whether the effects of hemorrhage in reperfused infarction can be mitigated. Given that therapeutic hypothermia has been shown to be effective in the brain, we hypothesized that localized mild hypothermia to the heart can reduce the effects of hemorrhage and improve left ventricular functional recovery in the setting of reperfused infarctions. We tested this in a swine model of hMI by imposing mild hypothermia and evaluating the tissue specific and functional changes using serial CMR with appropriate controls.Methods
Swine (n=6) underwent balloon occlusion of left anterior descending coronary artery for 90 minutes of ischemia followed by reperfusion. A catheter was inserted into the pericardial space and verified to circumnavigate the heart via fluorescence imaging. Thirty minutes post-reperfusion, the catheter was infused with either normal saline (room temperature, control group) or refrigerated saline (8°C, experimental group) for 60 minutes. Animals were then recovered and followed-up with cardiac MRI at 3-5 days post-ischemia and again at 1 month. Cardiac MRI exams were performed in anesthetized animals, where breath-held cine (balanced SSFP, 1.4mm x 1.4mm x 6mm, TR/TE=3.22/1.61ms, flip angle=40°), T2* (multi-gradient echo, 1.6mm x 1.6mm x 6mm, TR=84ms, 8 echoes (TE=1.4ms-10ms), flip angle=12°) and LGE (1.3mm x 1.3mm x 6mm, TE=1.45ms, flip angle=20°) images were acquired in full short-axis stacks covering the left ventricle in a whole-body 3.0T MRI system (Verio, Siemens Healthineers). Presence and extent of hemorrhage and its remnants were identified based on T2* and LGE images. Left-ventricular ejection fraction (LVEF) was calculated from cine datasets. All data analysis was completed using CVI42.Results
Both the experimental group and control group showed significant infarction and hemorrhage on day 3 post-MI. Results from representative animals are shown in Fig. 1. In the experimental group (cardiac hypothermia), the remnants of hemorrhage decreased by 85.5% ± 0.4% between 3 and 30 days post-MI compared to a reduction of 47.3% ± 12.0% in the control group (normothermia). In addition, in the animals subjected to hypothermia, LVEF increased by 22.8% ± 1.4% between days 3 and 30 post-MI, compared to nearly no change (0.6% ± 8.8%) in LVEF in the control group receiving normothermia. This is shown in Fig. 2.Discussion
While therapeutic hypothermia has been investigated in reperfused acute myocardial infarction with inconclusive findings, previous studies have not specifically targeted hemorrhagic myocardial infarction, which has an incidence of approximately 50% in reperfused MIs. In this study, using T2* MRI (a validated approach for detecting intramyocardial hemorrhage) to confirm the hemorrhage status following reperfusion of epicardial coronary artery, we show that in the first month post-MI, mild hypothermia can reduce hemorrhagic remnants and significantly improve functional recovery in hMI. Additional follow-up studies are underway to test whether this finding holds in a larger sample size and to determine whether further improvement in functional recovery is attainable at future timepoints (i.e., at > 1 month). Notably, this study also provides the basis for future investigations utilizing therapeutic hypothermia to target functional recovery in subjects with hMI.Conclusion
Hemorrhagic infarction has been associated with adverse remodeling, which is a key driver of post-infarction heart failure. Thus, therapies to mitigate the potential deleterious effects of hemorrhage can be highly beneficial in patients experiencing hMI. Our early findings here illuminate an important step towards that end. While further studies are required to uncover the physiological mechanisms behind the cardioprotective effect of mild hypothermia, our results show promise in defining a new treatment option for hMI patients and establishing a causal connection between hemorrhage and functional recovery of the heart. If the results hold in a larger cohort of animals, it would pave the way for clinical translational studies aimed at improving functional recovery in hMI patients.Acknowledgements
No acknowledgement found.References
1. Andresen, Max et al. “Therapeutic Hypothermia for Acute Brain Injuries.” Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine23 (2015): 42. PMC. Web. 18 Sept. 2018.
2. Kali A, et al. Chronic manifestation of post-reperfusion intramyocardial hemorrhage as regional iron deposition: a cardiovascular MR study withex-vivo validation. Circulation: Cardiovascular Imaging 2013; 6(2):218-28.
3. Mather AN, Fairbairn TA, Ball SG, Greenwood JP, Plein S. Reperfusion haemorrhage as determined by cardiovascular MRI is a predictor of adverseleft ventricular remodelling and markers of late arrhythmic risk. Heart. 2011;97:453–9.
4. Kali, Avinash, et al. "Persistent Microvascular Obstruction After Myocardial Infarction Culminates in the Confluence of Ferric Iron OxideCrystals,Pro-inflammatory Burden, and Adverse Remodeling." Circulation: Cardiovascular Imaging 9.11 (2016): e004996.
Figures
