Author + information
- Received June 1, 2017
- Revision received July 28, 2017
- Accepted August 9, 2017
- Published online January 15, 2018.
- Rajesh Dash, MD, PhDa,b,∗ (, )
- Yoshiaki Mitsutake, MDa,
- Wook Bum Pyun, MD, PhDa,c,
- Fady Dawoud, PhDd,
- Jennifer Lyons, RVTa,
- Atsushi Tachibana, RTa,
- Kazuyuki Yahagi, MDe,
- Yuka Matsuura, MSa,
- Frank D. Kolodgie, PhDe,
- Renu Virmani, MDe,
- Michael V. McConnell, MD, MSEEa,b,f,g,
- Uday Illindala, MSd,
- Fumiaki Ikeno, MDa,b and
- Alan Yeung, MDa,b
- aDivision of Cardiovascular Medicine, Stanford University, Stanford, California
- bCardiovascular Institute, Stanford University, Stanford, California
- cSchool of Medicine, Ewha Womans University, Seoul, South Korea
- dZOLL Circulation, Inc., San Jose, California
- eCVPath Institute, Inc., Gaithersburg, Maryland
- fDepartment of Electrical Engineering; Stanford University, Stanford, California
- gVerily Life Sciences, Mountain View, California
- ↵∗Address for correspondence:
Dr. Rajesh Dash, Department of Medicine, Division of Cardiovascular Medicine, Stanford Medical Center, 300 Pasteur Drive, H2157, Stanford, California 94305-5233.
Objectives The study investigated whether a dose response exists between myocardial salvage and the depth of therapeutic hypothermia.
Background Cardiac protection from mild hypothermia during acute myocardial infarction (AMI) has yielded equivocal clinical trial results. Rapid, deeper hypothermia may improve myocardial salvage.
Methods Swine (n = 24) undergoing AMI were assigned to 3 reperfusion groups: normothermia (38°C) and mild (35°C) and moderate (32°C) hypothermia. One-hour anterior myocardial ischemia was followed by rapid endovascular cooling to target reperfusion temperature. Cooling began 30 min before reperfusion. Target temperature was reached before reperfusion and was maintained for 60 min. Infarct size (IS) was assessed on day 6 using cardiac magnetic resonance, triphenyl tetrazolium chloride, and histopathology.
Results Triphenyl tetrazolium chloride area at risk (AAR) was equivalent in all groups (p = 0.2), but 32°C exhibited 77% and 91% reductions in IS size per AAR compared with 35°C and 38°C, respectively (AAR: 38°C, 45 ± 12%; 35°C, 17 ± 10%; 32°C, 4 ± 4%; p < 0.001) and comparable reductions per LV mass (LV mass: 38°C, 14 ± 5%; 35°C, 5 ± 3%; 32°C 1 ± 1%; p < 0.001). Importantly, 32°C showed a lower IS AAR (p = 0.013) and increased immunohistochemical granulation tissue versus 35°C, indicating higher tissue salvage. Delayed-enhancement cardiac magnetic resonance IS LV also showed marked reduction at 32°C (38°C: 10 ± 4%, p < 0.001; 35°C: 8 ± 3%; 32°C: 3 ± 2%, p < 0.001). Cardiac output on day 6 was only preserved at 32°C (reduction in cardiac output: 38°C, –29 ± 19%, p = 0.041; 35°C: –17 ± 33%; 32°C: –1 ± 28%, p = 0.041). Using linear regression, the predicted IS reduction was 6.7% (AAR) and 2.1% (LV) per every 1°C reperfusion temperature decrease.
Conclusions Moderate (32°C) therapeutic hypothermia demonstrated superior and near-complete cardioprotection compared with 35°C and control, warranting further investigation into clinical applications.
The study was partially sponsored by ZOLL Circulation, Inc., who also played a role in study design, data collection, and review of technical details within manuscript. CV Path, Inc., played a role in data collection, production of immunohistochemistry results, and review of technical details within the manuscript. Neither ZOLL nor CVPath played a role in data interpretation, decision to publish, or manuscript writing. Dr. Dash was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute. Drs. Dawoud and Kieno are employees of ZOLL Circulation. Drs. Kolodgie, Virmani, and Yeung are employees of CVPath. Dr. McConnell is currently on partial leave of absence from Stanford; and is an employee at Verily Life Sciences, Inc. Dr. Dash has received research grant support from ZOLL Circulation. Dr. Illindala is an employee of Shockwave Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received June 1, 2017.
- Revision received July 28, 2017.
- Accepted August 9, 2017.
- 2018 American College of Cardiology Foundation