TY - JOUR
T1 - Pharmacological Cardioprotection against Ischemia Reperfusion Injury—The Search for a Clinical Effective Therapy
AU - Wang, Qian
AU - Zuurbier, Coert J.
AU - Huhn, Ragnar
AU - Torregroza, Carolin
AU - Hollmann, Markus W.
AU - Preckel, Benedikt
AU - van den Brom, Charissa E.
AU - Weber, Nina C.
N1 - Funding Information: Q.W. is supported by the Chinese Scholarship Council (CSC no: 202107720012) fellowship program. C.B. is supported by the Dutch Research Council (Veni 2019). The research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Publisher Copyright: © 2023 by the authors.
PY - 2023/5/1
Y1 - 2023/5/1
N2 - Pharmacological conditioning aims to protect the heart from myocardial ischemia-reperfusion injury (IRI). Despite extensive research in this area, today, a significant gap remains between experimental findings and clinical practice. This review provides an update on recent developments in pharmacological conditioning in the experimental setting and summarizes the clinical evidence of these cardioprotective strategies in the perioperative setting. We start describing the crucial cellular processes during ischemia and reperfusion that drive acute IRI through changes in critical compounds (∆GATP, Na+, Ca2+, pH, glycogen, succinate, glucose-6-phosphate, mitoHKII, acylcarnitines, BH4, and NAD+). These compounds all precipitate common end-effector mechanisms of IRI, such as reactive oxygen species (ROS) generation, Ca2+ overload, and mitochondrial permeability transition pore opening (mPTP). We further discuss novel promising interventions targeting these processes, with emphasis on cardiomyocytes and the endothelium. The limited translatability from basic research to clinical practice is likely due to the lack of comorbidities, comedications, and peri-operative treatments in preclinical animal models, employing only monotherapy/monointervention, and the use of no-flow (always in preclinical models) versus low-flow ischemia (often in humans). Future research should focus on improved matching between preclinical models and clinical reality, and on aligning multitarget therapy with optimized dosing and timing towards the human condition.
AB - Pharmacological conditioning aims to protect the heart from myocardial ischemia-reperfusion injury (IRI). Despite extensive research in this area, today, a significant gap remains between experimental findings and clinical practice. This review provides an update on recent developments in pharmacological conditioning in the experimental setting and summarizes the clinical evidence of these cardioprotective strategies in the perioperative setting. We start describing the crucial cellular processes during ischemia and reperfusion that drive acute IRI through changes in critical compounds (∆GATP, Na+, Ca2+, pH, glycogen, succinate, glucose-6-phosphate, mitoHKII, acylcarnitines, BH4, and NAD+). These compounds all precipitate common end-effector mechanisms of IRI, such as reactive oxygen species (ROS) generation, Ca2+ overload, and mitochondrial permeability transition pore opening (mPTP). We further discuss novel promising interventions targeting these processes, with emphasis on cardiomyocytes and the endothelium. The limited translatability from basic research to clinical practice is likely due to the lack of comorbidities, comedications, and peri-operative treatments in preclinical animal models, employing only monotherapy/monointervention, and the use of no-flow (always in preclinical models) versus low-flow ischemia (often in humans). Future research should focus on improved matching between preclinical models and clinical reality, and on aligning multitarget therapy with optimized dosing and timing towards the human condition.
KW - cardioprotection
KW - drug development
KW - ischemia-reperfusion injury
UR - http://www.scopus.com/inward/record.url?scp=85160675410&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cells12101432
DO - https://doi.org/10.3390/cells12101432
M3 - Review article
C2 - 37408266
SN - 2073-4409
VL - 12
JO - Cells
JF - Cells
IS - 10
M1 - 1432
ER -