Coronary artery bypass grafting (CABG) remains the gold standard therapy for patients with advanced multivessel coronary artery disease. Central to the success of this procedure is effective myocardial protection during periods of intentional ischemia created by aortic cross-clamping. The review by Lazović and colleagues provides a detailed and timely synthesis of the molecular and cellular mechanisms through which cardioplegia protects the heart during surgical myocardial revascularization .
Cardioplegia is far more than a technical means of stopping the heart. Modern cardioplegic strategies represent an active therapeutic intervention designed to preserve cardiomyocyte integrity during ischemia and to minimize the damage associated with reperfusion. Myocardial ischemia occurs when coronary blood flow is insufficient to meet metabolic demands, forcing cardiomyocytes to shift from aerobic to anaerobic metabolism. This shift leads to ATP depletion, intracellular acidosis, and disruption of ionic homeostasis—particularly calcium overload. While ischemia itself is damaging, the review emphasizes that much of the injury actually occurs during reperfusion, when oxygen reintroduction triggers a surge in reactive oxygen species (ROS), inflammatory signaling, endothelial dysfunction, and activation of apoptotic and necrotic pathways.
Cardioplegic arrest fundamentally alters this pathological cascade. By suppressing electromechanical activity, cardioplegia reduces myocardial oxygen consumption by up to 80–90%, dramatically extending the window of reversible ischemia. High-potassium depolarizing solutions or alternative hyperpolarizing strategies prevent action potential propagation and myocardial contraction, thereby lowering ATP demand. This metabolic suppression is one of the most powerful protective effects of cardioplegia and underpins its clinical value in CABG surgery.
At the molecular level, calcium homeostasis emerges as a central theme. During ischemia–reperfusion, uncontrolled calcium influx activates calpains, phospholipases, and endonucleases, leading to structural damage and cell death. Cardioplegic solutions counteract this process by limiting calcium entry through membrane depolarization, magnesium-mediated calcium antagonism, sodium-channel blockade with agents such as lidocaine, and reduced extracellular calcium concentrations. By preventing calcium overload, cardioplegia also inhibits opening of the mitochondrial permeability transition pore (mPTP), a critical trigger of irreversible mitochondrial dysfunction and apoptosis.
Mitochondrial preservation is another cornerstone of cardioplegic protection. Ischemia impairs oxidative phosphorylation and collapses mitochondrial membrane potential, while reperfusion further stresses mitochondria through oxidative bursts. The review highlights how cardioplegia stabilizes mitochondrial membranes, preserves respiratory chain function, and supports rapid recovery of aerobic metabolism after reperfusion. Substrate-enriched solutions containing glucose, glutamate, and aspartate help sustain residual ATP production and replenish energy stores, while adenosine supports mitochondrial ATP synthesis and activates pro-survival signaling pathways.
Oxidative stress and inflammation are tightly intertwined in ischemia–reperfusion injury. Reperfusion-associated ROS damage lipids, proteins, and nucleic acids, while also activating transcription factors such as NF-κB and MAPKs that amplify inflammatory responses. Cardioplegic solutions mitigate these effects through hypothermia, controlled reperfusion strategies, and the inclusion of antioxidants such as mannitol, ascorbate, and glutathione. Blood-based cardioplegia further enhances antioxidant capacity through endogenous buffering systems and oxygen delivery, reducing anaerobic metabolism and limiting oxidative injury.
The review also provides a clinically relevant classification of cardioplegic solutions. Crystalloid solutions, including St. Thomas and Bretschneider (Custodiol), laid the foundation for modern myocardial protection by controlling electrolytes and pH. Blood-based cardioplegia improves oxygen delivery and buffering capacity, while hybrid formulations such as Del Nido cardioplegia combine prolonged ischemic tolerance with reduced calcium overload and simplified intraoperative workflow. Del Nido cardioplegia, originally developed for pediatric surgery, has gained increasing acceptance in adult CABG due to its ability to provide extended myocardial protection with a single dose.
Temperature management remains a debated but critical component of cardioplegic strategy. Hypothermia reduces metabolic demand and ROS generation, while normothermic cardioplegia avoids the adverse effects of cold-induced cellular dysfunction. The authors highlight evidence suggesting that mild hypothermia combined with tepid blood cardioplegia may offer an optimal balance, reducing ischemic injury while facilitating rapid functional recovery and potential neuroprotection.
Beyond established techniques, the review explores emerging experimental strategies aimed at transforming cardioplegia into a precision therapeutic platform. These include cytoprotective additives such as adenosine and nitric oxide donors, pharmacologic modulators targeting ion channels and inflammatory pathways, metabolic substrates supporting mitochondrial energetics, and even nanotechnology-based delivery systems targeting mitochondria directly. Such approaches reflect a broader shift in cardiac surgery toward biologically informed myocardial protection tailored to patient risk and procedural complexity.
In conclusion, this review underscores that cardioplegia is not merely a passive method of inducing cardiac arrest, but an active modulator of cellular survival pathways. By regulating calcium handling, preserving mitochondrial integrity, reducing oxidative stress, and modulating inflammation and apoptosis, cardioplegic solutions play a decisive role in postoperative myocardial recovery. A deeper understanding of these mechanisms provides a foundation for refining existing protocols and developing next-generation cardioplegic strategies that improve outcomes in coronary artery bypass surgery.
