Microvascular dysfunction following cardiopulmonary bypass plays a central role in postoperative organ dysfunction

Abstract

Despite significant advances in surgical technique and strategies for tissue/organ protection, cardiac surgery involving cardiopulmonary bypass is a profound stressor on the human body and is associated with numerous intraoperative and postoperative collateral effects across different tissues and organ systems. Of note, cardiopulmonary bypass has been shown to induce significant alterations in microvascular reactivity. This involves altered myogenic tone, altered microvascular responsiveness to many endogenous vasoactive agonists, and generalized endothelial dysfunction across multiple vascular beds. This review begins with a survey of in vitro studies that examine the cellular mechanisms of microvascular dysfunction following cardiac surgery involving cardiopulmonary bypass, with a focus on endothelial activation, weakened barrier integrity, altered cell surface receptor expression, and changes in the balance between vasoconstrictive and vasodilatory mediators. Microvascular dysfunction in turn influences postoperative organ dysfunction in complex, poorly understood ways. Hence the second part of this review will highlight in vivo studies examining the effects of cardiac surgery on critical organ systems, notably the heart, brain, renal system, and skin/peripheral tissue vasculature. Clinical implications and possible areas for intervention will be discussed throughout the review.

Keywords: cardiac surgery; ischemia-reperfusion; microvasculature; organ damage; vasomotor tone.

FIGURE 1

Ischemia-reperfusion injury following cardioplegic arrest may lead to multisystem dysfunction through multiple mechanisms. These mechanisms include endothelial activation and inflammation leading to oxidative stress and altered vasomotor and myogenic tone leading to vasospasm and organ malperfusion.

FIGURE 2

Ischemia-reperfusion injury is complex and multifactorial. At the cellular level, initial transient hypoxia due to cardiopulmonary bypass (CPB) leads to a switch from mitochondrial oxidative phosphorylation to anaerobic glycolysis, with a marked reduction in ATP yield. In poorly oxygenated tissues, pyruvate (the end-product of glycolysis) is shunted away from mitochondria and instead undergoes conversion to lactate by cytosolic lactate dehydrogenase (LDH). The resulting lactic acidosis in combination with high extracellular potassium and hypothermia due to cold cardioplegia inhibits the activity of Na⁺/K⁺-ATPase, an enzyme critical for maintaining physiologic resting membrane potential of cardiomyocytes close to the Nerst equilibrium potential of potassium (approximately –85 to –90 millivolts). Metabolic acidosis dually increases H⁺/Na⁺-antiporter activity, resulting in a small but notable increase in intracellular sodium, further exacerbating the sodium “window current” phenomenon during hyperkalemic cardioplegia. These electrochemical events drive the new membrane potential closer to –50 millivolts. The Na⁺/Ca²⁺-exchanger begins to operate in reverse, moving three Na⁺ ions out of the cardiomyocyte for every Ca²⁺ ion in. Voltage-gated slow calcium channels also begin to activate, leading to further calcium influx. This myocardial calcium loading in turn activates proteases, nucleases, and phospholipases, resulting in phospholipid membrane degradation, organelle destruction, accumulation of catabolic byproducts, compromised ultrastructural integrity of sarcolemma membrane integral to calcium homeostasis, and accelerated depletion of intracellular ATP stores. Prolonged exposure to ischemia increases mitochondrial calcium uptake through reversal of mitochondrial Na⁺/Ca²⁺-exchanger in a manner akin to reversal of cardiomyocyte Na⁺/Ca²⁺-exchanger. This leads to critical and irreversible damage to mitochondria. Following reperfusion, mitochondria have reduced capacity for neutralizing reactive oxygen species (ROS) and contribute to sustained oxidative stress by way of ROS production. This mitochondrial oxidative stress occurs in both cardiomyocytes as well as in the microvasculature, compounding the effects. Cytosolic cytochrome c is implicated in activating caspases involved in intrinsic apoptotic pathways. Reperfusion results in additional cardiac injury independent of ischemic insult which manifests as dysrhythmia, myocardial stunning, and myocardial necrosis. Notably, concurrent oxidative stress within the microvasculature results in microvascular dysfunction, further compounding cardiac injury. Figure created using BioRender.com.

FIGURE 3

Factors leading to renal dysfunction during and after cardiopulmonary bypass. Perioperative hypotension, renal microvascular inflammation, glomerular fibrin deposition, and cardiopulmonary bypass (CPB) circuit shear forces all act in concert to impair renal perfusion and glomerular filtration rate (GFR), ultimately leading to acute kidney injury. Figure created using BioRender.com.

FIGURE 4

Factors leading to cerebrovascular dysfunction during and after cardiopulmonary bypass. Inflammation, microemboli, and macroemboli all lead to microvascular dysfunction. This in turn leads to neuronal ischemia and disruption of blood brain barrier integrity, resulting in brain injury. Figure created using BioRender.com.

FIGURE 5

Factors leading to pulmonary injury during and after cardiopulmonary bypass. Cardiopulmonary bypass (CPB) triggers a pathological series of impaired vasomotor tone, ischemia, and inflammation that drives pulmonary microvascular dysfunction. This in turn can lead to disruption of the alveolar-capillary membranes, pulmonary edema, acute respiratory distress syndrome (ARDS), and atelectasis. In addition, pathologic pulmonary microvascular remodeling can lead to postoperative pulmonary hypertension. Figure created using BioRender.com.