Mitochondrial Dysfunction in Cardiac Surgery

INTRODUCTION

The human heart has one of highest metabolic requirements in the body: even in a resting physiologic state it must work to circulate approximately 5 L/min to 8 L/min of blood against systemic vascular afterload. In addition, overall cardiac mechanical efficiency is only 20% to 25%,¹ with cellular maintenance and heat production accounting for the balance of energetic requirements. A dense network of mitochondria, which contain the machinery of oxidative phosphorylation, is needed to maintain the balance of cellular adenosine triphosphate (ATP) utilization and production in the setting of such a high energetic demand. Indeed, cardiac myocytes have one of highest mitochondrial volume densities of any cell in the body, with mitochondria occupying almost one-third of the cell volume.²

This network is highly vulnerable to injury, and therefore impaired function, due to a combination of patient factors and stressors encountered in the context of cardiac surgery. A discussion of normal and pathologic cardiac mitochondrial function, specific perioperative stressors, and protective strategies for cardiac surgical patients follows.

CARDIAC MITOCHONDRIA IN HEALTH AND DISEASE

Under normoxic conditions, cardiac ATP production is accomplished primarily through oxidation of fatty acids, and toa lesser degree, carbohydrates.³ Ketone bodies, lactate, and amino acids can also be used as substrate, but they contribute little to maintaining the ATP/ADP balance at baseline.⁴ However, cardiac metabolism is dynamic, and adapts in response to both chronic and acute pathologic perturbations. Chronic pathologies most relevant to cardiac surgical patients include heart failure and diabetes.

Heart Failure

In heart failure, there is a decrease in fatty acid oxidation with mixed evidence of an increase in glucose utilization in humans,⁵ which has been compared to a shift back toward fetal cardiac metabolism.⁶ Failing hearts also increasingly rely on ketone bodies and lactate as alternative fuel sources.^5,7 Overall, failing hearts demonstrate a reduction in energy reserves as reflected by a decline in the phosphocreatine (PCr)/ATP ratio in the long term, which predicts mortality in heart failure.⁸

Diabetes

In diabetes on the other hand, fatty acid uptake and oxidation is increased and glucose metabolism is decreased, with an overall decrease in metabolic efficiency and increased oxidative stress. Despite the increased fatty acid oxidation, there is also a relative abundance of lipid substrate. The resulting accumulation of toxic metabolic intermediates and contractile failure has been termed “lipotoxic cardiomyopathy”.⁹ Impaired mitochondrial function and dynamics are associated with contractile dysfunction in type 2 diabetic patients^10,11 and are associated with an increased risk of arrhythmia and sudden cardiac death.¹²

Ischemia and Reperfusion

Ischemia and reperfusion are the most studied acute pathologies that impact cardiac surgical patients. Within seconds of the onset of ischemia, high-energy phosphate reserves are exhausted and anaerobic glycolysis becomes the only source of ATP. As a consequence, mitochondrial succinate and intracellular H¹ accumulate, pH decreases, and contractile function is impaired.^13,14 With reperfusion, oxidative phosphorylation is restored rapidly, but mechanical efficiency is diminished due to disproportionately increased fatty acid oxidation with continued upregulation of anaerobic glycolysis. The preexisting and ongoing accumulation of intracellular H⁺ is normalized, but at the expense of increased intracellular Ca²⁺ (via the H⁺/Na⁺ and 2Na¹⁺/Ca²⁺ exchangers). Intracellular Ca²⁺ overload increases the risk of mitochondrial permeability transition pore (MPTP) opening and activation of cell death.^15,16

In all, maintaining the cellular ATP supply is one of the fundamental roles of mitochondria. The chronic and acute perturbations discussed demonstrate how dynamic cardiac metabolism can be, and illuminate therapeutic opportunities for improving mitochondrial efficiency and limiting damage in the setting of cardiac surgery (please see the “Opportunities for intervention” section).

OTHER ROLES OF MITOCHONDRIA: BEYOND ENERGY SUPPLY

In addition to their central role in energy supply, mitochondria are important to several other cellular processes, including reactive oxygen species (ROS) signaling, calcium hemostasis, and regulation of apoptosis and necrosis pathways.

Reactive Oxygen Species Signaling

First, mitochondria are a source of intracellular ROS, which are normal byproducts of the electron transport chain (ETC) complex in oxidative phosphorylation. Although ROS can contribute to oxidative stress, it is important not to overlook that at low levels, ROS activate crucial intracellular signaling pathways (termed redox signaling,¹⁷ which may underlie the mechanisms of ischemic preconditioning,¹⁸ postconditioning,¹⁹ and remote ischemic preconditioning²⁰). ROS are balanced by antioxidant systems, preventing damage to cellular components. However, ROS production is tied to the rate of respiration and increases disproportionately when there are perturbations in respiratory chain complex activity or cofactor availability. Ischemia and reperfusion are examples of such perturbations, in which ROS production is increased first due to inadequate substrate availability,²¹ followed by increased electron leakage by ETC complexes and decreased ROS scavenging (antioxidant) capacity during the hyperoxic period of reperfusion.²²

Calcium Hemostasis and Regulation of Cell Death

Second, mitochondria play a role in Ca²⁺ hemostasis²³; mitochondrial Ca²⁺ uptake serves as a buffer for cytoplasmic levels, and increased Ca²⁺ within the mitochondrial matrix activates ATP synthesis. As mentioned, this capacity can be overwhelmed in pathologic states, and Ca²⁺ overload can contribute to mitochondrial activation of cell death. In addition, excessive levels of ROS, such as those produced in the reperfusion phase of ischemia/reperfusion (I/R) injury,²⁴ heart failure,²⁵ and other cardiomyopathies²⁶ result in damage to lipids, proteins, mitochondrial DNA (mtDNA), and ETC complexes themselves, perpetuating oxidative stress. When there is overwhelming oxidative stress or mitochondrial Ca²⁺ overload, as can occur during reperfusion, mitochondria serve as central hubs for cell death signaling pathways.²⁷ Apoptosis is a well-known mitochondrial pathway of cell death activation, in which permeabilization of the mitochondrial outer membrane, with release of cytochrome c and other mitochondrial proteins into the cytosol, leads to caspase activation. Other cell-death modalities in which mitochondria play a role are necroptosis, pyroptosis, and ferroptosis.

MITOCHONDRIAL DYSFUNCTION IN CARDIAC SURGERY PATIENTS

Mitochondria impact myocardial function through their roles in energy and calcium balance, ROS signaling, and regulation of cell death. Cardiac surgical patients may present with preexisting mitochondrial dysfunction due to prior insult or chronic pathology,²⁸ as discussed above. In addition, cardiac surgery involves its own period of cardiac I/R, as well as the induction of systemic inflammatory responses due to surgical tissue trauma and cardiopulmonary bypass (CPB) exposure, all of which can impact mitochondrial function.

The inflammatory response to CPB includes activation of both humoral and cellular components in early and late phases, attributed to blood interaction with nonendothelial bypass circuit surfaces and I/R injury respectively. The result is a cascading release of cytokines, enzymes, and other vasoactive substances, which manifest as a systemic inflammatory response syndrome picture.²⁹ The impact of systemic inflammatory states on mitochondrial function can be substantial.³⁰ Generally, mitochondrial respiration is impaired by inflammation, a response that is conserved across a variety of inflammatory states and organisms, suggesting that energetic conservation may confer adaptive advantages as long as the response is temporary.³¹ Inflammation can also activate mitochondrial quality control and antioxidant programs to facilitate recovery. However, if inflammation is severe, cellular (including mitochondrial) components can be damaged, which further interferes with energy production and may lead to cell death. As such, the level of inflammatory response due to surgical tissue trauma and exposure to CPB would be expected to correlate with the degree of mitochondrial dysfunction and cell death in cardiac surgical patients.

Furthermore, mitochondrial dysfunction and damage can itself exacerbate the inflammatory response. Certain pathways of cell death can result in the extracellular release of intracellular products, which are then known as damage-associated molecular patterns (DAMPs). DAMPs interact with pattern recognition receptors to upregulate proinflammatory or antiinflammatory responses³² and inflammasome activation.³³ DAMPs of mitochondrial origin include mtDNA, cytochrome c, mitochondrial transcription factor A, ATP, high-mobility group box 1 and others. Intracellularly, mitochondrial dysfunction causes translocation of mtDNA into the cytoplasm, where it upregulates proinflammatory signaling through nuclear factor kappa light-chain-enhancer of activated B cells and inflammasome activation.

Fortunately, there is some capacity for recovery after mitochondrial injury (Fig. 1). Recovery is facilitated through the induction of a group of mitochondrial quality control (MQC) mechanisms that separate and degrade unhealthy mitochondria and mitochondrial components while retaining healthy elements (through the processes of fission, fusion, and mitophagy), and generate new mitochondrial components (biogenesis). The actions of these processes are at once oppositional and complementary; as such, they must be tightly regulated by complex machinery both at baseline and in response to stress to maintain an optimally functioning mitochondrial network. Indeed, proteins that regulate mitochondrial fission and fusion are the targets of signaling pathways activated in normal development, exercise/metabolic demand, or by heart failure, diabetes, cardiomyopathy, or I/R, among other pathologies.³⁴ Similarly, mitophagy is upregulated through several different pathways depending on the stimulus (eg, the Parkin-PINK1 pathway for decreased membrane potential and I/R and Fundc1 in hypoxic stress). Clearance of dysfunctional mitochondria is complemented by mitochondrial biogenesis, which requires activation of both nuclear and mitochondrial gene transcription and translation. A master regulator of this process is peroxisome proliferator activated receptor gamma coactivator 1-alpha, which, interestingly, also has downstream targets involved in oxidative metabolism and antioxidant defenses. MQC processes are of obvious interest due to their potential to improve cardiac recovery in a variety of clinical settings and have recently been extensively reviewed.³⁵

Fig. 1.

Perioperative I/R and inflammation induce oxidative stress (reactive oxygen and nitrogen species), which modulate MQC programs through redox signaling. Excessive oxidative stress may also contribute to mitochondrial dysfunction, resulting in energetic failure and cell death. RNS, reactive nitrogen species.

Given the variety of perturbations that may impact mitochondrial function in the perioperative period, what is the evidence that mitochondrial dysfunction is clinically relevant for cardiac surgical patients? First, in adults undergoing coronary artery bypass or valve surgery on CPB, mitophagy, mitochondrial biogenesis, and mtDNA damage (strand breaks) immediately post-CPB are increased compared with pre-CPB in atrial tissue.³⁶ The upregulation in mitochondrial biogenesis, in particular, seems to be driven by posttranscriptional mechanisms, highlighting those mechanisms as potential therapeutic targets. There is also extensive literature addressing mitochondrial dysfunction and cognitive decline, including postoperative neurocognitive disorders. A recent small study in cardiac surgical patients demonstrated increased DNA hypermethylation and decreased complex I activity in blood samples of patients with postcoronary artery bypass grafting mild-cognitive decline (vs those without).³⁷

Cardiac surgical patients are also at high risk for atrial fibrillation (AF), which is associated with increased morbidity and mortality. The risk of developing AF may be increased by inflammation or changes in calcium signaling,³⁸ both of which are central features of mitochondrial dysfunction and I/R injury. Recent studies have demonstrated that high levels of mtDNA in peripheral blood before cardiac surgery,³⁹ or significant increases from precardiac to postcardiac surgery (indicating tissue injury)⁴⁰ are predictive of developing new-onset postoperative AF, as are high levels of mtDNA in pericardial fluid postoperatively.⁴¹ In addition, cardiac surgery patients with preexisting mitochondrial dysfunction (decreased respiration and increased sensitivity to MPTP opening with calcium) in right atrial tissue also had a higher incidence of new-onset postoperative AF,⁴² and in patients with preexisting AF, mitochondrial ETC activity is lower and oxidative stress higher than in those without.⁴³

SPECIFIC CARDIAC SURGICAL PATIENT POPULATIONS AND MITOCHONDRIAL DYSFUNCTION

As previously discussed, mitochondrial dysfunction also plays a role in the pathogenesis of heart failure;^3,8,9 long-term mechanical unloading with a left ventricular assist device may improve mitochondrial function⁴⁴ and ultrastructural remodeling, particularly in ischemic cardiomyopathy patients. For heart failure patients who progress to heart transplantation, mitochondrial dysfunction can occur in the donor heart, increasing the risk of early graft failure. Donor factors that may contribute to donor heart mitochondrial dysfunction include increased catecholamine exposure and cytosolic calcium, as well as decreased hormone levels following brain death. Contributing procedural factors are primarily the cold and warm ischemic times for organ transport and implantation, and the duration of CPB (in heart transplant, graft ischemic time, and recipient CPB time may be mutually exclusive). Recipient factors that may contribute to mitochondrial dysfunction include the systemic inflammatory response to intra-procedure CPB and any preoperative exposure to mechanical circulatory support.

Finally, apart from the comorbidities already discussed (heart failure, diabetes), 2 other conditions that may predispose to mitochondrial dysfunction in cardiac surgical patients are worth discussion: aging and cardiomyopathies. With aging, oxidative phosphorylation is increasingly disrupted,^45,46 which plays a part in the declining organ functional reserve. The decreased energetic capacity may be explained by increases in mtDNA deletions in cardiac tissue from aging patients (Fig. 2).⁴⁷ Conversely, ROS production is progressively elevated with age.⁴⁸ These changes may increase the propensity for injury after cardiac I/R with aging, which has been shown in both rats and human patients.^49,50 Cardiomyopathies can reflect a wide variety of underlying disease processes, some with a notable component of mitochondrial dysfunction. Viral⁵¹ or bacterial infections (particularly sepsis⁵²) can cause myocarditis and/or a systemic inflammatory response, and thereby contribute to perioperative cardiac mitochondrial dysfunction. A number of mitochondrial diseases are associated with cardiomyopathies.^53–55 These are important to consider for 2 reasons: (1) because the heart has a relatively high energy requirement, cardiac dysfunction may be the first or only clinical manifestation of mitochondrial dysfunction that is as yet subclinical in other organ systems, and (2) cardiomyopathies (or other organ dysfunctions) in these patients can be precipitated by stressors including febrile illness or surgery, with metabolic decompensation and/or acute heart failure. One important cardiomyopathy subset that is regularly encountered in the perioperative space is hypertrophic cardiomyopathy (HCM). Although a variety of genetic mutations cause the HCM phenotype, it is thought that common features are mitochondrial dysfunction and morphologic disorganization, mechanical inefficiency, impaired Ca2 1 handing, increased oxidative stress, and overall myocardial remodeling.^56,57 In other words, HCM hearts may appear to be strong, but reduced metabolic efficiency and energy reserve may result in systolic and/or diastolic dysfunction. This has not been described for HCM patients specifically in context of cardiac surgery, but should be considered when there is otherwise unexplained poor perioperative cardiac function.

Fig. 2.

Hypothesis for the mechanism of age-related progression of oxidative phosphorylation (OXPHOS) diseases. The upper panel shows the proposed accumulation of somatic mtDNA mutations with age.^47,48 Patients are born with a certain percentage of mutant mtDNAs, some patients with more than others. The dashed lines indicate the relative ages when sufficient mutations accumulate to cause disease. The lower panel shows the decline of OXPHOS capacity of healthy individuals and patients with underlying mtDNA mutations. Different tissues have different minimum energy thresholds, below which dysfunction is clinically apparent, shown by dashed lines. OXPHOS declines for both healthy individuals and patients, consistent with the accumulation of somatic mtDNA damage. However, because of the inherited mtDNA mutation, patients start with a lower initial OXPHOS capacity and thus drop below the expression thresholds much earlier than normal individuals. (Wallace, D. C. (1992). Diseases of the mitochondrial DNA. Annual Review of Biochemistry, 61(1), 1175–1212. https://doi.org/10.1146/annurev.bi.61.070192.005523.)

OPPORTUNITIES FOR INTERVENTION

The mechanisms of mitochondrial dysfunction discussed prompt consideration of opportunities for intervention to prevent or modulate damage, or encourage repair after mitochondrial injury. A number of physiologic, anesthetic, and surgical factors can be modulated in the perioperative period to protect mitochondrial function (summarized in Fig. 3). A brief categorical overview follows here, but a detailed discussion of evidence for (or against) these strategies is beyond the scope of this work; recent reviews are referenced in each section.

Fig. 3.

Strategies for protection or augmentation of mitochondrial function in cardiac surgical patients. (Theoretical or preclinical benefit but mixed or equivocal results in clinical practice). ^aTheoretical or preclinical benefit without adequate clinical study/in further development.

Glycemic Control

Hyperglycemia in the perioperative setting has several detrimental effects, including increased oxidative stress and I/R injury in cardiac tissue.⁵⁸ In adult cardiac surgery patients, acute hyperglycemia is particularly common during CPB, even in nondiabetic atients. As might be expected, there is a well-established association with hyperglycemia during CPB and increased morbidity and mortality, including AKI and infection.^59–61 As such, intraoperative glycemic control, perhaps particularly during the I/R phase, is recommended for diabetic and nondiabetic patients alike, although there is some debate over treatment thresholds due to the potential risk of hypoglycemia with aggressive treatment.⁶² Strategies to augment myocardial glucose uptake and utilization, such as hyperinsulinemic normoglycemia⁶³ and glucose-insulin-potassium regimens⁶⁴ have been investigated over several decades with mixed results. There may be logistical barriers to wide adoption of these protocols. There have been preliminary studies investigating perioperative use of insulin1 additional agents to accomplish glucose modulation, such as glucagon-like peptide-1 (GLP-1) receptor agonists, but their impact on outcomes in cardiac surgical patients is yet to be determined.^65,66

Calcium Supplementation

Hypercalcemia at the time of I/R and inflammatory stress would also be expected to exacerbate mitochondrial injury due to intracellular calcium overload and increased activation of cell death. It is common practice, however, for calcium supplementation to given at the time of separation from CPB (after cross-clamp removal and some period of reperfusion has elapsed), with the goals of augmenting myocardial contractility and systemic vascular resistance.⁶⁷ In considering the competing risk of injury versus augmented contractility, calcium supplementation should be judicious with regard to magnitude, administration (avoiding large, rapid boluses), and timing.⁶⁸ A phase 4 clinical trial investigating the clinical efficacy of calcium administration at the time of separation from CPB (ICARUS Trial) is in the recruitment phase on ClinicalTrials.gov.⁶⁹

Anesthetics

Anesthetics may also have an impact on mitochondrial function. Propofol is known to have antioxidant effects due to a structural similarity to vitamin E, and demonstrates myocardial mitochondrial preservation in preclinical studies. Outcomes in studies with cardiac surgical patients have been mixed.^70–72 Somewhat confusingly, there is also clinical evidence that inhalational agents may confer a preconditioning effect, and may provide enhanced cardioprotection when compared with propofol.^73,74 A large randomised controlled trial in Europe⁷⁵ and the majority of recent meta-analyses have not shown impacts on mortality. Overall, heterogeneity of protocols (timing, duration, dosing) is cited as a reason for heterogenous results. Accordingly, in clinical practice, although there are geographic differences and one 2019 European guideline recommended that “volatile anaesthetics should be considered during CPB”,⁷⁶ neither inhalational agents nor propofol infusion have been strongly favored as the preferred anesthetic technique in cardiac surgery.⁷⁷

Cardioplegia

The impact of I/R injury on mitochondria can be limited through the administration of cardioplegia, which minimizes ischemic time, cools myocardial tissue, and induces diastolic electromechanical arrest to lower metabolic requirements. The protective effects of cardioplegia depend first on distribution in the myocardium; patients with coronary pathology or other microvascular abnormalities may benefit from retrograde administration. Although there is wide variation in practice, cardioplegia solutions are typically either crystalloid or blood-based, and most contain a high concentration of potassium to induce cardiac arrest. The previously mentioned flexibility in myocardial substrate metabolism results in increased carbohydrate metabolism in the immediate reperfusion phase after aortic cross-clamp removal.⁷⁸ These transient perioperative changes in substrate use, as well as preexisting alterations in myocardial metabolism due to prior ischemia or other comorbid conditions point to the potential for therapeutic adjustments of substrate supply during cardiac surgery.³ A number of cardioplegia and organ preservation solutions incorporate components to facilitate substrate utilization, such as glycolytic substrates, amino acids, and specifically ketoglutarate in histidine-tryptophan-ketoglutarate (HTK) cardioplegia.^79,80 More generally, the addition or adjustment of several other cardioplegia components have been studied, including potassium, calcium, sodium, histidine, tryptophan, adenosine, magnesium, and lidocaine (Table 1). These have shown promise in animal studies, but variable impact on outcomes in clinical studies.^81,82 Some of these additives are in so called long-acting cardioplegia solutions, which can be dosed less frequently during surgery to minimize surgical interruption, shortening ischemic times for long or complex procedures. Despite intense interest in long-acting solutions, clinical studies have not reliably shown an improvement in myocardial injury or other outcomes.⁸³ Other supplements/augmentation strategies that have shown potential for I/R cardioprotection (such as NAD1 precursors⁸⁴) may also be compelling as additives to cardioplegia or organ preservation solutions.

Table 1.

Categories of cardioplegia strategies used for cardioprotection, with example solutions, representative component concentrations, and additives for each category^85–88

Cardioplegia Type	Example Solutions and Concentrations	Na+ (mM/L)	K+ (mM/L)	Mg2+ (mM/L)	Ca2+ (mM/L)	HTK (mM/L)	Mannitol	Glucose (mM/L)	Lidocaine	Adenosine	NaHCO3	Modifications:
Crystalloid-based
Intracellular	Custodiol®, HTK, 15 9 Bretschneider’s, University of Wisconsin Solution	15	9	4	0.015	198/2/1	x	—	—	—	—	Glutamate, aspartate
Extracellular	Plegisol®, Celsior®, St. Thomas, Stanford solution	110–120	16–26	32	2.4	—	x	—	—	—	—	Glutamate, aspartate
Blood-based (includes endogenous oxygen carrying, substrates, buffers, antioxidants, oncotic pressure, inflammatory factors)
4:1 Blood:Crystalloid	Buckberg	140	20–10 (i-m)	13–9 (i-m)	—	—	—	6	260 mg/L (induction)	—	—	Glutamate, aspartate, CPD, tromethamine
1:4 Blood:Crystalloid, Long-Acting	del Nido (in 1L Plasma-Lyte A)	Plasma-Lyte	26 meq	2 mg	—	—	3.2 g	—	130 mg	—	13 meq	Glutamate, aspartate
Microplegia (blood-based cardioplegia principles apply; with relatively less edema, but increased neutrophil accumulation and endothelial dysfunction)
Various additive and concentration options	ALM with insulin (8 mL additive:1L (i-m) blood)	—	30–8 meq/L (i-m)	2 g/20 mL	—	—	—	—	25 mg/1 mL	6 mg/2 mL	—	2.5 IU Insulin added to ALM volume

Abbreviations: ALM, adenosine and lidocaine with magnesium; CPD, Citrate-Phosphate-Dextrose; HTK, histidine, tryptophan, ketoglutarate; i-m, concentrations for induction or maintenance of cardioplegia.

Plasma-Lyte A concentrations/L (Baxter): 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate, and 23 mEq gluconate; x, may be added as a modifier.

Component and additive concentration information is for reference and comparison between solutions only; not for clinical use.

Reperfusion Strategies

Strategies to optimize the composition and conditions of reperfusion at the end of ischemia have also been investigated in efforts to minimize reperfusion injury, and may be of particular use in settings of prolonged ischemia or hypoxia (heart or lung transplants, or cyanotic pediatric cardiac surgery).⁸⁹ Administration of warm cardioplegia before cross-clamp removal (terminal warm induction or hot shot) is meant to allow washout of ischemic metabolic byproducts and augment aerobic metabolism while continued electromechanical arrest minimizes energy demand. Clinical evidence is limited but interest remains: some small studies show improvements in biochemical markers of I/R injury and/or hemodynamic parameters, but none have demonstrated clinical outcome differences.⁹⁰

Antioxidant Therapies

The application of antioxidant therapies is an intuitive approach to counteracting the damaging effect of increased oxidative stress in tissues secondary to I/R injury, inflammation, and/or mitochondrial dysfunction.⁷² It is common practice for free radical scavenging drugs like mannitol to be included in CPB circuit priming fluid⁹¹ or in cardioplegia solutions (eg, HTK, del Nido).⁹² Beyond this, clinical outcomes with experimental antioxidant therapies have not been promising. This is perhaps not surprising when we consider oxidative stress by the following definition: “an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage”.⁹³ With this view, it becomes clear that the most fundamental concern in broadly applied or poorly timed antioxidant treatment is the potential to mask or prevent critical intracellular ROS signaling mechanisms, and interfere with cellular stress response pathways. Targeted approaches that take these issues into consideration through improved precision of delivery and dosing, such as synthetic mitochondrial antioxidants (eg, MitoQ or MitoVit-E), have been tested, but have not yet translated into widespread clinical application.⁹⁴

On the other side of the oxidant:antioxidant balance lies the potential for therapeutic manipulation of ROS signaling, which underlies the concept of ischemic conditioning. Preischemic, postischemic , and remote ischemic conditioning have all been investigated widely in several settings,⁹⁵ and generally involve the application of short cycles of ischemia and reperfusion (directly to the tissue at risk, or to a remote tissue in the case of remote ischemic preconditioning), with the goal of increasing ischemic tolerance and minimizing I/R injury. The complex and fascinating mechanisms of these conditioning phenomena converge on a number of subcellular targets, notably including mitochondria; these pathways have been intensely studied and reviewed.⁹⁶ As is also the case for many of the therapies and approaches already discussed, cardiac surgery represents an appealing platform for application of these strategies, because the timing of perioperative stress and potential tissue injury can be anticipated, and along with it the timing of therapy. Clinical studies of both preconditioning and postconditioning in adult and pediatric cardiac surgery demonstrate promising results, but adoption has not been robust due to the requirement for repeated clamping and unclamping of the aorta. Remote (limb) conditioning has obvious practical advantages, and has been promising in preclinical and small clinical trials. In large multicenter trials in cardiac surgical patients, there have been mixed results.⁹⁷ This is likely due to several factors, including limited additional advantage over the multitude of cardioprotective strategies already in place in the perioperative period, and the impact of patient comorbidities and medications (including, importantly, the use of propofol,⁹⁸ which has a free-radical scavenging role). Still, 1 meta-analysis demonstrated that remote conditioning may reduce AKI after cardiac surgery, an effect that was “mainly evident during volatile only anesthesia”.⁹⁹

MQC Targeted Therapies

Finally, strategies that would enhance recovery in the setting of chronic pathology or after acute injury are also intuitive and appealing. As outlined briefly previously, MQC mechanisms work in concert to clear defective mitochondrial components and generate new ones, maintaining a functional mitochondrial network. There is documented evidence of MQC dysregulation in several pathologies and stressors that are highly relevant to cardiac surgical patients, including diabetes, heart failure, aging, and I/R injury.^34,100,101 As such, interest exists in targeting elements of the MQC pathways. However, MQC mechanisms can have both pathologic or beneficial effects, depending on the conditions under which they are applied; for example, overexpression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a), a transcriptional regulator of mitochondrial biogenesis and antioxidant defense mechanisms, results in cardiac hypertrophy and heart failure. On the other hand, PGC-1a knockdown and impaired biogenesis upregulation in mice results in heart failure in the setting of increased afterload, and increased tissue damage in sepsis.^102,103 Similarly dichotomous results have been observed for mitophagy and mitochondrial dynamics pathways,¹⁰⁰ suggesting that, as in the case of antioxidant therapies, highly specific application of MQC therapies (patient selection, dosing, timing, and precision treatment at the subtissue level) will be keys to their effective use. Mitochondrial transplantation has also been investigated as an alternative strategy for augmenting mitochondrial mass and/or function; further mechanistic investigations are needed to establish plausibility and optimal methods for clinical translation, as has been reviewed elsewhere.¹⁰⁴

Organ Preservation in Transplantation

Ex vivo organ-preservation systems (and normothermic regional perfusion during procurement) afford opportunities for therapeutic interventions in donor hearts that are (1) timely and (2) completely isolated from the recipient circulation (ie, no or minimized systemic effects). The use of these technologies is evolving rapidly, especially with donation after circulatory death (DCD) transplants. The initial period of warm ischemia with DCD procedures (which is not needed in donation after brain death) has driven the use of this technology, although ex vivo perfusion alternatives to static cold storage of donor organs has theoretical metabolic advantages regardless of procurement conditions. Currently, the most common choice for ex vivo perfusion of donor hearts is with warm, blood-based, oxygenated perfusate.¹⁰⁵ Cold cardioplegia is administered just before ex vivo perfusion (end procurement) and at the end (begin transplantation). Areas of investigation include temperature modulation (eg, hypothermic oxygenated perfusion), perfusate composition (viscosity, choice of oxygen carrier, substrate or other additives, cell-based or biologic therapies, etc.¹⁰⁶), pulsatility of perfusion, and combination/variation of these interventions at different time points during machine perfusion.¹⁰⁷

SUMMARY

In summary, mitochondria are key to the cellular response to energetic demand, but are also vital to ROS signaling, calcium hemostasis, and regulation of apoptosis and necrosis pathways in cell death. Mitochondrial dysfunction and disruption of any of these vital processes can lead to chronic or acute pathology, particularly in tissues with high metabolic demand and mitochondrial content, such as the heart. In cardiac surgery, several perioperative factors can impact mitochondrial function, including I/R injury and an increased systemic inflammatory response due to exposure to CPB and surgical tissue trauma. Patients with diabetes, heart failure, advanced age, or cardiomyopathies may have underlying mitochondrial dysfunction or be more sensitive to perioperative injury. Mitochondrial dysfunction most immediately impacts postoperative myocardial contractility, but also predisposes to arrhythmias. A multitude of strategies to minimize the impact of perioperative factors on mitochondrial function have been incorporated into routine clinical care (hypothermia, avoidance of hyperglycemia or hypercalcemia, substrate and other additions to cardioplegia solutions, anesthetic choice), whereas other more targeted therapies (antioxidants, ischemic conditioning, modulators of MQC mechanisms), remain under investigation or are in development for use in selected settings.

KEY POINTS.

• Mitochondria are key to cellular energy production, but are also vital to reactive oxygen species signaling, calcium haemostasis, and regulation of cell death.

• Cardiac surgical patients with chronic comorbidities (diabetes, heart failure, advanced age, cardiomyopathies) may have preexisting mitochondrial dysfunction or be more sensitive to perioperative injury.

• Mitochondrial dysfunction from ischemia/reperfusion injury and inflammatory responses to cardiopulmonary bypass and surgical tissue trauma impact myocardial contractility and predispose to arrhythmias.

• Strategies for perioperative mitochondrial protection or recovery after injury include well-established cardioprotective protocols as well as a number of targeted therapies that remain under investigation.

CLINICS CARE POINTS.

• Glycemic control, controlled calcium supplementation, cooling to reduce metabolic rate, and cardioplegia administration are evidence-based ways of protecting mitochondria during cardiac surgery.

• There is mixed evidence for improved outcomes with differing anesthetic regimens, glucose-insulin-potassium strategies, short vs. long acting cardioplegia solutions, ischemic preconditioning, and systemic antioxidants.

• There is yet insufficient clinical evidence for promising strategies to protect or augment mitochondrial function including cardioplegia additives/supplements, targeted antioxidant or MQC therapies, and in the setting of heart transplantation, alternative perfusion strategies for donor organs.

Abbreviations

AF

Atrial fibrillation

ATP

Adenosine triphosphate

CPB

Cardiopulmonary bypass

DAMPs

Damage-associated molecular patterns

DCD

Donation after circulatory death

ETC

Electron transport chain

I/R

Ischemia/reperfusion

MPTP

Mitochondrial permeability transition pore

MQC

Mitochondrial quality control

mtDNA

Mitochondrial DNA

PGC-1a

proliferator-activated receptor gamma coactivator 1-alpha

ROS

Reactive oxygen species