Cardioprotection in cardiovascular surgery

Abstract

Since the invention of cardiopulmonary bypass, cardioprotective strategies have been investigated to mitigate ischemic injury to the heart during aortic cross-clamping and reperfusion injury with cross-clamp release. With advances in cardiac surgical and percutaneous techniques and post-operative management strategies including mechanical circulatory support, cardiac surgeons are able to operate on more complex patients. Therefore, there is a growing need for improved cardioprotective strategies to optimize outcomes in these patients. This review provides an overview of the basic principles of cardioprotection in the setting of cardiac surgery, including mechanisms of cardiac injury in the context of cardiopulmonary bypass, followed by a discussion of the specific approaches to optimizing cardioprotection in cardiac surgery, including refinements in cardiopulmonary bypass and cardioplegia, ischemic conditioning, use of specific anesthetic and pharmaceutical agents, and novel mechanical circulatory support technologies. Finally, translational strategies that investigate cardioprotection in the setting of cardiac surgery will be reviewed, with a focus on promising research in the areas of cell-based and gene therapy. Advances in this area will help cardiologists and cardiac surgeons mitigate myocardial ischemic injury, improve functional post-operative recovery, and optimize clinical outcomes in patients undergoing cardiac surgery.

Introduction

The invention of the heart lung machine in 1953 by John Gibbon built the foundation of modern cardiac surgery, allowing for a bloodless field for revascularization, repair, and reconstruction of the heart, while maintaining end organ perfusion [127]. Since the establishment of cardiopulmonary bypass, cardioprotective strategies have been investigated to mitigate ischemic injury to the heart during aortic cross-clamping and the reperfusion injury that ensues with cross-clamp release. With advances in cardiac surgical and percutaneous techniques and post-operative management strategies including mechanical circulatory support, cardiac surgeons are able to operate on more complex patients. Therefore, there is a growing need for improved cardioprotective strategies to optimize outcomes in patients undergoing cardiac surgery [41, 53, 72, 205]. In the following review, we will provide an overview of the basic principles of cardioprotection in the setting of cardiac surgery, including mechanisms of cardiac injury in the context of cardiopulmonary bypass. We will then discuss specific approaches to optimizing cardioprotection in cardiac surgery, including refinements in cardiopulmonary bypass and cardioplegia, ischemic conditioning, use of specific anesthetic and pharmaceutical agents, and mechanical circulatory support technologies. Finally, we will discuss translational strategies that can be used to investigate cardioprotection in the setting of cardiac surgery, with a focus on promising research in the areas of cell-based and gene therapy.

Methodology

In order to construct this review, a comprehensive literature review was conducted using major scientific databases, particularly PubMed and Google Scholar, using relevant keywords that were pertinent to the field of cardioprotection and cardiovascular surgery, including the following: cardiovascular surgery, cardiac surgery, cardioprotection, cardiopulmonary bypass, cardioplegia, mechanical circulatory support, temporary left ventricular assist device, extracorporeal membrane oxygenation, ischemic conditioning, ischemia reperfusion, cardiac surgery anesthesia, perioperative cardioprotection, extracellular vesicles, and mitochondrial transplant. Studies were selected based on relevance as determined by author review of whether manuscript was pertinent to the topic of cardioprotection in the specific context of cardiovascular surgery, credibility as determined by author review of study methodology and that study was published in a peer-reviewed journal, date of publication which spanned from 1961 to 2024, with the majority of articles cited in the current review published in the last decade, and impact on the field of cardioprotection in the setting of cardiac surgery as determined by comprehensive review of the literature and identification of select studies that have been highly cited and referenced in the field of cardioprotection in cardiovascular surgery. The literature on cardioprotection is vast, therefore some articles were selected as examples of methodology on how studies in this field are conducted. We sought to provide a comprehensive overview of recent literature while highlighting key advances and future research directions in the evolving field of cardioprotection in the setting of cardiovascular surgery.

Basic principles of cardioprotection

Mechanisms of injury

As with any tissue, myocardium is susceptible to damage when exposed to ischemia. It has been well established that the myocardium has the highest oxygen extraction from blood, therefore lack of perfusion to cardiomyocytes leaves not only a dearth of oxygen for metabolic processes but makes it also bereft of critical ions and metabolites thereby disrupting homeostatic equilibrium [75, 185]. Metabolic pathways essential for cell survival rapidly change from favoring an oxidative phosphorylation state to a predominately glycolytic state [185]. This acutely results in an 90–95% reduction in available adenosine triphosphate (ATP) by sixty minutes at which point myocyte death is observed [185].

Given the sensitivity of myocardium to ischemic injury, the standard of care for myocardial ischemia has been prompt coronary reperfusion. However, reperfusion itself, as occurs with coronary revascularization in the setting of coronary artery bypass grafting (CABG) or with release of aortic cross-clamp following cardioplegic arrest, carries considerable risk to the myocardium. Ischemia reperfusion injury (IRI) refers to dichotomous injuries caused both by the initial ischemic insult and the resulting injury caused by reperfusion of that injured tissue. Rather than restoring homeostasis as expected, reperfusion results in a myriad of alterations to the tissue microenvironment, including pH dysregulation, accumulation of oxygen free radicals, and cell death. There is a growing body of evidence that this IRI can be mitigated via certain cardioprotective strategies such as ischemic preconditioning or remote ischemic preconditioning [84]. These concepts will be explored later in this manuscript however this field is broad and cannot be discussed in its entirety within bounds of this article, however several recent comprehensive reviews by Heusch et al. cover this topic in great detail [85].

With regard to pH, a glycolytic switch secondary to ischemic buildup of metabolic waste products results in a low pH environment yet restoration of physiologic pH by reperfusion can further cell damage as Na is shunted into the myocyte by the Na/H exchanger with restoration of normal extracellular H + levels. The increase in intracellular Na in turn causes a calcium overload leading the Na/Ca exchanger to exchange intracellular sodium for extracellular calcium to compensate. Resulting elevated levels of intracellular calcium then cause disturbances in regulation of a multitude of intracellular pathways, most notably upregulating mitochondrial release of cytochrome C and thus activating the intrinsic apoptotic pathway ultimately leading to cell death [185].

Ischemic injury to the myocardium also results in accumulation of oxygen free radicals, and this can be compounded with restored coronary blood flow which has been shown to accelerate tissue damage [148, 225]. These ROS can cause cellular damage via lipid peroxidation and damaging nucleic acids. In the setting of IRI there are multiple mechanisms that lead to inappropriately increased ROS levels including dysregulation of the enzymes NADPH and NOX and increased free radical production from mitochondrial electron transport chain [225]. In the setting of IRI these ROS contribute to damaging what may have been viable cells and causing increased tissue death.

Cell death caused by both the initial ischemic insult and IRI results in yet another mechanism of cellular injury, increased inflammation and complement deposition. As with any cell death damage associated molecular patterns (DAMPs) are released into the milieu attracting immune cells such as leukocytes. These leukocytes in turn release a cascade of proinflammatory cytokines which have been shown to exacerbate the damage caused by ischemic injury. For example, studies have established increased levels of TNFa in the penumbra of the infarcted tissue post MI [185, 199]. Furthermore, animal models such as knockout TNFa receptors mice have demonstrated decreased infarct size and resistance to IRI when compared with controls [137, 185]. Other mediators of inflammation, such as interleukin 1 and interleukin 6, have also been implicated in exacerbating the pathologic response to ischemic insult [51, 148]. The release of DAMPs has also been associated with complement activation. Animal models have shown increased presence of the C5b-9 aka the membrane attack complex (MAC) in infarcted tissue [140, 148]. These findings were later demonstrated in cadaveric tissue of patients who died from ischemic cardiac events compared to controls [148, 212]. Given the role of the MAC in neutrophil activation this increase in complement further contributes to the damage seen in cardiac ischemia.

Therefore, there are a number of mechanisms involved in injury to the heart during ischemia and subsequent reperfusion (Fig. 1). These mechanisms are relevant during revascularization of chronically ischemic myocardium in the setting of CABG for coronary artery disease. However more importantly, these mechanisms may be involved in cardiac injury in the setting of cardioplegic arrest and subsequent reperfusion during cardiopulmonary bypass, which will be discussed in the following section.

Fig. 1.

Mechanisms and contributors to myocardial injury in cardiac surgery. Cardiac surgery involving cardioplegic arrest and reperfusion leads to a variety of insults to the myocardium including generation of reactive oxygen species, microvascular dysfunction, abnormal calcium signaling, altered metabolism, and increased inflammation

Overview of cardiopulmonary bypass and cardioplegia

Fundamental to cardiac surgery is cardiopulmonary bypass. While open-heart surgery had been performed previously, widespread open-heart surgery was not possible until 1953 with the creation of viable cardiopulmonary bypass (CPB) by Gibbon [122, 159]. CPB in short functions to allow a bloodless field of surgery by bypassing and replacing the circulatory function of the heart while oxygenating blood. This is accomplished by the CPB circuit in which venous blood is drained via a cannula to the reservoir. De-oxygenated blood is then pumped from this reservoir and passed through a heat exchanger and oxygenator prior to returning to the arterial circulation [182].

During CPB, the heart is often arrested in order to create a bloodless field while maintaining end organ perfusion. This is not only to facilitate the operation by removing intrinsic cardiac motion but also aids in reducing the metabolic demands of cardiac tissue while on CPB [182]. The arrest is accomplished via administration of cardioplegia solution, which may be a potassium rich solution or a solution with low concentration of Na and Ca to induce diastolic arrest, as well as cross-clamping the aorta to prevent warm oxygen-rich blood from perfusing the coronaries. It is worth noting that another strategy for cardiac arrest are the polarizing cardioplegic solutions that use esmolol, adenosine, and high concentrations of magnesium to arrest the heart. These polarization solutions have shown some promise demonstrating cardioprotection in preclinical large animal models [1, 179]. There are a wide variety of cardioplegic solutions but in general they can be divided into two categories, blood-based cardioplegia and crystalloid cardioplegia. Blood-based cardioplegia solutions, such as St. Thomas blood cardioplegia or Buckberg cardioplegia, are blood-based solutions in which electrolytes including potassium and medication are added. These solutions are designed to provide an appropriate facsimile of the physiologic environment created by blood. Crystalloid cardioplegia, such as Bretschneider solution, uses a crystalloid solution of electrolytes and medication in order to arrest the heart and while is not inherently as physiologic as its blood cardioplegia counterpart it may offer cardioprotective benefits [59]. While cardioplegia solution is essential to both arrest and protect the heart during CPB it is further augmented by inducing a hypothermic environment. Reducing temperature to 31–32 degrees Celsius aids in arresting this heart and reduces the metabolic demands of the myocardium [182] (Table 1). However, the actual reduction in oxygen consumption attributed to temperature reduction is marginal. [25]. While covered in brief in this review, the role of various specific types and variations of cardioplegia in cardioprotection is extensive and reviewed in more detail by Mukharyamov and others [150].

Table 1.

Types of common cardioplegia and their constituent components

	Type	Concentration	Components
Del Nido solution [24]	Extracellular	294 mOsmol/Kg	Na (150 mmol/L), Cl (132 mmol/L), K (24 mmol/L), Mg (6 mmol/L), Ca (0.4 mmol/L), Lidocaine (140 mg/L), Mannitol (14.5 mmol/L),
St. Thomas solution No 2 [124]	Extracellular	285–300 mOsm/Kg	Na (110 mmol/L), K (16 mmol/L), Mg (16 mmol/L), Ca (1.2 mmol/L), NaHCO3 (10 mmol/L)
Bretschneider solution [60]	Intracellular	310 mOsmol/L	Na (15 mmol/L), K (9 mmol/L), Mg (4 mmol/L), Ca (0.015 mmol/L), Mannitol (30 mmol/L), Histidine (198 mmol/L), Tryptophan (2 mmol/L), Ketoglutarate (1 mmol/L)
Cold blood cardioplegia [24]	Extracellular	304–320 mOsmol/Kg	Na (136–152), Cl (126–132), K (13–24), Mg (2–13), Ca (0–1), Lidocaine (27 mg/L), Mannitol (0–12 mmol/L)

Types of injury that cardioprotection can attenuate

The cardioprotection provided by both cardioplegia solution and hypothermia represent some of the many strategies used to mitigate damage caused both by cardiac ischemia and IRI in the setting of cardiac surgery. Given the global ischemic state, followed by a global ischemic reperfusion state caused by CPB, enhancing cardioprotective strategies in cardiac surgery has been an area of great interest and research. Initially, global hypothermia was use to lower overall metabolic demand and preserve tissue ATP during ischemia [29]. However, this alone failed to provide adequate cardioprotection and lead to the advent of diastolic arrest cardioplegia solutions used today. The use of cardioplegic solution has been demonstrated to significantly lower myocardial tissue oxygen demand [29]. By lowering myocardial oxygen demand and preserving stores of ATP these protective strategies mitigate some of the damage caused by large shifts in metabolic disturbances, pH imbalance, and, intracellular calcium shifts seen with ischemia and subsequent repersion [198]. However, reducing damage caused by ischemia and reperfusion are not the only benefits of cardioprotection, as cardioprotection has been shown to modify clinical outcomes, such as transfusion requirements, as well as cellular signaling, such as altered expression of inflammatory mediators. These concepts will be explored further below.

Approaches to cardioprotection in cardiac surgery

Cardiopulmonary bypass and cardioplegia

A fundamental aspect of cardioprotection in relation to cardiac surgery involves optimizing CPB and cardioplegia. This section will begin with an overview of the limitations of CPB and cardioplegia in order to highlight some advances that have been made to improve these adjuncts to cardiac surgery.

While necessary for many aspects of cardiothoracic surgery, CPB inherently alters the physiologic status quo and carries with it risks and complications. Roller pumps were the first substitute for the pump action of the human heart used in CPB. Unfortunately, the mechanical compression of these pumps induces hemolysis and can result in anemia [182]. Centrifugal pumps are often used to circumvent this issue; however, these pumps rely on a pressure differential in order to propel blood antegrade through the circuit so output can diminish if patients’ systemic vascular resistance increases. Furthermore, in the event of termination of pump action, there can be retrograde flow through CPB circuits driven by centrifugal pumps [182]. Blood itself is also altered by the CPB circuit. Clotting can be a catastrophic complication and with the increase in blood viscosity caused with induction of hypothermia and contact with artificial surfaces increases the propensity of clots to form through activation of the intrinsic coagulation cascade [158]. Additionally, it has been well established that CPB induces a proinflammatory state that can further injure the coronary endothelium and the myocardium. In particular CPB has been demonstrated to increase inflammation via increased levels of TNFα, IL-6, and IL-8 [158, 182]. However, this inflammation has been shown to be reduced of multiple strategies such as the use of nitric oxide or leukocyte reduction [198]. Furthermore, the act of cross-clamping the aorta inherently induces a myocardial ischemic state exposing the myocardium to risk of both ischemic injury and IRI.

Over time, refinements have been made in order mitigate the complications and myocardial injury inherit to CPB. Ultrafiltration is now used and is demonstrated to decrease transfusion requirements [182]. The use of thromboelastography has added in product specific resuscitation and reduced overall transfusion requirements [70]. However, none of these advances directly address the myocardium at risk from CPB. To that end, cardioprotection in the form of changes in cardioplegia has been an area of interest in order to improve clinical outcomes. Historically cardioplegia was blood-based, but centers have increasingly been using crystalloid-based solutions. There has been much debate as to the relative merits of each of these solutions. In a 2006 meta-analysis of outcomes of blood vs crystalloid cardioplegia, blood cardioplegia appeared to offer a mild cardioprotection advantage with lower rates of early CKMB release, however, no difference was seen in myocardial infarction (MI) or death [64]. More recently, in a study comparing matched cohorts of 143 patients undergoing CABG with St. Thomas blood cardioplegia vs Del Nido Crystalloid (DNC) cardioplegia, outcomes, such as CKMB, transfusion rates, and 30-day mortality, were not significantly different, however there was less need to re-dose DNC compared with blood cardioplegia and post-operative left ventricular ejection fraction (LVEF) was slightly higher in the blood cardioplegia cohort (53.4 vs 56.0) [59].

Several additives to cardioplegic solutions have been investigated to target the coronary endothelium. Coronary endothelium maintains homeostasis and regulates coronary perfusion by releasing several vasoactive compounds, most notably nitric oxide, which has a number of effects including coronary vasodilation, free radical scavenging, lusotropy, and regulation of myocardial contractility [165, 173]. As previously mentioned, CPB is known to induce endothelial dysfunction, therefore targeting endothelial cells has been proposed as an important approach to cardioprotection [165]. Specific additives that have been investigated in this regard include free radical scavengers, bradykinin, angiotensin converting enzyme antagonists, calcium antagonists, and substrates and cofactors of endothelial nitric oxide synthase, which are thoroughly reviewed elsewhere [164, 165]. Some of these agents have been investigated in clinical trials with mixed results [164], and further investigation is needed as to whether these additives have a role in standard practice to optimize perioperative cardioprotection.

The milieu of cardioplegia solution is but one of many factors that aid in cardioprotection. One major area of debate is warm vs hypothermic delivery of cardioplegia solution. The concept of reducing metabolic demand through hypothermia, though intuitive, comes with its own host of complications, namely arrhythmogenicity. While this shortcoming was largely overcome by the advent of depolarization cardioplegia solutions (i.e., with the addition of potassium to arrest the heart) more recent advances in using arm blood cardioplegia have become popular and shown potential cardioprotective benefits. However, this remains a controversial area that is still being actively researched. In one retrospective cohort study of patients undergoing CABG with either intermittent cold blood cardioplegia or intermittent warm blood cardioplegia, no difference was seen in 30-day or 1-,3-, and 6-year survivial [224]. In the largest known study of 2188 patients intermittent cold blood cardioplegia and intermittent warm blood cardioplegia lead to no significant difference in 30-day mortality, stroke, renal failure or atrial fibrillation between groups. Interestingly, in this same study patients undergoing emergent surgery warm cardioplegia solution did lead to a significantly reduced 30-day mortality [209].

In addition to the specific cardioplegia solutions, there are also important technical aspects with regard to cardioplegic administration that must be considered to achieve adequate myocardial protection (Fig. 2). There are multiple strategies for administering cardioplegia solution to the heart during CPB. The most basic forms are described as antegrade and retrograde. In antegrade cardioplegia, the cardioplegia solution is administered proximal to the aortic cross-clamp and flows in an antegrade fashion through the coronary system. In retrograde cardioplegia, a window is made in the right atrium and cardioplegia solution is delivered through the coronary sinus thereby traveling backwards to normal physiologic blood flow [224]. Each of these delivery strategies has its limitations. Antegrade administration depends on a patent coronary arteries so in cases where there is flow-limiting severe coronary stenosis or if the patient has non-physiologic anatomy (i.e., a previous CABG with LIMA graft) this administration method will fail to deliver cardioplegia and provide cardioprotection to the myocardium [153, 178]. Furthermore, in cases of aortic valve insufficiency, antegrade cardioplegia cannot reliably be used due to regurgitation into the left ventricle rather. In the case of LV hypertrophy, both antegrade and retrograde cardioplegia may provide suboptimal protection to the vulnerable subendocardial myocardium in the hypertrophied ventricle [8, 28, 134], and other strategies including cold blood cardioplegia or cardioplegic additives have been investigated and may be useful approaches [198]. Notably, retrograde cardioplegia does not provide cardioprotection to the right ventricle as the coronary sinus does not provide drainage for this area [5].

Fig. 2.

Technical considerations of cardioplegia administration. Several technical considerations should be considered when administering cardioplegia in the setting of cardiopulmonary bypass (CPB). Considerations specific to antegrade cardioplegia include presence of coronary artery disease, aberrant coronary arterial anatomy, presence of aortic regurgitation. Considerations specific to retrograde cardioplegia presence of aberrant venous anatomy and awareness of inadequate right ventricular (RV) perfusion. Both antegrade and retrograde cardioplegia may provide suboptimal protection in the setting of left ventricular (LV) hypertrophy

Ischemic conditioning

An important area of investigation into cardioprotection in the setting of cardiac surgery has been ischemic conditioning. As an approach to mitigate injury from ischemic and/or ischemic/reperfusion injury during cardiac surgery, ischemic conditioning refers to the exposure of myocardium to periods of ischemia to reduce a prior or anticipated ischemic injury. There are three major subtypes of ischemic conditioning that warrant discussion in the setting of cardiac surgery: ischemic preconditioning, ischemic postconditioning, and remote ischemic conditioning. First, we will review the mechanisms of ischemic conditioning.

Brief overview of mechanisms of ischemic conditioning

The topic of mechanisms and molecular signaling of ischemic conditioning is vast and more thoroughly reviewed elsewhere [81], but a few important mechanisms will be highlighted. Conditioning can be elicited by physical stimuli, such as myocardial stretch, chemical stimuli including calcium, reactive oxygen species, and nitric oxide, and other molecules or proteins including neurohormones, growth factors, cytokines, peptides, lipids, and autacoids, such as adenosine and bradykinin [81]. Adenosine, which is released by cardiomyocytes and endothelial cells, is a particularly important mediator of cardioprotection in the setting of reperfusion [81] via activation of the reperfusion injury salvage kinase (RISK) pathway. The RISK pathway involves activation of PI3K, phosphoinositide-dependent kinase, Akt, and ERK during early reperfusion and is a necessary for preconditioning and exogenous agonist-mediated infarct reduction [81]. An additional pathway that is activated in both ischemic preconditioning, postconditioning, and possibly remote ischemic conditioning, is the survival activating factor enhancement (SAFE) pathway, in which STAT3, TNFalpha, and TNF receptor 2, are central components [81, 115]. Finally, it is important to highlight the central role of mitochondria in the cardioprotective response to conditioning [81, 112]. Mitochondria generate ATP for cardiomyocytes which is foundational to cardiomyocyte excitation, contractility, and survival. Cardioprotective signaling in the mitochondria occurs at the level several subcomponents, including mitochondrial permeability transition pores, respiratory chain complexes, and endoplasmic/sarcoplasmic reticulum, and these mechanisms are reviewed in detail elsewhere [81].

Ischemic preconditioning

Ischemic preconditioning, as implied in the name, refers to the exposure of myocardium to periods of ischemia prior to an anticipated ischemic insult to mitigate ischemic injury. In the context of cardiac surgery, the anticipated ischemic insult is the cardiac surgical procedure itself particularly cardiac arrest with aortic cross-clamping. The first clinical study of ischemic preconditioning in the setting of cardiac surgery was conducted by Yellon and others [222]. In this study, fourteen patients undergoing CABG were randomized into two groups, one of which received ten minutes of cross-clamp fibrillation, and the other which underwent two 3 min periods of aortic cross-clamping followed by 2 min of reperfusion, followed by ten minutes of cross-clamp fibrillation. Importantly, left ventricular ATP concentration was higher in the preconditioned group compared to control after the ten minute ischemic insult [222]. Jenkins, Yellon and others, using the same preconditioning protocol a few years later, further demonstrated that serum troponin T, a marker of ischemic injury, was decreased in the preconditioned group compared to control [99]. It is important to note that this strategy of repeated aortic cross-clamping would be clinically challenging to implement in older populations with atherosclerotic and calcified aortas due to risk of atheroembolization particularly to the cerebral circulation.

Pharmacological preconditioning has also been investigated as a means of conferring cardioprotection in the setting of cardiac surgery. Teoh et al. conducted a randomized trial of thirty patients undergoing CABG who were assigned to intermittent cross-clamp fibrillation, ischemic preconditioning as conducted in the earlier studies by Yellon, or pharmacological preconditioning with an adenosine A1 receptor agonist [202], which activates the RISK pathway as previously discussed. Using serum troponin T as a marker of ischemic injury, they found that decreased serum troponin T in patients who underwent ischemic preconditioning but not pharmacologic preconditioning [202]. This study was also unique compared to the aforementioned preconditioning studies in that it investigated clinically relevant parameters including myocardial function, inotrope requirement, and post-operative complications [202]. Importantly, there were no differences in these clinical parameters across all groups, suggesting that ischemic preconditioning may confer some biological protection, but the clinical relevance of these changes was unclear.

Preconditioning using noble gasses has also been investigated as an approach to cardioprotection. For instance, helium has been shown in rat models of ischemia/reperfusion to induce preconditioning and reduce infarct size [80]. However a clinical trial investigating helium pre-conditioning in patients undergoing CABG found no changes in troponin release or molecular signaling markers related to conditioning [192]. Argon gas has been shown in preclinical studies to reduce inflammation and improve cardiac function in the setting of ischemia/reperfusion. One study, using a rat model, found that following in the setting of cardioplegic arrest and reperfusion, argon preconditioning was associated with improved cardiac functional parameters and coronary flow [109]. Similar preclinical studies have been conducted in the setting of postconditioning [126]. However, clinical studies have yet to investigate the role of argon in cardioprotection [143]. Therefore noble gasses may be a potential approach for cardioprotective preconditioning though there is still a lack of clinical data to support the use of these agents in practice.

Many other studies have investigated ischemic preconditioning in the setting of cardiac surgery, most of which determined that ischemic injury as measured by reduction in either serum troponin or CKMB is reduced with preconditioning [88], but the changes in clinically relevant parameters in these studies are mixed. There are a handful of studies that found clinically relevant differences in patients subjected to ischemic preconditioning in the setting of cardiac surgery, including reduced inotropic support, decreased post-operative arrhythmias, and decreased hospital stay [26, 88, 98, 128], but many others that found no differences in functional or clinical parameters outside of biomarker differences [88]. Therefore, the role of ischemic preconditioning in the setting of cardiac surgery is still poorly defined.

Ischemic postconditioning

Ischemic postconditioning refers to the exposure of the myocardium to ischemia following an ischemic insult. Safaei and others investigated ischemic postconditioning as a cardioprotective strategy in the setting of CABG in a double blinded study of 51 patients [176]. Following surgical revascularization, ischemic postconditioning was induced with three cycles of 60 s of ischemia followed by reperfusion by intermittent occlusion and release, respectively, of the coronary grafts. Patients were divided into three groups, with one group undergoing ischemic postconditioning as described above, and the other two groups undergoing pressure-controlled reperfusion from the aortic root alone or combined with the postconditioning strategy. They found that patients in the ischemic postconditioning group had improved post-operative ejection fraction recovery, inotrope requirement, and post-operative dysrhythmias [176]. The major limitation of this study however was in methodology, as patients in the postconditioning group had full reperfusion with systemic pressure earlier than in the pressure-controlled reperfusion group and the combined group, and the lack of pronounced benefit in the combined group compared to the control group detracts from the perceived benefit of the ischemic postconditioning strategy. Durdu and others had investigated postconditioning by a similar approach with intermittent graft occlusion and release, and they found reduced ischemic biomarkers with postconditioning, though the clinical relevance of these findings are not clear [47].

Two major studies investigated the effect of postconditioning in patients undergoing elective valve replacement. A smaller study of fifty adult patients undergoing elective valve replacement who underwent ischemic postconditoning with three cycles of ischemia/reperfusion by aortic clamping and unclamping found postconditioning was associated with reduced ischemic biomarkers and reduced post-operative inotrope requirements [136]. A more recent randomized trial of 209 patients undergoing elective aortic valve replacement investigated ischemic postconditioning with three cycles of ischemia/reperfusion antegrade cardioplegia, with less promising results [101]. Though there were some sex-specific benefits in post-operative cardiac function with postconditioning, there was no overall difference in post-operative ischemic biomarkers, cardiac function, hemodynamics, or dysrhythmias between groups. [101] Thus, ischemic postconditioning in the setting of cardiac surgery has shown some promise in clinical trials [88], though results are mixed and effects on post-operative functional recovery are limited.

Remote ischemic conditioning

Remote ischemic conditioning, in the context of cardiac cardioprotection, refers to exposure of a non-cardiac vascular bed to ischemia/reperfusion in order to confer cardioprotective effects. In cardiac surgical clinical trials, this is typically achieved by several cycles of cuff inflation and release at the right upper extremity to induce ischemia/reperfusion to the peripheral muscular bed.

Several randomized control trials have shown cardiac benefits to remote ischemic conditioning in the setting of coronary and valvular surgery. Hausenloy and others, in a study of 57 patients undergoing elective CABG, demonstrated that remote ischemic conditioning was associated with reduced post-operative ischemic biomarkers [74]. Thielmann and others, in a larger randomized trial of patients undergoing elective CABG, also found that this intervention was associated with reduced post-operative ischemic biomarkers, in addition to reduced all-cause one year mortality and reduced major adverse cardiac and cerebral events at thirty days and one year. Smaller studies including patients undergoing valvular surgery have similarly demonstrated reduced post-operative ischemic biomarkers and in some cases improved cardiac functional parameters with remote conditioning. [15, 16] Though these findings are promising, subsequent randomized trials with notably larger patient enrollment (RIPHeart and ERICCA trials) found that in patients undergoing elective CABG, remote conditioning was not associated with mortality or other outcomes including post-operative ischemic biomarker concentrations, myocardial infarction, length of stay, dysrhythmias, among other clinical parameters [73, 145, 146]. Importantly, most patients in these larger trials received propofol for anesthesia, which may blunt the cardioprotective effect of remote ischemic conditioning [118].

Other smaller randomized trials have also shown neutral results with regard to remote conditioning and cardiac surgery [149, 163]. One clinical trial also utilized tissue analysis with harvest of human ventricular tissue following cardiac surgery with remote conditioning, and found no differences in troponin release or inflammatory markers between groups [149]. A Cochrane review from 2017, which included 29 studies involving over 5000 patients undergoing CABG with or without valve surgery, concluded that there is moderate quality evidence that remote ischemic conditioning reduces troponin release post-operatively, but no strong evidence of improvement in clinical outcomes including mortality, MI, or stroke [11]. Comprehensive reviews focused on remote ischemic conditioning, including in the setting of cardiac surgery, provide a more detailed analysis of disparate methodology and findings of these trials [82, 83, 86], but it is reasonable to conclude that trials of remote ischemic conditioning in the setting of cardiac surgery have had mixed results, and the role of ischemic conditioning in clinical practice is poorly defined.

Role of ischemic conditioning in cardiac surgery

We have provided a brief overview of the strategies of ischemic conditioning in cardiac surgery, and key clinical trials of ischemic pre and post conditioning as well as remote ischemic conditioning, which have had mixed results. Heusch and Rassaf outline a detailed and comprehensive review of ischemic conditioning for cardioprotection [88], inclusive of studies involving cardiovascular surgery, which highlights the heterogeneity in methodology and overall scarcity of rigorously designed and high-powered clinical trials in this area [88]. Therefore, while there is inadequate evidence to incorporate ischemic conditioning into standardized cardiac surgical practice, further investigations are necessary to more definitely elucidate whether there is a role of ischemic conditioning in cardiac surgery.

Anesthesia and pharmaceutical agents

While reduction of myocardial metabolic demand and cardioplegia remain central to cardioprotective strategies, augmentation with anesthesia and pharmaceutical agents has shown promise. Preclinical animal models have demonstrated that a variety of pharmaceutical agents have the potential to provide cardioprotection. For example, in a rat model, cangrelor and endonuclease III given at the time of reperfusion demonstrated reduced infarct size [37]. Similarly, esmolol and milrinone have demonstrated reduced MI size and decreased apoptosis in rat models [37]. Unfortunately, many of these compounds have yet to demonstrate the same effects when tested in the clinical setting. For example, phase III trials of cyclosporine, which initially showed promise in smaller studies, failed to improve clinical outcomes [36, 111]. Similarly, attempts to study the cardioprotective effects of volatile anesthetic agents, such as sevoflurane, have been met with mixed results with some studies reporting improvement in biomarkers levels such as troponin release and some clinical benefit while others report no benfit [38].

We previously discussed the potential relationship between remote preconditioning efficacy and anesthetic agents, specifically propofol. Thus it is important to consider that other anesthetic agents may optimize cardioprotection from remote conditioning. One randomized trial of remote ischemic preconditioning used in conjunction with isoflurane and sufentanil showed decreased serum troponin I levels during CABG, yet remote conditioning with propofol and sufentanil did not show the same results [119]. Further studies are necessary in this area which may potentially unlock the clinical potential of remote preconditioning as a cardioprotective strategy in cardiac surgery.

It is important to realize that cardioprotection is not limited to the operative time window. Pre-operative optimization has a large role to play. Beta blockers for example have been shown to be cardioprotective in numerous populations especially in those with comorbidities, such as hypertension and diabetes [48]. However, data regarding the role of metoprolol in myocardial protection is mixed. One study of an ischemia reperfusion model in adult Gottingen minipigs showed no reduction in infarct size in the metoprolol treatment group when compared with controls [95, 114]. Human trials have had more mixed results with METOCARD-CNIC) trial demonstrating reduced infarct size when metoprolol was administered early (i.e., in the ambulance) [110]. However, these results failed to be replicated in STEMI patients randomized to metoprolol vs placebo before PCI [171].

Similarly, preoperative management of low density lipoprotein via statin therapy has been shown to improve cardiovascular outcomes [154]. It is for this reason that the ACC/AHA guidelines on treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults recommends high intensity statin therapy for patients with clinical atherosclerotic cardiovascular disease [154, 226]. More recently antidiabetic medications have garnered interest for their role in cardioprotection. Sodium glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated not only reduced cardiovascular events in patients with DM, but more recently have demonstrated decreased risk of cardiovascular death in patients with heart failure [211]. GLP1R agonists, another class of antidiabetic drugs, has also shown cardioprotective effects. One trial demonstrated that patients with type II DM and high cardiovascular risk had a reduction in the composite outcome of CV death, non-fatal MI, and nonfatal stroke compared with placebo [4, 139].The inotrope levosimendan has also been identified as a cardioprotective agent. This drug has shown in randomized control trials to be superior to placebo at lowering troponin levels and preserving cardiac index after cardiac surgery [181]. Nitrates too have a role in cardioprotection. Nitrates have clinically demonstrated reduction in mortality post-acute MI and have been demonstrated to improve post infarct remodeling [142]. Therefore there is a diverse and growing armamentarium of pharmacologic interventions to aid in cardioprotection.

Mechanical support and myocardial protection

Myocardial protection, as described earlier, refers to the measures taken to prevent heart muscle damage during periods of compromised blood flow. Myocardial protection is traditionally thought of as a key component in cardiac surgery and cardiopulmonary bypass, but it is also important to consider myocardial preservation in the setting of acute heart failure and cardiogenic shock. Mechanical circulatory support (MCS) has become a pivotal component in the management algorithm for cardiogenic shock and heart failure [201]. In this section, we will review the three main types of MCS for cardiogenic shock and explore the use of ex vivo perfusion for myocardial protection in donor hearts during transplantation.

Intra-aortic balloon pump (IABP)

Developed in the 1960s, the intra-aortic balloon pump (IABP) was the initial and, for many years, the sole MCS option for patients with acute cardiogenic shock [103]. A percutaneous technique is employed to position the balloon just below the ostium of the left subclavian artery [23]. The balloon inflates during diastole and deflates during systole to provide counterpulsation [23]. IABP support enhances coronary perfusion, reduces afterload, and decreases myocardial oxygen consumption [201]. By increasing coronary blood flow and reducing myocardial oxygen consumption, IABPs contribute to myocardial protection, often resulting in improved cardiac function and cardiac output [201]. However, the clinical data for IABPs have shown mixed results with some studies suggesting that IABPs are not associated with increased cardiac function or long-term survival [52, 203, 204]. However, IABPs still maintain a valuable clinical role as a bridge to myocardial recovery or more definitive therapy such as revascularization or transplantation.

Venoarterial extracorporeal membrane oxygenation (VA ECMO)

VA ECMO allows for more complete cardiopulmonary support [201]. In cases of emergent cardiogenic shock, the patient is typically cannulated peripherally using the femoral artery and vein or centrally using the aorta and left atrium after failed weaning from bypass following cardiac surgery [161]. VA ECMO allows for cardiac unloading by decreasing preload which results in decreased stress on the myocardium and decreased myocardial oxygen consumption [210]. While VA ECMO oxygenates blood and returns it to the arterial system, the extent to which it augments coronary perfusion remains a subject of debate. Studies conducted on swine and lambs have yielded mixed results, with some indicating no change in coronary perfusion and others demonstrating an increase in coronary perfusion [108, 152, 193]. This likely helps to decrease inflammation and oxidative stress in the setting of increased oxygenation [71]. Despite the variability in coronary perfusion, VA ECMO significantly contributes to myocardial protection and has shown, in limited human studies, to reduce mortality in patients with cardiogenic shock from acute myocardial ischemia [54, 156, 183, 189]. The overall survival with VA ECMO is still poor with studies showing and up to 70% of patients surviving to discharge and only 30–40% long-term survival [15, 92]. ECMO can play an important role in allowing time for myocardial recovery or bridging patients to definitive therapy.

Temporary ventricular assist device

Temporary ventricular assist devices are a growing area of interest. Temporary ventricular assist devices can be divided into two categories; temporary right ventricular assist devices (TRVAD) or left ventricular assist devices (TLVAD) [201].

TRVADs function to unload the right ventricle and augment right ventricular outflow [2]. They come in various forms, with the Impella RP and TandemHeart RVAD being among the most common options. Both the Impella RP and TandemHeart RVAD are inserted percutaneously via femoral vein access. Another option is the Protek Duo, which is inserted through the right internal jugular vein allowing for patient ambulation [104]. TRVADs provide support to the heart by augmenting right ventricular outflow, thereby reducing preload and strain on the right heart. This supports myocardial protection by decreasing ventricular oxygen consumption[21]. TRVADs are particularly usefully in right heart MI[120] TRVAD have been shown to decrease mortality in limited human studies with survival ranges from 40 to 80% depending on the indication for TRVAD support [2, 14].

TLVADs function by unloading the left ventricle and increasing cardiac output. They come in various forms, with the Impella and TandemHeart being the most common [201]. The Impella is inserted via a single arterial cannula, while the TandemHeart requires percutaneous femoral vein and artery access. Transseptal puncture is utilized to place the drainage catheter into the left atrium [105]. TLVADs offer myocardial protection by enhancing coronary perfusion and reducing left ventricular myocardial oxygen consumption by improving ventricular unloading [6, 177]. In a canine model of myocardial infarction, TLVAD use has demonstrated decreased infarct size and heart failure rates, and swine models of Impella support have shown decreased myocardial oxidative stress likely related to decreased myocardial oxygen consumption and stress [214] In humans with cardiogenic shock, it has been shown to improve survival with survival rates ranging from 50 to 80%.[46, 94, 133, 177, 217].

Ex Vivo perfusion

Traditional donor heart preservation involves static cold storage. However, there is increasing interest in using ex vivo perfusion for donor heart preservation. This can be achieved through hypothermic machine perfusion (HMP) or normothermic machine perfusion (NMP) [169]. HMP provides continuous perfusion of a cold storage solution and oxygen, supplying oxygen to the myocardium while reducing oxygen consumption. Clinical studies have shown that HMP is non-inferior and, in some cases, may improve outcomes for donor grafts [90, 151, 216]. NMP, on the other hand, perfuses the coronary arteries with oxygenated donor blood at physiological temperatures [169]. It allows for continuous oxygen supply to the myocardium while avoiding potential complications associated with cooling and rewarming. NMP has demonstrated non-inferiority to normal cold storage [56, 169] and has been valuable for assessing high-risk donors and potential use in donor after cardiac death heart transplants [33, 144, 194]. The use of machine perfusion for myocardial protection in transplantation is rapidly expanding, with ongoing clinical trials. Machine perfusion has the potential to significantly broaden the field of transplantation by expanding the donor pool, utilizing higher-risk donors, accommodating longer ischemic times, and introducing medications in the perfusion circuit [169].

Ex vivo perfusion also allows for the use of myocardial protective agents in the perfusate. Rat studies have shown that the addition of melatonin enhances myocardial protection via inhibition of NLRP3 inflammasome-mediated pyroptosis [135]. Further rodent studies have also shown perfusion with NLRP3 inflammasome inhibitor Mcc950 treatment improves cardiac function [221]. A swine study showed that adenosine-lidocaine cardioplegic solution, subnormothermic initial reperfusion and controlled rewarming, hemofiltration and supplementation of methylprednisolone and pyruvate resulted in significant preservation of myocardial function [213].

In the field of organ perfusion, there is also growing interest in the use of whole-body perfusion with cryprotectant solutions such as organEx [7]. Whole-body perfusion utilizes the extracorporeal circulation of preservation solution to decreased cell death and restored selected molecular and cellular processes across multiple vital organs [7]. This technology has shown promise in swine model with 1 h warm ischemic times and is an important target to increase the donor pool for organ transplant [7].

In summary, MCS is a promising field for myocardial protection. It can protect patients with acute ischemic insult or heart failure. The use of MCS will continue to grow as less invasive mechanical support and ex vivo perfusion develop further. Consequently, studying myocardial protection in the context of MCS will become increasingly important (Fig. 3).

Fig. 3.

Approaches to cardioprotection in cardiac surgery. Several strategies have been investigated and used to optimize cardioprotection in the setting of cardiac surgery. Cardiopulmonary bypass and cardioplegia is the foundation of modern cardiac surgery and allowing for a bloodless field while protecting the heart from ischemic injury. Mechanical circulatory support is a rapidly evolving area that allows for support of the heart and coronary and systemic perfusion in and out of the operating room. Additional areas of investigation in optimization of cardioprotection have been performed in the areas of ischemic conditioning and with regard to various anesthetic and pharmaceutical agents

Investigating cardioprotection: from bench to bedside

Much of this paper has discussed clinical myocardial protection; however, it is important to acknowledge key and developing basic science work that supports myocardial protection. This section will focus on translational studies in myocardial protection and future directions of research in this field.

Cell models of cardioprotection

Cell models are important for modeling multiple biological processes. Modeling ischemia, reperfusion injury, and myocardial protection in cells is particularly difficult [31]. However, several effective cell culture models have been developed to model ischemia and reperfusion injury [42, 43, 102, 130]. Cell models induce ischemia using several different techniques, including hypoxia, hyperkalemia, acidosis, nutrient deprivation, and waste accumulation [42, 43, 102]. Reperfusion is established in cell models by adding nutrient-rich media and oxygen to the ischemic cells [30, 157]. The use of cell models can provide important information on specific pathways involved in ischemic injury. However, the use of cell models to model ischemia and myocardial protection has several limitations, including oversimplification of ischemia and reperfusion, cell culture variability, and lack of standardized timing [31]. In cell models, the time of ischemic exposure is not clearly defined; studies have used times ranging from 90 min to nine hours [77, 166]. Cell studies ultimately attempt to emulate ischemia in a non-physiological setting and can miss the complex response to ischemia seen in humans [31, 102].

Animal models of cardioprotection

Animal models play an important role in modeling myocardial ischemia and thus, play an important role in modeling cardioprotection. Some of the most popular models include rodents, rabbits, swine, sheep, canines, and primates.

Small animal models

Rodent and rabbit models for myocardial protection include both in vivo and ex vivo models [96, 123]. In vivo models allow for long-term and cognitive assessment but are challenging due to animal size and blood volume [123]. Ex vivo models are more common in small animals and allow for the assessment of response to a specific intervention [20, 45, 206]. Small animal models are versatile and allow for the modeling of several clinically relevant disease states including acute myocardial infarction, chronic myocardial infarction, or chronic pressure overload. This damage is crucial and can be reproduced in mice and rats. With advancing technology, we are able to obtain more information from small animal studies than ever before. Magnetic resonance imaging and ultrasound are both valuable tools that allow for precise minimally invasive functional assessment [57, 180]. This allows for the assent of infraction and myocardial recovery at multiple time points including both preischemic bassline and postischemic recovery. The rise of high sensitivity multiomics allows for a much deeper investigation into the understanding of myocardial injury and recovery [61]. Small animal models provide an excellent model for preliminary experiments developing new agents for myocardial protection [20, 45, 206]. However, small animal models fail to mimic all of the physiological changes seen in humans [147].

Large animal models

Large animal models use a variety of animals, including swine, sheep, canines, and primates [191]. Each animal has its own benefits and drawbacks. Dogs have similar electrophysiological characteristics to humans, but they have extensive collateral circulation in the myocardium not seen in humans [17, 78, 147, 191]. Sheep have scant collateral arteries, creating predictable infarct size, but have different coronary anatomy [44]. Swine have similar cardiac function dynamics and coronary anatomy, but a different ventricular activation sequence due to a different distribution of Purkinje fibers [44, 125, 215]. Primate models have many advantages, including physiological and genetic similarities, but they are costly and have significant regulatory considerations [35]. Large animal models have greatly expanded our understanding of myocardial protection. Canine models have been used to compare different types of cardioplegia and additives [93, 218]. Swine studies have shown that pyruvate, ischemic preconditioning, and diazoxide can reduce injury after cardioplegic arrest [89, 116, 167, 197]. Sheep models have demonstrated that ischemic preconditioning can reduce oxygen consumption during bypass [141, 200]. Primates have been used in models for myocardial protection, including studying the addition of adenosine to cardioplegia [19]. Much like small animal models, large animal models have seen a growth in the use of less invasive imaging including magnetic resonance imaging and ultrasound [16, 91, 172, 196]. As with small animals, the use of high sensitivity multiomics allows for a much deeper investigation into the understanding of myocardial injury and recovery in large animals [22, 66].

Human tissue analysis

Animal models provide valuable information; however, the most valuable information is obtained from human subjects. Human studies are limited by the amount of tissue that can be obtained, but studies have been conducted using small portions of atrial and ventricular tissue. The study of small segments of the atrium received at the time of cardiac surgery have shown that preconditioning can protect against ischemia, adenosine can reduce inflammation, and ischemic preconditioning can improve mitochondrial and contractile function [34, 112, 131]. These findings have been supported by studies using human ventricular biopsies obtained during cardiac surgery, which have demonstrated that STAT5 activation plays a role in cardioprotection through remote ischemic preconditioning [87]. There are advancements in the use of human tissue and with improving technology and researchers can perform more complex analysis with smaller amounts of tissue including complex mitochondrial respiration analysis [49]. The advancement of multiomics is particularly usefully for humans as it allows for the extraction of large amounts of information from small samples [121]

Failure of most clinical trials to improve outcomes

Whereas myocardial protection has been investigated since the dawn of cardiovascular surgery using cardiopulmonary bypass and cardioplegic arrest since the 1950’s, few drugs or adjuvants have definitively improved clinical outcomes compared to contemporaneous controls. This is despite thousands of preclinical studies in animal models showing conclusive benefit in their studies. Oxygen derived free radical scanvengers [162, 223], neutrophil adhesion inhibitors [65], sodium-hydrogen exchange inhibitors, anti-inflammatory agents such as complement inhibitors [160, 188], and metabolic enhancers have generally failed to show any evidence of improved outcomes in well-designed clinical studies. The reason for this lack of efficacy in trials with preclinical experiments being markedly positive may be in part be explained by experiments being performed in animal models do not replicate clinical cardiovascular surgery, a heterogeneous groups of patients in clinical trials with a mix of co-morbid conditions, such as diabetes, hypertension, and atherosclerosis, while animal experiments generally utilized a very homogeneous set of animals without any other illness or condition. Indeed, pigs fed a high fat diet for several weeks markedly changes the ischemic injury and apoptosis in response to brief ischemia reperfusion [155]. Challenges in creating animal models that adequately reflect clinical populations are further compounded by a lack of standardization of preclinical research, an area that the consortium for preclinical assessment of cardioprotective therapies (CAESAR) network is working to address with standardized, rigorous, and reproducible protocols in the area of cardioprotection [100]. Despite the aforementioned challenges, there have been factors that have markedly improved clinical outcomes, such as advances in anesthetic management, hemodynamic monitoring, refinements in oxygenators and bonded tubing and filters, improvements in surgical techniques which have improved survival and reduced morbidity, so continued research in this area can yield important clinical benefits.

Future directions/emerging areas

Myocardial protection continues to be an active area of research. This section will discuss some of the active research areas, including mitochondrial transplantation, exosomes, gene therapy, and stem cells.

Mitochondrial transplantation

Mitochondrial transplantation is an emerging therapy that infuses or injects the target tissue with muscle-derived mitochondria. The goal is to replace mitochondria damaged by ischemia with respiration competent mitochondria to increase ATP formation resulting in increased cardiac vitality and contraction [13]. The exact mechanism remains unclear as some believe that the transplanted mitochondria might not survive in the hypercalcemic environment of myocardial ischemia and the benefits of the transplant are possible related to change in peptides, glutathione, adenosine di- or triphosphate, mitochondrial DNA [12, 13]. It has been extensively studied in swine models of ischemic reperfusion injury and transplant-related ischemia, showing increased cardiac function and reduced infarct size [18, 32, 62, 76, 190]. Swine studies using mitochondrial transplantation in the setting of donation after circulatory death showed significantly preserves myocardial function and decreased oxygen consumption compared to control [62]. Swine models of ischemia–reperfusion injury have shown decreases myocardial infarct size, increasing regional and global myocardial function with mitochondrial transplantation [18]. Based on promising results from swine studies, mitochondrial transplantation has been used in a small sample of pediatric patients, resulting in increased weaning from ECMO without short-term complications [50, 63].

Stem cells and extracellular vesicles

The use of stem cells for the treatment of cardiovascular disease has been an active area of interest for over 20 years. In theory, stem cell therapy has the potential to improve the function of injured myocardium and restore cardiac function [39]. However, clinical studies using stem cell therapy have shown mixed results [184, 207, 208, 219]. Studies, such as the TOPCARE-AMI and BOOST trials, showed increased ejection fraction and decreased myocardial remodeling. Other studies such as the Late-TIME study showed no significant benefit [184, 207, 208, 219]. As a result of the lack of clear clinical benefits, stem cell therapy is not currently recommended in humans. Stem cells and stem cell components continue to be an active area of interest, with research focusing on different types of cells and preconditioning in the hopes of finding consistently effective therapy [10, 39].

Extracellular vesicles (EVs) are cell-derived products, including exosomes, microvesicles, and apoptotic bodies, which have shown promise in the treatment of a variety of diseases, including cardiovascular disease [9]. EVs allow for the delivery of mRNA, proteins, and other signaling molecules [106]. In rodent models, EVs have been shown to decrease infarct size, decrease apoptosis, and improve function [40, 132]. In swine models, EVs have been shown to improve myocardial collateralization, coronary perfusion, and reduce inflammation [168, 174, 175, 187]. EVs can further be conditioned in hypoxic environments to function optimally in the ischemic myocardium. In rodents, hypoxia-modified EVs have been shown to decrease apoptosis and infarct size [138]. In swine, hypoxia-modified EVs have been shown to improve myocardial perfusion, reduce myocardial apoptosis and modulate myocardial oxidative stress [67, 68, 175]. However, EVs have been limited by variability from laboratory to laboratory and limited uptake from the vascular system [9, 186, 220]. Despite these limitations, extracellular vesicles have the potential to play an important role in myocardial protection and the reduction of myocardial injury. EVs have also been proposed to play a role in remote ischemic preconditioning. It was found that remote ischemic preconditioning resulted in increases venous blood EVs five minutes after preconditioning [55]. EVs collected from humans that undergoing remote ischemic preconditioning decrease hypoxia evoked apoptosis of cardio-myoblasts after isoflurane but not propofol exposure [3].

Gene therapy

Technology continues to evolve, and gene therapy is becoming a viable therapy for the treatment of many diseases [27]. Gene therapy utilizes a viral vector to introduce or increase the expression of various genes into the myocardium. It has been used in animal models of cardiovascular disease, resulting in increased cardiac function and angiogenesis [58, 97, 117]. However, similar to stem cell therapy, gene therapy has shown mixed results in human studies. Some studies have demonstrated increased cardiac function, while others have shown no difference or even worse cardiac function with gene therapy [69, 79, 107, 170, 195]. Like stem cell therapy, gene therapy research is ongoing to identify the ideal target for the treatment of cardiovascular disease. Despite the variability in results, gene therapy holds significant potential as a therapeutic approach for myocardial protection in future (Fig. 4).

Fig. 4.

Future directions in myocardial protection. Figure shows major four areas of investigation in myocardial protection including mitochondrial transplantation, extracellular vesicles, stem cells and gene therapy. The figure includes the most common source, the therapeutic substrate, and the most common method of administration

Triiodothyronine

Subclinical hypothyroidism is common in patients with ischemic heart disease. There is growing interest in the use of triiodothyronine in myocardial protection. Rodent studies have shown decreased infarct size, increased the phosphorylation of protein kinase B, and improved mitochondrial function [113]. It appears that triiodothyronine at reperfusion reduces infarct size by activation of the RISK pathway [113]. This has been further validated by human studies showing increases in contractile recovery of human right atrial trabeculae subjected to hypoxia/reoxygenation [129].

Conclusions

Optimization of cardioprotective strategies will be essential to support the increasingly complex patient population undergoing cardiac surgery. Despite decades of research into cardioplegia, there is still no consensus on the optimal cardioplegic solution for cardioprotection during cardiac arrest. Ischemic conditioning offers a promising approach to cardioprotection, but data are still mixed and more rigorously designed and powered studies will also be necessary. Continued research into optimization of anesthetic agents and mechanical circulatory support options will also help mitigate myocardial injury and promote functional recovery post-operatively. There are promising cell-based and gene therapies that may play an important role in cardioprotection, but clinically relevant translational studies will be necessary to better define the role of these strategies prior to incorporating them into clinical practice. With advances in these areas, cardiovascular surgeons and cardiologists will be able to mitigate myocardial ischemic injury, improve functional post-operative recovery, and optimize clinical outcomes in patients undergoing cardiac surgery.