Myocardial protection (MP) is the key for cardiopulmonary bypass (CPB) heart surgery. MP during cardiac surgery (CS) aims to preserve myocardial function while providing a bloodless and motionless operating field. Strategies on how to attenuate or prevent post-ischemic myocardial dysfunction that occurs intra-operatively during CS have been discussed for more than half a century. In 1950, Bigelow et al1 first reported to decrease myocardial oxygen demand by means of hypothermia. Moreover, Melrose and coworkers2 described the use of electromechanical cardiac arrest induced by potassium infusion, permitting CS to be performed on a non-beating flaccid heart and clear surgical field. The combination of both of these techniques has been the golden standard in MP during surgery until now, allowing surgery with excellent clinical outcome. In 1975, Braimbridge et al3 introduced a crystalloid solution into clinical practice at St. Thomas Hospital. By the 1980s, blood-based potassium solutions were advocated to further improve MP and to reduce myocardial enzymes release4 based on the theory that blood would be a superior delivery vehicle for its oxygenating and buffering capacity.5,6 Fortunately, the majority of MP strategies now available do allow patients to undergo conventional and complex CS with an operative mortality rate ranging from less than 2% to 4%.
In China, Dr. Su7 successfully finished first case open-heart surgery under CPB in 1958. This led to rapid progress on CS procedures in China. Unfortunately, the Cultural Revolution occurred from 1966 to 1976 in China, and research on CS was discontinued.8 In the past two decades, studies on MP have widely improved throughout China, with refinement of medical instruments, such as the ECG and ECHO and the use of myocardium enzymes such as creatine kinase and troponin I9 or T10 to evaluate levels of myocardial injury. We reviewed the published literature by Chinese investigators relating to topic of MP during CPB, evaluated current techniques of MP aimed at improving the results of contemporary CS, and summarized future perspectives of MP under investigation in China.
A computerized search in the Medline, Google and Wanfang databases was conducted for literature published from 1995 to 2006. Key words, used in the title heading, were MP (In English or Chinese) and CS or CPB. Literature included the original, English written and Chinese written, clinical trials and animal or in vitro experimental studies, and invited editorial and review manuscripts on the topic of MP during CS. Publications reporting on MP related with non-CPB CS, some comments on other papers, and some case reports about this topic were excluded.
MYOCARDIAL ISCHEMIA/REPERFUSION INJURY
Myocardial injury is unavoidable during CS, and significant evidence now exists that the primary mediators of reversible and irreversible myocardial ischemia/reperfusion (I/R) injury include intracellular Ca2+ overload during ischemia and reperfusion, and oxidative stress induced by reactive oxygen species (ROS) generated at the onset of reperfusion. The molecule nitric oxide (NO) can also interact with ROS to generate various reactive nitrogen species that appear capable of both contributing to and reducing injury. In addition, metabolic alterations occurring during ischemia can contribute directly and indirectly to Ca2+ overload and ROS formation.
Factors related to injury include ischemia and I/R, inflammatory response, operative trauma, inadequate MS and oxidative stress.11–13 All these factors have been reported to trigger myocyte death. In evaluating the strategies of MP during CPB surgery, it is important to understand the mechanisms implicated in the etiology of the various types of myocardial ischemia/reperfusion injury. Although the etiology of post-ischemic myocardial dysfunction after CS is multi-factorial, three basic types of injury occur during heart surgery: myocardial stunning, apoptosis, and myocardial infarction.
COLD CRYSTALLOID CARDIOPLEGIA AND BLOOD CARDIOPLEGIA
In China, early cardioplegic techniques employed cold crystalloid solutions to initiate and maintain intra-operative cardiac arrest. Instead of crystalloid cardioplegia, cold blood cardioplegia was regarded as clinical practice in 1994 in Fuwai Hospital for adult patients and provided benefits over cold crystalloid cardioplegia. Over 30 000 open-heart operations have been performed with cold blood cardioplegia from 1994 to 2006 in Fuwai Hospital. Based on our literature search, some results showed that blood cardioplegia provided better protection than crystalloid cardioplegia not only in adult patients but also in pediatric patients.14–21
WARM HEART SURGERY
In 1991, Lichtenstein and coworkers22 suggested that the heart be maintained at a temperature of 37°C throughout the cross-clamp period to enhance perioperative myocardial metabolic function. The concept of warm heart surgery was proposed in the late 1990's in China. Subsequently, evidence showed that warm blood cardioplegia23–25 or induced and terminal perfusion with warm blood cardioplegia reduced myocardial enzyme levels and improved postoperative ventricular function25–31 when compared with cold blood cardioplegia. Recently, some investigators reported that tepid cardioplegia reduced myocardial injury during CPB, and improved postoperative ventricular function.32,33 Compared with cold blood cardioplegia, some investigators found that warm blood cardioplegia avoided cold contracture.27–31 In addition, with warm blood cardioplegia reperfusion before clamp release myocardial metabolic recovery was improved, high-energy phosphates were better preserved, metabolic response to stress was normal, diastolic function was preserved, and products of anaerobic metabolism were washed out.26–28
TECHNIQUES OF CARDIOPLEGIA DELIVERY
Retrograde cardioplegic delivery, or combining antegrade and retrograde cardioplegic delivery, reduced myocardial enzyme leakage, preserved ATP stores, and improved metabolic recovery after cross-clamp release.34–38 The application of retrograde perfusion in coronary sinus has been shown effective to reduce cardioplegic interruptions, shorten CPB time, allow distribution of cardioplegia to regions supplied by stenosed vessels and improve subendocardial cardioplegic delivery.34–38 Although the technique of retrograde cardioplegia is simple, it requires correct catheter placement and maintenance of safe perfusion pressure (<40 mmHg) to prevent perivascular hemorrhage and edema. It is known that the effectiveness of this technique is limited by the shunting of blood directly into atrial and ventricular cavities due to the presence of the besian channels and arterio-sinusoidal vessels. Despite such limitations, coronary sinus perfusion has been used successfully for CABG and for valvular procedures. Recent studies show that the combined benefits of antegrade and retrograde perfusion can be achieved by simultaneous antegrade and retrograde delivery via the coronary sinus and aorta or vein grafts; a manifold has been developed to facilitate intra-operative delivery.34,35
IPC produces a powerful endogenous protective effect. The phenomenon of IPC was described by Murry et al41 in 1986. Various animal and clinical researches show that the tolerance of the myocardium is induced by ischemia and reperfusion following a more prolonged ischemic insult.39–41 Several membrane receptors seem to be involved in the phenomenon of ischemic preconditioning including A-1 and B-adrenoceptors, opioids and adenosine A1 and A3 receptors.
Yellon et al42 initialed the human practice with IPC in 1993. After that a great number of clinical studies followed to address the basic mechanisms of IPC during cardiac surgery. A group from Hunan Xiangya Medical University finished a series of investigations43–46 about this topic not only on animals but also on clinical patients; and published a series of papers in the majority of heart surgery journals. Another group from Beijing Fuwai Hospital did some clinical studies and got positive results.47,48 Based on the literature about IPC, the possible mechanisms of IPC vary between acute and delayed models and between local versus remote. It may be dependent on different types of IPC. Brief episodes of ischemia result in the production of these trigger substrates, such as adenosine, bradykinin, and nitrite oxide (NO) from coronary vascular endothelial cells or plasma kallikrein, norepinephrine, acetylcholine, prostanoids, oxygen free radicals and tumor necrosis factor alpha (TNF-α).49 These factors act on the myocyte receptors: adenosine A1, muscarinic receptor, bradykinin B2, and α sympathetic receptor. Then tyrosine kinase and protein kinase C are activated and transferred to cellular membrane, working with inhibitory G-protein. Finally, ATP sensitive potassium channels (KATP) trigger the IPC response followed by the activation of transcription factors, of which the role of nuclear factor κ-B (NFκ-B) is often studied.50 NFκ-B is a transcription factor that regulates transcription of genes that produce pro-inflammatory substances such as cytokines and adhesion molecules.51
ADENOSINE AND VOLATILE ANESTHETICS
Although many studies showed the cardioprotective effect of IPC on the myocardium, the limitation of IPC in clinical practice is still cautioned, since reports exist showing that the risk of stroke is increased during clamp “on or off” if there is calcification in the ascending aorta. Recently, there has been an attempt to find a pharmacologic way to create the IPC effect without cross-clamping the aorta. There is considerable experimental evidence that the pre- ischemic administration of the nucleoside adenosine retards the rate of ischemia-induced ATP depletion, prolongs the time to onset of ischemic contracture, attenuates myocardial stunning, enhances post- ischemic myocardial energetics, and reduces infarct size.52–56 Recent studies have convincingly shown that volatile anesthetics, including isoflurane, desflurane and sevoflurane can also be cardioprotective.57,58 This protection, termed anesthetic-induced preconditioning, mimics ischemic preconditioning with mechanisms not yet completely understood. Studies in vitro have shown evidence of an indirect enhancement of ischemic preconditioning resulting in cardioprotection against myocardial infarction with the potassium ATP channels playing an important role.
It is well known that, in routinely depolarizing cardioplegia with hyperkalemia to achieve myocardial arrest during CPB, high potassium concentrations can damage vascular endothelial cells directly, as well as enhance endothelial and myocyte calcium entry. Recently, the potassium channel openers (PCO), which open the adenosine triphosphate-sensitive potassium channel, have been reported to possess cardioprotective properties by achieving its hyperpolarized cardiac arrest under global ischemic conditions. These agents arrest the heart at hyperpolarized potentials, close to the natural resting state of the cell membrane, and thus theoretically may avoid many of the detrimental aspects of depolarized arrest. The PCOs also have the advantage of being inherently cardioprotective during both regional and global ischemia and have been shown to play a critical role in ischemic preconditioning.59–61
Glucose-insulin-potassium solutions have been commonly used to treat ischemic myocardium in a variety of medical and surgical situations. By stimulating the rate-limiting enzyme pyruvate dehydrogenase (PDH), insulin may facilitate the conversion from anaerobic to aerobic metabolism thus improving the results of CS.62,63 Despite encouraging results obtained by smaller non-randomized studies or by randomized trial in elective CABG,64 the recent insulin cardioplegia trial failed to demonstrate a significant benefit of insulin- cardioplegic solution in the setting of high-risk patients undergoing isolated myocardial revascularization.65
NA+/H+ EXCHANGE INHIBITION
Recently, some reports have shown that sodiumhydrogen exchangers, which play a central role in the regulation of intracellular sodium, calcium and pH homeostasis, may be contributing to ischemia/reperfusion myocardial damage. A possible mechanism of sodium-hydrogen exchanger may be that protons accumulating during ischemia are extruded at the time of reperfusion in exchange for Na+; excessive sodium cannot be adequately transported by the sodium/potassium pump, because it is operating inefficiently due to ischemia- induced shortage of ATP. This excess of intracellular sodium is then extruded from cells through the sodium/calcium exchanger, which functions in a reverse mode. It brings Ca2+ into the cells allowing a dangerous calcium overload, responsible for ischemia/reperfusion tissue injury. Specific inhibition of the sodium-hydrogen exchanger isoform 1, located on the plasma membrane of the cardiac myocyte, with HOE-642 (cariporide),66 seems to decrease myocardial infarct size and to improve post-ischemic functional recovery and reperfusion ion homeostasis in experimental animal studies.67 Whether sodium-hydrogen exchanger inhibition is an effective form of protection against myocardial stunning, apoptosis, infarction, ventricular remodeling, and heart failure in humans during heart surgery awaits further study.
NITRIC OXIDE/L-ARGININE SUPPLEMENTED CARDIOPLEGIA
Nitric oxide has been demonstrated to reduce myocardial ischemia-reperfusion damage in experimental animal models; moreover, it seems to exert a myocite protective role as an anti-apoptotic factor and mediator in IPC. Many experimental investigations have suggested that blood cardioplegia enriched with L-arginine may improve myocardial protection by increasing nitric oxide release, allowing a better ventricular function recovery in areas and increasing myocardial tissue pH recovery in animal models.68–71
The clinical experience in CS with L-arginine is limited: Wallace and colleagues,72 in a small randomized trial, found a significant decrease in coronary vascular resistance and an increase in blood flow through saphenous vein grafts in the group of patients in which L-arginine was administered after coronary artery bypass grafting. Moreover, in this category of patients they also showed an increase in the serum level of L-citrulline, as a consequence of an increase in the production of nitric oxide after administration of L-arginine.
In summary, the changes in cardioplegic composition, temperature, and delivery route have been successful in optimizing intra-operative MP. However, the ideal cardioplegic solution, temperature, and delivery method have yet to be identified. Further investigations on strategies of MP will allow us to supply adequate MP to high-risk patients with poor ventricular function.
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