A novel versatile concept of cardioplegia delivery in cardiac surgery: The ReverseTWO cardioplegia circuit system.

Nowadays, the necessity of having a cardioplegia circuit capable of being adapted in order to administer different types of cardioplegia is strategically fundamental, both for the perfusionist and for the cardiac surgeon. This allows to avoid cutting tubes, guarantees sterility and, most of all, limits the number of cardioplegia circuits for the different strategies of cardiac arrest. The novel "ReverseTWO cardioplegia circuit system" is the development of the precedent "Reverse system" where mainly the 4:1 and crystalloid cardioplegia were used, It has the advantage of allowing immediate change of cardioplegia set-up versus four types of cardioplegia technique, when the strategy is unexpectedly changed before the beginning of cardiopulmonary bypass (CPB), is safe and enables the perfusionist to use one single custom pack of cardioplegia. Two pediatric roller pumps are usually used in our centre for cardioplegia administration; they have a standardized calibration (the leading with » inch and the follower with 1/8 inch) and the circuit consequently has two different tube diameters for the two different pumps. The presence in the circuit of two different shunts coupled with two different coloured clamps allows the immediate set-up for different cardioplegia administration techniques utilizing a colour-coding mechanism The aim of this manuscript is to present the new ReverseTWO Circuit. This novel system allows to administer four different cardioplegic solutions (4:1, 1:4, crystalloid, ematic) based on multiple tubes, which can be selectively clamped, identified through a color-coding method. The specificity of this circuit is the great versatility, which leads to numerous advantages, such as reduced risk of perfusion accident and reduced costs related not only to the purchase of different cardioplegia kits but also to the storage. https://youtu.be/ovJBE4ok2Ds.

Del Nido cardioplegia or potassium induces Nrf2 and protects cardiomyocytes against oxidative stress.

Open heart surgery is often an unavoidable procedure for the treatment of coronary artery disease. The procedure-associated reperfusion injury affects postoperative cardiac performance and long-term outcomes. We addressed here whether cardioplegia essential for cardiopulmonary bypass surgery activates Nrf2, a transcription factor regulating the expression of antioxidant and detoxification genes. With commonly used cardioplegic solutions, high K+, low K+, Del Nido (DN), histidine-tryptophan-ketoglutarate (HTK), and Celsior (CS), we found that DN caused a significant increase of Nrf2 protein in AC16 human cardiomyocytes. Tracing the ingredients in DN led to the discovery of KCl at the concentration of 20-60 mM capable of significant Nrf2 protein induction. The antioxidant response element (ARE) luciferase reporter assays confirmed Nrf2 activation by DN or KCl. Transcriptomic profiling using RNA-seq revealed that oxidation-reduction as a main gene ontology group affected by KCl. KCl indeed elevated the expression of classical Nrf2 downstream targets, including TXNRD1, AKR1C, AKR1B1, SRXN1, and G6PD. DN or KCl-induced Nrf2 elevation is Ca2+ concentration dependent. We found that KCl decreased Nrf2 protein ubiquitination and extended the half-life of Nrf2 from 17.8 to 25.1 mins. Knocking out Keap1 blocked Nrf2 induction by K+. Nrf2 induction by DN or KCl correlates with the protection against reactive oxygen species generation or loss of viability by H2O2 treatment. Our data support that high K+ concentration in DN cardioplegic solution can induce Nrf2 protein and protect cardiomyocytes against oxidative damage.NEW & NOTEWORTHY Open heart surgery is often an unavoidable procedure for the treatment of coronary artery disease. The procedure-associated reperfusion injury affects postoperative cardiac performance and long-term outcomes. We report here that Del Nido cardioplegic solution or potassium is an effective inducer of Nrf2 transcription factor, which controls the antioxidant and detoxification response. This indicates that Del Nido solution is not only essential for open heart surgery but also exhibits cardiac protective activity.

The impact of del Nido cardioplegia solution on blood morphology parameters.

BACKGROUND: Crystalloid cardioplegic solutions are believed to reduce hemoglobin significantly and increase the transfusion rate. However, recent reports indicate that the del Nido cardioplegia may preserve blood morphology parameters. METHODS: In "The del Nido versus cold blood cardioplegia in aortic valve Replacement" trial patients undergoing aortic valve replacement were randomized into the del Nido (DN) or cold blood cardioplegia (CB) group. For the subanalysis, patients who underwent blood transfusions were excluded from the study. Red blood cell (RBC) count, hemoglobin, white blood cell (WBC) count and platelet (PLT) count were measured before the surgery, 24-, 48-, and 96 hours postoperatively. Furthermore, percental variation in first-last measure was compared in groups. In addition, indexed normalized ratio (INR) and activated partial thromboplastin time (aPTT) were compared preoperatively and 24 hours after the surgery. RESULTS: Eighteen (24%) patients from the del Nido group and 22 (29.3%) patients from the CB group received blood product transfusions (p = 0.560) and were excluded from further analysis. As such, 57 patients remained in DN group and 53 patients remained in CB group. No difference was found in RBC, hemoglobin, WBC, and platelet count in time intervals. Percental variation in first-last measure revealed higher fall in RBC (p = 0.0024) and hemoglobin (p = 0.0028) in the CB group. No difference was shown in preoperative and 24-hour postoperative INR and aPTT. CONCLUSIONS: The del Nido cardioplegia does not decrease blood morphology parameters when compared to cold blood cardioplegia and may be used alternatively regardless of bleeding and coagulopathy risk.

Oxygen Nanocarriers for Improving Cardioplegic Solution Performance: Physico-Chemical Characterization.

Nanocarriers for oxygen delivery have been the focus of extensive research to ameliorate the therapeutic effects of current anti-cancer treatments and in the organ transplant field. In the latter application, the use of oxygenated cardioplegic solution (CS) during cardiac arrest is certainly beneficial, and fully oxygenated crystalloid solutions may be excellent means of myocardial protection, albeit for a limited time. Therefore, to overcome this drawback, oxygenated nanosponges (NSs) that can store and slowly release oxygen over a controlled period have been chosen as nanocarriers to enhance the functionality of cardioplegic solutions. Different components can be used to prepare nanocarrier formulations for saturated oxygen delivery, and these include native α-cyclodextrin (αCD), αcyclodextrin-based nanosponges (αCD-NSs), native cyclic nigerosyl-nigerose (CNN), and cyclic nigerosyl-nigerose-based nanosponges (CNN-NSs). Oxygen release kinetics varied depending on the nanocarrier used, demonstrating higher oxygen release after 24 h for NSs than the native αCD and CNN. CNN-NSs presented the highest oxygen concentration (8.57 mg/L) in the National Institutes of Health (NIH) CS recorded at 37 °C for 12 h. The NSs retained more oxygen at 1.30 g/L than 0.13 g/L. These nanocarriers have considerable versatility and the ability to store oxygen and prolong the amount of time that the heart remains in hypothermic CS. The physicochemical characterization presents a promising oxygen-carrier formulation that can prolong the release of oxygen at low temperatures. This can make the nanocarriers suitable for the storage of hearts during the explant and transport procedure.

St. Thomas Modified Cardioplegia Effects on Myoblasts' Viability and Morphology.

Background and Objectives: The cardioplegic arrest of the heart during cardiosurgical procedures is the crucial element of a cardioprotection strategy. Numerous clinical trials compare different cardioplegic solutions and cardioprotective protocols, but a relatively small number of papers apply to in vitro conditions using cultured cells. This work aimed to analyze whether it is possible to use the rat heart myocardium cells as an in vitro model to study the protective properties of St. Thomas cardioplegia (ST2C). Methods: The rat heart myocardium cells-H9C2 were incubated with cold cardioplegia for up to 24 h. After incubation, we determined: viability, confluency, and cell size, the thiol groups' level by modifying Ellman's method, Ki67, and Proliferating Cell Nuclear Antigen expression (PCNA). The impact on cells' morphology was visualized by the ultrastructural (TEM) study and holotomograpic 3D imaging. Results: The viability and confluency analysis demonstrated that the safest exposure to ST2C, should not exceed 4h. An increased expression of Ki67 antigen and PCNA was observed. TEM and 3D imaging studies revealed vacuolization after the longest period of exposure (24). Conclusions: According to obtained results, we conclude that STC can play a protective role in cardiac surgery during heart arrest.

Comparison of Del Nido and Blood Cardioplegia in Pediatric Patients Undergoing Surgical Repair for Congenital Heart Disease.

The aim of the study is to investigate the impact of two different cardioplegia solutions, the del Nido (dN) and blood cardioplegia (BC), on postoperative troponin concentrations, vasoactive-inotrope score, and length of hospital stay in pediatric patients undergoing cardiovascular surgery for CHD. 80 subjects aged between 1 and 120 months who were scheduled for surgical repair for a CHD were prospectively enrolled in this study. Study subjects were allocated to one of the study groups using simple randomization technique as follows: The del Nido cardioplegia group (n = 40, median age 8.5 [5.5-14] months) and conventional blood cardioplegia group (n = 40, median age 11 [5-36] months). Aortic cross-clamp time and cardiopulmonary bypass time were recorded in all subjects. Troponin I and vasoactive-inotropic score, which indicates the amount of cardiovascular support by various inotropes or vasopressors, were recorded following the repair. The difference in troponin I, vasoactive-inotropic score (VIS), length of ICU stay, and length of hospital stay between the two groups was the primary outcome measure of this study. The volume of cardioplegia was significantly lower in dN group than that of the BC group (p < 0.001). Cardiopulmonary bypass time and aortic cross-clamp time were significantly shorter in subjects receiving dN cardioplegia than those receiving BC (p = 0.006, and p = 0.001, respectively). Subjects assigned to BC had higher Troponin I concentrations at postoperative 24th hour compared to subjects receiving dN cardioplegia [1.60 (0.92-2.49) ng/mL vs. 1.03 (0.55-1.83) ng/mL, p = 0.045]. VIS was also significantly higher in BC group at 24th [10 (10-13) vs. 10 (5-10), p = 0.032] and 48th hours [10 (1.5-10) vs. 0 (0-10), p = 0.005] compared to that of the dN cardioplegia group. The median extubation time was 7.5 (3.5-20.5) hours in dN cardioplegia group and 5 (4-10) hours in the BC group (p = 0.384). There were no significant differences between the groups with respect to the length of ICU stay and length of hospital stay. No mortality and no significant arrhythmias requiring medical or electrical cardioversion were noted in any of the groups. In conclusion, dN cardioplegia provides shorter aortic cross-clamp time and cardiopulmonary bypass time, and lower postoperative troponin I concentration and vasoactive-inotrope scores compared to BC in pediatric subjects undergoing surgical repair for CHD. However, lengths of ICU and hospital stay are similar in dN cardioplegia and BC groups.

The Effects of Amino Acids Enriched Del Nido Cardioplegia on Myocardial Leucocyte Accumulation and Ventricular Functions in Patients Undergoing Coronary Artery Bypass Grafting Surgery.

BACKGROUND: One of the main sources of ischemia/reperfusion injury (IRI) and release of free oxygen radicals (FORs) during extracorporeal circulation (ECC) during cardiac surgery is neutrophils. In this study, we investigated the potential effects of our modification of del Nido cardioplegia (mDNC) (amino acids enriched del Nido cardioplegia) on myocardial polymorphonuclear leucocyte (PMNL) accumulation. We also compared the effects of our mDND and classical del Nido cardiplegia (cDNC) on ventricular contractile functions in coronary artery bypass grafting (CABG) surgery. PATIENTS AND METHODS: Our study included 100 isolated CABG patients with similar characteristics, including age, gender, preoperative medications, diabetes, hypertension, and left ventricular ejection fraction (LVEF). The patients were divided into two groups. Amino acids supplemented del Nido cardioplegia (L-aspartate and L-glutamate at a dose of 13 milimol/L) in 50 patients (study group, G1). In the remaining 50 patients, we used a classical del Nido cardioplegic solution (cDNC) (control group, G2). Myocardial Tru-Cut biopsy from the right ventricle was taken before the institution of ECC and after weaning from ECC in all patients. Cardiac troponine-I (cTn-I), tumor necrosis factor-alpha (TNF-Alpha), Pro-Brain Natriuretic Peptide (Pro-BNP), and lactate levels were measured pre- and postoperatively. Invasive monitoring was performed to provide the left ventricular functions in both groups in the operating room and noted by a blinded anaesthesiologist. RESULTS: Five patients died post-surgery (5%) (two from SG and three from CG (P = .67), due to low cardiac output syndrome or multiorgan failure. At the postoperative period, cardiac output (CO) and stroke volume index (SVI) was higher in mDNC (mean ± SDS; 32.1 ± 7 versus 22.2 ± 6.9 mL/min/m² (P < .001). CI was significantly higher in mDNC after surgery (3.10 ± 0.76 versus 2.40 ± 0.30L/min/m² (P = .002). Ten patients (20%) in mDNC and 16 patients (32%) in cDNC required inotropic support (P < .001). The postoperative inotropic requirement was less in mDNC (6.1 ± 1.8 mg/kg versus 9.2 ± 1.9 mg/kg, P < .004). Blood gas analyses from the coronary sinus showed that myocardial acidosis was more severe in the control group [pH (0.10 ± 0.09 versus 0.054 ± 0.001; P = .34)]. Blood lactate levels were significantly high in the control group (1.01 ± 0.007 mmol/L versus 1.92 ± 0.35 mmol/L) (P = .22). No difference was found when compared with cardioplegia volume in the mDNC and cDNC groups (mDNC= 990.00 ± 385 mL in DNC = 960 ± 240 mL, P = .070). An aortic cross-clamp time in the mDNC and cDNC groups were 88.4 ± 8.9 min, and 93 ± 11 min, (P = .76), but cardiopulmonary bypass time was significantly low in mDNC (mDNC = 98.3 ± 22.5 min, DNC = 126 ± 19.5 min, P = .0020). TNF-Alpha and Pro-BNP levels in patients received mDNC were significantly low (P = .022). Postoperative cardiac enzyme levels (creatine kinase-MB and high sensitive troponin-I) were significantly low in the mDNC group (P = .0034). Myocardial biopsy results showed that myocardial PMNL accumulation was significantly high in the control group (P = .001). The amount of inotropic agent use was significantly high in the control group (P = .003). After weaning from ECC, the left ventricular stroke work index (LVSWI), cardiac index (CI), and heart rate (HR) were significantly high in the study group (P = .032; P = .002; P = .01). Postoperative blood and blood products requirements were significantly low in the mDNC group (P = .002). At pre-discharge echocardiography, the mDNC group demonstrated significantly higher ventricular ejection fraction (37.9 ± 4.3% and 29.7 ± 3.8%, respectively (P = .003). CONCLUSION: Our study findings show that glutamate-aspartate supplemented del Nido cardioplegia significantly decrease myocardial PMNL accumulation with reduced release of biochemical markers, including cardiac troponin-I, TNF-alpha, and Pro-Bnp. Our study results demonstrated that amino acids supplementation in del Nido cardioplegia has some advantages in CABG patients, including the decrease of perioperative myocardial infarction and increase significantly the left ventricular functions including ventricular SVI and CI.

Effects of Del Nido and Terminal Warm Blood Cardioplegia on Myocardial Protection and Rhythm in Isolated CABG Patients.

OBJECTIVE: To investigate the effect of using del Nido cardioplegia+terminal hot-shot blood cardioplegia on myocardial protection and rhythm in isolated coronary bypass patients. MATERIAL AND METHODS: A total of 122 patients were given cold (+4-8C') del Nido cardioplegia antegrade and evaluated. Del Nido+terminal warm blood cardioplegia (TWBCP) was applied to 63 patients out of 122 patients, while del Nido cardioplegia alone was applied to the other 59 patients. The preoperative and postoperative data of the patients were recorded and compared. RESULTS: There was a significant statistical difference between the groups, in terms of volume with more cardioplegia in the del Nido+terminal warm blood cardioplegia group. Although there was no significant difference between cardiac arrest times in both groups, a statistically significant difference was found in the del Nido+terminal warm blood cardioplegia group in the starting to work time of the heart. No difference found between the groups regarding myocardial preservation. CONCLUSIONS: We can add a return to spontaneous sinus rhythm to the advantages of terminal warm blood cardioplegia and del Nido cardioplegia in literature. We think it would be a good strategy to extend the safe ischemic time limit of del Nido to 120 minutes with a terminal warm blood cardioplegia. It seems that cardioplegia techniques that will be developed by adding the successful and superior results of crystalloid cardioplegia applications, such as single dose del Nido in various open heart surgery operations and the superior myocardial return effects of terminal warm blood cardioplegia, will be used routinely in the future.

Intact coronary and myocardial functions after 24 hours of non-ischemic heart preservation.

Objectives. The aim of this study was to investigate endothelium dependent relaxation (EDR) in coronary artery and the myocardial contractility after 24 h of non-ischemic heart preservation (NIHP). Design. Explanted cardioplegic hearts from six pigs were preserved by NIHP for 24 h. The perfusion medium consisted of an albumin containing hyperoncotic cardioplegic nutrition-hormone solution with erythrocytes to a hematocrit of 10%. Coronary artery ring segments were then studied in organ baths. Thromboxane A2 was used for vasocontraction and Substance P to elicit endothelium dependent relaxation. A heart trabecula from the right ventricle was mounted in an organ bath and a special stimulation protocol was used to characterize myocardial contractility. Fresh cardioplegic hearts from 11 pigs were used as controls. The water content of the hearts was calculated. Results. There was no significant difference between NIHP and fresh controls regarding EDR (91.2 ± 1.2% vs 93.1 ± 1.8%). The contraction force, potentiation and calcium recirculation fraction did not differ between the groups. The water content of the myocardium was 79.3 ± 0.2% for NIHP and 79.5 ± 0.2% for controls. Conclusions. NIHP for 24 h keeps coronary artery EDR and myocardial contractility intact and causes no edema.

Comparison of del Nido Cardioplegia and Blood Cardioplegia in Aortic Root Surgery.

AIM: To compare del Nido cardioplegia (DNC) with conventional blood cardioplegia (BC) in aortic root surgery. METHODS: Subjects who underwent aortic root surgery during a 3-year period were included. A DNC group was compared with a matched BC group. RESULTS: A total of 72 subjects were included, 36 who underwent DNC compared with 36 propensity-matched subjects who underwent BC. Fifty-one (70.8%) were male, and 21 (29.2%) were female, with a mean age of 66.19 ± 7.02 years (range 51 to 81). No significant differences in baseline characteristics, preoperative echocardiogram parameters, or intraoperative parameters were found between the groups. For DNC versus BC, cardiopulmonary bypass time, aortic clamp time, cardioplegia volume (all P = .001), and defibrillation (P = .007) were significantly lower. For postoperative biochemical parameters, creatinine levels at hour 24, potassium levels at hours 1 and 24, and glucose levels at hours 6 and 24 did not differ between the groups (P > .05). Creatine kinase-MB and troponin T levels at hours 1 and 24 were significantly lower in DNC versus BC (all P = .001). Hematocrit levels at hours 6 and 24 were significantly higher in DNC (P = .001). The groups did not differ in terms of postoperative inotropic support, postoperative complications, intubation period, or duration of intensive care unit stay (P > .05). Although the need for thrombocyte transfusion did not differ between groups (P > .05), DNC resulted in less use of erythrocyte and fresh frozen plasma transfusions (both P = .001). Postoperative ejection fraction was significantly better in the DNC group than in the BC group (P = .006). CONCLUSION: The results indicate better intraoperative parameters and better ejection fraction rates with DNC than with BC. DNC is an effective and safe alternative to blood cardioplegia for aortic root surgery.

Myocardial Protection by Blood-Based Del Nido versus St. Thomas Cardioplegia in Cardiac Surgery for Adults and Children.

BACKGROUND: St. Thomas (ST) and Del Nido (DN) cardioplegic solutions are widely used for myocardial protection during cardiac surgery. In 2016, our university hospital shifted from modified St. Thomas to Del Nido solution for both adult and pediatric cardiac surgery. This retrospective study was conducted to compare ST and DN solutions regarding surgical workflow and clinical outcome in pediatric and adult patients undergoing cardiac surgery. METHODS: We reviewed 220 patients who underwent cardiac surgery requiring cardioplegic arrest. Patients were categorized in 2 groups: ST (n = 110) and DN (n = 110). Each group included 60 pediatric and 50 adult patients. Demographic, intraoperative, and postoperative variables were collected. RESULTS: In pediatric patients, no significant difference was found between the 2 groups regarding clamping time, bypass time, need for defibrillation, inotropic score, postoperative ejection fraction (EF), period of mechanical ventilation, intensive care unit stay, or postoperative arrhythmias. One patient in the ST group required mechanical support by extracorporeal membrane oxygenation. We had 5 cases of pediatric mortality (3 in DN and 2 in ST, P = .64). In adult patients, significantly fewer patients in the DN group needed defibrillation than in the ST group. No significant difference was found regarding clamping time, inotropic score, or intraaortic balloon pump use. Mortality in adult patients was 6 cases (4 in ST group and 2 in DN group). CONCLUSION: DN cardioplegia solution is as safe as ST solution in pediatric and adult cardiac surgery. It has comparable results of myocardial protection and clinical outcome, with superiority regarding uninterrupted surgery and lower rate of defibrillation.

Effectiveness of Brain Protection With Histidine-Tryptophan-Ketoglutarate Solutions.

BACKGROUND: Tissue-protective solutions increase resistance of cells to ischemic conditions. Especially in carotid and aortic arch surgeries where the brain perfusion is at risk, these solutions may be beneficial to prevent ischemic brain damage. This study was designed to demonstrate the effectiveness of histidine-tryptophan-ketoglutarate (HTK) solution in increasing resistance of brain tissue to ischemic conditions. METHODS: Three separate randomized groups were created, each consisting of eight rabbits. The groups were called the ischemia, HTK and sham groups, respectively. In the ischemia group, temporary brain ischemia was created for 15 minutes by placing clamps on the bilateral subclavian and common carotid arteries. Then the clamps were removed, and the brain was reperfused for 30 minutes. In the HTK group, HTK solution was sent to the brain through the internal carotid artery before the same ischemia-reperfusion protocol was applied. Histopathological analyses using a visual scoring system to assess the degree of ischemic changes and the apoptotic cell index by TUNEL test were performed in all brain tissue samples. RESULTS: Apoptotic cell indices of the HTK (20.6%) and sham (17.8%) groups were lower than the ischemia group (56.8%) (P < .05). Statistically significant differences were detected between all groups in categorical scores (P < .05). CONCLUSIONS: It was shown that less ischemic damage occurs in the brain tissue with the use of HTK solution, and it may be a candidate approach to prevent the brain from ischemic insults during cerebrovascular surgery. Further studies are required to demonstrate its exact effectiveness, in terms of dose, duration, and temperature.

Long-Term Protective Effects of Single-Dose Cardioplegic Solutions in Cell Culture Models.

Despite the popularity of single-dose cardioplegic techniques, the time window and targeted population for successful reperfusion remain unclear. We tested currently available techniques based on cell viability and integrity to demonstrate long-term cardioprotection and clarify whether these solutions were performed on neonatal/adult endothelium and myocardium by examining different cell lines. Cell viability with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test proliferation assay and membrane integrity with the lactic dehydrogenase (LDH) cytotoxicity test were documented in a cell culture/microscopy setting on adult (human umbilical vein endothelium [HUVEC]), neonatal (H9C2-cardiomyocytes), and myofibroblast (L929) cell lines. Apoptotic cell activity and necrosis were evaluated by acridine orange/propidium iodide (AO/PI) staining. Twenty-four hours after seeding, cells were incubated in control (Dulbecco's modified Eagle), St. Thomas and blood cardioplegia (4:1), histidine-tryptophan-ketoglutarate (HTK), and del Nido solutions at 32°C followed by an additional 6, 24, and 48 hours in standard conditions (37°C, 5% CO2). Experiments were repeated eight times. In MTT cell viability analysis, HTK protection was significantly better than the control medium in L929 cell lines at 48th hours follow-up and acted markedly better on the HUVEC cell line at 24th and 48th hours. del Nido and HTK provided significantly better protection on H9C2 (at 24th and 48th hours). Apoptotic and necrotic cell scoring as a result of AO/PI staining was found consistent with MTT results. The LDH test demonstrated that the level of cell disruption was significantly higher for St. Thomas and blood cardioplegia in H9c2 cells. Experimental studies on cardioplegia aimed at assessing myocardial protection use time-consuming and often expensive approaches that are unrealistic in clinical practice. We have focused on identifying the most effective cell types and the direct consequences of different cardioplegia solutions to document long-term effects that we believe are the most underestimated ones in the cardioplegia literature.

Safe cross-clamp time using Custodiol®-histidine-tryptophan-ketoglutarate cardioplegia in the adult.

INTRODUCTION: Safe cross-clamp time using single-dose Custodiol®-histidine-tryptophan-ketoglutarate cardioplegia has not been established conclusively. METHODS: Immediate post-operative outcomes of 1,420 non-consecutive, cardiac surgery patients were reviewed retrospectively. Predictors of a combined endpoint made of in-hospital mortality and any major complication post-surgery were found with the multivariable method. Analysis of variance was used to evaluate the impact of cross-clamp time on most relevant complications. Discriminatory power and cut-off value of cross-clamp time were established for in-hospital mortality and each of the major complications (receiver operating characteristic curve analysis). A comparative analysis (with propensity matching) with multidose cold blood cardioplegia on in-hospital mortality post-surgery was performed in non-coronary surgery patients. RESULTS: Coronary, aortic valve and mitral valve surgery and surgery on thoracic aorta were performed in 45.4%, 41.9%, 49.5%, 20.6% of cases, respectively. In-hospital mortality and the rate of any major complication post-surgery were 6.5% and 41.9%, respectively. Cross-clamp time had significant impact on in-hospital mortality and almost all major post-operative complications, except neurological dysfunctions (p = 0.084), myocardial infarction (p = 0.12) and mesenteric ischaemia (p = 0.85). Areas under the receiver operating characteristic curve and the optimal cut-off values for in-hospital mortality and any major complication were of 0.657, 0.594, >140 and >127 minutes, respectively. Comorbidities-adjusted odds ratio for any major complication of cross-clamp time <127 minutes was 1.86 (p < 0.0001). Despite similar in-hospital mortality (p = 0.57), there was an earlier significant increase of mortality in Custodiol-HTK than in multidose cold blood propensity-matched, non-coronary surgery patients. CONCLUSIONS: The use of Custodiol-HTK cardioplegia is associated with a low risk of serious post-operative complications provided that cross-clamp time is of 2 hours or less.

Antegrade Versus Continuous Retrograde del Nido Cardioplegia in the David I Operation.

BACKGROUND: The efficacy of continuous retrograde del Nido cardioplegia for myocardial protection is still controversial. We hypothesised that antegrade and retrograde cardioplegia offer equivalent safety for myocardial protection in the David I procedure. METHODS: We retrospectively reviewed 33 patients undergoing the David I operation with antegrade or retrograde del Nido solution from June 2014 to January 2016. The outcomes were compared. The follow-up was 1 month to 15 months. RESULTS: There was no hospital mortality or reoperation in both groups. Cardiopulmonary bypass, and aortic clamp times were similar. Troponin I level (TnI), creatine kinase level (CKMB), left ventricular ejection fraction (LVEF), ventilation times, intensive care unit (ICULOS) and hospital stay times (THLOS) were similar between the two groups. The lactate level was slightly higher (9.26±2.56 vs 7.17±1.58, p=0.01) in the antegrade group compared with the retrograde group. The incidence of heart block was higher (four patients) in the retrograde group (26.7% vs 0%, p=0.019). Only one patient (6.7%) required implantation of a permanent cardiac pacemaker. CONCLUSION: Antegrade and continuous retrograde del Nido cardioplegia can be used safely and effectively in the David I operation. The continuous retrograde del Nido cardioplegia is associated with a higher rate of temporary AV block which does not require permanent pacing, and a lower lactate level.

Danshen-Enhanced Cardioprotective Effect of Cardioplegia on Ischemia Reperfusion Injury in a Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Model.

Myocardial ischemia-reperfusion (I/R) injury is unavoidable during cardioplegic arrest and open-heart surgery. Danshen is one of the most popular traditional herbal medicines in China, which has entered the Food and Drug Administration-approved phase III clinical trial. This study was aimed to develop a human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) model to mimic I/R injury and evaluate the cardioprotective effect of regular cardioplegic solution with Danshen. hiPSC-CMs were cultured with the crystalloid cardioplegic solution (Thomas group) and Thomas solution with 2 or 10 µg/mL Danshen (Thomas plus Danshen groups). The cells under normoxic culture condition served as baseline group. Then, the cells were placed in a modular incubator chamber. After 45 min hypoxia and 3 h reoxygenation, hiPSC-CMs subjected to hypoxia/reoxygenation resulted in a sharp increase of reactive oxygen species (ROS) content in Thomas group versus baseline group. Compared with the Thomas group, ROS accumulation was significant suppressed in Thomas plus Danshen groups, which might result from elevating the content of glutathione and enhanced activities of superoxide dismutase and glutathione peroxidase. The enhanced L-type Ca2+ current in hiPSC-CMs after I/R injury was also significantly decreased by Danshen, and meanwhile intracellular Ca2+ level was reduced and calcium overload was suppressed. Thomas plus Danshen groups also presented less irregular transients and lower apoptosis rates. As a result, Danshen could improve antioxidant and calcium handling in cardiomyocytes during I/R and lead to reduced arrhythmia events and apoptosis rates. hiPSC-CMs model offered a platform for the future translational study of the cardioplegia.

Intact endothelial and contractile function of coronary artery after 8 hours of heart preservation.

OBJECTIVES: The aim of the study was to investigate if adequate preservation of coronary artery endothelium-dependent relaxation and contractility may be obtained after 8 hours of non-ischemic heart preservation. DESIGN: Porcine hearts were perfused for 8 hours at 8 °C, either in cycles of 15 minutes perfusion and 60 minutes non-perfusion, or by continuous perfusion. The perfusate consisted of a cardioplegic, hyperoncotic nutrition solution with oxygenated red cells, and the perfusion pressure was 20 mmHg. In organ baths, coronary artery segments from the preserved hearts were studied and compared to fresh controls. RESULTS: Endothelium-dependent relaxation and contractility were fully preserved after both intermittent and continuous perfusion, as compared to fresh controls. No myocardial edema was seen; water content of the myocardium was 79.5 ± 0.2%, 79.0 ± 0.4% and 79.0 ± 0.3% (ns) for fresh controls, intermittently perfused, and continuously perfused hearts, respectively. CONCLUSION: Intact endothelial and contractile function of coronary artery may be obtained after 8 hours of non-ischemic heart preservation.

Protecting the aged heart during cardiac surgery: single-dose del Nido cardioplegia is superior to multi-dose del Nido cardioplegia in isolated rat hearts.

BACKGROUND: Aged hearts are particularly vulnerable to reperfusion injury. We recently showed that single-dose del Nido cardioplegia was superior to 'standard' multi-dose 4:1 blood cardioplegia in aged rat hearts. This study seeks to determine if multi-dose del Nido cardioplegia offers additional benefits over single-dose del Nido cardioplegia. METHODS: Functional recovery after 60 min of cardioplegic arrest was assessed in isolated, working, senescent rat hearts. Single-dose del Nido cardioplegia (n=14) was compared to multi-dose del Nido cardioplegia (n=12) delivered every 20 min. RESULTS: Troponin release during reperfusion was similar in the single (0.263 ± 0.056 ng/ml) and multi-dose groups (0.261 ± 0.055 ng/ml). Although functional recovery was similar early after reperfusion (stroke work 91 ± 6 ml*mmHg*g(-1) vs. 91 ± 8 ml*mmHg*g(-1) for single- vs. multi-dose), it declined over time in the multi-dose group (71 ± 9 vs. 43 ± 9 ml*mmHg*g(-1) at 60 min, p=0.0175) CONCLUSIONS: In aged rat hearts, a single-dose del Nido cardioplegia strategy results in superior functional recovery compared to a multi-dose del Nido cardioplegia strategy.

Potential cardioprotective effects of Ginseng preparations.

Ginseng has shown potential cardioprotective effects by way of anti-oxidative, anti-arrhythmic, calcium- channel antagonistic, anti-inflammatory and anti-apoptotic properties. The underlying mechanisms may also lie in certain complex signaling pathways. Clinical evidence seemed to be less convincing as the potential cardioprotective effects of Ginseng have been investigated by using combined preparations rather than by purified bioactive ingredients in most occasions. The exact actions of Ginseng verified by using its individual bioactive ingredients will be our future research work.

Altered apoptosis-related signaling after cardioplegic arrest in patients with uncontrolled type 2 diabetes mellitus.

BACKGROUND: We investigated the effects of cardioplegic arrest and reperfusion (CP/Rep) on myocardial apoptosis and key apoptotic mediators, such as apoptosis-inducing factor, caspase 3, caspase 8, caspase 9, poly(adenosine diphosphate-ribose) polymerase, B-cell lymphoma 2 (Bcl-2) family proteins, and protein kinase C (PKC), in uncontrolled type 2 diabetic, controlled type 2 diabetic, and nondiabetic patients. METHODS AND RESULTS: Right atrial tissue was harvested pre- and post-CP/Rep from uncontrolled type 2 diabetic patients (hemoglobin A1c=9.6 ± 0.25), controlled type 2 diabetic patients (hemoglobin A1c=6.5 ± 0.15), and nondiabetic patients (hemoglobin A1c=5.4 ± 0.12) undergoing coronary artery bypass grafting (n=8/group). Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining was used for the identification of apoptotic cells. Total and modified apoptosis-inducing factor, Bcl-2 family proteins, phospho-PKC-α, phospho-PKC-ß1, and poly(adenosine diphosphate-ribose) polymerase were quantified by immunoblotting or immunohistochemistry. At baseline, the number of apoptotic cells and expression of total apoptosis-inducing factor, Bcl-2, Bak, and Bax in the pre-CP/Rep atrial tissue from uncontrolled type 2 diabetic patients were significantly increased compared with those of nondiabetic or controlled type 2 diabetic patients (P<0.05). After CP/Rep, the amount of apoptotic cells, apoptosis-inducing factor, phospho-Bad, phospho-PKC-α, phospho-PKC-ß1, and cleaved poly(adenosine diphosphate-ribose) polymerase in post-CP/Rep atrial tissue were increased in all 3 groups compared with pre-CP/Rep. These increases after CP/Rep were more pronounced in the uncontrolled type 2 diabetic group. In addition, there were significant increases in the expression of cleaved caspase 8 and caspase 9 in the basal and post-CP/Rep atrium of uncontrolled type 2 diabetic group compared with nondiabetic or controlled type 2 diabetic group. CONCLUSIONS: Uncontrolled diabetes mellitus is associated with increases in myocardial apoptosis and expression of key apoptosis mediators at baseline and in the setting of CP/Rep.