Hypothermic Cardioplegia Research Articles

Minimally invasive and robotic approaches to mitral valve surgery: Transthoracic aortic crossclamping is optimal

Minimally invasive and robotic approaches to mitral valve surgery: Transthoracic aortic crossclamping is optimal

Selective cerebral and coronary perfusion in the correction of coarctation of the aorta with tubular aortic arch hypoplasia (literature review)

This literature review presents the analysis of different techniques for approaches and cerebral and cardiac protection in surgical correction of coarctation of the aorta (CoA) with tubular aortic arch hypoplasia. Various definitions of tubular hypoplasia are reviewed. The attempt is made to bring together theoretical basis and data concerning the results of particular methods. The authors investigate up-to-date literature data based on results using thoracotomy and sternotomy approaches in CoA correction with tubular aortic arch hypoplasia. Literature results of operations using these approaches and authors' rival opinions for different methods are presented. The impact of hypothermia and its physiological effects on the brain and the late neurological outcomes of deep hypothermic circulatory arrest are discussed. Advantages and disadvantages of deep hypothermic circulatory arrest and selective cerebral perfusion and authors' opposite opinions on these techniques are presented. The methods of selective cerebral perfusion control and strategies to assess its adequacy are briefly described. Coronary perfusion peculiarities, hypothermic cardioplegia effects on the myocardium, and disadvantages of hyperkalemic cardioplegia are summarized. Based on literature data, the authors justify the implementation of selective coronary perfusion for the correction of CoA with tubular aortic arch hypoplasia.

Velocimetric ultrasound thermometry applied to myocardium protection monitoring

Tissue temperature control during cardiac surgery is crucial for myocardial protection. To preserve the tissue, a hypothermic cardioplegia is applied in order to decrease the heart temperature down to around 10°C. The monitoring of the thermal evolution of the myocardium is then of importance to minimize deleterious effects on the heart. The present work aims at evaluating the potential of an ultrasonic velocimetric thermometry on the monitoring of in vitro tissues heating. An indentation process is first proposed to identify the experimental linear relationship linking, in myocardia, the speed of the ultrasonic longitudinal wave to the tissue temperature. An extension of this method based on the echo-tracking principle is then proposed to approach surgical conditions. Temperature changes are measured by monitoring the induced time delays of backscattered ultrasonic echoes. These results are compared to T-type thermocouple reference measurements. They are then discussed in terms of measurement precision and in situ applications.

Murine Isolated Heart Model of Myocardial Stunning Associated with Cardioplegic Arrest.

The following protocol is of use to evaluate impaired cardiac function or myocardial stunning following moderate ischemic insults. The technique is useful for modeling ischemic injury associated with numerous clinically relevant phenomenon including cardiac surgery with cardioplegic arrest and cardiopulmonary bypass, off-pump CABG, transplant, angina, brief ischemia, etc. The protocol presents a general method to model hypothermic hyperkalemic cardioplegic arrest and reperfusion in rodent hearts focusing on measurement of myocardial contractile function. In brief, a mouse heart is perfused in langendorff mode, instrumented with an intraventricular balloon, and baseline cardiac functional parameters are recorded. Following stabilization, the heart is then subject to brief infusion of a cardioprotective hypothermic cardioplegia solution to initiate diastolic arrest. Cardioplegia is delivered intermittently over 2 hr. The heart is then reperfused and warmed to normothermic temperatures and recovery of myocardial function is monitored. Use of this protocol results in reliable depressed cardiac contractile function free from gross myocardial tissue damage in rodents.

In and ex-vivo Myocardial Tissue Temperature Monitoring by Combined Infrared and Ultrasonic Thermometries

The success of cardiac surgery essentially depends on tissue preservation during intervention. Consequently a hypothermic cardio-plegia is applied in order to avoid ischemia. However, myocardial temperature is not monitored during operation. The aim of this study is then to find a relevant and simple method for myocardial global temperature estimation in real time using both ultrasounds and infra-red thermography. In order to quantify the sensitivity of ultrasonic velocity to temperature, a 2.25MHz ultrasonic probe was used for ex-vivo tests. Pig myocards (n=25) were placed in a thermostatically-controlled water bath and measurements of the ultrasound velocity were realized from 10 to 30 ˚C. The results of this study indicate that the specificity and sensitivity of the ultrasonic echo delay induced by the modification of temperature can be exploited for in-depth thermometry. In parallel, for TIR experiments, a bolometer was used to detect the myocardium surface thermal evolution during in-vivo pig heart experiments. Hypothermic cardioplegic solutions were injected and infra-red surface imaging was performed during one hour. In the near futur, the correlation of the ultrasound and the infrared measurements should allow the real time estimation of the global temperature of the heart. The final objective being to realize in vivo measurements on human hearts, this information may have a very high importance in terms of per-operation inspection as well as decision making process during medical interventions.

Hot shot induction and reperfusion with a specific blocker of the es-ENT1 nucleoside transporter before and after hypothermic cardioplegia abolishes myocardial stunning in acutely ischemic hearts despite metabolic derangement: Hot shot drug delivery before hypothermic cardioplegia

Simultaneous inhibition of the cardiac equilibrative-p-nitrobenzylthioinosine (NBMPR)-sensitive (es) type of the equilibrative nucleoside transport 1 (ENT1) nucleoside transporter, with NBMPR, and adenosine deaminase, with erythro-9-[2-hydroxy-3-nonyl]adenine (EHNA), prevents release of myocardial purines and attenuates myocardial stunning and fibrillation in canine models of warm ischemia and reperfusion. It is not known whether prolonged administration of hypothermic cardioplegia influences purine release and EHNA/NBMPR-mediated cardioprotection in acutely ischemic hearts. Anesthetized dogs (n=46), which underwent normothermic aortic crossclamping for 20 minutes on-pump, were divided to determine (1) purine release with induction of intermittent antegrade or continuous retrograde hypothermic cardioplegia and reperfusion, (2) the effects of postischemic treatment with 100 μM EHNA and 25 μM NBMPR on purine release and global functional recovery, and (3) whether a hot shot and reperfusion with EHNA/NBMPR inhibits purine release and attenuates ventricular dysfunction of ischemic hearts. Myocardial biopsies and coronary sinus effluents were obtained and analyzed using high-performance liquid chromatography. Warm ischemia depleted myocardial adenosine triphosphate and elevated purines (ie, inosine>adenosine) as markers of ischemia. Induction of intermittent antegrade or continuous retrograde hypothermic (4°C) cardioplegia releases purines until the heart becomes cold (<20°C). During reperfusion, the levels of hypoxanthine and xanthine (free radical substrates) were >90% of purines in coronary sinus effluent. Reperfusion with EHNA/NBMPR abolished ventricular dysfunction in acutely ischemic hearts with and without a hot shot and hypothermic cardioplegic arrest. Induction of hypothermic cardioplegia releases purines from ischemic hearts until they become cold, whereas reperfusion induces massive purine release and myocardial stunning. Inhibition of cardiac es-ENT1 nucleoside transporter abolishes postischemic reperfusion injury in warm and cold cardiac surgery.

Trimetazidina e resposta inflamatória em cirurgia de revascularização do miocárdio

Organic inflammatory response is a pathophysiological mechanism present at every coronary artery bypass grafting with extracorporeal circulation (CABG-ECC), the release of inflammatory mediators being one of its defense mechanisms. To assess, in a prospective double-blind randomized and placebo-controlled study, the effects of trimetazidine (Tmz) on the inflammatory response, by using the variation in interleukins 6 and 8, TNF-α, complements C3 and C5, and highly sensitive C-reactive protein (HS-CRP) levels in the pre- and post-operative periods. This study assessed 30 patients undergoing CABG-ECC with intermittent hypothermic cardioplegia, and having, at most, mild ventricular dysfunction. The patients were divided into two groups (placebo and Tmz), stratified by echocardiography, and received drug/placebo at the dose of 60 mg/day. Measurements were taken as follows: in the pre-operative period with no drug; on the day of surgery, corresponding to 12 to 15 days on drug/placebo; five minutes after aortic unclamping; 12 and 24 hours after surgery, for interleukins and complements; and 48 hours after surgery, for HS-CRP. No significant difference between the levels of interleukin 8, TNF-α, C3 and C5, and HS-CRP was observed. However, the interleukin 6 levels were significantly lower in the group treated as compared with those in the control group at all time points assessed. Trimetazidine proved to be effective only for reducing interleukin 6 in patients undergoing CABG.

Hypothermic cardiopulmonary bypass surgery in a 7-year-old boy with a cold agglutinin

Dear Editor, Cold agglutinins (CA) are predominately IgM auto-antibodies that optimally react with surface antigens on red blood cells (RBCs) at low temperatures. Subsequently, agglutination of RBCs can occur followed by complement fixation and haemolysis. CAs seldom cause significant intraand extravascular haemolysis under normothermic conditions. However, they could be of relevance in patients undergoing cardiac surgery when hypothermic cardiopulmonary bypass (CPB) and cardioplegia are used [1]. There are conflicting opinions in the literature about screening patients for CAs prior to hypothermic CPB. CAs are rare and low levels can be found in healthy individuals. The incidence of CAs in screened cardiac surgery patients is approximately 0.8–4 % [1–4]. Although serious complications (haemolysis, micro-vascular occlusion and organ failure) have been described, it has also been demonstrated that patients with low titre, low thermal amplitude CAs can safely undergo CPB [1–4]. Therefore, and following Dutch guidelines recommendations (CBO consensus Bloedtransfusie, http://www.cbo.nl/thema/Richtlijnen/ Overzicht-richtlijnen/Bloedtransfusie/), we do not screen for CAs in adults. However, as described also by others recently, we do perform screening for CAs in children undergoing cardiac surgery for which deep hypothermia is indicated [5]. A 7-year-old boy was referred for serological testing prior to hypothermic cardiac surgery. The patient’s blood group was O positive and antibody screening tests were negative. The cold agglutinin assay (saline, 16 °C) revealed the presence of a cold autoantibody with IH specificity. CAs are often directed against the Ii blood group collection [1]. Anti-IH antibodies have been implicated as the cause of a haemolytic transfusion reaction in a couple of cases [6–8]. CAs are generally produced in response to infections or secondary to a lymphoproliferative disorder [9]. Our patient had recently been treated with antibiotics for an infection. The importance of a CA is determined by the thermal amplitude (highest temperature at which the antibody binds to RBCs) and titre. The IH-antibody in our patient displayed wide thermal amplitude (28 °C; titre 1:2). Because of the associated risk of intravascular haemolysis during CPB, and the fact that postponing the elective surgery was safe for the patient, the procedure was cancelled. The presence of CAs is often transient and therefore the thermal amplitude of the antibody was determined periodically. The thermal amplitude decreased slowly to 24 °C after 3 months (titre 1:1) and 22 °C after 5 months (Fig. 1). After 7 months, the thermal amplitude of the antibody remained stable and we decided to perform the procedure under less extensive hypothermic conditions. The patient was cooled to 24.9 °C and surgery was performed successfully. The antibody did not show any reactivity at this temperature and accordingly, the patient did not show signs of hemolysis. The patient received 2 units of RBC, as a consequence of the CPB procedure, and had stable post-surgery haemoglobin of 11.3 g/dL, without any signs of hemolysis. In conclusion, CAs can cause haemolysis in patients undergoing hypothermic cardiac surgery. Although screening for CAs in all patients is not recommended it can be useful in specific patient groups (e.g. children undergoing I. Hubeek :W. W. van Solinge :K. M. K. de Vooght Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands

Editorial Comment: Myocardial protection with postconditioning in cardiac surgery: the importance of the model

In this issue of the European Journal of Cardio-Thoracic Surgery, Maruyama and Chambers [1] pose the question of whether postconditioning (POC) enhances the protection provided by normothermic St Thomas’ number 2 (ST2) cardioplegia solution. This is an excellent question, posed by a highly productive group, and whether POC provides protection in addition to that exerted by cardioplegia is a question that has been asked by others [2]. Maruyama and Chambers found that a POC algorithm applied after increasing durations of arrest induced by a single infusion of warm St Thomas’ number 2 (ST2) cardioplegia did not enhance the primary end points of recovery of contractile function or reduce infarct size relative to that observed after arrest and reperfusion alone. It is important that the intervention targets the end points or relevant mechanisms. POC has been shown to target mechanisms impacting these two end points; the improvement in global contractile function is likely through the reduction in infarct size since no effect has been demonstrated on contractile function per se. POC did not enhance the postcardioplegic outcomes at any duration of ischaemia, but was only effective when the magnesium concentration of ST2 cardioplegia solution was reduced to zero. Maruyama and Chambers conclude that POC has limited efficacy after arrest with ST2 cardioplegia solution, and there is likely a magnesium-sensitive component of POC protection. POC is defined as reperfusion interrupted by brief periods of ischaemia applied during the opening minutes of reflow [3]. In cardiac surgery, POC can be applied by directly clamping and declamping the aorta, as performed by Luo et al. [4], or by iteratively infusing and halting the cardioplegia solution using a dedicated delivery system (Quest Medical Inc.’ MPS, Terumo Cardiovascular Systems System 1 Master/Follower, etc). In contrast to cardioplegia solutions and adjunct strategies such as hypothermia that are designed to reduce the severity of ischaemia that, in part, also determines the severity of reperfusion injury, POC exclusively targets reperfusion injury. Conceptually, both cardioplegia and POC could reduce post-ischaemic injury. If the cardioplegia solution and related strategies successfully limit ischaemic injury, then there is little subsequent reperfusion injury on which POC may exert protection. If, on the other hand, the majority of injury occurs during ischaemia with or without cardioplegia, there may be little room for protection from reperfusion injury, and again POC may not play a role as in the 45 and 60 min ischaemia-only group (Figure 2). It was important for the authors to show that the POC algorithm was effective in improving functional recovery and reducing infarct size, at least after 30 min of normothermic ischaemia alone (no cardioplegia). However, the observation that POC did not improve functional recovery or reduce infarct size does not necessarily represent a failure or loss of cardioprotection, but rather represents a limitation of that algorithm to stimulate the triggers and cardioprotective pathways [5] that impact the effectors of POC; this phenomenon has been called the ‘threshold’ of protection [6]. When a threshold is encountered, whereby protection is no longer observed after longer durations of ischaemia, increasing the number of postconditioning cycles has been shown to re-establish cardioprotection. The authors may have encountered such a threshold at the 45 and 60 min of index ischaemia in the present study. This should be determined in further studies. The model often profoundly affects the outcomes of a study. In the Langendorff isolated perfused, non-working (not ejecting and performing external work) heart preparation, there may be fundamental species differences in biology, metabolic differences that effect the time course of ischaemic injury and efficacy of interventions. Whether the injury occurs primarily during ischaemia or during reperfusion is a fundamental question in this study. ST2 cardioplegia solution was used at 37°C, which differs from its use clinically, and is not consistent with clinical studies testing the efficacy of POC after hypothermic cardioplegia. Tables 2 and 3 show left ventricular end-diastolic pressures >30 mmHg at the end of ischaemia (0 min reperfusion), suggesting that contracture has already occurred to some extent during ischaemia with or without cardioplegia; contracture is associated with the onset of irreversible injury at the end of ischaemia that would not be amenable to reperfusion therapy such as POC. In addition, the isolated perfused heart preparation inherently lacks components of the inflammatory response, i.e. plasma-borne inflammatory cells, proteases and cytokines that contribute to reperfusion injury. POC has been shown to inhibit neutrophil accumulation, activation of the coronary vascular endothelium,

Type A Aortic Dissection With Cold Agglutinin Disease

Cold agglutinin disease is an uncommon condition characterized by hemagglutination and microvascular thrombosis of red blood cells at low temperatures during cardiopulmonary bypass. We report the rare case of an ambulatory 74-year-old woman with a relatively high thermal amplitude for antibody activation. We performed aortic arch repair for type A aortic dissection using moderately hypothermic cardiopulmonary bypass and warm blood cardioplegia in a retrograde manner. This case report provides evidence that these are safe and suitable techniques for selected aortic arch repair patients with cold agglutinin disease.

Myocardial energy metabolism and functional recovery in coronary bypass surgery: A comparative study between continuous retrograde warm and mild hypothermic blood cardioplegia

The optimal temperature for delivery of continuous retrograde blood cardioplegia is not known. Twenty-two patients admitted to the hospital for elective coronary artery bypass grafting were randomized into the warm (37°) and mild hypothermic (28°C) cardioplegia groups. Changes in myocardial energy metabolism during cardiopulmonary bypass, postoperative efflux of the creatine kinase MB isoform (CK-MB), functional hemodynamic recovery, and postoperative complications were followed. During aortic cross-clamp, the average oxygen consumption was higher in the warm than in the mild hypothermic group (3.4±0.4 vs 2.4±0.3 ml/minute,p=0.06), as was the average transcardiac (outflow-inflow) pCO2-difference (1.1±0.1 vs 0.7±0.1 kPa,p=0.02). The average transcardiac pH-difference during aortic cross-clamp was lower in the warm group (−0.08±0.01 vs −0.06±0.01 U,p=0.02), reflecting more profound tissue acidosis. In accordance with this, warm hearts produced more lactate, especially towards the end of the aortic cross-clamp period (p=0.001). The net efflux of adenosine and its degradation products was more prominent during warm than during mild hypothermic cardioplegia (p=0.016), indicating less degradation of high energy adenylates in the hypothermic group. The functional hemodynamic recovery during the first postoperative day was similar in both patient groups, although the myocardial injury estimated as postoperative leakage of CK-MB was less extensive in the hypothermic group (p=0.011). There were no major differences in the postoperative complications between the study groups. We conclude that continuous retrograde mild hypothermic blood cardioplegia offers better myocardial protection during coronary bypass surgery than does continuous retrograde warm cardioplegia. The clinical significance of this should be tested in a larger series of patients, especially those with recent myocardial infarction, unstable angina, or severely depressed left ventricular function.

How does hypothermia protect cardiomyocytes during cardioplegic ischemia?

Insufficient myocardial protection is still a considerable cause for in-hospital mortality in children. The purpose of our study was to investigate underlying the basic mechanisms of cardioplegic cardioprotection during hypothermic and normothermic ischemia in a cardiomyocyte cell culture model. We cooled cardiomyocytes to 20°C for 20min; during this time, cardiac arrest was simulated by oxidative damage with 2mM H₂O₂ and cardioplegic solution, followed by rewarming to 37°C. Later on, we analyzed cardiomyocyte cell morphology (phase-contrast-microscopy), viability (trypan blue staining), inflammation (cyclooxygenase-2 (Cox-2) and phosphorylated-extracellular signal-regulated kinase (pERK) 1/2 expression in Western blot analysis), and expression of Akt survival protein (Western blot technique). Hypothermia increases cell survival of cardiomyocytes after cardioplegic ischemia, as demonstrated in significantly higher cell viability and less cell death in these cells compared with normothermic H₂O₂-damaged cardiomyocytes. As a possible underlying cellular mechanism, we found that, during cold cardioplegic ischemia, ERK 1/2 enzyme is less phosphorylated than under conditions of normothermic cardioplegic ischemia. This is in line with significantly diminished Cox-2 expression during cold cardioplegic ischemia. Moreover, hypothermic cardioplegia preserved cell survival by upregulation of Akt transcription factor in cardiomyocytes. In the present cell culture study, we clearly demonstrated that hypothermia exerts additional protection for cardiomyocytes during cardioplegic ischemia. The understanding of underlying basic mechanisms is evident to improve current techniques of myocardial protection.

722 Characterisation of gene expression profiles in HeLa cells expressing BRCA1 missense variants

We investigated in vivo in aortic valve stenosis (AVS) whether there is: 1) thermal heterogeneity within the valve leaflets; 2) temperature difference between the leaflets and the ascending aortic wall; and 3) a possible correlation between heat production, inflammation, and neoangiogenesis.Histological studies have demonstrated a potential role of inflammation and neoangiogenesis in AVS.We examined 96 leaflets scheduled for aortic valve replacement. Twenty-five patients had AVS, and 7 had aortic valve insufficiency (AVI). Temperature measurements were performed right before hypothermic cardioplegia. Temperature difference (ΔT) was assigned as the mean temperature of each leaflet minus the temperature of the aortic wall. Histological, immunohistological analysis, and vascular endothelial growth factor (VEGF) immunoreactivity was performed.Significant thermal heterogeneity was recorded within the leaflets of AVS, compared with AVI (1.52 ± 1.35°C vs. 0.13 ± 0.11°C, p < 0.01). In AVS ΔT was greater in all leaflets compared with the AVI group (p < 0.01). Leaflets of AVS had increased inflammatory cell infiltration, calcium deposit, and anti-VEGF expression compared with AVI (p < 0.01).Thermal heterogeneity is increased in AVS and correlates with inflammatory mononuclear cell infiltration, expression of pro-inflammatory cytokines and neoangiogenic factors.

Functional, Metabolic, and Morphological Aspects of Continuous, Normothermic Heart Preservation: Effects of Different Preparation and Perfusion Techniques

Continuous blood perfusion of donor hearts for transplantation has been the focus of an increasing amount of research, but the optimal preparation and perfusion techniques have not been clearly defined. Therefore, we investigated the effectiveness of different preservation strategies using continuous, normothermic heart perfusion after donor heart harvesting. Hearts of 12 pigs were randomly assigned to two groups receiving a constant pressure perfusion in a modified Langendorff system after different preparation techniques. In Group 1, six hearts were arrested with Bretschneider HTK cardioplegia (4 degrees C) and then reperfused with a circulating pressure of 80 to 90 mmHg using leukocyte depleted autologous blood. In Group 2, beating hearts of six pigs were explanted while being perfused, without cardioplegic arrest. Post-harvesting perfusion was similar to Group 1 except for a lower circulating pressure (40-50 mm Hg). At different time points (baseline and 1, 6, and 12 h after reperfusion), myocardial biopsies were taken, and contractility was assessed by measuring the maximum rate of left ventricular pressure rise (Deltap/Deltat (max)). Adenosine triphosphate (ATP) concentration was measured in all biopsies using a bioluminescence technique. Additionally, ultrastructural alterations were investigated using electron microscopy. Hypothermic cardioplegia and a higher reperfusion pressure (Group 1) were associated with an earlier and sharper decline in contractile function and intracellular ATP concentration. Ultrastructural alterations in Group 1 appeared earlier and were more distinctive than in Group 2. Endothelial ultrastructure, in particular, was better preserved in Group 2. Significant alterations were present in both groups after 12 h of perfusion but were more severe in Group 1. Blood perfusion provides protection against severe ischemic damage for a limited time. The use of a lower perfusion pressure, as well as avoiding cardioplegia and hypothermia, led to significantly better and longer preservation of perfused hearts.

Abstract 5864: In Vivo Aortic Valve Thermal Heterogeneity In Patients With Non-rheumatic Aortic Valve Stenosis: First In Vivo Experience In Humans

Background: Histological studies have demonstrated a potential role of inflammation and neoangiogenesis in aortic valve stenosis (AVS). Inflammatory activation may generate heat. We investigated in vivo in patients with AVS whether there is: thermal heterogeneity within the valve leaflets, temperature difference between the leaflets and the ascending aortic wall and a possible correlation between heat production, inflammation and neoangiogenesis. Methods: We examined 96 leaflets from 32 patients scheduled for aortic valve replacement. Seventy-five leaflets were from 25 patients with AVS and 21 from 7 patients with aortic valve insufficiency (AVI) (control group). Temperature measurements were performed right before the hypothermic cardioplegia. Temperature difference (ΔT) was assigned as the mean temperature of each aortic leaflet minus the temperature of the aortic wall. Results: Histological, immunohistological analysis for inflammatory cells and vascular endothelial growth factor (VEGF) immunoreactivity was performed. Significant thermal heterogeneity was recorded within the leaflets of AVS, compared AVI (1.52±1.35°C vs 0.13±0.11°C, p&lt;0.01). In AVS ΔT was 1.09±1.16°C for the non-coronary (NC), 1.24±1.03°C for the right and 1.53±1.23°C, for the left leaflet. ΔT was lower in AVI (0.10±0.10°C for the NC, 0.02±0.19°C for the right and 0.05±0.19°C, for the left leaflet, p&lt;0.01 for all comparisons). Leaflets of AVS had increased inflammatory cell infiltration, calcium deposit, and anti-VEGF expression compared to AVI (p&lt;0.01). Conclusions: Thermal heterogeneity is increased in AVS and correlates with inflammatory mononuclear cell infiltration, expression of pro-inflammatory cytokines and neoangiogenic factors. Future studies need to be performed to investigate possible prognostic and therapeutic implications.

In Vivo Aortic Valve Thermal Heterogeneity in Patients With Nonrheumatic Aortic Valve Stenosis: The First In Vivo Experience in Humans

We investigated in vivo in aortic valve stenosis (AVS) whether there is: 1) thermal heterogeneity within the valve leaflets; 2) temperature difference between the leaflets and the ascending aortic wall; and 3) a possible correlation between heat production, inflammation, and neoangiogenesis. Histological studies have demonstrated a potential role of inflammation and neoangiogenesis in AVS. We examined 96 leaflets scheduled for aortic valve replacement. Twenty-five patients had AVS, and 7 had aortic valve insufficiency (AVI). Temperature measurements were performed right before hypothermic cardioplegia. Temperature difference (DeltaT) was assigned as the mean temperature of each leaflet minus the temperature of the aortic wall. Histological, immunohistological analysis, and vascular endothelial growth factor (VEGF) immunoreactivity was performed. Significant thermal heterogeneity was recorded within the leaflets of AVS, compared with AVI (1.52 +/- 1.35 degrees C vs. 0.13 +/- 0.11 degrees C, p < 0.01). In AVS DeltaT was greater in all leaflets compared with the AVI group (p < 0.01). Leaflets of AVS had increased inflammatory cell infiltration, calcium deposit, and anti-VEGF expression compared with AVI (p < 0.01). Thermal heterogeneity is increased in AVS and correlates with inflammatory mononuclear cell infiltration, expression of pro-inflammatory cytokines and neoangiogenic factors.

The use of nicorandil in cardioplegia solution

EDITOR: We would like to comment on the article by Chinnan and co-workers [1] written on myocardial protection by nicorandil during open-heart surgery under cardiopulmonary bypass (CPB). In relation to cardioplegia, coronary artery spasm (CAS) is frequently underestimated during CPB. Until now, CAS was not detectable with current monitoring techniques during CPB and its impact on cardiac surgery has not been elucidated in previous studies. During CAS the blood flow to the myocardium decreases depending on the degree of coronary vasoconstriction, thereby increasing anaerobic metabolites and myocardial ischaemia. Consequently, CAS could be responsible for right and left ventricular failure after leaving CPB. Therefore, apart from being a potassium channel opening drug preventing intracellular Ca2+ loading [2], the fact that nicorandil is a coronary vasodilator might have contributed to favourable results in your study. The link between vasospastic angina and vulnerability for ventricular tachycardia or ventricular fibrillation outside the setting of cardiac surgery has already been described in several case reports [3-5]. Iida and colleagues [5] reported that ventricular fibrillation improved and disappeared with the start of treatment with nitrates and suggested that CAS should be considered as a differential diagnosis in the presence of ST-segment changes and/or intractable ventricular arrhythmias. Extending this conclusion into CPB surgery, this could imply that rather than giving an anti-arrhythmic drug, a coronary vasodilator should be used to prevent and to treat arrhythmias secondary to ischaemic episodes caused by CAS. As your results show, a link between CAS and ventricular fibrillation seems to be apparent. After cross-clamp removal in coronary artery bypass grafting (CABG) patients, two patients in the nicorandil group developed significant cardiac dysrythmias vs. six patients in the placebo group. Unfortunately, the number of your patients is limited and it would be interesting to pursue your study as a multicentre trial on a larger scale. The relationship between nicorandil and coronary vasodilatation also explains the enhanced distribution of cardioplegia solution, a faster time until electromechanical arrest in the nicorandil group and a faster return of electromechanical activity after aortic cross clamp removal in patients under nicorandil in the mitral valve replacement group. Interestingly, although not significantly different, in CABG patients four nicorandil patients compared to two placebo patients had creatine kinase (CK-MB) levels higher than 75 IU L−1. Within the patients treated with nicorandil in the CABG group, as far as it can be concluded from Table 3, the rise in CK-MB mainly occurred between 6 and 24 h postoperatively, which is delayed in respect to the nicorandil patients for mitral valve replacement where the peak is at 6 h postoperatively. You conclude that these patients receiving nicorandil had a lower incidence of significant elevation of postoperative myocardial damage, suggesting that ongoing myocardial injury in the postoperative period might possibly be due to reperfusion injury and that nicorandil may have attenuated this due to its anti-inflammatory property. This could be correct but is in contrast to the finding that four nicorandil CABG patients compared to two placebo CABG patients had significantly elevated CK-MB levels. Theoretically, the incidence of significantly elevated CK-MB levels should be lower in the nicorandil group. Nonetheless, this could mean that there are multifactorial causes for postoperative myocardial infarction in your patients. When did the myocardial infarction actually happen in both groups and could other factors have been responsible such as the quality of coronary vessels? In addition, could postoperative factors rather than perioperative management have influenced the occurrence of postoperative infarction in the cases you mentioned? Unfortunately, the limited number of patients in your study precludes any conclusion on this issue. Ideally, troponin I should also have been measured. Nevertheless, the general outcome in your publication is favourable for the use of nicorandil during cardioplegia. Just as a remark, because enzymes of the potassium channel openers work more efficiently during normothermia, warm cardioplegia could have improved results due to increased potassium permeability leading to rapid sinus node arrest. In addition, Cohen and colleagues [6] concluded that terminal infusion of warm blood cardioplegia repleted myocardial ATP levels and improved postoperative myocardial function. In general, hypothermic cardioplegia should be avoided because it can trigger CAS, thereby inducing ventricular fibrillation leading to depletion of myocardial ATP. Warm cardioplegia was not applied in your study. On the other hand, CK-MB levels under cold cardioplegia were improved in mitral valve replacement patients with nicorandil, which make your results even more interesting because CAS is more enhanced by hypothermia. In spite of above remarks, we want to congratulate Chinnan and co-workers for their excellent paper which brings us one step further ahead to optimize coronary blood flow during CPB and thereby decreasing events of myocardial ischaemia.

Cardiac surgery in type-1-myotonic muscular dystrophy (Steinert syndrome) associated to Barlow disease

No data exist in the English-language literature about patients with Barlow disease associated to Steinert syndrome and little is known about the employment of hypothermic cardiopulmonary bypass (CPB) and hyperkalemic cardioplegia in these patients. We present our experience with six patients affected by myxomatous degeneration associated to Steinert disease undergoing complex mitral valve repair. In all patients we employed mild hypothermic CPB (31 degrees C) and myocardial protection was achieved, in the entire cohort, by the use of blood hyperkalemic cold cardioplegia. The postoperative course was uneventful in all patients and neither shivering nor generalized muscle contraction were observed. Furthermore, all patients have remained well on an outpatient basis. Hypothermic CPB and hyperkalemic cardioplegia can be safely employed in patients with Steinert syndrome requiring complex cardiac surgery. Further large studies are necessary to confirm our findings.

Cardioprotection of neonatal heart using normothermic hyperkalaemia: the importance of delivery and terminal cardioplegia

Cardioprotection of immature hearts remains controversial and largely based on the use of hypothermic cardioplegia. Recent clinical trials in pediatric open-heart surgery suggest that normothermic cardioplegic arrest is also cardioprotective. However, the advantages of using normothermic cardioplegia delivered as single- or multi-dose with or without terminal cardioplegia are unknown. This work investigates the efficacy of these techniques and the mechanism(s) underlying their protective effect. Neonatal (7-10 days) rabbit hearts in a working mode were exposed to normothermic global ischemia (60 or 90 min) protected with one of the following cardioplegic (hyperkalaemic buffer) protocols: single-dose, multi-dose infused every 30 min, single-dose or multi-dose with terminal cardioplegia. The extent of functional recovery (e.g., aortic and coronary flow), ischemic stress (e.g., myocardial ATP, lactate) and reperfusion injury (lactate dehydrogenase (LDH) release) were assessed. Recovery following 60 min global ischemia was improved (p < 0.05) by single-dose and multi-dose cardioplegic delivery (from 5% to 60% and 80%, respectively). Improved recovery was augmented by 2 min terminal cardioplegia (to 90% and 97% for single-dose and multi-dose, respectively). Extending ischemia to 90 min with single-dose resulted in 0% recovery that was not improved by 2 min terminal cardioplegia. However, 5 min (not 10 min) terminal cardioplegia significantly improved recovery (32%). Multi-dose followed by 5 min terminal cardioplegia resulted in full recovery. Cardioprotective interventions were associated with a reduction in LDH release and attenuated changes in myocardial metabolites. During normothermic cardioplegic arrest of neonatal heart: (i) multi-dose is superior to single-dose; (ii) terminal cardioplegia confers additional protection to single-dose and multi-dose; and (iii) protection is likely to be due to metabolic preservation.

Effects of KR‐33028, a novel Na+/H+ exchanger‐1 inhibitor, on ischemia and reperfusion‐induced myocardial infarction in rats and dogs

The present study was performed to evaluate the cardioprotective effects of KR-33028, a novel Na+/H+ exchanger subtype 1 (NHE-1) inhibitor, in rat and dog models of coronary artery occlusion and reperfusion. In anesthetized rats subjected to a 45-min coronary occlusion and a 90-min reperfusion, KR-33028 at 5 min before occlusion (i.v. bolus) dose-dependently reduced myocardial infarct size from 58.0% to 46.6%, 40.3%, 39.7%, 33.1%, and 27.8% for 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg respectively (P < 0.05). In anesthetized beagle dogs that underwent a 1.0-h occlusion followed by a 3.0-h reperfusion, KR-33028 (3 mg/kg, i.v. bolus) markedly decreased infarct size from 45.6% in vehicle-treated group to 16.4% (P < 0.05), and reduced the reperfusion-induced release in creatine kinase myocardial band isoenzyme (MB), lactate dehydrogenase, troponin-I, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase. In separate experiments to assess the effects of timing of treatment, KR-33028 (1 mg/kg, i.v. bolus) given 10 min before or at reperfusion in rat models also significantly reduced the myocardial infarct size (46.3% and 44.1% respectively) compared with vehicle-treated group. In all studies, KR-33028 caused no significant changes in any hemodynamic profiles. In an isolated rat heart model of hypothermic cardioplegia, KR-33028 (30 mum), which was added to the heart preservation solution (histidin-tryptophan-ketoglutarate) during hypothermic cardioplegic arrest, significantly improved the recovery of left ventricular developed pressure, heart rate and dP/dt(max) after reperfusion. Taken together, these results indicate that KR-33028 significantly reduced the myocardial infarction induced by ischemia and reperfusion in rats and dogs, without affecting hemodynamic profiles.