Recommendations from the Association for European Paediatric and Congenital Cardiology for clinical training in paediatric heart failure and transplantation.

Advanced medical and surgical treatment of heart failure and management of patients following heart transplantation is an emerging area. Treatment options at various levels are becoming available in an increasing number of countries. This rapidly evolving field involves a complex multi-disciplinary approach with a number of complementary medical and surgical strategies, including pharmacotherapy, structural cardiac interventions, electrophysiological optimisation, mechanical circulatory support, and heart transplantation. Furthermore, the importance of psycho-social support and care of patients and their families cannot be overstated. The aforementioned challenges and dynamics of new developments require guidance for core and advanced medical training in heart failure and transplantation. The Association for European Paediatric and Congenital Cardiology working group "pulmonary hypertension, heart failure and transplantation" has produced this document as an expert consensus statement; however, all recommendations must be considered and applied in the context of the local and national infrastructure and legal regulations.

Simulations reveal adverse hemodynamics in patients with multiple systemic to pulmonary shunts.

For newborns diagnosed with pulmonary atresia or severe pulmonary stenosis leading to insufficient pulmonary blood flow, cyanosis can be mitigated with placement of a modified Blalock-Taussig shunt (MBTS) between the innominate and pulmonary arteries. In some clinical scenarios, patients receive two systemic-to-pulmonary connections, either by leaving the patent ductus arteriosus (PDA) open or by adding an additional central shunt (CS) in conjunction with the MBTS. This practice has been motivated by the thinking that an additional source of pulmonary blood flow could beneficially increase pulmonary flow and provide the security of an alternate pathway in case of thrombosis. However, there have been clinical reports of premature shunt occlusion when more than one shunt is employed, leading to speculation that multiple shunts may in fact lead to unfavorable hemodynamics and increased mortality. In this study, we hypothesize that multiple shunts may lead to undesirable flow competition, resulting in increased residence time (RT) and elevated risk of thrombosis, as well as pulmonary overcirculation. Computational fluid dynamics-based multiscale simulations were performed to compare a range of shunt configurations and systematically quantify flow competition, pulmonary circulation, and other clinically relevant parameters. In total, 23 cases were evaluated by systematically changing the PDA/CS diameter, pulmonary vascular resistance (PVR), and MBTS position and compared by quantifying oxygen delivery (OD) to the systemic and coronary beds, wall shear stress (WSS), oscillatory shear index (OSI), WSS gradient (WSSG), and RT in the pulmonary artery (PA), and MBTS. Results showed that smaller PDA/CS diameters can lead to flow conditions consistent with increased thrombus formation due to flow competition in the PA, and larger PDA/CS diameters can lead to insufficient OD due to pulmonary hyperfusion. In the worst case scenario, it was found that multiple shunts can lead to a 160% increase in RT and a 10% decrease in OD. Based on the simulation results presented in this study, clinical outcomes for patients receiving multiple shunts should be critically investigated, as this practice appears to provide no benefit in terms of OD and may actually increase thrombotic risk.

Catheter interventions in the staged management of hypoplastic left heart syndrome.

AIM: To analyse the current practice and contribution of catheter interventions in the staged management of patients with hypoplastic left heart syndrome. METHODS: This study is a retrospective case note review of 527 patients undergoing staged Norwood/Fontan palliation at a single centre between 1993 and 2010. Indications and type of catheter interventions were reviewed over a median follow-up period of 7.5 years. RESULTS: A staged Norwood/Fontan palliation for hypoplastic left heart syndrome was performed in 527 patients. The 30-day survival rate after individual stages was 76.5% at Stage I, 96.3% at Stage II, and 99.4% at Stage III. A total of 348 interventions were performed in 189 out of 527 patients. Freedom from catheter intervention in survivors was 58.2% before Stage II and 46.7% before Stage III. Kaplan-Meier freedom from intervention post Fontan completion was 55% at 10.8 years of follow-up. Post-stage I interventions were mostly directed to relieve aortic arch obstruction--84 balloon angioplasties--and augment pulmonary blood flow--15 right ventricle-to-pulmonary conduit interventions; post-Stage II interventions centred on augmenting size of the left pulmonary artery--73 procedures and abolishing systemic venous collaterals--32 procedures. After Stage III, the focus was on manipulating the size of the fenestration--42 interventions--and the left pulmonary artery -31 procedures. CONCLUSION: Interventional cardiac catheterisation constitutes an integral part in the staged palliative management of patients with hypoplastic left heart syndrome. Over one-third (37%) of patients undergoing staged palliation required catheter intervention over the follow-up period.

Long-term Outcome After Repair of Transposition of the Great Arteries With Aortic Arch Obstruction.

BACKGROUND: This study compares the long-term outcomes of patients after repair of transposition of the great arteries (TGA) with and without aortic arch obstruction (AAO). METHODS: This is a single-institution, retrospective study between October 2004 and February 2023. Patients who underwent arterial switch operation and aortic arch repair (ASO-AAR group) with patch augmentation were compared with those without AAO (ASO group). The primary end point was survival; freedom from reintervention was a secondary end point. RESULTS: We identified 176 patients, 31 in the ASO-AAR group and 145 in the ASO group. The median follow-up period was 10.3 years. There were no differences between the ASO-AAR group and the ASO group in early deaths (3.2% vs 0.7%) and late deaths (3.2% vs 2.8%), or 15-year survival rates (92.6% vs 96.2%). Surgical and catheter-based reinterventions were higher in the ASO-AAR group, involving the pulmonary arteries (41.9% vs 4.8%, P < .001), aortic arch (16.1% vs 0.7%, P < .001), and residual ventricular septal defects (11.4% vs 0%, P = .05). The ASO-AAR group showed a higher prevalence of double-outlet right ventricle TGA-type (61.3% vs 4.1%, P < .001) and a lower aortopulmonary index (0.67 vs 1.01, P < .001). CONCLUSIONS: Patients undergoing surgical repair of TGA and AAO achieved excellent survival rates, comparable to patients with simple transposition. A higher rate of surgical and catheter-based reinterventions was observed in patients with arch obstruction and/or a low aortopulmonary index. AAR with patch augmentation proved to be an effective surgical technique with a low incidence of aortic reinterventions.

Coronary transfer for complex looping and intramural variants in the arterial switch procedure.

Achieving a safe and accurate coronary transfer in the context of the precise geometry of the realigned great arterial connections is the essence of the arterial switch operation for transposition. Because the incidence of variant coronary patterns is not low, one needs to be familiar with techniques to transfer all types of coronary patterns when performing the arterial switch operation. Both closed and open techniques for coronary transfer have been widely adopted for the arterial switch operation. We routinely use the open technique for coronary transfer combined with a liberal use of trapdoor incisions. We demonstrate that this technique, with appropriate technical modifications, serves as a template for achieving accurate coronary transfer even in the context of complex looping and intramural variants.

Recapitulation of developmental cardiogenesis governs the morphological and functional regeneration of adult newt hearts following injury.

Urodele amphibians, like the newt, are the "champions of regeneration" as they are able to regenerate many body parts and tissues. Previous experiments, however, have suggested that the newt heart has only a limited regeneration capacity, similar to the human heart. Using a novel, reproducible ventricular resection model, we show for the first time that adult newt hearts can fully regenerate without any evidence of scarring. This process is governed by increased proliferation and the up-regulation of cardiac transcription factors normally expressed during developmental cardiogenesis. Furthermore, we are able to identify cells within the newly regenerated regions of the myocardium that express the LIM-homeodomain protein Islet1 and GATA4, transcription factors found in cardiac progenitors. Information acquired from using the newt as a model organism may help to shed light on the regeneration deficits demonstrated in damaged human hearts.

Changing attitudes to the management of hypoplastic left heart syndrome: a European perspective.

BACKGROUND AND AIMS: Several years ago, one of us described the difference in attitude to patients with hypoplastic left heart syndrome in the United States of America and Europe as similar to that between Mars and Venus. Uncertainty remains with regard to the long-term prognosis for patients with hypoplastic left heart syndrome. This prognosis may be considered in terms of survival, functional performance, including exercise capacity and neurodevelopment, as well as psychosocial effects on the patient, family, and siblings. Counselling parents where either an antenatal or postnatal diagnosis of hypoplastic left heart syndrome has been made requires practitioners to give information on these prognostic aspects. We wanted to see how attitudes among European surgeons have changed over the last few years. METHODS: We performed a review of recent European data for hypoplastic left heart syndrome and conducted a survey among surgeons in major European centres to ascertain key aspects of their attitudes to the management of patients with hypoplastic left heart syndrome and how they counsel parents. RESULTS AND CONCLUSIONS: As of January, 2011, 2392 citations in the PubMed database were available for the search string "hypoplastic left heart". The majority of these were from the centres from the United States of America and Europe. The European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Database shows an annual increase in the number of Norwood (Stage I) operations for hypoplastic left heart syndrome from 2003 to 2009, with a corresponding reduction in mortality. European rates of antenatal detection vary widely between centres, as do the rates of termination for a prenatal diagnosis of hypoplastic left heart syndrome. We observed a wide variation in the estimates of surgeons for survival and quality of life for surgical palliation of hypoplastic left heart syndrome, as well as in their estimates for actual rates of termination of pregnancy in their centres. Further, there was marked inconsistency in the information given to parents as part of the process of counselling. These issues remain to be resolved if parents are to make a fully informed decision for their child.

Two-patch transannular repair of tetralogy of Fallot with complete atrioventricular canal defect.

We demonstrate the repair in an infant of tetralogy of Fallot with complete atrioventricular canal defect using a 2-patch technique with transannular reconstruction of the right ventricular outflow tract due to a diminutive pulmonary valve annulus. This approach is reproducible and particularly valuable to surgeons who routinely use a 2-patch technique to repair an isolated complete atrioventricular canal defect.

Ascending aorta and aortic root replacement (with or without valve sparing) in early childhood: surgical strategies and long-term outcomes.

OBJECTIVES: Aortic root and ascending aorta replacements (AARs) are rarely required in the paediatric population. We report here a series of AAR performed in young children using different surgical techniques. METHODS: Between 1995 and 2017, 32 children under the age of 10 years (median age 5.4 years) underwent AAR procedures at our institution. Twenty-two (69%) had a connective tissue disease (infantile Marfan syndrome or Loeys-Dietz syndrome). We performed 11 AAR using a composite graft with a mechanical prosthesis and 21 valve-sparing procedures (10 Yacoub operations and 11 David operations). Median follow-up for operative survivors was 7.7 years (interquartile range 4.2-12.8 years). RESULTS: The cardiac-related early mortality rate was 6%. Patient survival was 91% at both 1 and 10 years. Eleven survivors (38%), all with a status of post-valve-sparing procedure, required an aortic root reintervention with an aortic valve replacement after a median interval of 4.2 years. Interestingly, only patients with infantile Marfan syndrome tended to be associated with risk of reoperation. CONCLUSIONS: Aortic root and AARs are safe in young children whatever the surgical procedure. Aortic valve-sparing procedures show good long-term results except in children with infantile Marfan syndrome whose ineluctable aortic annulus dilatation or aortic valve regurgitation requires reintervention after a short period.

Anomalous aortic origin of coronary arteries: an alternative to the unroofing strategy.

OBJECTIVES: Anomalous aortic origin of a coronary artery (AAOCA) is the second leading cause of sudden death in children and young adults. The most threatening anatomy is an interarterial and an intramural course, both probably involved in ischaemic phenomena and sudden death. The treatment of interarterial AAOCA remains controversial. Most of the published studies describe the results of the unroofing technique. Our study aims to evaluate the results of a different surgical approach. METHODS: From 2005 to 2019, 61 patients were operated on for an interarterial AAOCA (median age 14.7 years). Forty patients had a right AAOCA, and 21 patients had a left AAOCA including 5 patients with intraseptal course. Seventy percent of patients were symptomatic. Five patients had an aborted sudden cardiac death. Two surgical techniques were used: an 'anatomical' repair for 35 patients (15 left and 22 right AAOCA) or a coronary translocation with creation of a neo-ostia in 19 patients (1 left and 18 right AAOCA). The 5 left AAOCA patients with an intra-septal course required a complete release of the coronary artery from the septum. RESULTS: There was no early or late postoperative death. Three patients had an acute postoperative ischaemic event. Two patients required immediate angioplasty and stenting: 1 patient (7 years) with a hypoplastic right AAOCA and 1 patient (66 years) for inadequate tailoring after septal release. The third patient required an immediate surgical revision (H-2) for left AAOCA thrombosis at the level of the pericardial patch with full myocardial recovery at discharge. During follow-up, 1 patient with right AAOCA translocation and chronic chest pain required subsequent stenting and finally a coronary artery bypass grafting 2 years after initial surgery. One patient who had an asymptomatic mild right coronary stenosis 1 year after anatomical repair was successfully treated by angioplasty alone. All patients but 1 who underwent coronary translocation are totally asymptomatic. All patients with anatomical repair or septal release are free from ischaemic symptoms. CONCLUSIONS: Anatomical repair might provide a better protective option for these patients. Unlike unroofing, it treats the entire intramural segment, relocates the ostium at the appropriate sinus level and corrects any acute take-off angle.

Current Readings on Surgery for the Neonate With Hypoplastic Aortic Arch.

Aortic arch hypoplasia is commonly present in neonates born with ductal-dependent coarctation of the aorta. The ideal surgical repair of neonates with proximal arch hypoplasia continues to be debated. Controversy exists about the fate of the hypoplastic proximal aortic arch following surgical repair and whether that will eventually grow to normal size upon relief of the distal obstruction or will persist as a residual lesion that can affect the long-term outlook of those patients. There is new evidence that residual proximal arch hypoplasia and the shape of the reconstructed arch both have an important impact on vascular remodeling and on the subsequent development of hypertension. Those concerns about late outcomes despite what was originally deemed a successful repair in infancy, coupled with improved cardiopulmonary bypass and cerebral perfusion techniques that allow surgeons to address proximal arch hypoplasia with low morbidity, have rekindled the debate on how to address proximal arch hypoplasia, with the aim to offer a neonatal surgery that would last for a lifetime and provide both optimal early recovery and late freedom from hypertension and related complications.

Bootlace Technique for Delayed Sternal Closure in Pediatric Cardiac Surgery.

Delayed sternal closure is commonly required following cardiac surgery. This strategy has proven itself very helpful, especially after cardiac transplantation with significant donor/recipient size mismatch. However, at the time of chest closure, acute changes in intrathoracic pressure may be challenging. In this study, we describe our technique of gradual chest approximation, which facilitates closure in difficult situations.

Impact of mode of failure and end-organ dysfunction on the survival of adult Fontan patients undergoing cardiac transplantation.

OBJECTIVES: Adults with failing Fontan circulation (FFC) represent a heterogeneous, high-risk group for cardiac transplantation with poor reported outcomes. We studied the impact of mode of Fontan failure (preserved versus impaired systolic ventricular function) and end-organ dysfunction on early survival in adults undergoing cardiac transplantation for FFC. METHODS: A single-centre, retrospective study of 26 adults (≥16 years) with FFC undergoing cardiac transplantation between 1990 and 2015. Patients were classified by the presence or absence of preserved systolic ventricular function (PVF). End-organ dysfunction was assessed by serum markers, including albumin, liver ultrasound and the presence of varices, ascites, splenomegaly and thrombocytopaenia (VAST score for portal hypertension). RESULTS: Thirty-day survival rate for the entire cohort was 69.2%, with 76.2% survival for the recent era. One-year Kaplan-Meier survival rate was 65.4%. Actuarial survival was poorer in those with PVF or heterotaxy (P = 0.01; log-rank test). Cox multivariable regression analysis confirmed PVF as an independent predictor for death (odds ratio, OR 5.38; confidence interval, CI 1.08-26.96; P = 0.04). In examining the PVF subset further, these patients had significantly higher VAST and liver ultrasound scores and lower serum albumin, compared with patients with impaired function. Patients with PVF and ≥moderate liver fibrosis on ultrasound or VAST score ≥2 accounted for two-thirds of the total mortality. CONCLUSIONS: Favourable cardiac transplantation outcomes can be achieved in adults with failing Fontan circulation. Patients with PVF may represent a distinct subset with more perturbed failing Fontan physiology and higher cardiac transplant mortality. We continue, however, to evolve and refine our strategies and are optimistic concerning future improvement in outcomes even in those with PVF.

Outcomes of palliative right ventricle to pulmonary artery connection for pulmonary atresia with ventricular septal defect.

OBJECTIVES: To determine the early, intermediate and long-term outcomes of pulmonary atresia with ventricular septal defect (PA/VSD) Types I, II and III initially palliated by a right ventricle to pulmonary artery (RVPA) connection. METHODS: We performed a retrospective study from 2000 to 2014 that included 109 patients with PA/VSD who had undergone an RVPA connection (tetralogy of Fallot and PA/VSD Type IV excluded). The end-points of this strategy were adequate pulmonary artery tree post-palliation, second palliation, biventricular repair, right ventricular pressure post-biventricular repair and late reoperation. Mean follow-up was 5.4 years (1 day to 14-78 years). RESULTS: Early mortality after an RVPA connection was 2.7% (3 of 109). The interstage mortality rate was 6.6% (7 of 106). Eighty-four (77%) patients had a biventricular repair and 8 patients (7%) are awaiting repair. Overall survival was 90% at 1 year and 81% at 10 years. The RVPA connection allowed significant growth of the native pulmonary artery with a Nakata index of 101 mm2/m2 before the RVPA connection and 274 mm2/m2 after (P = 0.001). Twenty-nine reinterventions for restrictive pulmonary blood flow have been done (9 before 2 months and 20 after 2 months). Of the 84 patients who had a repair, 22 patients (26%) initially had a right ventricular pressure greater than 40 mmHg. Twenty-eight patients (33%) required late reoperation. CONCLUSIONS: Hospital deaths after the RVPA connection were low. The procedure allowed good growth of the native pulmonary artery. Biventricular repair was possible in a large number of cases. The late morbidity rate remains significant. Early reinterventions could be avoided by appropriate calibration. This technique appears to be suitable for any type of PA/VSD with central pulmonary arteries.

Comparison of paracorporeal and continuous flow ventricular assist devices in children: preliminary results.

Objectives: With the scarcity of organs, a durable, reliable ventricular assist device (VAD) is required. The Berlin Heart EXCOR ® (BH) remains the most established VAD in the paediatric population. Implantable continuous flow (CF) VADs have been introduced to the paediatric field with encouraging early results. In this study, we compared the results of a newly introduced CF VAD (HeartWare VAD [HVAD] ® ) to results in a matched group of BH recipients. Methods: The study included patients aged <16 years who received mechanical left VAD (LVAD) support between December 2005 and January 2016. The preimplant characteristics and postimplant outcomes of patients who received the HVAD were compared with those of a matched group who received the BH. Patients with congenital heart disease were excluded. Results: Thirty patients were included in the study: 13 had received the HVAD and were matched with 17 patients who had received the BH LVAD. The only difference in preimplant characteristics was the need for higher inotropic support in the BH group. There was no difference in the need for right ventricular (RV) support (58.8% for BH vs 53.8% for HVAD, P = 1.00) or in the incidence of cerebrovascular accidents (12.5% vs 7.7%, respectively, P = 1.00), though the BH group showed prolonged mechanical ventilation (31.3% vs 0%, P = 0.047). There were no deaths while on VAD support in either group. Patients with the HVAD showed a bimodal distribution for the primary end point (transplant/explant): All HVAD recipients who also required early RV support reached this end point within 30 days of receiving the implant. Conclusions: Our early experience with the CF intracorporeal LVAD system (HVAD) indicates outcomes comparable to those with the well-established pulsatile flow paracorporeal LVAD (BH). The theoretical durability of the CF device, which might also allow for the possibility of hospital discharge and better quality of life, is yet to be proven.

Human cytomegalovirus immediate-early protein IE2-86, but not IE1-72, causes graft coronary arteriopathy in the transplanted rat heart.

BACKGROUND: Graft coronary arteriopathy (GCA) after heart transplantation is a major factor limiting the long-term survival of the recipients. Human cytomegalovirus (HCMV) infection is a possible cause of this disease which is characterized by diffuse intimal thickening resulting from smooth muscle cell migration and proliferation. It has been reported that HCMV immediate-early (IE) proteins, IE1 and IE2, could play an important role in the development of this disease; however, the precise in vivo role of these proteins in causing GCA has not been clarified. METHODS AND RESULTS: Excised Lewis rat hearts were transfected with HCMV IE1-72, IE2-86 or control plasmid by intra-coronary infusion of Hemagglutinating Virus of Japan-liposome, and transplanted into syngeneic recipients' abdomens. All cardiac grafts continued to beat well throughout the incubation period in the absence of immunosuppression. Exclusive expression of IE1-72 or IE2-86 protein in coronary artery walls was demonstrated after IE1-72 or IE2-86 gene transfection, respectively. Luminal occlusion as a consequence of intimal thickening of graft coronary arteries developed in the IE2-86 transfected hearts at day 21 after transplantation (30.1+/-3.4% occlusion, P<0.0001), compared with the IE1-72 and control transfected ones (8.2+/-1.6 and 6.8+/-1.1%, respectively). In contrast, there was no significant difference in luminal occlusion between the IE1-72 and control transfected hearts. CONCLUSIONS: We have demonstrated that expression of IE2-86 alone, but not IE1-72, causes intimal hyperplasia after cardiac transplantation. IE2-86 protein may therefore prove to be a useful target in therapies aimed at preventing HCMV-related GCA and improving the long-term result of cardiac transplantation.

Targeted cell delivery into infarcted rat hearts by retrograde intracoronary infusion: distribution, dynamics, and influence on cardiac function.

BACKGROUND: Intracoronary infusion for cell transplantation has potential advantages in disseminating cells globally into the myocardium with less injury over direct intramuscular injection. Arterial route, however, has a risk of coronary embolism and a limitation in cell delivery into ischemic or infarcted areas. We assessed the efficiency of retrograde intracoronary cell implantation into infarcted hearts using a novel rat model. METHODS AND RESULTS: After left coronary artery ligation in rat, a catheter was inserted into the left cardiac vein, which drains the left ventricular free wall. Through this, 1x10(6) skeletal muscle precursor cells expressing nuclear beta-galactosidase were infused retrogradely into the vein. In situ staining demonstrated that beta-galactosidase-expressing donor cells had disseminated throughout the left ventricular free wall, including both infarcted and surrounding border areas, at 10 minutes after infusion. At 28 days, in contrast, positively stained multinuclear myotubes were found in border zones, whereas no positive cells were seen in infarcted areas. Measurement of beta-galactosidase enzyme activity estimated that 29.8+/-6.9% of total infused cells were retained within the myocardium at 10 minutes and that this number decreased to 23.7+/-8.1% at 3 days but rapidly increased thereafter, reaching a plateau at 90.2+/-17.1% by 14 days. Echocardiography and Langendorff perfusion demonstrated that cell implantation improved cardiac function and dimensions by 28 days, compared with both sham-treated and phosphate-buffered saline-infused infarcted hearts, and this was associated with decreased collagen deposition. CONCLUSIONS: Retrograde intracoronary cell transplantation could provide an effective cell delivery into infarcted hearts and could be a useful strategy for treating myocardial infarction.

Heat shock protein 72 enhances manganese superoxide dismutase activity during myocardial ischemia-reperfusion injury, associated with mitochondrial protection and apoptosis reduction.

BACKGROUND: Heat shock protein 72 (HSP72) is known to provide myocardial protection against ischemia-reperfusion injury by its chaperoning function. Target molecules of this effect are presumed to include not only structural proteins but also other self-preservation proteins. The details, however, remain unknown. Manganese superoxide dismutase (Mn-SOD) is an enzyme that preserves mitochondria, a key organelle for cellular respiration, from reperfusion injury and limits mitochondria-related apoptosis. We hypothesized that Mn-SOD would play a role in HSP72-mediated cardioprotection. METHODS AND RESULTS: Rat hearts were transfected with human HSP72 by intra-coronary infusion of Hemagglutinating Virus of Japan-liposome, resulting in global myocardial overexpression of HSP72. After ischemia-reperfusion injury, cardiac function (left ventricular systolic pressure, maximum dP/dt, minimum dP/dt, and coronary flow) was improved in the HSP72-transfected hearts compared with control-transfected ones, corresponding with less leakage of creatine kinase and mitochondrial aspartate aminotransferase. Postischemic Mn-SOD content and activity in the HSP72-transfected hearts were enhanced in comparison with the controls (content: 96.9+/-4.1 versus 85.5+/-2.5% to the preischemic level, P=0.038; activity: 93.9+/-2.2 versus 82.2+/-3.7%, P=0.022), associated with improved mitochondrial respiratory function (postischemic percent respiratory control index; NAD(+)-linked: 81.3+/-3.8 versus 18.5+/-4.4%; FAD-linked: 71.8+/-5.5 versus 20.7+/-5.3%, P<0.001). In addition, incidence of postischemic cardiomyocyte apoptosis was attenuated in the HSP72-transfected hearts (4.0+/-1.1 versus 10.3+/-3.3%, P=0.036), correlating with an increased Bcl-2 level and reduced up-regulation of caspase-3. CONCLUSIONS: These data suggest that the enhanced Mn-SOD activity during ischemia-reperfusion injury, which is associated with mitochondrial protection and apoptosis reduction, is a possible mechanism of HSP72-induced cardioprotection.

Role of interleukin-1beta in acute inflammation and graft death after cell transplantation to the heart.

BACKGROUND: Poor survival of grafted cells is a major factor hindering the therapeutic effect of cell transplantation; however, the causes of cell death remain unclear. We hypothesized that interleukin-1beta (IL-1beta) might play a role in the acute inflammatory response and graft death after cell transplantation and that inhibition of IL-1beta might improve graft survival. METHODS AND RESULTS: 14C-labeled male skeletal muscle precursor cells were implanted into female mouse hearts by direct intramuscular injection. The amount of 14C-label provides an estimate of the surviving cell number, whereas the amount of male-specific Smcy gene measured by polymerase chain reaction indicates the total (surviving+proliferated) number of donor-derived cells. At 10 minutes after implantation, 44.8+/-2.4% of the grafted cells survived and this steadily decreased to 14.6+/-1.1% by 24 hours, and to 7.9+/-0.6% by 72 hours (n=6 in each point). Proliferation of the surviving cells, which began after 24 hours, resulted in an increase in the total cell number from 15.5+/-0.8% at 24 hours to 24.4+/-1.6% at 72 hours. Acute inflammation was prominent at 24 hours and was reduced by 72 hours, in parallel with IL-1beta expression. Administration of anti-IL-1beta antibody improved graft survival at both 24 (25.6+/-1.6%) and 72 hours (14.8+/-1.1%) and resulted in a 2-fold increase in the total cell number at 72 hours (45.8+/-2.4%). The effects of IL-1beta inhibition corresponded with a reduced inflammatory response. CONCLUSIONS: IL-1beta is involved in acute inflammation and graft death after direct intramyocardial cell transplantation. Targeted inhibition of IL-1beta may be a useful strategy to improve graft survival.