OBJECTIVES:Many models of bioprosthesis are available for pulmonary valve replacement in adults with congenital heart disease, but there is a lack of randomized evidence to guide practice. We surveyed congenital cardiac surgeons to establish current practice and willingness to change within a clinical trial. METHODS:An online survey was sent to all consultant congenital cardiac surgeons in adult congenital centres in the United Kingdom and Ireland. Information was sought on preferred prostheses, factors influencing decision-making, implant technique, postoperative anticoagulation, practice variations in adolescents, and willingness to randomize patients to different prostheses within a trial. RESULTS:Responses were obtained from 27 (69%) surgeons. A total of 19 (70%) preferred an Edwards bovine pericardial valve, most commonly the Inspiris Resilia (7, 26%). Only 2 (7%) favoured the Hancock II valve; the remaining 6 (22%) preferred pulmonary homografts. Data regarding long-term freedom from reintervention (23, 85%) was the most important factor influencing prosthesis choice. A total of 22 (81%) surgeons were willing to randomize adult patients to either a bovine pericardial valve or a porcine xenograft in a clinical trial, with Perimount Magna Ease and Hancock II being the most acceptable, respectively. Willingness to randomize dropped to 11 (41%) surgeons for adolescent patients. CONCLUSIONS:This survey demonstrates heterogeneity in the choice of pulmonary valve prosthesis. Combined with a lack of evidence from clinical trials, our findings support the presence of clinical equipoise. Most surgeons are willing to change practice, suggesting that a pragmatic, multicentre, randomized controlled trial comparing bovine pericardial versus porcine xenograft for pulmonary valve replacement in adults is feasible.

IntroductionNeonatal aortic arch surgery is associated with neurological morbidity of varying severity which is detected and potentially limited through neuroprotective strategies. We conducted a survey of healthcare professionals at all neonatal cardiac surgery centres in the United Kingdom and Ireland to determine current intraoperative neuromonitoring and neuroprotection practice.MethodsAn online cross-sectional survey was sent to congenital cardiac surgeons, cardiac anaesthetists, clinical perfusion scientists, and clinical neurophysiology professionals in all 12 level 1 paediatric cardiac surgical centres. Information was sought on their current clinical practice in neonates undergoing aortic arch surgery, including pharmacological management, cardiopulmonary bypass, acid-base and blood pressure management, neuromonitoring, and hypothermic circulatory arrest, and the feasibility and willingness to participate in a future clinical trial of neuroprotective strategies in these patients.ResultsWe received 55 (34%) responses, including representatives of all four clinical disciplines in 9 (75%) centres. Cooling to a nasopharyngeal temperature of 18°C before hypothermic circulatory arrest, selective antegrade cerebral perfusion, and near-infrared spectroscopy (NIRS) monitoring are common practice, whereas pharmacology, acid-base management, blood pressure and flow parameters, and NIRS-based interventions vary. In 7 (58%) centres, respondents from all four disciplines were willing to consider participation in a future clinical trial on neuroprotection.ConclusionsAspects of intraoperative neuroprotection and neuromonitoring are common across centres, although key areas of practice differ between practitioners and institutions. Most respondents were willing to participate in a future multi-centre clinical trial, which suggests clinical equipoise in the optimal strategy to protect the neonatal brain during aortic arch surgery.

Background:The incidence of mechanical circulatory support (MCS) for early graft dysfunction (EGD) following heart transplantation varies from 2.3% to 28.2%. Low pulmonary pulsatility index (PAPI) is associated with higher mortality in advanced heart failure and cardiogenic shock. We hypothesized that a lower pulmonary pulsatility index following heart transplantation is associated with MCS use for EGD. Methods:Two-center study of consecutive heart transplantation from May 2018 to December 2022. Hemodynamic parameters and inotropic/vasoconstrictor data were investigated on admission to the intensive care unit (T0) and at 6 hours later (T6). Results:Of the 173 patients included in this study, 24 had MCS for EGD. PAPI in the group that required MCS was lower at T0 (1.21 (0.84) vs 1.67 (1.23), p = 0.001) and T6 (0.77 (0.52) vs 1.44 (0.82), p = <0.001). There was no significant difference in recipient characteristics, donor characteristics (donor age and sex matching), and operative factors (warm/cold ischemic time, total ischemic time, cardiopulmonary bypass time) between the 2 groups. On multiple variable regression, PAPI at T6 was associated with delayed MCS independent of total donor organ ischemic time and short-term MCS bridge to transplantation (odds ratio, OR 0.1 (0.036-0.276), p = <0.001). Receiver operating characteristic (ROC) analysis showed an area under the ROC curve of 0.694 for T0 PAPI and 0.832 for T6 PAPI; a cut-off T6 PAPI of 1.22 had sensitivity and specificity of 81% and 65%, respectively. Conclusions:Lower PAPI at T6 (<1.22) is independently associated with MCS use for severe EGD postheart transplantation.

Abstract Wave intensity analysis (WIA) uses simultaneous changes in pressure and flow velocity to determine wave energy, type, and timing of traveling waves in the circulation. In this study, we characterized wave propagation in the pulmonary artery in patients with pulmonary hypertension associated with left‐sided heart disease (PHLHD) and the effects of dobutamine. During right heart catheterization, pressure and velocity data were acquired using a dual‐tipped pressure and Doppler flow sensor wire (Combowire; Phillips Volcano), and processed offline using customized Matlab software (MathWorks). Patients with low cardiac output underwent dobutamine challenge. Twenty patients with PHLHD (all heart failure with reduced left ventricular ejection fraction) were studied. Right ventricular systole produced a forward compression wave (FCW), followed by a forward decompression wave (FDW) during diastole. Wave reflection manifesting as backward compression wave (BCW) following the FCW was observed in 14 patients. Compared to patients without BCW, patients with BCW had higher mean pulmonary artery pressure (28.7 ± 6.12 vs. 38.6 ± 6.5 mmHg, p = 0.005), and lower pulmonary arterial capacitance (PAC: 2.88 ± 1.75 vs. 1.73 ± 1.16, p = 0.002). Pulmonary vascular resistance was comparable. Mean pulmonary artery pressure of 34.5 mmHg (area under the curve [AUC]: 0.881) and PAC of 2.29 mL/mmHg (AUC: 0.833) predicted BCW. The magnitude of the FCW increased with dobutamine (n = 11) and correlated with pulmonary artery wedge pressure. Wave reflection in PHLHD is more likely at higher pulmonary artery pressures and lower PAC and the magnitude of reflected waves correlated with pulmonary artery wedge pressure. Dobutamine increased FCW but did not affect wave reflection.

Objective:The study objective was to determine whether adequately delivered bilateral remote ischemic preconditioning is cardioprotective in young children undergoing surgery for 2 common congenital heart defects with or without cyanosis. Methods:We performed a prospective, double-blind, randomized controlled trial at 2 centers in the United Kingdom. Children aged 3 to 36 months undergoing tetralogy of Fallot repair or ventricular septal defect closure were randomized 1:1 to receive bilateral preconditioning or sham intervention. Participants were followed up until hospital discharge or 30 days. The primary outcome was area under the curve for high-sensitivity troponin-T in the first 24 hours after surgery, analyzed by intention-to-treat. Right atrial biopsies were obtained in selected participants. Results:Between October 2016 and December 2020, 120 eligible children were randomized to receive bilateral preconditioning (n = 60) or sham intervention (n = 60). The primary outcome, area under the curve for high-sensitivity troponin-T, was higher in the preconditioning group (mean: 70.0 ± 50.9 μg/L/h, n = 56) than in controls (mean: 55.6 ± 30.1 μg/L/h, n = 58) (mean difference, 13.2 μg/L/h; 95% CI, 0.5-25.8; P = .04). Subgroup analyses did not show a differential treatment effect by oxygen saturations (pinteraction = .25), but there was evidence of a differential effect by underlying defect (pinteraction = .04). Secondary outcomes and myocardial metabolism, quantified in atrial biopsies, were not different between randomized groups. Conclusions:Bilateral remote ischemic preconditioning does not attenuate myocardial injury in children undergoing surgical repair for congenital heart defects, and there was evidence of potential harm in unstented tetralogy of Fallot. The routine use of remote ischemic preconditioning cannot be recommended for myocardial protection during pediatric cardiac surgery.

Background Reinterventions may influence the outcomes of children with functionally single‐ventricle (f‐SV) congenital heart disease. Methods and Results We undertook a retrospective cohort study of children starting treatment for f‐SV between 2000 and 2018 in England, using the national procedure registry. Patients were categorized based on whether they survived free of transplant beyond 1 year of age. Among patients who had transplant‐free survival beyond 1 year of age, we explored the relationship between reinterventions in infancy and the outcomes of survival and Fontan completion, adjusting for complexity. Of 3307 patients with f‐SV, 909 (27.5%), had no follow‐up beyond 1 year of age, among whom 323 (35.3%) had ≥1 reinterventions in infancy. A total of 2398 (72.5%) patients with f‐SV had transplant‐free survival beyond 1 year of age, among whom 756 (31.5%) had ≥1 reinterventions in infancy. The 5‐year transplant‐free survival and cumulative incidence of Fontan, among those who survived infancy, were 93.4% (95% CI, 92.4%–94.4%) and 79.3% (95% CI, 77.4%–81.2%), respectively. Both survival and Fontan completion were similar for those with a single reintervention and those who had no reinterventions. Patients who had >1 additional surgery (adjusted hazard ratio, 3.93 [95% CI, 1.87–8.27] P <0.001) had higher adjusted risk of mortality. Patients who had >1 additional interventional catheter (adjusted subdistribution hazard ratio, 0.71 [95% CI, 0.52–0.96] P =0.03) had a lower likelihood of achieving Fontan. Conclusions Among children with f‐SV, the occurrence of >1 reintervention in the first year of life, especially surgical reinterventions, was associated with poorer prognosis later in childhood.

The Fontan circulation predisposes to multiple morbidities typically associated with older age but occurring in their third and fourth decades, consistent with premature aging. In this pilot study, we evaluated whether the Fontan circulation is associated with premature epigenetic aging. We found that in whole blood, Δage, the difference between chronological age and estimated epigenetic DNAge™, was significantly higher in those living with a Fontan circulation than in a reference cohort ( z =5.59, p<0.0001), with a mean Δage in adults post-Fontan of +4.9 years (95% CI 3.3-6.5, p<0.0001). Our results suggest that the Fontan circulation is associated with accelerated epigenetic aging, mirroring the premature aging clinical phenotype. In a life-limiting condition with few treatment options, targeting epigenetic aging may represent a novel opportunity for intervention.### Competing Interest StatementWG, XY and YCC are employees of Zymo Research Corporation. All other authors have no conflicts of interest to disclose.### Funding StatementThis study was funded by a generous donation from the Charlie Ramsey Research Fund to the Birmingham Childrens Hospital Charity (37-6-175). Nigel Drury was funded by an Intermediate Clinical Research Fellowship from the British Heart Foundation (FS/15/49/31612).### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The North West-Haydock NHS Research Ethics Committee gave ethical approval for this work via application ref: 20/NW/0001 on 20 February 2020.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors.

Intermittent cardiac output (CO) studies using thermodilution are considered the gold standard. We have developed a stroke volume (SV) calculator from pulmonary pulse pressure (PP) to allow continuous monitoring of SV and CO from PP. Hemodynamic data on 169 patients following orthotopic heart transplantation were used to compare our calculator-derived SV (and SV index, or SVi) against thermodilution-derived SV on admission into intensive care unit immediately following heart transplantation (T0) and 6 h after admission (T6). The calculated SV correlated with thermodilution-derived SV T0 (r = 0.920, p < 0.001, coefficient of 0.539 and the constant of 2.06). The median calculator SV, adjusted for coefficient and constant, was 48.4 ml (37.7, 60.7), comparable to the median thermodilution-derived SV 47.9 ml (37.5, 61.0), p = 0.737 with acceptable agreement on Bland–Altman plots. The thermodilution-derived SVi was 28.1 ml (19.7, 38.7) and adjusted calculator-derived SVi 28.9 ml (19.7, 39.9), p = 0.781. At T6, median thermodilution-derived SVi was 27.7 ml (19.5, 35.9) compared to the calculator-derived SVi median of 26.1 ml (17.7, 37.7), p = 0.203. Changes in PP can be used to track changes in SV using this calculator. Changes in PP may be used to assess response to treatment in the early post-operative period.

Introduction Children with congenital heart disease (CHD) are at risk of delayed motor development with increased risk for those requiring cardiac surgical intervention. We conducted a scoping review to identify the provision and impact of physiotherapy -delivered rehabilitation in children and young people with CHD following cardiac surgery. Methods CINAHL, EMBASE, PUBMED, AHMED, EMCARE, Cochrane Database of Systematic Reviews, NHS Evidence databases were searched (2000-2022). Included studies were published in full, in English and reported the use of physiotherapy in CHD (participants 0-18years) post -surgical procedure. Articles were screened by title and abstract and through full -text review with results structured in accordance with the PAGER framework and PRISMA- ScR checklist. Results Seven full text peer reviewed papers published 2014-2021 were identified from 5747 papers screened. Included papers were predominantly non -randomised cohort studies with a sample size of between one and 247. Study participants ranged from eight days to 16 years, with a variety of congenital heart defects and surgical procedures. The provision of physiotherapy varied with a range of rehabilitation formats and physiotherapeutic interventions utilised. Physiotherapy provision appeared to have a positive impact on functional/ developmental outcomes and muscle strength. Discussion Assessing the impact and provision of physiotherapy in CHD post -surgical intervention is challenging based on the published literature, due to small sample sizes, lack of control groups, heterogeneous demographics and variable intervention and formats delivered. Further research is required to identify the optimum format of physiotherapy provision and establish the potential impact of physiotherapy delivered rehabilitation on motor function and development. Contribution of the paper center dot In this study we highlight that the role of physiotherapy in the rehabilitation of children with CHD is an emerging area of research which needs further exploration. To the authors knowledge there are currently no published articles that have fully explored and reviewed the literature surrounding this topic. center dot Children with CHD are at increased risk of motor developmental delay and loss of motor function, thus requiring a period of rehabilitation by a physiotherapist. Currently, clinical practice is widely based on anecdotal evidence and local service provision. center dot The articles included in this review suggest that physiotherapeutic intervention can be helpful. However, due to the heterogeneous methodologies employed it is not possible to use the current published literature to generate universal guidelines that can be transferred into clinical practice. Key themes highlighted in the literature were the need for clarification regarding what format is optimal and the impact physiotherapeutic interventions have on outcomes. (c) 2023 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

OBJECTIVES:Right heart failure (RHF) is a major complication following left ventricular assist device (LVAD) implantation. Pulmonary artery pulsatility index (PAPi) has been evaluated as a haemodynamic marker for RHF, but PAPi is dependent on pulmonary vascular resistance (PVR). We conducted a systematic review to assess the relationship between PAPi and RHF and death in patients undergoing LVAD implantation and examined the relationship between PAPi cut-off and PVR. METHODS:We searched PubMed, EMBASE, CENTRAL and manually screened retrieved references to identify all clinical studies reporting PAPi in adult patients with a durable LVAD. Eligibility criteria were prespecified and 2 reviewers independently screened and extracted data; the Newcastle-Ottawa Scale was used to assess quality of non-randomized studies. This study was prospectively registered on PROSPERO (CRD42021259009). RESULTS:From 283 unique records, we identified 16 studies reporting haemodynamic assessment in 20 634 adult patients with an implanted durable LVAD. Only 2 studies reported on mortality and in both, a lower PAPi was significantly associated with death. Fifteen studies reported RHF data and, in 10 studies, a lower PAPi was significantly associated with RHF. Six studies reported on PAPi cut-offs ranging from 0.88 to 3.3; and the cut-offs were directly related to PVR (r = 0.6613, P = 0.019). CONCLUSIONS:Lower PAPi was associated with RHF and death following LVAD implantation, but a single PAPi cut-off cannot be defined, as it is dependent on PVR.

BACKGROUND:Appropriate costing and allocation of resources is vital to ensure that recruitment to a study is achieved on time and on target. However, there is little guidance concerning the workload associated with qualitative research.AIM:To review the planned versus actual workloads in a qualitative sub-study following elective cardiac surgery in children.DISCUSSION:Parents of children approached for a clinical trial were invited to participate in a semi-structured interview to explore their views about making decisions concerning their children's participation in the trial. A workload audit was conducted using anticipated points of contact with participants, and the duration of activities identified in the protocol and Health Research Authority statement of activities; these were compared with timed activities documented by the research team.CONCLUSION:The current system did not anticipate or capture the workload associated with conducting a relatively straightforward qualitative sub-study of a clinical trial with a research-engaged patient group.IMPLICATIONS FOR PRACTICE:Understanding the hidden workload associated with qualitative research is vital in ensuring that project timelines, recruitment targets and funding for research staff are realistic.

Abstract OBJECTIVES The aim of this study was to describe the early and late outcomes of the arterial switch for transposition. METHODS A single-centre retrospective cohort study was conducted to assess the early and late outcomes of arterial switch performed during infancy using a standardized institutional approach between 1988 and 2018, compared by morphological groups. RESULTS A total of 749 consecutive patients undergoing arterial switch during infancy were included, 464 (61.9%) with intact septum, 163 (21.8%) with isolated ventricular septal defect and 122 (16.3%) with complex transposition with associated lesions, including 67 (8.9%) with Taussig–Bing anomaly. There were 34 early deaths [4.5%, 95% confidence interval (CI) 3.1–6.1] with only 10 (2.6%) early deaths since 2000. Complex morphology (odds ratio 11.44, 95% CI 4.76–27.43) and intramural coronary artery (odds ratio 5.17, 95% CI 1.61–15.91) were identified as the most important risk factors for 90-day mortality. Overall survival was 92.7% (95% CI 90.8–94.6) at 5 years and 91.9% (95% CI 89.9–94.1) at 20 years; in hospital survivors, there were 15 (2.1%) late deaths during a median follow-up of 13.7 years. Cumulative incidence of surgical or catheter reintervention was 16.0% (95% CI 14.5–17.5) at 5 years and 22.7% (95% CI 21.0–24.0) at 20 years; early and late reinterventions were more common in the complex group, with no difference between the other groups. CONCLUSIONS Using a standardized approach, the arterial switch can be performed with low early mortality, moderate rates of reintervention and excellent long-term survival. Concomitant lesions were the most important risk factor for early death and were associated with increased risk of late reintervention.

In this viewpoint, we respond to the recently published national priorities for research in congenital heart disease (CHD) among adults, established through the James Lind Alliance Priority Setting Partnership, with specific attention to priority 3 (mental health) and priority 5 (maternal health). Our recent policy impact project explored how maternal mental health is currently addressed in adult congenital heart disease (ACHD) services in the National Health Service, identified gaps and discussed possible ways forward. Our multidisciplinary discussion groups, which included women with lived experience of CHD and pregnancy, cardiology and obstetrics clinicians and medical anthropologists, found that while pregnancy and the postnatal period increase the mental health challenges faced by women with CHD, current services are not yet equipped to address them. Based on this work, we welcome the prioritisation of both mental health and maternal health in ACHD, and suggest that future research should focus on the overlaps between these two priority areas.

HomeCirculationVol. 148, No. 17Risk Factors for Reintervention With Functionally Single-Ventricle Disease Undergoing Staged Palliation in England and Wales: A Retrospective Cohort Study Open AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessResearch ArticlePDF/EPUBRisk Factors for Reintervention With Functionally Single-Ventricle Disease Undergoing Staged Palliation in England and Wales: A Retrospective Cohort Study Qi Huang, Deborah Ridout, Victor Tsang, Nigel E. Drury, Timothy J. Jones, Hannah Bellsham-Revell, Elena Hadjicosta, Anna N. Seale, Chetan Mehta, Christina Pagel, Sonya Crowe, Ferran Espuny-Pujol, Rodney C.G. Franklin and Kate L. Brown Qi HuangQi Huang Correspondence to: Qi Huang, PhD, Clinical Operational Research Unit, University College London, London, WC1H 0BT. Email E-mail Address: [email protected] https://orcid.org/0000-0003-4456-2999 Clinical Operational Research Unit, Department of Mathematics (Q.H., E.H., C.P., S.C., F.E.-P. , Deborah RidoutDeborah Ridout Population, Policy and Practice Programme, Great Ormond Street Institute of Child Health (D.R.), University College London. , Victor TsangVictor Tsang Institute of Cardiovascular Science (V.T., K.L.B.), University College London. Great Ormond Street Hospital Biomedical Research Centre, London (V.T., K.L,B,). , Nigel E. DruryNigel E. Drury https://orcid.org/0000-0001-9012-6683 Paediatric Cardiology and Cardiac Surgery, Birmingham Children's Hospital, Birmingham (N.E.D., T.J.J., A.N.S., C.M.). Institute of Cardiovascular Sciences, University of Birmingham (N.E.D., T.J.J., A.N.S.). , Timothy J. JonesTimothy J. Jones https://orcid.org/0000-0001-8870-3496 Paediatric Cardiology and Cardiac Surgery, Birmingham Children's Hospital, Birmingham (N.E.D., T.J.J., A.N.S., C.M.). Institute of Cardiovascular Sciences, University of Birmingham (N.E.D., T.J.J., A.N.S.). , Hannah Bellsham-RevellHannah Bellsham-Revell https://orcid.org/0000-0002-0360-944X Paediatric Cardiology, Evelina London Children's Hospital (H.B.-R.). , Elena HadjicostaElena Hadjicosta Clinical Operational Research Unit, Department of Mathematics (Q.H., E.H., C.P., S.C., F.E.-P. , Anna N. SealeAnna N. Seale Paediatric Cardiology and Cardiac Surgery, Birmingham Children's Hospital, Birmingham (N.E.D., T.J.J., A.N.S., C.M.). Institute of Cardiovascular Sciences, University of Birmingham (N.E.D., T.J.J., A.N.S.). , Chetan MehtaChetan Mehta https://orcid.org/0000-0002-4527-5265 Paediatric Cardiology and Cardiac Surgery, Birmingham Children's Hospital, Birmingham (N.E.D., T.J.J., A.N.S., C.M.). , Christina PagelChristina Pagel https://orcid.org/0000-0002-2857-1628 Clinical Operational Research Unit, Department of Mathematics (Q.H., E.H., C.P., S.C., F.E.-P. , Sonya CroweSonya Crowe https://orcid.org/0000-0003-1882-5476 Clinical Operational Research Unit, Department of Mathematics (Q.H., E.H., C.P., S.C., F.E.-P. , Ferran Espuny-PujolFerran Espuny-Pujol https://orcid.org/0000-0001-9085-7400 Clinical Operational Research Unit, Department of Mathematics (Q.H., E.H., C.P., S.C., F.E.-P. , Rodney C.G. FranklinRodney C.G. Franklin Paediatric Cardiology, Royal Brompton and Harefield NHS Foundation Trust, London (R.C.G.F.). and Kate L. BrownKate L. Brown https://orcid.org/0000-0002-0729-4959 Institute of Cardiovascular Science (V.T., K.L.B.), University College London. Great Ormond Street Hospital Biomedical Research Centre, London (V.T., K.L,B,). Originally published23 Oct 2023https://doi.org/10.1161/CIRCULATIONAHA.123.065647Circulation. 2023;148:1343–1345Our study aimed to evaluate population-based rates of, and risk factors for, cardiac reinterventions in children with functionally single-ventricle (f-SV) congenital heart disease. A retrospective cohort study was undertaken, including all children born in England and Wales with f-SV congenital heart disease1 between 2000 and 2018 who underwent any initial or staged palliative procedures.1,2 The National Congenital Heart Diseases Audit (registry) was used, with National Health Service Research Ethics Committee approval; the study dataset is available only on this basis. Five-year survival, as ascertained in 2020, was 72.1% (95% CI, 70.6%–73.7%).1 The study outcome was any cardiac operation or interventional catheter undertaken in addition to the planned treatment pathway. The association between prespecified risk factors (see Table) and the cumulative incidence of additional procedures was investigated using multivariable Fine-Gray regression. Competing events were death and next staged treatment completion or heart transplant without additional procedures.Table. Adjusted Subdistribution Hazard Ratios (With 95% CIs) for the Occurrence of Additional Procedures in Children With Functionally Single-Ventricle Disease at the 3 Stages of Interventional TreatmentRisk factor, by total patients in study (N=3307)Additional off-pathway surgeriesAdditional off-pathway catheter interventionsStage 1 to the next staged treatment (n=2916)Stage 2 to stage 3 (n=2435)Post stage 3† (n=1592)Stage 1 to the next staged treatment (n=2916)Stage 2 to stage 3 (n=2435)Post–stage 3† (n=1592)Noncardiac variables Male, 1937 (58.6%; Ref: female)0.98 (0.83–1.15)0.95 (0.74–1.22)0.95 (0.67–1.35)1.03 (0.87–1.22)1.05 (0.89–1.24)0.96 (0.78–1.18) Prematurity, 199 (6%; Ref: Born >37 wk gestation)1.18 (0.87– 1.61)1.00 (0.59–1.72)2.60 (1.35–4.99)**0.96 (0.67–1.37)1.52 (1.08–2.14)*0.91 (0.51–1.62) Congenital noncardiac comorbidity, 553 (16.7%; Ref: none)1.09 (0.89–1.34)1.31 (0.97–1.77)1.96 (1.30–2.97)**1.18 (0.96–1.45)1.34 (1.10–1.64)**1.66 (1.26–2.17)*** Low weight at first procedure, 339 (10.3%; Ref: >2.5 kg)‡1.05 (0.82–1.33)1.08 (0.68–1.70)1.24 (0.69–2.22)1.09 (0.83–1.43)0.81 (0.59–1.10)1.07 (0.73–1.56) Acquired comorbidity at first procedure, 159 (4.8%; Ref: none)1.09 (0.77–1.54)0.64 (0.31–1.32)N/A§1.12 (0.81–1.53)0.87 (0.57–1.32)0.94 (0.44–2.04) Increased severity of illness at first procedure, 384 (11.6%; Ref: none)1.50 (1.19–1.89)***1.13 (0.74–1.72)0.99 (0.45–2.21)1.09 (0.86–1.37)1.22 (0.94–1.59)1.62 (1.04–2.52) Age (y) at first procedure, median 6 days (interquartile range: 4–27)0.39 (0.13–1.11)0.97 (0.84–1.11)0.78 (0.58– 1.04)0.79 (0.32–1.99)1.04 (0.91–1.18)0.94 (0.79–1.13) Born after April 2009, 1697 (51.3%; Ref: born before April 2009)‖1.03 (0.86–1.22)1.07 (0.83–1.40)0.94 (0.62–1.42)1.55 (1.29–1.87)***1.31 (1.09–1.56)**0.73 (0.56–0.95)*** Additional cardiac risk factor (at any time, 234 (7.1%; Ref: none)1.56 (1.20–2.03)***2.51 (1.77–3.55)***2.36 (1.26–4.42)*1.23 (0.94–1.62)1.22 (0.89–1.67)1.38 (0.89–2.14)Stage 1 subtypes at first stage 2 (Ref: Norwood type, 1368 [46.9%]) No stage 1 procedure, 391 (11.8%)–1.52 (0.96–2.41)1.38 (0.74–2.55)–0.65 (0.46–0.93)*0.56 (0.36–0.86)** Isolated arch repair, 188 (6.5%)3.32 (2.51–4.39)***0.77 (0.35–1.71)0.77 (0.35–1.71)0.87 (0.61–1.23)0.70 (0.45–1.09)0.54 (0.32–0.92)* Hybrid procedure, 137 (4.7%)3.45 (2.56–4.65)***1.26 (0.59–2.69)0.44 (0.10–2.05)2.84 (2.13–3.79)***1.83 (1.14–2.93)*0.47 (0.14–1.53) Procedures to secure pulmonary blood flow, 829 (28.4%)2.12 (1.71–2.64)***0.84 (0.59–1.18)0.71 (0.45–1.12)0.97 (0.68–1.38)0.85 (0.69–1.04)0.62 (0.48–0.80)*** Pulmonary artery band, 394 (13.5%)2.02 (1.51–2.70)***1.19 (0.79–1.80)0.68 (0.38–1.24)0.40 (0.28–0.59)***0.57 (0.42–0.79)***0.74 (0.53–1.03)Surgical variables Pre–stage 1 procedure (any type), 339 (10.7%; Ref: none)0.95 (0.70–1.30)1.07 (0.70–1.98)0.94 (0.52–1.69)0.97 (0.68–1.38)1.36 (1.05–1.78)*1.19 (0.83–1.69) Stage 1 with concurrent surgery 157 (5.4%; Ref: none)0.89 (0.61–1.30)1.35 (0.79–2.32)0.81 (0.25–2.61)0.90 (0.65–1.24)1.21 (0.83–1.77)0.82 (0.44–1.51) No stage 2 procedure, 391 (11.8%; Ref: Glenn)––2.88 (1.30–6.39)**––1.25 (0.63–2.48) Comprehensive stage 2, 165 (5.0%; Ref: Glenn)–1.18 (0.70–1.98)2.02 (0.89–4.58)–1.15 (0.76–1.73)0.64 (0.37–1.13) Stage 2 with concurrent surgery, 951 (39.1%; Ref: none)–1.69 (1.29–2.21)***0.65 (0.42–1.01)–1.62 (1.36–1.93)***1.68 (1.35–2.08)*** Stage 3 with concurrent surgery, 254 (16.4%; Ref: none)––1.72 (1.15–2.59)**––1.38 (1.06–1.79)* Previous additional procedure (any type; Ref: none)–1.16 (0.86–1.55)1.31 (0.91–1.89)–1.40 (1.17–1.68)***1.06 (0.86–1.30)We performed 6 models (2 intervention types ×3 surgical stages) to investigate the relationship between the cumulative incidence of additional procedures and risk factors. In each model, only those patients who completed the staged procedure were included. The most common concurrent procedure was pulmonary arterioplasty at all 3 stages. The most common additional procedures were (1) stage 1 to next staged treatment: redo systemic-to-pulmonary arterial shunt (surgery, 4.1%) and balloon dilation of aortic re-coarctation (catheter, 5.4%); (2) stage 2 to 3: operative pulmonary arterial repair (1.2%) and transcatheter pulmonary artery stenting (5.5%); (3) post–stage 3: operative pacemaker placement (2%) and transcatheter Fontan fenestration closure (7.9%). Significance level (P value): *0.05, **0.01, ***0.001. N/A indicates not available; and Ref., reference.† In the post–stage 3 analysis, we censored patients who underwent competing events due to limited sample size (death or heart transplant after Fontan without additional surgeries 3.0% and catheter interventions 2.3%). We used a conventional multivariable Cox regression model and presented the adjusted cause-specific hazard ratio as the results.‡ Low weight includes imputed data in 64 patients (2.1%).§ Not included due to nonoccurrence.‖ Externally validated national capture of all cardiac procedures for National Audit in England and Wales occurred from the year 2000, but procedures for capture of noncardiac variables were improved from 2009; hence, we added an era variable (born after vs before 2009) to the models.Among 3307 children with f-SV there were 1266 (38.3%) children with hypoplastic left heart syndrome; 448 (13.6%) with tricuspid atresia; 328 (9.9%) with double-inlet left ventricle; 243 (7.4%) with f-SV with atrial isomerism; 231 (7.0%) with unbalanced atrioventricular septal defect; 138 (4.2%) with pulmonary atresia; 112 (3.4%) with mitral atresia without hypoplastic left heart syndrome; and 541 (16.4%) with other f-SV. Median first procedure age was 6 days (interquartile range [first and third quartiles], 4–27); at this timepoint 384 (11.6%) had increased severity of illness. Congenital comorbidity was present in 553 (16.7%) patients, and 199 (6.0%) had premature birth.We identified the following cardiac procedures as on the planned treatment pathway2 (not the study outcome): interventions before stage 1 in 339 (10.3%) patients (eg, balloon atrial septostomy 195 [5.8%]); first stage 1 procedure in 2916 (88.2%) patients (subtypes in Table); second stage in 2435 (73.6%) patients (Glenn 2270 [68.6%]) and comprehensive stage 2 operation in 165 (5.0%); third stage (Fontan-type) operation in 1592 (48.1%) patients; and heart transplant in 47 (1.4%) patients.Over a median follow-up of 5.4 years (interquartile range [first and third quartiles], 0.8–10.8) of 3307 patients, 1730 (52.3%) patients had at least 1 additional procedure (ie, the study outcome), and 887 (26.8%) patients had multiple additional procedures. Of 3427 additional procedures, 1289 (37.4%) were cardiac surgery in 921 patients, and 2138 (62.4%) were interventional catheters in 1293 patients. In the Table, we show the adjusted subdistribution hazard ratios with each risk factor for additional procedures, from the first stage 1 procedure to the next stage, whichever stage occurred next (additional surgery in 596 [20.4%], and catheter intervention in 596 [20.4%] patients); from stage 2 to 3 (265 [10.9%] and 616 [25.3%]); and after stage 3 (135 [8.5%] and 387 [24.3%]).Between stage 1 and the next stage that occurred, all stage 1 subtypes were associated with higher risk of additional surgery, compared with the reference category of Norwood, most notably hybrid (adjusted subdistribution hazard ratio, 3.45 [95% CI, 2.56–4.65]; P<0.001). The hybrid was also associated with higher risk of additional catheter intervention after stage 1 (2.84 [2.13–3.79]; P<0.001); and between stages 2 and 3 (1.83 [1.14–2.93]; P<0.05). Nonhybrid stage 1 subtypes were all associated with lower risk than the Norwood, of additional catheter procedures at later stages.Increased severity of illness (ie, ventilation, shock) before the first procedure was associated with higher risk of additional surgery after stage 1 (1.50 [1.19–1.89]; P<0.001).When children underwent more interventions than the 3 planned palliative stages, subsequent additional procedures were more likely, as shown by increased risk of additional catheter interventions between stages 2 and 3, after a pre–stage 1 procedure (1.36 [1.05–1.78]; P<0.05); or after an additional procedure between stages 1 and 2 (1.40 [1.17–1.68]; P<0.001). Concurrent surgery with stage 2, was associated with increased risk for additional surgery (1.69 [1.29–2.21]; P<0.001), and additional catheters between stages 2 and 3 (1.62 [1.36–1.93]; P<0.001); and after stage 3 (1.68 [1.35–2.08]; P<0.001). Concurrent surgery with stage 3 was associated with higher risk of subsequent additional surgery (1.72 [1.15–2.59]; P<0.01) and catheter intervention (1.38 [1.06–1.79]; P<0.05).Children with complex features3 were overrepresented; with acquired cardiac risk factors (eg, impaired ventricular function, raised pulmonary vascular resistance), there was increased risk of additional surgery after stage 1 (1.56 [1.20–2.03]; P<0.001), between stages 2 and 3 (2.51 [1.77–3.55]; P<0.001), and after stage 3 (2.36 [1.26–4.42]; P<0.05). With congenital comorbidity, there was increased risk of additional catheter interventions after stage 2 (1.34 [1.10–1.64]; P<0.01) and stage 3 (1.66 [1.26–2.17]; P<0.001); and additional surgery after stage 3 (1.96 [1.30–2.97]; P<0.01). With premature birth, there was increased risk after stage 3 of additional surgery (2.60 [1.35–4.99]; P<0.01) and after stage 2 catheter intervention (1.52 [1.08–2.14]; P<0.05).Parents and clinicians should be prepared for additional procedures in the early years for most children with f-SV disease. Although it is infeasible to adjust for all aspects of case complexity, additional procedures could represent a disadvantage of the hybrid pathway. As previously reported,4,5 the pulmonary arteries most often require additional interventions in f-SV, especially transcatheter beyond stage 2. Strategies to minimize pulmonary arterial distortion, preserve ventricular function, and maintain lower pulmonary vascular resistance may protect children from additional procedures during childhood.ARTICLE INFORMATIONSources of FundingThis study was funded by the British Heart Foundation (Project Grant No. PG/17/88/33401). Drs Tsang and Brown received support from the NIHR Biomedical Research Centre at Great Ormond Street Hospital.Disclosures The study was approved by the UK National Health Service Stanmore Research Ethics Committee (Reference 18/LO/1688) and the need for patient consent was waived.FootnotesFor Sources of Funding and Disclosures, see page 1345.Circulation is available at www.ahajournals.org/journal/circCorrespondence to: Qi Huang, PhD, Clinical Operational Research Unit, University College London, London, WC1H 0BT. Email Qi_Huang@ucl.ac.ukREFERENCES1. Brown KL, Huang Q, Hadjicosta E, Seale AN, Tsang V, Anderson D, Barron D, Bellsham-Revell H, Pagel C, Crowe S, et al. Long-term survival and center volume for functionally single-ventricle congenital heart disease in England and Wales.J Thorac Cardiovasc Surg. 2023; 166:306–316.e3. doi: 10.1016/j.jtcvs.2022.11.018CrossrefMedlineGoogle Scholar2. Feinstein JA, Benson DW, Dubin AM, Cohen MS, Maxey DM, Mahle WT, Pahl E, Villafañe J, Bhatt AB, Peng LF, et al. Hypoplastic left heart syndrome: current considerations and expectations.J Am Coll Cardiol. 2012; 59:S1–S42. doi: 10.1016/j.jacc.2011.09.022CrossrefMedlineGoogle Scholar3. Brown KL, Rogers L, Barron DJ, Tsang V, Anderson D, Tibby S, Witter T, Stickley J, Crowe S, English K, et al. Incorporating comorbidity within risk adjustment for UK pediatric cardiac surgery.Ann Thorac Surg. 2017; 104:220–226. doi: 10.1016/j.athoracsur.2016.12.013CrossrefMedlineGoogle Scholar4. Shearer L, Justo RN, Marathe SP, Betts K, Venugopal P, Winlaw DS, Bullock A, Robertson T, Gentles TL, Celermajer D, et al. Augmentation of the pulmonary arteries at or prior to the Fontan procedure is not associated with worse long-term outcomes: a propensity-matched analysis from the Australia-New Zealand Fontan Registry.Eur J Cardiothorac Surg. 2019; 55:829–836. doi: 10.1093/ejcts/ezy376CrossrefMedlineGoogle Scholar5. Newburger JW, Sleeper LA, Gaynor JW, Hollenbeck-Pringle D, Frommelt PC, Li JS, Mahle WT, Williams IA, Atz AM, Burns KM, et al; Pediatric Heart Network Investigators. Transplant-free survival and interventions at 6 years in the SVR trial.Circulation. 2018; 137:2246–2253. doi: 10.1161/CIRCULATIONAHA.117.029375LinkGoogle Scholar eLetters(0) eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate. Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page. Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails October 24, 2023Vol 148, Issue 17 Advertisement Article Information Metrics © 2023 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.https://doi.org/10.1161/CIRCULATIONAHA.123.065647PMID: 37871240 Originally publishedOctober 23, 2023 Keywordscardiac surgical proceduresheart defects, congenitalrisk factorsPDF download Advertisement Subjects Cardiovascular Surgery Catheter-Based Coronary and Valvular Interventions Congenital Heart Disease

ABSTRACT Background and Aims Previous trials evaluating remote ischaemic preconditioning in children undergoing cardiac surgery showed mixed results. We sought to determine whether adequately delivered bilateral preconditioning is cardioprotective in young children, with or without cyanosis, undergoing surgery. Methods Prospective, double-blind, randomised controlled trial at two UK centres. Children aged 3-36 months undergoing tetralogy of Fallot repair or ventricular septal defect closure were randomised in a 1:1 ratio to receive either bilateral preconditioning or sham intervention. Participants were followed up until hospital discharge or 30 days. The primary outcome was area under the curve for high-sensitivity troponin-T in the first 24 hours after surgery, analysed by intention-to-treat. Right atrial biopsies were obtained in selected patients. Trial registration: ISRCTN12923441 . Results Between 24 October 2016 and 8 December 2020, 120 eligible children were randomised to receive either bilateral preconditioning (n=60) or sham intervention (n=60). Participants had a median age of 7 months and 42 (35%) were female. The primary outcome, area under the curve for hs-troponin-T was higher in the preconditioning group (mean: 70.0±50.9µg/L/hr, n=56) than in controls (mean: 55.6±30.1µg/L/hr, n=58), p=0.04. Sub-group analyses did not show a differential treatment effect by oxygen saturations (p interaction =0.25) but showed evidence of differential treatment effect by underlying defect (p interaction =0.04). Myocardial metabolism, quantified in atrial biopsies, and secondary outcomes were not different between randomised groups. Conclusions Bilateral remote ischemic preconditioning does not attenuate myocardial injury in children undergoing surgical repair for congenital heart defects, and there was evidence of potential harm in unstented tetralogy of Fallot.

Background:Given their importance as a metric for health care evaluation, this study's aim was to evaluate the rates of surgical and catheter reinterventions for children with functionally single-ventricle (f-SV) congenital heart disease (CHD) undergoing staged palliation. Methods:We undertook a retrospective cohort study of children born with f-SV CHD between 2000 and 2018 in England and Wales, using the national registry, with survival ascertained in 2020. Competing risk analysis was used to describe the incidence of additional procedures that occurred first, during follow-up, accounting for competing events of death or transplantation. Results:Of 56,039 patients who received an intervention for CHD, 3307 (5.9%) had f-SV. The largest diagnostic subcategories were hypoplastic left heart syndrome (1266 [38.3%]), tricuspid atresia (448 [13.5%]), and double-inlet left ventricle (328 [9.9%]). During a median follow-up of 5.4 (interquartile range, 0.8-10.8) years, 921 (27.9%) patients had at least 1 additional interstage surgery and 1293 (39.1%) had at least 1 additional interstage catheter intervention. The cumulative incidence of additional surgery at 6 months after stage 1 was 17.6% (95% CI, 16.2%-19.0%); at 2 years after stage 2, 8.3% (7.2%-9.5%); and at 5 years after stage 3, 8.4% (7.0%-9.9%). The cumulative incidence of additional catheter at 6 months after stage 1 was 18.0% (16.6%-19.4%); at 2 years after stage 2, 14.7% (13.3%-16.2%); and at 5 years after stage 3, 23.7% (21.5%-26.0%). Conclusions:It is important to quantify additional procedures for children with f-SV disease to inform parents and health professionals, potentially facilitating the development of interventions that aim to reduce these important adverse outcomes.

Following myocardial infarction (MI), elderly patients have a poorer prognosis than younger patients, which may be linked to increased coronary microvessel susceptibility to injury. Interleukin-36 (IL-36), a newly discovered proinflammatory member of the IL-1 superfamily, may mediate this injury, but its role in the injured heart is currently not known. We first demonstrated the presence of IL-36(α/β) and its receptor (IL-36R) in ischemia/reperfusion-injured (IR-injured) mouse hearts and, interestingly, noted that expression of both increased with aging. An intravital model for imaging the adult and aged IR-injured beating heart in real time in vivo was used to demonstrate heightened basal and injury-induced neutrophil recruitment, and poorer blood flow, in the aged coronary microcirculation when compared with adult hearts. An IL-36R antagonist (IL-36Ra) decreased neutrophil recruitment, improved blood flow, and reduced infarct size in both adult and aged mice. This may be mechanistically explained by attenuated endothelial oxidative damage and VCAM-1 expression in IL-36Ra–treated mice. Our findings of an enhanced age-related coronary microcirculatory dysfunction in reperfused hearts may explain the poorer outcomes in elderly patients following MI. Since targeting the IL-36/IL-36R pathway was vasculoprotective in aged hearts, it may potentially be a therapy for treating MI in the elderly population.

Abstract OBJECTIVES Cardiac surgery with hypothermic circulatory arrest (HCA) is associated with neurological morbidity of variable severity and electroencephalography (EEG) is a sensitive proxy measure of brain injury. We conducted a narrative review of the literature to evaluate the role of perioperative EEG monitoring in cardiac surgery involving HCA. METHODS Medline, Embase, Central and LILACS databases were searched to identify studies utilizing perioperative EEG during surgery with HCA in all age groups, published since 1985 in any language. We aimed to compare EEG use with no use but due to the lack of comparative studies, we performed a narrative review of its utility. Two or more reviewers independently screened studies for eligibility and extracted data. RESULTS Fourty single-centre studies with a total of 3287 patients undergoing surgery were identified. Most were observational cohort studies (34, 85%) with only 1 directly comparing EEG use with no use. EEG continuity (18, 45%), seizures (15, 38%) and electrocerebral inactivity prior to circulatory arrest (15, 38%) were used to detect, monitor, prevent and prognose neurological injury. Neurological dysfunction was reported in almost all studies and occurred in 0–21% of patients. However, the heterogeneity of reported clinical and EEG outcome measures prevented meta-analysis. CONCLUSIONS EEG is used to detect cortical ischaemia and seizures and predict neurological abnormalities and may guide intraoperative cerebral protection. However, there is a lack of comparative data demonstrating the benefit of perioperative EEG monitoring. Use of a standardized methodology for performing EEG and reporting outcome metrics would facilitate the conduct of high-quality clinical trials.

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): British Heart Foundation Introduction Whilst blood flow restoration is critical following myocardial infarction (MI), ischemia-reperfusion injury (IRI) accounts for ~50% of the final infarct size. Elderly patients have a poorer prognosis which may be linked to increased coronary microvessels susceptibility to injury. The newly discovered and inflammatory cytokine, interleukin-36 (IL-36), could potentially mediate these disturbances. However, its role in myocardial IRI is not known. Aim This study firstly aimed to determine whether IL-36 and its receptor (IL-36R) were present in the heart, whether their expression varied in an injury and age-related manner, and whether topical application of its cytokines on the beating heart induces an inflammatory response. Secondly, we determined whether coronary microcirculatory disturbances, overall blood ventricular perfusion, and infarct size post-IRI were modified by age. Lastly, we investigated whether an IL-36 receptor antagonist (IL-36Ra) could confer vasculoprotection and reduce myocardial infarction. Methods Myocardial IRI was induced in adult (3-months) and aged (>18-months) mice. In some studies, recombinant mouse IL-36Ra (15ug/mouse) was injected intra-arterially. IL-36R/α/β, and VCAM-1 expression were investigated immunohistochemically or using western blots. Beating heart coronary microcirculation was imaged intravitally in vivo and also ex vivo using multiphoton microscopy. Topical cytokine application was also observed intravitally. Laser speckle contrast imaging was used to determine perfusion, and infarct size was measured using dual TTC/Evans Blue staining. Results IL-36R/α/β were expressed predominantly on the microvasculature of murine hearts, with some cardiomyocyte expression also observed. Expression of IL-36R/α/β and VCAM-1 significantly increased with injury and age (see Table). Topical application of all IL-36 cytokines induced a significant (p<0.0001) inflammatory response in vivo. Significantly increased basal (p<0.0001) and IRI-induced (p<0.0001) neutrophil recruitment, and greater decreases in functional capillary density, was observed in aged mice compared to adults. Neutrophils primarily adhered within coronary capillaries although in aged hearts remarkable venular adhesion was also identified. These events were mirrored in deeper myocardial layers when imaged using multiphoton microscopy. IL-36Ra significantly reduced inflammation (p<0.0001), infarct size (p<0.0001) and improved blood perfusion (p<0.0001) in both adult and aged mice. Conclusion These novel results are the first to demonstrate myocardial presence of IL-36 and its receptor. Our novel findings of enhanced coronary microcirculatory perturbations associated with age may explain the poorer outcomes in elderly MI patients. Importantly, we are the first to demonstrate that targeting IL-36 was vasculoprotective and may be a potential novel therapy for treatment of myocardial IRI.