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Abstract Background Racemic isometheptene [(RS)-isometheptene] is an antimigraine drug that due to its cardiovascular side-effects was separated into its enantiomers, (R)- and (S)-isometheptene. This study set out to characterize the contribution of each enantiomer to its vasoactive profile. Moreover, rat neurogenic dural vasodilatation was used to explore their antimigraine mechanism of action. Methods Human blood vessel segments (middle meningeal artery, proximal and distal coronary arteries, and saphenous vein) were mounted in organ baths and concentration response curves to isometheptene were constructed. Calcitonin gene-related peptide (CGRP)-induced neurogenic dural vasodilation was elicited in the presence of the enantiomers using a rat closed cranial window model. Results The isometheptene enantiomers did not induce any significant contraction in human blood vessels, except in the middle meningeal artery, when they were administered at the highest concentration (100 μM). Interestingly in rats, (S)-isometheptene induced more pronounced vasopressor responses than (R)-isometheptene. However, none of these compounds affected the CGRP-induced vasodilator responses. Conclusion The isometheptene enantiomers displayed a relatively safe peripheral vascular profile, as they failed to constrict the human coronary artery. These compounds do not appear to modulate neurogenic dural CGRP release, therefore, their antimigraine site of action remains to be determined.

Abstract Background The objective of this study is to investigate the role and experience of early stage non-small cell lung cancer (NSCLC) patient in decision making process concerning treatment selection in the current clinical practice. Methods Stage I-II NSCLC patients (surgery 55 patients, SBRT 29 patients, median age 68) were included in this prospective study and completed a questionnaire that explored: (1) perceived patient knowledge of the advantages and disadvantages of the treatment options, (2) experience with current clinical decision making, and (3) the information that the patient reported to have received from their treating physician. This was assessed by multiple-choice, 1–5 Likert Scale, and open questions. The Decisional Conflict Scale was used to assess the decisional conflict. Health related quality of life (HRQoL) was measured with SF-36 questionnaire. Results In 19% of patients, there was self-reported perceived lack of knowledge about the advantages and disadvantages of the treatment options. Seventy-four percent of patients felt that they were sufficiently involved in decision-making by their physician, and 81% found it important to be involved in decision making. Forty percent experienced decisional conflict, and one-in-five patients to such an extent that it made them feel unsure about the decision. Subscores with regard to feeling uninformed and on uncertainty, contributed the most to decisional conflict, as 36% felt uninformed and 17% of patients were not satisfied with their decision. HRQoL was not influenced by patient experience with decision-making or patient preferences for shared decision making. Conclusions Dutch early-stage NSCLC patients find it important to be involved in treatment decision making. Yet a substantial proportion experiences decisional conflict and feels uninformed. Better patient information and/or involvement in treatment-decision-making is needed in order to improve patient knowledge and hopefully reduce decisional conflict.

Objective Cardiac surgery may cause temporarily impaired ventricular performance and myocardial injury. We aim to characterise the response to perioperative injury for patients undergoing repair or pulmonary valve replacement (PVR) for tetralogy of Fallot (ToF).Methods We enrolled children undergoing ToF repair or PVR from four tertiary centres in a prospective observational study. Assessment—including blood sampling and speckle tracking echocardiography—occurred before surgery (T1), at the first follow-up (T2) and 1 year after the procedures (T3). Ninety-two serum biomarkers were expressed as principal components to reduce multiple statistical testing. RNA Sequencing was performed on right ventricular (RV) outflow tract samples.Results We included 45 patients with ToF repair aged 4.3 (3.4 – 6.5) months and 16 patients with PVR aged 10.4 (7.8 – 12.7) years. Ventricular function following ToF repair showed a fall-and-rise pattern for left ventricular global longitudinal strain (GLS) (−18±4 to −13±4 to −20±2, p < 0.001 for each comparison) and RV GLS (−19±5 to −14±4 to 20±4, p < 0.002 for each comparison). This pattern was not seen for patients undergoing PVR. Serum biomarkers were expressed as three principal components. These phenotypes are related to: (1) surgery type, (2) uncorrected ToF and (3) early postoperative status. Principal component 3 scores were increased at T2. This increase was higher for ToF repair than PVR. The transcriptomes of RV outflow tract tissue are related to patients’ sex, rather than ToF-related phenotypes in a subset of the study population.Conclusions The response to perioperative injury following ToF repair and PVR is characterised by specific functional and immunological responses. However, we did not identify factors relating to (dis)advantageous recovery from perioperative injury.Trial registration number Netherlands Trial Register: NL5129.

Abstract Background Neonates with critical congenital heart disease (CCHD) undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at risk of brain injury that may result in adverse neurodevelopment. To date, no therapy is available to improve long-term neurodevelopmental outcomes of CCHD neonates. Allopurinol, a xanthine oxidase inhibitor, prevents the formation of reactive oxygen and nitrogen species, thereby limiting cell damage during reperfusion and reoxygenation to the brain and heart. Animal and neonatal studies suggest that allopurinol reduces hypoxic-ischemic brain injury and is cardioprotective and safe. This trial aims to test the hypothesis that allopurinol administration in CCHD neonates will result in a 20% reduction in moderate to severe ischemic and hemorrhagic brain injury. Methods This is a phase III, randomized, quadruple-blinded, placebo-controlled, multicenter trial. Neonates with a prenatal or postnatal CCHD diagnosis requiring cardiac surgery with CPB in the first 4 weeks after birth are eligible to participate. Allopurinol or mannitol-placebo will be administered intravenously in 2 doses early postnatally in neonates diagnosed antenatally and 3 doses perioperatively of 20 mg/kg each in all neonates. The primary outcome is a composite endpoint of moderate/severe ischemic or hemorrhagic brain injury on early postoperative MRI, being too unstable for postoperative MRI, or mortality within 1 month following CPB. A total of 236 patients (n = 188 with prenatal diagnosis) is required to demonstrate a reduction of the primary outcome incidence by 20% in the prenatal group and by 9% in the postnatal group (power 80%; overall type 1 error controlled at 5%, two-sided), including 1 interim analysis at n = 118 (n = 94 with prenatal diagnosis) with the option to stop early for efficacy. Secondary outcomes include preoperative and postoperative brain injury severity, white matter injury volume (MRI), and cardiac function (echocardiography); postnatal and postoperative seizure activity (aEEG) and regional cerebral oxygen saturation (NIRS); neurodevelopment at 3 months (general movements); motor, cognitive, and language development and quality of life at 24 months; and safety and cost-effectiveness of allopurinol. Discussion This trial will investigate whether allopurinol administered directly after birth and around cardiac surgery reduces moderate/severe ischemic and hemorrhagic brain injury and improves cardiac function and neurodevelopmental outcome in CCHD neonates. Trial registration EudraCT 2017-004596-31. Registered on November 14, 2017. ClinicalTrials.gov NCT04217421. Registered on January 3, 2020

Background: Right ventricular failure (RVF) is a significant cause of morbidity and mortality in patients with a left ventricular assist device (LVAD). This study is aimed to investigate the influence of a pectus excavatum on early and late outcomes, specifically RVF, following LVAD implantation. Methods: A retrospective study was performed, that included patients with a HeartMate 3 LVAD at our tertiary referral center. The Haller index (HI) was calculated using computed tomography (CT) scan to evaluate the chest-wall dimensions. Results: In total, 80 patients (median age 57 years) were included. Two cohorts were identified: 28 patients (35%) with a normal chest wall (HI 30 days) recurrent readmission for RVF occurred more often in patients with pectus excavatum (p = 0.008). The onset of late RVF started around 18 months after implantation and increased thereafter in the overall study cohort. Conclusions: Pectus excavatum is observed frequently in patients with a LVAD implantation. These patients have an increased rate of readmissions and late RVF. Further investigation is required to explore the extent and severity of chest-wall abnormalities on the risk of RVF.

Fontan patients undergo multiple cardiothoracic surgeries in childhood. Following these procedures, ventricular function is temporarily decreased, and recovers over months. This is presumably related to cardiopulmonary bypass, but this is incompletely understood. Throughout the Fontan palliation, cardiac function is also affected by volume unloading. We aimed to gain insight into the biological processes related to impaired ventricular function and recovery following Fontan palliations using a panel of biomarkers. Furthermore, we described changes in ventricular function across the Fontan palliation due to volume unloading. We performed a prospective multicenter observational study in patients undergoing partial (PCPC) or total cavo-pulmonary connection (TCPC). Patients underwent assessment—including echocardiography and blood sampling—before surgery (T1), at first follow-up (T2), and 1 year after their procedures (T3). Blood samples were analyzed using a biomarker panel (OLINK CVD-III). Ninety-two biomarkers were expressed as principal components (PC) to limit multiple statistical testing. We included 32 PCPC patients aged 7.2 [5.3–10.3] months, and 28 TCPC patients aged 2.7 [2.2–3.8] years. The single ventricular longitudinal strain (SV GLS) temporarily decreased for PCPC patients at T2 (−15.1 ± 5.6 (T1) to −13.5 ± 5.2 (T2) to −17.3 ± 4.5 (T3), p < 0.047 for all differences), but not following TCPC. The serum biomarkers were expressed as 4 PCs. PC1, including biomarkers of cell–cell adhesion, was not related to any patient characteristic. PC2, including biomarkers of superoxide anion regulation, increased at T2. PC3, including biomarkers of cardiovascular development, related to the stage of Fontan palliation. PC4 was of uncertain biological or clinical significance. No PC was found that related to ventricular performance. The SV GLS was temporarily diminished following PCPC, but not following TCPC. Several biomarkers were related to post-operative stress and adaptation to the PCPC or TCPC circulation, but none were related to the outcome.

We report a patient with COVID-19 requiring hospitalization for two weeks, complicated by multiple segmental pulmonary embolisms for which dabigatran was initiated. After clearing the infection, the patient remained asymptomatic for 5 months. He was then readmitted with a spontaneous haemothorax, most likely related to the use of dabigatran, which progressed to a pleural empyema with a trapped lung. The patient underwent a video assisted thoracoscopy (VATS) with decortication. Because of focal abnormalities, biopsies for histopathology were taken from the lung parenchyma. These showed an organizing pneumonia with progression towards fibrosis and arteries with intimal fibrosis. So far, no histopathological reports exist on late pulmonary changes after a COVID-19 infection. The unusual combined presence of microvascular damage and interstitial fibrosis may reflect a pathophysiological concept in which early endothelial damage by SARS-CoV-2 can lead to a chronic state of microvascular damage, low grade inflammation, and early progression towards pulmonary fibrosis.

Abstract Associated cardiovascular malformations in congenitally corrected transposition of the great arteries (CCTGA) should not be missed when a patient requires surgical correction. We present a case of an adult CCTGA patient who required redo surgery for recurrent tricuspid (left atrioventricular) valve regurgitation and previously unidentified partial anomalous pulmonary venous return.

For-profit biotechnological and pharmaceutical companies have played an essential role in the research and development (R&D) of innovative medical products and drugs for many decades and embody a trillion-dollar industry. The past decades have been marked by an increase in growth of social non-profit biotechnology companies and organizations led by entrepreneurs committed to solve (global) health issues. In this review, we define the concept of social bioentrepreneurship and consider the potential impact of such ventures on global health. We analyse the current status of non-profit biotechnology and clarify the strategy, motivation, funding, and marketing techniques of these enterprises. We find that these non-profit ventures mainly focus on neglected and rare diseases by using different but also similar funding, marketing, and business strategy approaches to for-profit biotechnology enterprises. We also identify good leadership, multidisciplinary teams, and public awareness as key components to achieve long-term survival and higher success rates. Challenges faced by bioentrepreneurs include the lack of a clearly defined regulatory environment or governmental incentives to support their endeavors. Overall, with this qualitative data review and market analysis we draw a promising picture of social non-profit bioentrepreneurship and underscore its current and future impact on global health issues.

Corticosteroids have been used to decrease the inflammatory response to cardiac surgery and cardiopulmonary bypass in children for decades. Sparse information is present concerning the pharmacokinetics and pharmacodynamics of corticosteroids in the context of pediatric cardiac surgery. There is large interindividual variability in plasma concentrations, with indications for a larger volume of distribution in neonates compared to other age groups. There is ample evidence that perioperative use of MP leads to a decrease in pro-inflammatory mediators and an increase in anti-inflammatory mediators, with no difference in effect between doses of 2 and 30 mg/kg. No differences in inflammatory mediators have been shown between different times of administration relative to the start of surgery in various studies. MP has been shown to have a beneficial effect in certain subgroups of patients but is also associated with side effects. In lower risk categories, the balance between risk and benefit may be shifted toward risk. There is limited information on short- to medium-term outcome (mortality, low cardiac output syndrome, duration of mechanical ventilation, length of stay in the intensive care unit or the hospital), mostly from underpowered studies. No information on long-term outcome, such as neurodevelopmental outcome, is available. MP may provide a small benefit that is easily abolished by patient characteristics, surgical techniques, and perfusion management. The lack of evidence leads to large differences in practice between and within countries, and even within hospitals, so there is a need for adequately powered randomized studies.

Introduction: To our knowledge, methylprednisolone pharmacokinetics and plasma concentrations have not been comprehensively investigated in children with congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass. It is unknown whether there is a significant influence of cardiopulmonary bypass on the plasma concentrations of methylprednisolone and whether this may be an explanation for the limited reported efficacy of steroid administration in cardiac surgery with cardiopulmonary bypass.Methods: The study was registered in the Dutch Trial Register (NTR3579; https://www.trialregister.nl/trial/3428). Methylprednisolone 30 mg/kg was administered as an intravenous bolus after induction of anesthesia. Methylprednisolone concentration was measured with liquid chromatography tandem mass spectrometry and analyzed using linear mixed-effects modeling.Results: Thirty-nine patients were included in the study, of which three were excluded. There was an acute decrease in observed methylprednisolone plasma concentration on initiation of cardiopulmonary bypass (median = 26.8%, range = 13.9–48.14%, p < 0.001). We found a lower intercept (p = 0.02), as well as a less steep slope of the model predicted methylprednisolone concentration vs. time curve for neonates (p = 0.048). A lower intercept (p = 0.01) and a less steep slope (p = 0.0024) if the volume of cell saver blood processed was larger than 91 ml/kg were also found.Discussion: We report similar methylprednisolone plasma concentrations as earlier studies performed in children undergoing cardiopulmonary bypass, and we confirmed the large interindividual variability in achieved methylprednisolone plasma concentrations with weight-based methylprednisolone administration. A larger volume of distribution and a lower clearance of methylprednisolone for neonates were suggested. The half-life of methylprednisolone in our study was calculated to be longer than 6 h for neonates, 4.7 h for infants, 3.6 h for preschool children and 4.7 h for school children. The possible influence of treatment of pulmonary hypertension with sildenafil and temperature needs to be investigated further.

Background In response to an increased need for patient information in congenital heart disease, we previously developed an online, evidence-based information portal for patients with congenital aortic and pulmonary valve disease. To assess its effectiveness, a stepped-wedge cluster randomised trial was conducted.Methods Adult patients and caregivers of paediatric patients with congenital aortic and/or pulmonary valve disease and/or tetralogy of Fallot who visited the outpatient clinic at any of the four participating centres in the Netherlands between 1 March 2016–1 July 2017 were prospectively included. The intervention (information portal) was introduced in the outpatient clinic according to a stepped-wedge randomised design. One month after outpatient clinic visit, each participant completed a questionnaire on disease-specific knowledge, anxiety, depression, mental quality of life, involvement and opinion/attitude concerning patient information and involvement.Results 343 participants were included (221 control, 122 intervention). Cardiac diagnosis (p=0.873), educational level (p=0.153) and sex (p=0.603) were comparable between the two groups. All outcomes were comparable between groups in the intention-to-treat analyses. However, only 51.6% of subjects in the intervention group (n=63) reported actually visiting the portal. Among these subjects (as-treated), disease-specific knowledge (p=0.041) and mental health (p=0.039) were significantly better than in control subjects, while other baseline and outcome variables were comparable.Conclusion Even after being invited by their cardiologists, only half of the participants actually visited the information portal. Only in those participants that actually visited the portal, knowledge of disease and mental health were significantly better. This underlines the importance of effective implementation of online evidence-based patient information portals in clinical practice.

Background The improved life expectancy of patients with congenital heart disease is often accompanied by the development of atrial tachyarrhythmias. Similarly, the number of patients requiring redo operations is expected to continue to rise as these patients are aging. Consequently, the role of arrhythmia surgery in the treatment of atrial arrhythmias is likely to become more important in this population. Although atrial arrhythmia surgery is a well‐established part of Fontan conversion procedures, evidence‐based recommendations for arrhythmia surgery for macroreentrant atrial tachycardia and atrial fibrillation in other patients with congenital heart disease are still lacking. Methods and Results Twenty‐eight studies were included in this systematic review. The median reported arrhythmia recurrence was 13% (interquartile range, 4%–26%) during follow‐up ranging from 3 months to 15.2 years. A large variation in surgical techniques was observed. Based on the acquired data, biatrial lesions are more effective in the treatment of atrial fibrillation than exclusive right‐sided lesions. Right‐sided lesions may be more appropriate in the treatment of macroreentrant atrial tachycardia; evidence for the superiority of additional left‐sided lesions is lacking. There are not enough data to support the use of exclusive left‐sided lesions. Theoretically, prophylactic atrial arrhythmia surgery may be beneficial in this population, but evidence is currently limited. Conclusions To be able to provide recommendations for arrhythmia surgery in patients with congenital heart disease, future studies should report outcomes according to the type of preoperative arrhythmia, underlying congenital heart disease, lesion set, and energy source. This is essential for determining which surgical techniques should ideally be applied under which circumstances.

Abstract Background Children with congenital heart disease (CHD) are at increased risk for behavioral, emotional, and cognitive problems. They often have reduced exercise capacity and participate less in sports, which is associated with a lower quality of life. Starting school may present more challenges for children with CHD and their families than for families with healthy children. Moreover, parents of children with CHD are at risk for psychosocial problems. Therefore, a family-centered psychosocial intervention for children with CHD when starting school is needed. Until now, the ‘Congenital Heart Disease Intervention Program (CHIP) – School’ is the only evidence-based intervention in this field. However, CHIP-School targeted parents only and resulted in non-significant, though positive, effects as to child psychosocial wellbeing. Hence, we expanded CHIP by adding a specific child module and including siblings, creating the CHIP-Family intervention. The CHIP-Family study aims to (1) test the effects of CHIP-Family on parental mental health and psychosocial wellbeing of CHD-children and to (2) identify baseline psychosocial and medical predictors for the effectiveness of CHIP-Family. Methods We will conduct a single-blinded randomized controlled trial comparing the effects of CHIP-Family with care as usual (no psychosocial intervention). Children with CHD (4–7 years old) who are starting or attending kindergarten or primary school (first or second year) at the time of first assessment and their families are eligible. CHIP-Family consists of a separate one-day workshop for parents and children. The child workshop consists of psychological exercises based on the evidence-based cognitive behavioral therapy Fun FRIENDS protocol and sports exercises. The parent workshop focuses on problem prevention therapy, psychoeducation, general parenting skills, skills specific to parenting a child with CHD, and medical issues. Approximately 4 weeks after the workshop, parents receive an individual follow-up session. The baseline (T1) and follow-up assessment (T2 = 6 months after T1) consist of online questionnaires filled out by the child, parents, and teacher (T2 only). Primary outcome measures are the CBCL for children and the SCL-90-R for parents. Discussion This trial aims to test the effects of an early family-centered psychosocial intervention to meet the compelling need of young children with CHD and their families to prevent (further) problems. If CHIP-Family proves to be effective, it should be structurally implemented in standard care. Trial registration Dutch Trial Registry; NTR6063 on 23 August, 2016.

Abstract Background Morphine is worldwide the analgesic of first choice after cardiac surgery in children. Morphine has unwanted hemodynamic and respiratory side effects. Therefore, post–cardiac surgery patients may potentially benefit from a non-opioid drug for pain relief. A previous study has shown that intravenous (IV) paracetamol is effective and opioid-sparing in children after major non-cardiac surgery. The aim of the study is to test the hypothesis that intermittent IV paracetamol administration in children after cardiac surgery will result in a reduction of at least 30% of the cumulative morphine requirement. Methods This is a prospective, multi-center, randomized controlled trial at four level-3 pediatric intensive care units (ICUs) in the Netherlands and Belgium. Children who are 0–36 months old will be randomly assigned to receive either intermittent IV paracetamol or continuous IV morphine up to 48 h post-operatively. Morphine will be available as rescue medication for both groups. Validated pain and sedation assessment tools will be used to monitor patients. The sample size (n = 208, 104 per arm) was calculated in order to detect a 30% reduction in morphine dose; two-sided significance level was 5% and power was 95%. Discussion This study will focus on the reduction, or replacement, of morphine by IV paracetamol in children (0–36 months old) after cardiac surgery. The results of this study will form the basis of a new pain management algorithm and will be implemented at the participating ICUs, resulting in an evidence-based guideline on post-operative pain after cardiac surgery in infants who are 0–36 months old. Trial registration Dutch Trial Registry (www.trialregister.nl): NTR5448 on September 1, 2015. Institutional review board approval (MEC2015–646), current protocol version: July 3, 2017

Background: The current paradigm is that fibrosis promotes electrophysiological disorders and drives atrial fibrillation (AF). In this current study, we investigated the relation between the degree of fibrosis in human atrial tissue samples of controls and patients in various stages of AF and the degree of electrophysiological abnormalities. Methods: The degree of fibrosis was measured in the atrial tissue and serum of patients in various stages of AF and the controls. Hereto, picrosirius and H&E staining were performed to quantify degree of total, endo-perimysial fibrosis, and cardiomyocyte diameter. Western blot quantified fibrosis markers: neural cell adhesion molecule, tissue inhibitor of metalloproteinase, lysyl oxidase, and α-smooth muscle actin. In serum, the ratio carboxyl-terminal telopeptide of collagen/matrix-metalloproteinase1 was determined. High-resolution epicardial mapping evaluated low-voltage areas and conduction abnormalities. Results: No significant differences were observed in the degree of fibrosis between the groups. Finally, no significant correlation—absolute nor spatial—was observed between all electrophysiological parameters and histological fibrosis markers. Conclusions: No differences in the degree of fibrosis were observed in patients from various stages of AF compared to the controls. Moreover, electrophysiological abnormalities did not correlate with any of the fibrosis markers. The findings indicate that fibrosis is not the hallmark of structural remodeling in AF.

Background: Complex aortic anatomy needs careful preoperative planning in which a patient-tailored approach with novel immersive techniques could serve as a valuable addition to current preoperative imaging. This pilot study aimed to investigate the technical feasibility of virtual reality (VR) as an additional imaging tool for preoperative planning in ascending aortic surgery. Methods: Ten cardiothoracic surgeons were presented with six patients who had each undergone a recent repair of the ascending aorta. Two-dimensional computed tomography images of each patient were assessed prior to the VR session. After three-dimensional (3D) VR rendering and 3D segmentation of the ascending aorta and aortic arch, the reconstructions were analyzed by each surgeon in VR via a head-mounted display. Each cardiothoracic surgeon completed a questionnaire after each planning procedure. The results of their assessments were compared to the performed operations. The primary endpoint of the present study was a change of surgical approach from open to clamped distal anastomosis, and vice versa. Results: Compared with conventional imaging, 80% of surgeons found that VR prepared them better for surgery. In 33% of cases (two out of six), the preoperative decision was adjusted due to the 3D VR-based evaluation of the anatomy. Surgeons rated CardioVR usefulness, user-friendliness, and satisfaction with median scores of 3.8 (IQR: 3.5–4.1), 4.2 (IQR: 3.8–4.6,) and 4.1 (IQR: 3.8–4.7) on a five-point Likert scale, respectively. Conclusions: Three-dimensional VR imaging was associated with improved anatomical understanding among surgeons and could be helpful in the future preoperative planning of ascending aortic surgery.

Objectives the exact timing of aortic valve replacement (AVR) in asymptomatic patients with severe aortic stenosis (AS) remains a matter of debate. Therefore, we described the natural history of asymptomatic patients with severe AS, and the effect of AVR on long-term survival. Methods: Asymptomatic patients who were found to have severe AS between June 2006 and May 2009 were included. Severe aortic stenosis was defined as peak aortic jet velocity Vmax ≥ 4.0 m/s or aortic valve area (AVA) ≤ 1 cm2. Development of symptoms, the incidence of AVR, and all-cause mortality were assessed. Results: A total of 59 asymptomatic patients with severe AS were followed, with a mean follow-up of 8.9 ± 0.4 years. A total of 51 (86.4%) patients developed AS related symptoms, and subsequently 46 patients underwent AVR. The mean 1-year, 2-year, 5-year, and 10-year overall survival rates were higher in patients receiving AVR compared to those who did not undergo AVR during follow-up (100%, 93.5%, 89.1%, and 69.4%, versus 92.3%, 84.6%, 65.8%, and 28.2%, respectively; p < 0.001). Asymptomatic patients with severe AS receiving AVR during follow-up showed an incremental benefit in survival of up to 31.9 months compared to conservatively managed patients (p = 0.002). Conclusions: The majority of asymptomatic patients turn symptomatic during follow-up. AVR during follow-up is associated with better survival in asymptomatic severe AS patients.

The bicuspid aortic valve (BAV) is the most common congenital cardiac malformation associated with aortopathy. The current study provides surgical clinical data on the patient characteristics and long-term survival of this less common adult purely BAV population undergoing surgical aortic valve replacement (SAVR) with concomitant aortic surgery. Adult patients with purely BAV who underwent SAVR and concomitant aortic surgery were included. Prevalence, predictors of survival, and outcomes for this patient population were analyzed. A total of 48 patients (mean age 58.7 ± 13.2 years, 33% female) with purely BAV underwent SAVR and concomitant aortic surgery between 1987 and 2016. The majority (62%) of the patients had pure aortic stenosis (AS). A total of 12 patients died. Survival was 92%, 73%, and 69% at 1, 5, and 20 years of follow-up. At 15 years of follow-up, the survival was close to that of the Dutch population, with a relative survival of 77%. Adult patients with a purely bicuspid aortic valve morphology undergoing SAVR and concomitant aortic root and/or ascending aorta present with excellent survival.

BackgroundEarly postoperative atrial fibrillation (EPoAF) is associated with thromboembolic events, prolonged hospitalization, and development of late PoAF (LPoAF). It is, however, unknown if EPoAF can be predicted by intraoperative AF inducibility. The aims of this study are therefore to explore (1) the value of intraoperative inducibility of AF for development of both EPoAF and LPoAF and (2) the predictive value of de novo EPoAF for recurrence of LPoAF. Methods and ResultsPatients (N=496, 75% male) undergoing cardiothoracic surgery for coronary and/or valvular heart disease were included. AF induction was attempted by atrial pacing, before extracorporeal circulation. All patients were on continuous rhythm monitoring until discharge to detect EPoAF. During a follow‐up period of 2 years, LPoAF was detected by ECGs and Holter recordings. Sustained AF was inducible in 56% of patients. There was no difference in patients with or without AF before surgery (P=0.159), or between different types of surgery (P=0.687). In patients without a history of AF, incidence of EPoAF and LPoAF was 37% and 2%, respectively. EPoAF recurred in 58% patients with preoperative AF, 53% developed LPoAF. There were no correlations between intraoperative inducibility and EPoAF or LPoAF (P>0.05). EPoAF was not correlated with LPoAF in patients without a history of AF (P=0.116), in contrast to patients with AF before surgery (P

BackgroundThe influence of underlying heart disease or presence of atrial fibrillation (AF) on atrial excitation during sinus rhythm (SR) is unknown. We investigated atrial activation patterns and total activation times of the entire atrial epicardial surface during SR in patients with ischemic and/or valvular heart disease with or without AF. Methods and ResultsIntraoperative epicardial mapping (N=128/192 electrodes, interelectrode distances: 2 mm) of the right atrium, Bachmann's bundle (BB), left atrioventricular groove, and pulmonary vein area was performed during SR in 253 patients (186 male [74%], age 66±11 years) with ischemic heart disease (N=132, 52%) or ischemic valvular heart disease (N=121, 48%). As expected, SR origin was located at the superior intercaval region of the right atrium in 232 patients (92%). BB activation occurred via 1 wavefront from right‐to‐left (N=163, 64%), from the central part (N=18, 7%), or via multiple wavefronts (N=72, 28%). Left atrioventricular groove activation occurred via (1) BB: N=108, 43%; (2) pulmonary vein area: N=9, 3%; or (3) BB and pulmonary vein area: N=136, 54%; depending on which route had the shortest interatrial conduction time (P

ObjectivesIn response to an increased need for patient information on congenital heart disease in the Netherlands, we initiated a nationwide initiative to develop an online, evidence-based patient information portal, starting with a pilot project aimed at the subgroup of patients with congenital aortic and pulmonary valve disease.Methods and resultsWe developed an information portal that aims to (1) improve patient knowledge and involvement and to subsequently reduce anxiety and decisional conflict and improve mental quality of life and (2) to support physicians in informing and communicating with their patients. The information portal was developed according to the systematic International Patient Decision Aid Standards development process employing Delphi techniques by a multidisciplinary workgroup of pediatric and adult congenital cardiologists, a congenital cardiothoracic surgeon, a psychologist, an epidemiologist, a patient representative, and web and industrial design experts. First, patients and physicians were surveyed and interviewed to assess the current state of patient information and explore their preferences and needs to determine the focus for the development of the information portal. We found that patient knowledge and numeracy are limited, reliable information is scarce, physicians inform patients selectively and patient involvement is suboptimal, and there is a need for more reliable, tailored, and multi-faceted information. Based on the findings of these surveys and interviews, a patient-tailored information portal was designed that presents evidence-based disease- and age-specific medical and psychosocial information about diagnosis, treatment, prognosis, and impact on daily life in a manner that is comprehensible and digestible for patients and that meets the needs expressed by both patients and physicians. The effect of the website on patient outcome is currently being assessed in a multicenter stepped-wedge implementation trial.ConclusionThe present pilot project succeeded in developing an online, evidence-based information portal that is supported by both patients and physicians. The information portal will be further developed and expanded to include all other major forms of congenital heart disease, translations into other languages, and a public information portal to serve patients’ relatives and the general public at large.

This study aims to investigate an explanation for the inadequate echo window in relation to positional variability of the heart in congenital heart disease. In 46 patients with congenital heart malformations anatomical and echocardiographic studies were done during cardiac surgery. All hearts had situs solitus. Looking in craniocaudal direction, the angle between the frontal plane and the line through the anterior margins of the atrial auricles was measured. This angle was called ß-anatomy (mean 24°, SD 31°, range-70–80°). To assess the validity of ß-anatomy in relation to the anatomic position of reference, a series of relevant anomalous and normal heart specimens was investigated. In the specimens the angle between the plane through the posterior borders of the atrioventricular valves and the plane through the anterior margins of the auricles was measured and reported as ?-anatomy (mean 0°, SD 12°, range-30–45°). The AVSD group showed some difference in this regard, with the right auricle more anterior than the (left 33°, SD 9°, range 20–45°, p<0.05). Intraoperatively and also looking in a craniocaudal direction, the angle between the frontal plane and the assumed midpoints of the semilunar valves was assessed. This angle was called a-anatomy (mean 188°, SD 51°, range 20–315°). The same assessment was done in 31 patients intraoperatively by epicardial echocardiography and called a-echocardiography (mean 158°, SD 30°, range 117–225°). The mean difference between a-anatomy and a-echocardiography was 4° (SD 4°, range 0–25°), with a correlation coefficient 0.92. Interindividual intrathoracic positional variability of the heart was demonstrated. Our study shows that the so-called anatomic golden standard shows positional variability as well. Our findings offer an explanation for the inadequate echo window. [ABSTRACT FROM AUTHOR]

Abstract Living myocardial slices (LMS) are beating sections of intact human myocardium that maintain 3D microarchitecture and multicellularity, thereby overcoming most limitations of conventional myocardial cell cultures. We introduce a novel method to produce LMS from human atria and apply pacing modalities to bridge the gap between in-vitro and in-vivo atrial arrhythmia studies. Human atrial biopsies from 15 patients undergoing cardiac surgery were dissected to tissue blocks of ~ 1 cm2 and cut to 300 µm thin LMS with a precision-cutting vibratome. LMS were placed in a biomimetic cultivation chamber, filled with standard cell culture medium, under diastolic preload (1 mN) and continuous electrical stimulation (1000 ms cycle length (CL)), resulting in 68 beating LMS. Atrial LMS refractory period was determined at 192 ± 26 ms. Fixed rate pacing with a CL of 333 ms was applied as atrial tachyarrhythmia (AT) model. This novel state-of-the-art platform for AT research can be used to investigate arrhythmia mechanisms and test novel therapies.

IntroductionThis study aims to provide an overview of outcomes after right ventricular outflow tract (RVOT) reconstruction using different valve substitutes in different age groups for different indications.MethodsThe literature was systematically searched for articles published between January 2000 and June 2021 reporting on clinical and/or echocardiographic outcomes after RVOT reconstruction with valve substitutes. A random-effects meta-analysis was conducted for outcomes, and time-related outcomes were visualized by pooled Kaplan–Meier curves. Subgroup analyses were performed according to etiology, implanted valve substitute and patient age.ResultsTwo hundred and seventeen articles were included, comprising 37,078 patients (age: 22.86 ± 11.29 years; 31.6% female) and 240,581 patient-years of follow-up. Aortic valve disease (Ross procedure, 46.6%) and Tetralogy of Fallot (TOF, 27.0%) were the two main underlying etiologies. Homograft and xenograft accounted for 83.7 and 32.6% of the overall valve substitutes, respectively. The early mortality, late mortality, reintervention and endocarditis rates were 3.36% (2.91–3.88), 0.72%/y (95% CI: 0.62–0.82), 2.62%/y (95% CI: 2.28–3.00), and 0.38%/y (95%CI: 0.31–0.47) for all patients. The early mortality for TOF and truncus arteriosus (TA) were 1.95% (1.31–2.90) and 10.67% (7.79–14.61). Pooled late mortality and reintervention rate were 0.59%/y (0.39–0.89), 1.41%/y (0.87–2.27), and 1.20%/y (0.74–1.94), 10.15%/y (7.42–13.90) for TOF and TA, respectively. Endocarditis rate was 0.21%/y (95% CI: 0.16–0.27) for a homograft substitute and 0.80%/y (95%CI: 0.60–1.09) for a xenograft substitute. Reintervention rate for infants, children and adults was 8.80%/y (95% CI: 6.49–11.95), 4.75%/y (95% CI: 3.67–6.14), and 0.72%/y (95% CI: 0.36–1.42), respectively.ConclusionThis study shows RVOT reconstruction with valve substitutes can be performed with acceptable mortality and morbidity rates for most patients. Reinterventions after RVOT reconstruction with valve substitutes are inevitable for most patients in their life-time, emphasizing the necessity of life-long follow-up and multidisciplinary care. Follow-up protocols should be tailored to individual patients because patients with different etiologies, ages, and implanted valve substitutes have different rates of mortality and morbidity.Systematic review registration[www.crd.york.ac.uk/prospero], identifier [CRD42021271622].

Background Ventricular performance is temporarily reduced following surgical atrial septal defect closure. Cardiopulmonary bypass and changes in loading conditions are considered important factors, but this phenomenon is incompletely understood. We aim to characterize biventricular performance following surgical and percutaneous atrial septal defect closure and to relate biomarkers to ventricular performance following intervention. Methods and Results In this multicenter prospective study, children scheduled for surgical or percutaneous atrial septal defect closure were included. Subjects were assessed preoperatively, in the second week postintervention (at 2‐weeks follow‐up), and 1‐year postintervention (1‐year follow‐up). At each time point, an echocardiographic study and a panel of biomarkers were obtained. Sixty‐three patients (median age, 4.1 [interquartile range, 3.1–6.1] years) were included. Forty‐three patients underwent surgery. At 2‐weeks follow‐up, right ventricular global longitudinal strain was decreased for the surgical, but not the percutaneous, group (−17.6±4.1 versus −27.1±3.4; P

Background:Sinus node dysfunction (SND) and atrial tachyarrhythmias frequently co-exist in the aging patient with congenital heart disease (CHD), even after surgical correction early in life. We examined differences in electrophysiological properties of the sino-atrial node (SAN) area between pediatric and adult patients with CHD.MethodsEpicardial mapping of the SAN was performed during sinus rhythm in 12 pediatric (0.6 [0.4–2.4] years) and 15 adult (47 [40–55] years) patients. Unipolar potentials were classified as single-, short or long double- and fractionated potentials. Unipolar voltage, relative R-to-S-amplitude ratio and duration of all potentials was calculated. Conduction velocity (CV) and the amount of conduction block (CB) was calculated.ResultsSAN activity in pediatric patients was solely observed near the junction of the superior caval vein and the right atrium, while in adults SAN activity was observed even up to the middle part of the right atrium. Compared to pediatric patients, the SAN region of adults was characterized by lower CV, lower voltages, more CB and a higher degree of fractionation. At the earliest site of activation, single potentials from pediatrics consisted of broad monophasic S-waves with high amplitudes, while adults had smaller rS-potentials with longer duration which were more often fractionated.ConclusionsCompared to pediatric patients, adults with uncorrected CHD have more inhomogeneous conduction and variations in preferential SAN exit site, which are presumable caused by aging related remodeling. Long-term follow-up of these patients is essential to demonstrate whether these changes are related to development of SND and also atrial tachyarrhythmias early in life.

PurposeBecause of the current lack of evidence-based antimicrobial treatment guidelines, Left Ventricular Assist Device (LVAD) infections are often treated according to local insights. Here, we propose a flowchart for protocolized treatment, in order to improve outcome.MethodsThe flowchart was composed based on literature, consensus and expert opinion statements. It includes choice, dosage and duration of antibiotics, and indications for suppressive therapy, with particular focus on Staphylococcus aureus (SA) (Figure 1). The preliminary treatment results of 28 patients (2 from start cephalexin suppressive therapy) after implementation in July 2018 are described.ResultsCumulative incidence for first episode of infection in a 3-year time period was 27% (26 of 96 patients with an LVAD). Twenty-one of 23 (91%) first episodes of driveline infection (10 superficial and 13 deep; nine of 13 caused by SA) were successfully treated with antibiotics according to flowchart with complete resolution of clinical signs and symptoms. For two patients with deep driveline infections, surgery was needed in addition. There were no relapses of deep driveline infections, and only 2 SA deep driveline re-infections after 6 months. Nine patients received cephalexin of whom four patients (44%) developed a breakthrough infection with cephalexin-resistant gram-negative bacteria.ConclusionsThe first results of this protocolized treatment approach of LVAD infections are promising. Yet, initiation of cephalexin suppressive therapy should be carefully considered given the occurrence of infections with resistant micro-organisms. The long-term outcome of this approach needs to be established in a larger number of patients, preferably in a multi-center setting.

Background The significance of endo‐epicardial asynchrony (EEA) and atrial conduction block (CB), which play an important role in the pathophysiology of atrial fibrillation (AF) during sinus rhythm is poorly understood. The aim of our study was therefore to examine 3‐dimensional activation of the human right atrium (RA). Methods and Results Eighty patients (79% men, 39% history of AF) underwent simultaneous endo‐epicardial sinus rhythm mapping of the inferior, middle and superior RA. Areas of CB were defined as conduction delays of ≥12 ms, EEA as activation time differences of opposite electrodes of ≥15 ms and transmural CB as CB at similar endo‐epicardial sites. CB was more pronounced at the endocardium (all locations P

Abstract Background Use of donor blood in congenital cardiac surgery increases the risk for post-operative morbidity and mortality. To reduce the need for allogenic blood transfusion a technique for peri-operative mechanical red cell salvage is applied. Blood from the operation site is collected in a reservoir, processed, passed through a lipophilic filter and returned to the patient. Influence of this cellsaver system on coagulation, fibrinolysis and inflammatory markers is known. To our knowledge no studies have been performed on the effects of autotransfusion on drug concentrations. A clinically relevant drug dose could potentially be returned to the patient through the auto-transfused blood, leading to unwanted drug reactions post-operatively. We aimed to measure drug concentrations in blood salvaged from the operation site and in the auto-transfused blood to determine if a clinically relevant drug dose is returned to the patient. Methods The study was performed at the Department of Cardiothoracic Surgery of a tertiary university hospital. Blood samples were taken from the reservoir, after processing before the lipophilic filter, the auto-transfused blood, and the waste fluid. Samples were stored at − 80 C and drug concentration for sufentanil, propofol, midazolam and cefazolin were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Drug concentrations measured in the reservoir and the auto-transfused blood were compared and the relative reduction was calculated for each patient. Results Blood samples were taken from 18 cellsaver runs in 18 patients, age 0–13 years. Drug concentrations in the reservoir were comparable to concomitant concentrations in the patient. For sufentanil 34% (median, IQR 27–50) of drug concentration was retained from the reservoir in the auto-transfused blood, for midazolam 6% (median, IQR 4–10), for cefazolin 5% (median, IQR 2–6) and for propofol 0% (median, IQR 0–0) respectively. Conclusion Depending on the drug, up to 34% of the drug concentration salvaged from the operation site is returned to the patient through autotransfusion, potentially causing unwanted drug reactions post-operatively. Additionally, influence of a cellsaver system should be considered in pharmacological research during and after congenital cardiac surgery and could result in dose adjustments in the postoperative phase. Trial registration Registration at the Dutch Trial Registry (NTR3579) at August 14 2012.

There is limited information about age-specific structural and functional properties of human heart valves, while this information is key to the development and evaluation of living valve replacements for pediatric and adolescent patients. Here, we present an extended data set of structure-function properties of cryopreserved human pulmonary and aortic heart valves, providing age-specific information for living valve replacements. Tissue composition, morphology, mechanical properties, and maturation of leaflets from 16 pairs of structurally unaffected aortic and pulmonary valves of human donors (fetal-53 years) were analyzed. Interestingly, no major differences were observed between the aortic and pulmonary valves. Valve annulus and leaflet dimensions increase throughout life. The typical three-layered leaflet structure is present before birth, but becomes more distinct with age. After birth, cell numbers decrease rapidly, while remaining cells obtain a quiescent phenotype and reside in the ventricularis and spongiosa. With age and maturation-but more pronounced in aortic valves-the matrix shows an increasing amount of collagen and collagen cross-links and a reduction in glycosaminoglycans. These matrix changes correlate with increasing leaflet stiffness with age. Our data provide a new and comprehensive overview of the changes of structure-function properties of fetal to adult human semilunar heart valves that can be used to evaluate and optimize future therapies, such as tissue engineering of heart valves. Changing hemodynamic conditions with age can explain initial changes in matrix composition and consequent mechanical properties, but cannot explain the ongoing changes in valve dimensions and matrix composition at older age.

Ad J J C Bogers1, Martin van den Burg1,2, Ronald Schepp2, Jan Klein21Department of Cardiothoracic Surgery; 2Department of Anesthesiology, Thoraxcentre, Erasmus University Medical Centre, Rotterdam, The NetherlandsBackground: In the initial postoperative period after a Fontan-type operation for a univentricular circulation, cardiac output information is important, but cannot be provided by conventional methods due to the surgical reconstruction of the heart. In this regard we investigated the feasibility of epi-aortic Doppler measurements in order to calculate cardiac output.Methods: Epi-aortic cardiac output measurement was compared with Fick measurements as the gold standard in eight patients with a univentricular circulation after a Fontan-type operation.Results: The mean diameter of the aorta by epi-aortic measurement was 18 mm (range 14 to 25), by angiography 17 mm (range 10 to 24), correlation coefficient 0.88 (p