Continuous Long-Term Assessment of Heart Rate Variability in Adults with Cyanotic Congenital Heart Disease after Surgical Repair.

Background: Heart rate variability (HRV) is an established, non-invasive parameter for the assessment of cardiac autonomic nervous activity and the health status in general cardiology. However, there are few studies on HRV in adults with congenital heart defects (CHDs). The aim of the present study was to evaluate the use of long-term continuous HRV measurement for the assessment of global health status in adults with cyanotic CHD. Methods: This prospective study included 45 adults (40% female, mean age = 35.2 ± 9.2 [range: 19-58] years) after cardiac surgical repair. HRV parameters were calculated from continuous 24 h measurements using a Bittium Faros 180 sensor (Bittium Corp., Oulu, Finland). Results: Postoperative patients with transposition of the great arteries (TGA) (n = 18) achieved significantly higher values of standard deviation of NN intervals (SDNN) (175.4 ± 59.9 ms vs. 133.5 ± 40.6 ms; p = 0.013) compared with patients with other conotruncal anomalies (n = 22). Comparing patients with TGA after a Senning-Brom or Mustard operation (n = 13) with all other heart surgery patients (n = 32), significantly higher HRV parameters were found after atrial switch (root mean square of successive RR interval differences: 53.6 ± 20.7 ms vs. 38.4 ± 18.3 ms; p = 0.019; SDNN: 183.5 ± 58.4 ms vs. 136.3 ± 45.3 ms; p = 0.006). A higher SDNN was also measured after Senning-Brom or Mustard operations than after a Rastelli operations (n = 2) (SDNN: 183.5 ± 58.4 ms vs. 84.5 ± 5.2 ms; p = 0.037). When comparing atrial switch operations (n = 3) with Rastelli operations, the SDNN value was significantly shorter in the Rastelli group (p = 0.004). Conclusions: Our results suggest that continuous HRV monitoring may serve as a marker of cardiac autonomic dysfunction in adults with cyanotic CHD after surgical repair. Impaired cardiac autonomic nervous activity may be associated with an increased risk of adverse reactions in patients with repaired CHD. Therefore, a longitudinal assessment of HRV patterns and trends may provide a deeper insight into dynamic changes in their autonomic regulation and disease progression, lifestyle changes, or treatments. As each person has individual variability in heart rate, HRV may be useful in assessing intra-individual disease progression and may help to improve personalized medicine. Further studies are needed to better understand the underlying mechanisms and to explore the full potential of HRV analysis to optimize medical care for ACHDs.

PATHFINDER-CHD: prospective registry on adults with congenital heart disease, abnormal ventricular function, and/or heart failure as a foundation for establishing rehabilitative, prehabilitative, preventive, and health-promoting measures: rationale, aims, design and methods.

BACKGROUND: Adults with congenital heart defects (ACHD) globally constitute a notably medically underserved patient population. Despite therapeutic advancements, these individuals often confront substantial physical and psychosocial residua or sequelae, requiring specialized, integrative cardiological care throughout their lifespan. Heart failure (HF) is a critical challenge in this population, markedly impacting morbidity and mortality. AIMS: The primary aim of this study is to establish a comprehensive, prospective registry to enhance understanding and management of HF in ACHD. Named PATHFINDER-CHD, this registry aims to establish foundational data for treatment strategies as well as the development of rehabilitative, prehabilitative, preventive, and health-promoting interventions, ultimately aiming to mitigate the elevated morbidity and mortality rates associated with congenital heart defects (CHD). METHODS: This multicenter survey will be conducted across various German university facilities with expertise in ACHD. Data collection will encompass real-world treatment scenarios and clinical trajectories in ACHD with manifest HF or at risk for its development, including those undergoing medical or interventional cardiac therapies, cardiac surgery, inclusive of pacemaker or ICD implantation, resynchronization therapy, assist devices, and those on solid organ transplantation. DESIGN: The study adopts an observational, exploratory design, prospectively gathering data from participating centers, with a focus on patient management and outcomes. The study is non-confirmatory, aiming to accumulate a broad spectrum of data to inform future hypotheses and studies. PROCESSES: Regular follow-ups will be conducted, systematically collecting data during routine clinical visits or hospital admissions, encompassing alterations in therapy or CHD-related complications, with visit schedules tailored to individual clinical needs. ASSESSMENTS: Baseline assessments and regular follow-ups will entail comprehensive assessments of medical history, ongoing treatments, and outcomes, with a focus on HF symptoms, cardiac function, and overall health status. DISCUSSION OF THE DESIGN: The design of the PATHFINDER-CHD Registry is tailored to capture a wide range of data, prioritizing real-world HF management in ACHD. Its prospective nature facilitates longitudinal data acquisition, pivotal for comprehending for disease progression and treatment impacts. CONCLUSION: The PATHFINDER-CHD Registry is poised to offer valuable insights into HF management in ACHD, bridging current knowledge gaps, enhancing patient care, and shaping future research endeavors in this domain.

Paediatric aortic valve replacement using decellularized allografts: a multicentre update following 143 implantations and five-year mean follow-up.

OBJECTIVES: Decellularized aortic homografts (DAH) were introduced in 2008 as a further option for paediatric aortic valve replacement (AVR). METHODS: Prospective, multicentre follow-up of all paediatric patients receiving DAH for AVR in 8 European centres. RESULTS: A total of 143 DAH were implanted between February 2008 and February 2023 in 137 children (106 male, 74%) with a median age of 10.8 years (interquartile range 6.6-14.6). Eighty-four (59%) had undergone previous cardiac operations and 24 (17%) had undergone previous AVR. The median implanted DAH diameter was 21 mm (interquartile range 19-23). The median operation duration was 348 min (227-439) with a median cardiopulmonary bypass time of 212 min (171-257) and a median cross-clamp time of 135 min (113-164). After a median follow-up of 5.3 years (3.3-7.2, max. 15.2 years), the primary efficacy end-points peak gradient (median 14 mmHg, 9-28) and regurgitation (median 0.5, interquartile range 0-1, grade 0-3) showed good results but an increase over time. Freedom from death/explantation/endocarditis/bleeding/thromboembolism at 5 years were 97.8 ± 1.2/88.7 ± 3.3/99.1 ± 0.9/100 and 99.2 ± 0.8%, respectively. Freedom from death/explantation/endocarditis/bleeding/thromboembolism at 10 years were 96.3 ± 1.9/67.1 ± 8.0/93.6 ± 3.9/98.6 ± 1.4 and 86.9 ± 11.6%, respectively. In total, 21 DAH were explanted. Seven were replaced by a mechanical AVR, 1 Ross operation was performed and a re-do DAH was implanted in 13 patients with no redo mortality. The calculated expected adverse events were lower for DAH compared to cryopreserved homograft patients (mean age 8.4 years), and in the same range as for Ross patients (9.2 years) and mechanical AVR (13.0 years). CONCLUSIONS: This large-scale prospective analysis demonstrates excellent mid-term survival using DAH with adverse event rates comparable to paediatric Ross procedures.

Changes of the nociceptive flexion reflex threshold in patients undergoing cardiac surgery-a prospective clinical pilot study.

Opioid dosage for general anaesthesia and sedation relies on surrogate parameters such as heartrate and blood pressure. This implies the risk of both under- and overdosing. A promising tool to provide target-oriented opioid dosing is measuring the nociceptive flexion reflex threshold (NFRT). The aim of this study was to investigate the individual trajectories and to determine this methods' clinical practicability in the perioperative setting of cardiac surgery. NFRT was measured preoperatively (twice as baseline), immediately after surgery and later in the general ward (primary outcomes). No intraoperative measurements were performed since neuromuscular blockade hinders NFRT assessment. Administered analgesics and pain scores were also recorded (secondary outcomes). Data were collected from August 2019 to March 2020. 264 patients scheduled for cardiac surgery were screened for eligibility. 55 patients were included, 30 rendered datasets for analysis. Thresholds after conclusion of surgery [TICU: median (IQR), 31.1 mA (21.5-50.0 mA)] were significantly higher than preoperatively [Tpre: 9.2 mA (5.4-13.4 mA); P < 0.001]. In 11 patients (36.7%), no immediate postoperative reflex response was elicited. Later, all reflexes returned, but thresholds remained significantly higher than preoperatively [Tpost: 11.9 mA (9.2-16.6 mA); P = 0.043]. NFRT values after surgery were higher compared to baseline measurements. Subsequently they decreased but did not reach their baseline levels. There was no corresponding dose-dependency, suggesting multimodal effects on the nociceptive system. Unless measurements are not prevented by technical issues NFRT-assessment appears to be a future tool to target analgesics in patients not able to self-report pain. Trial registration Study registration: DRKS00021617. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00021617 (registered retrospectively).

Mobility and freedom of movement: A novel out-of-hospital treatment for pediatric patients with terminal cardiac insufficiency and a ventricular assist device.

Background: Due to rapid medical and technological progress, more and more pediatric patients with terminal cardiac insufficiency are being implanted with a ventricular assist device as a bridge to transplant without legal approval for hospital discharge. EXCOR® Active is a recently developed mobile driving unit for the EXCOR® ventricular assist device (EXCOR® VAD) with a long-lasting battery life that can manage small blood pumps, offering improved mobility for pediatric patients. This study strives to elaborate the requirements necessary for a safe home healthcare environment (HHE) for pediatric patients on EXCOR® VAD powered by the EXCOR® Active driving unit. Materials and methods: Patient- and device-related preconditions (medical, ethical, psychological, technical, structural, organizational) were analyzed with regard to feasibility and safety in three individual patient cases. Included were pediatric patients with terminal cardiac insufficiency in a stable medical condition receiving in-hospital treatment with a univentricular or biventricular EXCOR® VAD powered by EXCOR® Active. Analysis was single-center, data was obtained 05/2020-02/2022. Results: A total of three patients on EXCOR® VAD were identified for HHE treatment with the EXCOR® Active driving unit. Switch was performed safely and increased mobility led to improved psychomotor development and improved quality of life. No complications directly related to HHE-treatment occurred. One patient recently underwent an orthotopic heart transplant, one patient remains in HHE, and one patient died due to a complication not related to the HHE. Ethical approval for off-label use was obtained and patients and parents were given the required technical training and psychological support. Caregivers and medical professionals involved in the patients' care at home were briefed intensely. Remote consultations were implemented and interdisciplinary in-hospital checks reduced to a long-term 4-week-scheme. Conclusion: While it is challenging to discharge pediatric patients being treated with a paracorporeal ventricular assist device (EXCOR® VAD) from hospital, it is feasible and can be managed safely with the novel driving unit EXCOR® Active. A HHE may help to improve patients' psychomotor development, offer normalized social contacts and strengthen both patients' and parents' physical and mental resources. Legal approval and another study with a larger sample size are warranted.

The focal adhesion protein ß-parvin controls cardiomyocyte shape and sarcomere assembly in response to mechanical load.

Physiological and pathological cardiac stress induced by exercise and hypertension, respectively, increase the hemodynamic load for the heart and trigger specific hypertrophic signals in cardiomyocytes leading to adaptive or maladaptive cardiac hypertrophy responses involving a mechanosensitive remodeling of the contractile cytoskeleton. Integrins sense load and have been implicated in cardiac hypertrophy, but how they discriminate between the two types of cardiac stress and translate mechanical loads into specific cytoskeletal signaling pathways is not clear. Here, we report that the focal adhesion protein ß-parvin is highly expressed in cardiomyocytes and facilitates the formation of cell protrusions, the serial assembly of newly synthesized sarcomeres, and the hypertrophic growth of neonatal rat ventricular cardiomyocytes (NRVCs) in vitro. In addition, physiological mechanical loading of NRVCs by either the application of cyclic, uni-axial stretch, or culture on physiologically stiff substrates promotes NRVC elongation in a ß-parvin-dependent manner, which is achieved by binding of ß-parvin to α/ß-PIX, which in turn activates Rac1. Importantly, loss-of-function studies in mice also revealed that ß-parvin is essential for the exercise-induced cardiac hypertrophy response in vivo. Our results identify ß-parvin as a novel mechano-responsive signaling hub in hypertrophic cardiomyocytes that drives cell elongation in response to physiological mechanical loads.

Psychological burden and coping in destination therapy patients with a left ventricular assist device: A qualitative content analysis.

BACKGROUND: Due to an increasing prevalence of heart failure and persistent shortage of donor hearts, the number of left ventricular assist device (LVAD) implantations is growing. As more patients live with LVADs for prolonged periods of time, psychosocial outcomes are becoming more relevant. This particularly applies to destination therapy (DT) patients, who live with the LVAD for the rest of their lives. METHODS: We used a cross-sectional qualitative design to explore psychological burden, coping strategies, and resources from the perspective of DT patients. Data were collected via semi-structured in-depth interviews with 18 patients who lived with the LVAD for 3 months to over 10 years. These were analyzed using an inductive content analysis. Due to the COVID-19 pandemic, changes to the recruitment strategy and data collection strategies of the original study protocol were applied. Patients and clinicians were involved throughout the research process to ensure the validity of the results and implications. RESULTS: We synthesized 10 psychosocial, health, and treatment-related burdens and identified 15 problem- and emotion-focused coping strategies and 5 personal and environmental resources patients used to cope with the burden. CONCLUSIONS: The findings provide deeper insights into the complex and specific situation of LVAD patients to better address the patient situation in health care and promote positive psychosocial outcomes. So far, health care practice and quality vary significantly between clinics due to individual treatment protocols. Our results highlight the need to improve medical and psychosocial care. Overarching care concepts may be developed based on the implications.

The value of perioperative biomarker release for the assessment of myocardial injury or infarction in cardiac surgery.

OBJECTIVES: Cardiac biomarkers are indicators of irreversible cell damage. Current myocardial infarction (MI) definitions require concomitant clinical characteristics. For perioperative MI, a correlation of biomarker elevations and mortality has been suggested. Definitions emerged relying on cardiac biomarker release only. This approach is questionable as several clinical and experimental scenarios exist where relevant biomarker release can occur apart from MI. METHODS: We reviewed the clinical and basic science literature and revealed important aspects regarding the use and interpretation of cardiac biomarker release with special focus on their interpretation in the perioperative setting. RESULTS: Ischaemic biomarkers may be released without cell death in multiple conditions, such as after endurance runs in athletes, temporary inotropic stimulation in animal models and flow variations in in vitro cell models. In addition, access through atrial tissue during cannulation or concomitant valve procedures adds sources of enzyme release that may not be related to ventricular ischaemia (i.e. MI). Such non-cell death-related mechanisms may explain the lack of poor correlations of enzyme release and long-term outcomes in recent trials. In addition, the 3 main biomarkers, troponin T, I and creatine kinase myocardial band, differ in their release kinetics, which may differentially trigger MI events in trial patients. CONCLUSIONS: The identification of irreversible myocardial injury in cardiac surgery based only on biomarker release is unreliable. Cell death- and non-cell death-related mechanisms create a mix in the perioperative setting that requires additional markers for proper identification of MI. In addition, the 3 most common ischaemic biomarkers display different release kinetics adding to the confusion. We review the topic.

[Disorientation and delirium assessment : A secondary analysis of a prospective, observational study]. / Bedeutung der Desorientierung bei der Delireinschätzung : Sekundäranalyse einer prospektiven, observationellen Studie.

Disorientation may present as a warning sign of developing delirium. The most commonly used delirium assessment tool in Germany, the Confusion Assessment Method for Intensive Care Unit (CAM-ICU), does not rate "disorientation", since intubated patients cannot communicate verbally. However, the majority of German ICU patients are not orally intubated, so they could be examined for their orientation. This study was carried out to investigate whether the delirium feature "disorientation" in extubated patients yields diverging findings in comparison to the CAM-ICU and whether the sensitivity of the CAM-ICU may be improved when combined with the feature "disorientation" (CAM-IMC). A total of 86 paired assessments were completed in 50 extubated patients. Delirium was found in 19.8% (N = 17). The CAM-ICU had a sensitivity of 71% (95% confidence interval [CI] 44-90%) and a specificity of 100% (95-100%). Disorientation, if taken as the only delirium feature, had a sensitivity of 77% (50-93%) and a specificity of 93% (89-100%). The CAM-IMC reached a sensitivity of 88% (64-99%) and a specificity of 100% (95-100%). The receiver operating characteristics (ROC) analyses found an area under the curve (AUC) of 0.941 (95%CI 0.851-1.000) for the CAM-IMC, which was the highest compared to the other delirium tests (CAM-ICU, AUC 0.853 [0.720-0.986]; disorientation, AUC 0.868 [0.745-0.991]). This research emphasizes the importance of the feature "disorientation" for delirium assessments in patients able to verbally communicate and explains some controversial delirium ratings in daily practice. The CAM-IMC appears to be an attractive tool for delirium assessment in nonintubated patients and deserves further research.

[Therapy and Outcome of Neonates with Congenital Diaphragmatic Hernia and Congenital Heart Defects]. / Therapie und Outcome von Neugeborenen mit kongenitaler Zwerchfellhernie und angeborenen Herzfehlern.

Die Mortalität von Patienten mit isoliert auftretenden angeborenen Zwerchfellhernien liegt in spezialisierten Zentren bei 20-40%. Wesentliche, das Outcome beeinflussende Faktoren, sind die bestehende Lungenhypoplasie, eine daraus resultierende pulmonale Hypertonie, sowie das Vorliegen weiterer Fehlbildungen. Begleitfehlbildungen wie angeborene Herzfehler treten bei ca. 18% aller Neonaten mit Zwerchfellhernie auf. Schwere angeborene Herzfehler wie das hypoplastische Linksherz Syndrom zeigen sich in ca. 8% der Fälle. In einer retrospektiven Analyse des Patientenkollektivs unserer Klinik zwischen 01/2012 und 12/2018 wurde das prä- und postnatale Management, sowie das Outcome von Neugeborenen mit der Kombination aus angeborenen Herzfehlern und Zwerchfellhernien untersucht. Im Studienzeitraum wurden in unserer Klinik 156 Neugeborene mit Zwerchfellhernie behandelt. Bei 10 Patienten (6,4%) lag zusätzlich ein schwerer, bei 11 Patienten (7,1%) ein moderater Herzfehler vor. 6/21 Patienten verstarben im Verlauf des Krankenhausaufenthaltes, davon 3 am ersten Lebenstag. Es zeigte sich eine deutlich geringere Mortalität bei Patienten mit Zwerchfellhernie und moderatem Herzfehler im Vergleich zu schwerem Herzfehler (9 vs. 50%). Besonders hoch lag die Mortalität bei Kindern mit einem univentrikulären Herzen. Trotz einer deutlich reduzierten Prognose bei der Kombination aus angeborenem Herzfehler und Zwerchfellhernie muss nicht generell mit einer infausten Prognose gerechnet werden. In spezialisierten Zentren kann ein kurativer Ansatz erfolgen.The mortality of patients with isolated congenital diaphragmatic hernia (CDH) in specialized centers is 20-40%. The main factors influencing the outcome are the underlying pulmonary hypoplasia, the resulting pulmonary hypertension and the presence of other malformations. Concomitant malformations such as congenital heart defects occur in around 18% of all neonates with a diaphragmatic hernia. Serious congenital heart defects such as hypoplastic left heart syndrome occur in approximately 8% of cases. In a retrospective analysis of the patient collective of our hospital between 01/2012 and 12/2018, the prenatal and postnatal management as well as the outcome of newborns with a combination of congenital heart defects and diaphragmatic hernias were examined. During the study period, 156 newborns with diaphragmatic hernias were treated at our institution. In 10 patients (6.4%) there was also a severe, and in 11 patients (7.1%) a moderate heart defect. 6/21 patients died during their hospital stay, 3 of them on the first day of life. There was a significantly lower mortality in patients with diaphragmatic hernia and moderate heart defects compared to severe heart defects (9 vs. 50%). The mortality in children with a univentricular heart was particularly high. Despite a significantly reduced prognosis for the combination of congenital heart defects and diaphragmatic hernia, generally a poor prognosis does not have to be expected. A curative approach can be achieved in specialized centers.

Impact of pre-existing comorbidities on outcomes of patients undergoing surgical aortic valve replacement - rationale and design of the international IMPACT registry.

BACKGROUND: Degenerative aortic valve disease accounts for 10-20% of all cardiac surgical procedures. The impact of pre-existing comorbidities on the outcome of patients undergoing surgical aortic valve replacement (SAVR) needs further research. METHODS: The IMPACT registry is a non-interventional, prospective, open-label, multicenter, international registry with a follow-up of 5 years to assess the impact of pre-existing comorbidities of patients undergoing SAVR with the INSPIRIS RESILIA aortic valve on outcomes. IMPACT will be conducted across 25 sites in Austria, Germany, The Netherlands and Switzerland and intends to enroll approximately 500 patients. Patients will be included if they are at least 18 years of age and are scheduled to undergo SAVR with the INSPIRIS RESILIA Aortic Valve with or without concomitant ascending aortic root replacement and/or coronary bypass surgery. The primary objective is to determine all-cause mortality at 1, 3, and 5 years post SAVR. Secondary objectives include cardiac-related and valve-related mortality and structural valve deterioration including hemodynamics and durability, valve performance and further clinical outcomes in the overall study population and in specific patient subgroups characterized by the presence of chronic kidney disease, hypertension, metabolic syndrome and/or chronic inflammation. DISCUSSION: IMPACT is a prospective, multicenter European registry, which will provide much-needed data on the impact of pre-existing comorbidities on patient outcomes and prosthetic valve performance, and in particular the performance of the INSPIRIS RESILIA, in a real-world setting. The findings of this study may help to support and expand appropriate patient selection for treatment with bioprostheses. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04053088 .

Preoperative Cognitive Impairment and Postoperative Delirium Predict Decline in Activities of Daily Living after Cardiac Surgery-A Prospective, Observational Cohort Study.

Cardiac surgery and subsequent treatment in the intensive care unit (ICU) has been shown to be associated with functional decline, especially in elderly patients. Due to the different assessment tools and assessment periods, it remains yet unclear what parameters determine unfavorable outcomes. This study sought to identify risk factors during the entire perioperative period and focused on the decline in activity of daily living (ADL) half a year after cardiac surgery. Follow-ups of 125 patients were available. It was found that in the majority of patients (60%), the mean ADL declined by 4.9 points (95% CI, -6.4 to -3.5; p < 0.000). In the "No decline" -group, the ADL rose by 3.3 points (2.0 to 4.6; p < 0.001). A multiple regression analysis revealed that preoperative cognitive impairment (MMSE ≤ 26; Exp(B) 2.862 (95%CI, 1.192-6.872); p = 0.019) and duration of postoperative delirium ≥ 2 days (Exp(B) 3.534 (1.094-11.411); p = 0.035) was independently associated with ADL decline half a year after the operation and ICU. Of note, preoperative ADL per se was neither associated with baseline cognitive function nor a risk factor for functional decline. We conclude that the preoperative assessment of cognitive function, rather than functional assessments, should be part of risk stratification when planning complex cardiosurgical procedures.

CpG postconditioning after reperfused myocardial infarction is associated with modulated inflammation, less apoptosis, and better left ventricular function.

Postconditioning attenuates inflammation and fibrosis in myocardial infarction (MI). The aim of this study was to investigate whether postconditioning with the cytosine-phosphate-guanine (CpG)-containing Toll-like receptor-9 (TLR9) ligand 1668-thioate (CpG) can modulate inflammation and remodeling in reperfused murine MI. Thirty minutes of left descending coronary artery (LAD) occlusion was conducted in 12-wk-old C57BL/6 mice. Mice were treated with CpG intraperitoneally 5 min before reperfusion. The control group received PBS; the sham group did not undergo ischemia. M-mode echocardiography (3, 7, and 28 days) and Millar left ventricular (LV) catheterization were performed (7 and 28 days) before the hearts were excised and harvested for immunohistochemical (6 h, 24 h, 3 days, 7 days, and 28 days), gene expression (6 h, 24 h, and 3 days; Taqman RT-qPCR), protein, and FACS analysis (24 h and 3 days). Mice treated with CpG showed significantly better LV function after 7 and 28 days of reperfusion. Protein and mRNA expressions of proinflammatory and anti-inflammatory cytokines were significantly induced after CpG treatment. Histology revealed fewer macrophages in CpG mice after 24 h, confirmed by FACS analysis with a decrease in both classically M1- and alternative M2a-monocytes. CpG treatment reduced apoptosis and cardiomyocyte loss and was associated with induction of adaptive mechanisms, e.g., of heme-oxigenase-1 and ß-/α-myosin heavy chain (MHC) ratio. Profibrotic markers collagen type Iα (Col-Ια) and Col-III induction was abrogated in CpG mice, accompanied by fewer myofibroblasts. This led to the formation of a smaller scar. Differential matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) expression contributed to attenuated remodeling in CpG, resulting in preserved cardiac function in a Toll-like receptor 1- and TLR9-dependent manner. Our study suggests a cardioprotective mechanism of CpG postconditioning, involving Toll-like receptor-driven modulation of inflammation. This is followed by attenuated remodeling and preserved LV function.NEW & NOTEWORTHY Cytosine-phosphate-guanine (CpG) postconditioning seems to mediate inflammation via Toll-like receptor-1 and Toll-like receptor-9 signaling. Enhanced cytokine and chemokine expressions are partly attenuated by IL-10 and matrix metalloproteinase-8 (MMP8) induction, being associated with lower macrophage infiltration and M1-monocyte differentiation. Furthermore, switch from α- to ß-MHC and balanced MMP/TIMP expression led to lesser cardiomyocyte apoptosis, smaller scar size, and preserved cardiac function. Data of pharmacological postconditioning have been widely disappointing to date. Our study suggests a new pathway promoting myocardial postconditioning via Toll-like receptor activation.

Timely extracorporeal membrane oxygenation assist reduces mortality after bypass surgery in patients with acute myocardial infarction.

BACKGROUND: Patients with acute myocardial infarction (AMI) are at high risk when undergoing emergency coronary artery bypass graft (CABG)-surgery. Their outcome remains poor despite increased use of extracorporeal membrane oxygenation (ECMO). We investigated the impact of timing for perioperative ECMO-support in these patients. METHODS: In this retrospective double-center study, we evaluated 201 patients with AMI undergoing CABG, dividing them into the following groups: No-ECMO (n = 101), preoperative ECMO (pre-ECMO, n = 6), intraoperative ECMO (ECC-ECMO, n = 67), and postoperative ECMO (post-ECMO, n = 27). We evaluated the impact of ECMO timing on postoperative mortality, organ function, and length of stay, comparing these to predicted outcome using different risk-scores. RESULTS: Post-ECMO patients showed lowest 30-day-survival (40.7%), while earlier ECMO-start was associated with better outcome (50.7% in extracorporeal circulation [ECC]-ECMO and 66.7% in pre-ECMO patients). On admission, only pre-ECMO and ECC-ECMO patients showed higher surgery- and intensive-care-unit (ICU)-related risk-scores. In pre- and ECC-ECMO patients, the first significant increase in lactate-levels (>4 mmol/L) was observed preoperatively, while this occurred 1 hour postoperatively in post-ECMO patients. Bilirubin was increased in all patients, decreasing after 3 and 12 days in pre- and ECC-ECMO patients, respectively, but only after 18 days in post-ECMO patients. Multiple ICU risk-scores did not discriminate survival-probability correctly. Only the ECMO-related survival after veno-arterial-ECMO-score correctly predicted the significantly lower survival in post-ECMO patients. CONCLUSION: Our study shows that timely ECMO-support is associated with earlier bilirubin-downtrend and higher survival in patients with AMI after CABG. Lactate-increase greater than 4 mmol/L seems to be a helpful threshold to trigger the timely onset of ECMO-therapy, providing better survival.

Myocardial maladaptation to pressure overload in CB2 receptor-deficient mice.

BACKGROUND: Adaptation to aortic valve stenosis leads to myocardial hypertrophy, which has been associated with inflammation, fibrosis and activation of the endocannabinoid system. Since the endocannabinoid system and the CB2 receptor provide cardioprotection and modulate immune response in experimental ischemia, we investigated the role of CB2 in a mouse model of cardiac pressure overload. METHODS: Transverse aortic constriction was performed in CB2 receptor-deficient (Cnr2-/-) mice and their wild-type littermates (Cnr2+/+). After echocardiography and Millar left heart catheter hemodynamic evaluation hearts were processed for histological, cellular and molecular analyses. RESULTS: The endocannabinoid system showed significantly higher anandamide production and CB2 receptor expression in Cnr2+/+ mice. Histology showed non-confluent, interstitial fibrosis with rare small areas of cardiomyocyte loss in Cnr2+/+ mice. In contrast, extensive cardiomyocyte loss and confluent scar formation were found in Cnr2-/- mice accompanied by significantly increased apoptosis and left ventricular dysfunction when compared with Cnr2+/+ mice. The underlying cardiac maladaptation in Cnr2-/- mice was associated with significantly reduced expression of myosin heavy chain isoform beta and less production of heme oxygenase-1. Cnr2-/- hearts presented after 7 days with stronger proinflammatory response including significantly higher TNF-alpha expression and macrophage density, but lower density of CD4+ and B220+ cells. At the same time, we found increased apoptosis of macrophages and adaptive immune cells. Higher myofibroblast accumulation and imbalance in MMP/TIMP-regulation indicated adverse remodeling in Cnr2-/- mice. CONCLUSIONS: Our study provides mechanistic evidence for the role of the endocannabinoid system in myocardial adaptation to pressure overload in mice. The underlying mechanisms include production of anandamide, adaptation of contractile elements and antioxidative enzymes, and selective modulation of immune cells action and apoptosis in order to prevent the loss of cardiomyocytes.

CB2-deficiency is associated with a stronger hypertrophy and remodeling of the right ventricle in a murine model of left pulmonary artery occlusion.

AIMS: Pulmonary hypertension (PH) leads to right ventricular (RV) adaptation and remodeling and has deleterious long-term effects on RV function. The endocannabinoid receptor CB2 has been associated with protective effects in adaptation and remodeling of the left ventricle after ischemia. Therefore, we investigated the role of CB2 receptor in RV adaptation after occlusion of the left pulmonary artery (LPA) in a murine model. MAIN METHODS: C57/Bl6 (WT)- and CB2 receptor-deficient (Cnr2-/-)-mice underwent paramedian sternotomy and LPA was occluded using a metal clip. Right heart hemodynamic study (Millar®) preceded organ harvesting for immunohistochemistry and mRNA analysis 7 and 21 days (d) post-occlusion. KEY FINDINGS: LPA occlusion led to higher RV systolic pressure in Cnr2-/--hearts, while hemodynamics were comparable with WT-hearts after 21d. Cnr2-/--hearts showed higher macrophage infiltration and lower interleukin-10 expression after 7 d, but otherwise a comparable inflammatory mediator expression profile. Cardiomyocyte-hypertrophy was stronger in Cnr2-/--mice, presenting with higher tenascin-C expression than WT-hearts. Planimetry revealed higher collagen area in Cnr2-/--hearts and small areas of cardiomyocyte-loss. Surrounding cardiomyocytes were cleaved caspase-3- and TUNEL positive in Cnr2-/--hearts. This was associated by maladaptation of myosin heavy-chain isoforms and lower reactive oxygen scavenger enzymes induction in Cnr2-/--hearts. We found comparable morphological changes in both lungs between the two genotypes. SIGNIFICANCE: LPA occlusion led to increased systolic pressure and adaptation of RV in CB2-deficient mice. CB2 receptor seems to modulate RV adaptation through expression of contractile elements, reactive oxygen scavenger enzymes, and inflammatory response in order to prevent cardiomyocyte apoptosis.

Extracorporeal membrane oxygenation support in a newborn with lower urinary tract obstruction and pulmonary hypoplasia: a case report.

BACKGROUND: Survival of neonates with intrauterine renal insufficiency and oligo- or anhydramnios correlates with the severity of secondary pulmonary hypoplasia. Early prenatal diagnosis together with repetitive amnioinfusions and modern intensive care treatment have improved the prognosis of these neonates. Extracorporeal membrane oxygenation is an established treatment option, mainly applied to neonates with pulmonary hypoplasia caused by congenital diaphragmatic hernia. However, a few case reports of extracorporeal membrane oxygenation in neonates with lower urinary tract obstruction have been published. CASE PRESENTATION: We describe a case of a Caucasian male infant with prenatally diagnosed lower urinary tract obstruction and secondary pulmonary hypoplasia who was delivered spontaneously at 36 + 2 weeks of gestation. Venovenous extracorporeal membrane oxygenation was initiated on the first day of life for severe respiratory failure and consecutive hypoxemia despite treatment with inhaled nitric oxide and high-frequency oscillation. The patient was supported by extracorporeal membrane oxygenation for 10 days and extubated 6 weeks later. Hemofiltration was required on the second day of life because of renal insufficiency and was later replaced by peritoneal dialysis. The child was discharged after 4 months with nasal high-flow mild oxygen therapy and peritoneal dialysis. CONCLUSION: Neonatal extracorporeal membrane oxygenation support is a possible treatment option for neonates with lower urinary tract obstruction and pulmonary hypoplasia.

The provision of pediatric cardiac anesthesia services in Germany: current status of structural and personnel organization.

BACKGROUND: Anesthesia for pediatric cardiac surgery requires a high level of expert knowledge. There are currently no recommendations and standards for anesthetic management for congenital cardiac surgery in Germany. AIM: The aim of the present study was to assess the current status of structural and personnel anesthetic standards at pediatric cardiac surgery centers in Germany. METHODS: All cardiac surgical centers in Germany were reviewed for an active program for congenital heart surgery. Centers with an active program were invited to respond to an online survey. The questionnaire containing 55 items in 16 categories assessed current practice in pediatric cardiac anesthesia. RESULTS: An active program for pediatric cardiac surgery was identified at 27 centers. The response rate to the survey was 96.3%. A specialized group of anesthesiologists for pediatric cardiac anesthesia was reported from 26 centers (92.3%). The mean size of this group was 4.8 anesthesiologists per center. However, the annual case load of centers and relative annual case load per specialized anesthesiologist varied considerably between 12.5 and 250. Nonanesthesiologists performed sedation and general anesthesia for diagnostic and therapeutic interventions outside the operating theater in children with congenital heart diseases in 24 centers (77%). Although special equipment, for example, pediatric TEE, near-infrared spectroscopy, and devices for mechanical auto transfusion were available in most centers, their routine use was not always part of standard operating procedures. The proposal for mean adequate training in pediatric cardiac anesthesia as estimated by the participating centers was 10.8 months. CONCLUSION: The present study represents the current structural situation for anesthesia at German pediatric cardiac surgery centers.