Early Extracorporeal CPR for Refractory Out-of-Hospital Cardiac Arrest.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (CPR) restores perfusion and oxygenation in a patient who does not have spontaneous circulation. The evidence with regard to the effect of extracorporeal CPR on survival with a favorable neurologic outcome in refractory out-of-hospital cardiac arrest is inconclusive. METHODS: In this multicenter, randomized, controlled trial conducted in the Netherlands, we assigned patients with an out-of-hospital cardiac arrest to receive extracorporeal CPR or conventional CPR (standard advanced cardiac life support). Eligible patients were between 18 and 70 years of age, had received bystander CPR, had an initial ventricular arrhythmia, and did not have a return of spontaneous circulation within 15 minutes after CPR had been initiated. The primary outcome was survival with a favorable neurologic outcome, defined as a Cerebral Performance Category score of 1 or 2 (range, 1 to 5, with higher scores indicating more severe disability) at 30 days. Analyses were performed on an intention-to-treat basis. RESULTS: Of the 160 patients who underwent randomization, 70 were assigned to receive extracorporeal CPR and 64 to receive conventional CPR; 26 patients who did not meet the inclusion criteria at hospital admission were excluded. At 30 days, 14 patients (20%) in the extracorporeal-CPR group were alive with a favorable neurologic outcome, as compared with 10 patients (16%) in the conventional-CPR group (odds ratio, 1.4; 95% confidence interval, 0.5 to 3.5; P = 0.52). The number of serious adverse events per patient was similar in the two groups. CONCLUSIONS: In patients with refractory out-of-hospital cardiac arrest, extracorporeal CPR and conventional CPR had similar effects on survival with a favorable neurologic outcome. (Funded by the Netherlands Organization for Health Research and Development and Maquet Cardiopulmonary [Getinge]; INCEPTION ClinicalTrials.gov number, NCT03101787.).

Atrial epicardial adipose tissue abundantly secretes myeloperoxidase and activates atrial fibroblasts in patients with atrial fibrillation.

BACKGROUND: Epicardial adipose tissue (EAT) secretome induces fibrosis. Fibrosis, primarily extracellular matrix (ECM) produced by fibroblasts, creates a substrate for atrial fibrillation (AF). Whether the EAT secretome from patients with AF activates human atrial fibroblasts and through which components, remains unexplored. RESEARCH AIMS: (a) To investigate if the EAT secretome from patients with versus without AF increases ECM production in atrial fibroblasts. (b) To identify profibrotic proteins and processes in the EAT secretome and EAT from patients with, who will develop (future onset), and without AF. METHODS: Atrial EAT was obtainded during thoracoscopic ablation (AF, n = 20), or open-heart surgery (future onset and non-AF, n = 35). ECM gene expression of human atrial fibroblasts exposed to the EAT secretome and the proteomes of EAT secretome and EAT were assessed in patients with and without AF. Myeloperoxidase and neutrophil extracellular traps (NETs) were assessed immunohistochemically in patients with paroxysmal, persistent, future onset, and those who remain free of AF (non-AF). RESULTS: The expression of COL1A1 and FN1 in fibroblasts exposed to secretome from patients with AF was 3.7 and 4.7 times higher than in patients without AF (p < 0.05). Myeloperoxidase was the most increased protein in the EAT secretome and EAT from patients with versus without AF (FC 18.07 and 21.57, p < 0.005), as was the gene-set neutrophil degranulation. Immunohistochemically, myeloperoxidase was highest in persistent (FC 13.3, p < 0.0001) and increased in future onset AF (FC 2.4, p = 0.02) versus non-AF. Myeloperoxidase aggregated subepicardially and around fibrofatty infiltrates. NETs were increased in patients with persistent versus non-AF (p = 0.03). CONCLUSION: In AF, the EAT secretome induces ECM gene expression in atrial fibroblasts and contains abundant myeloperoxidase. EAT myeloperoxidase was increased prior to AF onset, and both myeloperoxidase and NETs were highest in persistent AF, highlighting the role of EAT neutrophils in the pathophysiology of AF.

MicroRNAs in atrial fibrillation target genes in structural remodelling.

We aim to elucidate how miRNAs regulate the mRNA signature of atrial fibrillation (AF), to gain mechanistic insight and identify candidate targets for future therapies. We present combined miRNA-mRNA sequencing using atrial tissues of patient without AF (n = 22), with paroxysmal AF (n = 22) and with persistent AF (n = 20). mRNA sequencing previously uncovered upregulated epithelial to mesenchymal transition, endothelial cell proliferation and extracellular matrix remodelling involving glycoproteins and proteoglycans in AF. MiRNA co-sequencing discovered miRNAs regulating the mRNA expression changes. Key downregulated miRNAs included miR-135b-5p, miR-138-5p, miR-200a-3p, miR-200b-3p and miR-31-5p and key upregulated miRNAs were miR-144-3p, miR-15b-3p, miR-182-5p miR-18b-5p, miR-4306 and miR-206. MiRNA expression levels were negatively correlated with the expression levels of a multitude of predicted target genes. Downregulated miRNAs associated with increased gene expression are involved in upregulated epithelial and endothelial cell migration and glycosaminoglycan biosynthesis. In vitro inhibition of miR-135b-5p and miR-138-5p validated an effect of miRNAs on multiple predicted targets. Altogether, the discovered miRNAs may be explored in further functional studies as potential targets for anti-fibrotic therapies in AF.

Persistent phrenic nerve palsy after atrial fibrillation ablation: Follow-up data from The Netherlands Heart Registration.

BACKGROUND: Persistent phrenic nerve palsy (PNP) is an established complication of atrial fibrillation (AF) ablation, especially during cryoballoon and thoracoscopic ablation. Data on persistent PNP reversibility is limited because most patients recover <24 h. This study aims to investigate persistent PNP recovery, freedom of PNP-related symptoms after AF ablation and identify baseline variables associated with the occurrence and early PNP recovery in a large nationwide registry study. METHODS: In this study, we used data from the Netherlands Heart Registration, comprising data from 9549 catheter and thoracoscopic AF ablations performed in 2016 and 2017. PNP data was available of 7433 procedures, and additional follow-up data were collected for patients who developed persistent PNP. RESULTS: Overall, the mean age was 62 ± 10 years, and 67.7% were male. Fifty-four (0.7%) patients developed persistent PNP and follow-up was available in 44 (81.5%) patients. PNP incidence was 0.07%, 0.29%, 1.41%, and 1.25%, respectively for patients treated with conventional-RF, phased-RF, cryoballoon, and thoracoscopic ablation respectively. Seventy-one percent of the patients fully recovered, and 86% were free of PNP-related symptoms after a median follow-up of 203 (113-351) and 184 (82-359) days, respectively. Female sex, cryoballoon, and thoracoscopic ablation were associated with a higher risk to develop PNP. Patients with PNP recovering ≤180 days had a larger left atrium volume index than those with late or no recovery. CONCLUSION: After AF ablation, persistent PNP recovers in the majority of patients, and most are free of symptoms. Female patients and patients treated with cryoballoon or thoracoscopic ablation are more prone to develop PNP.

Autologous red blood cell transfusion does not result in a more profound increase in pulmonary capillary wedge pressure compared to saline in critically ill patients: A randomized crossover trial.

BACKGROUND AND OBJECTIVES: Transfusion-associated circulatory overload (TACO) is a major cause of severe transfusion-related morbidity. Transfusion of red blood cells (RBCs) has been shown to induce hydrostatic pressure overload. It is unclear which product-specific factors contribute. We set out to determine the effect of autologous RBC transfusion versus saline on pulmonary capillary wedge pressure (PCWP) change. MATERIALS AND METHODS: In a randomized crossover trial, patients who had undergone coronary bypass surgery were allocated to treatment post-operatively in the intensive care unit with either an initial 300 ml autologous RBC transfusion (salvaged during surgery) or 300 ml saline infusion first, followed by the other. Primary outcome was the difference in PCWP change. Secondary outcome measures were the difference in extra-vascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI). RESULTS: Change in PCWP was not higher after autologous RBC transfusion compared to saline (ΔPCWP 0.3 ± 0.4 vs. 0.1 ± 0.4 mmHg). ΔEVLWI and ΔPVPI were significantly decreased after autologous RBC transfusion compared to saline (ΔEVLWI -1.6 ± 0.6 vs. 0.2 ± 0.4, p = 0.02; ΔPVPI -0.3 ± 0.1 vs. 0.0 ± 0.1, p = 0.01). Haemodynamic variables and colloid osmotic pressure were not different for autologous RBC transfusion versus saline. CONCLUSION: Transfusion of autologous RBCs did not result in a more profound increase in PCWP compared to saline. RBC transfusion resulted in a decrease of EVLWI and PVPI compared to saline. Our data suggest that transfusing autologous RBCs may lead to less pulmonary oedema compared to saline. Future studies with allogeneic RBCs are needed to investigate other factors that may mediate the increase of PCWP, resulting in TACO.

Perioperative Care Standards in Cardiac Surgery Patients Aiming at Enhancing Recovery: A Nationwide Survey in the Netherlands and Belgium.

OBJECTIVE: The aim of this survey was to describe existing perioperative care standards and best practices in the Netherlands and Belgium. DESIGN: An online survey was followed up by an in-depth personal interview. The main outcomes were the existing standards of perioperative care for patients undergoing cardiac surgery. SETTING: The online survey and subsequent interviews were targeted to one representative in the intensive care unit (ICU), cardiac surgery, and anesthesiology department from each cardiac surgical center in the Netherlands and Belgium. PARTICIPANTS: A representative intensive care physician, cardiac surgeon, and cardiac anesthesiologist. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The response rate was 60% (71% for the Netherlands, and 44% in Belgium). Agreement across centers was found for discontinuation of proton-pump inhibitors (80%) and avoiding intra- and postoperative (92%) nonsteroidal antiinflammatory drugs. Additionally, 98% of respondents stated that physiotherapy should be started immediately in the ICU. Major divergence was found for elements such as the discontinuation of angiotensin-converting enzyme inhibitors (55%) or the postoperative use of chest support vests (44%). CONCLUSIONS: The authors demonstrated a wide range of different local protocols. Strategies differed among disciplines, hospitals, and countries. This emphasized the need for the implementation of a more universal protocol to further reduce variance and improve recovery practices. This nationwide survey was the first of its kind simultaneously studying best practices for cardiac surgery through the entire care pathway at the advent of Enhanced Recovery After Surgery (ERAS) Cardiac implementation. A multinational randomized controlled trial to test the implementation of an evidence-based ERAS Cardiac protocol is the next step to pave the way for further outcome improvements in this high-risk population.

Complications in pulmonary vein isolation in the Netherlands Heart Registration differ with sex and ablation technique.

AIMS: Pulmonary vein isolation (PVI) has become a cornerstone of the invasive treatment of atrial fibrillation. Severe complications are reported in 1-3% of patients. This study aims to compare complications and follow-up outcome of PVI in patients with atrial fibrillation. METHODS AND RESULTS: The data were extracted from the Netherlands Heart Registration. Procedural and follow-up outcomes in patients treated with conventional radiofrequency (C-RF), multielectrode phased RF (Ph-RF), or cryoballoon (CB) ablation from 2012 to 2017 were compared. Subgroup analysis was performed to identify variables associated with complications and repeat ablations. In total, 13 823 patients (69% male) were included. The reported complication incidence was 3.6%. Patients treated with C-RF developed more cardiac tamponades (C-RF 0.8% vs. Ph-RF 0.3% vs. CB 0.3%, P ≤ 0.001) and vascular complications (C-RF 1.7% vs. Ph-RF 1.2% vs. CB 1.3%, P ≤ 0.001). Ph-RF was associated with fewer bleeding complications (C-RF: 1.0% vs. Ph-RF: 0.4% vs. CB: 0.7%, P = 0.020). Phrenic nerve palsy mainly occurred in patients treated with CB (C-RF: 0.1% vs. Ph-RF: 0.2% vs. CB: 1.5%, P ≤ 0.001). In total, 18.4% of patients were referred for repeat ablation within 1 year. Female sex, age, and CHA2DS2-VASc were independent risk factors for cardiac tamponade and bleeding complications, with an adjusted OR for female patients of 2.97 (95% CI 1.98-4.45) and 2.02 (95% CI 1.03-4.00) respectively. CONCLUSION: The reported complication rate during PVI was low. Patients treated with C-RF ablation were more likely to develop cardiac tamponades and vascular complications. Female sex was associated with more cardiac tamponade and bleeding complications.

Early initiation of extracorporeal life support in refractory out-of-hospital cardiac arrest: Design and rationale of the INCEPTION trial.

Return of spontaneous circulation occurs in less than 10% of patients with cardiac arrest undergoing cardiopulmonary resuscitation (CPR) for more than 15 minutes. Studies suggest that extracorporeal life support during cardiopulmonary resuscitation (ECPR) improves survival rate in these patients. These studies, however, are hampered by their non-randomized, observational design and are mostly single-center. A multicenter, randomized controlled trial is urgently warranted to evaluate the effectiveness of ECPR. HYPOTHESIS: We hypothesize that early initiation of ECPR in refractory out-of-hospital cardiac arrest (OHCA) improves the survival rate with favorable neurological status. STUDY DESIGN: The INCEPTION trial is an investigator-initiated, prospective, multicenter trial that will randomly allocate 110 patients to either continued CPR or ECPR in a 1:1 ratio. Patients eligible for inclusion are adults (≤ 70 years) with witnessed OHCA presenting with an initial rhythm of ventricular fibrillation (VF) or ventricular tachycardia (VT), who received bystander basic life support and who fail to achieve sustained return of spontaneous circulation within 15 minutes of cardiopulmonary resuscitation by emergency medical services. The primary endpoint of the study is 30-day survival rate with favorable neurological status, defined as 1 or 2 on the Cerebral Performance Category score. The secondary endpoints include 3, 6 and 12-month survival rate with favorable neurological status and the cost-effectiveness of ECPR compared to CCPR. SUMMARY: The INCEPTION trial aims to determine the clinical benefit for the use of ECPR in patients with refractory OHCA presenting with VF/VT. Additionally, the feasibility and cost-effectiveness of ECPR will be evaluated.

Absence of Functional Nav1.8 Channels in Non-diseased Atrial and Ventricular Cardiomyocytes.

PURPOSE: Several studies have indicated a potential role for SCN10A/NaV1.8 in modulating cardiac electrophysiology and arrhythmia susceptibility. However, by which mechanism SCN10A/NaV1.8 impacts on cardiac electrical function is still a matter of debate. To address this, we here investigated the functional relevance of NaV1.8 in atrial and ventricular cardiomyocytes (CMs), focusing on the contribution of NaV1.8 to the peak and late sodium current (INa) under normal conditions in different species. METHODS: The effects of the NaV1.8 blocker A-803467 were investigated through patch-clamp analysis in freshly isolated rabbit left ventricular CMs, human left atrial CMs and human-induced pluripotent stem cell-derived CMs (hiPSC-CMs). RESULTS: A-803467 treatment caused a slight shortening of the action potential duration (APD) in rabbit CMs and hiPSC-CMs, while it had no effect on APD in human atrial cells. Resting membrane potential, action potential (AP) amplitude, and AP upstroke velocity were unaffected by A-803467 application. Similarly, INa density was unchanged after exposure to A-803467 and NaV1.8-based late INa was undetectable in all cell types analysed. Finally, low to absent expression levels of SCN10A were observed in human atrial tissue, rabbit ventricular tissue and hiPSC-CMs. CONCLUSION: We here demonstrate the absence of functional NaV1.8 channels in non-diseased atrial and ventricular CMs. Hence, the association of SCN10A variants with cardiac electrophysiology observed in, e.g. genome wide association studies, is likely the result of indirect effects on SCN5A expression and/or NaV1.8 activity in cell types other than CMs.

The change in circulating galectin-3 predicts absence of atrial fibrillation after thoracoscopic surgical ablation.

Aims: Galectin-3 (Gal-3) is an important mediator of cardiac fibrosis, particularly in heart failure. Increased Gal-3 concentration (Gal-3), associated with increased risk of developing atrial fibrillation (AF), may reflect atrial fibrotic remodelling underlying AF progression. We aimed to investigate whether the change in serum Gal-3 reflects alterations of the arrhythmogenic atrial substrate following thoracoscopic AF surgery, and predicts absence of AF. Methods and results: Consecutive patients undergoing thoracoscopic AF surgery were included. Left atrial appendages (LAAs) and serum were collected during surgery and serum again 6 months thereafter. Gal-3 was determined in tissue and serum. Interstitial collagen in the LAA was quantified using Picrosirius red staining. Ninety-eight patients (76% male, mean age 60 ± 9 years) underwent thoracoscopic surgery for advanced AF. Patients with increased Gal-3 after ablation compared to baseline had a higher recurrence rate compared to patients with decreased or unchanged Gal-3 (HR 2.91, P = 0.014). These patients more frequently had persistent AF, longer AF duration and thick atrial collagen strands (P = 0.049). At baseline, Gal-3 was similar between patients with and without AF recurrence: 14.8 ± 3.9 µg/L vs. 13.7 ± 3.7 µg/L, respectively in serum (P = 0.16); 94.5 ± 19.4 µg/L vs. 93.3 ± 30.8µg/L, respectively in atrial myocardium (P = 0.83). There was no correlation between serum Gal-3 and left atrial Gal-3 (P = 0.20), nor between serum Gal-3 and the percentage of fibrosis in LAA (P = 0.18). Conclusion: The change of circulating Gal-3, rather than its baseline value, predicts AF recurrence after thoracoscopic ablation. Patients in whom Gal-3 increases after ablation have a high recurrence rate reflecting ongoing profibrotic signalling, irrespective of arrhythmia continuation.

Assessment of the Extravascular Implantable Defibrillator: Feasibility of Substernal Ventricular Pacing.

INTRODUCTION: The objective of this study was to assess feasibility of ventricular pacing and thresholds from within the substernal space to examine a new extravascular ICD configuration with pacing capabilities. METHODS: In patients undergoing midline sternotomy, a duodecapolar diagnostic pacing catheter was positioned in the substernal space anterior to the pericardium, and a cutaneous patch in left lateral position. Different unipolar and bipolar pacing configurations were assessed. Strength-duration curves were performed to identify the optimal output, starting at 25 mA with a pulse width of 10 milliseconds. RESULTS: Eight patients with mean age 69 ± 9 years were included. In 5, ventricular capture was achieved in ≥1 configuration. The mean bipolar pacing thresholds at PW 10, 5, 3, 1 milliseconds were 12.4 ± 3.7 mA (5 patients), 13.3 ± 5.8 mA (3 patients), 18.3 ± 5.7 mA (3 patients), and 25 ± 0 mA (2 patients), respectively. The 60-mm electrode spacing was the most successful bipolar configuration. Unipolar pacing was successful in 3 out of 4 patients with mean thresholds of 10 ± 0 mA at 10 milliseconds (3 patients), 15 ± 0 mA at 5 milliseconds (3 patients), 16.7 ± 2.9 mA at 3 milliseconds (3 patients), and 20 ± 7.1 mA at 1 milliseconds (2 patients). CONCLUSION: Ventricular pacing from the substernal space in patients with midline sternotomy is feasible. Closed sternum studies are needed to determine pacing thresholds more accurately.

Primary cilia suppress the fibrotic activity of atrial fibroblasts from patients with atrial fibrillation in vitro.

Atrial fibrosis serves as an arrhythmogenic substrate in atrial fibrillation (AF) and contributes to AF persistence. Treating atrial fibrosis is challenging because atrial fibroblast activity is multifactorial. We hypothesized that the primary cilium regulates the profibrotic response of AF atrial fibroblasts, and explored therapeutic potentials of targeting primary cilia to treat fibrosis in AF. We included 25 patients without AF (non-AF) and 26 persistent AF patients (AF). Immunohistochemistry using a subset of the patients (non-AF: n = 10, AF: n = 10) showed less ciliated fibroblasts in AF versus non-AF. Acetylated α-tubulin protein levels were decreased in AF, while the gene expressions of AURKA and NEDD9 were highly increased in AF patients' left atrium. Loss of primary cilia in human atrial fibroblasts through IFT88 knockdown enhanced expression of ECM genes, including FN1 and COL1A1. Remarkably, restoration or elongation of primary cilia by an AURKA selective inhibitor or lithium chloride, respectively, prevented the increased expression of ECM genes induced by different profibrotic cytokines in atrial fibroblasts of AF patients. Our data reveal a novel mechanism underlying fibrotic substrate formation via primary cilia loss in AF atrial fibroblasts and suggest a therapeutic potential for abrogating atrial fibrosis by restoring primary cilia.

Doxycycline induces mitochondrial dysfunction in aortic smooth muscle cells.

The antibiotic doxycycline is known to inhibit inflammation and was therefore considered as a therapeutic to prevent abdominal aortic aneurysm (AAA) growth. Yet mitochondrial dysfunction is a key-characteristic of clinical AAA disease. We hypothesize that doxycycline impairs mitochondrial function in the aorta and aortic smooth muscle cells (SMCs). Doxycycline induced mitonuclear imbalance, reduced proliferation and diminished expression of typical contractile smooth muscle cell (SMC) proteins. To understand the underlying mechanism, we studied krüppel-like factor 4 (KLF4). The expression of this transcription factor was enhanced in SMCs after doxycycline treatment. Knockdown of KLF4, however, did not affect the doxycycline-induced SMC phenotypic changes. Then we used the bioenergetics drug elamipretide (SS-31). Doxycycline-induced loss of SMC contractility markers was not rescued, but mitochondrial genes and mitochondrial connectivity improved upon elamipretide. Thus while doxycycline is anti-inflammatory, it also induces mitochondrial dysfunction in aortic SMCs and causes SMC phenotypic switching, potentially contributing to aortic aneurysm pathology. The drug elamipretide helps mitigate the harmful effects of doxycycline on mitochondrial function in aortic SMC, and may be of interest for treatment of aneurysm diseases with pre-existing mitochondrial dysfunction.

Minimised closed circuit coronary artery bypass grafting in the elderly is associated with lower levels of organ-specific biomarkers: a prospective randomised study.

BACKGROUND: Restrictive fluid management may protect organ function and improve postoperative outcome in elderly coronary artery bypass grafting (CABG) patients. OBJECTIVE: We assessed organ-specific biomarker release to study the contribution of a fluid restrictive closed circuit concept to organ protection in elderly CABG patients. Cardiac, respiratory and abdominal organ injury was measured during and following minimal fluid coronary artery bypass grafting (mCABG), off-pump coronary artery bypass (opCAB) surgery and conventional CABG with high volume prime and cold crystalloid cardioplegia (cCABG). The results were related to differences in clinical outcome. DESIGN: Prospective randomised trial. SETTING: Dutch tertiary single centre study. PATIENTS: Sixty patients over 70 years of age (38 men and 22 women) were randomised to one of the three different techniques. Inclusion criteria were as follows: first time CABG, elective surgery, ejection fraction more than 30% and multivessel disease. Acetylsalicylic acid and clopidogrel administration or requiring less than three distal anastomoses were an exclusion. MAIN OUTCOME MEASURES: Organ-specific markers of the heart--heart fatty acid binding protein (HFABP), troponin T, pro-brain natriuretic peptide (pro-BNP) and creatinine phosphokinase (CPK), lung clara cell 16 protein, pneumoprotein (CC16), intestinal fatty acid binding protein (IFABP) and liver glutathione S-transferase (α-GST)--were measured perioperatively. Postoperative PaO2 levels, ventilation time, blood product consumption and adverse events were noted. RESULTS: Myocardial organ-specific biomarker troponin T showed significantly lower median levels during mCABG compared with the cCABG and opCAB groups [troponin 0.25 mg l(-1) (interquartile range, IQR 0.18 to 0.40), 0.39 mg l(-1) (IQR 0.23 to 0.49) and 0.36 mg l(-1) (IQR 0.23 to 0.50), respectively (P<0.003)]. HFABP, IFABP and α-GST levels were significantly higher during cCABG compared with opCAB and mCABG [HFABP 38.6 mg l(-1) (IQR 29.6 to 47.1), 23.3 mg l(-1) (IQR 16.5 to 31.0) and 21.1 mg l(-1) (IQR 15.7 to 28.8; P<0.001), IFABP 0.57 mg l(-1) (IQR 0.37 to 1.11), 0.44 mg l(-1) (IQR 0.16 to 0.74) and 0.37 mg l(-1) (IQR 0.13 to 1.05; P<0.02) and α-GST 11.5 mg l(-1) (IQR 7.7 to 15.7), 7.0 mg l(-1) (IQR 4.5 to 13.8) and 7.3 mg l(-1) (IQR 6.2 to 11.2), respectively (P<0.009)]. There was a trend towards higher median CC16 levels in the cCABG group (P<0.07). CPK and pro-BNP were not significantly different. On the first postoperative day, PaO2 levels and duration of mechanical ventilation were significantly improved, and there was lower use of blood products in the mCABG group than in the cCABG and opCAB groups (P<0.05). CONCLUSION: Following mCABG with low volume myocardial preservation and restrictive fluid management, early respiratory performance was improved and consumption of blood products reduced compared with opCAB and cCABG.

Timing and mid-term outcomes of using leadless pacemakers as replacement for infected cardiac implantable electronic devices.

BACKGROUND: Cardiac implantable electronic device (CIED) infections have a high morbidity and mortality and are an indication of device extraction. As a replacement, leadless pacemakers (LPs) may be preferable due to a low infection risk, but mid-term data on reinfections is lacking. Moreover, early LP reimplantation in pacemaker-dependent patients would circumvent the need for temporary pacemakers. METHODS: We included all patients with LP implantation as a replacement for an infected CIED, between January 2013 and December 2021. The occurrence of reinfection was assessed during standard follow-up visits. RESULTS: Twenty-nine patients (mean age 81 ± 9 years) were included, of which 21 (73%) had a pocket infection, 7 (24%) endocarditis, and 1 (3%) a systemic infection without endocarditis. All LP implantations were successful. LPs were implanted before extraction (n = 4, 13%), simultaneously with extraction (n = 5, 17%) and after extraction (n = 20, 70%). No reinfection occurred during the follow-up of median 32 months (IQR 13-66 months). Repeat blood cultures obtained in 9 (30%) patients and transthoracic echocardiography in all 7 patients with pacemaker endocarditis were negative for reinfection. In a subset of 6 LPs extracted during follow-up due to early battery depletion, prophylactically after the battery advisory or due to non-capture (median 36 months (range 0-67 months) post-implantation), histopathologic examination of tissues around the LPs showed no signs of infection. CONCLUSIONS: After replacing infected CIEDs for an LP, no reinfections occurred in over 2.5 years follow-up. These results confirm that in case of CIED infection, the LP is an appealing replacement device. LP implantation before CIED extraction is feasible.

Differential Sodium Current Remodelling Identifies Distinct Cellular Proarrhythmic Mechanisms in Paroxysmal vs Persistent Atrial Fibrillation.

BACKGROUND: The cellular mechanisms underlying progression from paroxysmal to persistent atrial fibrillation (AF) are not fully understood, but alterations in (late) sodium current (INa) have been proposed. Human studies investigating electrophysiological changes at the paroxysmal stage of AF are sparse, with the majority employing right atrial appendage cardiomyocytes (CMs). We here investigated action potential (AP) characteristics and (late) INa remodelling in left atrial appendage CMs (LAA-CMs) from patients with paroxysmal and persistent AF and patients in sinus rhythm (SR), as well as the potential contribution of the "neuronal" sodium channel SCN10A/NaV1.8. METHODS: Peak INa, late INa and AP properties were investigated through patch-clamp analysis on single LAA-CMs, whereas quantitative polymerase chain reaction was used to assess SCN5A/SCN10A expression levels in LAA tissue. RESULTS: In paroxysmal and persistent AF LAA-CMs, AP duration was shorter than in SR LAA-CMs. Compared with SR, peak INa and SCN5A expression were significantly decreased in paroxysmal AF, whereas they were restored to SR levels in persistent AF. Conversely, although late INa was unchanged in paroxysmal AF compared with SR, it was significantly increased in persistent AF. Peak or late Nav1.8-based INa was not detected in persistent AF LAA-CMs. Similarly, expression of SCN10A was not observed in LAAs at any stage. CONCLUSIONS: Our findings demonstrate differences in (late) INa remodeling in LAA-CMs from patients with paroxysmal vs persistent AF, indicating distinct cellular proarrhythmic mechanisms in different AF forms. These observations are of particular relevance when considering potential pharmacologic approaches targeting (late) INa in AF.

A failed catheter ablation of atrial fibrillation is associated with more advanced remodeling and reduced efficacy of further thoracoscopic ablation.

INTRODUCTION AND OBJECTIVES: Recent observations suggest that patients with a previous failed catheter ablation have an increased risk of atrial fibrillation (AF) recurrence after subsequent thoracoscopic AF ablation. We assessed the risk of AF recurrence in patients with a previous failed catheter ablation undergoing thoracoscopic ablation. METHODS: We included patients from 3 medical centers. To correct for potential heterogeneity, we performed propensity matching to compare AF freedom (freedom from any atrial tachyarrhythmia> 30 s during 1-year follow-up). Left atrial appendage tissue was analyzed for collagen distribution. RESULTS: A total of 705 patients were included, and 183 had a previous failed catheter ablation. These patients had fewer risk factors for AF recurrence than ablation naïve controls: smaller indexed left atrial volume (40.9± 12.5 vs 43.0±12.5 mL/m2, P=.048), less congestive heart failure (1.5% vs 8.9%, P=.001), and less persistent AF (52.2% vs 60.3%, P=.067). However, AF history duration was longer in patients with a previous failed catheter ablation (6.5 [4-10.5] vs 4 [2-8] years; P<.001). In propensity matched analysis, patients with a failed catheter ablation were at a 68% higher AF recurrence risk (OR, 1.68; 95%CI, 1.20-2.15; P=.034). AF freedom was 61.1% in patients with a previous failed catheter ablation vs 72.5% in ablation naïve matched controls. On histology of the left atrial appendage (n=198), patients with a failed catheter ablation had a higher density of collagen fibers. CONCLUSIONS: Patients with a prior failed catheter ablation had fewer risk factors for AF recurrence but more frequently had AF recurrence after thoracoscopic AF ablation than ablation naïve patients. This may in part be explained by more progressed, subclinical, atrial fibrosis formation.

Effect of the machine learning-derived Hypotension Prediction Index (HPI) combined with diagnostic guidance versus standard care on depth and duration of intraoperative and postoperative hypotension in elective cardiac surgery patients: HYPE-2 - study protocol of a randomised clinical trial.

INTRODUCTION: Hypotension is common during cardiac surgery and often persists postoperatively in the intensive care unit (ICU). Still, treatment is mainly reactive, causing a delay in its management. The Hypotension Prediction Index (HPI) can predict hypotension with high accuracy. Using the HPI combined with a guidance protocol resulted in a significant reduction in the severity of hypotension in four non-cardiac surgery trials. This randomised trial aims to evaluate the effectiveness of the HPI in combination with a diagnostic guidance protocol on reducing the occurrence and severity of hypotension during coronary artery bypass grafting (CABG) surgery and subsequent ICU admission. METHODS AND ANALYSIS: This is a single-centre, randomised clinical trial in adult patients undergoing elective on-pump CABG surgery with a target mean arterial pressure of 65 mm Hg. One hundred and thirty patients will be randomly allocated in a 1:1 ratio to either the intervention or control group. In both groups, a HemoSphere patient monitor with embedded HPI software will be connected to the arterial line. In the intervention group, HPI values of 75 or above will initiate the diagnostic guidance protocol, both intraoperatively and postoperatively in the ICU during mechanical ventilation. In the control group, the HemoSphere patient monitor will be covered and silenced. The primary outcome is the time-weighted average of hypotension during the combined study phases. ETHICS AND DISSEMINATION: The medical research ethics committee and the institutional review board of the Amsterdam UMC, location AMC, the Netherlands, approved the trial protocol (NL76236.018.21). No publication restrictions apply, and the study results will be disseminated through a peer-reviewed journal. TRIAL REGISTRATION NUMBER: The Netherlands Trial Register (NL9449), ClinicalTrials.gov (NCT05821647).

Women Have More Recurrences of Atrial Fibrillation than Men after Thoracoscopic Ablation and Suffer More from Established Risk Factors.

INTRODUCTION: Atrial fibrillation (AF) is more prevalent in men than in women. However, women with AF are more symptomatic, have a worse quality of life, a higher stroke risk and may therefore benefit most from ablation. In this study we aim to identify the risk of recurrent AF after thoracoscopic ablation, and assess the differential impact of the risk factors for recurrence between women and men. METHOD: This is a single center cohort study, including patients undergoing thoracoscopic ablation for advanced AF between 2008 and 2019. All patients were clinically followed up for two years with quarterly 24 h Holter monitoring and ECGs for the detection of recurrent AF. Left atrial appendage (LAA) tissue was collected for collagen analysis. RESULTS: We included 571 patients, of whom 143 (25%) were women. Women were older than men (63 ± 8.3 y vs. 59 ± 8.5, p < 0.001), but had fewer cardiovascular risk factors, myocardial infarctions (1.4% vs. 6.5%, p = 0.03) and, in particular, vascular disease (7.0% vs. 16.1%, p = 0.01). Women suffered more from AF recurrence, driven by more atrial tachycardias, and sex was an independent risk factor for recurrence (HR1.41 [1.04-1.91], p = 0.028]). The presence of vascular disease was associated with an increased risk for AF recurrence in women, but not in men. In LAA histology, women had more collagen than men, as had patients with persistent compared to paroxysmal AF. CONCLUSION: Women had 15% more recurrences, driven by more atrial tachycardias, which may be explained by a more fibrotic atrial substrate. What's new? Women undergoing thoracoscopic AF ablation have a higher risk of recurrent AF, driven by more atrial tachycardias. Among patients with left atrial enlargement or persistent AF, women have worse outcomes than men. Vascular disease was a risk factor for recurrence in women, but not in men. In a histopathologic analysis of the left atrial appendage, women had more collagen than men, as had patients with persistent compared to paroxysmal AF.

MicroRNAs in extracellular vesicles released from epicardial adipose tissue promote arrhythmogenic conduction slowing.

Background: Patients with excess epicardial adipose tissue (EAT) are at increased risk of developing cardiac arrhythmias. EAT promotes arrhythmias by depolarizing the resting membrane of cardiomyocytes, which slows down conduction and facilitates re-entrant arrhythmias. We hypothesized that EAT slows conduction by secreting extracellular vesicles (EVs) and their microRNA (miRNA) cargo. Objective: We aimed to determine the role of EAT-derived EVs and their miRNA cargo in conduction slowing. Methods: EAT and subcutaneous adipose tissue (SAT) were collected from patients with atrial fibrillation. Adipose tissue explants were incubated in culture medium and secretome was collected. The numbers of EVs in the EAT and SAT secretome were measured by calibrated flow cytometry. EVs in the EAT secretome were isolated by size exclusion chromatography and miRNAs were sequenced. Pathway analysis was performed to predict candidates involved in cardiac electrophysiology. The candidates were validated in the EAT and SAT by quantitative real-time polymerase chain reaction. Finally, miRNA candidates were overexpressed in neonatal rat ventricular myocytes. Results: The EV concentration was higher in the EAT secretome than in the SAT and control secretomes. miRNA sequencing of EAT-derived EVs detected a total of 824 miRNAs. Pathway analysis led to the identification of 7 miRNAs potentially involved in regulation of cardiac resting membrane potential. Validation of those miRNA candidates showed that they were all expressed in EAT, and that miR-1-3p and miR-133a-3p were upregulated in EAT in comparison with SAT. Overexpression of miR-1-3p and miR-133a-3p in neonatal rat ventricular myocytes led to conduction slowing and reduced Kcnj2 and Kcnj12 expression. Conclusion: miR-1-3p and miR-133a-3p are potential mediators of EAT arrhythmogenicity.