Anticoagulation for post-operative atrial fibrillation after isolated coronary artery bypass grafting: a meta-analysis.

BACKGROUND AND AIMS: This study aimed to evaluate clinical outcomes in patients developing post-operative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG) and characterize variations in oral anticoagulation (OAC) use, benefits, and complications. METHODS: A systematic search identified studies on new-onset POAF after CABG and OAC initiation. Outcomes included risks of thromboembolic events, bleeding, and mortality. Furthermore, a meta-analysis was conducted on these outcomes, stratified by the use or non-use of OAC. RESULTS: The identified studies were all non-randomized. Among 1 698 307 CABG patients, POAF incidence ranged from 7.9% to 37.6%. Of all POAF patients, 15.5% received OAC. Within 30 days, thromboembolic events occurred at rates of 1.0% (POAF: 0.3%; non-POAF: 0.8%) with 2.0% mortality (POAF: 1.0%; non-POAF: 0.5%). Bleeding rates were 1.1% for POAF patients and 2.7% for non-POAF patients. Over a median of 4.6 years, POAF patients had 1.73 thromboembolic events, 3.39 mortality, and 2.00 bleeding events per 100 person-years; non-POAF patients had 1.14, 2.19, and 1.60, respectively. No significant differences in thromboembolic risks [effect size -0.11 (-0.36 to 0.13)] and mortality [effect size -0.07 (-0.21 to 0.07)] were observed between OAC users and non-users. However, OAC use was associated with higher bleeding risk [effect size 0.32 (0.06-0.58)]. CONCLUSIONS: In multiple timeframes following CABG, the incidence of complications in patients who develop POAF is low. The use of OAC in patients with POAF after CABG is associated with increased bleeding risk.

Light transmittance in human atrial tissue and transthoracic illumination in rats support translatability of optogenetic cardioversion of atrial fibrillation.

BACKGROUND: Optogenetics could offer a solution to the current lack of an ambulatory method for the rapid automated cardioversion of atrial fibrillation (AF), but key translational aspects remain to be studied. OBJECTIVE: To investigate whether optogenetic cardioversion of AF is effective in the aged heart and whether sufficient light penetrates the human atrial wall. METHODS: Atria of adult and aged rats were optogenetically modified to express light-gated ion channels (i.e., red-activatable channelrhodopsin), followed by AF induction and atrial illumination to determine the effectivity of optogenetic cardioversion. The irradiance level was determined by light transmittance measurements on human atrial tissue. RESULTS: AF could be effectively terminated in the remodeled atria of aged rats (97%, n = 6). Subsequently, ex vivo experiments using human atrial auricles demonstrated that 565-nm light pulses at an intensity of 25 mW/mm2 achieved the complete penetration of the atrial wall. Applying such irradiation onto the chest of adult rats resulted in transthoracic atrial illumination as evidenced by the optogenetic cardioversion of AF (90%, n = 4). CONCLUSION: Transthoracic optogenetic cardioversion of AF is effective in the aged rat heart using irradiation levels compatible with human atrial transmural light penetration.

Optimal antegrade cerebral perfusion flow in patients undergoing surgery for acute type A aortic dissection: A retrospective single-center analysis.

BACKGROUND: Systemic hypothermia with bilateral antegrade selective cerebral perfusion (ASCP) is the preferred cerebral protective strategy for type A aortic dissection surgery. The optimal ASCP flow rate remains uncertain and the target flow cannot always be reached due to pressure limitations. The aim of this study was to assess the correlation between ASCP flow and regional cerebral oxygen saturation (rSO2). METHODS: A retrospective analysis was performed on 140 patients with acute type A aortic dissection who underwent surgery with moderate hypothermic circulatory arrest and bilateral ASCP between 2015 and 2021. Pearson correlation analysis was performed between ASCP flow and rSO2. RESULTS: The median circulatory arrest duration was 46.5 (IQR:37.0-61.0) minutes. There was no significant correlation between ASCP flow and rSO2 for both the right (r = -.02, p = .851), and the left hemisphere (r = - .04, p = .618). The rSO2 values for ten patients who received > 10 mL/kg/min flow did not differ significantly from 130 patients who received 10 mL/kg/min or less for both the left hemisphere (p = .135), and the right hemisphere (p = .318). The ASCP flow was 5.1 (IQR:5.0- 6.5) mL/kg/min in five patients with, and 7.2 (IQR:5.8-8.3) mL/kg/min in 135 patients without a watershed infarction (p = .098). CONCLUSIONS: There was no correlation between ASCP flow rate and rSO2 in patients with acute type A aortic dissection. Furthermore, ASCP flow below 10 mL/kg/min was not associated with a reduction in rSO2. Definitive associations between ASCP flow and neurological outcome after type A aortic dissection surgery need further investigation.

Computed tomography follow-up after elective proximal aortic surgery: Less is more?

STUDY OBJECTIVE: The added value of computed tomography (CT) follow-up after elective proximal aortic surgery is unclear. We evaluated the benefit of CT follow-up by assessing the incidence of aorta-related complications and reinterventions detected during routine CT follow-up. METHODS: Data on 314 patients undergoing first time elective proximal aortic surgery between 2000 and 2015 were collected. The primary study end points were aorta-related complications and reinterventions, detected during routine CT follow-up. Secondary study endpoints included all aorta-related complications and reinterventions, irrespective of the mode of detection and survival. RESULTS: Median CT follow-up time was 6.8 (IQR 4.1-9.8) years, during which a total of 1303 routine follow-up CT-scans (median 4, IQR 3-5) were performed. During CT follow-up, aorta-related complications were detected in 18 (5.7%) patients, of which 6 (1.6%) underwent reintervention. In total, 28 aorta-related complications were observed in 23 (7.3%) patients, of which 9 led to reintervention. In order to detect 1 aorta-related complication leading to reintervention, 218 routine follow-up CT-scans were required. The unadjusted and EuroSCORE II adjusted hazard ratios of not undergoing CT follow-up on mortality were 1.260 (95% CI 0.705-2.251) and 0.830 (95% CI 0.430-1.605), respectively. CONCLUSIONS: Following first time elective proximal aortic surgery, aorta-related complications are uncommon, are not always detected during CT follow-up and, if detected, often do not result in reintervention. Therefore, a more conservative CT follow-up protocol could be considered in selected patients to reduce lifetime radiation burden and health care costs.

Peri-operative nutrition in cardiovascular surgery: current pitfalls and future directions.

In the field of cardiovascular surgery, many areas are frequently evaluated to improve patient outcomes. Even though cardiac surgery has advanced significantly, peri-operative nutrition remains an area needing special attention and is under-considered in patient results. The three portions of cardiac surgical nutrition optimization are pre-operative, intra-operative and post-operative. All these, merit important clinical intervention which when done properly can significantly improve patient recovery and reduce morbidity and mortality. Here we provide a narrative review and recommendations for peri-operative nutritional optimization in cardiac surgery.

Human epicardium-derived cells reinforce cardiac sympathetic innervation.

RATIONALE: After cardiac damage, excessive neurite outgrowth (sympathetic hyperinnervation) can occur, which is related to ventricular arrhythmias/sudden cardiac death. Post-damage reactivation of epicardium causes epicardium-derived cells (EPDCs) to acquire a mesenchymal character, contributing to cardiac regeneration. Whether EPDCs also contribute to cardiac re/hyperinnervation, is unknown. AIM: To investigate whether mesenchymal EPDCs influence cardiac sympathetic innervation. METHODS AND RESULTS: Sympathetic ganglia were co-cultured with mesenchymal EPDCs and/or myocardium, and neurite outgrowth and sprouting density were assessed. Results showed a significant increase in neurite density and directional (i.e. towards myocardium) outgrowth when ganglia were co-cultured with a combination of EPDCs and myocardium, as compared to cultures with EPDCs or myocardium alone. In absence of myocardium, this outgrowth was not directional. Neurite differentiation of PC12 cells in conditioned medium confirmed these results via a paracrine effect, in accordance with expression of neurotrophic factors in myocardial explants co-cultured with EPDCs. Of interest, EPDCs increased the expression of nerve growth factor (NGF) in cultured, but not in fresh myocardium, possibly due to an "ischemic state" of cultured myocardium, supported by TUNEL and Hif1α expression. Cardiac tissues after myocardial infarction showed robust NGF expression in the infarcted, but not remote area. CONCLUSION: Neurite outgrowth and density increases significantly in the presence of EPDCs by a paracrine effect, indicating a new role for EPDCs in the occurrence of sympathetic re/hyperinnervation after cardiac damage.

Pneumonectomy for Lung Cancer Treatment in The Netherlands: Between-Hospital Variation and Outcomes.

BACKGROUND: Pneumonectomy in lung cancer treatment is associated with considerable morbidity and mortality. Its use is reserved only for patients in whom a complete oncological resection by (sleeve) lobectomy is not possible. It is unclear whether a patients' risk of receiving a pneumonectomy is equally distributed. This study examined between-hospital variation of pneumonectomy use for primary lung cancer in the Netherlands. METHODS: Data from the Dutch Lung Cancer Audit for Surgery from 2012 to 2016 were used to study the use of pneumonectomy for primary lung cancer in the Netherlands. Using multivariable logistic regression, factors associated with pneumonectomy use were identified and the expected number of pneumonectomies per hospital was determined. Subsequently, the observed/expected ratio (O/E ratio) per hospital was calculated to study between-hospital differences. RESULTS: Of the 8446 included patients, 659 (7.8%) underwent a pneumonectomy with a mean postoperative mortality of 7.1% (n = 47). Factors associated with receiving a pneumonectomy were age, gender, cardiac and pulmonary comorbidities, tumor side, size and histopathology. The pneumonectomy use in the Netherlands varied considerably between hospitals (IQR 5.5-10.1%). Three hospitals out of 51 performed significantly less pneumonectomies than expected (O/E ratio < 0.5) and three significantly more (O/E ratio > 1.7). In the latter group, severe complications were more frequent, taking other influencing factors into account (OR 1.51, 95% CI 1.05-2.19). CONCLUSIONS: There is a considerable between-hospital variation in pneumonectomy use in lung cancer treatment. To further optimize surgical lung cancer care, we suggest center-specific feedback on pneumonectomy use and the development of a risk-adjusted pneumonectomy indicator.

Concomitant atrial fibrillation ablation in minimally invasive cardiac surgery.

Concomitant atrial fibrillation (AF) ablation in cardiac surgery effectively restores sinus rhythm and may reduce morbidity and mortality. Cardiac surgery has witnessed the transition from the historical Cox Maze procedure to more modern and less invasive approaches for concomitant AF treatment. As minimally invasive cardiac surgery gains traction, ablation methods and careful patient selection become crucial to optimize results. Emerging techniques, including bipolar epicardial radiofrequency and endo/epicardial cryoablation, are central to these advances, targeting specific arrhythmogenic areas within the atria. While pulmonary vein isolation (PVI) is essential, it may be insufficient for patients with persistent or longstanding persistent AF. In such cases, left atrial posterior wall isolation has proven beneficial. Furthermore, recent studies emphasize the significance of left atrial appendage occlusion in concurrent AF treatments, highlighting its role in stroke risk reduction. Notably, the left atrium remains the focal point for concomitant AF surgery over the right, primarily due to concerns like high pacemaker implantation rates and complexities of right atrial ablation sets. Although guidelines support its widespread use, concomitant AF ablation outcomes vary based on patient selection, surgeon's expertise, and clinical context and thus the Heart Team's input is crucial for individualized decisions. In the upcoming sections, we present our patient selection and a visual guide to our techniques for concomitant AF surgery in minimally invasive mitral valve, coronary artery bypass and aortic valve surgery.

Continuous erector spinae plane block versus thoracic epidural analgesia in video-assisted thoracoscopic surgery: a prospective randomized open-label non-inferiority trial.

BACKGROUND AND OBJECTIVES: The evolving surgical techniques in thoracoscopic surgery necessitate the exploration of anesthesiological techniques. This study aimed to investigate whether incorporating a continuous erector spinae plane (ESP) block into a multimodal analgesia regimen is non-inferior to continuous thoracic epidural analgesia (TEA) in terms of quality of postoperative recovery for patients undergoing elective unilateral video-assisted thoracoscopic surgery. METHODS: We conducted a multicenter, prospective, randomized, open-label non-inferiority trial between July 2020 and December 2022. Ninety patients were randomly assigned to receive either continuous ESP block or TEA. The primary outcome parameter was the Quality of Recovery-15 (QoR-15) score, measured before surgery as a baseline and on postoperative days 0, 1, and 2. Secondary outcome parameters included pain scores, length of hospital stay, morphine consumption, nausea and vomiting, itching, speed of mobilization, and urinary catheterization. RESULTS: Analysis of the primary outcome showed a mean QoR-15 difference between the groups ESP block versus TEA of 1 (95% CI -9 to -12, p=0.79) on day 0, -1 (95% CI -11 to -8, p=0.81) on day 1 and -2 (95% CI -14 to -11, p=0.79) on day 2. CONCLUSIONS: The continuous ESP block is non-inferior to TEA in video-assisted thoracoscopic surgery. TRIAL REGISTRATION NUMBER: Dutch Trial Register (NL6433).

The Aortic Root in Acute Type A Dissection: Repair or Replace?

BACKGROUND: The effect of an "aggressive" approach on the aortic root in acute type A aortic dissection (ATAAD) remains insufficiently explored. METHODS: Retrospective analysis was conducted between 1992 and 2020 of a single-center, prospective cohort of consecutive patients aged ≥18 years diagnosed with ATAAD. Patients were divided into 2 groups: aortic root replacement (ARR; prosthetic or valve-sparing root replacement, n = 141) and conservative root approach (CRA; root sparing of partially dissected root, n = 90; and supracoronary ascending replacement in nondissected root, n = 68). Inverse probability weighting was used to compare patients with different preoperative characteristics. Mean follow-up was 5.1 (0-21) years in ARR and 7.1 (0-25) years in CRA. RESULTS: The frequency of ARR increased over the years, with 19% and 78% of patients undergoing ARR in the earliest and most recent periods, respectively. Early mortality decreased over the years, despite a more aggressive approach, and remained lower in ARR. CRA was associated with a higher hazard of late mortality (hazard ratio, 1.38; 95% CI, 1.12-1.68; P = .001) and reintervention (hazard ratio, 2.08; 95% CI, 1.44-3.56; P = .001). After CRA, new-onset aortic valve insufficiency was a common cause of reintervention. CONCLUSIONS: Over the years, there was a gradual increase in the root replacement approach in ATAAD. Root replacement was associated with better long-term survival and fewer reinterventions compared with the conservative approach, whereas the in-hospital mortality decreased during these years. Hence, aggressive root replacement is safe and may be applied in ATAAD with good long-term clinical results, without increased hospital mortality.

Outcomes after cardiac rehabilitation in patients following repair of thoracic aortic aneurysm or dissection: a protocol for a systematic review and meta-analysis.

BACKGROUND: Patients receiving thoracic aortic repair suffer from long-term impairment in daily functioning and quality of life following intervention due to a combination of their life-threatening condition (i.e. aortic aneurysm or dissection), undergoing major surgery, as well as long-term exercise restrictions thereafter. Despite the known risks of exercise, it is vital that patients regain physical activity in order to recover their daily functioning and quality of life. Cardiac rehabilitation could be a safe and effective treatment to support patients to become physically active by providing exercise training, comprehensive rehabilitation services, and safety recommendations. Despite new insights in recent literature and clinical practice, international guidelines do not recommend cardiac rehabilitation due to limited evidence. We aim to fill this knowledge gap by performing a systematic review and meta-analysis on the effectiveness of cardiac rehabilitation in patients following thoracic aortic repair. METHODS: This protocol has been developed following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). MEDLINE, Embase, and CINAHL will be searched for eligible observational and interventional studies from inception up to April 2022. Screening (title/abstract and full text), data extraction, risk of bias assessment, and therapeutic validity rating will be conducted by two independent reviewers. A random-effects model will be used to meta-analyse performance-based outcomes, patient-reported outcomes, clinician-reported outcomes, and researcher-reported outcomes. Subsequently, meta-bias and confidence in evidence will be analysed by two independent reviewers. DISCUSSION: To exercise or not to exercise in patients following thoracic aortic repair has been a topic of discussion for years. The intended systematic review and meta-analysis will provide comprehensive evidence on the effectiveness of phase III outpatient exercise-based cardiac rehabilitation in patients following thoracic aortic repair. Findings from this review may inform future guidelines for the management of patients with thoracic aortic disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022301204.

Aortic valve visualization and pressurization device: a novel device for intraoperative evaluation of aortic valve repair procedures.

OBJECTIVES: Aortic valve repair procedures are technically challenging, and current intraoperative evaluation methods often fail to predict the final echocardiographic result. We have developed a novel intraoperative aortic valve visualization and pressurization (AVP) device, enabling valve inspection under physiological conditions, and measuring aortic valve insufficiency (AI) during cardioplegic arrest. METHODS: The AVP device is attached to the (neo)aorta, after any type of aortic valve repair, while the heart is arrested. The root is pressurized (60-80 mmHg) using a saline solution and an endoscope is introduced. The valve is inspected, and the amount of valvular leakage is measured. Postoperative 'gold standard' transesophageal echocardiogram measurements of AI are performed and compared against regurgitation volume measured. RESULTS: In 24 patients undergoing valve-sparing root replacement, the AVP device was used. In 22 patients, postoperative echocardiographic AI was ≤ grade 1. The median leakage was 90 ml/min, IQR 60-120 ml/min. In 3 patients, additional adjustments after visual inspection was performed. In 2 patients, with complex anatomy, the valve was replaced. In one, after evaluation with the device, there was undesirable result visually and residual AI of 330 ml/min, and in another, 260 ml/min residual AI was measured and valve restriction on visual inspection. CONCLUSIONS: The novel AVP device enables intraoperative evaluation of the valve under physiological conditions, while still on arrested heart, and allows for targeted adjustments. The AVP device can be an important aid for intraoperative evaluation of the aortic valve, during valve repair and valve-sparing procedures, thereby making the operative result more predictable and the operation more efficient.

Improved Maximal Workload and Systolic Blood Pressure After Cardiac Rehabilitation Following Thoracic Aortic Repair: A SYSTEMATIC REVIEW AND META-ANALYSIS.

PURPOSE: It is of clinical importance to gain more knowledge about the risks and benefits of exercise in patients recovering from thoracic aortic repair. Therefore, the aim of this review was to perform a meta-analysis on changes in cardiorespiratory fitness, blood pressure, and the incidence of adverse events during cardiac rehabilitation (CR) in patients recovering from thoracic aortic repair. REVIEW METHODS: We performed a systematic review and random-effects meta-analysis of outcomes before versus after outpatient CR in patients recovering from thoracic aortic repair. The study protocol was registered (PROSPERO CRD42022301204) and published. MEDLINE, EMBASE, and CINAHL were systematically searched for eligible studies. Overall certainty of evidence was scored with Grading of Recommendations Assessment, Development, and Evaluation (GRADE). SUMMARY: We included five studies with data from in total 241 patients. Data from one study could not be used in our meta-analysis because they were provided in a different unit of measure. Four studies with data of 146 patients were included in the meta-analysis. The mean maximal workload increased with 28.7 W (95% CI: 21.8-35.6 W, n = 146, low certainty of evidence). The mean systolic blood pressure during exercise testing increased with 25.4 mm Hg (95% CI: 16.6-34.3, n = 133, low certainty of evidence). No exercise-induced adverse events were reported. These outcomes indicate that CR seems beneficial and safe to improve exercise tolerance in patients recovering from thoracic aortic repair, although outcomes were based on data from a small, heterogeneous group of patients.

A multicentre, propensity score matched analysis comparing a valve-sparing approach to valve replacement in aortic root aneurysm: Insight from the AVIATOR database.

OBJECTIVES: Our goal was to evaluate the outcome of valve-sparing root replacement (VSRR) and to compare the outcomes to those of patients having composite valve-graft conduit aortic root replacement (CVG-ARR) in a cohort of patients with aortic root aneurysm ± valve insufficiency, without valvular stenosis. Although valve-sparing procedures are preferable in young patients, there is a lack of comparative data in comparable patients. METHODS: The VSRR procedures were performed in 2005 patients, and 218 patients underwent a CVG-ARR procedure. Exclusion criteria included aortic dissection, endocarditis and valvular stenosis. Propensity score matching (3:1 ratio) was applied to compare VSRR (reimplantation 33% and remodelling 67%) and CVG-ARR. RESULTS: We matched 218 patients with CVG-ARR to 654 patients with VSRR (median age, 56.0; median follow-up was 4 years in both groups; interquartile range 1-5 years). Early mortality was 1.1% of those who had VSRR versus 2.3% in those who had CVG-ARR. Survival was 95.4% [95% confidence interval (CI) 94-97%] at 5 years in patients who had VSRR versus 85.4% (95% CI 82-92%) in those who had CVG-ARR; P = 0.002. Freedom from reintervention at 5 years was 96.8% (95% CI 95-98%) with VSRR and 95.4% (95% CI 91-99%) with CVG-ARR (P = 0.98). Additionally, there were more thromboembolic, endocarditis and bleeding events in the patients who had CVG-ARR (P = 0.02). CONCLUSIONS: This multicentre study shows excellent results after valve-sparing root replacement in patients with an ascending aortic aneurysm with or without valve insufficiency. Compared to composite valve-graft aortic root replacement, survival is better and valve-related events are fewer. Consequently, valve-sparing procedures should be considered whenever a durable repair is feasible. We advocate a valve-sparing strategy even in more complex cases when performed in experienced centres.

Long-term follow-up of thoracoscopic ablation in long-standing persistent atrial fibrillation.

OBJECTIVES: Catheter ablation of long-standing persistent atrial fibrillation (LSPAF) remains challenging, with suboptimal success rates obtained following multiple procedures. Thoracoscopic ablation has shown effective at creating transmural lesions around the pulmonary veins and box; however, long-term rhythm follow-up data are lacking. This study aims, for the first time, to assess the long-term outcomes of thoracoscopic pulmonary vein and box ablation in LSPAF. METHODS: Rhythm follow-up consisted of continuous rhythm monitoring using implanted loop recorders or 24-h Holter recordings. Rhythm status and touch-up interventions were assessed up to 5 years. RESULTS: Seventy-seven patients with symptomatic LSPAF underwent thoracoscopic ablation in 2 centres. Freedom from atrial arrhythmias at 5 years was 50% following a single thoracoscopic procedure and 68% allowing endocardial touch-up procedures (performed in 21% of patients). The mean atrial fibrillation burden in patients with continuous monitoring was reduced from 100% preoperatively to 0.1% at the end of the blanking period and 8.0% during the second year. Antiarrhythmic drug use decreased from 49.4% preoperative to 12.1% and 14.3% at 2 and 5 years, respectively (P < 0.001). Continuous rhythm monitoring resulted in higher recurrence detection rates compared to 24-h Holter monitoring at 2-year follow-up (hazard ratio: 6.5, P = 0.003), with comparable recurrence rates at 5-year follow-up. CONCLUSIONS: Thoracoscopic pulmonary vein and box isolation are effective in long-term restoration of sinus rhythm in LSPAF, especially when complemented by endocardial touch-up procedures, as demonstrated by the 68% freedom rate at 5 years. Continuous rhythm monitoring revealed earlier, but not more numerous documentation of recurrences at 5-year follow-up.

Optical ventricular cardioversion by local optogenetic targeting and LED implantation in a cardiomyopathic rat model.

AIMS: Ventricular tachyarrhythmias (VTs) are common in the pathologically remodelled heart. These arrhythmias can be lethal, necessitating acute treatment like electrical cardioversion to restore normal rhythm. Recently, it has been proposed that cardioversion may also be realized via optically controlled generation of bioelectricity by the arrhythmic heart itself through optogenetics and therefore without the need of traumatizing high-voltage shocks. However, crucial mechanistic and translational aspects of this strategy have remained largely unaddressed. Therefore, we investigated optogenetic termination of VTs (i) in the pathologically remodelled heart using an (ii) implantable multi-LED device for (iii) in vivo closed-chest, local illumination. METHODS AND RESULTS: In order to mimic a clinically relevant sequence of events, transverse aortic constriction (TAC) was applied to adult male Wistar rats before optogenetic modification. This modification took place 3 weeks later by intravenous delivery of adeno-associated virus vectors encoding red-activatable channelrhodopsin or Citrine for control experiments. At 8-10 weeks after TAC, VTs were induced ex vivo and in vivo, followed by programmed local illumination of the ventricular apex by a custom-made implanted multi-LED device. This resulted in effective and repetitive VT termination in the remodelled adult rat heart after optogenetic modification, leading to sustained restoration of sinus rhythm in the intact animal. Mechanistically, studies on the single cell and tissue level revealed collectively that, despite the cardiac remodelling, there were no significant differences in bioelectricity generation and subsequent transmembrane voltage responses between diseased and control animals, thereby providing insight into the observed robustness of optogenetic VT termination. CONCLUSION: Our results show that implant-based optical cardioversion of VTs is feasible in the pathologically remodelled heart in vivo after local optogenetic targeting because of preserved optical control over bioelectricity generation. These findings add novel mechanistic and translational insight into optical ventricular cardioversion.

Conditional immortalization of human atrial myocytes for the generation of in vitro models of atrial fibrillation.

The lack of a scalable and robust source of well-differentiated human atrial myocytes constrains the development of in vitro models of atrial fibrillation (AF). Here we show that fully functional atrial myocytes can be generated and expanded one-quadrillion-fold via a conditional cell-immortalization method relying on lentiviral vectors and the doxycycline-controlled expression of a recombinant viral oncogene in human foetal atrial myocytes, and that the immortalized cells can be used to generate in vitro models of AF. The method generated 15 monoclonal cell lines with molecular, cellular and electrophysiological properties resembling those of primary atrial myocytes. Multicellular in vitro models of AF generated using the immortalized atrial myocytes displayed fibrillatory activity (with activation frequencies of 6-8 Hz, consistent with the clinical manifestation of AF), which could be terminated by the administration of clinically approved antiarrhythmic drugs. The conditional cell-immortalization method could be used to generate functional cell lines from other human parenchymal cells, for the development of in vitro models of human disease.

Activin A and ALK4 Identified as Novel Regulators of Epithelial to Mesenchymal Transition (EMT) in Human Epicardial Cells.

The epicardium, the mesothelial layer covering the heart, is a crucial cell source for cardiac development and repair. It provides cells and biochemical signals to the heart to facilitate vascularization and myocardial growth. An essential element of epicardial behavior is epicardial epithelial to mesenchymal transition (epiMT), which is the initial step for epicardial cells to become motile and invade the myocardium. To identify targets to optimize epicardium-driven repair of the heart, it is vital to understand which pathways are involved in the regulation of epiMT. Therefore, we established a cell culture model for human primary adult and fetal epiMT, which allows for parallel testing of inhibitors and stimulants of specific pathways. Using this approach, we reveal Activin A and ALK4 signaling as novel regulators of epiMT, independent of the commonly accepted EMT inducer TGFß. Importantly, Activin A was able to induce epicardial invasion in cultured embryonic mouse hearts. Our results identify Activin A/ALK4 signaling as a modulator of epicardial plasticity which may be exploitable in cardiac regenerative medicine.