Atrial Dysrhythmia Research Articles

Chronic Atrial and Intestinal Dysrhythmia: A Rare Syndrome Presenting as Intestinal Pseudoobstruction

Chronic atrial and intestinal dysrhythmia (CAID) syndrome is a rare disorder affecting the heart and digestive systems. It results in bradycardia and arrhythmia due to sinoatrial node involvement. Concurrently, intestinal pseudoobstruction arises from anomalies in the Cajal cells, recognized as the pacemakers of the intestine. Patients may experience dizziness, drowsiness, syncope, and palpitations attributed to the arrhythmia, while abdominal pain, distension, vomiting, and constipation can occur due to intestinal pseudoobstruction. This report discusses the treatment management for two patients diagnosed with CAID syndrome.

Incidence and Impact of Preoperative Hiatal Hernia in Patients with Esophageal Carcinoma Undergoing Curative Surgical Resection.

Hiatal hernia (HH) and gastroesophageal reflux disease (GERD) are risk factors for esophageal adenocarcinoma. High positive margin rates and poor survival were described among HH patients undergoing esophagectomy. We sought to describe incidence and impact of HH on outcomes following esophagectomy. Patients who underwent esophagectomy 2012-2019 for esophago-junctional carcinoma were included. CT studies were blindly reviewed by two radiologists. A third radiologist reviewed cases of disagreement. Hernias ≥ 3 cm were included in the HH group. Overall, 66 patients (33%) had HH ≥ 3 cm. The no hernia group included 12 patients (6%) with < 3 cm HH and 106 (53%) without HH. Preoperative variables were comparable among groups. Location of anastomosis was similar among cohorts and predominantly cervical (n = 97, 82.2% vs 61, 92.4%, p = 0.113). Postoperatively, HH patients had higher incidence of atrial dysrhythmia (n = 11, 16.7% vs n = 6, 5.1% p = 0.015). Rates of R0 resections were similar (n = 62, 93.9%, vs n = 113, 95.8%, p = 0.724). HH patients had higher rates of signet ring cell histology (n = 14, 21.2% vs n = 9, 7.6% p = 0.025); this was confirmed on subgroup analysis including only adenocarcinoma patients (n = 14, 28.6% vs n = 8, 12.3%, p = 0.042). On Cox regression analysis, HH was not associated with disease-free or overall survival (HR 1.308, p = 0.274 and HR .905, p = 0.722). Patients with preoperative HH had higher rates of postoperative atrial dysrhythmias and signet ring cell features on pathology. In a population with predominant cervical anastomosis, positive margin rates were low and survival comparable among cohorts.

Myosin light-chain 4 gene-transfer attenuates atrial fibrosis while correcting autophagic flux dysregulation

ObjectivesTo determine the role of MYL4 regulation of lysosomal function and its disturbance in fibrotic atrial cardiomyopathy. BackgroundWe have previously demonstrated that the atrial-specific essential light chain protein MYL4 is required for atrial contractile, electrical, and structural integrity. MYL4 mutation/dysfunction leads to atrial fibrosis, standstill, and dysrhythmia. However, the underlying pathogenic mechanisms remain unclear. Methods and resultsRats subjected to knock-in of a pathogenic MYL4 mutant (p.E11K) developed fibrotic atrial cardiomyopathy. Proteome analysis and single-cell RNA sequencing indicate enrichment of autophagy pathways in mutant-MYL4 atrial dysfunction. Immunofluorescence and electron microscopy revealed undegraded autophagic vesicles accumulated in MYL4p.E11K rat atrium. Next, we identified that dysfunctional MYL4 protein impairs autophagy flux in vitro and in vivo. Cardiac lysosome positioning and mobility were regulated by MYL4 in cardiomyocytes, which affected lysosomal acidification and maturation of lysosomal cathepsins. We then examined the effects of MYL4 overexpression via adenoviral gene-transfer on atrial cardiomyopathy induced by MYL4 mutation: MYL4 protein overexpression attenuated atrial structural remodeling and autophagy dysfunction. ConclusionsMYL4 regulates autophagic flux in atrial cardiomyocytes via lysosomal mobility. MYL4 overexpression attenuates MYL4 p.E11K induced fibrotic atrial cardiomyopathy, while correcting autophagy and lysosomal function. These results provide a molecular basis for MYL4-mutant induced fibrotic atrial cardiomyopathy and identify a potential biological-therapy approach for the treatment of atrial fibrosis.

608. INCIDENCE AND IMPACT OF PREOPERATIVE HIATAL HERNIA IN PATIENTS WITH ESOPHAGEAL CARCINOMA UNDERGOING CURATIVE SURGICAL RESECTION

Abstract Hiatal hernia (HH) and gastroesophageal reflux disease (GERD) are risk factors for esophageal adenocarcinoma. High positive margin rates and poor survival were previously described among HH patients undergoing esophagectomy. We sought to describe incidence and impact of HH on outcomes following esophagectomy in a population of patients undergoing predominantly cervical anastomosis. Patients who underwent esophagectomy 2012-2019 for esophago-junctional carcinoma were included. CT studies were blindly reviewed by two radiologists. A third radiologist reviewed cases of disagreement. Hernias &amp;gt;3 cm were included in the HH group. Overall, 66 patients (33%) had HH &amp;gt;3 cm. The control group included 12 patients (6%) with &amp;lt;3 cm HH and 106 (53%) without HH. Patients with HH had higher Charlson Comorbidity Index (CCI) (p=0.017). Location of anastomosis was similar among cohorts (cervical anastomosis 82.2% vs 92.4%, p=0.113). HH patients had higher incidence of atrial dysrhythmia (16.7% vs 5.1% p=0.015). Rates of R0 resections were similar (95.8% vs 93.9%, p=0.724). Subgroup analysis on adenocarcinoma patients confirmed higher rates of signet ring cell features among HH patients (28.6% vs 12.3%, p=0.034). HH was not associated with poor disease free survival (p=0.274). Patients with preoperative HH had higher CCI, higher rates of postoperative atrial dysrhythmias and signet ring cell features on pathology. In a population with predominant cervical anastomosis, positive margin rates were low and survival comparable among cohorts.

207. THE EVOLUTION OF THE PERIOPERATIVE ENHANCED RECOVERY PROTOCOL IN ESOPHAGEAL SURGERY DURING 10 YEARS

Abstract The perioperative enhanced recovery protocol routinely uses in esophageal surgery. It acquired new aspects which were adapted to reduce the rate of morbidity and mortality. Esophagectomy still remains a high-risk operation, which carries out in high-volume centers on patients with significant comorbidities. It challenges the multidisciplinary team to personalize approach to create a safe recovery after surgery. The objective of the study is to show the aspects of evolution of the protocol after esophageal surgery. A total 393 patients with benign and malignant esophageal diseases underwent esophagectomy with simultaneous reconstruction between December 2012 and December 2021. The median age was 59 years (47;67), females were 39,7% and males—60,3%. The prevalence of the patient with nutritional deficiency was 20% (BIM &amp;lt; 18.5) and ASA score III-IV—66,9%. The tranthoracic and transhiatal esophagectomy were used for 42,2% and 57,8% of patients with the reconstruction by gastric pull up (92,1%), colon conduit (6,4%), jejunal loop interpostion with gastric pull-up 1% and with colon conduit 0,5%. 169 patients (43%) had postoperative complications, while 28,9% of them had one complication and 3,6% more than 4 complications at the same time. The prevalence of complications: pneumonia—8,2%, atrial dysrhythmia requiring intervention—7,7%, pulmonary embolism—1%, acute renal failure requiring dialysis—1,5%. The anastomotic leak occured in 5,4% patients and conduit necrosis—in 2,8% (2,3% extensive) patients. The prevalence of patients required repeated surgery was 6,4%. The rate of severe complications (&amp;gt;IIIb- Clavien-Dindo) was 14,4%. Median postoperative day was 9 (8;11). The postoperative mortality rate 1,8%. The aspects of the perioperative enhanced recovery protocol were modified to complicated surgery with simultaneous resection of other organs, esophagogastrectomy or reconstruction by combined conduit with jejunal loop with early oral feeding and rapid recovery. The decade-long experience of the evolution of the perioperative enhanced recovery protocol has led to the development of the personalized approach to the patients with significant comorbidities that allowed reducing the incidence of postoperative complications and mortality after esophagectomy.

548 COMPARISON OF ESOPHAGECTOMY OUTCOMES BETWEEN A NATIONAL CENTER, A NATIONAL AUDIT COLLABORATIVE, AND AN INTERNATIONAL DATABASE USING ECCG STANDARDIZED DEFINITIONS

Abstract The ECCG developed a standardized platform for reporting operative complications, with consensus definitions, and DUCA adopted these definitions and have reported a comparison against these benchmarks. The aim of this study was to report five year complications data using the standardized definitions of the Esophageal Complications Consensus Group (ECCG), and to compare with published ECCG benchmark studies from the collaborative group and from the Dutch Upper Gastrointestinal Cancer Audit (DUCA). Methods All patients undergoing multimodal therapy or surgery with curative intent from 2014 to 2018 inclusive were studied. All data were recorded prospectively and maintained internally as well as entered onto a secure online database (Esodata.org) from 2015. Statistical analysis was performed using SPSS® (version 18.0). Results 219 patients (mean age 67; 77% male) underwent open resection, 66.6% via transthoracic en bloc resection. 30-day and 90-day mortality were 0.0 and 0.9%, respectively. The anastomotic leak rate was 5.4%, and chyle leak 5.4%. Pneumonia was recorded in 18.2%, respiratory failure 10.9%, and ARDS in 2.7%. Atrial dysrhythmia occurred in 22.8%, recurrent nerve injury 3.1%, and delirium in 5.0%. Compared with both ECCG and DUCA, where MIE constituted 47% and 86% of surgical approaches, respectively, overall complications were similar in this open series, as was complications severity, however anastomotic leak rate were several-fold less, and mortality rates were lower. Conclusion In this unselected consecutive series and comparative audit with benchmark averages from the ECCG and DUCA publication, a low mortality and anastomotic leak rate were the key differential findings. Although not risk-stratified or directly matched, the severity of complications from this ‘open’ series is consistent with series containing large numbers of total or hybrid MIE, highlighting a need to adhere to these strictly defined definitions in further prospective research and randomized studies.

Cohesin-protein Shugoshin-1 controls cardiac automaticity via HCN4 pacemaker channel

Endogenous cardiac pacemaker function regulates the rate and rhythm of cardiac contraction. The mutation p.Lys23Glu in the cohesin protein Shugoshin-1 causes severe heart arrhythmias due to sinoatrial node dysfunction and a debilitating gastrointestinal motility disorder, collectively termed the Chronic Atrial and Intestinal Dysrhythmia Syndrome, linking Shugoshin-1 and pacemaker activity. Hyperpolarization-activated, cyclic nucleotide-gated cation channel 4 (HCN4) is the predominant pacemaker ion-channel in the adult heart and carries the majority of the “funny” current, which strongly contributes to diastolic depolarization in pacemaker cells. Here, we study the mechanism by which Shugoshin-1 affects cardiac pacing activity with two cell models: neonatal rat ventricular myocytes and Chronic Atrial and Intestinal Dysrhythmia Syndrome patient-specific human induced pluripotent stem cell derived cardiomyocytes. We find that Shugoshin-1 interacts directly with HCN4 to promote and stabilize cardiac pacing. This interaction enhances funny-current by optimizing HCN4 cell-surface expression and function. The clinical p.Lys23Glu mutation leads to an impairment in the interaction between Shugoshin-1 and HCN4, along with depressed funny-current and dysrhythmic activity in induced pluripotent stem cell derived cardiomyocytes derived from Chronic Atrial and Intestinal Dysrhythmia Syndrome patients. Our work reveals a critical non-canonical, cohesin-independent role for Shugoshin-1 in maintaining cardiac automaticity and identifies potential therapeutic avenues for cardiac pacemaking disorders, in particular Chronic Atrial and Intestinal Dysrhythmia Syndrome.

Predictors of Acute Atrial Fibrillation and Flutter Hospitalization across 7 U.S. Emergency Departments: A Prospective Study.

International rates of hospitalization for atrial fibrillation and flutter (AFF) from the emergency department (ED) vary widely without clear evidence to guide the identification of high-risk patients requiring inpatient management. We sought to determine (1) variation in hospital admission and (2) modifiable factors associated with hospitalization of AFF patients within a U.S. integrated health system. This multicenter prospective observational study of health plan members with symptomatic AFF was conducted using convenience sampling in 7 urban community EDs from 05/2011 to 08/2012. Prospective data collection included presenting symptoms, characteristics of atrial dysrhythmia, ED physician impression of hemodynamic instability, comorbid diagnoses, ED management, and ED discharge rhythm. All centers had full-time on-call cardiology consultation available. Additional variables were extracted from the electronic health record. We identified factors associated with hospitalization and included predictors in a multivariate Poisson Generalized Estimating Equations regression model to estimate adjusted relative risks while accounting for clustering by physician. Among 1,942 eligible AFF patients, 1,074 (55.3%) were discharged home and 868 (44.7%) were hospitalized. Hospitalization rates ranged from 37.4% to 60.4% across medical centers. After adjustment, modifiable factors associated with increased hospital admission from the ED included non-sinus rhythm at ED discharge, no attempted cardioversion, and heart rate reduction. Within an integrated health system, we found significant variation in AFF hospitalization rates and identified several modifiable factors associated with hospital admission. Standardizing treatment goals that specifically address best practices for ED rate reduction and rhythm control may reduce hospitalizations.

Aidi Injection as Adjuvant Drug Combined with Chemotherapy in Treatment of Breast Cancer: A Systematic Meta-Analysis.

Objective To compare the efficacy and safety of combination of Aidi injection and chemotherapy and chemotherapy alone in treatment of breast cancer. Methods The related control and randomized studies till August 1st, 2020, were retrieved in the database including PubMed, Embase, Cochrane Library, CNKI, CBM, Wang-Fang, and VIP. Primary outcomes were response rate (RR) and performance status (KPS) improvement rate; secondary outcomes were rate of adverse drug reactions (ADR) including myelosuppression, digestive tract reaction, liver dysfunction, and cardiac toxicity. Review Manager 5.3 was used in the present analysis. Results In total, 20 studies (18 articles) were included in the present analysis. RR (OR 1.76 (1.32, 2.35); p=0.0001) and KPS improvement rate (OR: 2.68 (1.34, 6.46); p=0.007) in Aidi injection plus chemotherapy group were significantly higher than those of chemotherapy alone group. Addition of Aidi injection significantly reduced the rate of myelosuppression, digestive tract reaction, leukocyte decrease, II-IV cardiac function abnormality, atrial dysrhythmia, ventricular arrhythmia, ST segment T wave inversion, and abnormal ECG (all p < 0.05). Conclusion Aidi injection could increase the efficacy of chemotherapy, could reduce myelosuppression, digestive tract reaction, and cardiac toxicity induced by chemotherapy, and did not lead to additional toxicity and side effect. Therefore, it is an anticancer drug with good efficacy and low toxicity, worth further popularization.

Overweight and aging increase the risk of atrial fibrillation after cardiac surgery independently of left atrial size and left ventricular ejection fraction

BackgroundBody mass index (BMI), age, left atrium (LA) dimension and left ventricular ejection fraction (LVEF) have been linked to post-operative atrial fibrillation (POAF) after cardiac surgery. The aim of this study was to better define the role of these risk factors.MethodsThis retrospective cohort study evaluated 249 patients (without prior atrial dysrhythmia) undergoing cardiac or aortic surgery. Prior to surgery, the following data were collected: age, BMI, LA diameter, LA area, LVEF, thyroid stimulating hormone (TSH), creatinine and the presence of arterial hypertension (AH) and diabetes. Intraoperative data such as operation time, total clamp time, cardiopulmonary bypass time, and presence of pericardial/pleural effusion were also collected. Only patients without pre- and post-surgery prophylactic anti-arrhythmic therapy were included.ResultsPatients with (N = 127, 51%) and without POAF (N = 122, 49%) were compared. No difference was observed for sex, LA diameter, LA area, LVEF, TSH, diabetes and use of ACE inhibitors or statins prior to intervention. Moreover, no difference was observed in terms of operation time, total clamp time, cardiopulmonary bypass time, and presence of pericardial/pleural effusion. However, patients with POAF were older (70.6 ± 10.7 vs. 60.4 ± 16.4 years, p = 0.001), had higher BMI (26.8 ± 4.5 vs. 24.9 ± 3.6 kg/m2, p = 0.001), higher baseline creatinine (1.06 ± 0.91 vs. 0.88 ± 0.32 mg/dL, p = 0.038) and a higher frequency of arterial hypertension (73.2% vs. 50%, p = 0.001) and Bentall procedure (24.4% vs. 9.8%, p = 0.023). Multivariate analysis showed that the only independent predictors of POAF were age (OR = 1.05, 95%CI 1.02–1.07, p = 0.001) and BMI (OR = 1.11 95%CI 1.03–1.2,p = 0.006).ConclusionsThese findings suggest that advanced age and a higher BMI are strong risk factors for POAF in patients without previous AF even in the presence of comparable LA dimensions and LVEF.

Atrial Dysfunction in Patients With Heart Failure With Preserved Ejection Fraction and Atrial Fibrillation

BackgroundParoxysmal and permanent atrial fibrillation (AF) are common in heart failure with preserved ejection fraction (HFpEF). ObjectivesThis study sought to determine the implications of left atrial (LA) myopathy and dysrhythmia across the spectrum of AF burden in HFpEF. MethodsConsecutive patients with HFpEF (n = 285) and control subjects (n = 146) underwent invasive exercise testing and echocardiographic assessment of cardiac structure, function, and pericardial restraint. ResultsPatients with HFpEF were categorized into stages of AF progression: 181 (65%) had no history of AF, 49 (18%) had paroxysmal AF, and 48 (17%) had permanent AF. Patients with permanent AF were more congested with greater pulmonary vascular disease and lower cardiac output. LA volumes increased, while LA compliance, LA reservoir strain, and right ventricular function decreased with increasing AF burden. The presence of permanent AF was characterized by a distinct pathophysiology, with greater total heart volume caused by atrial dilatation, leading to elevated filling pressures through heightened pericardial restraint. Survival decreased with increasing AF burden. Ten-year progression to permanent AF was common, particularly in paroxysmal AF (52%), and the likelihood of AF progression increased with higher AF stage, poorer LA compliance, and lower LA strain. ConclusionsLA compliance and mechanics progressively decline with increasing AF burden in HFpEF, increasing risk for new onset AF and progressive AF. These changes promote development of a unique phenotype of HFpEF characterized by heightened ventricular interaction, right heart failure, and worsening pulmonary vascular disease. Further study is required to identify therapeutic interventions targeting LA myopathy to improve outcomes in HFpEF.

Comparison of Esophagectomy outcomes between a National Center, a National Audit Collaborative, and an International database using the Esophageal Complications Consensus Group (ECCG) standardized definitions.

The ECCG developed a standardized platform for reporting operative complications, with consensus definitions. The Dutch Upper Gastrointestinal Cancer Audit (DUCA) published a national comparison against these benchmarks. This study compares ECCG data from the Irish National Center (INC) with both published benchmark studies. All patients undergoing multimodal therapy or surgery with curative intent from 2014 to 2018 inclusive were studied, with data recorded prospectively and entered onto a secure online database (Esodata.org). 219 patients (mean age 67; 77% male) underwent open resection, 66.6% via transthoracic en bloc resection. 30-day and 90-day mortality were 0.0 and 0.9%,nrespectively. Anastomotic leak rate was 5.4%, pneumonia 18.2%, respiratory failure 10%, ARDS 2.7%, atrial dysrhythmia 22.8%, recurrent nerve injury 3%, and delirium in 5% of patients. Compared with both ECCG and DUCA, where MIE constituted 47 and 86% of surgical approaches, respectively, overall complications were similar, as were severity of complications; however, anastomotic leak rate was several-fold less, and mortality was significantly lower (P < 0.001). In this consecutive series and comparative audit with benchmark averages from the ECCG and DUCA publications, a low mortality and anastomotic leak rate were the key differential findings. Although not risk stratified, the severity of complications from this 'open' series is consistent with series containing large numbers of total or hybrid MIE, highlighting a need to adhere to these strictly defined definitions in further prospective research and randomized studies.

Impact of postoperative complications on disease recurrence and long-term survival following oesophagogastric cancer resection.

Postoperative complications after resection of oesophagogastric carcinoma can result in considerable early morbidity and mortality. However, the long-term effects on survival are less clear. All patients undergoing intentionally curative resection for oesophageal or gastric cancer between 2006 and 2016 were selected from an institutional database. Patients were categorized by complication severity according to the Clavien-Dindo classification (grades 0-V). Complications were defined according to an international consensus statement. The effect of leak and severe non-leak-related complications on overall survival, recurrence and disease-free survival was assessed using Kaplan-Meier analyses to evaluate differences between groups. All factors significantly associated with survival in univariable analysis were entered into a Cox multivariable regression model with stepwise elimination. Some 1100 patients were included, with a median age of 69 (range 28-92) years; 48·1 per cent had stage III disease and cancer recurred in 428 patients (38·9 per cent). Complications of grade III or higher occurred in 244 patients (22·2 per cent). The most common complications were pulmonary (29·9 per cent), with a 13·0 per cent incidence of pneumonia. Rates of atrial dysrhythmia and anastomotic leak were 10·0 and 9·6 per cent respectively. Patients with a grade III-IV leak did not have significantly reduced overall survival compared with those who had grade 0-I complications. However, patients with grade III-IV non-leak-related complications had reduced median overall survival (19·7 versus 42·7 months; P < 0·001) and disease-free survival (18·4 versus 36·4 months; P < 0·001). Cox regression analysis identified age, tumour stage, resection margin and grade III-IV non-leak-related complications as independent predictors of poor overall and disease-free survival. Beyond the acute postoperative period, anastomotic leak does not adversely affect survival, however, other severe postoperative complications do reduce long-term overall and disease-free survival.

P159 THE IMPACT OF POSTOPERATIVE COMPLICATIONS ON LONG-TERM SURVIVAL AND DISEASE RECURRENCE FOLLOWING OESOPHAGO-GASTRIC CANCER RESECTION

Abstract Aim Postoperative complications following the resection of oesophago-gastric carcinoma can result in considerable early morbidity and mortality, however the long-term effects are less clear. Literature reports are mixed, so it remains unclear if complications reduce survival, as has been demonstrated in colorectal cancer. Background &amp; Methods Some 1100 patients who underwent oesophago-gastric resection between 2006-16 were stratified by complication severity to determine the effect of leak and severe non-leak related complications on overall survival, recurrence and disease free survival. Results The median age was 69 years, 48% had stage III disease, with cancer recurrence in 39%. Clavien-Dindo (CD) complications ≥ III occurred in 22.2% of patients. The most common complications were pulmonary (30%), with a 13% incidence of pneumonia, 10% atrial dysrhythmia and 9.6% anastomotic leak. In comparison to CD 0-I complication free patients, those with CD III-IV leak did not suffer a significantly reduced survival. However patients with CD III-IV non-leak related complications were associated with a significant reduction in median overall survival (19.7 vs. 42.7 months) and disease free survival (18.4 vs. 36.4 months). Cox regression revealed age, stage, resection margin, and CD III-IV non-leak complications as independently associated with poor overall and disease free survival. Conclusion This cohort demonstrates that whilst leak does not affect long-term survival, other severe postoperative complications do significantly reduce overall survival and disease recurrence. A reduction in these complications, such as pneumonia, seen with adoption of hybrid / minimally invasive surgery may help change this pattern of disease recurrence and reduced survival.

Benchmarking Complications Associated with Esophagectomy.

Utilizing a standardized dataset with specific definitions to prospectively collect international data to provide a benchmark for complications and outcomes associated with esophagectomy. Outcome reporting in oncologic surgery has suffered from the lack of a standardized system for reporting operative results particularly complications. This is particularly the case for esophagectomy affecting the accuracy and relevance of international outcome assessments, clinical trial results, and quality improvement projects. The Esophageal Complications Consensus Group (ECCG) involving 24 high-volume esophageal surgical centers in 14 countries developed a standardized platform for recording complications and quality measures associated with esophagectomy. Using a secure online database (ESODATA.org), ECCG centers prospectively recorded data on all resections according to the ECCG platform from these centers over a 2-year period. Between January 2015 and December 2016, 2704 resections were entered into the database. All demographic and follow-up data fields were 100% complete. The majority of operations were for cancer (95.6%) and typically located in the distal esophagus (56.2%). Some 1192 patients received neoadjuvant chemoradiation (46.1%) and 763 neoadjuvant chemotherapy (29.5%). Surgical approach involved open procedures in 52.1% and minimally invasive operations in 47.9%. Chest anastomoses were done most commonly (60.7%) and R0 resections were accomplished in 93.4% of patients. The overall incidence of complications was 59% with the most common individual complications being pneumonia (14.6%) and atrial dysrhythmia (14.5%). Anastomotic leak, conduit necrosis, chyle leaks, recurrent nerve injury occurred in 11.4%, 1.3%, 4.7%, and 4.2% of cases, respectively. Clavien-Dindo complications ≥ IIIb occurred in 17.2% of patients. Readmissions occurred in 11.2% of cases and 30- and 90-day mortality was 2.4% and 4.5%, respectively. Standardized methods provide contemporary international benchmarks for reporting outcomes after esophagectomy.

Reporting National Outcomes After Esophagectomy and Gastrectomy According to the Esophageal Complications Consensus Group (ECCG)

This nation-wide population-based study aimed to report postoperative morbidity and mortality after esophagectomy and gastrectomy in the Netherlands according to the definitions of the Esophagectomy Complications Consensus Group (ECCG). To standardize international outcome reporting in esophageal surgery, the ECCG developed a standardized outcomes set. For this national cohort study, all patients undergoing esophagectomy or gastrectomy for cancer between 2016 and 2017 were selected from the Dutch Upper gastrointestinal Cancer Audit. In a random sample of hospitals, data completeness and accuracy were validated by reabstraction of the data. The investigated outcomes in the present study were postoperative complications, major complications (Clavien-Dindo grade ≥III), and 30-day mortality, according to definitions of the ECCG. A total of 2545 patients from 22 hospitals were included. The completeness of the Dutch Upper gastrointestinal Cancer Audit was estimated at 99.8%. Data accuracy on different items was 94% to 100%. After esophagectomy, 1046 of 1617 patients (65%) had a postoperative complication including 468 patients (29%) with a major complication. Most common complications were pneumonia (21%), esophago-enteric leak from anastomosis, staple line or localized conduit necrosis (19%), and atrial dysrhythmia (15%). The 30-day mortality was 1.7%. After gastrectomy, 397 of 928 patients (42%) had a postoperative complication including 180 patients (19%) with a major complication. Most common complications were pneumonia (12%), esophago-enteric leak from anastomosis, staple line or localized conduit necrosis (9%), and acute delirium (5%). The 30-day mortality was 4.4%. Reporting complications according to the ECCG platform is feasible in the Netherlands and facilitates international benchmarking.

Inferring Transmission Histories of Rare Alleles in Population-Scale Genealogies

Learning the transmission history of alleles through a family or population plays an important role in evolutionary, demographic, and medical genetic studies. Most classical models of population genetics have attempted to do so under the assumption that the genealogy of a population is unavailable and that its idiosyncrasies can be described by a small number of parameters describing population size and mate choice dynamics. Large genetic samples have increased sensitivity to such modeling assumptions, and large-scale genealogical datasets become a useful tool to investigate realistic genealogies. However, analyses in such large datasets are often intractable using conventional methods. We present an efficient method to infer transmission paths of rare alleles through population-scale genealogies. Based on backward-time Monte Carlo simulations of genetic inheritance, we use an importance sampling scheme to dramatically speed up convergence. The approach can take advantage of available genotypes of subsets of individuals in the genealogy including haplotype structure as well as information about the mode of inheritance and general prevalence of a mutation or disease in the population. Using a high-quality genealogical dataset of more than three million married individuals in the Quebec founder population, we apply the method to reconstruct the transmission history of chronic atrial and intestinal dysrhythmia (CAID), a rare recessive disease. We identify the most likely early carriers of the mutation and geographically map the expected carrier rate in the present-day French-Canadian population of Quebec.

Molecular Signature of CAID Syndrome: Noncanonical Roles of SGO1 in Regulation of TGF-β Signaling and Epigenomics.

Background & AimsA generalized human pacemaking syndrome, chronic atrial and intestinal dysrhythmia (CAID) (OMIM 616201), is caused by a homozygous SGO1 mutation (K23E), leading to chronic intestinal pseudo-obstruction and arrhythmias. Because CAID patients do not show phenotypes consistent with perturbation of known roles of SGO1, we hypothesized that noncanonical roles of SGO1 drive the clinical manifestations observed.MethodsTo identify a molecular signature for CAID syndrome, we achieved unbiased screens in cell lines and gut tissues from CAID patients vs wild-type controls. We performed RNA sequencing along with stable isotope labeling with amino acids in cell culture. In addition, we determined the genome-wide DNA methylation and chromatin accessibility signatures using reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing. Functional studies included patch-clamp, quantitation of transforming growth factor-β (TGF-β) signaling, and immunohistochemistry in CAID patient gut biopsy specimens.ResultsProteome and transcriptome studies converge on cell-cycle regulation, cardiac conduction, and smooth muscle regulation as drivers of CAID syndrome. Specifically, the inward rectifier current, an important regulator of cellular function, was disrupted. Immunohistochemistry confirmed overexpression of Budding Uninhibited By Benzimidazoles 1 (BUB1) in patients, implicating the TGF-β pathway in CAID pathogenesis. Canonical TGF-β signaling was up-regulated and uncoupled from noncanonical signaling in CAID patients. Reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing experiments showed significant changes of chromatin states in CAID, pointing to epigenetic regulation as a possible pathologic mechanism.ConclusionsOur findings point to impaired inward rectifier potassium current, dysregulation of canonical TGF-β signaling, and epigenetic regulation as potential drivers of intestinal and cardiac manifestations of CAID syndrome. Transcript profiling and genomics data are as follows: repository URL: https://www.ncbi.nlm.nih.gov/geo; SuperSeries GSE110612 was composed of the following subseries: GSE110309, GSE110576, and GSE110601.

PS01.136: POSTOPERATIVE OUTCOMES OF THE DUTCH UPPER GASTROINTESTINAL CANCER AUDIT ACCORDING TO THE PLATFORM OF THE ESOPHAGEAL COMPLICATIONS CONSENSUS GROUP

Abstract Background To standardize outcome reporting in esophageal surgery, the Esophageal Complications Consensus Group (ECCG) developed a standardized platform. Recently, this group published outcomes of 2704 patients that underwent an esophagectomyin 24 high-volume hospitals in the period 2015–2016. The aim of this study was to report postoperative morbidity and mortality in the Netherlands using the definitions of the ECCG. Methods All patients who underwent esophagectomy for cancer of the esophagus or esophagogastric junction in the Netherlands in 2016 were selected from the Dutch Upper gastrointestinal Cancer Audit (DUCA). Patient outcomes including postoperative complications, 30-day/in-hospital mortality readmission rate were reported according to the definitions of the ECCG platform (Low et al. Ann Surg 2017). Outcomes of the DUCA were compared with the recently published outcomes of the ECCG with Chi-square analysis. Results Some 797 patients were included from 22 hospitals. In 1 patient, the postoperative outcome was unkown. In 17 patients readmission status was unknown. Some 168 (21%) patients had an ASA score of ≥ III and 250 (31%) patients a Charlson comorbidity score of ≥ 2. In total, 498 patients (63%) had at least one postoperative complication (versus ECCG: 57%, P = 0.07). The most common complications were pneumonia (21% DUCA versus 15% ECCG, P &lt; 0.01), anastomotic/staple-line failure or localized conduit necrosis (18% DUCA versus 11% ECCG, P &lt; 0.01) and atrial dysrhythmia requiring treatment (13% DUCA versus 15% ECCG, P = 0.28). Readmissions occurred in 105 of 780 patients (13% DUCA versus 11% ECCG, P = 0.13). The 30-day/in-hospital mortality was 2.5% for the DUCA group and 2.4% for the ECCG group (P = 0.88). Conclusion The registration of complications according to the ECCG platform in the national audit promotes the use of uniform definitions and allows international comparison of outcomes. The overall complication rate, readmission rate and mortality in the Netherlands were comparable with the outcomes of the ECGG. However, anastomotic leakage and pneumonia were more frequently reported in the Netherlands. Disclosure All authors have declared no conflicts of interest.

Total or Sub-Total Correction of a Marked and Long-standing Cardiac Dysrhythmia after Sofosbuvir/Ledispavir Treatment

Cardiac dysrhythmias (atrial and/or ventricular fibrillation) represent a major medical problem, with possibly life-threatening complications, necessitating costly, life-long treatments or complicated procedures. We report here a case of a sustained correction of a severe and long-standing atrial dysrhythmia (hyperexcitability) and at a lesser degree, a ventricular hyperexcitability, occurring after treatment with a combination of sofosbuvir plus ledispavir administered to treat a chronic Hepatitis C virus infection (HCV). The correction appeared within the first days of anti-HCV treatment and was totally maintained 3 months after drug cessation and still noticeable 3 more months. The mechanism of such an antiarrhythmic action has still to be elucidated. If confirmed, the potential antiarrhythmic effect of sofosbuvir combined with another antiviral drug, could represent a real advance in atrial and maybe ventricular hyperexcitability treatment.