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Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genomewide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with >= 9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

Atrial fibrillation (AF) is a common arrhythmia among patients scheduled for open heart surgery and is associated with increased morbidity and mortality. According to international guidelines, symptomatic and selected asymptomatic patients should be offered concomitant surgical AF ablation in conjunction with valvular or coronary surgery. The gold standard in AF surgery is the Cox Maze III ("cut-and-sew") procedure, with surgical incisions in both atria according to a specified pattern, in order to prevent AF reentry circuits from developing. Over 90% of patients treated with the Cox Maze III procedure are free of AF after 1 year. Recent developments in ablation technology have introduced several energy sources capable of creating nonconducting atrial wall lesions. In addition, simplified lesion patterns have been suggested, but results with these techniques have been unsatisfactory. There is a clear need for standardization in AF surgery. The Swedish Arrhythmia Surgery Group, represented by surgeons from all Swedish units for cardiothoracic surgery, has therefore reached a consensus on surgical treatment of concomitant AF. This consensus emphasizes adherence to the lesion pattern in the Cox Maze III procedure and the use of biatrial lesions in nonparoxysmal AF.

In the Cox-Maze IV procedure, or in endocardial left atrial ablation, correct positioning of the surgical ablation probe within the left atrium might be difficult due to bulging or folds in the posterior left atrial wall. The Berglin apical stitch is a simple trick of the trade to create a smooth surface in the posterior left atrium that facilitates performing a safe transmural lesion and, consequently, may increase antiarrhythmic efficiency.

BACKGROUND: The cut-and-sew Cox-maze III procedure is the gold standard for surgical treatment of atrial fibrillation. The aim was to study early and long-term mortality based on registry analyses in Swedish Cox-maze III patients.

METHODS: Preoperative and early postoperative data were analyzed in 536 patients (male/female (425/111), mean age 57 ± 8.6 years), operated from 1994 to 2009 in 4 centers; 422 (79%) underwent stand-alone Cox-maze III. Atrial fibrillation was paroxysmal in 38% and non-paroxysmal in 62%, mean duration was 7.8 ± 6.3 years. Patients were followed for survival or death in a validated national Cause-of-Death registry. Risk factors associated with observed survival were identified in univariable and multivariable analyses in a standard Cox proportional hazards model.

RESULTS: Four early deaths (0.7%) occurred due to technical complications. At follow-up, 41 of 536 (7.6%) patients had died. Cause of death was cardiovascular in 19 of 536 (3.5%). No ischemic stroke-related death was registered. Univariable risk factors for all-cause mortality included hypertension (hazard ratio [HR] 2.8, confidence interval [CI] 1.5 to 5.3), heart failure (HR 2.4, CI 1.3 to 4.3), concomitant surgery (HR 2.2, CI 1.1 to 4.1), and postoperative complications (HR 2.5, CI 1.3 to 4.8). Gender, non-paroxysmal atrial fibrillation and long arrhythmia duration did not confer increased risk of death. Multivariable risk factors were hypertension (HR 2.9, CI 1.5 to 5.5) and postoperative complications (HR 2.4, CI 1.2 to 4.6). Survival for cardiovascular death at 5, 10, and 15 years was 98%, 96%, and 93%, respectively.

CONCLUSIONS: Registry-based follow-up showed low early and long-term cardiovascular mortality and no stroke-related mortality. This is important baseline information when evaluating current surgical and nonsurgical treatment of atrial fibrillation.

Background. The Cox-maze III (CM-III) procedure is the gold standard for surgical treatment of atrial fibrillation (AF). Excellent short-term results have been reported, but long-term outcomes are lesser known. The aim was to evaluate current cardiac rhythm in a nationwide cohort of CM-III patients with very long follow-up.

Methods. Perioperative characteristics were retrospectively analyzed in 536 "cut-and-sew" CM-III patients operated on from 1994 to 2009 in 4 centers. Of these, 54 patients had died and 20 were unavailable at follow-up. The remaining 462 patients received a survey concerning arrhythmia symptoms, rhythm, and medication; of these, 320 patients (69%), comprising 252 men, with a mean age of 67 years (range, 47 to 87 years), and 83% with stand-alone CM-III, returned a current 12-lead electrocardiogram. Long-term monitoring was evaluated in 40 sinus rhythm patients. Postoperative stroke/transient ischemic attack was evaluated by register analysis.

Results. Mean follow-up was 111 44 months (range, 36-223 months). Electrocardiogram analysis showed sinus rhythm in 219 of 320 patients (68%), and regular supraventricular rhythm (sinus, nodal, or atrial pacing) in 262 (82%), with 75% off class I/III antiarrhythmic medication. This group had lower arrhythmia symptom scores and medication use. Rhythm outcome did not differ by gender, age, type of AF, or stand-alone vs concomitant operation. Patients with more than 10 years of follow-up had a lower rate of regular supraventricular rhythm (69% vs 91%, p = 0.02). Long-term monitoring showed freedom from AF/atrial flutter in 38 of 40 patients (95%). The incidence of stroke/transient ischemic attack was 0.37% per year (11 patients).

Conclusions. In a single-moment electrocardiogram evaluation 9 years after the cut-and-sew CM-III, 82% of patients were in sinus rhythm or other regular supraventricular rhythm. These findings support a long-lasting positive effect of the CM-III procedure, which is relevant when evaluating current nonpharmacologic therapies for AF. (C) 2016 by The Society of Thoracic Surgeons

Tricuspid and pulmonary valve replacement in patients with advanced carcinoid heart disease (CaHD) reduces right heart failure and improves prognosis. The surgical literature is limited concerning description of technical aspects of valve replacement in CaHD. Although a dedicated multidisciplinary care is required for these frail patients, optimization of surgical technique is important and may lead to better postoperative outcomes.

Background. The long-term risk of stroke after surgical treatment of atrial fibrillation is not well known. We performed an observational cohort study with long follow-up after the "cut-and-sew" Cox-maze III procedure (CM-III), including left atrial appendage excision. The aim was to analyze the incidence of stroke/transient ischemic attack (TIA) and the association to preoperative CHA(2)DS(2)-VASc (age in years, sex, congestive heart failure history, hypertension history, stroke/TIA, thromboembolism history, vascular disease history, diabetes mellitus) score. Methods. Preoperative and perioperative data were collected in 526 CM-III patients operated in four centers 1994 to 2009, 412 men, mean age of 57.1 +/- 8.3 years. The incidence of any stroke/TIA was identified through analyses of the Swedish National Patient and Cause-ofDeath Registers and from review of individual patient records. The cumulative incidence of stroke/TIA and association with CHA(2)DS(2)-VASc score was estimated using methods accounting for the competing risk of death. Results. Mean follow-up was 10.1 years. There were 29 patients with any stroke/TIA, including 6 with intracerebral bleedings (2 fatal) and 4 with perioperative strokes (0.76%). The remaining 13 ischemic strokes and six TIAs occurred at a mean of 7.1 +/- 4.0 years postoperatively, with an incidence of 0.36% per year (19 events per 5,231 patient-years). In all CHA(2)DS(2)-VASc groups, observed ischemic stroke/TIA rate was lower than predicted. A higher risk of ischemic stroke/TIA was seen in patients with CHA(2)DS(2)-VASc score 2 or greater compared with score 0 or 1 (hazards ratio 2.15, 95% confidence interval: 0.87 to 5.32) but no difference by sex or stand-alone versus concomitant operation. No patient had ischemic stroke as cause of death. Conclusions. This multicenter study showed a low incidence of perioperative and long-term postoperative ischemic stroke/TIA after CM-III. Although general risk of ischemic stroke/TIA was reduced, patients with CHA(2)DS(2)-VASc score 2 or greater had a higher risk compared with score 0 or 1. Complete left atrial appendage excision may be an important reason for the low ischemic stroke rate. (C) 2017 by The Society of Thoracic Surgeons

Objective. The study aimed to investigate relevant clinical risk factors for re-exploration due to bleeding after primary coronary artery bypass graft (CABG) surgery, and to evaluate the influence of antiplatelet and antifibrinolytic drugs. Design. Three retrospective analyses were performed on patients who underwent CABG: (1) Logistic regression was used to identify clinical risk factors for re-exploration (n = 3000). (2) A case-control study (n = 228) was used to obtain information on exposure of antithrombotic and hemostatic therapy. (3) Based on exposure to antiplatelet and antifibrinolytic therapy, and odds ratios (ORs) in multivariate logistic models, the proportion of re-explorations attributed to these drugs was calculated. Results. A receiver operating characteristic curve was created for clinical risk factors. The C-index was 0.64, indicating limited ability to predict re-exploration for bleeding. Clopidogrel was the only drug influencing the risk of re-exploration (OR 3.2, 95% CI 1.7-5.9). The harmful effect of clopidogrel was confirmed in multivariate model (OR 4.7, 95% CI 2.2-9.9), and aprotinin had a protective effect of the same magnitude (OR 0.2, 95% CI 0.1-0.6). Conclusions. Clopidogrel is an essential risk factor for re-exploration due to bleeding, and attributable to at least one-quarter of surveyed cases. Aside from pharmaceuticals, there are no strong clinical risk factors.

INTRODUCTION: A substantial number of patients with coronary artery disease undergo cardiac surgery within five days of discontinuing anti-platelet treatment with aspirin and clopidogrel. The aims of this study were to describe the degree of platelet inhibition in patients with dual anti-platelet treatment scheduled for coronary artery bypass graft (CABG) surgery and to investigate whether the measured platelet inhibition correlated to intra- and postoperative risk for bleeding and transfusion requirements. MATERIAL AND METHODS: Sixty patients were included. Platelet inhibition was analysed with flow cytometry including phosphorylation status of the vasodilator-stimulated phosphoprotein (VASP-assay) and two bed-side analyzers, VerifyNow-System and PlateletMapping, a modified thrombelastograph. All 60 patients were analysed with VerifyNow and PlateletMapping, and 48 were analysed with flow cytometry and VASP-assay. RESULTS: There was a correlation between the ADP-receptor inhibition as measured by VASP-assay and VerifyNowP2Y(12) (r = -0.29, p<0.05), and between VASP-assay and the expression of P-selectin (r = 0.29, p<0.05) as measured by flow cytometry when platelets were stimulated with 5 microM ADP. VerifyNowP2Y(12) was the only measurement of platelet inhibition correlated to total blood loss (Spearman r = 0.29, p=0.03) and red blood cell transfusion (Spearman r = 0.43, p<0.01) requirements, although this might be confounded by aprotinin treatment. CONCLUSION: We found a modest agreement between the methods for preoperative platelet inhibition, though not for PlateletMapping-MA(ADP). There was a correlation between preoperative platelet inhibition measured by VerifyNowP2Y(12) and surgical blood loss or transfusion requirements. However, for the individual patient, preoperative use of VerifyNowP2Y(12) as an instrument to decide bleeding and transfusion risk does not seem helpful.

BACKGROUND:

Re-exploration for bleeding after cardiac surgery is an indicator of substantial haemorrhage and is associated with increased hospital resource utilization. This study aimed to analyse the costs of re-exploration and estimate the costs of haemostatic prophylaxis.

METHODS:

A total of 4232 patients underwent isolated, first-time, coronary artery bypass graft (CABG) surgery during 2005-8. Each patient re-explored for bleeding (n=127) was matched with two controls not requiring re-exploration (n=254). Cost analysis was based on resource utilization from completion of CABG until discharge. A mean cost per patient for re-exploration was calculated. Based on this, the net cost of prophylactic treatment with haemostatic drugs for preventing re-exploration was calculated.

RESULTS:

Patients undergoing re-exploration had higher exposure to clopidogrel before operation, prolonged stays in the intensive care unit, and more blood transfusions than controls. The mean incremental cost for re-exploration was (sic)6290 [95% confidence interval (CI) (sic)3408-(sic)9173] per patient, of which 48% [(sic)3001 (95% CI (sic)249-(sic)2147)] was due to prolonged stay, 31% [(sic)1928 (95% CI (sic)1710-(sic)2147)] to the cost of surgery/anaesthesia, 20% [(sic)1261 (95% CI (sic)1145-(sic)1378)] to the increased number of blood transfusions, and <2% [(sic)100 (95% CI (sic)39-(sic)161)] to the cost of haemostatic drugs. A cost model, at an estimated 50% efficacy for recombinant activated clotting factor VIIa and a 50% expected risk for re-exploration without prophylaxis, demonstrated that to be cost neutral, prophylaxis of four patients needed to result in one avoided re-exploration.

CONCLUSIONS:

The resource utilization costs were substantially higher in patients requiring re-exploration for bleeding. From a strict cost-effectiveness perspective, clinical interventions to prevent haemorrhage might be underutilized.

Objective - To study changes in cerebrospinal fluid (CSF) protein markers of blood-CSF barrier integrity and immunological reactions during surgical stress. Subjects and methods - Thirty-five patients without neurological or psychiatric disorders undergoing knee replacements had CSF and serum samples drawn from spinal and arterial catheters before, 3 h after and the morning after surgery. Results - Serum albumin decreased during surgery and CSF albumin decreased during and after surgery, and, as a consequence, the CSF/serum albumin ratio decreased significantly during the study period, especially after the intervention. In contrast, CSF concentrations of beta-2-microglobuline (β2M) increased significantly during surgery and remained high. The CSF general marker beta-trace protein (βTP) remained unchanged. Conclusions - Central nervous system protein reactions to a non-neurological surgical intervention include sharply decreased permeability of albumin into the CSF and signs of intrathecal inflammatory activity.

OBJECTIVES: The limited information available on thoracoscopic pulmonary vein isolation combined with ganglionated plexi ablation and the lack of studies regarding its effect on quality of life and physical capacity urged us to study its acute and long-term results in patients with atrial fibrillation. METHODS: Forty-three patients (mean age 57.1 years) with symptomatic atrial fibrillation referred for thoracoscopic off-pump epicardial pulmonary vein isolation and ganglionated plexi ablation using radiofrequency energy were included. RESULTS: The physical capacity improved significantly at 6-month follow-up compared with baseline (mean +/- standard deviation, 165.2 +/- 65 Watt versus 155.9 +/- 57 Watt, P = .02). Quality of life (Short Form-36 health survey) significantly improved 12 months after surgery compared with baseline in all subscales except for bodily pain. The symptom severity questionnaire score decreased significantly from mean 15.2 +/- 4.0 points to 10.7 +/- 4.8 points (P = .02). Overall, 25 of 33 patients (76%) followed up for 12 months had no symptomatic atrial fibrillation recurrences or atrial fibrillation episodes on 24-hour Holter recordings. The corresponding figures were 79% (19/24) for patients with paroxysmal atrial fibrillation, 100% (2/2) for persistent atrial fibrillation, and 57% (4/7) for permanent atrial fibrillation. The most common complication was bleeding events (9%) during pulmonary vein dissection. CONCLUSIONS: Epicardial off-pump pulmonary vein isolation combined with ganglionated plexi ablation improved quality of life, symptoms, and exercise capacity and therefore may be considered for patients with atrial fibrillation who fail endocardial pulmonary vein ablation or as a first-line procedure if left atrial appendage exclusion is warranted.

Aims

Concomitant surgical ablation of atrial fibrillation (AF) in patients undergoing mitral valve surgery (MVS) has almost become routine despite lack of convincing information about improved quality-of-life (QOL) and clinical benefit. Quality-of-life was therefore assessed after MVS with or without epicardial left atrial cryoablation.

Methods and results

Sixty-five patients with permanent AF randomized to MVS with or without left atrial cryoablation, in the double-blinded multicentre SWEDMAF trial, replied to the Short Form 36 QOL survey at 6 and 12 months follow-up. The QOL scores at 12 month follow-up did not differ significantly between patients undergoing MVS combined with cryoablation vs. those undergoing MVS alone regarding Physical Component Summary mean 42.8 (95% confidence interval 38.3–47.3) vs. mean 44.0 (40.1–47.7), P = 0.700 or Mental Component Summary mean 53.1 (49.7–56.4) vs. mean 48.4 (44.6–52.2), P = 0.075. All patients, irrespective of allocated procedure, reached the same QOL after surgery as an age-matched Swedish general population. The Physical Component Summary in patients with sinus rhythm did also not differ from those in AF at 12 months; mean 45.4 (42.0–48.7) vs. mean 40.5 (35.5–45.6), P = 0.096) nor was there a difference in Mental Component Summary; mean 51.0 (48.0–54.1) vs. mean 49.6 (44.6–54.5), P = 0.581).

Conclusion

Left atrial cryoablation added to MVS does not improve health-related QOL in patients with permanent AF, a finding that raises concerns regarding recommendations made for this combined procedure.

Carcinoid disease is caused by neuroendocrine tumors, most often located in the gut, and leads in approximately 20% of cases to specific, severe heart disease, most prominently affecting right-sided valves. If cardiac disease occurs, it determines the patient's prognosis more than local growth of the tumor. Surgical treatment of carcinoid-induced valve disease has been found to improve survival in observational studies. Cardiac imaging is crucial for both diagnosis and management of carcinoid heart disease; in the past, imaging was accomplished largely by echocardiography, but more recently, imaging for carcinoid heart disease has increasingly become multimodal and warrants awareness of the particular diagnostic challenges of this disease. This paper reviews the pathophysiology and manifestations of carcinoid heart disease in light of the different imaging modalities.

Stem cells (SCs) have been proven to possess regenerative and immunomodulatory properties and can be used to treat diseases that involve loss of cells due to tissue damage or inflammation. For this approach to succeed, SCs or their derivatives should be able to engraft in the target tissue at least for a short period of time. Unfortunately, once injected, therapeutic SCs will encounter a hostile environment, including hypoxia, lack of nutrients and stromal support, and cells may also be targeted and rejected by the immune system. Therefore, SC's stress-response mechanisms likely play a significant role in survival of injected cells and possibly contribute to their therapeutic efficacy. Autphagy, a stress-response pathway, is involved in many different cellular processes, such as survival during hypoxia and nutrient deprivation, cellular differentiation and de-differentiation, and it can also contribute to their immunovisibility by regulating antigen presentation and cytokine secretion. Autophagy machinery interacts with many proteins and signaling pathways that regulate SC properties, including PI3K/Akt, mammalian target of rapamycin (mTOR), Wnt, Hedgehog and Notch, and it is also involved in regulating intracellular reactive oxygen species (ROS) levels. In this review, we contend that autophagy is an important therapeutic target that can be used to improve the outcome of SC-based tissue repair and regeneration. Further research should reveal whether inhibition or stimulation of autophagy increases the therapeutic utility of SCs and it should also identify appropriate therapeutic regimens that can be applied in the clinic.

AIMS: Valvular surgery has improved long-term prognosis in severe carcinoid heart disease (CaHD). Experience is limited and uncertainty remains about predictors for survival and strategy regarding single vs. double-valve surgery. The aim was to review survival and echocardiographic findings after valvular surgery for CaHD at our institution.

METHODS AND RESULTS: Between 1986 and 2019, 60 consecutive patients, median age 64 years, underwent valve surgery for severe CaHD. Operations involved combined tricuspid valve replacement (TVR) and pulmonary valve replacement (PVR) in 42 cases, and TVR-only or TVR with pulmonary valvotomy (no PVR) in 18 patients. All implanted valves were bioprosthetic. Preoperative echocardiography, creatinine, NT-pro-brain natriuretic peptide (NT-pro-BNP), and 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) were obtained. 30-Day mortality was 12% (n=7), and 8% for the most recent decade 2010-2019. Median survival was 2.2 years and maximum survival 21 years. Patients undergoing combined TVR and PVR had significantly higher survival compared with operations without PVR (median 3.0 vs. 0.9 years, P = 0.02). Preoperative levels of NT-pro-BNP and 5-HIAA in the top quartile predicted poor survival. On preoperative echocardiograms, pulmonary regurgitation was severe in 51% and indeterminate in 17%. Postoperative echocardiography confirmed relatively good durability of bioprostheses, relative to the patients' limited oncological life expectancy.

CONCLUSION: Valvular surgery in CaHD has an acceptable perioperative risk. Survival for combined TVR and PVR was significantly higher compared with operations without PVR. Bioprosthetic valve replacement appears to have adequate durability. Preoperative echocardiography may underestimate pulmonary pathology. Combined TVR and PVR should be considered in most patients.