Impaired Intracellular Calcium Buffering Contributes to the Arrhythmogenic Substrate in Atrial Myocytes From Patients With Atrial Fibrillation.

BACKGROUND: Alterations in the buffering of intracellular Ca2+, for which myofilament proteins play a key role, have been shown to promote cardiac arrhythmia. It is interesting that although studies report atrial myofibrillar degradation in patients with persistent atrial fibrillation (persAF), the intracellular Ca2+ buffering profile in persAF remains obscure. Therefore, we aimed to investigate the intracellular buffering of Ca2+ and its potential arrhythmogenic role in persAF. METHODS: Transmembrane Ca2+ fluxes (patch-clamp) and intracellular Ca2+ signaling (fluo-3-acetoxymethyl ester) were recorded simultaneously in myocytes from right atrial biopsies of sinus rhythm (Ctrl) and patients with persAF, alongside human atrial subtype induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). Protein levels were quantified by immunoblotting of human atrial tissue and induced pluripotent stem cell-derived cardiac myocytes. Mouse whole heart and atrial electrophysiology were measured on a Langendorff system. RESULTS: Cytosolic Ca2+ buffering was decreased in atrial myocytes of patients with persAF because of a depleted amount of Ca2+ buffers. In agreement, protein levels of selected Ca2+ binding myofilament proteins, including cTnC (cardiac troponin C), a major cytosolic Ca2+ buffer, were significantly lower in patients with persAF. Small interfering RNA (siRNA)-mediated knockdown of cTnC (si-cTNC) in atrial iPSC-CM phenocopied the reduced cytosolic Ca2+ buffering observed in persAF. Si-cTnC treated atrial iPSC-CM exhibited a higher predisposition to spontaneous Ca2+ release events and developed action potential alternans at low stimulation frequencies. Last, indirect reduction of cytosolic Ca2+ buffering using blebbistatin in an ex vivo mouse whole heart model increased vulnerability to tachypacing-induced atrial arrhythmia, validating the direct mechanistic link between impaired cytosolic Ca2+ buffering and atrial arrhythmogenesis. CONCLUSIONS: Our findings suggest that loss of myofilament proteins, particularly reduced cTnC protein levels, causes diminished cytosolic Ca2+ buffering in persAF, thereby potentiating the occurrence of spontaneous Ca2+ release events and atrial fibrillation susceptibility. Strategies targeting intracellular buffering may represent a promising therapeutic lead in persAF management.

Transmural myocardial repair with engineered heart muscle in a rat model of heterotopic heart transplantation - A proof-of-concept study.

Engineered heart muscle (EHM) can be implanted epicardially to remuscularize the failing heart. In case of a severely scarred ventricle, excision of scar followed by transmural heart wall replacement may be a more desirable application. Accordingly, we tested the hypothesis that allograft (rat) and xenograft (human) EHM can also be administered as transmural heart wall replacement in a heterotopic, volume-loaded heart transplantation model. We first established a novel rat model model to test surgical transmural left heart wall repair. Subsequently and in continuation of our previous allograft studies, we tested outcome after implantation of contractile engineered heart muscle (EHM) and non-contractile engineered connective tissue (ECT) as well as engineered mesenchymal tissue (EMT) allografts as transmural heart wall replacement. Finally, proof-of-concept for the application of human EHM was obtained in an athymic nude rat model. Only in case of EHM implantation, remuscularization of the surgically created transmural defect was observed with palpable graft vascularization. Taken together, feasibility of transmural heart repair using bioengineered myocardial grafts could be demonstrated in a novel rat model of heterotopic heart transplantation.

Diagnostic Value of Cholinesterase Activity for the Development of Postoperative Delirium after Cardiac Surgery.

BACKGROUND: Depression of cholinesterase (CHE) activity has been reported to lead to an amplified neuroinflammatory response, which clinically manifests as postoperative delirium (PD). This observational study investigates the association between CHE activity and the development of PD following elective cardiac surgery. METHODS: Patients with preexisting neurologic deficits or carotid artery disease as well as patients undergoing reoperations or procedures under circulatory arrest have been excluded from this study. The Mini-Mental State Examination, the Confusion Assessment Method for the Intensive Care Unit, and the Intensive Care Delirium Screening Checklist were performed at regular intervals. CHE activity was estimated pre- and postoperatively until postoperative day (POD) 5 and at discharge. RESULTS: A total of 107 patients were included. PD was diagnosed in 34 (31.8%) patients, who have been compared with those without PD. Time on ventilator, length of ICU, and hospital stay were longer in patients with PD (p = 0.001, p < 0.001, and p = 0.004, respectively). MMSE scores were lower in patients with PD (p < 0.001; p = 0.015). CHE activity on POD 1 to 4 as well as at discharge were lower in the delirium group (p = 0.041; p = 0.029; p = 0.015; p = 0.035; p = 0.028, respectively). A perioperative drop of CHE activity of more than 50% and a postoperative CHE activity below 4,800 U/L (on POD 0) were independently associated with an increased risk of development of PD (p = 0.038; p = 0.008, respectively). CONCLUSION: In addition to the established functional tests, routine estimation of CHE activity may serve as an additional diagnostic tool allowing for the timely diagnosis and treatment of PD in cardiac surgery patients.

Complex Valve Surgery in Elderly Patients: Increasingly Necessary and Surprisingly Feasible.

OBJECTIVES: The increasing proportion of elderly patients in cardiac surgery poses additional challenges for the clinical management and leads to a higher operative risk due to multiple comorbidities of these patients. We reviewed the outcome of patients who were 75 years and older and underwent complex multiple valve surgery at our institution. METHODS: A retrospective review was performed to identify patients who were 75 years and older and underwent multiple valve surgery between January 2011 and May 2016 at our institution. Patients were assigned to one out of four subgroups: combined aortic and mitral valve surgery (group AM), aortic and tricuspid valve surgery (group AT), mitral and tricuspid valve surgery (group MT), and aortic, mitral, and tricuspid valve surgery (group AMT). RESULTS: A total of 311 patients underwent multiple valve surgery, of whom 119 (38.3%) were 75 years and older (median: 78 [25th-75th quartile: 76-80]). The estimated operative mortality (EuroSCORE II) in the overall cohort was 10.7%. The observed 30-day mortality was 4.2% (7% in group AM, 0% in group AT, 2.2% in group MT, 3.8% in group AMT; p = 0.685). Main complications were reexplorative surgery in 16%, adverse cerebrovascular events in 6.7%, prolonged mechanical ventilation in 10.1%, renal replacement therapy in 15.1%, nosocomial pneumonia in 15.1%, and pacemaker implantation in 18.5%. CONCLUSIONS: This study demonstrates the feasibility of complex multiple valve surgery in elderly patients. The observed perioperative mortality was lower than predicted. However, we observed a substantial rate of adverse events; therefore, careful patient selection is required in this high-risk patient population.

Turning Things Around: The Role of Prone Positioning in the Management of Acute Respiratory Failure After Cardiac Surgery.

OBJECTIVES: The aim of this study was to determine the benefit of prone positioning (PP) in patients developing acute respiratory failure (ARF) after cardiac surgery. DESIGN: A retrospective analysis. SETTING: Review of the institutional database between October 2016 and October 2018 revealed 24 patients who underwent PP for the treatment of ARF after cardiac surgery. PARTICIPANTS: The authors found 24 patients who underwent PP for the treatment of ARF after cardiac surgery. This included 10 patients who required extracorporeal membrane oxygenation (ECMO) therapy. Among them, 6 patients with simultaneous PP and ECMO therapy. INTERVENTIONS: Data were collected at the time of PP, 6 hours after PP, at the end of PP, and 6 hours after return to supine position (SP). MEASUREMENTS AND MAIN RESULTS: The median duration of postoperative mechanical ventilation was 281 hours (183-528 hours). Prone positioning was carried out on the fourth postoperative day (POD), with a total of 5 patients undergoing PP within 24 hours following surgery. The median duration of PP before return to SP was 12 hours (12-16 hours), with the maximal duration of PP being 22 hours in this cohort. The authors observed an increase in Horowitz index (HI) at the end of PP (p < 0.001) as well as 6 hours after supine positioning. In the subgroup of patients who underwent PP on ECMO (v-a ECLS = 3, v-v ECMO = 3), a significant reduction of ECMO support was achieved from 3.0 (2.2-5.6) liters/min to 2.5 (2.0-4.6) liters/min (p = 0.023). No adverse events occurred during the positioning of the patients. CONCLUSIONS: Prone positioning can be considered for the treatment of ARF after cardiac surgery to improve short-term respiratory conditions and possibly facilitate ECMO weaning.

The DZHK research platform: maximisation of scientific value by enabling access to health data and biological samples collected in cardiovascular clinical studies.

The German Centre for Cardiovascular Research (DZHK) is one of the German Centres for Health Research and aims to conduct early and guideline-relevant studies to develop new therapies and diagnostics that impact the lives of people with cardiovascular disease. Therefore, DZHK members designed a collaboratively organised and integrated research platform connecting all sites and partners. The overarching objectives of the research platform are the standardisation of prospective data and biological sample collections among all studies and the development of a sustainable centrally standardised storage in compliance with general legal regulations and the FAIR principles. The main elements of the DZHK infrastructure are web-based and central units for data management, LIMS, IDMS, and transfer office, embedded in a framework consisting of the DZHK Use and Access Policy, and the Ethics and Data Protection Concept. This framework is characterised by a modular design allowing a high standardisation across all studies. For studies that require even tighter criteria additional quality levels are defined. In addition, the Public Open Data strategy is an important focus of DZHK. The DZHK operates as one legal entity holding all rights of data and biological sample usage, according to the DZHK Use and Access Policy. All DZHK studies collect a basic set of data and biosamples, accompanied by specific clinical and imaging data and biobanking. The DZHK infrastructure was constructed by scientists with the focus on the needs of scientists conducting clinical studies. Through this, the DZHK enables the interdisciplinary and multiple use of data and biological samples by scientists inside and outside the DZHK. So far, 27 DZHK studies recruited well over 11,200 participants suffering from major cardiovascular disorders such as myocardial infarction or heart failure. Currently, data and samples of five DZHK studies of the DZHK Heart Bank can be applied for.

Safety and efficacy of digital chest drainage units compared to conventional chest drainage units in cardiac surgery.

OBJECTIVES: The use of digital chest drainage units (CDUs) has become increasingly common in thoracic surgery due to several advantages. However, in cardiac surgery, its use is still limited in favour of conventional analogue CDUs. In order to investigate the potential benefit of digital CDUs in cardiac surgery, we compared the safety and efficacy of both systems in patients undergoing cardiac surgery at our centre. METHODS: We retrospectively investigated 265 consecutive patients who underwent cardiac surgery at our institution between June 2017 and October 2017. These patients were divided into 2 groups: patients with analogue (A, n = 65) and digital CDUs (D, n = 200). Postoperative outcome was analysed and compared between both groups. In addition, the 'user experience' was evaluated by means of a questionnaire. RESULTS: The median age of the cohort was 70 years (P = 0.167), 25.3% of patients were female (P = 0.414). There were no differences in terms of re-explorative surgery or use of blood products. Nor was there a difference in the overall amount of fluid collected. However, during the first 6 h, more fluid was collected by the digital CDUs. The overall rate of technical failure was 0.4%. We observed a significantly higher rate of clotting in the tubing system of the digital CDUs (P = 0.042). Concerning the user experience, the digital CDUs were associated with a more favourable ease of use on the regular wards (P < 0.001). With regard to the overall user experience, the digital CDUs outperformed the analogue systems (P = 0.002). CONCLUSIONS: Digital CDUs can be safely and effectively applied in patients after cardiac surgery. Due to the improved patient mobility and simplified chest tube management, the use of digital CDUs may be advantageous for patients after cardiac surgery. However, the issue of clotting of the tubing systems should be addressed by further technical improvements.

Latissimus Dorsi Flap in the Treatment of Thoracic Wall Defects After Medial Sternotomy.

Background: This study aimed to describe the subjective and objective results of the latissimus dorsi muscle flap and propose it as a reconstructive option for postoperative thoracic defects. Methods: A systematic search for cases with pedicle-based latissimus dorsi flaps performed after medial sternotomy was conducted, and all cases occurred between 2010 and August 2017. Preoperative, intraoperative, and postoperative factors were retrospectively analyzed and then the correlations between prognostic factors and outcomes of flap surgery were calculated. Furthermore, an evaluation of the subjective quality of life after flap surgery was performed using questionnaires. Results: A total of 25 cases were identified (8 female and 17 male patients) with the mean age of 75.28 years (range, 55-88 years). The average survival rate was 39.63 ± 23.03 months. The proportion of patients with a survival rate of 1 year was 84.00% (21 patients), and the proportion of patients with a 2-year survival rate was 80.00% (20 patients). While 24% of all patients who had latissimus dorsi flap operations experienced no complications, 64% of them developed minor complications (non-life-threatening, Clavien-Dindo grades I-IIIb) and 12% of them developed major complications (life-threatening, Clavien-Dindo grades IV-V). There was a significant correlation between the low survival rate and risk factors such as a positive history of smoking (P = .034), renal insufficiency (P = .022), metabolic syndrome (P = .004), and the presence of postoperative complications (P < .00002). No significant correlation was observed between the survival rate and obesity (P = .396), hyperlipoproteinemia (P = .684), arterial hypertonia (P = .0450), diabetes (P = .891), cardiovascular comorbidities (P = .794), the interval between sternotomy and latissimus flap surgery (P = .075), the duration of flap surgery (P = .207), sternal osteitis (P = .78), and intraoperative application of norepinephrine (P = .818). We identified metabolic syndrome (hazard ratio: 6.27), renal insufficiency (hazard ratio: 3.935), and the presence of postoperative complications (hazard ratio: 2.965) as high-risk prognostic factors. The subjective evaluations revealed positive reports from the patients with an average score of 1.86 ± 1.03 (1.0 = very good; 5.0 = poor). Conclusions: The majority of the patients with defects after median sternotomy were treated successfully with the latissimus dorsi flap. High survival rates, low rates of severe complications, and subjective scoring of improved life quality make this procedure relative safe and reliable. However, some prognostic risk factors limit the outcome, so these factors should be considered during surgical planning.

Design and training effects of a physical reality simulator for minimally invasive mitral valve surgery.

OBJECTIVES: Minimally invasive mitral valve surgery (MIMVS) through an endoscopic right minithoracotomy is a well-established yet complex procedure that has a challenging learning curve. We have developed a simulator for MIMVS and evaluated its short- and long-term training effects. METHODS: Trainees without simulator experience or training in MIMVS were divided into 2 groups (10 students and 10 residents) and participated in a 5-day training course after initial instruction. Each trainee performed a ring annuloplasty. Scores were given by a supervisor who assessed 5 skills. The duration of each procedure was also measured. To evaluate the long-term effect of the training course, trainees performed the same procedure 4 weeks after the last session. RESULTS: Trainees in the resident group were significantly older compared to those in the student group and had a mean surgical experience of 4.4 ± 0.78 years standard error of the mean. All other demographic data were similar. Significant learning curves could be achieved in both groups over the course of 5 days with regard to total skill scores and total duration. However, when we compared the learning curves of both groups, no significant difference could be seen. Long-term performance in both groups was still significantly better compared to that in the first training session. CONCLUSIONS: Training with our simulator provided a significant enhancement of a trainee's performance. This learning effect was achieved in both groups and was still evident 4 weeks later. We strongly recommend our simulator for simulation-based surgical education of cardiac surgeons interested in MIMVS.

Viabahn stent graft compared with prosthetic surgical above-knee bypass in treatment of superficial femoral artery disease: Long-term results of a retrospective analysis.

The prosthetic surgical above-knee bypass (pAKB) is a standard therapy in superficial femoral artery (SFA) occlusive disease in absence of suitable vein. Viabahn graft has been established as a promising alternative. Since limited comparative data are available, we conducted a retrospective study to compare long-term outcomes of these 2 therapies in a real-world setting.Records of 52 patients (60 limbs), who were treated by pAKB (29 limbs) or Viabahn (31 limbs) were reviewed. Patients were followed up by clinical assessment, physical examination, and resting ankle brachial index (ABI) after 3, 6, 12 months and yearly thereafter. Long-term data were available for 97% in the Viabahn and 93% for pAKB after 73 ±â€Š3.7 months (mean ±â€Šstandard error [SE]).Long-term primary and secondary patencies in Viabahn group were 40% and 70%, respectively, after 63 ±â€Š2.8 months (mean ±â€ŠSE). Total lesion length was 19 ±â€Š11.06 cm (mean ±â€ŠSE), graft size was 6 ±â€Š0.72 mm (mean ±â€ŠSE). Hospital stay was 4.8 ±â€Š0.72 days (mean ±â€ŠSE). Limb salvage was achieved in 90%. Patients in the pAKB group showed a total lesion length of 24.39 ±â€Š1.97 cm (mean ±â€ŠSE), graft size was 7 ±â€Š0.99 mm (mean ±â€ŠSE). Long-term analysis after 83 ±â€Š6.8 months (mean ±â€ŠSE) revealed a primary patency of 78% with a secondary patency of 94%. Hospital stay was 10.4 ±â€Š1.27 days (mean ±â€ŠSE). Limb salvage was ensured in 97%. Long-term primary patency was lower for Viabahn (P = .044), secondary patency (P = .245), and leg salvage (P = .389) were not significantly different. However, hospital stay was shorter (P = .0002) for Viabahn.Long-term analysis of Viabahn revealed a significantly lower primary patency, a similar secondary patency, limb salvage, and significantly shorter hospital stay when compared with pAKB. Our data suggest that pAKB is still a valuable option in patients suitable for an open operation. However, Viabahn can be used as a less invasive treatment in high risk patients.

Is there a correlation between late re-exploration after cardiac surgery and removal of epicardial pacemaker wires?

BACKGROUND: Re-exploration for bleeding accounts for increased morbidity and mortality after major cardiac operations. The use of temporary epicardial pacemaker wires is a common procedure at many departments. The removal of these wires postoperatively can potentially lead to a serious bleeding necessitating intervention. METHODS: From Jan 2011 till Dec 2015 a total of 4244 major cardiac procedures were carried out at our department. We used temporary epicardial pacemaker wires in all cases. We collected all re-explorations for bleeding and pericardial tamponade from our surgical database and then we focused on the late re-explorations, meaning on the 4th postoperative day and thereafter, trying to identify the removal of the temporary pacemaker wires as the definite cause of bleeding. Patients' records and medication were examined. RESULTS: Thirty-nine late re-explorations for bleeding, consisting of repeat sternotomies, thoracotomies and subxiphoid pericardial drainages, were gathered. Eight patients had an acute bleeding incidence after removal of the temporary wires (0.18%). In four of these patients, a pericardial drainage was inserted, whereas the remaining patients were re-explorated through a repeat sternotomy. Two patients died of the acute pericardial tamponade, three had a blood transfusion and one had a wound infection. Seven out of eight patients were either on dual antiplatelet therapy or on combination of aspirin and vitamin K antagonist. CONCLUSIONS: A need for re-exploration due to removal of the temporary pacemaker wires is a very rare complication, which however increases morbidity and mortality. Adjustment of the postoperative anticoagulation therapy at the time of removal of the wires could further minimize or even prevent this serious complication.

Long term biventricular support with Berlin Heart Excor in a Septuagenarian with giant-cell myocarditis.

Giant-cell myocarditis (GCM) is known as a rare, rapidly progressive, and frequently fatal myocardial disease in young and middle-aged adults. We report about a 76 year old male patient who underwent implantation with a biventricular Berlin Heart Excor system at the age of 74 due to acute biventricular heart failure caused by giant-cell myocarditis. The implantation was without any surgical problems; however, a difficulty was the immunosuppressive therapy after implantation. Meanwhile the patient is 76 years old and lives with circulatory support for about 3 years without major adverse events. Also, in terms of mobility in old age there are no major limitations. It seems that in even selected elderly patients an implantation of a long term support with the biventricular Berlin Heart Excor is a useful therapeutic option with an acceptable outcome.

Aneurysm of the pulmonary vein: an unusual cause of stroke.

This clinical report deals with a giant true pulmonary venous aneurysm, which was partially thrombosed. The overall incidence of pulmonary venous aneurysms is unknown, and they are reported only occasionally. We present the case of a previously healthy man with acute onset of ischemic cerebral stroke. The cause was a thrombus in a huge aneurysm of the left superior pulmonary vein. The patient subsequently underwent uncomplicated therapy for stroke, including thrombolysis followed by excision of the giant pulmonary venous aneurysm. As curative therapy we recommend complete resection of this rare entity.

Rapid healing of cutaneous leishmaniasis by high-frequency electrocauterization and hydrogel wound care with or without DAC N-055: a randomized controlled phase IIa trial in Kabul.

BACKGROUND: Anthroponotic cutaneous leishmaniasis (CL) due to Leishmania (L.) tropica infection is a chronic, frequently disfiguring skin disease with limited therapeutic options. In endemic countries healing of ulcerative lesions is often delayed by bacterial and/or fungal infections. Here, we studied a novel therapeutic concept to prevent superinfections, accelerate wound closure, and improve the cosmetic outcome of ACL. METHODOLOGY/PRINCIPAL FINDINGS: From 2004 to 2008 we performed a two-armed, randomized, double-blinded, phase IIa trial in Kabul, Afghanistan, with patients suffering from L. tropica CL. The skin lesions were treated with bipolar high-frequency electrocauterization (EC) followed by daily moist-wound-treatment (MWT) with polyacrylate hydrogel with (group I) or without (group II) pharmaceutical sodium chlorite (DAC N-055). Patients below age 5, with facial lesions, pregnancy, or serious comorbidities were excluded. The primary, photodocumented outcome was the time needed for complete lesion epithelialization. Biopsies for parasitological and (immuno)histopathological analyses were taken prior to EC (1(st)), after wound closure (2(nd)) and after 6 months (3(rd)). The mean duration for complete wound closure was short and indifferent in group I (59 patients, 43.1 d) and II (54 patients, 42 d; p = 0.83). In patients with Leishmania-positive 2(nd) biopsies DAC N-055 caused a more rapid wound epithelialization (37.2 d vs. 58.3 d; p = 0.08). Superinfections occurred in both groups at the same rate (8.8%). Except for one patient, reulcerations (10.2% in group I, 18.5% in group II; p = 0.158) were confined to cases with persistent high parasite loads after healing. In vitro, DAC N-055 showed a leishmanicidal effect on pro- and amastigotes. CONCLUSIONS/SIGNIFICANCE: Compared to previous results with intralesional antimony injections, the EC plus MWT protocol led to more rapid wound closure. The tentatively lower rate of relapses and the acceleration of wound closure in a subgroup of patients with parasite persistence warrant future studies on the activity of DAC N-055. TRIAL REGISTRATION: ClinicalTrials.gov NCT00947362.

Hemodynamic effects of peri-operative statin therapy in on-pump cardiac surgery patients.

BACKGROUND: Peri-operative statin therapy in cardiac surgery cases is reported to reduce the rate of mortality, stroke, postoperative atrial fibrillation, and systemic inflammation. Systemic inflammation could affect the hemodynamic parameters and stability. We set out to study the effect of statin therapy on perioperative hemodynamic parameters and its clinical outcome. METHODS: In a single center study from 2006 to 2007, peri-operative hemodynamic parameters of 478 patients, who underwent cardiac surgery with cardiopulmonary bypass, were measured. Patients were divided into those who received perioperative statin therapy (n = 276; statin group) and those who did not receive statin therapy (n = 202; no-statin group). The two groups were compared together using Kolmogorov-Smirnov-Test, Fisher's-Exact-Test, and Student's-T-test. A p value < 0.05 was considered as significant. RESULTS: There was no significant difference in the preoperative risk factors. Onset of postoperative atrial fibrillation was not affected by statin therapy. Extended hemodynamic measurements revealed no significant difference between the two groups, apart from Systemic Vascular Resistance Index (SVRI). The no-statin group had a significantly higher SVRI (882 ± 206 vs. 1050 ± 501 dyn s/cm5/m2, p = 0.022). Inotropic support was the same in both groups and no significant difference in the mortality rate was noticed. Also, hemodynamic parameters were not affected by different types and doses of statins. CONCLUSIONS: Perioperative statin therapy for patients undergoing on-pump coronary bypass grafting or valvular surgery, does not affect the hemodynamic parameters and its clinical outcome.