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 aim to investigate the intracellular buffering of calcium and its potential arrhythmogenic role in persAF. METHODS: Simultaneous transmembrane fluxes (patch-clamp) and intracellular Ca2+ signaling (fluo-3-acetoxymethyl ester) were recorded in myocytes from right atrial biopsies of sinus rhythm (control) 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 was 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 in induced pluripotent stem cell-derived cardiac myocytes (si-cTnC) phenocopied the reduced cytosolic Ca2+ buffering observed in persAF. Si-cTnC induced pluripotent stem cell-derived cardiac myocytes 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 AF susceptibility. Strategies targeting intracellular buffering may represent a promising therapeutic lead in AF management.

Preoperative Delirium Risk Screening in Patients Undergoing a Cardiac Surgery: Results from the Prospective Observational FINDERI Study.

OBJECTIVE: Postoperative delirium (POD) is a common complication of cardiac surgery that is associated with higher morbidity, longer hospital stay, cognitive decline, and mortality. Preoperative assessments may help to identify patients´ POD risk. However, a standardized screening assessment for POD risk has not been established. DESIGN: Prospective observational FINd DElirium RIsk factors (FINDERI) study. PARTICIPANTS: Patients aged ≥50 years undergoing cardiac surgery. MEASUREMENTS: The primary aim was to analyze the predictive value of the Delirium Risk Screening Questionnaire (DRSQ) prior to cardiac surgery. Secondary aims are to investigate cognitive, frailty, and geriatric assessments, and to use data-driven machine learning (ML) in predicting POD. Predictive properties were assessed using receiver operating characteristics analysis and multivariate approaches (regularized LASSO regression and decision trees). RESULTS: We analyzed a data set of 504 patients (68.3 ± 8.2 years, 21.4% women) who underwent cardiac surgery. The incidence of POD was 21%. The preoperatively administered DRSQ showed an area under the curve (AUC) of 0.68 (95% CI 0.62, 0.73), and the predictive OR was 1.25 (95% CI 1.15, 1.35, p <0.001). Using a ML approach, a three-rule decision tree prediction model including DRSQ (score>7), Trail Making Test B (time>118), and Montreal Cognitive Assessment (score ≤ 22) was identified. The AUC of the three-rule decision tree on the training set was 0.69 (95% CI 0.63, 0.75) and 0.62 (95% CI 0.51, 0.73) on the validation set. CONCLUSION: Both the DRSQ and the three-rule decision tree might be helpful in predicting POD risk before cardiac surgery.

Prehabilitation in older patients prior to elective cardiac procedures (PRECOVERY): study protocol of a multicenter randomized controlled trial.

BACKGROUND: Previous studies have demonstrated the efficacy of rehabilitation after a cardiovascular procedure. Especially older and multimorbid patients benefit from rehabilitation after a cardiac procedure. Prehabilitation prior to cardiac procedures may also have positive effects on patients' pre- and postoperative outcomes. Results of a current meta-analysis show that prehabilitation prior to cardiac procedures can improve perioperative outcomes and alleviate adverse effects. Germany currently lacks a structured cardiac prehabilitation program for older patients, which is coordinated across healthcare sectors. METHODS: In a randomized, controlled, two-arm parallel group, assessor-blinded multicenter intervention trial (PRECOVERY), we will randomize 422 patients aged 75 years or older scheduled for an elective cardiac procedure (e.g., coronary artery bypass graft surgery or transcatheter aortic valve replacement). In PRECOVERY, patients randomized to the intervention group participate in a 2-week multimodal prehabilitation intervention conducted in selected cardiac-specific rehabilitation facilities. The multimodal prehabilitation includes seven modules: exercise therapy, occupational therapy, cognitive training, psychosocial intervention, disease-specific education, education with relatives, and nutritional intervention. Participants in the control group receive standard medical care. The co-primary outcomes are quality of life (QoL) and mortality after 12 months. QoL will be measured by the EuroQol 5-dimensional questionnaire (EQ-5D-5L). A health economic evaluation using health insurance data will measure cost-effectiveness. A mixed-methods process evaluation will accompany the randomized, controlled trial to evaluate dose, reach, fidelity and adaptions of the intervention. DISCUSSION: In this study, we investigate whether a tailored prehabilitation program can improve long-term survival, QoL and functional capacity. Additionally, we will analyze whether the intervention is cost-effective. This is the largest cardiac prehabilitation trial targeting the wide implementation of a new form of care for geriatric cardiac patients. TRIAL REGISTRATION: German Clinical Trials Register (DRKS; http://www.drks.de ; DRKS00030526). Registered on 30 January 2023.

Progression and interventional therapy of a coronary pseudoaneurysm: a case report.

Background: Coronary pseudoaneurysms (PSAs) occur as a rare complication following drug-eluting stent implantation and have been reported to occur between 1 week and 4 years after implantation. Most of them remain in a stable state, but progression of PSAs increases the risk of rupture and haemorrhagic cardiac tamponade. Case summary: Here, we present a case of a 55-year-old patient, who developed a PSA of the proximal left circumflex artery after stent implantation of the left main artery, left anterior descending artery, and left circumflex artery. Within <1 year, the patient was readmitted to different hospitals due to cardiac decompensation and myocardial infarction. Thereafter, coronary angiography and computed tomography scans were performed, and progression of the PSA could be documented. Interventional therapy was chosen due to the high surgical risk of the patient. Implantation of a covered stent from the left main artery into the left anterior descending artery was chosen to treat the PSA, thereby silencing the chronically occluded left circumflex artery, followed by dilatation with a non-compliant balloon. The patient has remained asymptomatic in a 6-month follow-up. Discussion: Coronary PSA should be controlled with respect to progression, and appropriate therapy can be chosen for treatment.

Identification of risk factors for delirium, cognitive decline, and dementia after cardiac surgery (FINDERI-find delirium risk factors): a study protocol of a prospective observational study.

BACKGROUND: Postoperative delirium is a common complication of cardiac surgery associated with higher morbidity, longer hospital stay, risk of cognitive decline, dementia, and mortality. Geriatric patients, patients undergoing cardiac surgery, and intensive care patients are at a high risk of developing postoperative delirium. Gold standard assessments or biomarkers to predict risk factors for delirium, cognitive decline, and dementia in patients undergoing cardiac surgery are not yet available. METHODS: The FINDERI trial (FINd DElirium RIsk factors) is a prospective, single-center, observational study. In total, 500 patients aged ≥ 50 years undergoing cardiac surgery at the Department of Cardiovascular and Thoracic Surgery of the University of Göttingen Medical Center will be recruited. Our primary aim is to validate a delirium risk assessment in context of cardiac surgery. Our secondary aims are to identify specific preoperative and perioperative factors associated with delirium, cognitive decline, and accelerated dementia after cardiac surgery, and to identify blood-based biomarkers that predict the incidence of postoperative delirium, cognitive decline, or dementia in patients undergoing cardiac surgery. DISCUSSION: This prospective, observational study might help to identify patients at high risk for delirium prior to cardiac surgery, and to identify important biological mechanisms by which cardiac surgery is associated with delirium. The predictive value of a delirium screening questionnaire in cardiac surgery might be revealed. Finally, the identification of specific blood biomarkers might help to predict delirium, cognitive decline, and dementia in patients undergoing cardiac surgery. TRIAL REGISTRATION: Ethics approval for this study was obtained from the IRB of the University of Göttingen Medical Center. The investigators registered this study in the German Clinical Trials Register (DRKS; https://www.drks.de ) (DRKS00025095) on April 19th, 2021.

Identification of risk factors for renal failure after cardiac surgery by RFILE classification.

OBJECTIVE: Acute kidney injury (AKI) is a major complication after cardiovascular surgery. The unclear etiology of this highly complex event challenges definition, diagnosis and prediction of AKI, and hence hampers adequate patient management. Identification of associated risk factors have the potential to overcome this limitation. METHODS: This retrospective study comprised 3574 patients who underwent cardiac surgery in a hospital in Germany. The patient cohort was interrogated for risk factors for AKI. RESULTS: The analysis identified risk factors for AKI development, such as type of surgery (particularly bypass surgery) (P = 0.02), previous coronary surgeries (P < 0.01), the application of intra-aortic balloon pump in surgery (P < 0.01), and blood loss during surgery (P < 0.01). In addition, old age, duration of surgery as well as ischemia, perfusion and reperfusion times contributed to AKI development (P < 0.01). Further, perioperative hypothermia also appeared as putative risk factor in the analysis (P < 0.01). CONCLUSIONS: This study identified several risk factors for the development of AKI after cardiac surgery. Further validation of these risk factors could allow the implementation of adequate patient management, and the appropriate implementation of risk-adverse interventions in cardiovascular surgery.

Chromatin Accessibility of Human Mitral Valves and Functional Assessment of MVP Risk Loci.

RATIONALE: Mitral valve prolapse (MVP) is a common valvopathy that leads to mitral insufficiency, heart failure, and sudden death. Functional genomic studies in mitral valves are needed to better characterize MVP-associated variants and target genes. OBJECTIVE: To establish the chromatin accessibility profiles and assess functionality of variants and narrow down target genes at MVP loci. METHODS AND RESULTS: We mapped the open chromatin regions in nuclei from 11 human pathogenic and 7 nonpathogenic mitral valves by an assay for transposase-accessible chromatin with high-throughput sequencing. Open chromatin peaks were globally similar between pathogenic and nonpathogenic valves. Compared with the heart tissue and cardiac fibroblasts, we found that MV-specific assay for transposase-accessible chromatin with high-throughput sequencing peaks are enriched near genes involved in extracellular matrix organization, chondrocyte differentiation, and connective tissue development. One of the most enriched motifs in MV-specific open chromatin peaks was for the nuclear factor of activated T cells family of TFs (transcription factors) involved in valve endocardial and interstitial cell formation. We also found that MVP-associated variants were significantly enriched (P<0.05) in mitral valve open chromatin peaks. Integration of the assay for transposase-accessible chromatin with high-throughput sequencing data with risk loci, extensive functional annotation, and gene reporter assay suggest plausible causal variants for rs2641440 at the SMG6/SRR locus and rs6723013 at the IGFBP2/IGFBP5/TNS1 locus. CRISPR-Cas9 deletion of the sequence including rs6723013 in human fibroblasts correlated with increased expression only for TNS1. Circular chromatin conformation capture followed by high-throughput sequencing experiments provided evidence for several target genes, including SRR, HIC1, and DPH1 at the SMG6/SRR locus and further supported TNS1 as the most likely target gene on chromosome 2. CONCLUSIONS: Here, we describe unprecedented genome-wide open chromatin profiles from human pathogenic and nonpathogenic MVs and report specific gene regulation profiles, compared with the heart. We also report in vitro functional evidence for potential causal variants and target genes at MVP risk loci involving established and new biological mechanisms. Graphic Abstract: A graphic abstract is available for this article.

Risk assessment of acute kidney injury following cardiopulmonary bypass.

BACKGROUND: Acute kidney injury (AKI) is a frequent and serious complication of cardiac surgery, associated with a high incidence of morbidity and mortality. Although the RIFLE criteria serve as a prominent tool to identify patients at high risk of AKI, an optimized diagnosis model in clinical practice is desired. METHODS: Based on the SOP-criteria, 365 patients (10%) developed AKI following surgery and were subjected to RRT. In contrast, the incidence of AKI, defined according to the RIFLE criteria, was only 7% (n = 251 patients). Prominent risk factors identified by SOP were patients' sex, valve and combined valve and bypass surgery, deep hypothermia, use of intra-aortic balloon pump (IABP) and previous coronary interventions. Ischemia, reperfusion, blood loss and surgery time also served as significant risk factors for patient evaluated by SOP. RESULTS: Risk assessment by RIFLE differed in as much as most patients with normothermia and those receiving only cardiovascular bypass developed AKI. However, patients' sex and valve surgery did not serve as a risk factor. CONCLUSION: Evaluation of patients by the RIFLE versus SOP criteria yielded different results with more AKI patients detected by SOP. Based on the present data, it is concluded that patients may not prone to AKI when surgery and ischemia time will be kept short, when blood loss is mitigated to a minimum and when surgery is performed under non-hypothermic conditions.

Altered atrial cytosolic calcium handling contributes to the development of postoperative atrial fibrillation.

AIMS: Atrial fibrillation (AF) is a commonly occurring arrhythmia after cardiac surgery (postoperative AF, poAF) and is associated with poorer outcomes. Considering that reduced atrial contractile function is a predictor of poAF and that Ca2+ plays an important role in both excitation-contraction coupling and atrial arrhythmogenesis, this study aims to test whether alterations of intracellular Ca2+ handling contribute to impaired atrial contractility and to the arrhythmogenic substrate predisposing patients to poAF. METHODS AND RESULTS: Right atrial appendages were obtained from patients in sinus rhythm undergoing open-heart surgery. Cardiomyocytes were investigated by simultaneous measurement of [Ca2+]i and action potentials (APs, patch-clamp). Patients were followed-up for 6 days to identify those with and without poAF. Speckle-tracking analysis of preoperative echocardiography revealed reduced left atrial contraction strain in poAF patients. At the time of surgery, cellular Ca2+ transients (CaTs) and the sarcoplasmic reticulum (SR) Ca2+ content were smaller in the poAF group. CaT decay was slower in poAF, but the decay of caffeine-induced Ca2+ transients was unaltered, suggesting preserved sodium-calcium exchanger function. In agreement, western blots revealed reduced SERCA2a expression in poAF patients but unaltered phospholamban expression/phosphorylation. Computational modelling indicated that reduced SERCA activity promotes occurrence of CaT and AP alternans. Indeed, alternans of CaT and AP occurred more often and at lower stimulation frequencies in atrial myocytes from poAF patients. Resting membrane potential and AP duration were comparable between both groups at various pacing frequencies (0.25-8 Hz). CONCLUSIONS: Biochemical, functional, and modelling data implicate reduced SERCA-mediated Ca2+ reuptake into the SR as a major contributor to impaired preoperative atrial contractile function and to the pre-existing arrhythmogenic substrate in patients developing poAF.

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.

Sarcopenia as Prognostic Factor in Lung Cancer Patients: A Systematic Review and Meta-analysis.

BACKGROUND/AIM: Sarcopenia describes the loss of skeletal muscle mass. While this condition is associated with a high mortality in cancer patients, its influence on survival is still underestimated. PATIENTS AND METHODS: A systematic review for articles was performed using the PubMed database, Cochrane Library, Biomed Central, Science Direct and by manual search. We used data of overall survival in sarcopenic patients for assessing the death risk. We extracted hazard ratio estimates from univariate and multivariate Cox proportional hazards models for meta-analysis. RESULTS: A total of 15 studies were eligible for meta-analysis including a total of 2,521 lung cancer patients. Univariate meta-analysis revealed a two-fold increased death risk in sarcopenic patients; multivariate meta-analysis yielded a significant, three-fold elevated risk of death. This higher mortality is independent of tumour stage. CONCLUSION: Muscle loss is an independent risk factor for increased death risk in lung cancer patients independent of cancer stage. This argues for implementing screening for sarcopenia into cancer care.

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.

Minimally invasive versus conventional extracorporeal circulation circuits in patients undergoing coronary artery bypass surgery: a propensity-matched analysis.

OBJECTIVES: Minimally invasive extracorporeal circulation circuits provide several advantages compared to conventional extracorporeal circulation circuits. We compared the results of a minimally invasive extracorporeal circulation system with those of conventional extracorporeal circulation system, in patients undergoing isolated coronary artery bypass grafting. METHODS: We identified 753 consecutive patients who underwent coronary artery bypass grafting at our centre between October 2014 and September 2016. These patients were divided into two groups: a minimally invasive extracorporeal circulation group (M, n = 229) and a conventional extracorporeal circulation group (C, n = 524). Baseline parameters, details of cardiac surgery as well as postoperative complications and outcomes were compared by means of a propensity-matched analysis of 180 matched pairs. RESULTS: The median EuroSCORE II was 1.3%. Transfusion requirement of packed red blood cells (p = 0.002) was lower in Group M compared to conventional extracorporeal circulation systems. There were no differences in hospital mortality or in rates of adverse events between the matched groups. Total in-hospital mortality of the cohort was 1.7%. CONCLUSION: The use of minimally invasive extracorporeal circulation is associated with a significantly lower use of blood products after isolated coronary revascularisation. There were no differences concerning duration of surgery, complication rates and mortality between the groups. Therefore, the application of minimally invasive extracorporeal circulation systems should be considered as preferred technique in isolated coronary artery bypass grafting procedures.

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.

Urinary neutrophil gelatinase-associated lipocalin-guided risk assessment for major adverse kidney events after open-heart surgery.

AIM: To assess weather doctors' clinical risk-assessment for major adverse kidney events (MAKE) and acute kidney injury (AKI) after open-heart surgery would improve when being informed about neutrophil gelatinase-associated lipocalin (NGAL) test result at ICU admission. PATIENTS & METHODS: Clinical risk-assessment for MAKE and AKI were performed with and without providing NGAL test result and compared in an exploratory- and a validation-cohort using reclassification metrics, exemplary category-free net reclassification improvement (cfNRI). RESULTS: Exploratory cohort: doctors' prediction of MAKE (cfNRI = 0.750 [0.130-1.370]; p = 0.018) and AKI (cfNRI = 0.565 [0.001-1.129]; p = 0.049) improved being provided with NGAL test information. This finding was confirmed in the validation-cohort (MAKE cfNRI = 0.930 [0.188-1.672]; p = 0.014) and the combined-cohort (MAKE: cfNRI = 0.847 [0.371-1.323], p < 0.001); AKI: cfNRI = 0.468 [0.099-0.836; p = 0.013]). Improvements mostly generated from correctly reclassifying patients who not developed events (p < 0.001). CONCLUSION: Biomarker informed risk-assessment is superior in predicting MAKE and AKI after open-heart surgery.

Generation of functional cardiomyocytes from rat embryonic and induced pluripotent stem cells using feeder-free expansion and differentiation in suspension culture.

The possibility to generate cardiomyocytes from pluripotent stem cells in vitro has enormous significance for basic research, disease modeling, drug development and heart repair. The concept of heart muscle reconstruction has been studied and optimized in the rat model using rat primary cardiovascular cells or xenogeneic pluripotent stem cell derived-cardiomyocytes for years. However, the lack of rat pluripotent stem cells (rPSCs) and their cardiovascular derivatives prevented the establishment of an authentic clinically relevant syngeneic or allogeneic rat heart regeneration model. In this study, we comparatively explored the potential of recently available rat embryonic stem cells (rESCs) and induced pluripotent stem cells (riPSCs) as a source for cardiomyocytes (CMs). We developed feeder cell-free culture conditions facilitating the expansion of undifferentiated rPSCs and initiated cardiac differentiation by embryoid body (EB)-formation in agarose microwell arrays, which substituted the robust but labor-intensive hanging drop (HD) method. Ascorbic acid was identified as an efficient enhancer of cardiac differentiation in both rPSC types by significantly increasing the number of beating EBs (3.6 ± 1.6-fold for rESCs and 17.6 ± 3.2-fold for riPSCs). These optimizations resulted in a differentiation efficiency of up to 20% cTnTpos rPSC-derived CMs. CMs showed spontaneous contractions, expressed cardiac markers and had typical morphological features. Electrophysiology of riPSC-CMs revealed different cardiac subtypes and physiological responses to cardio-active drugs. In conclusion, we describe rPSCs as a robust source of CMs, which is a prerequisite for detailed preclinical studies of myocardial reconstruction in a physiologically and immunologically relevant small animal model.

A Rare Complication of TEVAR Performed for Complex Acute Stanford B Aortic Dissection.

Management of aortic dissection with a novel endovascular technique known as thoracic endovascular aortic repair (TEVAR) paired with surgical debranching as a less invasive alternative to conventional repair has gained widespread acceptance. However, experience for complicated, Stanford type B dissection involving the aortic arch is still limited.

Impact of minimally invasive extracorporeal circuits on octogenarians undergoing coronary artery bypass grafting. Have we been looking in the wrong direction?

OBJECTIVES: Minimally invasive extracorporeal circuits (MiECCs) aim at the preservation of physiologic reserves, the impact of which is expected to be most evident in patients in whom these are depleted. In this context, octogenarians present a subpopulation of specific interest. METHODS: Based on the type of the utilized ECC, we performed a retrospective comparison between all octogenarians (n = 324) who received a primary coronary artery bypass in our institution from 2003 until 2010. RESULTS: An MiECC was used in 52% of patients. Preoperative variables showed that the MiECC patients were older (83 ± 2 vs 82 ± 2 years; P = 0.001), had higher incidence of renal dysfunction (8% vs 3%; P = 0.04), moderately reduced left ventricular function (43 vs 33%; P = 0.07) and lower incidence of unstable angina (20% vs 28%; P = 0.06). To overcome these differences, a propensity score matching was performed and yielded 126 matched pairs of patients. The overall transfusion of packed red blood cells (2.3 ± 2.3 vs 3.4 ± 3.2 units per patint; P = <0.001), the rate of low cardiac output (0% vs 6%; P = 0.01) and the 30-day postoperative mortality (2.4% vs 9.5%; P = 0.02) were all in favour of the MiECC group in the matched patient population. CONCLUSIONS: The MiECC concept has shown its benefits regarding both morbidity and mortality in this high-risk patient population. We believe that this beneficial effect finds its reason in a better preservation of physiologic reserves that are essential for a positive outcome in this patient group.

Transplantation of purified iPSC-derived cardiomyocytes in myocardial infarction.

BACKGROUND: Induced pluripotent stem cells (iPSC) can be differentiated into cardiomyocytes and represent a possible autologous cell source for myocardial repair. We analyzed the engraftment and functional effects of murine iPSC-derived cardiomyocytes (iPSC-CMs) in a murine model of myocardial infarction. METHODS AND RESULTS: To maximize cardiomyocyte yield and purity a genetic purification protocol was applied. Murine iPSCs were genetically modified to express a Zeocin™ resistance gene under control of the cardiac-specific α-myosin heavy chain (α-MHC, MYH6) promoter. Thus, CM selection was performed during in vitro differentiation. iPSC-CM aggregates ("cardiac bodies", CBs) were transplanted on day 14 after LAD ligation into the hearts of previously LAD-ligated mice (800 CBs/animal; 2-3x106 CMs). Animals were treated with placebo (PBS, n = 14) or iPSC-CMs (n = 35). Myocardial remodeling and function were evaluated by magnetic resonance imaging (MRI), conductance catheter (CC) analysis and histological morphometry. In vitro and in vivo differentiation was investigated. Follow up was 28 days (including histological assessment and functional analysis). iPSC-CM purity was >99%. Transplanted iPSC-CMs formed mature grafts within the myocardium, expressed cardiac markers and exhibited sarcomeric structures. Intramyocardial transplantation of iPSC-CMs significantly improved myocardial remodeling and left ventricular function 28 days after LAD-ligation. CONCLUSIONS: We conclude that iPSCs can effectively be differentiated into cardiomyocytes and genetically enriched to high purity. iPSC derived cardiomyocytes engraft within the myocardium of LAD-ligated mice and contribute to improve left ventricular function.

Perioperative Hemodynamic Instability and Fluid Overload are Associated with Increasing Acute Kidney Injury Severity and Worse Outcome after Cardiac Surgery.

PURPOSE: The study aimed to investigate patients' characteristics, fluid and hemodynamic management, and outcomes according to the severity of cardiac surgery-associated acute kidney injury (CSA-AKI). METHODS: In a single-center, prospective cohort study, we enrolled 282 adult cardiac surgical patients. In a secondary analysis, we assessed preoperative patients' characteristics, physiological variables, and medication for intra- and postoperative fluid and hemodynamic management and outcomes according to CSA-AKI stages by the Renal risk, Injury, Failure, Loss, End-stage renal disease (RIFLE) classification. Variables of fluid and hemodynamic management were further assessed with regard to the need for postoperative renal replacement therapy (RRT) and in-hospital mortality by the area under the curve for the receiver operating characteristic (AUC-ROC) and multivariate regression analysis. RESULTS: Patients with worsening RIFLE stage, were significantly older, had lower estimated glomerular filtration rate and higher body mass index, more peripheral vascular and chronic obstructive pulmonary disease, atrial fibrillation, and prolonged duration of cardiopulmonary bypass (all p < 0.01). Patients with more severe AKI stage stayed longer in the intensive care and hospital, had higher in-hospital mortality, and requirement for RRT (all p < 0.001). Also, with worsening RIFLE stage, patients had lower intraoperative mean arterial pressure (MAP); p = 0.047, despite higher doses of norepinephrine (p < 0.001). The intraoperative MAP showed the best discriminatory ability (AUC-ROC: >0.8) for and was independently associated with RRT and in-hospital mortality. Moreover, with increasing AKI severity, patients received significantly more fluid infusion, and required higher dose of furosemide; nonetheless, they had increased postoperative fluid balance. CONCLUSIONS: In this cohort, reduced MAP and increased fluid balance were independently associated with increased mortality and need for RRT after cardiac surgery.