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.

Membrane saturable absorber mirror (MESAM) in a red-emitting VECSEL for the generation of stable ultrashort pulses.

We present a new saturable absorber device principle which has the potential for broad spectral range applications. An active region membrane is separated from the substrate and placed on a dielectric end mirror. By combining the absorbing membrane with the dielectric mirror to one device we get a membrane saturable absorber mirror (MESAM) which is similar to the well-known semiconductor saturable absorber mirror (SESAM) without the restriction of the stop-band reflectivity of the distributed Bragg reflector (DBR). Stable mode-locking with the MESAM was achieved in a red-emitting VECSEL at a pump power of 4.25 W with a pulse duration of 3.06 ps at 812 MHz repetition rate. We compare the performance and pulses of both SESAM and MESAM in a z-shaped VECSEL cavity.

InGaAsP VECSEL for watt-level output at a wavelength around 765 nm.

We demonstrate a deep-red-emitting vertical external-cavity surface-emitting laser (VECSEL) with an emission wavelength around λ = 765 nm based on InGaAsP/GaInP quantum wells. The quaternary material system was characterized with x-ray diffraction of thin films as the basis for InGaAsP quantum wells, which are incorporated into an 11 × 1 quantum well active region. The surface morphology of the fabricated VECSEL structure is analyzed with atomic force microscopy and the laser is evaluated in a linear cavity for various heatsink temperatures resulting in a watt-level output power of Pmax,-15°C = 1.71 W in a fundamental transverse mode.

High-power quasi-CW diode-pumped 750-nm AlGaAs VECSEL emitting a peak power of 29.6†W and an average power of 8.5†W.

A peak output power of 29.6 W and an average output power of 8.5 W at a wavelength of 750 nm were demonstrated in quasi-CW multi-mode operation using an AlGaAs-based vertical external-cavity surface-emitting laser (VECSEL) diode-pumped at a wavelength of 675 nm. The comparatively low bandgap of the barrier material that was tuned to the pump-photon energy allowed a good compromise between low heat generation due to the quantum defect and strong absorptance of the pump radiation. The limitations for the average output power came mainly from insufficient heat flow from the intra-cavity heat spreader to the heat sink. These results show the potential for power scaling of diode-pumped VECSELs and the importance of effective heat removal.

Microcavity-enhanced Kerr nonlinearity in a vertical-external-cavity surface-emitting laser: erratum.

We correct a mistake in [Opt. Express27, 11914 (2019)10.1364/OE.27.011914] when calculating the focal length of the Kerr lens with the measured values of the nonlinear refractive index n2 and parameters of a prototypical self-mode-locking VECSEL cavity. We therefore update Fig. 1 of the original publication. The new calculation yields a significantly larger value of the Kerr lens focal length leading to a smaller perturbation of the cavity beam profile.

Therapeutic nihilism is inadequate in geriatric medicine.

Patients' wishes should guide therapeutic considerations in the face of options and necessities, particularly when an intervention carries the risk of death. Therefore, in the medical management of the young and the old, everything should be attempted as long as the patient has a strong will to live.

Microcavity-enhanced Kerr nonlinearity in a vertical-external-cavity surface-emitting laser.

Self-mode-locking has become an emerging path to the generation of ultrashort pulses with vertical-external-cavity surface-emitting lasers. In our work, a strong Kerr nonlinearity that is so far assumed to give rise to mode-locked operation is evidenced and a strong nonlinearity enhancement by the microcavity is revealed. We present wavelength-dependent measurements of the nonlinear absorption and nonlinear refractive index change in a gain chip using the Z-scan technique. We report negative nonlinear refraction up to 5x10-12 cm2/W in magnitude in the (InGa)As/Ga(AsP) material system close to the laser design wavelength, which can lead to Kerr lensing. We show that by changing the angle of incidence of the probe beam with respect to the gain chip, the Kerr nonlinearity can be wavelength-tuned, shifting with the microcavity resonance. Such findings may ultimately lead to novel concepts with regard to tailored self-mode-locking behavior achievable by peculiar Kerr-lens chip designs for cost-effective, robust and compact fs-pulsed semiconductor lasers.

Supra-aortic interventions for endovascular exclusion of the entire aortic arch.

OBJECTIVE: Our aim was to analyze the outcomes of endovascular exclusion of the entire aortic arch (proximal landing in zone 0, distal landing in zone III or beyond, after Ishimaru) in which complete surgical debranching of the supra-aortic vessels (I), endovascular supra-aortic revascularization (chimney, fenestrated, or branched grafts) with partial surgical debranching (II), or total endovascular supra-aortic revascularization (III) was additionally performed. METHODS: Publications describing endovascular repair of the aortic arch (2000-2016) were systematically searched and reviewed. RESULTS: From a total of 53 relevant studies including 1853 patients, only 1021 patients undergoing 35 different total aortic arch procedures were found eligible for further evaluation and included in group I, II, or III (429, 190, and 402 patients, respectively). Overall early mortality was higher in group I vs groups II and III (P = .001; 1 - ß = 95.6%) but exceeded in group III (18.6%) and group II (14.0%) vs group I (8.0%; P = .044; 1 - ß = 57.4%) for diseases involving zone 0. Mortality was higher in all subgroups treated for zone 0 disease compared with corresponding subgroups treated for zone I to zone III disease. The incidence of cerebral ischemic events was increased in groups I and II vs group III (7.5% and 11% vs 1.7%; P = .0001) and correlated with early mortality (R2 = .20; P = .033). The incidence of type II endoleaks and endovascular reintervention was similar between groups and correlated with each other (R2 = .37; P = .004). Type Ia endoleak occurred more often in groups II and III than in group I (7.1% and 12.1% vs 5.8%; P = .023) and correlated with midterm mortality (R2 = .53; P = .005). Retrograde type A dissection was low in all groups, whereas aneurysm growth was higher in group III (2.6%, 4.2%, 10.7%; P = .002), correlating with midterm mortality (R2 = .311; P = .009). Surgical revision slightly correlated with surgical complications (R2 = .18; P = .044) but not with mortality (R2 = .10; P = .214). CONCLUSIONS: Because early mortality was significantly higher in patients receiving endovascular treatment for proximal aortic disease, endovascular-based approaches proved to be feasible alternatives to hybrid surgical procedures, especially when they were performed for aneurysms located in the distal aortic arch. Whereas cerebral ischemia accompanies both surgical and endovascular involvement of the supra-aortic vessels, endoleaks and aneurysm growth remain hallmarks of endovascular supra-aortic repair. Because surgical revision had no impact on mortality, complete surgical debranching may become the option of choice for patients with good life expectancy suffering from proximal aortic arch disease, whereas total endovascular procedures could be particularly advantageous in patients with short life expectancy and distal aortic arch disease.

Heart Transplantation in a Toddler with Cardiac Kawasaki Disease.

Kawasaki disease is very rare in Western Europe. The disease may involve coronary arteries. A 2-year-old boy diagnosed with Kawasaki disease had had seizure-like symptoms. Further evaluation revealed recurrent myocardial ischemia and myocardial infarction. Due to extraordinary extension of the coronary disease, myocardial revascularization was not feasible and the toddler underwent successful heart transplantation after 97 days on waiting list.

A minimally invasive approach for open surgical thoracoabdominal aortic replacement: experimental concept for a novel surgical procedure.

Objectives: We aimed to develop a simple, reliable, and timesaving technique for the therapy of thoracoabdominal aortic (TAA) aneurysms that are not suitable for endovascular repair. Methods: In this pilot study, we sought to combine the advantages of classic open vascular procedure with the use of endoscopic surgical tools and small skin incisions to develop a minimally invasive approach for TAA replacement. The following procedures were used: endoscopic exposure and closure of the lower intercostal arteries; small posterolateral thoracotomy and left retroperitoneal incisions to expose the anastomotic regions of the aorta; partial anticoagulation; passive bypass and sequential aortic clamping; tunnelling of the graft through the native aortic lumen (endoaneurysmorrhaphy) and open performance of vascular anastomosis. Results: Five mixed-breed dogs (25-35 kg) underwent minimally invasive TAA replacement. All animals survived the operation without blood transfusion (lowest Hb = 5.5 mg/dl). Total operation time was 364 ± 46.3 min. Clamping times were 17.6 ± 3.2 min for proximal anastomosis, 33.2 ± 2.48 min for visceral patch and 11 ± 2.3 min for distal anastomosis. The pull-through procedure of graft through the native aorta was performed during the visceral clamp time. Conclusions: Surgical replacement of the TAA through small transverse incisions of the thoracic and abdominal wall is feasible and allows open performance of all vascular anastomosis with no leakage at any anastomotic site. Further experimental studies and clinical implementation are needed to establish the safety and long-term outcome of minimally invasive TAA replacement as a possible primary therapeutic tool for complex aneurysms that are not suitable for endovascular treatment and require open surgical repair.

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.

Incidence of deep sternal wound infection is not reduced with autologous platelet rich plasma in high-risk cardiac surgery patients.

BACKGROUND: Deep sternal wound infections (DSWI) remain a devastating complication in cardiac surgery applying full sternotomy. As the risk profile in cardiac surgery changed toward an older and sicker population, the incidence of DSWI increases. Platelet rich plasma (PRP) holds promise in tissue regeneration with respect to bone regeneration, reduction of bleeding, and accelerated wound healing. The effect of PRP on DSWI was investigated in high-risk patients undergoing cardiac surgery with full sternotomy. METHODS: 196 consecutive patients at risk of DSWI were randomized to application of autologous PRP before sternal wiring (n = 97) or control (n = 99). All patients underwent cardiac surgery on cardiopulmonary bypass with cardioplegic cardiac arrest. Endpoint was occurrence of DSWI requiring revision surgery. RESULTS: Demographic, intraoperative, and perioperative variables as well as risk factors were comparable between groups. Incidence of DSWI was not different between the PRP-group and the control-group (6/97 (6.2%) vs. 3/99 (3.0%); n.s.). CONCLUSIONS: Local application of autologous PRP in cardiac surgery patients with full sternotomy at high risk for sternal complications did not reduce the incidence of DSWI.

A three-group model to predict mortality in emergent coronary artery bypass graft surgery.

BACKGROUND: Emergent coronary artery bypass graft surgery (CABG) for acute myocardial infarction is associated with an increased operative risk. For estimation of mortality risk, the European System for Cardiac Operative Risk Evaluation (EuroSCORE) is appropriate up to a medium risk score (<6 points). To predict mortality risk more accurately in cases of higher EuroSCORE, additional cardiac data can be helpful. METHODS: Over a 3-year period, patient data including acute myocardial infarction and emergent CABG were retrospectively reviewed. Univariate and multivariate analysis for in-hospital mortality was performed. The EuroSCORE analysis and follow-up was investigated. RESULTS: Overall in-hospital mortality was 18.3%. Preoperative cardiac related predictors for in-hospital mortality were cardiogenic shock (p < 0.001), very poor left ventricular function (p = 0.001), and ST-segment elevation (p = 0.012). In multivariate regression analysis, age, cardiogenic shock, and pulmonary hypertension were independent preoperative risk factors. According to the EuroSCORE, we could define three statistically different groups: intermediate-risk, high-risk, and very high risk, with an observed mortality of 3.3%, 20.0%, and 63.2%, respectively. The EuroSCORE correlates with but overestimates the mortality risk. In subgroup analysis, the creatine kinase-myocardial band/hour ratio for the intermediate-risk group and ST-segment elevation for the high-risk group were additional cardiac risk factors. CONCLUSIONS: Patients with an acute myocardial infarction and emergency aortocoronary CABG have an elevated operative risk. Logistic EuroSCORE overestimates the mortality rate. Three different risk groups can be defined, in which creatine kinase-MB/h-ratio and ST-segment elevation can more accurately predict operative risk.

[Norman Edward Shumway - pioneer of cardiac surgery (February 9, 1923 to February 10, 2006)]. / Norman Edward Shumway - Pionier der Herzchirurgie (9. Februar 1923 bis 10. Februar 2006).

After a fulfilled life, Norman E. Shumway, the great pioneer of cardiac transplantation, died of lung cancer 1 day after his 83rd birthday in Palo Alto, California, USA. Already at the beginning of the 1960s, he and his colleague Richard R. Lower did revolutionary experimental work on developing and establishing the technique of orthotopic cardiac transplantation in dogs. Several studies on cardiac transplantation were carried out in his department and a few years later, Shumway and his team were on their way to perform the worldwide first human-to-human cardiac transplantation. On December 3, 1967, Christiaan Neethling Barnard, a cardiac surgeon from South Africa, forestalled Shumway and performed this operation in Cape Town, South Africa. This event initiated a global boom of cardiac transplantations in the following years." Many heart centers started their own cardiac transplant programs but high mortality rates led again to stagnancy of transplant activities. Shumway remained stable in believing in good results of cardiac transplantation and continued his program steadily. At the beginning of the 1970s, he and his group were responsible for most cardiac transplantations worldwide.

Angiotensin II and myosin light-chain phosphorylation contribute to the stretch-induced slow force response in human atrial myocardium.

AIMS: Stretch is an important regulator of atrial function. The functional effects of stretch on human atrium, however, are poorly understood. Thus, we characterized the stretch-induced force response in human atrium and evaluated the underlying cellular mechanisms. METHODS AND RESULTS: Isometric twitch force of human atrial trabeculae (n = 252) was recorded (37 degrees C, 1 Hz stimulation) following stretch from 88 (L88) to 98% (L98) of optimal length. [Na(+)](i) and pH(i) were measured using SBFI and BCECF epifluorescence, respectively. Stretch induced a biphasic force increase: an immediate increase [first-phase, Frank-Starling mechanism (FSM)] to approximately 190% of force at L88 followed by an additional slower increase [5-10 min; slow force response (SFR)] to approximately 120% of the FSM. FSM and SFR were unaffected by gender, age, ejection fraction, and pre-medication with major cardiovascular drugs. There was a positive correlation between the amplitude of the FSM and the SFR. [Na(+)](i) rose by approximately 1 mmol/L and pH(i) remained unchanged during the SFR. Inhibition of Na(+)/H(+)-exchange (3 microM HOE642), Na(+)/Ca(2+)-exchange (5 microM KB-R7943), or stretch-activated channels (0.5 microM GsMtx-4 and 80 microM streptomycin) did not reduce the SFR. Inhibition of angiotensin-II (AngII) receptors (5 microM saralasin and 0.5 microM PD123319) or pre-application of 0.5 microM AngII, however, reduced the SFR by approximately 40-60%. Moreover, stretch increased phosphorylation of myosin light chain 2 (MLC2a) and inhibition of MLC kinase (10 microM ML-7 and 5 microM wortmannin) decreased the SFR by approximately 40-85%. CONCLUSION: Stretch elicits a SFR in human atrium. The atrial SFR is mediated by stretch-induced release and autocrine/paracrine actions of AngII and increased myofilament Ca(2+) responsiveness via phosphorylation of MLC2a by MLC kinase.

Miniaturized HIA microdiagonal pump as left ventricular assist device in a sheep model.

We evaluated the newly developed miniaturized HIA microdiagonal blood pump (MDP) as a continuous flow left ventricular assist device. In a sheep model (n = 6), the MDP was implanted through left lateral thoracotomy and placed paracorporeally with inflow conduit to left atrium and outflow conduit to descending aorta. The sheep were pumped at a mean flow rate of 2.5 L/min for 7 days. Anticoagulation was applied by intravenous heparin administration. Postoperatively, activated clotting time was held stable with values of 200 seconds. During follow-up, blood samples (creatinine kinase, creatinine, glutamic-oxaloacetic transaminase (aspartate aminotransferase) (GOT), glutamate dehydrogenase (GLDH), gamma-GT, plasma-free hemoglobin, and hemoglobine) were taken daily. After 7 days, the sheep were killed for macroscopic examination. Systemic artery pressures remained stable during the whole test period. Because of operative reasons, the hemoglobin value (7.5 +/- 0.61 g/dl) decreased perioperatively, but recovered within the test period, whereas creatinine kinase increased initially after thoracotomy, but decreased to normal within days. Renal and liver functions were slightly impaired perioperatively, indicated by temporarily enhanced values of GOT, gamma-GT, GLDH, and creatinine. The MDP did not produce significant hemolysis as measured by plasma-free hemoglobin levels. Wound infections did not occur. We conclude that the MDP ran successfully as an left ventricular assist device for 7 days in sheep has potential for long-term support, and may serve as an alternative to current technologies. Presented data were not obtained in a clinical trial; however, the results are promising enough to proceed with longer duration animal studies.