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In heart failure and atrial fibrillation, a persistent Na+ current (INaL) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that NaV1.8 contributes to arrhythmogenesis by inducing a INaL. Genome-wide association studies indicate that mutations in the SCN10A gene (NaV1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these NaV1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion. We used CRISPR/Cas9 technology to generate homozygous atrial SCN10A-KO-iPSC-CMs. Ruptured-patch whole-cell patch-clamp was used to measure the INaL and action potential duration. Ca2+ measurements (Fluo 4-AM) were performed to analyze proarrhythmogenic diastolic SR Ca2+ leak. The INaL was significantly reduced in atrial SCN10A KO CMs as well as after specific pharmacological inhibition of NaV1.8. No effects on atrial APD90 were detected in any groups. Both SCN10A KO and specific blockers of NaV1.8 led to decreased Ca2+ spark frequency and a significant reduction of arrhythmogenic Ca2+ waves. Our experiments demonstrate that NaV1.8 contributes to INaL formation in human atrial CMs and that NaV1.8 inhibition modulates proarrhythmogenic triggers in human atrial CMs and therefore NaV1.8 could be a new target for antiarrhythmic strategies.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used for personalised medicine and preclinical cardiotoxicity testing. Reports on hiPSC-CM commonly describe heterogenous functional readouts and underdeveloped or immature phenotypical properties. Cost-effective, fully defined monolayer culture is approaching mainstream adoption; however, the optimal age at which to utilise hiPSC-CM is unknown. In this study, we identify, track and model the dynamic developmental behaviour of key ionic currents and Ca2+-handling properties in hiPSC-CM over long-term culture (30–80 days). hiPSC-CMs > 50 days post differentiation show significantly larger ICa,L density along with an increased ICa,L-triggered Ca2+-transient. INa and IK1 densities significantly increase in late-stage cells, contributing to increased upstroke velocity and reduced action potential duration, respectively. Importantly, our in silico model of hiPSC-CM electrophysiological age dependence confirmed IK1 as the key ionic determinant of action potential shortening in older cells. We have made this model available through an open source software interface that easily allows users to simulate hiPSC-CM electrophysiology and Ca2+-handling and select the appropriate age range for their parameter of interest. This tool, together with the insights from our comprehensive experimental characterisation, could be useful in future optimisation of the culture-to-characterisation pipeline in the field of hiPSC-CM research.

The sodium channel Na

An interplay between Ca2+/calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na+ current (INaL) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform NaV1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of NaV1.8, we demonstrate that NaV1.8 contributes to INaL formation. In addition, we reveal a direct interaction between NaV1.8 and CaMKIIδc in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of NaV1.8 and CaMKIIδc, we show that NaV1.8-driven INaL is CaMKIIδc-dependent and that NaV1.8-inhibtion reduces diastolic SR-Ca2+ leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKIIδc-overexpressing HF mice is reduced when a NaV1.8 knock-out is introduced. Cellular and in vivo experiments reveal reduced ventricular arrhythmias without changes in HF progression. Our work therefore identifies a proarrhythmic CaMKIIδc downstream target which may constitute a prognostic and antiarrhythmic strategy., In heart failure, increased CaMKII activity is decisively involved in arrhythmia formation. Here, the authors introduce the neuronal sodium channel NaV1.8 as a CaMKII downstream target as its specific knock-out reduces arrhythmias and improves survival in a CaMKII-overexpressing mouse model.

Background In heart failure (HF) both Ca2+/Calmodulin-dependent protein-kinase II (CaMKII) and late sodium current (INaL) are known to contribute to arrhythmogenesis as they contribute to action-potential (AP) prolongation and the occurrence of early- (EADs) and delayed afterdepolarizations (DADs). Further, augmented CaMKII and INaL maintain a vicious cycle as they both can activate each other. We recently found that the sodium channel isoform NaV1.8 is upregulated in HF and hypertrophy and that it is involved in INaL-generation. In the current study we investigated the effects of NaV1.8-knock-out (KO) on HF-progression and arrhythmogenesis in a CaMKII-overexpressing HF mouse model. Methods/Results CaMKII overexpressing mice (CaMKII+/T) were crossbred with NaV1.8-KO mice (SCN10A−/−). To our surprise knock-out of NaV1.8 in CaMKII+/T mice (SCN10A−/−/CaMKII+/T) significantly improved survival (median survival 103 days vs 74.5 CaMKII+/T, p Conclusion We found a survival benefit by selective knock-out of the neuronal sodium channel isoform NaV1.8 in a proarrhythmic HF mouse model with augmented CaMKII expression. However, in our model NaV1.8-knock-out showed no effects on HF progression, while cellular proarrhythmic triggers were attenuated. Taken together with our findings in IPS-cardiomyocytes treated with the CRSIPR/Cas9 technology NaV1.8 plays a significant role for the generation of INaL and cellular arrhythmogenic triggers in the cardiomyocyte. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Deutsche Stiftung für Herzforschung

Aims In heart failure (HF), enhanced persistent Na+ current (I-NaL) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. However, the underlying regulatory mechanisms remain unclear. Our aim was to potentially investigate the regulation and electrophysiological contribution of neuronal sodium channel Na(V)1.8 in failing human heart and eventually to reveal a novel anti-arrhythmic therapy Methods and results By western blot, we found that Na(V)1.8 protein expression is significantly up-regulated, while of the predominant cardiac isoform Na(V)1.5 is inversely reduced in human HF. Furthermore, to investigate the relation of Na(V)1.8 regulation with the cellular proarrhythmic events, we performed comprehensive electrophysiology recordings and explore the effect of Na(V)1.8 on I-NaL, action potential duration (APD), Ca2+ spark frequency, and arrhythmia induction in human failing cardiomyocytes. Na(V)1.8 inhibition with the specific blockers A-803467 and PF-01247324 decreased I-NaL, abbreviated APD and reduced cellular-spontaneous Ca2+-release and proarrhythmic events in human failing cardiomyocytes. Consistently, in mouse cardiomyocytes stressed with isoproterenol, pharmacologic inhibition and genetically knockout of Na(V)1.8 (SCN10A(-/-)), were associated with reduced I-NaL and abbreviated APD Conclusion We provide first evidence of differential regulation of Na(V)1.8 and Na(V)1.5 in the failing human myocardium and their contribution to arrhythmogenesis due to generation of I-NaL. We propose inhibition of Na(V)1.8 thus constitutes a promising novel approach for selective anti-arrhythmic therapy in HF.

In heart failure, left ventricular assist device (LVAD) implantation is performed to ensure sufficient cardiac output. Whereas some patients are subsequently weaned from LVAD support, other patients still need heart transplantation. To elucidate underlying mechanisms, we assessed the arrhythmogenic SR-Ca(2+) leak at the time of LVAD implantation (HF-Im) and heart transplantation (HF-Tx) and evaluated the effects of CaMKII-inhibition. Human left-ventricular cardiomyocytes were isolated, paced at 1 Hz for 10 beats to ensure SR-Ca(2+) loading and scanned for diastolic Ca(2+) sparks (confocal microscopy). In HF-Im, the high diastolic spark frequency (CaSpF) of 0.76 ± 0.12 × 100 μm(-1) × s(-1) could be reduced to 0.48 ± 0.10 × 100 μm(-1) × s(-1) by CaMKII inhibition (AIP, 1 μM). The amplitude of Ca(2+) sparks, width, and length was not significantly altered. In sum, CaMKII inhibition yielded a clear tendency toward a reduction of the SR-Ca(2+) leak (n cells/patients = 76/6 vs. 108/6, P = 0.08). In HF-Tx, we detected an even higher CaSpF of 1.00 ± 0.10 100 μm(-1) × s(-1) and a higher SR-Ca(2+) leak compared with HF-Im (increase by 81 ± 33%, n cells/patients = 156/7 vs. 130/7, P

Aims Clinical studies have shown differences in the propensity for malignant ventricular arrhythmias between women and men suffering from cardiomyopathies and heart failure (HF). This is clinically relevant as it impacts therapies like prophylactic implantable cardioverter-defibrillator implantation but the pathomechanisms are unknown. As an increased sarcoplasmic reticulum (SR) Ca2+ leak is arrhythmogenic, it could represent a cellular basis for this paradox. Methods/Results We evaluated the SR Ca2+ leak with respect to sex differences in (i) afterload-induced cardiac hypertrophy (Hy) with preserved left ventricular (LV) function and (ii) end-stage HF. Cardiac function did not differ between sexes in both cardiac pathologies. Human cardiomyocytes isolated from female patients with Hy showed a significantly lower Ca2+ spark frequency (CaSpF, confocal microscopy, Fluo3-AM) compared with men ( P < 0.05). As Ca2+ spark width and duration were similar in women and men, this difference in CaSpF did not yet translate into a significant difference of the calculated SR Ca2+ leak between both sexes at this stage of disease ( P = 0.14). Epifluorescence measurements (Fura2-AM) revealed comparable Ca2+ cycling properties (diastolic Ca2+ levels, amplitude of systolic Ca2+ transients, SR Ca2+ load) in patients of both sexes suffering from Hy. Additionally, the increased diastolic CaSpF in male patients with Hy did not yet translate into an elevated ratio of cells showing arrhythmic events (Ca2+ waves, spontaneous Ca2+ transients) ( P = 0.77). In the transition to HF, both sexes showed an increase of the CaSpF ( P < 0.05) and the sex dependence was even more pronounced. Female patients had a 69 ± 10% lower SR Ca2+ leak ( P < 0.05), which now even translated into a lower ratio of arrhythmic cells in female HF patients compared with men ( P < 0.001). Conclusion These data show that the SR Ca2+ leak is lower in women than in men with comparable cardiac impairment. Since the SR Ca2+ leak triggers delayed afterdepolarizations, our findings may explain why women are less prone to ventricular arrhythmias and confirm the rationale of therapeutic measures reducing the SR Ca2+ leak.

Patients Singleton–Merten syndrome is an extremely rare autosomal dominant condition with less than 10 reported cases in the literature. It is characterized by abnormal aortic calcifications and dental abnormalities. The goal of this case report is to discuss the abnormal oral clinical features and the modified treatment protocol that was used in order to achieve osseointegration of dental implants in a patient having abnormal bone density and bone turnover associated with Singleton–Merten Syndrome. Discussion Following extraction of the remaining teeth, titanium implants (Friadent GmbH, Mannheim, Germany and Straumann ® , Basel, Switzerland) were placed in the upper and lower jaw of the patient. The upper jaw which was treated with dental implants, received a bar supported implant retained prosthesis and the lower jaw an implant retained telescopic prosthesis. The patient was regularly followed up for the past 13 years during which, clinical and radiological evaluation of osseointegration was undertaken. All the loaded implants showed clinical and radiographic evidence of osseointegration. With a follow up of 13 years after insertion of the first implant, the patient reported functioning well with no complications. Conclusion The treatment with dental implants in the extremely rare Singleton–Merten syndrome patients is a reasonable treatment option to rehabilitate maxillofacial aesthetics and establish normal function of the jaws.

Aims Enhanced cardiac late Na current (late I Na) and increased sarcoplasmic reticulum (SR)-Ca2+-leak are both highly arrhythmogenic. This study seeks to identify signalling pathways interconnecting late I Na and SR-Ca2+-leak in atrial cardiomyocytes (CMs). Methods and results In murine atrial CMs, SR-Ca2+-leak was increased by the late I Na enhancer Anemonia sulcata toxin II (ATX-II). An inhibition of Ca2+/calmodulin-dependent protein kinase II (Autocamide-2-related inhibitory peptide), protein kinase A (H89), or late I Na (Ranolazine or Tetrodotoxin) all prevented ATX-II-dependent SR-Ca2+-leak. The SR-Ca2+-leak induction by ATX-II was not detected when either the Na+/Ca2+ exchanger was inhibited (KBR) or in CaMKIIδc-knockout mice. FRET measurements revealed increased cAMP levels upon ATX-II stimulation, which could be prevented by inhibition of adenylyl cyclases (ACs) 5 and 6 (NKY 80) but not by inhibition of phosphodiesterases (IBMX), suggesting PKA activation via an AC-dependent increase of cAMP levels. Western blots showed late I Na-dependent hyperphosphorylation of CaMKII as well as PKA target sites at ryanodine receptor type-2 (-S2814 and -S2808) and phospholamban (-Thr17, -S16). Enhancement of late I Na did not alter Ca2+-transient amplitude or SR-Ca2+-load. However, upon late I Na activation and simultaneous CaMKII inhibition, Ca2+-transient amplitude and SR-Ca2+-load were increased, whereas PKA inhibition reduced Ca2+-transient amplitude and load and additionally slowed Ca2+ elimination. In atrial CMs from patients with atrial fibrillation, inhibition of late I Na, CaMKII, or PKA reduced the SR-Ca2+-leak. Conclusion Late I Na exerts distinct effects on Ca2+ homeostasis in atrial myocardium through activation of CaMKII and PKA. Inhibition of late I Na represents a potential approach to attenuate CaMKII activation and decreases SR-Ca2+-leak in atrial rhythm disorders. The interconnection with the cAMP/PKA system further increases the antiarrhythmic potential of late I Na inhibition.

Background and objectives Aggressive Periodontitis is associated with higher risk of periimplantitis and lower implant survival. Glucose-6-phosphate dehydrogenase (G6pd) deficiency is an enzymatic disorder which may produce hemolytic anemia in red blood cells. Since G6pd helps to maintain intracellular redox potential, a deficiency produces a weak interface at the marginal gingiva and additionally a reduced wound healing due to hemolysis. This case report discusses the clinical features and treatment protocol used to achieve osseointegration of dental implants in grafted and non grafted regions in a patient having aggressive periodontitis, congenital G6pd deficiency, refractory to conventional periodontal therapy. Methods Following extraction of the remaining teeth, 10 titanium implants (Straumann AG) were placed, starting with 4 implants in the mandible. After 5 years, augmentation of the extremely atrophic maxilla was performed. On one side the augmentation failed, however a total of 6 implants could be placed in the maxilla. The patient was followed up regularly for 15 years. Results The long term follow up (9 years in the maxilla and 15 years in the mandible) of the inserted implants showed 100% success rate. Conclusion Rehabilitation with dental implants in patients having aggressive periodontitis is a reasonable treatment option to restore maxillo-mandibular function and esthetics.

Increased sarcoplasmic reticulum (SR) Ca2+ leak via the cardiac ryanodine receptor (RyR2) has been suggested to play a mechanistic role in the development of heart failure (HF) and cardiac arrhythmia. Mice treated with a selective RyR2 stabilizer, rycal S36, showed normalization of SR Ca2+ leak and improved survival in pressure overload (PO) and myocardial infarction (MI) models. The development of HF, measured by echocardiography and molecular markers, showed no difference in rycal S36- versus placebo-treated mice. Reduction of SR Ca2+ leak in the PO model by the rycal-unrelated RyR2 stabilizer dantrolene did not mitigate HF progression. Development of HF was not aggravated by increased SR Ca2+ leak due to RyR2 mutation (R2474S) in volume overload, an SR Ca2+ leak-independent HF model. Arrhythmia episodes were reduced by rycal S36 treatment in PO and MI mice in vivo and ex vivo in Langendorff-perfused hearts. Isolated cardiomyocytes from murine failing hearts and human ventricular failing and atrial nonfailing myocardium showed reductions in delayed afterdepolarizations, in spontaneous and induced Ca2+ waves, and in triggered activity in rycal S36 versus placebo cells, whereas the Ca2+ transient, SR Ca2+ load, SR Ca2+ adenosine triphosphatase function, and action potential duration were not affected. Rycal S36 treatment of human induced pluripotent stem cells isolated from a patient with catecholaminergic polymorphic ventricular tachycardia could rescue the leaky RyR2 receptor. These results suggest that SR Ca2+ leak does not primarily influence contractile HF progression, whereas rycal S36 treatment markedly reduces ventricular arrhythmias, thereby improving survival in mice.

The aim of the study was to determine the characteristics of the late Na current (INaL) and its arrhythmogenic potential in the progression of pressure-induced heart disease. Transverse aortic constriction (TAC) was used to induce pressure overload in mice. After one week the hearts developed isolated hypertrophy with preserved systolic contractility. In patch-clamp experiments both, INaL and the action potential duration (APD90) were unchanged. In contrast, after five weeks animals developed heart failure with prolonged APDs and slowed INaL decay time which could be normalized by addition of the INaL inhibitor ranolazine (Ran) or by the Ca/calmodulin-dependent protein kinase II (CaMKII) inhibitor AIP. Accordingly the APD90 could be significantly abbreviated by Ran, tetrodotoxin and the CaMKII inhibitor AIP. Isoproterenol increased the number of delayed afterdepolarizations (DAD) in myocytes from failing but not sham hearts. Application of either Ran or AIP prevented the occurrence of DADs. Moreover, the incidence of triggered activity was significantly increased in TAC myocytes and was largely prevented by Ran and AIP. Western blot analyses indicate that increased CaMKII activity and a hyperphosphorylation of the Nav1.5 at the CaMKII phosphorylation site (Ser571) paralleled our functional observations five weeks after TAC surgery. In pressure overload-induced heart failure a CaMKII-dependent augmentation of INaL plays a crucial role in the AP prolongation and generation of cellular arrhythmogenic triggers, which cannot be found in early and still compensated hypertrophy. Inhibition of INaL and CaMKII exerts potent antiarrhythmic effects and might therefore be of potential therapeutic interest. This article is part of a Special Issue entitled “Na+ Regulation in Cardiac Myocytes”.

TBC1D10C is a protein previously demonstrated to bind and inhibit Ras and Calcineurin. In cardiomyocytes, also CaMKII is inhibited and all three targeted enzymes are known to promote maladaptive cardiomyocyte hypertrophy. Here, in accordance with lack of Calcineurin inhibition in vivo, we did not observe a relevant anti-hypertrophic effect despite inhibition of Ras and CaMKII. However, cardiomyocyte-specific TBC1D10C overexpressing transgenic mice exhibited enhanced longevity. Ejection fraction and exercise capacity were enhanced in transgenic mice, but shortening of isolated cardiomyocytes was not increased. This suggests longevity resulted from enhanced cardiac performance but independent of cardiomyocyte contractile force. In further search for mechanisms, a transcriptome-wide analysis revealed expressional changes in several genes pertinent to control of heart rate (HR) including Hcn4, Scn10a, Sema3a and Cacna2d2. Indeed, telemetric holter recordings demonstrated slower atrial conduction and significantly lower HR. Pharmacological reduction of HR was previously demonstrated to enhance survival in mice. Thus, in addition to inhibition of stress signaling, TBC1D10C economizes generation of cardiac output via HR reduction, enhancing exercise capacity and survival. TBC1D10C may be a new target for HR reduction and longevity.

Background Cardiac type 2 ryanodine receptors (RyR2s) play a pivotal role in cellular electrophysiology and contractility. Increased RyR2-mediated diastolic sarcoplasmic reticulum (SR) Ca2+ release is linked to heart failure (HF) and arrhythmias. Dantrolene, a drug used for the treatment of malignant hyperthermia, is known to stabilize RyRs in skeletal muscle. Objective The purpose of this study was to investigate the effects of dantrolene on arrhythmogenic triggers and contractile function in human atrial fibrillation (AF) and HF cardiomyocytes (CM). Methods Human CM were isolated from either patients with HF (ventricular) or patients with AF (atrial), and Ca2+ imaging, patch-clamp, or muscle strip experiments were performed. Results After exposure to dantrolene, human atrial AF and left ventricular HF CM showed significant reductions in proarrhythmic SR Ca2+ spark frequency and diastolic SR Ca2+ leak. Moreover, dantrolene decreased the frequency of Ca2+ waves and spontaneous Ca2+ transients in HF CM. Patch-clamp experiments revealed that dantrolene significantly suppressed delayed afterdepolarizations in HF and AF CM. Importantly, dantrolene had no effect on action potential duration in AF or in HF CM. In addition, dantrolene had neutral effects on contractile force of human isometrically twitching ventricular HF trabeculae. Conclusion Our study showed that dantrolene beneficially influenced disrupted SR Ca2+ homeostasis in human HF and AF CM. Cellular arrhythmogenic triggers were potently suppressed by dantrolene, whereas action potential duration and contractility were not affected. As a clinically approved drug for the treatment of malignant hyperthermia, dantrolene may be a potential antiarrhythmic drug for patients with rhythm disorders and merits further clinical investigation.

In heart failure, left ventricular assist device (LVAD) implantation is performed to ensure sufficient cardiac output. Whereas some patients are subsequently weaned from LVAD support, other patients still need heart transplantation. To elucidate underlying mechanisms, we assessed the arrhythmogenic SR-Ca(2+) leak at the time of LVAD implantation (HF-Im) and heart transplantation (HF-Tx) and evaluated the effects of CaMKII-inhibition. Human left-ventricular cardiomyocytes were isolated, paced at 1 Hz for 10 beats to ensure SR-Ca(2+) loading and scanned for diastolic Ca(2+) sparks (confocal microscopy). In HF-Im, the high diastolic spark frequency (CaSpF) of 0.76 ± 0.12 × 100 μm(-1) × s(-1) could be reduced to 0.48 ± 0.10 × 100 μm(-1) × s(-1) by CaMKII inhibition (AIP, 1 μM). The amplitude of Ca(2+) sparks, width, and length was not significantly altered. In sum, CaMKII inhibition yielded a clear tendency toward a reduction of the SR-Ca(2+) leak (n cells/patients = 76/6 vs. 108/6, P = 0.08). In HF-Tx, we detected an even higher CaSpF of 1.00 ± 0.10 100 μm(-1) × s(-1) and a higher SR-Ca(2+) leak compared with HF-Im (increase by 81 ± 33%, n cells/patients = 156/7 vs. 130/7, P 0.05), which fits to the further decreased LV function. Here, CaMKII inhibition likewise reduced CaSpF (0.35 ± 0.09 100 μm(-1) × s(-1,) P = 0.06) and significantly reduced spark duration (n sparks/patients = 58/3 vs. 159/3, P 0.05). Conclusively, the SR-Ca(2+) leak was reduced by 69 ± 12% in HF-Tx upon CaMKII inhibition (n cells/patients = 53/3 vs. 91/3, P 0.05). These data show that the SR-Ca(2+) leak correlates with the development of LV function after LVAD implantation and may represent an important pathomechanism. The fact that CaMKII inhibition reduces the SR-Ca(2+) leak in HF-Tx suggests that CaMKII inhibition may be a promising option to beneficially influence clinical course after LVAD implantation.

Introduction Pharmacological rhythm control of atrial fibrillation (AF) in patients with structural heart disease is limited. Ranolazine in combination with low dose dronedarone remarkably reduced AF-burden in the phase II HARMONY trial. We thus aimed to investigate the possible mechanisms underlying these results. Methods and results Patch clamp experiments revealed that ranolazine (5 μM), low-dose dronedarone (0.3 μM), and the combination significantly prolonged action potential duration (APD90) in atrial myocytes from patients in sinus rhythm (prolongation by 23.5 ± 0.1%, 31.7 ± 0.1% and 25.6 ± 0.1% respectively). Most importantly, in atrial myocytes from patients with AF ranolazine alone, but more the combination with dronedarone, also prolonged the typically abbreviated APD90 (prolongation by 21.6 ± 0.1% and 31.9 ± 0.1% respectively). It was clearly observed that neither ranolazine, dronedarone nor the combination significantly changed the APD or contractility and twitch force in ventricular myocytes or trabeculae from patients with heart failure (HF). Interestingly ranolazine, and more so the combination, but not dronedarone alone, caused hyperpolarization of the resting membrane potential in cardiomyocytes from AF. As measured by confocal microscopy (Fluo-3), ranolazine, dronedarone and the combination significantly suppressed diastolic sarcoplasmic reticulum (SR) Ca2 + leak in myocytes from sinus rhythm (reduction by ranolazine: 89.0 ± 30.7%, dronedarone: 75.6 ± 27.4% and combination: 78.0 ± 27.2%), in myocytes from AF (reduction by ranolazine: 67.6 ± 33.7%, dronedarone: 86.5 ± 31.7% and combination: 81.0 ± 33.3%), as well as in myocytes from HF (reduction by ranolazine: 64.8 ± 26.5% and dronedarone: 65.9 ± 29.3%). Conclusions Electrophysiological measurements during exposure to ranolazine alone or in combination with low-dose dronedarone showed APD prolongation, cellular hyperpolarization and reduced SR Ca2 + leak in human atrial myocytes. The combined inhibitory effects on various currents, in particular Na+ and K+ currents, may explain the anti-AF effects observed in the HARMONY trial. Therefore, the combination of ranolazine and dronedarone, but also ranolazine alone, may be promising new treatment options for AF, especially in patients with HF, and merit further clinical investigation.

The use of dental implants for the rehabilitation of missing teeth has broadened the treatment options for patients and clinicians equally. As a result of advances in research in implant design, materials and techniques the use of dental implants has increased dramatically in the past two decades and is expected to expand further in the future. However the clinical complexity of the patient who present with limited bone volume often requires additional biomaterials and surgical procedures to ensure successful implant treatment. This review outlines the various biomaterials used in augmenting bone deficiencies encountered and the different surgical techniques that are used in order to achieve a predictable long term success of dental implants.

Autofahrer erwarten von jeder neuen Fahrzeuggeneration mehr Komfort, Sicherheit und Zuverlassigkeit. Entsprechend wachsen der Anteil der Automobilelektronik und die Anzahl elektronischer Funktionen. Dadurch erhohen sich nicht nur die Komplexitat in der Entwicklung, sondern auch die Anforderungen an das Testen. Am Beispiel der Bedieneinheit fur einen Dachhimmel beschreibt die Mbtech Group den automatisierten Test von Steuergeraten.

Objective Enhanced late Na current (late I Na ) induces Na-dependent Ca overload as well as proarrhythmogenic events on the cellular level that include spatio-temporally uncoordinated diastolic Ca release from the sarcoplasmic reticulum (SR) and delayed afterdepolarizations (DADs). The Ca/calmodulin-dependent protein kinase II (CaMKII) gets activated upon increases in [Ca] i and mediates diastolic SR Ca leak as well as DADs. Rationale We hypothesized that increased late I Na (in disease-comparable ranges) exerts proarrhythmogenic events in isolated ventricular mouse myocytes in a manner depending on CaMKII-dependent SR Ca leak. We further tested whether inhibition of disease-related late I Na may reduce proarrhythmogenic SR Ca leak in myocytes from failing human hearts. Methods Ventricular myocytes were isolated from healthy wildtype (WT), failing CaMKIIδ C transgenic (TG) mouse, and failing human hearts. ATX-II (0.25–10 nmol/L) was used to enhance late I Na . Spontaneous Ca loss from the SR during diastole (Ca sparks), DADs, non-triggered diastolic Ca transients in myocytes and premature beats of isometrically twitching papillary muscles were used as readouts for proarrhythmogenic events. CaMKII autophosphorylation was assessed by immunoblots. Late I Na was inhibited using ranolazine (Ran, 10 μmol/L) or TTX (2 μmol/L), and CaMKII by KN-93 (1 μmol/L) or AIP (1 μmol/L). Results In WT myocytes, sub-nanomolar ATX-II exposure (0.5 nmol/L) enhanced late I Na by ~ 60%, which resulted in increased diastolic SR Ca loss despite unaltered SR Ca content. In parallel, DADs and non-triggered diastolic Ca transients arose. Inhibition of enhanced late I Na by RAN or TTX significantly attenuated diastolic SR Ca loss and suppressed DADs as well as mechanical alternans in mouse and diastolic SR Ca loss in failing human myocytes. ATX-II caused Ca-dependent CaMKII-activation without changes in protein expression, which was reversible by Ran or AIP. Conversely, CaMKII-inhibition decreased diastolic SR Ca loss, DADs and non-triggered diastolic Ca transients despite ATX-II-exposure. Finally, failing mouse myocytes with increased CaMKII activity (TG CaMKIIδ C ) showed an even aggravated diastolic SR Ca loss that was associated with an increased frequency of non-triggered diastolic Ca transients upon enhanced late I Na. Conclusions Increased late I Na (in disease-comparable ranges) induces proarrhythmogenic events during diastole in healthy and failing mouse myocytes, which are mediated via CaMKII-dependent SR Ca loss. Inhibition of late I Na not only attenuated these cellular arrhythmias in mouse myocytes but also in failing human myocytes indicating some antiarrhythmic potential for an inhibition of the elevated late I Na /CaMKII signaling pathway in this setting.

Drivers have come to expect an increase in comfort, safety, and reliability from every new vehicle generation. Consequently the share of electronics in the total value of a car is rising with the ever increasing number of available electronic functions. The resulting increase in complexity is not solely a development issue, but more importantly, leads to an ever greater importance of testing and validation. By example of the Roof Control Module the Mbtech Group shows automatic testing of control units.