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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

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.

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.

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.

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.

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.