Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF.

AIMS: Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality. Importantly, atrial remodeling and atrial fibrillation is frequently observed in HFpEF. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently been shown to improve clinical outcomes in HFpEF, and post-hoc analyses suggest atrial antiarrhythmic effects. We tested if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx, which is known to cause atrial arrhythmias, and if that is responsive to treatment with the SGTL2i empagliflozin. METHODS AND RESULTS: Cardiomyocytes were isolated from atrial biopsies of 124 patients (82 with HFpEF) undergoing elective cardiac surgery. Na influx was measured with the Na-dye Asante Natrium Green-2 AM (ANG-2). Compared to patients without heart failure (NF), Na influx was doubled in HFpEF patients (NF vs HFpEF: 0.21±0.02 vs 0.38±0.04 mmol/L/min (N=7 vs 18); p=0.0078). Moreover, late INa (measured via whole-cell patch clamp) was significantly increased in HFpEF compared to NF. Western blot and HDAC4 pulldown assay indicated a significant increase in CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKII-dependent NaV1.5 phosphorylation in HFpEF compared to NF, whereas NaV1.5 protein and mRNA abundance remained unchanged. Consistently, increased Na influx was significantly reduced by treatment with the CaMKII inhibitor autocamtide-2 related inhibitory peptide (AIP), late INa inhibitor tetrodotoxin (TTX) but also with NHE1 inhibitor cariporide. Importantly, empagliflozin abolished both increased Na influx and late INa in HFpEF. Multivariate linear regression analysis, adjusting for important clinical confounders, revealed HFpEF to be an independent predictor for changes in Na handling in atrial cardiomyocytes. CONCLUSION: We show for the first time increased Na influx in human atrial cardiomyocytes from HFpEF patients, partly due to increased late INa and enhanced NHE1-mediated Na influx. Empagliflozin inhibits Na influx and late INa, which could contribute to antiarrhythmic effects in patients with HFpEF.

Inhibition of cardiac potassium currents by oxidation-activated protein kinase A contributes to early afterdepolarizations in the heart.

Reactive oxygen species (ROS) have been shown to prolong cardiac action potential duration resulting in afterdepolarizations, the cellular basis of triggered arrhythmias. As previously shown, protein kinase A type I (PKA I) is readily activated by oxidation of its regulatory subunits. However, the relevance of this mechanism of activation for cardiac pathophysiology is still elusive. In this study, we investigated the effects of oxidation-activated PKA I on cardiac electrophysiology. Ventricular cardiomyocytes were isolated from redox-dead PKA-RI Cys17Ser knock-in (KI) and wild-type (WT) mice and exposed to H2O2 (200 µmol/L) or vehicle (Veh) solution. In WT myocytes, exposure to H2O2 significantly increased oxidation of the regulatory subunit I (RI) and thus its dimerization (threefold increase in PKA RI dimer). Whole cell current clamp and voltage clamp were used to measure cardiac action potentials (APs), transient outward potassium current (Ito) and inward rectifying potassium current (IK1), respectively. In WT myocytes, H2O2 exposure significantly prolonged AP duration due to significantly decreased Ito and IK1 resulting in frequent early afterdepolarizations (EADs). Preincubation with the PKA-specific inhibitor Rp-8-Br-cAMPS (10 µmol/L) completely abolished the H2O2-dependent decrease in Ito and IK1 in WT myocytes. Intriguingly, H2O2 exposure did not prolong AP duration, nor did it decrease Ito, and only slightly enhanced EAD frequency in KI myocytes. Treatment of WT and KI cardiomyocytes with the late INa inhibitor TTX (1 µmol/L) completely abolished EAD formation. Our results suggest that redox-activated PKA may be important for H2O2-dependent arrhythmias and could be important for the development of specific antiarrhythmic drugs.NEW & NOTEWORTHY Oxidation-activated PKA type I inhibits transient outward potassium current (Ito) and inward rectifying potassium current (IK1) and contributes to ROS-induced APD prolongation as well as generation of early afterdepolarizations in murine ventricular cardiomyocytes.

The novel CaMKII inhibitor GS-680 reduces diastolic SR Ca leak and prevents CaMKII-dependent pro-arrhythmic activity.

RATIONALE: Ca/calmodulin-dependent protein kinase II (CaMKII) was shown to increase diastolic sarcoplasmic reticulum (SR) Ca leak, which can result in delayed afterdepolarizations and triggered arrhythmias. Since increased CaMKII expression and activity has been mechanistically linked to arrhythmias in human heart failure (HF) and atrial fibrillation (AF), specific strategies aimed at CaMKII inhibition may have therapeutic potential. OBJECTIVE: We tested the antiarrhythmic and inotropic effects of a novel selective and ATP-competitive CaMKII inhibitor (GS-680). METHODS AND RESULTS: Trabeculae were isolated from right atrial appendage biopsies of patients undergoing cardiac surgery. Premature atrial contractions (PACs) were induced by stimulation with isoproterenol (ISO, 100 nM) at increased [Ca]o (3.5 mM). Interestingly, compared to vehicle, PACs were significantly inhibited by exposure to GS-680 (at 100 and 300 nM). GS-680 also significantly decreased early and delayed afterdepolarizations in isolated human atrial myocytes. Moreover, GS-680 (at 100 or 300 nM) significantly inhibited diastolic SR Ca leak, measured as frequency of spontaneous SR Ca release events (Ca sparks) in isolated human atrial myocytes (Fluo-4 loaded) similar to the well-established peptide CaMKII inhibitor AIP. In accordance, GS-680 significantly reduced CaMKII autophosphorylation (Western blot) but enhanced developed tension after 10 or 30 s pause of electrical stimulation (post-rest behavior). Surprisingly, we found a strong negative inotropic effect of GS-680 in atrial trabeculae at 1 Hz stimulation rate, which was not observed at 4 Hz and abolished by beta-adrenergic stimulation. In contrast, GS-680 did not impair systolic force of isolated ventricular trabeculae from explanted hearts of heart transplant recipients at 1 Hz, blunted the negative force-frequency relationship (1-3 Hz) and significantly increased the Ca transient amplitude. CONCLUSION: The novel ATP-competitive and selective CaMKII inhibitor GS-680 inhibits pro-arrhythmic activity in human atrium and improves contractility in failing human ventricle, which may have therapeutic implications.

Immediate fullweightbearing after tarsometatarsal arthrodesis for hallux valgus correction--Does it increase the complication rate?

BACKGROUND: The arthrodesis of the first tarsometatarsal joint has a high correction potential in the treatment of hallux valgus deformity. Compared to distal correction procedures, a pseudarthrosis rate of 12-20% is quoted, however. In a prospective study the results of two different treatment procedures after correction arthrodesis were compared. METHODS: In 17 cases the patients were mobilised with a short arthrodeses shoe with floor contact (NWB group) and in 17 cases in a short arthrodeses shoe with immediate fullweightbearing (FWB group). Clinical and radiological evaluation was done preoperatively, six weeks and one year postoperatively, including visual analogue pain scale and AOFAS score pre- and one year postoperatively. RESULTS: There was no increased complication rate in the group with FWB group. The patients in the FWB group were significantly earlier fit for work. CONCLUSION: Immediate fullweightbearing after TMT I arthrodesis using a plantar plate should be established as a standard posttreatment.

[Orthopaedic Treatment for Patients with Myelomeningocele]. / Orthopädische Behandlung bei Myelomeningozele.

BACKGROUND: Due to prenatal diagnostic and folic acid prophylaxis less children with myelomeningocele are now being born. But they become older and need increasingly more orthopaedic care. The orthopaedic care is aimed at the improvement or the preservation of function. METHOD: In this review the current knowledge from the literature and our approach are presented. This is done in the context of the functional aspects within certain periods of life. Treatment Concept: In the first two years of life, the mobility of MMC children is supported by physiotherapy and orthoses irrespective of the level of the lesion. Afterwards, the optimal orthoses are chosen depending on the muscle power, emerging bone deformities, associated CNS malformation, shunt revisions, obesity and limitations in perception as well as the child's motivation. At school age, it is paramount to encourage independence. Orthotic treatment should be continued as long as the children benefit from it. Orthopaedic operations serve the orthosis fitting and the avoidance of pressure sores. Pathological fractures are common. They should be rapidly recognised in order to avoid further bony deformities. CONCLUSION: The aim of any orthopaedic treatment consists of the avoidance of musculoskeletal deformities in order to support the patient's self employment.

[Epiphyseolysis of the femoral head: new aspects of diagnostics and therapy]. / Epiphyseolysis capitis femoris : Neue Aspekte in Diagnostik und Therapie.

BACKGROUND: Slipped capital femoral epiphysis (SCFE) is the most common hip disease in adolescents and is always surgically treated with the aim to avoid further slippage and to reduce the risk of degenerative arthritis at young age. OBJECTIVES: A summary of the etiology, pathogenesis, clinical features, radiographic imaging and current therapy concepts is given. MATERIAL AND METHODS: A selective review of the literature was performed. RESULTS: With an increasing body mass index in adolescents the incidence of SCFE also increases. The diagnostic routine is comprised of a clinical examination with the evaluation of Drehmann's sign and a radiographic evaluation including anterior-posterior aspect and frog's legs view. In situ stabilization with a single screw is the standard treatment for the most prevalent mild or moderate stable slippages. In cases of acute slippage a gentle reduction maneuver may be attempted. Hardware removal must not be performed before epiphyseal closure. Common bilateral but not simultaneous occurrence of the disease requires prophylactic pinning of the unaffected side by default, at least in central Europe. Various surgical treatment options exist to reduce the femoroacetabular impingement caused by the slippage. CONCLUSIONS: Current treatment algorithms result in satisfactory long-term outcomes. If the risk of developing degenerative arthritis after SCFE may be reduced even more with modern arthroscopic or open surgical procedures to restore the anatomic pre-slip conditions has to be confirmed through further long-term studies. The implementation of programs to prevent obesity in adolescents may also reduce the incidence of SCFE.

[Ankle arthrodesis with an posterolateral approach using a polyaxial angle stable Talarlock® plate]. / OSG-Arthrodese über einen posterolateralen Zugang mit der polyaxial-winkelstabilen Talarlock®-Platte.

OBJECTIVE: Safe arthrodesis of the ankle as well as load carrying capacity free of pain. INDICATION: Painful arthritis of the ankle joint occurring idiopathic or posttraumatic, resulting from rheumatoid arthritis or neuromuscular diseases. Extensive bony defects in varus or valgus ankle deformities and after failed prosthesis. Complex hindfoot deformities in neurological disease, paralysis and instabilities. Joint destruction after infection. CONTRAINDICATIONS: Active osteitis, extensive skin ulcers in the approach area, periphery artery occlusive disease. SURGICAL TECHNIQUE: Posterolateral skin incision. Sparing cartilage resection. Penetrating sclerosis zones. Reorientating anatomic positioning of the talus thereby correcting axis deformities. Talarlock(®) plate positioning and tibiotalar arthrodesis. POSTOPERATIVE MANAGEMENT: Full weight bearing in an arthodesis boot for 6 weeks. After bone grafting partial weight bearing (20 kg) in an arthrodesis boot for 8 weeks. Full weight bearing after 10weeks. RESULTS: Ten patients were operated on using this procedure. The follow-up time was 1 year. There were no complications requiring further surgical procedures. Ankle fusion and a good clinical outcome could be achieved in all cases.

Comparative study of Lapidus bunionectomy using different osteosynthesis methods.

The treatment of hallux valgus in patients with pathology of the first tarsometatarsal (TMT I) joint by fusion is an established procedure. Multiple osteosynthesis methods for the fixation of the TMT I joint are available. In comparison to the distal procedures the Lapidus bunionectomy is associated with a pseudarthrosis rate of up to 12% [9-11]. We present results after TMT-I arthrodesis using an interfragmentary screw and a plantar plate compared with an interfragmentary screw and a dorsomedial locking plate. Clinical and radiological examinations were performed preoperatively, six weeks and one year postoperatively. The AOFAS (American Orthopaedic Foot and Ankle Society) score and Visual Analogue Pain Scale (VAS) were evaluated preoperatively and 12 months after surgery. We observed a significantly increased rate of undesirable effects in mediodorsal plate positioning.

Is it feasible to rely on intraoperative X ray in correcting hallux valgus?

BACKGROUND: The aim of the study was to prove whether the intraoperatively taken fluoroscopy pictures compared to the X rays taken 8 weeks and 3 months postoperatively picture the achieved correction reliably. METHOD: In a prospective study, the pre- and postoperative standing foot X rays as well as the intraoperatively taken fluoroscopy pictures of 31 patients were analysed. The intermetatarsal angle (IMA) and the hallux valgus angle (HVA) were measured. In all cases, a tarso-metatarsal joint I arthrodesis combined with a distal soft tissue release was performed. The mean age was 54 (17-73) years. RESULTS: There was no significant difference between the measured angles in intraoperative fluoroscopy and standing X rays postoperatively taken. CONCLUSIONS: Despite the consideration that fluoroscopic pictures lack the loading criteria, we found reliable results in IMA and HVA.

[Correction arthrodesis of the proximal interphalangeal joint with wire cerclage for rigid small toe deformities : a prospective study]. / Korrekturarthrodese des PIP-Gelenks mittels Drahtcerclage bei fixierter Kleinzehdeformität : Eine prospektive Studie.

Deformities of the small toes often occur with complex forefoot deformities. Proximal interphalangeal joint arthrodesis is a reliable correction procedure for rigid flexed proximal interphalangeal joints. The most often performed technique by far is K-wire fixation; however, pin tract infections, malrotation due to deficient securing of the rotation and irritation of the metatarsophalangeal joints are common complications. By using a 0.4 mm wire cerclage an individual position of the proximal interphalangeal joint in slight flexion is enabled whereby good compression can be achieved and malrotation can be avoided. In 32 patients with 64 fixed claw or hammer toes such a proximal interphalangeal joint arthrodesis was performed. The follow-up time was 2 years. In all cases clinical and radiological osteotomy healing occurred 6 weeks postoperatively and there were no complications. This technically simple and cost-efficient procedure appears to be a good alternative to known proximal interphalangeal joint arthrodesis methods.

[Comparison of treatment results of idiopathic and non-idiopathic congenital clubfoot : prospective evaluation of the Ponseti therapy]. / Vergleich der Behandlungsergebnisse bei kongenitalen idiopathischen und nichtidiopathischen Klumpfüßen : Prospektive Evaluation der Ponseti-Therapie.

BACKGROUND: Clubfoot deformity is one of the most common congenital musculoskeletal deformities and occurs in newborns with different neuromuscular diseases. To date the Ponseti method is the gold standard for the treatment of idiopathic clubfeet but not for non-idiopathic clubfeet which are associated with neuromuscular diseases. The results of the treatment for congenital idiopathic and non-idiopathic clubfeet according to Ponseti performed in our department since 2004 were compared concerning results and relapse surgery with particular reference to the compliance of the parents concerning the use of an abduction splint. PATIENTS AND METHODS: A total of 101 children (28 female and 73 male) with 159 clubfeet were treated with the Ponseti method and included in this prospective non-randomized cohort study. Of these children 27 with 48 affected feet suffered from neuromuscular diseases which are associated with clubfoot deformity, such as myelomeningocele (n=4), arthrogryposis (n=9) and various other syndromes (n=14). The degree of the deformity was evaluated with the Pirani score initially, after casting and at follow-up. Parents were asked at follow-up to state subjectively how compliant they were with the abduction splint treatment. The necessity of surgical treatment of relapses was recorded. Statistical analysis was performed applying χ(2) and Kruskal-Wallis tests for the comparison of idiopathic and non-idiopathic clubfeet. RESULTS: The average period of follow-up was 36 month (range 6-75 months) and non-idiopathic clubfeet were initially significantly more severely deformed according to the Pirani-score (p=0.013). Treatment of non-idiopathic clubfeet was started significantly later than that of idiopathic clubfeet (p=0.003) and took significantly longer (p <0.001). A correlation between the initiation of casting and the duration of casting was not found (p=0.399). At the end of the casting period no significant differences were found between correction of idiopathic and non-idiopathic clubfeet with respect to the Pirani score (p=0.8). The mean score after casting was 0.1 in both groups. At mid-term follow-up the score increased in both groups but stayed below 0.5 with non-idiopathic clubfeet showing a significantly higher score than idiopathic clubfeet (p=0.014). Relapse surgery was necessary in 11% of the patients. No significant difference in the revision rate was found between the two groups (p=0.331) and peritalar release was not necessary in either group. The rate of revisions correlated with the compliance concerning the use of the abduction splint (p <0.001). Only 61% of the parents stated that they adhered strictly to the abduction splint treatment recommendations with no significant difference between the groups (p=0.398). CONCLUSION: This study shows good initial results after Ponseti treatment for idiopathic as well as non-idiopathic clubfeet. Based on the good functional results all clubfeet should initially be treated with the Ponseti method regardless of the etiology.

Clinical, endocrinological and radiography features in a child with McCune-Albright syndrome and pituitary adenoma.

McCune-Albright syndrome is a rare syndrome presenting with polyostotic dysplasia, cafe-au-lait spots and multiple endocrinopathies that is very often combined with precocious puberty. We examined the clinical, endocrinological and radiological features in a boy with McCune-Albright syndrome and pituitary adenoma. X-rays, magnetic resonance (MRI) scan, whole body scintigraphy, single photon emission computer tomography (SPECT) and 3D-reconstruction from bone SPECT was performed to evaluate clinical improvement after treatment with sandostatin and pamidronic acid. After a six-month period of treatment with sandostatin and pamidronate, bone scintigraphy revealed significantly reduced activity. Treatment with bromocriptine and methimazole led to normalization of prolactin and thyroid hormone levels. Mobility of the patient improved. A significant improvement as a result of treatment with sandostatin and pamidronic acid was found in this patient with generalized fibrous dysplasia. So far, this condition has been treated with pamidronate only in adults, but severely affected children also benefit from this treatment regimen.

Posteroplantar release for congenital clubfoot in children younger than 1 year.

One hundred thirty-three resistant congenital clubfeet in 93 patients between 3 and 10 months of age were operated on using a standardized posteroplantar release. Clinical and radiographic assessments were done with a mean followup of 7 years 4 months (range, 3-12 years). Using the McKay score, 79.7% of the surgically treated clubfeet were classified as having a good or excellent result. Three patients had relapse of their clubfoot that required additional surgery. Seventeen feet in 15 patients had residual forefoot adduction at the time of followup. The radiographs showed that the early posteroplantar release led to sufficient hindfoot correction in all but the three patients who had relapse of the clubfoot. With this standardized surgical treatment, satisfactory results can be achieved in most patients younger than 1 year with congenital clubfoot. However, in patients with persistent talonavicular subluxation after conservative treatment, an additional talonavicular release combined with the posteroplantar release is recommended.

Substitution of tibial bony defects with allogeneic and autogeneic cancellous bone: encouraging preliminary results in 18 knee replacements.

Eighteen knee replacements in 15 patients with severe gonarthritis or loosening of total knee arthroplasty (TKA) requiring bone grafting for bony deficiencies were studied before and after operation. The average follow-up was 2.4 years. Fifteen knees showed satisfactory clinical and radiographic results of the integration of the bone grafts. The Hospital for Special Surgery knee score improved from an average of 39 points preoperatively to 83 points at the most recent follow-up examination. Two of 3 knees with loosening of the tibial component required revision. These results are encouraging. Success depends as much on rigid fixation of the grafted bone and protected weight-bearing as on rigid, micromotion-preventing fixation of the tibial component.

Biomechanical and densitometric bone properties after callus distraction in sheep.

Assessment of biomechanical stability of diaphyseal bone lengthened by callus distraction is an unsolved problem. A middiaphyseal corticotomy was performed in the left tibia of 24 sheep. After 7 days, callus distraction was begun at a rate of 0.5 mm every 12 hours for 30 days using a standard unilateral fixator system. Animals were euthanized 4, 8, or 12 weeks after the end of distraction. The lengthened tibia and the contralateral control tibia from each animal were evaluated by radiographic, densitometric (dual energy xray absorptiometry, quantitative computed tomography), and biomechanical (axial compression testing, torsion testing to failure) methods. The bone mineral density and maximum torque for the lengthened tibia were significantly greater in the 8-week group than in the 4-week group. However, the values in the 12-week group were significantly smaller than in the 8-week group. In the lengthened tibias, there was a correlation between the maximum torque and the bone mineral density, and between the maximum torque and the bone density. Bone density measurements are useful prognosticators for the safe removal of external fixators after leg lengthening procedures. By using these methods, clinical fractures after leg lengthening could be avoided in the future.