Atrioventricular 2:1-conduction via an accessory pathway during left atrial flutter unmasking WPW syndrome: a case report.

Background: Implantable cardioverter defibrillators (ICDs) are most effective in treating sudden cardiac death. However, accurate diagnostic workup of broad complex tachycardia is crucial to ensure correct indication for ICD treatment and to avoid unnecessary invasive treatment and device-associated morbidity.

Case Summary: We present a case of atypical atrial flutter with 2:1 atrioventricular (AV) conduction via a left-posterior accessory pathway (AP), leading to the diagnosis of Wolff-Parkinson-White (WPW) syndrome.

Sacubitrilat reduces pro-arrhythmogenic sarcoplasmic reticulum Ca leak in human ventricular cardiomyocytes of patients with end-stage heart failure.

Aims: Inhibition of neprilysin and angiotensin II receptor by sacubitril/valsartan (Val) (LCZ696) reduces mortality in heart failure (HF) patients compared with sole inhibition of renin-angiotensin system. Beneficial effects of increased natriuretic peptide levels upon neprilysin inhibition have been proposed, whereas direct effects of sacubitrilat (Sac) (LBQ657) on myocardial Ca cycling remain elusive.

Methods And Results: Confocal microscopy (Fluo-4 AM) was used to investigate pro-arrhythmogenic sarcoplasmic reticulum (SR) Ca leak in freshly isolated murine and human ventricular cardiomyocytes (CMs) upon Sac (40 μmol/L)/Val (13 μmol/L) treatment.

Protein kinase/phosphatase balance mediates the effects of increased late sodium current on ventricular calcium cycling.

Increased late sodium current (late I) is an important arrhythmogenic trigger in cardiac disease. It prolongs cardiac action potential and leads to an increased SR Ca leak. This study investigates the contribution of Ca/Calmodulin-dependent kinase II (CaMKII), protein kinase A (PKA) and conversely acting protein phosphatases 1 and 2A (PP1, PP2A) to this subcellular crosstalk.

A context-specific cardiac β-catenin and GATA4 interaction influences TCF7L2 occupancy and remodels chromatin driving disease progression in the adult heart.

Chromatin remodelling precedes transcriptional and structural changes in heart failure. A body of work suggests roles for the developmental Wnt signalling pathway in cardiac remodelling. Hitherto, there is no evidence supporting a direct role of Wnt nuclear components in regulating chromatin landscapes in this process.

Interactions of Calcium Fluctuations during Cardiomyocyte Contraction with Real-Time cAMP Dynamics Detected by FRET.

Calcium (Ca2+) and 3',5'-cyclic adenosine monophosphate (cAMP) play a critical role for cardiac excitation-contraction-coupling. Both second messengers are known to interact with each other, for example via Ca2+-dependent modulation of phosphodiesterase 1 (PDE1) and adenylyl cyclase 5/6 (AC 5/6) activities, which is supposed to occur especially at the local level in distinct subcellular microdomains. Currently, many studies analyze global and local cAMP signaling and its regulation in resting cardiomyocytes devoid of electrical stimulation.

Antiarrhythmic effects of dantrolene in human diseased cardiomyocytes.

Background: Cardiac type 2 ryanodine receptors (RyRs) play a pivotal role in cellular electrophysiology and contractility. Increased RyR-mediated diastolic sarcoplasmic reticulum (SR) Ca 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.

Inhibition of CaMKII Attenuates Progressing Disruption of Ca(2+) Homeostasis Upon Left Ventricular Assist Device Implantation in Human Heart Failure.

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.

Sex-dependent alterations of Ca2+ cycling in human cardiac hypertrophy and heart failure.

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) Ca(2+) leak is arrhythmogenic, it could represent a cellular basis for this paradox.

Late INa increases diastolic SR-Ca2+-leak in atrial myocardium by activating PKA and CaMKII.

Aims: Enhanced cardiac late Na current (late INa) and increased sarcoplasmic reticulum (SR)-Ca(2+)-leak are both highly arrhythmogenic. This study seeks to identify signalling pathways interconnecting late INa and SR-Ca(2+)-leak in atrial cardiomyocytes (CMs).

Methods And Results: In murine atrial CMs, SR-Ca(2+)-leak was increased by the late INa enhancer Anemonia sulcata toxin II (ATX-II).

Ca(2+) /calmodulin-dependent protein kinase II equally induces sarcoplasmic reticulum Ca(2+) leak in human ischaemic and dilated cardiomyopathy.

Aims: The sarcoplasmic reticulum (SR) Ca(2+) leak is an important pathomechanism in heart failure (HF). It has been suggested that Ca(2+) /calmodulin-dependent protein kinase II (CaMKII) is only relevant for the induction of the SR Ca(2+) leak in non-ischaemic but not in ischaemic HF. Therefore, we investigated CaMKII and its targets as well as the functional effects of CaMKII inhibition in human ischaemic cardiomyopathy (ICM, n = 37) and dilated cardiomyopathy (DCM, n = 40).

Enhanced late INa induces proarrhythmogenic SR Ca leak in a CaMKII-dependent manner.

Objective: Enhanced late Na current (late INa) 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 INa (in disease-comparable ranges) exerts proarrhythmogenic events in isolated ventricular mouse myocytes in a manner depending on CaMKII-dependent SR Ca leak.

Ca2+/calmodulin-dependent protein kinase II and protein kinase A differentially regulate sarcoplasmic reticulum Ca2+ leak in human cardiac pathology.

Background: Sarcoplasmic reticulum (SR) Ca(2+) leak through ryanodine receptor type 2 (RyR2) dysfunction is of major pathophysiological relevance in human heart failure (HF); however, mechanisms underlying progressive RyR2 dysregulation from cardiac hypertrophy to HF are still controversial.

Methods And Results: We investigated healthy control myocardium (n=5) and myocardium from patients with compensated hypertrophy (n=25) and HF (n=32). In hypertrophy, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and protein kinase A (PKA) both phosphorylated RyR2 at levels that were not different from healthy myocardium.

Role of late sodium current as a potential arrhythmogenic mechanism in the progression of pressure-induced heart disease.

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.