Electrophysiological Effects of the Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitor Dapagliflozin on Human Cardiac Potassium Channels.

The sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin is increasingly used in the treatment of diabetes and heart failure. Dapagliflozin has been associated with reduced incidence of atrial fibrillation (AF) in clinical trials. We hypothesized that the favorable antiarrhythmic outcome of dapagliflozin use may be caused in part by previously unrecognized effects on atrial repolarizing potassium (K+) channels. This study was designed to assess direct pharmacological effects of dapagliflozin on cloned ion channels Kv11.1, Kv1.5, Kv4.3, Kir2.1, K2P2.1, K2P3.1, and K2P17.1, contributing to IKur, Ito, IKr, IK1, and IK2P K+ currents. Human channels coded by KCNH2, KCNA5, KCND3, KCNJ2, KCNK2, KCNK3, and KCNK17 were heterologously expressed in Xenopus laevis oocytes, and currents were recorded using the voltage clamp technique. Dapagliflozin (100 µM) reduced Kv11.1 and Kv1.5 currents, whereas Kir2.1, K2P2.1, and K2P17.1 currents were enhanced. The drug did not significantly affect peak current amplitudes of Kv4.3 or K2P3.1 K+ channels. Biophysical characterization did not reveal significant effects of dapagliflozin on current-voltage relationships of study channels. In conclusion, dapagliflozin exhibits direct functional interactions with human atrial K+ channels underlying IKur, IKr, IK1, and IK2P currents. Substantial activation of K2P2.1 and K2P17.1 currents could contribute to the beneficial antiarrhythmic outcome associated with the drug. Indirect or chronic effects remain to be investigated in vivo.

Differential Effects of the Betablockers Carvedilol, Metoprolol and Bisoprolol on Cardiac Kv4.3 (Ito) Channel Isoforms.

Cardiac Kv4.3 channels contribute to the transient outward K+ current, Ito, during early repolarization of the cardiac action potential. Two different isoforms of Kv4.3 are present in the human ventricle and exhibit differential remodeling in heart failure (HF). Cardioselective betablockers are a cornerstone of HF with reduced ejection fraction therapy as well as ventricular arrhythmia treatment. In this study we examined pharmacological effects of betablockers on both Kv4.3 isoforms to explore their potential for isoform-specific therapy. Kv4.3 isoforms were expressed in Xenopus laevis oocytes and incubated with the respective betablockers. Dose-dependency and biophysical characteristics were examined. HEK 293T-cells were transfected with the two Kv4.3 isoforms and analyzed with Western blots. Carvedilol (100 µM) blocked Kv4.3 L by 77 ± 2% and Kv4.3 S by 67 ± 6%, respectively. Metoprolol (100 µM) was less effective with inhibition of 37 ± 3% (Kv4.3 L) and 35 ± 4% (Kv4.3 S). Bisoprolol showed no inhibitory effect. Current reduction was not caused by changes in Kv4.3 protein expression. Carvedilol inhibited Kv4.3 channels at physiologically relevant concentrations, affecting both isoforms. Metoprolol showed a weaker blocking effect and bisoprolol did not exert an effect on Kv4.3. Blockade of repolarizing Kv4.3 channels by carvedilol and metoprolol extend their pharmacological mechanism of action, potentially contributing beneficial antiarrhythmic effects in normal and failing hearts.

Epigenetic regulation of cardiac electrophysiology in atrial fibrillation: HDAC2 determines action potential duration and suppresses NRSF in cardiomyocytes.

Atrial fibrillation (AF) is associated with electrical remodeling, leading to cellular electrophysiological dysfunction and arrhythmia perpetuation. Emerging evidence suggests a key role for epigenetic mechanisms in the regulation of ion channel expression. Histone deacetylases (HDACs) control gene expression through deacetylation of histone proteins. We hypothesized that class I HDACs in complex with neuron-restrictive silencer factor (NRSF) determine atrial K+ channel expression. AF was characterized by reduced atrial HDAC2 mRNA levels and upregulation of NRSF in humans and in a pig model, with regional differences between right and left atrium. In vitro studies revealed inverse regulation of Hdac2 and Nrsf in HL-1 atrial myocytes. A direct association of HDAC2 with active regulatory elements of cardiac K+ channels was revealed by chromatin immunoprecipitation. Specific knock-down of Hdac2 and Nrsf induced alterations of K+ channel expression. Hdac2 knock-down resulted in prolongation of action potential duration (APD) in neonatal rat cardiomyocytes, whereas inactivation of Nrsf induced APD shortening. Potential AF-related triggers were recapitulated by experimental tachypacing and mechanical stretch, respectively, and exerted differential effects on the expression of class I HDACs and K+ channels in cardiomyocytes. In conclusion, HDAC2 and NRSF contribute to AF-associated remodeling of APD and K+ channel expression in cardiomyocytes via direct interaction with regulatory chromatin regions. Specific modulation of these factors may provide a starting point for the development of more individualized treatment options for atrial fibrillation.

Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes.

BACKGROUND/AIMS: Cardiac arrhythmias are triggered by environmental stimuli that may modulate expression of cardiac ion channels. Underlying epigenetic regulation of cardiac electrophysiology remains incompletely understood. Histone deacetylases (HDACs) control gene expression and cardiac integrity. We hypothesized that class I/II HDACs transcriptionally regulate ion channel expression and determine action potential duration (APD) in cardiac myocytes. METHODS: Global class I/II HDAC inhibition was achieved by administration of trichostatin A (TSA). HDAC-mediated effects on K+ channel expression and electrophysiological function were evaluated in murine atrial cardiomyocytes (HL-1 cells) using real-time PCR, Western blot, and patch clamp analyses. Electrical tachypacing was employed to recapitulate arrhythmia-related effects on ion channel remodeling in the absence and presence of HDAC inhibition. RESULTS: Global HDAC inhibition increased histone acetylation and prolonged APD90 in atrial cardiomyocytes compared to untreated control cells. Transcript levels of voltage-gated or inwardly rectifying K+ channels Kcnq1, Kcnj3 and Kcnj5 were significantly reduced, whereas Kcnk2, Kcnj2 and Kcnd3 mRNAs were upregulated. Ion channel remodeling was similarly observed at protein level. Short-term tachypacing did not induce significant transcriptional K+ channel remodeling. CONCLUSION: The present findings link class I/II HDAC activity to regulation of ion channel expression and action potential duration in atrial cardiomyocytes. Clinical implications for HDAC-based antiarrhythmic therapy and cardiac safety of HDAC inhibitors require further investigation.

Therapeutic targeting of two-pore-domain potassium (K(2P)) channels in the cardiovascular system.

The improvement of treatment strategies in cardiovascular medicine is an ongoing process that requires constant optimization. The ability of a therapeutic intervention to prevent cardiovascular pathology largely depends on its capacity to suppress the underlying mechanisms. Attenuation or reversal of disease-specific pathways has emerged as a promising paradigm, providing a mechanistic rationale for patient-tailored therapy. Two-pore-domain K(+) (K(2P)) channels conduct outward K(+) currents that stabilize the resting membrane potential and facilitate action potential repolarization. K(2P) expression in the cardiovascular system and polymodal K2P current regulation suggest functional significance and potential therapeutic roles of the channels. Recent work has focused primarily on K(2P)1.1 [tandem of pore domains in a weak inwardly rectifying K(+) channel (TWIK)-1], K(2P)2.1 [TWIK-related K(+) channel (TREK)-1], and K(2P)3.1 [TWIK-related acid-sensitive K(+) channel (TASK)-1] channels and their role in heart and vessels. K(2P) currents have been implicated in atrial and ventricular arrhythmogenesis and in setting the vascular tone. Furthermore, the association of genetic alterations in K(2P)3.1 channels with atrial fibrillation, cardiac conduction disorders and pulmonary arterial hypertension demonstrates the relevance of the channels in cardiovascular disease. The function, regulation and clinical significance of cardiovascular K(2P) channels are summarized in the present review, and therapeutic options are emphasized.

[Digital precision medicine in rhythmology : Risk prediction of recurrences, sudden cardiac death, and outcome]. / Digitale Präzisionsmedizin in der Rhythmologie : Risikoprädiktion für Rezidive, plötzlichen Herztod und Outcome.

Digital precision medicine is gaining increasing importance in rhythmology, especially in the treatment of cardiac arrhythmias. This trend is driven by the advancing digitization in healthcare and the availability of large amounts of data from various sources such as electrocardiograms (ECGs), implants like pacemakers and implantable cardioverter-defibrillators (ICDs), as well as wearables like smartwatches and fitness trackers. Through the analysis of this data, physicians can develop more precise and individualized diagnoses and treatment strategies for patients with cardiac arrhythmias. For example, subtle changes in ECGs can be identified, indicating potentially dangerous arrhythmias. Genetic analyses and resulting large datasets also play an increasingly significant role, especially in hereditary ion channel disorders such as long QT syndrome (LQTS) and Brugada syndrome (BrS), as well as in lone atrial fibrillation (AF). Precision medicine enables the development of individualized treatment approaches tailored to the specific needs and risk factors of each patient. This can help improve screening strategies, reduce adverse events, and ultimately enhance the quality of life for patients. Technological advancements such as big data, artificial intelligence, machine learning, and predictive analytics play a crucial role in predicting the risk of arrhythmias and sudden cardiac death. These concepts enable more precise and personalized predictions and support physicians in the treatment and monitoring of their patients.

Cardiac stereotactic body radiotherapy to treat malignant ventricular arrhythmias directly affects the cardiomyocyte electrophysiology.

BACKGROUND: Promising as a treatment option for life-threatening ventricular arrhythmias, cardiac stereotactic body radiotherapy (cSBRT) has demonstrated early antiarrhythmic effects within days of treatment. The mechanisms underlying the immediate and short-term antiarrhythmic effects are poorly understood. OBJECTIVES: We hypothesize that cSBRT has a direct antiarrhythmic effect on cellular electrophysiology through reprogramming of ion channel and gap junction protein expression. METHODS: Following exposure to 20Gy of X-rays in a single fraction, neonatal rat ventricular cardiomyocytes (NRVCs) were analyzed 24 and 96h post-radiation to determine changes in conduction velocity, beating frequency, calcium transients, and action potential duration (APD) in both monolayers and single cells. Additionally, the expression of gap junction proteins, ion channels, and calcium handling proteins was evaluated at protein and mRNA levels. RESULTS: Following irradiation with 20Gy, NRVCs exhibited increased beat rate and conduction velocities 24 and 96h after treatment. mRNA and protein levels of ion channels were altered, with the most significant changes observed at the 96h-mark. Upregulation of Cacna1c (Cav1.2), Kcnd3 (Kv4.3), Kcnh2 (Kv11.1), Kcnq1 (Kv7.1), Kcnk2 (K2P2.1), Kcnj2 (Kir2.1), and Gja1 (Cx43) was noted, along with improved gap junctional coupling. Calcium handling was affected, with increased Ryr2 (RYR2) and Slc8a1 (NCX) expression and altered properties 96h post-treatment. Fibroblast and myofibroblast levels remained unchanged. CONCLUSIONS: CSBRT modulates expression of various ion channels, calcium handling proteins, and gap-junction proteins. The described alterations in cellular electrophysiology may be the underlying cause of the immediate antiarrhythmic effects observed following cSBRT.

Imaging approaches for pulmonary vein isolation in patients after lobectomy or pneumonectomy: a case series.

Background: In patients who underwent pneumonectomy, pulmonary vein isolation for atrial fibrillation by catheter ablation may be complicated by the anatomical alterations caused by the surgical intervention. Pre- and peri-procedural imaging can visualize and guide the procedure to assure safety and procedural success. Case summary: This case series describes different imaging and ablation strategies in three cases from three different ablation centres with the unusually challenging and complex anatomical conditions in patients following lobectomy or pneumonectomy. Discussion: Pulmonary vein isolation in patients with previous pulmonary resection was feasible by both radiofrequency and cryocatheter ablation despite the anatomical alterations caused by the surgery. Pre- and peri-procedural imaging by cardiac computed tomography and transoesophageal echocardiography contributed to an increased understanding of the complex anatomical substrate.

Implementation of the multielectrode radiofrequency-balloon in real-world clinical practice-operator learning curve and procedural outcome at a high-volume center.

Background: The novel multielectrode radiofrequency (RF) balloon catheter (HELIOSTAR™, Biosense Webster) is a new technology for pulmonary vein isolation (PVI) in atrial fibrillation (AF), combining RF-ablation and 3D-mapping visualization with the concept of a "single-shot"-ablation device. This study evaluates the operator learning curve und procedural outcome during implementation of the multielectrode RF-balloon at a high-volume center. Methods: The first 40 patients undergoing PVI by multielectrode RF-balloon catheter at Heidelberg University Hospital were included in this prospective study. Procedural outcome was analyzed over the course of increasing experience with the device. Results: 157/157 pulmonary veins (PVs) were successfully isolated with the RF-balloon catheter, in 73.2% by a single RF-application. Median time to isolation (TTI) was 11.0 s (Q1 = 8.0 s; Q3 = 13.8 s). Median procedure time was 62.5 min (Q1 = 50.0 min; Q3 = 70.5 min). LA-dwell time was 28.5 min (Q1 = 23.3 min; Q3 = 36.5 min). Median fluoroscopy duration was 11.6 min (Q1 = 10.1 min; Q3 = 13.7 min). No serious procedure-related complications were observed, apart from one case of unclear, post-procedural acute-on-chronic kidney injury. With increasing operator experience, an additional reduction in procedure duration was observed. Conclusion: Rapid implementation of a "single shot"-ablation device combining RF-ablation and 3D-mapping can be achieved with high acute procedural efficacy and safety at a high-volume center. Previous experience with "single-shot" ablation devices may be advantageous for time-efficient introduction of the novel RF-balloon catheter into clinical practice. Clinical Trial Registration: ClinicalTrials.gov; Identifier NCT0560361.

Oral Anticoagulants after Heart Transplantation-Comparison between Vitamin K Antagonists and Direct Oral Anticoagulants.

AIMS: Patients after heart transplantation (HTX) often require oral anticoagulants (OACs) due to atrial arrhythmias or thromboembolic events but little is known about the post-transplant use of direct oral anticoagulants (DOACs). We investigated the frequency, indications, and complications of DOACs and vitamin K antagonists (VKAs) after HTX. METHODS: We screened all adult patients for the use of post-transplant OACs who underwent HTX at Heidelberg Heart Center between 2000 and 2021. Patients were stratified by type of OAC (DOAC or VKA) and by DOAC agents (apixaban, dabigatran, edoxaban, or rivaroxaban). Indications for OACs comprised atrial fibrillation, atrial flutter, pulmonary embolism, upper and lower extremity deep vein thrombosis, as well as intracardiac thrombus. RESULTS: A total of 115 of 459 HTX recipients (25.1%) required OACs, including 60 patients with DOACs (52.2%) and 55 patients with VKAs (47.8%). Concerning DOACs, 28 patients were treated with rivaroxaban (46.7%), 27 patients with apixaban (45.0%), and 5 patients with edoxaban (8.3%). We found no significant differences between both groups concerning demographics, immunosuppressive drugs, concomitant medications, indications for OACs, ischemic stroke, thromboembolic events, or OAC-related death. Patients with DOACs after HTX had a significantly lower one-year rate of overall bleeding complications (p = 0.002) and a significantly lower one-year rate of gastrointestinal hemorrhage (p = 0.011) compared to patients with VKAs after HTX in the Kaplan-Meier estimator. CONCLUSIONS: DOACs were comparable to VKAs concerning the risk of ischemic stroke, thromboembolic events, or OAC-related death but were associated with significantly fewer bleeding complications in HTX recipients.

Verapamil inhibits Kir2.3 channels by binding to the pore and interfering with PIP2 binding.

The inwardly rectifying potassium current of the cardiomyocyte (IK1) is the main determinant of the resting potential. Ion channels Kir2.1, Kir2.2, and Kir2.3 form tetramers and are the molecular correlate of macroscopic IK1 current. Verapamil is an antiarrhythmic drug used to suppress atrial and ventricular arrhythmias. Its primary mechanism of action is via blocking calcium channels. In addition, it has been demonstrated to block IK1 current and the Kir2.1 subunit. Its effect on other subunits that contribute to IK1 current has not been studied to date. We therefore analyzed the effect of verapamil on the Kir channels 2.1, 2.2, and 2.3 in the Xenopus oocyte expression system. Kir2.1, Kir2.2, and Kir2.3 channels were heterologously expressed in Xenopus oocytes. Respective currents were measured with the voltage clamp technique and the effect of verapamil on the current was measured. At a concentration of 300 µM, verapamil inhibited Kir2.1 channels by 41.36% ± 2.7 of the initial current, Kir2.2 channels by 16.51 ± 3.6%, and Kir2.3 by 69.98 ± 4.2%. As a verapamil effect on kir2.3 was a previously unknown finding, we analyzed this effect further. At wash in with 300 µM verapamil, the maximal effect was seen within 20 min of the infusion. After washing out with control solution, there was only a partial current recovery. The current reduction from verapamil was the same at - 120 mV (73.2 ± 3.7%), - 40 mV (85.5 ± 6.5%), and 0 mV (61.5 ± 10.6%) implying no voltage dependency of the block. Using site directed mutations in putative binding sites, we demonstrated a decrease of effect with pore mutant E291A and absence of verapamil effect for D251A. With mutant I214L, which shows a stronger affinity for PIP2 binding, we observed a normalized current reduction to 61.9 ± 0.06% of the control current, which was significantly less pronounced compared to wild type channels. Verapamil blocks Kir2.1, Kir2.2, and Kir2.3 subunits. In Kir2.3, blockade is dependent on sites E291 and D251 and interferes with activation of the channel via PIP2. Interference with these sites and with PIP2 binding has also been described for other Kir channels blocking drugs. As Kir2.3 is preferentially expressed in atrium, a selective Kir2.3 blocking agent would constitute an interesting antiarrhythmic concept.

[Acceptance of telemetric care for patients with sICD safety advice : Qualitative interview study in cardiological health services research]. / Akzeptanz einer telemetrischen Versorgung bei Patienten mit sICD-Sicherheitshinweis : Qualitative Interviewstudie der kardiologischen Versorgungsforschung.

BACKGROUND: Telemonitoring is used to monitor implantable cardioverter defibrillators (ICDs). Despite the scientifically proven effectiveness and safety of telemetric care, studies show that the offer is not used and accepted by all patients. OBJECTIVES: The aim of this study is to investigate the attitudes of ICD patients towards telemonitoring, including which aspects influence attitudes and decision-making. METHODS: Data were collected using semi-structured, guideline-based individual interviews. A total of 14 patients with a subcutaneous ICD (sICD) and both primary and secondary prophylactic indications were recruited. Data analysis followed a content-structuring qualitative approach. RESULTS: Patients with telemonitoring perceived a high benefit with low concerns about digital technology, while the opposite was observed for patients without telemonitoring. The patients' previous medical experience has a crucial impact on the acceptance of telemonitoring. All age groups reported the technical implementation and practical handling of telemonitoring to be simple and uncomplicated. CONCLUSION: The results suggest that the primary and secondary prophylactic indication for ICD implantation have an influence on the attitude towards telemonitoring and, thus, on acceptance. Further qualitative research regarding user acceptance of telemonitoring of other ICD systems is needed.

Five-year results of heart rate control with ivabradine or metoprolol succinate in patients after heart transplantation.

BACKGROUND: Cardiac graft denervation causes inadequate sinus tachycardia in patients after heart transplantation (HTX) which is associated with reduced survival. This study investigated the 5-year results of heart rate control with ivabradine or metoprolol succinate in patients after HTX. METHODS: This registry study analyzed 104 patients receiving either ivabradine (n = 50) or metoprolol succinate (n = 54) within 5 years after HTX. Analysis included patient characteristics, medication, echocardiographic features, cardiac catheterization data, cardiac biomarkers, heart rates, and post-transplant survival including causes of death. RESULTS: Demographics and post-transplant medication revealed no significant differences except for ivabradine and metoprolol succinate use. At 5-year follow-up, patients with ivabradine had a significantly lower heart rate (73.3 bpm) compared to baseline (88.6 bpm; P < 0.01) and to metoprolol succinate (80.4 bpm; P < 0.01), a reduced left ventricular mass (154.8 g) compared to baseline (179.5 g; P < 0.01) and to metoprolol succinate (177.3 g; P < 0.01), a lower left ventricular end-diastolic pressure (LVEDP; 12.0 mmHg) compared to baseline (15.5 mmHg; P < 0.01) and to metoprolol succinate (17.1 mmHg; P < 0.01), and a reduced NT-proBNP level (525.4 pg/ml) compared to baseline (3826.3 pg/ml; P < 0.01) and to metoprolol succinate (1038.9 pg/ml; P < 0.01). Five-year post-transplant survival was significantly better in patients with ivabradine (90.0%) versus metoprolol succinate (68.5%; P < 0.01). CONCLUSION: Patients receiving ivabradine showed a superior heart rate reduction and a better left ventricular diastolic function along with an improved 5-year survival after HTX.

Frequency, Risk Factors, and Clinical Outcomes of Late-Onset Atrial Flutter in Patients after Heart Transplantation.

Aims: Atrial flutter (AFL) is a common late-onset complication after heart transplantation (HTX) and is associated with worse clinical outcomes. Methods: This study investigated the frequency, risk factors, and outcomes of late-onset post-transplant AFL. We analyzed 639 adult patients undergoing HTX at the Heidelberg Heart Center between 1989 and 2019. Patients were stratified by diagnosis and type of late-onset post-transplant AFL (>90 days after HTX). Results: A total of 55 patients (8.6%) were diagnosed with late-onset post-transplant AFL, 30 had typical AFL (54.5%) and 25 had atypical AFL (45.5%). Patients with AFL were younger at HTX (p = 0.028), received more biatrial anastomosis (p = 0.001), and presented with moderate or severe tricuspid regurgitation (56.4%). Typical AFL was associated with graft rejection (p = 0.016), whereas atypical AFL was associated with coronary artery disease (p = 0.028) and stent implantation (p = 0.042). Patients with atypical AFL showed a higher all-cause 1-year mortality (p = 0.010) along with a higher rate of graft failure after diagnosis of AFL (p = 0.023). Recurrence of AFL was high (83.6%). Patients with catheter ablation after AFL recurrence had a higher 1-year freedom from AFL (p = 0.003). Conclusions: Patients with late-onset post-transplant AFL were younger at HTX, received more biatrial anastomosis, and showed a higher rate of moderate or severe tricuspid regurgitation. Typical AFL was associated with graft rejection, whereas atypical AFL was associated with myocardial ischemia, graft failure, and mortality. Catheter ablation represents a viable option to avoid further episodes of late-onset AFL after HTX.

Catheter Ablation of Atrial Fibrillation in Patients With Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Coexistence of atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) is common, affecting morbidity and prognosis. This study evaluates outcome after cryoballoon ablation for AF in HFpEF compared with patients without heart failure. METHODS: A total of 102 AF patients with left ventricular ejection fraction ≥50% undergoing cryoballoon ablation were prospectively enrolled. Baseline evaluation included echocardiography, stress echocardiography, 6-minute walk test, biomarkers, and quality of life assessment (Short-Form-36). Procedural parameters and clinical, functional and echocardiographic end points at follow-up ≥12 months after AF ablation were compared between patients with and without HFpEF. RESULTS: Patients with HFpEF (n=24) were older (median, 74 years versus 65 years; P=0.001) more often female (83% versus 28%; P<0.001) and characterized by more pronounced AF-related symptoms (median European Heart Rhythm Association score 3 versus 2; P<0.001), higher left atrial pressures (median, 14 mm Hg versus 10 mm Hg; P=0.008), reduced left atrial-appendage velocity (median, 36 cm/s versus 59 cm/s; P<0.001), and reduced distance in the 6-minute walk test (median, 488 m versus 539 m; P<0.001). Patients with HFpEF more often experienced AF recurrence (57% versus 23%; P=0.003), repeat AF ablation (39% versus 14%; P=0.01) and AF-related rehospitalization (26% versus 7%; P=0.016). Heart failure symptoms and elevated cardiac biomarkers persisted, even in patients with HFpEF with successful rhythm control at follow-up. Echocardiographic follow-up showed progression of adverse left atrial remodeling and no relevant improvement in diastolic function in HFpEF. Quality of life improved in patients without HFpEF, whereas patients with HFpEF still exhibited a lower physical component summary score (median, 41.5 versus 53.4; P<0.004). CONCLUSIONS: Patients with HFpEF constitute a distinct subgroup with elevated risk for AF recurrence after cryoballon ablation. Functional hallmarks of HFpEF persist, irrespective of rhythm status at follow-up. Future research is needed to optimize treatment strategies in patients with HFpEF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04317911.

Alternative splicing determines mRNA translation initiation and function of human K(2P)10.1 K+ channels.

Potassium-selective ion channels regulate cardiac and neuronal excitability by stabilizing the resting membrane potential and by modulating shape and frequency of action potentials. The delicate control of membrane voltage requires structural and functional diversity of K+ channel subunits expressed in a given cell. Here we reveal a previously unrecognized biological mechanism. Tissue-specific mRNA splicing regulates alternative translation initiation (ATI) of human K(2P)10.1 K+ background channels via recombination of 5 nucleotide motifs. ATI-dependent expression of full-length protein or truncated subunits initiated from two downstream start codons determines macroscopic current amplitudes and biophysical properties of hK(2P)10.1 channels. The interaction between hK(2P)10.1 mRNA splicing, translation and function increases K+ channel complexity and is expected to contribute to electrophysiological plasticity of excitable cells.

Electrical Ventricular Remodeling in Dilated Cardiomyopathy.

Ventricular arrhythmias contribute significantly to morbidity and mortality in patients with heart failure (HF). Pathomechanisms underlying arrhythmogenicity in patients with structural heart disease and impaired cardiac function include myocardial fibrosis and the remodeling of ion channels, affecting electrophysiologic properties of ventricular cardiomyocytes. The dysregulation of ion channel expression has been associated with cardiomyopathy and with the development of arrhythmias. However, the underlying molecular signaling pathways are increasingly recognized. This review summarizes clinical and cellular electrophysiologic characteristics observed in dilated cardiomyopathy (DCM) with ionic and structural alterations at the ventricular level. Furthermore, potential translational strategies and therapeutic options are highlighted.

Histone deacetylase 2-dependent ventricular electrical remodeling in a porcine model of early heart failure.

AIMS: Heart failure (HF) is linked to electrical remodeling that promotes ventricular arrhythmias. Underlying molecular signaling is insufficiently understood, in particular concerning patients with early disease stages. Previous observations suggest a key role for epigenetic mechanisms in cardiac remodeling processes. We hypothesized that histone deacetylases (HDACs) 1 and 2 contribute to cellular electrophysiological dysregulation in ventricular cardiomyocytes during HF development. MATERIALS AND METHODS: HDAC and ion channel expression was quantified in a porcine model of early HF induced by short-term atrial tachypacing, resulting in atrial fibrillation with rapid ventricular rate response. Anti-Hdac1 and anti-Hdac2 siRNA treatment was employed in neonatal murine cardiomyocytes (NMCM) to study effects of HDACs on ion channel mRNA expression and action potential duration (APD). KEY FINDINGS: Early HF was characterized by mild reduction of left ventricular ejection fraction, prolonged QTc intervals, and increased ventricular effective refractory periods. Delayed repolarization was linked to significant downregulation of HDAC2 in left ventricular (LV) tissue. In addition, there was a tendency towards reduced transcript expression of KCNJ2/Kir2.1 K+ channels. In NMCM, knock-down of Hdac2 recapitulated AP prolongation. Finally, siRNA-mediated suppression of Hdac2 reduced Kcnh2/Kv11.1 K+ channel expression. SIGNIFICANCE: Suppression of HDAC2 is linked to ventricular electrical remodeling of APD and ion channel expression in early stages of heart failure. This previously unrecognized mechanism may serve as basis for future approaches to prevention and treatment of ventricular arrhythmias.

Newly acquired complete right bundle branch block early after heart transplantation is associated with lower survival.

AIMS: Right bundle branch block (RBBB) after heart transplantation (HTX) is a common finding, but its impact on post-transplant survival remains uncertain. This study investigated the post-transplant outcomes of patients with complete RBBB (cRBBB) ≤ 30 days after HTX. METHODS: This registry study analysed 639 patients receiving HTX at Heidelberg Heart Center between 1989 and 2019. Patients were stratified by diagnosis of cRBBB ≤ 30 days after HTX. Analysis included recipient and donor data, medication, echocardiographic features, graft rejections, atrial fibrillation, heart rates, permanent pacemaker implantation and mortality after HTX including causes of death. RESULTS: One hundred thirty-nine patients showed cRBBB ≤ 30 days after HTX (21.8%), 20 patients with pre-existing cRBBB in the donor heart (3.2%) and 119 patients with newly acquired cRBBB (18.6%). Patients with newly acquired cRBBB had a worse 1-year post-transplant survival (36.1%, P < 0.01) compared with patients with pre-existing cRBBB (85.0%) or without cRBBB (86.4%), along with a higher percentage of death due to graft failure (P < 0.01). Multivariate analysis indicated cRBBB ≤ 30 days after HTX as significant risk factor for 1-year mortality after HTX (HR: 2.20; 95% CI: 1.68-2.87; P < 0.01). Secondary outcomes showed a higher rate of an enlarged right atrium (P = 0.01), enlarged right ventricle (P < 0.01), reduced right ventricular function (P < 0.01), 30-day atrial fibrillation (P < 0.01) and 1-year permanent pacemaker implantation (P = 0.02) in patients with cRBBB after HTX. CONCLUSIONS: Newly acquired cRBBB early after HTX is associated with increased post-transplant mortality.

Differential regulation of KCa 2.1 (KCNN1) K+ channel expression by histone deacetylases in atrial fibrillation with concomitant heart failure.

Atrial fibrillation (AF) with concomitant heart failure (HF) poses a significant therapeutic challenge. Mechanism-based approaches may optimize AF therapy. Small-conductance, calcium-activated K+ (KCa , KCNN) channels contribute to cardiac action potential repolarization. KCNN1 exhibits predominant atrial expression and is downregulated in chronic AF patients with preserved cardiac function. Epigenetic regulation is suggested by AF suppression following histone deacetylase (HDAC) inhibition. We hypothesized that HDAC-dependent KCNN1 remodeling contributes to arrhythmogenesis in AF complicated by HF. The aim of this study was to assess KCNN1 and HDAC1-7 and 9 transcript levels in AF/HF patients and in a pig model of atrial tachypacing-induced AF with reduced left ventricular function. In HL-1 atrial myocytes, tachypacing and anti-Hdac siRNAs were employed to investigate effects on Kcnn1 mRNA levels. KCNN1 expression displayed side-specific remodeling in AF/HF patients with upregulation in left and suppression in right atrium. In pigs, KCNN1 remodeling showed intermediate phenotypes. HDAC levels were differentially altered in humans and pigs, reflecting highly variable epigenetic regulation. Tachypacing recapitulated downregulation of Hdacs 1, 3, 4, 6, and 7 with a tendency towards reduced Kcnn1 levels in vitro, indicating that atrial high rates induce remodeling. Finally, Kcnn1 expression was decreased by knockdown of Hdacs 2, 3, 6, and 7 and enhanced by genetic Hdac9 inactivation, while anti-Hdac 1, 4, and 5 siRNAs did not affect Kcnn1 transcript levels. In conclusion, KCNN1 and HDAC expression is differentially remodeled in AF complicated by HF. Direct regulation of KCNN1 by HDACs in atrial myocytes provides a basis for mechanism-based antiarrhythmic therapy.