Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality. Importantly, atrial remodelling and atrial fibrillation are 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 anti-arrhythmic 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. 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 I_Na (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 Na_V1.5 phosphorylation in HFpEF compared to NF, whereas Na_V1.5 protein and mRNA abundance remained unchanged. Consistently, increased Na influx was significantly reduced by treatment not only with the CaMKII inhibitor autocamtide-2-related inhibitory peptide (AIP), late I_Na inhibitor tetrodotoxin (TTX) but also with sodium/hydrogen exchanger 1 (NHE1) inhibitor cariporide. Importantly, empagliflozin abolished both increased Na influx and late I_Na 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. We show for the first time increased Na influx in human atrial cardiomyocytes from HFpEF patients, partly due to increased late I_Na and enhanced NHE1-mediated Na influx. Empagliflozin inhibits Na influx and late I_Na, which could contribute to anti-arrhythmic effects in patients with HFpEF.

Ventricular assist devices (VADs) invigorated the management of patients with advanced heart failure, providing a lifeline for patients awaiting transplantation or requiring long-term circulatory support. This article reviews recent advances in VAD technologies, focusing on key areas of progress to overcome existing challenges and the potential for future applications. The reduction or possible elimination of infection-prone components and the evolution to transcutaneous energy transfer systems are two main research fields to reach a new quality of life category for VADs patients. Miniaturization and enhanced biocompatibility have resulted in smaller, less invasive devices with a significantly reduced risk of complications and mortality. Advances in percutaneous ventricular assist devices have emerged, contributing to the creation of less invasive options with or without intracardiac pumps, and facilitating their use for both left and right ventricles. These devices have gained more and more features, including the use of artificial intelligence. Moreover, the possibility of long-term use of intracardiac pumps offers a potential bridge to transplantation, allowing ambulation and probably also long-term circulatory support. Despite considerable advances, challenges remain, particularly in terms of improving durability, reducing the risk of ischemic events, further refining materials, and more sophisticated control and synchronization between systems that adapt to changing physiological demands.

Background: In reverse-mode, cardiac sodium-calcium exchanger (NCX) can increase the cytoplasmic Ca²⁺ concentration in response to high intracellular Na⁺ levels, which may contribute to diastolic contractile dysfunction. Furthermore, increased spontaneous Ca²⁺ release from intracellular stores can activate forward mode NCX. The resulting transient inward current causes delayed afterdepolarization (DAD)-dependent arrhythmias. Moreover, recently, NCX has been associated with impaired relaxation and reduced cardiac function in heart failure with preserved ejection fraction (HFpEF). Since NCX is upregulated in human chronic atrial fibrillation (AF) as well as heart failure (HF), specific inhibition may have therapeutic potential. Objective: We tested the antiarrhythmic, lusitropic and inotropic effects of a novel selective NCX-inhibitor (SAR296968) in human atrial myocardium. Methods and Results: Right atrial appendage biopsies of 46 patients undergoing elective cardiac surgery in a predominant HFpEF cohort (n = 24/46) were investigated. In isolated human atrial cardiomyocytes, SAR296968 reduced the frequency of spontaneous SR Ca²⁺ release events and increased caffeine transient amplitude. In accordance, in isolated atrial trabeculae, SAR296968 enhanced the developed tension after a 30 s pause of electrical stimulation consistent with reduced diastolic sarcoplasmic reticulum (SR) Ca²⁺ leak. Moreover, compared to vehicle, SAR296968 decreased steady-state diastolic tension (at 1 Hz) without impairing developed systolic tension. Importantly, SAR296968 did not affect the safety parameters, such as resting membrane potential or action potential duration as measured by patch clamp. Conclusion: The novel selective NCX-inhibitor SAR296968 inhibits atrial pro-arrhythmic activity and improves diastolic and contractile function in human atrial myocardium, which may have therapeutic implications, especially for treatment of HFpEF.