Aims There is a lack of diagnostic and therapeutic options for patients with atrial cardiomyopathy and paroxysmal atrial fibrillation. Interestingly, an abnormal P-wave terminal force in electrocardiogram lead V₁ (PTFV₁) has been associated with atrial cardiomyopathy, but this association is poorly understood. We investigated PTFV₁ as a marker for functional, electrical, and structural atrial remodelling. Methods and results Fifty-six patients with acute myocardial infarction and 13 kidney donors as control cohort prospectively underwent cardiac magnetic resonance imaging to evaluate the association between PTFV₁ and functional remodelling (atrial strain). To further investigate underlying pathomechanisms, right atrial appendage biopsies were collected from 32 patients undergoing elective coronary artery bypass grafting. PTFV₁ was assessed as the product of negative P-wave amplitude and duration in lead V₁ and defined as abnormal if ≥4000 ms*μV. Activity of cardiac Ca/calmodulin-dependent protein kinase II (CaMKII) was determined by a specific HDAC4 pull-down assay as a surrogate for electrical remodelling. Atrial fibrosis was quantified using Masson's trichrome staining as a measure for structural remodelling. Multivariate regression analyses were performed to account for potential confounders. A total of 16/56 (29%) of patients with acute myocardial infarction, 3/13 (23%) of kidney donors, and 15/32 (47%) of patients undergoing coronary artery bypass grafting showed an abnormal PTFV₁. In patients with acute myocardial infarction, left atrial (LA) strain was significantly reduced in the subgroup with an abnormal PTFV₁ (LA reservoir strain: 32.28 ± 12.86% vs. 22.75 ± 13.94%, P = 0.018; LA conduit strain: 18.87 ± 10.34% vs. 10.17 ± 8.26%, P = 0.004). Abnormal PTFV₁ showed a negative correlation with LA conduit strain independent from clinical covariates (coefficient B: −7.336, 95% confidence interval −13.577 to −1.095, P = 0.022). CaMKII activity was significantly increased from (normalized to CaMKII expression) 0.87 ± 0.17 to 1.46 ± 0.15 in patients with an abnormal PTFV₁ (P = 0.047). This increase in patients with an abnormal PTFV₁ was independent from clinical covariates (coefficient B: 0.542, 95% confidence interval 0.057 to 1.027, P = 0.031). Atrial fibrosis was significantly lower with 12.32 ± 1.63% in patients with an abnormal PTFV₁ (vs. 20.50 ± 2.09%, P = 0.006), suggesting PTFV₁ to be a marker for electrical but not structural remodelling. Conclusions Abnormal PTFV₁ is an independent predictor for impaired atrial function and for electrical but not for structural remodelling. PTFV₁ may be a promising tool to evaluate patients for atrial cardiomyopathy and for risk of atrial fibrillation.

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.

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.

Heart failure with preserved ejection fraction (HFpEF) is emerging as a widespread disease with global socioeconomic impact. Patients with HFpEF show a dramatically increased morbidity and mortality, and, unfortunately, specific treatment options are limited. This is due to the various etiologies that promote HFpEF development. Indeed, cluster analyses with common HFpEF comorbidities revealed the existence of several HFpEF phenotypes. One especially frequent, yet underappreciated, comorbidity is sleep-disordered breathing (SDB), which is closely intertwined with the development and progression of the “obese HFpEF phenotype”. The following review article aims to provide an overview of the common HFpEF etiologies and phenotypes, especially in the context of SDB. As general HFpEF therapies are often not successful, patient- and phenotype-individualized therapeutic strategies are warranted. Therefore, for the “obese HFpEF phenotype”, a better understanding of the mechanistic parallels between both HFpEF and SDB is required, which may help to identify potential phenotype-individualized therapeutic strategies. Novel technologies like single-cell transcriptomics or CRISPR-Cas9 gene editing further broaden the groundwork for deeper insights into pathomechanisms and precision medicine.

Left ventricular diastolic dysfunction is a predictor of adverse outcome after acute myocardial infarction (AMI). We aimed to test if sleep-disordered breathing (SDB) contributes to the development of diastolic dysfunction in patients with preserved left ventricular ejection fraction after AMI. Patients with AMI, percutaneous coronary intervention and an ejection fraction ≥50% were included in this sub-analysis of a prospective observational study. Patients with AMI (n = 41) underwent cardiovascular magnetic resonance imaging (volume-time curve analysis) to define diastolic function by means of the normalised peak filling rate [nPFR; (end diastolic volume/second)]. In patients with AMI, the nPFR was assessed within <5 days and three months after AMI. Patients with AMI were stratified in patients with (apnoea-hypopnoea index, AHI ≥15/h) and without (AHI <15/h) SDB as assessed by polysomnography. At the time of AMI, the nPFR was similar between patients with and without SDB (2.90 ± 0.54 vs. 3.03 ± 1.20, p = 0.662). Within three months after AMI, diastolic function was significantly lower in patients with SDB than in patients without SDB (ΔnPFR: -0.83 ± 0.14 vs. 0.03 ± 0.14; p < 0.001; ANCOVA, adjusted for baseline nPFR). In contrast to central AHI, obstructive AHI was associated with a lower nPFR three months after AMI, after accounting for established risk factors for diastolic dysfunction [multiple linear regression analysis, B (95%CI): -0.036 (-0.063 to -0.009), p = 0.011]. Our data indicate that obstructive sleep apnoea impairs diastolic function early after myocardial infarction.

Background: Dyspnea is a frequent symptom in patients with stable coronary artery disease (CAD) and is recognized as a possible angina equivalent. Objectives: This study was to assess the impact of percutaneous coronary intervention (PCI) on dyspnea, quality of life, and angina pectoris in patients with stable CAD. Methods: The prospective, multi-center PLA-pCi-EBO-pilot trial included 144 patients with symptomatic stable CAD and successful PCI. The prespecified endpoints angina pectoris (Seattle Angina Questionnaire–SAQ) and dyspnea (NYHA scale) were assessed 6 months after PCI. Predictors for symptomatic improvement were assessed with uni- and multivariable logistic regression analyses. Results: Patients with concomitant dyspnea had worse SAQ physical limitation scores at baseline (49.5 ± 21.0 vs 58.9 ± 22.0, p = 0.013) but showed no difference for angina frequency or quality of life. Overall, symptomatic burden of angina pectoris and dyspnea was alleviated by PCI. However, patients with concomitant dyspnea had markedly worse scores for physical limitation (78.9 ± 25.0 vs 94.3 ± 10.6, p < 0.001), angina frequency (77.9 ± 22.8 vs 91.1 ± 12.4, p < 0.001), and quality of life (69.4 ± 24.1 vs 82.5 ± 14.4, p < 0.001) after PCI. The prevalence of dyspnea (NYHA class ≥ 2) declined from 73% before PCI to 54%. Of 95 initially dyspneic patients, 57 (60%) improved at least one NYHA class 6 months after PCI. In a multivariable logistic regression analysis, “atypical angina pectoris” was associated with improved NYHA class, whereas “diabetes mellitus” had a negative association. Conclusion: PCI effectively reduced dyspnea, which is a frequent and demanding symptom in patients with CAD. The German Clinical Trials Register registration number is DRKS0001752 (www.drks.de). Graphical