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Purpose of review SGLT2 inhibitors (SGLT2i) are new drugs for patients with heart failure (HF) irrespective of diabetes. However, the mechanisms of SGLT2i in HF remain elusive. This article discusses the current clinical evidence for using SGLT2i in different types of heart failure and provides an overview about the possible underlying mechanisms. Recent findings Clinical and basic data strongly support and extend the use of SGLT2i in HF. Improvement of conventional secondary risk factors is unlikely to explain the prognostic benefits of these drugs in HF. However, different multidirectional mechanisms of SGLT2i could improve HF status including volume regulation, cardiorenal mechanisms, metabolic effects, improved cardiac remodelling, direct effects on cardiac contractility and ion-homeostasis, reduction of inflammation and oxidative stress as well as an impact on autophagy and adipokines. Summary Further translational studies are needed to determine the mechanisms of SGLT2i in HF. However, basic and clinical evidence encourage the use of SGLT2i in HFrEF and possibly HFpEF.

Aims Recent clinical trials have proven gliflozins to be cardioprotective in diabetic and non‐diabetic patients. However, the underlying mechanisms are incompletely understood. A potential inhibition of cardiac Na+/H+ exchanger 1 (NHE1) has been suggested in animal models. We investigated the effect of empagliflozin on NHE1 activity in human atrial cardiomyocytes. Methods and results Expression of NHE1 was assessed in human atrial and ventricular tissue via western blotting. NHE activity was measured as the maximal slope of pH recovery after NH4+ pulse in isolated carboxy‐seminaphtarhodafluor 1 (SNARF1)‐acetoxymethylester‐loaded murine ventricular and human atrial cardiomyocytes. NHE1 is abundantly expressed in human atrial and ventricular tissue. Interestingly, compared with patients without heart failure (HF), atrial NHE1 expression was significantly increased in patients with HF with preserved ejection fraction and atrial fibrillation. The largest increase in atrial and ventricular NHE1 expression, however, was observed in patients with end‐stage HF undergoing heart transplantation. Importantly, acute exposure to empagliflozin (1 μmol/L, 10 min) significantly inhibited NHE activity to a similar extent in human atrial myocytes and mouse ventricular myocytes. This inhibition was also achieved by incubation with the well‐described selective NHE inhibitor cariporide (10 μmol/L, 10 min). Conclusions This is the first study systematically analysing NHE1 expression in human atrial and ventricular myocardium of HF patients. We show that empagliflozin inhibits NHE in human cardiomyocytes. The extent of NHE inhibition was comparable with cariporide and may potentially contribute to the improved outcome of patients in clinical trials.

Abstract Aims The EMPA-REG OUTCOME study showed reduced mortality and hospitalization due to heart failure (HF) in diabetic patients treated with empagliflozin. Overexpression and Ca2+-dependent activation of Ca2+/calmodulin-dependent kinase II (CaMKII) are hallmarks of HF, leading to contractile dysfunction and arrhythmias. We tested whether empagliflozin reduces CaMKII- activity and improves Ca2+-handling in human and murine ventricular myocytes. Methods and results Myocytes from wild-type mice, mice with transverse aortic constriction (TAC) as a model of HF, and human failing ventricular myocytes were exposed to empagliflozin (1 μmol/L) or vehicle. CaMKII activity was assessed by CaMKII–histone deacetylase pulldown assay. Ca2+ spark frequency (CaSpF) as a measure of sarcoplasmic reticulum (SR) Ca2+ leak was investigated by confocal microscopy. [Na+]i was measured using Na+/Ca2+-exchanger (NCX) currents (whole-cell patch clamp). Compared with vehicle, 24 h empagliflozin exposure of murine myocytes reduced CaMKII activity (1.6 ± 0.7 vs. 4.2 ± 0.9, P < 0.05, n = 10 mice), and also CaMKII-dependent ryanodine receptor phosphorylation (0.8 ± 0.1 vs. 1.0 ± 0.1, P < 0.05, n = 11 mice), with similar results upon TAC. In murine myocytes, empagliflozin reduced CaSpF (TAC: 1.7 ± 0.3 vs. 2.5 ± 0.4 1/100 μm−1 s−1, P < 0.05, n = 4 mice) but increased SR Ca2+ load and Ca2+ transient amplitude. Importantly, empagliflozin also significantly reduced CaSpF in human failing ventricular myocytes (1 ± 0.2 vs. 3.3 ± 0.9, P < 0.05, n = 4 patients), while Ca2+ transient amplitude was increased (F/F0: 0.53 ± 0.05 vs. 0.36 ± 0.02, P < 0.05, n = 3 patients). In contrast, 30 min exposure with empagliflozin did not affect CaMKII activity nor Ca2+-handling but significantly reduced [Na+]i. Conclusions We show for the first time that empagliflozin reduces CaMKII activity and CaMKII-dependent SR Ca2+ leak. Reduced Ca2+ leak and improved Ca2+ transients may contribute to the beneficial effects of empagliflozin in HF.

Strain echocardiography (SE) may be used for surveillance in patients after heart transplantation (HTx); however, data on atrial strain are lacking. We aimed to compare the significance of ventricular and atrial strain with respect to an associated acute cellular rejection (ACR). Patients who underwent an endomyocardial biopsy (EMB) within 1 year after HTx were eligible for this retrospective analysis. The relationship between SE and ACR was assessed. EMB results of 52 patients (median age, 53 years; 63% male) at a median of 181 days post-HTx were identified. Mild ACR was present in 19 patients and ≥ moderate ACR in 6 patients. ACR ≥ moderate was associated with right ventricular free wall strain (OR 1.20, 95%CI 1.02–1.46, P = 0.04) and right atrial contraction strain (RASct; OR 1.55, 95%CI 1.18–2.43, P = 0.01). The RASct cut-off value of −9.3% had a sensitivity of 100% and a specificity of 79% for ≥ moderate ACR. None of these associations were observed for left ventricular or left atrial strain. A validation analysis was performed on another group of 23 HTx patients, which yielded similar results with regard to the specified RASct cut-off value. Our comprehensive strain analysis confirmed the association between reduced right ventricular strain and ACR and further identified robust associations between RASct and ACR. Right atrial strain analysis may be a promising method for excluding subclinical ACR after HTx.

An interplay between Ca 2+ /calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na + current (I NaL ) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform Na V 1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of Na V 1.8, we demonstrate that Na V 1.8 contributes to I NaL formation. In addition, we reveal a direct interaction between Na V 1.8 and CaMKIIδc in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of Na V 1.8 and CaMKIIδc, we show that Na V 1.8-driven I NaL is CaMKIIδc-dependent and that Na V 1.8-inhibtion reduces diastolic SR-Ca 2+ leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKIIδc-overexpressing HF mice is reduced when a Na V 1.8 knock-out is introduced. Cellular and in vivo experiments reveal reduced ventricular arrhythmias without changes in HF progression. Our work therefore identifies a proarrhythmic CaMKIIδc downstream target which may constitute a prognostic and antiarrhythmic strategy. In heart failure, increased CaMKII activity is decisively involved in arrhythmia formation. Here, the authors introduce the neuronal sodium channel Na V 1.8 as a CaMKII downstream target as its specific knock-out reduces arrhythmias and improves survival in a CaMKII-overexpressing mouse model.

The objective of the present study was to evaluate the association between liver cirrhosis (LC) and subsequent Heart failure (HF). This retrospective cohort study utilized data from the Disease Analyzer database (IQVIA) and included adults with a first-time diagnosis of LC in 1293 general practices in Germany between January 2005 and December 2023. A comparison cohort without liver diseases was matched to the cirrhosis group using 5:1 propensity score matching. Univariable Cox proportional hazards models were used to assess the association between alcoholic vs. non-alcoholic LC and HF. The final study cohort included 5530 patients with alcoholic LC and 27,650 matched patients without liver disease, as well as 7063 patients with non-alcoholic LC and 35,315 matched patients without liver disease. After up to 10 years of follow-up, HF was diagnosed in 20.9% of patients with alcoholic LC compared to 10.3% of matched cohort, and in 23.0% of patients with non-alcoholic LC, compared to 14.2% in matched cohort. Alcoholic LC (Hazard Ratio (HR): 2.07 (95% CI: 1.85–2.31) and non-alcoholic LC (HR: 1.70; 95% CI: 1.56–1.82) were associated with an increased risk of HF. The association was also stronger in men than in women. LC, both alcoholic and non-alcoholic, is significantly associated with an increased long-term risk of HF. The association is particularly pronounced in patients with alcoholic cirrhosis and in men. To the best of the authors’ knowledge, this is the first real-world evidence for the positive association between LC and subsequent HF from Europe.

Background Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice and is associated with considerable morbidity and mortality. Chronic systemic inflammation is increasingly recognized as a contributing factor in AF pathogenesis. Autoimmune diseases (AIDs), with their prototypical inflammatory conditions, may therefore be associated with AF. However, evidence from routine outpatient care regarding these potential associations across multiple AIDs remains limited. Objective We aimed to examine whether autoimmune diseases are associated with increased odds of atrial fibrillation and to assess whether these associations differ between women and men. Methods We conducted a retrospective 1:1 matched case-control study using data from the Disease Analyzer database (IQVIA). Adult patients with AF (2010–2024) were matched to AF-free controls based on age, sex, comorbidities, medication use and observation time. The presence of predefined AIDs prior to AF diagnosis was identified using ICD-10 codes. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) and sex-stratified data were analyzed. Results A total of 174,992 AF cases and 174,992 matched controls were included (mean age 74.0 years, 48% female). Overall, any AID was associated with AF (OR 1.12; 95% CI 1.09–1.15). Significant associations were observed for rheumatoid arthritis (OR 1.14; 95% CI 1.10–1.18), inflammatory bowel disease (OR 1.16; 95% CI 1.06–1.27), psoriasis (OR 1.10; 95% CI 1.05–1.15), and Graves’ disease (OR 1.29; 95% CI 1.18–1.41). Conclusion Several AIDs were modestly associated with atrial fibrillation in routine outpatient care. Sex-stratified analyses suggested variation in point estimates for some associations, while interaction analyses showed limited evidence for true sex-specific effect modification. These findings support the role of systemic inflammation in AF pathogenesis and underscore the need for interdisciplinary cardiovascular risk assessment in patients with autoimmune conditions.

ObjectiveTo evaluate changes in cardiac magnetic resonance (CMR) tissue characteristics in patients with active cardiac sarcoidosis (CS) confirmed by positron emission tomography (PET)-CT undergoing immunomodulatory therapy (IMT), and to explore their potential use for inflammation monitoring.DesignRetrospective observational cohort study.SettingTertiary care referral centre in Germany.ParticipantsFrom a cohort of 47 patients with CS, 24 patients with PET-confirmed active myocardial inflammation and complete baseline and follow-up CMR imaging after ≥6 months of IMT were included.Primary and secondary endpointsPrimary outcome: Changes in CMR-derived tissue characteristics (T1, T2 mapping, late gadolinium enhancement (LGE) mass). Secondary outcomes: Changes in functional (ejection fraction (EF) and global longitudinal strain (GLS)) and morphological parameters (end-diastolic/systolic volume indices (EDVi/ESVi)).ResultsPatients with PET-confirmed active CS show increased global T1 and T2 compared with healthy volunteers. Over the course of IMT, significant reductions in global T2 (median (IQR): 39 (38–41) ms vs 37 (36–39) ms; p=0.002), LGE-region T2 (43 (40–46) ms vs 41 (38–42) ms; p=0.003), and relative LGE mass (23% (17–38) vs 15% (8–32); p=0.006) were observed. No significant differences were found in EF (p=0.78), GLS (p=0.49), EDVi (p=0.56), ESVi (p=0.28) or native T1 values (p=0.23).ConclusionIn patients with PET-confirmed active CS undergoing IMT, serial CMR demonstrated measurable changes in T2 mapping and LGE parameters, suggesting a potential role for CMR tissue characterisation in monitoring myocardial inflammation. However, due to the observational design and absence of a control group, causal treatment effects cannot be confirmed. Further prospective studies are needed to validate the utility of CMR for treatment monitoring in CS.

The initiation of sodium–glucose cotransporter 2 (SGLT2) inhibitor treatment was shown to reduce pulmonary artery pressure (PAP) in New York Heart Association (NYHA) class III heart failure (HF) patients with an implanted PAP sensor. We aimed to investigate the impact of SGLT2-I initiation on pulmonary vascular resistance (PVR), pulmonary capillary wedge pressure (PCWP), pulmonary arterial capacitance (PAC), and right ventricle (RV) to PA (RV-PA) coupling in a pilot cohort of HF with preserved/mildly reduced ejection fraction (HFpEF/HFmrEF) patients and whether PVR and PCWP can be serially calculated non-invasively using PAP sensor data during follow-up. Methods: Right heart catheterization parameters (PVR, PCWP, and PAC) were obtained at sensor implantation and echocardiographic assessments (E/E’, RV-PA coupling, and RV cardiac output) were made at baseline and every 3 months. SGLT2 inhibition was initiated after 3 months of telemedical care. Three methods for calculating PVR and PCWP were compared using Bland–Altman plots and Spearman’s correlation. Results: In 13 HF patients (mean age 77 ± 4 years), there were no significant changes in PAP, PVR, PCWP, RV-PA coupling, or PAC over 9 months (all p-values > 0.05), including after SGLT2-I initiation. PVR values were closely correlated across the three methods (PVRNew and PVRNew Tedford (r = 0.614, p < 0.001), PVREcho and PVRNew Tedford (r = 0.446, p = 0.006), and PVREcho and PVRNew (r = 0.394, p = 0.016)), but PCWP methods lacked reliable association (PCWPEcho and PCWPNew (r = 0.180, p = 0.332). Conclusions: No changes in cardiopulmonary hemodynamics were detected after hemodynamic telemonitoring either prior to or following SGLT2-I initiation. Different PVR assessment methods yielded comparable results, whereas PCWP methods were not associated with each other. Further investigations with larger cohorts including repeated right heart catheterization are planned.

Diabetes increases oxidant stress and doubles the risk of dying after myocardial infarction, but the mechanisms underlying increased mortality are unknown. Mice with streptozotocin-induced diabetes developed profound heart rate slowing and doubled mortality compared with controls after myocardial infarction. Oxidized Ca(2+)/calmodulin-dependent protein kinase II (ox-CaMKII) was significantly increased in pacemaker tissues from diabetic patients compared with that in nondiabetic patients after myocardial infarction. Streptozotocin-treated mice had increased pacemaker cell ox-CaMKII and apoptosis, which were further enhanced by myocardial infarction. We developed a knockin mouse model of oxidation-resistant CaMKIIδ (MM-VV), the isoform associated with cardiovascular disease. Streptozotocin-treated MM-VV mice and WT mice infused with MitoTEMPO, a mitochondrial targeted antioxidant, expressed significantly less ox-CaMKII, exhibited increased pacemaker cell survival, maintained normal heart rates, and were resistant to diabetes-attributable mortality after myocardial infarction. Our findings suggest that activation of a mitochondrial/ox-CaMKII pathway contributes to increased sudden death in diabetic patients after myocardial infarction.