Cardiovascular diseases are the leading cause of morbidity and mortality worldwide, underscoring the urgent need for novel therapeutic targets and strategies. The kinase MARK4 (MAP (microtubule-associated proteins)/microtubule affinity-regulating kinase 4) regulates microtubule-associated proteins pivotal for cell polarity, protein stability, and intracellular signaling. Animal models of heart failure revealed elevated MARK4 levels, which correlated with impaired cardiac contractility. However, the involvement of MARK4 and its potential as a molecular drug target has not yet been explored in the myocardium of cardiovascular patients. We investigated the MARK4 mRNA expression in human myocardial biopsies of 152 high-risk cardiovascular patients undergoing cardiac surgery. Comprehensive echocardiography as well as testing for sleep-disordered breathing (SDB), a critical comorbidity in heart failure, were assessed preoperatively. We observed a substantial upregulation of myocardial MARK4 expression in patients with impaired cardiac contractility, resulting in an inverse correlation with the left ventricular ejection fraction. Myocardial MARK4 expression also correlated with echocardiographic E/e’, a central parameter of diastolic dysfunction. Mechanistically, our analyses revealed that MARK4 expression increases in SDB and under hypoxic conditions, as evidenced by significant correlations between myocardial MARK4 expression and factors like mean oxygen saturation, time with oxygen saturation below 90%, and the oxygen desaturation index. Multivariable regression analysis revealed that both left ventricular ejection fraction and mean oxygen saturation were independently associated with dysregulated MARK4 levels, even when controlling for important clinical covariables as potential confounders. Taken together, our findings demonstrate that MARK4 expression is highly increased in the myocardium of cardiovascular high-risk patients, suggesting it is a potential molecular target against cardiovascular diseases.

Heart failure and cardiovascular disease represent a significant burden on healthcare systems worldwide. Recent evidence associates an increased expression of the dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) with an impaired cardiac function in mice. However, there remains a paucity of data on myocardial DYRK1B expression in patients with cardiovascular disease in the context of other comorbidities. In our study, we examined DYRK1B mRNA expression in human right atrial appendage biopsies from 159 patients undergoing elective coronary artery bypass surgery. Each patient was tested for sleep-disordered breathing the night prior to surgery. In this large representative study cohort with cardiovascular high-risk patients, we found that an impaired cardiac function as well as sleep-disordered breathing (SDB), including various oxidative stress parameters, were associated with an increased myocardial DYRK1B expression. A multivariate regression analysis revealed left ventricular ejection fraction and the presence of SDB as significant predictors of the myocardial DYRK1B expression independent of other clinical covariates. Based on these findings, DYRK1B represents a promising molecular target in patients with heart failure and reduced ejection fraction as well in patients with sleep-disordered breathing.

Delayed sternal closure (DSC) is a well-established strategy used to manage patients with hemodynamic instability and perioperative coagulopathy following cardiac surgery. The study aims to present our 15-year surgical experiences with DSC.Between 2007 and 2022, DSC was performed in 227 out of 14,210 patients (1.7%) who underwent cardiac surgery at our institution. Perioperative data, outcomes, and long-term survival were analyzed. Quality of life (QoL) was assessed utilizing the EuroQol-5D-5L questionnaire.Indications for DSC included low cardiac output syndrome (LCOS) (44.1%) and coagulopathy during the index procedure (32.2%), as well as postoperative tamponade (22.9%). In coronary artery bypass grafting, LCOS was the primary indication for DSC (72.7%), whereas in acute type A aortic dissection, coagulopathy was the leading indication (70.6%). For other procedures, DSC indications were more evenly distributed. The overall 30-day survival was 57.5%, with survival rates of 43.3% for LCOS, 72.0% for coagulopathy, and 65.4% for tamponade. Multivariate logistic regression identified body mass index, postoperative renal replacement therapy, aggravated heart failure, and intraoperative packed red blood cell transfusion as negatively associated with 30-day survival. The mean follow-up period was 6.58 ± 3.19 years. Younger patients and DSC patients upon bleeding related indications reported higher QoL in comparison to older patients and patients with LCOS. Longer follow-up interval correlated with higher QoL.The study emphasizes the significant impact of LCOS on outcomes in patients undergoing DSC. We provide QoL data demonstrating good rehabilitation potential upon survival of the acute phase.

AIMS:Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has shown promising effects in reducing cardiovascular events in patients with obesity and heart failure (HF) with preserved ejection fraction (HFpEF) irrespective of concomitant diabetes. However, the exact mechanisms underlying its cardioprotective actions remain unclear. Our study investigates the direct effects of semaglutide on human cardiomyocytes, focusing on calcium (Ca) and sodium (Na) handling and its potential to improve myocardial contractility. METHODS AND RESULTS:Human left ventricular cardiomyocytes were isolated from non-failing (NF) hearts, patients with aortic stenosis and a HFpEF-like phenotype (AS), and those with end-stage HF with reduced ejection fraction (HFrEF). Late Na current (INa), sarcoplasmic reticulum (SR) Ca leak, and contractility were assessed in isolated cardiomyocytes treated with semaglutide. CaMKII inhibitor autocamtide-2-related inhibitory peptide and GLP-1 receptor antagonist exendin 9-39 (Ex-9-39) were used to elucidate signalling pathways. Semaglutide reduced late INa in AS and HFrEF cardiomyocytes to levels comparable to NF. Additionally, semaglutide decreased diastolic SR Ca leak and improved systolic Ca transients and contractility in AS and HFrEF tissue. These effects were mediated through GLP-1 receptor agonism and were comparable to CaMKII inhibition. In multicellular preparations, semaglutide differentially improved myocardial contractility in AS and HFrEF in a dose-dependent manner. CONCLUSION:Semaglutide directly modulates ion homeostasis in human cardiomyocytes, reducing proarrhythmic diastolic SR Ca leak and enhancing systolic function, which may explain its observed clinical benefits. These findings provide mechanistic insights into the cardioprotective effects of semaglutide and suggest its potential therapeutic use in HF.

Heart failure with preserved ejection fraction (HFpEF) constitutes approximately half of all patients with heart failure and causes mortality similar to heart failure with reduced ejection fraction [1]. HFpEF is highly relevant as novel evidence-based therapies emerge but treatment options remain limited [1]. Diastolic dysfunction is a hallmark of HFpEF and is also very common in up to 80% of high-risk cardiovascular patients undergoing cardiac surgery [2]. Even without overt HFpEF, echocardiographic diastolic dysfunction is independently associated with increased mortality [3]. Another important characteristic of HFpEF is the frequent presence of comorbidities with one of the most important being sleep-disordered breathing (SDB). SDB affects over one billion patients in the general population and is highly prevalent in cardiovascular high-risk patients, which underscores its high socio-economic relevance [4]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: MA received honoraria from ResMed, Philips Respironics, Inspire and Zoll and grant supports from Philips Respironics, ResMed Foundation, and ResMed. Conflict of interest: The other authors declare no conflict of interest.

Background: Native (NVE) and prosthetic (PVE) aortic valve endocarditis (AVE) remain a surgical challenge with an ongoing trend towards more complex surgical procedures. Methods: First-time NVE was compared with PVE, focusing on pathogens, risk factors, perioperative course, postoperative follow-up, including recurrent infection, as well as health-related quality of life (HRQOL). Results: From 2007 to 2022, surgical intervention for AVE was necessary in 231 patients with 233 episodes of infective aortic valve endocarditis, i.e., there were only two cases of reinfection (NVE group). The study group consisted of 130 cases with NVE and 103 with PVE. Overall, a median of 40.3% of survivors were in NYHA class I or II. In-hospital mortality was higher in the PVE group with 13.3%. The most common pathogen was Staphylococcus aureus, with 24.9% across both groups. EuroSCORE II was higher in the PVE group (19.0 ± 14.3% total, NVE 11.1 ± 8.1%, PVE 27.8 ± 14.6%; p < 0.05), reflecting an older, more co-morbid patient cohort. Abscess formation was also more common in the PVE group, while vegetations were more common in the NVE group. The 5-year and 10-year survival rates did not differ significantly between NVE and PVE and were 74.4% and 52.2% for the NVE group, respectively, and 67.4% and 52.9% for the PVE group, respectively. The HRQOL as assessed by the Minnesota Living with HF Questionnaire (MLHFQ) demonstrated no significant difference between both groups. Conclusions: Long-term survival and QoL after surgical treatment of infective aortic valve endocarditis are excellent and do not depend on the type of replacement.

BackgroundObstructive sleep apnea (OSA) has been linked to various pathologies, including arrhythmias such as atrial fibrillation. Specific treatment options for OSA are mainly limited to symptomatic approaches. We previously showed that increased production of reactive oxygen species (ROS) stimulates late sodium current through the voltage-dependent Na+ channels via Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ), thereby increasing the propensity for arrhythmias. However, the impact on atrial intracellular Na+ homeostasis has never been demonstrated. Moreover, the patients often exhibit a broad range of comorbidities, making it difficult to ascertain the effects of OSA alone.ObjectiveWe analyzed the effects of OSA on ROS production, cytosolic Na+ level, and rate of spontaneous arrhythmia in atrial cardiomyocytes isolated from an OSA mouse model free from comorbidities.MethodsOSA was induced in C57BL/6 wild-type and CaMKIIδ-knockout mice by polytetrafluorethylene (PTFE) injection into the tongue. After 8 weeks, their atrial cardiomyocytes were analyzed for cytosolic and mitochondrial ROS production via laser-scanning confocal microscopy. Quantifications of the cytosolic Na+ concentration and arrhythmia were performed by epifluorescence microscopy.ResultsPTFE treatment resulted in increased cytosolic and mitochondrial ROS production. Importantly, the cytosolic Na+ concentration was dramatically increased at various stimulation frequencies in the PTFE-treated mice, while the CaMKIIδ-knockout mice were protected. Accordingly, the rate of spontaneous Ca2+ release events increased in the wild-type PTFE mice while being impeded in the CaMKIIδ-knockout mice.ConclusionAtrial Na+ concentration and propensity for spontaneous Ca2+ release events were higher in an OSA mouse model in a CaMKIIδ-dependent manner, which could have therapeutic implications.

CoS (Schmidt C.) and FW have filed patent application on TASK-1-based gene therapy and pharmacotherapy of atrial arrhythmias. CoS received research funding from Boehringer Ingelheim. All other authors report no conflict of interest regarding the publication of this article.

AIMS: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. METHODS AND RESULTS: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 INa (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 NaV1.5 phosphorylation in HFpEF compared to NF, whereas NaV1.5 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 INa inhibitor tetrodotoxin (TTX) but also with sodium/hydrogen exchanger 1 (NHE1) inhibitor cariporide. Importantly, empagliflozin abolished both increased Na influx and late INa 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. CONCLUSION:We show for the first time increased Na influx in human atrial cardiomyocytes from HFpEF patients, partly due to increased late INa and enhanced NHE1-mediated Na influx. Empagliflozin inhibits Na influx and late INa, which could contribute to anti-arrhythmic effects in patients with HFpEF.

Background: Nocturnal hypoxemia has been linked to increased cardiovascular morbidity and mortality. Several common diseases, such as sleep-disordered breathing (SDB), heart failure (HF), obesity, and pulmonary disease, coincide with an elevated nocturnal hypoxemic burden with and without repetitive desaturations. Research question: This study aimed to evaluate the association of relevant common diseases with distinctive metrics of nocturnal hypoxemic burden with and without repetitive desaturations in patients undergoing coronary artery bypass grafting surgery. Study design and methods: In this subanalysis of the prospective observational study, CONSIDER-AF (NCT02877745) portable SDB monitoring was performed on 429 patients with severe coronary artery disease the night before cardiac surgery. Pulse oximetry was used to determine nocturnal hypoxemic burden, as defined by total recording time spent with oxygen saturation levels < 90% (T90). T90 was further characterized as T90 due to intermittent hypoxemia (T90desaturation) and T90 due to nonspecific and noncyclic SpO2-drifts (T90non-specific). Results: Multivariable linear regression analysis identified SDB (apnea–hypopnea-index ≥ 15/h; B [95% CI]: 6.5 [0.4; 12.5], p = 0.036), obesity (8.2 [2.5; 13.9], p = 0.005), and mild-to-moderate chronic obstructive pulmonary disease (COPD, 16.7 [8.5; 25.0], p < 0.001) as significant predictors of an increased nocturnal hypoxemic burden. Diseases such as SDB, obesity and HF were significantly associated with elevated T90desaturation. In contrast, obesity and mild-to-moderate COPD were significant modulators of T90non-specific. Interpretation: SDB and leading causes for SDB, such as obesity and HF, are associated with an increased nocturnal hypoxemic burden with repetitive desaturations. Potential causes for hypoventilation syndromes, such as obesity and mild-to-moderate COPD, are linked to an increased hypoxemic burden without repetitive desaturations. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT02877745.

Abstract Background Emerging evidence is linking sleep-disordered breathing (SDB) to diastolic dysfunction. SDB-induced hypoxia may stimulate the development of cardiac fibrosis which then causes diastolic dysfunction. We investigated the association between SDB and myocardial collagen and PDGF mRNA levels and how collagen mRNA levels are linked to parameters of diastolic dysfunction. Methods RA biopsies were collected from 31 patients undergoing elective coronary artery bypass grafting in the prospective observational study CONSIDER-AF. Tissue mRNA levels of collagen type I (Col1A), PDGFα, and PDGFβ were quantified using real-time qPCR on ViiA 7 real-time PCR system. NT-pro-BNP levels were measured in the serum via ELISA blots. The apnea-hypopnea-index (AHI) was registered in portable SDB-monitoring. Echocardiography was performed to assess diastolic function. Results First, we investigated an association of SDB and cardiac fibrosis. AHI was correlated with tissue mRNA levels of Col3a (p = 0.0239, Fig A), PDGFα (p = 0.0414, Fig B), and PDGFβ (p = 0.0024, Fig C). Then, we investigated an association between cardiac fibrosis and diastolic dysfunction. Tissue mRNA levels of Col3A were inversely correlated with lateral (p = 0.0196, Fig D) and septal E’ (p = 0.0006, Fig E) as a marker for diastolic relaxation. Higher ratios of E/E’mean were correlated with increased tissue mRNA levels of Col3A (p = 0.0368, Fig F). NT-pro-BNP which is a diagnostic criterion for heart failure with preserved ejection fraction was correlated with Col3 levels (p = 0.0247, Fig G). Discussion: Our findings indicate that SDB is linked to fibrosis which is associated with diastolic dysfunction.

Left ventricular contractile dysfunction and arrhythmias frequently occur in patients with sleep-disordered breathing (SDB). The CaMKII-dependent dysregulation of cellular Ca homeostasis has recently been described in SDB patients, but these studies only partly explain the mechanism and are limited by the patients' heterogeneity. Here, we analyzed contractile function and Ca homeostasis in a mouse model of obstructive sleep apnea (OSA) that is not limited by confounding comorbidities. OSA was induced by artificial tongue enlargement with polytetrafluorethylene (PTFE) injection into the tongue of wildtype mice and mice with a genetic ablation of the oxidative activation sites of CaMKII (MMVV knock-in). After eight weeks, cardiac function was assessed with echocardiography. Reactive oxygen species (ROS) and Ca transients were measured using confocal and epifluorescence microscopy, respectively. Wildtype PTFE mice exhibited an impaired ejection fraction, while MMVV PTFE mice were fully protected. As expected, isolated cardiomyocytes from PTFE mice showed increased ROS production. We further observed decreased levels of steady-state Ca transients, decreased levels of caffeine-induced Ca transients, and increased pro-arrhythmic activity (defined as deviations from the diastolic Ca baseline) only in wildtype but not in MMVV PTFE mice. In summary, in the absence of any comorbidities, OSA was associated with contractile dysfunction and pro-arrhythmic activity and the inhibition of the oxidative activation of CaMKII conveyed cardioprotection, which may have therapeutic implications.

Abstract Background Structural remodelling, which includes increased fibrosis and collagen production, is a hallmark of atrial cardiomyopathy. Echocardiographic strain measurements allow detailed assessment of atrial function. We investigated the association between right atrial (RA) strain and collagen mRNA levels in human RA. Methods RA biopsies were collected from 21 patients undergoing elective coronary artery bypass grafting in the prospective observational study CONSIDER-AF. Tissue mRNA levels of collagen type I (Col1A) and of collagen type III (Col3A) were quantified using real-time qPCR on ViiA 7 real-time PCR system. Echocardiographic RA strain (reservoir, conduit, and booster function) was measured in the four-chamber view using the designated software Philips QLAB. We performed uni- and multivariable linear regression analysis to elucidate the relationship between RA strain and collagen mRNA levels. Results There was a strong correlation between RA reservoir strain and Col1A mRNA levels (p=0.0152, r²=0.2608, Fig A) and Col3A mRNA levels (p=0.0058, r²=0.3374, Fig B) as well as between RA conduit strain and Col1A mRNA levels (p=0.0301, r²=0.2141, Fig C) and Col3A mRNA levels (p=0.0232, r²=0.2430, Fig D). However, there was no correlation between RA booster function and Col1A levels (p=0.5572, Fig E) or Col3A levels (p=0.3426, Fig F). Multivariate regression analysis revealed that RA conduit and RA reservoir function are predictors for Col1A and Col3A mRNA levels independent from clinical covariates (age, sex, body-mass index, systolic blood pressure). Discussion Our findings show that RA strain measurements are associated with RA collagen mRNA levels in humans and therefore highlight the potential of strain analysis to identify structural remodelling in atrial cardiomyopathy.FigureTable

Background: Nocturnal hypoxemic burden (T90) has been linked to increased cardiovascular morbidity and mortality. Several previuous studies fell short to identify, in addition to sleep-disordered breathing (SDB), common diseases that may contribute to increased nocturnal T90. Aims and objectives: to evaluate the association of relevant common diseases with distinctive metrics of nocturnal T90 with and without repetitive desaturations. Methods: In this sub-analysis of the prospective observational study, CONSIDER-AF (NCT02877745) portable SDB monitoring was performed in 429 patients with severe coronary artery disease. Nocturnal T90 was defined by total recording time spent with oxygen saturation <90%. Distinctive metrics included T90 due to intermittent hypoxemia (T90desaturation) and T90 due to non-specific and non-cyclic SpO2-drifts (T90non-specific). Results: Multivariable linear regression analysis identified SDB (apnea-hypopnea-index ≥15/hour; B [95% CI]: 8.2 [3.3;13.1], p=0.001), obesity (8.5 [3.6;13.3], p=0.001) and mild to moderate chronic obstructive pulmonary disease (COPD, 16.9 [6.9;26.9], p=0.001) as predictors of increased T90. While SDB, obesity and chronic heart failure (HF) were significantly associated with an elevated T90desaturation, obesity and COPD were significant modulators of T90non-specific. Conclusions: In addition to SDB, also obesity and COPD, but not chronic HF, contribute to increased nocturnal T90. SDB and leading causes for SDB, such as obesity and chronic HF, are associated with an increased nocturnal T90desaturation. Potential causes for hypoventilation syndromes such as obesity and COPD are linked to an increased nocturnal T90non-specific.

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.

"Voltage-Gated Sodium Channel NaV1.8 Dysregulates Na and Ca, Leading to Arrhythmias in Patients with Sleep-Disordered Breathing." American Journal of Respiratory and Critical Care Medicine, 206(11), pp. 1428–1431

Sleep apnea is a highly prevalent disorder with increasing impact on healthcare systems worldwide. Previous studies have been conducted primarily with male subjects, and prevalence and severity of sleep apnea in women are underestimated. Recent clinical and basic science evidence increasingly points to different mechanisms in men and women with sleep-disordered breathing (SDB). SDB is associated with a variety of comorbidities, including cardiovascular disease, heart failure, diabetes, and atrial fibrillation. In this review, we discuss sex-dependent mechanisms of SDB in select associated conditions to sharpen our clinical understanding of these sex-dependent inherent differences.