Search Results (461)

L-type Ca²⁺ channels, particularly Ca_V1.2, play a crucial role in cardiac excitation-contraction coupling and are known to exhibit mechanosensitivity. However, the mechanisms regulating their response to mechanical stress remain poorly understood. To investigate the mechanosensitivity and nitric oxide (NO)-dependent regulation of L-type Ca²⁺ channels in rat ventricular cardiomyocytes, we used RNA sequencing to assess isoform expression and whole-cell patch-clamp recordings to measure L-type Ca²⁺ current (I_Ca,L) under controlled mechanical and pharmacological conditions. RNA sequencing revealed predominant expression of Ca_V1.2 (TPM: 0.1170 ± 0.0075) compared to Ca_V1.3 (0.0021 ± 0.0002) and Ca_V1.1 (0.0002 ± 0.0002). Local axial stretch (6–10 μm) consistently reduced I_Ca,L in proportion to stretch magnitude. The NO donor SNAP (200 μM) had variable effects on basal I_Ca,L in unstretched cells (stimulatory, inhibitory, or biphasic) but consistently restored stretch-reduced I_Ca,L to control levels. Ascorbic acid (10 μM), which reduces S-nitrosylation, increased basal I_Ca,L and partially restored the reduction caused by stretch, implicating S-nitrosylation in channel regulation. The sGC inhibitor ODQ (5 μM) decreased I_Ca,L in both stretched and unstretched cells, indicating involvement of the NO–cGMP pathway. Mechanical stress modulates L-type Ca²⁺ channels through a complex interplay between S-nitrosylation and NO–cGMP signaling, with S-nitrosylation playing a predominant role in stretch-induced effects. This mechanism may represent a key component of cardiac mechanotransduction and could be relevant for therapeutic targeting in cardiac pathologies involving mechanically induced dysfunction. Full article

Cardiovascular disease encompasses a wide group of conditions that affect the heart and blood vessels. Of these diseases, cardiomyopathies and arrhythmias specifically have been well-studied in their relationship to cardiac dyads, nanoscopic structures that connect electrical signals to muscle contraction. The proper development and positioning of dyads is essential in excitation–contraction (EC) coupling and, thus, beating of the heart. Three proteins, namely CMYA5, JPH2, and BIN1, are responsible for maintaining the dyadic cleft between the T-tubule and junctional sarcoplasmic reticulum (jSR). Various other dyadic proteins play integral roles in the primary function of the dyad—translating a propagating action potential (AP) into a myocardial contraction. Ca²⁺, a secondary messenger in this process, acts as an allosteric activator of the sarcomere, and its cytoplasmic concentration is regulated by the dyad. Loss-of-function mutations have been shown to result in cardiomyopathies and arrhythmias. Adeno-associated virus (AAV) gene therapy with dyad components can rescue dyadic dysfunction, which results in cardiomyopathies and arrhythmias. Overall, the dyad and its components serve as essential mediators of calcium homeostasis and excitation–contraction coupling in the mammalian heart and, when dysfunctional, result in significant cardiac dysfunction, arrhythmias, morbidity, and mortality. Full article

New approach methodologies (NAMs), including microphysiological systems (MPSs), can recapitulate structural and functional complexities of organs. Vanoxerine was reported to induce cardiac adverse events, including torsade de points (TdP), in a Phase III clinical trial. Despite earlier nonclinical animal models and Phase I–II clinical trials, events of QT prolongation or proarrhythmia were not observed. Here, we utilized cardiac NAMs to evaluate the functional consequences of vanoxerine treatment on human cardiac excitation–contraction coupling. The cardiac MPS used in this study was a microfabricated fluidic culture platform with human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) capable of evaluating voltage, intracellular calcium handling, and contractility. Likewise, the hiPSC-CM comprehensive in vitro proarrhythmia assay (CiPA) was employed based on multielectrode array (MEA). Vanoxerine treatment delayed repolarization in a concentration-dependent manner and induced proarrhythmic events in both NAM platforms. The complex cardiac MPS displayed a frequency-dependent vanoxerine response such that EADs were eliminated at a faster pacing rate (1.5 Hz). Moreover, exposure analysis revealed a 99% vanoxerine loss in the cardiac MPS. TdP risk analysis demonstrated high to intermediate TdP risk at clinically relevant concentrations of vanoxerine and frequency-independent EAD events in the hiPSC-CM CiPA model. These findings demonstrate that nonclinical cardiac NAMs can recapitulate clinical outcomes, including detection of vanoxerine-induced delayed repolarization and proarrhythmic effects. Moreover, this work provides a foundation to evaluate the safety and efficacy of novel compounds to reduce the dependence on animal studies. Full article

Background: Premature ventricular contractions (PVCs) are common arrhythmias associated with symptoms such as fatigue and, in severe cases, PVC-induced cardiomyopathy. Catheter ablation (CA) is a primary treatment for symptomatic PVCs, particularly when pharmacological therapies fail or are undesired. While improvements in: quality-of-life following ablation are documented, its impact on functional capacity remains underexplored. Objectives: This study evaluated the impact of CA on functional capacity and cardiac stress markers in patients with symptomatic PVCs using cardiopulmonary exercise testing (CPET) and NT-proBNP levels. Methods: A total of 30 patients underwent successful PVC ablation and completed baseline and follow-up CPET evaluations under the Bruce protocol. PVC burden, left ventricular ejection fraction (LVEF), NT-proBNP levels, and CPET parameters, including VO₂ max, METS, ventilatory efficiency, and anaerobic threshold (AT), were analyzed pre- and post-ablation. Results: PVC burden significantly decreased post-ablation (23,509.3 ± 10,700.47 to 1759 ± 1659.15, p < 0.001). CPET revealed improved functional capacity, with VO₂ max increasing from 24.97 ± 4.16 mL/kg/min to 26.02 ± 4.34 mL/kg/min (p = 0.0096) and METS from 7.16 ± 1.17 to 7.48 ± 1.24 (p = 0.0103). NT-proBNP significantly decreased (240.93 ± 156.54 pg/mL to 138.47 ± 152.91 pg/mL, p = 0.0065). LVEF and ventilatory efficiency metrics (VE/VO₂ and VE/VCO₂) remained stable. Conclusions: Catheter ablation improves functional capacity, reduces cardiac stress, and minimizes medication dependency in patients with symptomatic PVCs. These findings support the utility of ablation in enhancing aerobic capacity and overall exercise performance. Full article

It was unknown whether hyperthermia increased the efficacy of histamine to raise the force of cardiac contractions via human H1-histamine receptors. To that end, we measured the force in isolated human atrial preparations (HAPs) excised from the right atrium of patients who underwent cardiac surgery due to severe two- or three-vessel coronary heart disease. For comparison, we also measured the force in paced (1 Hz) left and spontaneously beating right atrial preparations of transgenic mice overexpressing cardiac human H1-histamine receptors (H1-TG). Histamine (100 µM) was less efficient in raising the force in left atrial preparations from H1 TG mouse atria under hyperthermia than under hypothermia. Oppositely, histamine was more efficient in augmenting force during hyperthermia than during hypothermia in isolated electrically stimulated (1 Hz) HAPs. In sum, the contractile response to activation of H1-histamine receptor in H1-TG mice and in HAPs are opposite with regard to hyperthermia dependence. In patients with fever, histamine might thus be important, to preserve cardiac contractile function as a compensatory mechanism. Full article

Living myocardial slices (LMSs) have shown great promise in cardiac research, allowing multicellular and complex interplay analyses with disease and patient specificity, yet their wider clinical use is limited by the large tissue sizes usually required. We therefore produced mini-LMSs (<10 mm²) from routine human cardiac surgery specimens and compared them with medium (10–30 mm²) and large (>30 mm²) slices. Size effects on biomechanical properties were examined with mathematical modeling, and viability, contraction profiles, and histological integrity were followed for 14 days. In total, 34 mini-, 25 medium, and 30 large LMS were maintained viable, the smallest measuring only 2 mm². Peak twitch force proved to be size-independent, whereas time-to-peak shortened as slice area decreased. Downsized LMSs displayed excellent contractile behavior for five to six days, after which a gradual functional decline and micro-architectural changes emerged. These findings confirm, for the first time, that mini-LMSs are feasible and viable, enabling short-term, patient-specific functional studies and pharmacological testing when tissue is scarce. Full article

Cardiovascular disease and hypertension are major global health challenges, and increasing dietary salt intake is a known contributor. Emerging evidence suggests that excessive salt exposure during pregnancy may impact fetal development, yet its effects on early embryogenesis remain poorly understood. In this study, we used zebrafish (Danio rerio) embryos as a model to investigate the developmental and molecular consequences of high-salt exposure during early vertebrate development. Embryos subjected to elevated salt levels exhibited delayed hatching, reduced heart rates, and significant alterations in gene expression profiles. Transcriptomic analysis revealed over 4000 differentially expressed genes, with key disruptions identified in calcium signaling, MAPK signaling, cardiac muscle development, and vascular smooth muscle contraction pathways. These findings indicate that early salt exposure can perturb crucial developmental processes and signaling networks, offering insights into how prenatal environmental factors may contribute to long-term cardiovascular risk. Full article

Redox regulation is crucial for the cardiac action potential, coordinating the sodium-driven depolarization, calcium-mediated plateau formation, and potassium-dependent repolarization processes required for proper heart function. Under physiological conditions, low-level reactive oxygen species (ROS), generated by mitochondria and membrane oxidases, adjust ion channel function and support excitation–contraction coupling. However, when ROS accumulate, they modify a variety of important channel proteins in cardiomyocytes, which commonly results in reducing potassium currents, enhancing sodium and calcium influx, and enhancing intracellular calcium release. These redox-driven alterations disrupt the cardiac rhythm, promote after-depolarizations, impair contractile force, and accelerate the development of heart diseases. Experimental models demonstrate that oxidizing agents reduce repolarizing currents, whereas reducing systems restore normal channel activity. Similarly, oxidative modifications of calcium-handling proteins amplify sarcoplasmic reticulum release and diastolic calcium leak. Understanding the precise redox-dependent modifications of cardiac ion channels would guide new possibilities for targeted therapies aimed at restoring electrophysiological homeostasis under oxidative stress, potentially alleviating myocardial infarction and cardiovascular dysfunction. Full article

Background/Objectives: Ellagic acid (EA) is a polyphenol found in several fruits and vegetables, including pomegranate, nuts and berries. It exhibits significant health benefits, mainly cardio- and vaso-protective; indeed, EA protects the myocardium against infarction and inhibits cardiac fibrosis. These beneficial effects may be, at least in part, promoted by calcium release from and uptake by the sarcoplasmic reticulum, which are crucial events for cardiac relaxation and contraction. Regardless, the exact mechanism is currently unclear. Methods: A deeper investigation of the role of EA in cardiac contractility and the underlying mechanism has been carried out by using an ex vivo model of isolated and perfused rat heart. Results and Discussion: EA perfusion (100 nM–10 µM) did not influence the coronary flow (CF), suggesting the absence of a vasoactivity, but significantly increased contractility parameters (LVDP and dP/dt). Interestingly, a more marked effect of EA on LVDP and dP/dt values was observed when it was perfused in the presence of AngII. Cyclopiazonic acid (CA) and red ruthenium (RR), specific antagonists of SERCA and RyRs, respectively, were used to explore the contribution of EA when the intracellular calcium handling was altered. In the presence of CA, EA, perfused at increasing concentrations, showed a very modest positive inotropism (significant only at 1 µM). Instead, RR, which significantly compromised all functional parameters, completely masked the effects of EA; furthermore, a marked reduction in CF and a dramatic impact on the positive inotropism occurred. Conclusions: These results demonstrate the positive inotropism of EA on isolated and perfused hearts and suggest that the RyRs may be a main target through which EA plays its effects, since inhibition with RR almost completely blocks the positive inotropism. Full article

Introduction: Ventricular arrhythmias may lead to sudden cardiac death and, when occurring during the recovery phase after exercise testing, are associated with increased cardiovascular risk. Aim: To investigate the association between psychosocial stress and the risk of premature ventricular contractions (PVCs) during the recovery phase after treadmill testing in asymptomatic individuals. Methods: A total of 282 asymptomatic adults underwent treadmill testing. Participants were categorized into a stress-present group (+S, n = 176) or a stress-absent group (−S, n = 106) based on their self-reported psychosocial stress levels. Inclusion criteria included exercising for at least 6 min and reaching at least 85% of the age-predicted maximum heart rate. Exclusion criteria comprised pre-exercise VAs, unreadable ECGs, chronic medication use, systolic blood pressure ≥180 mmHg, and diastolic blood pressure ≥110 mmHg. This study was registered on ClinicalTrials.gov (NCT05987891). Results: Compared to the −S group, the +S group had a higher body mass index (BMI) (p = 0.0025); 26.5 (23.9; 29.0) and larger waist circumference (p = 0.0001); 95 (86; 103), and reported lower physical activity levels (p = 0.0004). Notably, only psychosocial stress and BMI were statistically associated with PVCs during the recovery phase, immediately following the stress test. For each 1 kg/m² increase in BMI, the risk of PVCs decreased by 9%. Participants reporting psychosocial stress had a 9.03-fold higher risk of PVCs compared to those who did not report stress. Conclusions: Self-reported psychosocial stress significantly increases the risk of PVC occurrence during the recovery phase of treadmill exercise testing in asymptomatic individuals. These findings may support the development of improved PVC detection strategies and enhance cardiovascular risk assessment in clinical settings. Full article

Background: Cardiac contractility modulation (CCM) is an established therapy for patients with heart failure with a reduced ejection fraction (HFrEF) who are still symptomatic despite guideline-directed medical therapy. It has been described previously that CCM leads to both an improvement of heart failure symptoms as well as of the parameters of left ventricular (LV) function, including LVEF and global longitudinal strain (GLS). However, so far there are no reports describing the effects of CCM on right ventricular (RV) or left atrial (LA) function, respectively. This might be of particular interest as RV global strain (RV GS) and LA strain are important prognostic parameters in heart failure. Methods: Adult patients with heart failure with reduced left ventricular function (LVEF <45%) and a QRS complex <130 ms despite guideline-directed medical therapy and with an indication for CCM were eligible for inclusion into this study. Patients receive a follow-up examination every 3 months, including a standardized echocardiographic examination with a special focus on strain analysis. While the effects of CCM on LV global longitudinal strain have been described before, this analysis reports the findings on the RV and LA strain. Results: Between 30.12.2021 and 10.09.2024, 22 patients were prospectively included in the study. CCM implantation was performed in 19 patients. Under active CCM therapy, there was an improvement in right ventricular global strain (CCM: −13.7 ± 4.5 vs. no CCM: −10.1 ± 5.0; p < 0.05), free wall strain (CCM: −14.6 ± 7.3 vs. no CCM: −10.3 ± 10.2; p < 0.05), left atrium strain rate (CCM: 19.7 ± 1.0 vs. no CCM: 15.3 ± 10.2; p < 0.05), and left atrium strain contraction (CCM: −11.5 ± 7.0 vs. no CCM: −7.1 ± 8.5; p < 0.05), whereas there was no difference in left atrium strain conduit (CCM: −9.0 ± 5.0 vs. no CCM: −8.1 ± 5.4; n.s.). To determine which of these parameters are linked to an improvement of quality of life, as seen in the Kansas City Heart Failure Questionnaire (KCCQ), a regression analysis was performed. It turned out that only the parameters of left atrial (LA) strain (LAS_R and LAS_CT) were significantly associated with improved quality of life, while other echocardiographic parameters, such as LV-EF, LV-GLS, and RV-GS, showed no clear association. Conclusions: CCM therapy is not only associated with improvements of left ventricular function but also restores right ventricular and left atrial strain in patients with HFrEF. Regarding the improvement in quality of life, the increase of LA strain seems to be of special importance. Full article

Background/Objectives: Although cardiac resynchronization therapy (CRT) plays an established role in the management of heart failure, a significant proportion of patients do not respond despite appropriate candidate selection. The optimization of CRT pacing is one strategy to enhance response. Fusion pacing algorithms aim to synchronize intrinsic right ventricular (RV) conduction with paced left ventricular (LV) activation, resulting in a more physiological ventricular depolarization pattern. This approach may improve electrical synchrony and enhance left ventricular contraction compared to conventional simultaneous biventricular pacing. The aim of this study was to compare the acute, beat-to-beat effects of standard biventricular pacing versus fusion pacing on myocardial function, using both conventional and speckle-tracking echocardiography in heart failure patients with left bundle branch block (LBBB). Methods: In total, 27 heart failure patients (21 men and 6 women) with reduced ejection fraction (EF < 35%), left bundle branch block (QRS > 150 ms), and newly implanted CRT-D systems (Abbott) underwent echocardiographic assessment immediately after device implantation. Echocardiographic parameters—including left atrial strain, left ventricular strain, TAPSE, mitral and tricuspid valve function, and cardiac output—were measured at 5 min intervals under three different pacing conditions: pacing off, simultaneous biventricular pacing, and fusion pacing using Abbott’s SyncAV^® algorithm. Results: In our study, CRT led to a significant shortening of the QRS duration from 169 ± 19 ms at baseline to 131 ± 17 ms with standard biventricular pacing, and further to 118 ± 16 ms with fusion pacing (p < 0.05). Despite the electrical improvement, no significant changes were observed in global longitudinal strain (GLS: −9.15 vs. −9.39 vs. −9.13; p = NS), left ventricular stroke volume (67.5 mL vs. 68.4 mL vs. 68.5 mL; p = NS), or left atrial parameters including strain, area, and ejection fraction. However, fusion pacing was associated with more homogeneous segmental strain patterns, improved aortic valve closure time, and enhanced right ventricular function as reflected by tissue Doppler-derived S’. Conclusions: Immediate QRS narrowing observed in CRT patients—particularly with fusion pacing optimization—is associated with a more homogeneous pattern of left ventricular contractility and improvements in selected measures of mechanical synchrony. However, these acute electrical changes do not translate into immediate improvements in stroke volume, global LV strain, or left atrial function. Longer-term follow-up is needed to determine whether the electrical benefits of CRT, especially with fusion pacing, lead to meaningful hemodynamic improvements. Full article

Premature ventricular contractions (PVCs) originating from the left ventricular summit (LVS) present a diagnostic and therapeutic challenge due to their complex anatomical location. The LVS includes an epicardial area of the left ventricle bordered by major coronary arteries, which has been increasingly recognized as an arrhythmic focus. Idiopathic ventricular arrhythmias from this area may exhibit specific electrocardiographic characteristics, making accurate localization essential for effective management. Methods: This narrative review explores the primary features of this arrhythmia, emphasizing key diagnostic and therapeutic aspects, including both pharmacological and interventional approaches, considering the recent technological advances in cardiac mapping and ablations. Conclusions: PVCs originating from the left ventricular summit (LVS) exhibit characteristic electrocardiographic features. Prompt recognition of this arrhythmia may facilitate appropriate referral for targeted treatment. Full article

Background and Clinical Significance: Mitral valve prolapse (MVP) is commonly benign, but may result in life-threatening arrhythmias and sudden cardiac death (SCD). Mitral annular disjunction (MAD) often coexists with mitral valve prolapse (MVP) and has been implicated in the development of ventricular arrhythmias through myocardial stretch and fibrosis. Case Presentation: Here, we present a case that highlights the diagnostic value of multimodal imaging in evaluating ventricular ectopy in the context of MVP and MAD. A 72-year-old male presented to the cardiology clinic with palpitations and fatigue, compounded by an arrhythmia identified by his Apple Watch. Holter monitoring revealed premature ventricular contractions (PVCs), with cardiac magnetic resonance imaging (CMR) demonstrating MAD and basal inferolateral scarring. Despite minimal symptoms and normal echocardiographic imaging, CMR findings highlight the utility of advanced cardiovascular imaging in patients with newly detected ventricular arrhythmias. Conclusion: This case highlights the importance of integrating consumer wearables and advanced imaging in evaluating ventricular ectopy and its evolving role in risk stratification for patients with MVP, even in the absence of overt symptoms. Full article

Background/Objectives: MS-222 is a commonly used anesthetic for fish. Research on the anesthetic mechanism of MS-222 is scarce, especially in largemouth bass. Therefore, this study investigated the tissue-specific transcriptomic and metabolomic effects of MS-222 anesthesia on largemouth bass (Micropterus salmoides). Methods: Experimental groups exposed to 40 mg/L MS-222 for 12 h were compared with untreated controls, and then transcriptomic and metabolomic analyses were performed on gill and liver samples. Results: Gill tissues exhibited 3252 differentially expressed genes (DEGs; 2309 upregulated and 943 downregulated) enriched in cardiac muscle contraction, cytoskeletal regulation, glycolysis, and toll-like receptor pathways for anesthetic adaptation. In contrast, liver tissues showed fewer DEGs (1140; 654 upregulated and 486 downregulated) primarily linked to metabolic network reorganization such as endoplasmic reticulum protein processing, PPAR signaling, and ribosome biogenesis. Metabolomic profiling demonstrated inverse patterns, with 173 differential metabolites in gills versus 297 in liver samples. Methyl nicotinate and N-acetyl-L-phenylalanine were the most significantly upregulated in the gill and liver samples. Metabolic pathway enrichment analysis revealed that MS-222-induced differential metabolites in the gill and liver of largemouth bass were predominantly associated with pathways involved in amino acid, fatty acid, phenylalanine, and nucleotide metabolism. Conclusions: These findings reveal that MS-222 anesthesia triggers organ-specific physiological adaptations through the differential regulation of metabolic and immune pathways, which provide multi-omics insights into the mechanistic basis of anesthetic responses in fish, highlighting distinct tissue strategies for managing chemical stress. Full article