ABSTRACT
The pro- and antiarrhythmic effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been extensively studied in preclinical and human trials. Despite early evidence of an antiarrhythmic role of n-3 PUFA in the prevention of sudden cardiac death and postoperative and persistent atrial fibrillation (AF), subsequent well-designed randomized trials have largely not shown an antiarrhythmic benefit. Two trials that tested moderate and high-dose n-3 PUFA demonstrated a reduction in sudden cardiac death, but these findings have not been widely replicated, and the potential of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to reduce arrhythmic death in combination, or as monotherapy, remains uncertain. The accumulated clinical evidence does not support supplementation of n-3 PUFA for postoperative AF or secondary prevention of AF. Several large, contemporary, randomized controlled trials of high-dose n-3 PUFA for primary or secondary cardiovascular prevention have demonstrated a small, significant, dose-dependent increased risk of incident AF compared with mineral oil or corn oil comparator. These findings were reproduced with both icosapent ethyl monotherapy and a mixed EPA+DHA formulation. The proarrhythmic mechanism of increased AF in contemporary cohorts exposed to high-dose n-3 PUFA is unknown. EPA and DHA and their metabolites have pleiotropic cardiometabolic and pro- and antiarrhythmic effects, including modification of the lipid raft microenvironment; alteration of cell membrane structure and fluidity; modulation of sodium, potassium, and calcium currents; and regulation of gene transcription, cell proliferation, and inflammation. Further characterization of the complex association between EPA, EPA+DHA, and DHA and AF is needed. Which formulations, dose ranges, and patient subgroups are at highest risk, remain unclear.
Subject(s)
Arrhythmias, Cardiac , Fatty Acids, Omega-3 , Humans , Fatty Acids, Omega-3/therapeutic use , Arrhythmias, Cardiac/prevention & control , Animals , Atrial Fibrillation/prevention & control , Atrial Fibrillation/drug therapy , Death, Sudden, Cardiac/prevention & control , Death, Sudden, Cardiac/etiology , Anti-Arrhythmia Agents/therapeutic use , Dietary Supplements , Eicosapentaenoic Acid/analogs & derivatives , Eicosapentaenoic Acid/therapeutic use , Randomized Controlled Trials as Topic , Docosahexaenoic Acids/therapeutic useABSTRACT
Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) were initially recommended as oral anti-diabetic drugs to treat type 2 diabetes (T2D), by inhibiting SGLT2 in proximal tubule and reduce renal reabsorption of sodium and glucose. While many clinical trials demonstrated the tremendous potential of SGLT2i for cardiovascular diseases. 2022 AHA/ACC/HFSA guideline first emphasized that SGLT2i were the only drug class that can cover the entire management of heart failure (HF) from prevention to treatment. Subsequently, the antiarrhythmic properties of SGLT2i have also attracted attention. Although there are currently no prospective studies specifically on the anti-arrhythmic effects of SGLT2i. We provide clues from clinical and fundamental researches to identify its antiarrhythmic effects, reviewing the evidences and mechanism for the SGLT2i antiarrhythmic effects and establishing a novel paradigm involving intracellular sodium, metabolism and autophagy to investigate the potential mechanisms of SGLT2i in mitigating arrhythmias.
Subject(s)
Anti-Arrhythmia Agents , Arrhythmias, Cardiac , Diabetes Mellitus, Type 2 , Sodium-Glucose Transporter 2 Inhibitors , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Humans , Animals , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/diagnosis , Anti-Arrhythmia Agents/therapeutic use , Anti-Arrhythmia Agents/adverse effects , Arrhythmias, Cardiac/drug therapy , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/prevention & control , Arrhythmias, Cardiac/metabolism , Treatment Outcome , Heart Rate/drug effects , Autophagy/drug effects , Sodium-Glucose Transporter 2/metabolism , Action Potentials/drug effects , Sodium/metabolismABSTRACT
BACKGROUND AND AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) can ameliorate arrhythmias; however, the mechanisms underlying their antiarrhythmic effect remain unclear. Therefore, we aimed to test the hypothesis that the SGLT2i empagliflozin (EMPA) ameliorates ventricular arrhythmias caused by myocardial infarction (MI) by inhibiting sympathetic remodeling. METHODS: Male nondiabetic Sprague-Dawley rats were divided into Sham ( n â=â10), MI ( n â=â13), low-EMPA (10âmg/kg/day; n â=â13), and high-EMPA (30âmg/kg/day; n â=â13) groups. Except for the Sham group, MI models were established by ligation of the left anterior descending coronary artery. After 4 weeks, the hearts were removed. Echocardiography, electrical stimulation, hematoxylin-eosin staining and Masson's staining, Western blotting, immunohistochemistry (IHC), and ELISA were performed. RESULTS: Except for left ventricular posterior wall thickness (LVPWT), EMPA treatment significantly ameliorated the left ventricular anterior wall thickness (LVAWT), interventricular septum thickness (IVST), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), and left ventricular ejection fraction (LVEF) in MI rats; there was no statistical difference between the low-EMPA and high-EMPA groups. The threshold for ventricular fibrillation induction and myocardial fibrosis was significantly ameliorated in EMPA-treated rats, and there was no statistical difference between the high-EMPA and low-EMPA groups. EMPA decreased the expression of nerve growth factor (NGF), tyrosine kinase receptor A (TrkA), tyrosine hydroxylase, and growth-associated protein 43 (GAP43) in the left ventricular infarction margin myocardium of MI rats, especially in the high-EMPA group, with a statistically significant difference between the high-EMPA and low-EMPA groups. High-EMPA significantly decreased noradrenaline (NE) levels in the blood of MI rats; however, there was no statistical difference between the low-EMPA and MI groups. CONCLUSION: EMPA ameliorated the occurrence of ventricular arrhythmias in MI rats, which may be related to a reduction in sympathetic activity, inhibition of the NGF/TrkA pathway, inhibition of sympathetic remodeling, and improvement in cardiac function and cardiac structural remodeling.
Subject(s)
Benzhydryl Compounds , Disease Models, Animal , Glucosides , Myocardial Infarction , Nerve Growth Factor , Rats, Sprague-Dawley , Signal Transduction , Sodium-Glucose Transporter 2 Inhibitors , Sympathetic Nervous System , Ventricular Remodeling , Animals , Male , Benzhydryl Compounds/pharmacology , Glucosides/pharmacology , Nerve Growth Factor/metabolism , Myocardial Infarction/physiopathology , Myocardial Infarction/drug therapy , Myocardial Infarction/complications , Myocardial Infarction/pathology , Myocardial Infarction/metabolism , Sympathetic Nervous System/drug effects , Sympathetic Nervous System/physiopathology , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Ventricular Remodeling/drug effects , Signal Transduction/drug effects , Receptor, trkA/metabolism , Receptor, trkA/antagonists & inhibitors , GAP-43 Protein/metabolism , Ventricular Function, Left/drug effects , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/prevention & control , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/drug therapy , Rats , Anti-Arrhythmia Agents/pharmacology , Connexin 43ABSTRACT
Cardiac remodeling is a commonly observed pathophysiological phenomenon associated with the progression of heart failure in various cardiovascular disorders. Carnosol, a phenolic compound extracted from rosemary, possesses noteworthy pharmacological properties including anti-inflammatory, antioxidant, and anti-apoptotic activities. Considering the pivotal involvement of inflammation, oxidative stress, and apoptosis in cardiac remodeling, the present study aims to assess the effects of carnosol on cardiac remodeling and elucidate the underlying mechanisms. In an in vivo model, cardiac remodeling was induced by performing transverse aortic constriction (TAC) surgery on mice, while an in vitro model was established by treating neonatal rat cardiomyocytes (NRCMs) with Ang II. Our results revealed that carnosol treatment effectively ameliorated TAC-induced myocardial hypertrophy and fibrosis, thereby attenuating cardiac dysfunction in mice. Moreover, carnosol improved cardiac electrical remodeling and restored connexin 43 expression, thereby reducing the vulnerability to ventricular fibrillation (VF). Furthermore, carnosol significantly reduced Ang II-induced cardiomyocyte hypertrophy in NRCMs and alleviated the upregulation of hypertrophy and fibrosis markers. Both in vivo and in vitro models of cardiac remodeling exhibited the anti-inflammatory, anti-oxidative, and anti-apoptotic effects of carnosol. Mechanistically, these effects were mediated through the Sirt1/PI3K/AKT pathway, as the protective effects of carnosol were abrogated upon inhibition of Sirt1 or activation of the PI3K/AKT pathway. In summary, our study suggests that carnosol prevents cardiac structural and electrical remodeling by regulating the anti-inflammatory, anti-oxidative, and anti-apoptotic effects mediated by Sirt1/PI3K/AKT signaling pathways, thereby alleviating heart failure and VF.
Subject(s)
Abietanes , Heart Failure , Myocytes, Cardiac , Ventricular Remodeling , Animals , Mice , Ventricular Remodeling/drug effects , Heart Failure/drug therapy , Abietanes/pharmacology , Myocytes, Cardiac/drug effects , Male , Rats , Mice, Inbred C57BL , Disease Models, Animal , Apoptosis/drug effects , Arrhythmias, Cardiac/drug therapy , Arrhythmias, Cardiac/prevention & control , Proto-Oncogene Proteins c-akt/metabolism , Oxidative Stress/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Signal Transduction/drug effects , Antioxidants/pharmacology , Fibrosis , Sirtuin 1/metabolism , Rats, Sprague-Dawley , Angiotensin II , Cardiomegaly/drug therapyABSTRACT
BACKGROUND: Voltage-gated potassium (Kv) channel growth is strongly associated with the development of arrhythmia. Salidroside (Sal), an active component from Rhodiola crenulata, has been shown to exert protective effects against heart disease. The present study was conducted to investigate the effects of Sal on Kv2.1 channel, and to explore the ionic mechanism of anti-arrhythmic. METHODS: In this study, we utilized cisapride (Cis., A stimulant that prolongs the QT interval and causes cardiac arrhythmias) by intravenous injection to establish an arrhythmia model, and detected the effects of Sal on electrocardiography (ECG) and pressure volume loop (P-V loop) in SD rats. The effect of Sal on ECG of citalopram (Cit., a Kv2 channel inhibition)-evoked arrhythmia rat models was further evaluated by monitoring the dynamic changes of multiple indicators of ECG. Then, we detected the effect of Sal on the viability of hypoxic H9c2 cells using CCK-8 assay. After that, the effect of Sal on Kv channel currents (IKv) and Kv2.1 channel currents (IKv2.1) in H9c2 cells under normal and hypoxic conditions was examined using whole-cell patch clamp technique. In addition, the effect of Sal on IKv and IKv2.1 in H9c2 cells was determined under the inhibition of Kv and Kv2.1 channels. HEK293 cells stably transfected with Kv2.1 plasmids were also used to investigate the IKv2.1 changes under Sal pre-treated and co-incubated conditions. In addition, potential interactions of Sal with Kv2.1 protein were predicted and tested by molecular docking, molecular dynamics simulation (MDS), localized surface plasmon resonance (LSPR), and cellular thermal shift assay (CETSA) techniques, respectively. Furthermore, gene and protein levels of Kv2.1 in Sal-treated H9c2 cell were estimated by qRT-PCR, Western blot (WB) and immunofluorescence (IF) analysis. RESULTS: Sal shortened the prolongated QT interval and ameliorated the cardiac impairment associated with arrhythmia in SD rats caused by Cis., as reflected in the ECG and P-V loop data. And Sal was also protective against arrhythmia in rats caused by Kv2 channel inhibition. At the cellular level, Sal increased cell viability after CoCl2-induced hypoxic injury in H9c2 cells. Whole-cell patch clamp assay confirmed that Sal inhibited both IKv and IKv2.1 in normal H9c2 cells, while enhanced IKv and IKv2.1 in cardiomyocytes after hypoxic injury. And Sal enhanced IKv inhibited by 1.5 mM 4-AP and upregulated all inhibition of Kv2 channels induced by 20 mM 4-AP administration, antagonized the IKv2.1 inhibitory effect of Cit. Moreover, Sal pre-administration for 24 h and immediate administration increased IKv2.1 in HEK293 cells stably transfected with Kv2.1 plasmids. Molecular docking demonstrated the potential binding of Sal to the Kv2.1 protein, with calculated binding energy of -5.4 kcal/mol. MDS test illustrated that the average hydrogen bonding of the Sal-Kv2.1 complexes was 30.89%. LSPR results verified the potential binding of Sal to Kv2.1 protein with an affinity value of 9.95 × 10-4 M. CETSA assay confirmed Sal can enhance the expression of Kv2.1 protein in H9c2 cells treated with heat, which suggests that Sal may bind to Kv2.1 protein. The results of WB, qRT-PCR, and IF further argued that Sal pre-administration for 24 h enhanced the levels of the Kv2.1 gene and protein (with no effects on the Kv2.1 gene and protein for H9c2 cells co-incubated with Sal for 6 h and 12 h). CONCLUSION: Overall, our findings indicate that Sal can resist drug-induced arrhythmias in SD rats, partially by modulating repolarization through stimulating Kv2.1.
Subject(s)
Glucosides , Phenols , Rats, Sprague-Dawley , Shab Potassium Channels , Animals , Shab Potassium Channels/metabolism , Shab Potassium Channels/genetics , Phenols/pharmacology , Rats , Glucosides/pharmacology , Male , Arrhythmias, Cardiac/drug therapy , Arrhythmias, Cardiac/metabolism , Arrhythmias, Cardiac/prevention & control , Arrhythmias, Cardiac/chemically induced , Cell Line , Molecular Docking Simulation , Humans , Anti-Arrhythmia Agents/pharmacology , HEK293 Cells , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Electrocardiography/drug effects , Cell Survival/drug effects , Action Potentials/drug effectsABSTRACT
BACKGROUND: We recently demonstrated that acute administration of ibrutinib, a Bruton's tyrosine kinase inhibitor used in chemotherapy for blood malignancies, increases ventricular arrhythmia (VA) vulnerability. A pathway of ibrutinib-induced vulnerability to VA that can be modulated for cardioprotection remains unclear. METHODS AND RESULTS: The effects of ibrutinib on cardiac electrical activity and Ca2+ dynamics were investigated in Langendorff-perfused hearts using optical mapping. We also conducted Western blotting analysis to evaluate the impact of ibrutinib on various regulatory and Ca2+-handling proteins in rat cardiac tissues. Treatment with ibrutinib (10 mg/kg per day) for 4 weeks was associated with an increased VA inducibility (72.2%±6.3% versus 38.9±7.0% in controls, P<0.002) and shorter action potential durations during pacing at various frequencies (P<0.05). Ibrutinib also decreased heart rate thresholds for beat-to-beat duration alternans of the cardiac action potential (P<0.05). Significant changes in myocardial Ca2+ transients included lower amplitude alternans ratios (P<0.05), longer times-to-peak (P<0.05), and greater spontaneous intracellular Ca2+ elevations (P<0.01). We also found lower abundance and phosphorylation of myocardial AMPK (5'-adenosine monophosphate-activated protein kinase), indicating reduced AMPK activity in hearts after ibrutinib treatment. An acute treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside ameliorated abnormalities in action potential and Ca2+ dynamics, and significantly reduced VA inducibility (37.1%±13.4% versus 72.2%±6.3% in the absence of 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside, P<0.05) in hearts from ibrutinib-treated rats. CONCLUSIONS: VA vulnerability inflicted by ibrutinib may be mediated in part by an impairment of myocardial AMPK activity. Pharmacological activation of AMPK may be a protective strategy against ibrutinib-induced cardiotoxicity.
Subject(s)
AMP-Activated Protein Kinases , Action Potentials , Adenine , Arrhythmias, Cardiac , Piperidines , Pyrazoles , Pyrimidines , Animals , Adenine/analogs & derivatives , Adenine/pharmacology , Piperidines/pharmacology , Action Potentials/drug effects , Pyrimidines/pharmacology , AMP-Activated Protein Kinases/metabolism , Pyrazoles/pharmacology , Male , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/metabolism , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/prevention & control , Protein Kinase Inhibitors/pharmacology , Heart Rate/drug effects , Isolated Heart Preparation , Calcium/metabolism , Rats , Disease Models, Animal , Rats, Sprague-Dawley , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/enzymology , Myocytes, Cardiac/pathology , Calcium Signaling/drug effects , Time FactorsABSTRACT
BACKGROUND: To evaluate the clinical efficacy and safety of intraoperative intravenous amiodarone for arrhythmia prevention in on-pump coronary artery bypass grafting (CABG) patients. METHODS: A meta-analysis of randomized controlled trials was conducted. Pubmed, Embase, Cochrane Library, Ovid, China National Knowledge Infrastructure, and the Wan Fang database until July 1th, 2023. The primary outcomes of interest included the incidences of intra- and post-operative atrial fibrillation (POAF), ventricular fibrillation, or any arrhythmia, including atrial fibrillation, ventricular fibrillation, ventricular tachycardia, premature ventricular contraction, and sinus bradycardia. For continuous and dichotomous variables, treatment effects were calculated as the weighted mean difference (WMD)/risk ratio (RR) and 95% confidence interval (CI). RESULTS: A database search yielded 7 randomized controlled trials including 608 patients, where three studies, including three treatments (amiodarone, lidocaine, and saline), contributed to the clinical outcome of atrial fibrillation, ventricular fibrillation, or any arrhythmia. Meta-analysis demonstrated that amiodarone can significantly reduce the incidence of POAF (RR, 0.39; 95%CI: 0.20, 0.77; P = 0.007, I2 = 0%) in patients undergoing on-pump CABG; there was no statistically significant influence on intra-operative atrial fibrillation, intra- and post-operative ventricular fibrillation, or any arrhythmia. CONCLUSIONS: The current study suggests that intraoperative administration of intravenous amiodarone may be safe and effective in preventing POAF in patients undergoing on-pump CABG. More well-designed clinical trials are needed to validate this result.
Subject(s)
Amiodarone , Anti-Arrhythmia Agents , Coronary Artery Bypass , Humans , Amiodarone/administration & dosage , Amiodarone/adverse effects , Coronary Artery Bypass/adverse effects , Anti-Arrhythmia Agents/administration & dosage , Anti-Arrhythmia Agents/adverse effects , Anti-Arrhythmia Agents/therapeutic use , Arrhythmias, Cardiac/prevention & control , Intraoperative Care/methods , Administration, Intravenous , Postoperative Complications/prevention & control , Treatment Outcome , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: New methods to identify patients who benefit from a primary prophylactic implantable cardioverter-defibrillator (ICD) are needed. T-wave alternans (TWA) has been shown to associate with arrhythmogenesis of the heart and sudden cardiac death. We hypothesized that TWA might be associated with benefit from ICD implantation in primary prevention. METHODS AND RESULTS: In the EU-CERT-ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter-Defibrillators) study, we prospectively enrolled 2327 candidates for primary prophylactic ICD. A 24-hour Holter monitor reading was taken from all recruited patients at enrollment. TWA was assessed from Holter monitoring using the modified moving average method. Study outcomes were all-cause death, appropriate shock, and survival benefit. TWA was assessed both as a contiguous variable and as a dichotomized variable with cutoff points <47 µV and <60 µV. The final cohort included 1734 valid T-wave alternans samples, 1211 patients with ICD, and 523 control patients with conservative treatment, with a mean follow-up time of 2.3 years. TWA ≥60 µV was a predicter for a higher all-cause death in patients with an ICD on the basis of a univariate Cox regression model (hazard ratio, 1.484 [95% CI, 1.024-2.151]; P=0.0374; concordance statistic, 0.51). In multivariable models, TWA was not prognostic of death or appropriate shocks in patients with an ICD. In addition, TWA was not prognostic of death in control patients. In a propensity score-adjusted Cox regression model, TWA was not a predictor of ICD benefit. CONCLUSIONS: T-wave alternans is poorly prognostic in patients with a primary prophylactic ICD. Although it may be prognostic of life-threatening arrhythmias and sudden cardiac death in several patient populations, it does not seem to be useful in assessing benefit from ICD therapy in primary prevention among patients with an ejection fraction of ≤35%.
Subject(s)
Death, Sudden, Cardiac , Defibrillators, Implantable , Electrocardiography, Ambulatory , Primary Prevention , Humans , Primary Prevention/methods , Male , Female , Death, Sudden, Cardiac/prevention & control , Death, Sudden, Cardiac/etiology , Middle Aged , Aged , Prospective Studies , Electrocardiography, Ambulatory/methods , Electric Countershock/instrumentation , Electric Countershock/adverse effects , Risk Assessment/methods , Risk Factors , Arrhythmias, Cardiac/therapy , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/diagnosis , Arrhythmias, Cardiac/prevention & control , Arrhythmias, Cardiac/mortality , Treatment Outcome , Predictive Value of Tests , Time Factors , Europe/epidemiology , Prognosis , Heart Rate/physiologyABSTRACT
AIMS: Gene therapy with cardiac phosphodiesterases (PDEs), such as phosphodiesterase 4B (PDE4B), has recently been described to effectively prevent heart failure (HF) in mice. However, exact molecular mechanisms of its beneficial effects, apart from general lowering of cardiomyocyte cyclic adenosine monophosphate (cAMP) levels, have not been elucidated. Here, we studied whether gene therapy with two types of PDEs, namely PDE2A and PDE4B, can prevent pressure-overload-induced HF in mice by acting on and restoring altered cAMP compartmentation in distinct subcellular microdomains. METHODS AND RESULTS: HF was induced by transverse aortic constriction followed by tail-vein injection of adeno-associated-virus type 9 vectors to overexpress PDE2A3, PDE4B3, or luciferase for 8 weeks. Heart morphology and function was assessed by echocardiography and histology which showed that PDE2A and especially PDE4B gene therapy could attenuate cardiac hypertrophy, fibrosis, and decline of contractile function. Live cell imaging using targeted cAMP biosensors showed that PDE overexpression restored altered cAMP compartmentation in microdomains associated with ryanodine receptor type 2 (RyR2) and caveolin-rich plasma membrane. This was accompanied by ameliorated caveolin-3 decline after PDE2A3 overexpression, reduced RyR2 phosphorylation in PDE4B3 overexpressing hearts, and antiarrhythmic effects of both PDEs measured under isoproterenol stimulation in single cells. Strong association of overexpressed PDE4B but not PDE2A with RyR2 microdomain could prevent calcium leak and arrhythmias in human-induced pluripotent stem-derived cardiomyocytes with the A2254V mutation in RyR2 causing catecholaminergic polymorphic ventricular tachycardia. CONCLUSION: Our data indicate that gene therapy with phosphodiesterases can prevent HF including associated cardiac remodelling and arrhythmias by restoring altered cAMP compartmentation in functionally relevant subcellular microdomains.
Subject(s)
Cyclic AMP , Cyclic Nucleotide Phosphodiesterases, Type 2 , Cyclic Nucleotide Phosphodiesterases, Type 4 , Disease Models, Animal , Genetic Therapy , Heart Failure , Myocytes, Cardiac , Ryanodine Receptor Calcium Release Channel , Animals , Cyclic AMP/metabolism , Heart Failure/enzymology , Heart Failure/genetics , Heart Failure/therapy , Heart Failure/physiopathology , Heart Failure/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 2/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 2/genetics , Myocytes, Cardiac/enzymology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4/genetics , Ryanodine Receptor Calcium Release Channel/metabolism , Ryanodine Receptor Calcium Release Channel/genetics , Humans , Mice, Inbred C57BL , Male , Arrhythmias, Cardiac/enzymology , Arrhythmias, Cardiac/genetics , Arrhythmias, Cardiac/metabolism , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/prevention & control , Ventricular Remodeling , Induced Pluripotent Stem Cells/enzymology , Induced Pluripotent Stem Cells/metabolism , Second Messenger Systems/drug effects , Ventricular Function, Left , Calcium Signaling , Phosphorylation , Heart RateABSTRACT
BACKGROUND: The results of the use of del-Nido(DN) solution using a different method or crystalloid blood cardioplegia in coronary bypass patients were compared. We aimed to investigate the effects on intraoperative and postoperative arrhythmias, arrhythmia durations and early results. METHODS: The study included 175 patients using crystalloid blood cardioplegia (Group 1) and 150 patients using DN solution(Group 2). In the DN group, 75% of the calculated plegia dose was given first. the remaining part was applied by giving from grafts. Intraoperative/postoperative data were compared. RESULTS: There was no significant difference between the groups in terms of demographic characteristics. Preop troponin level was similar.(p = 0.190) However, there was a statistical difference between the postoperative 6th hour.(p = 0.001) There was no difference in troponin values at the postoperative 24th hour. (p = 0.631) Spontaneous rhythm occurred at the cardiopulmonary by pass (CPB) weaning stage in most of the patients in Group 2 (95.3%). Although the need for temporary pacing was less in Group 2, it was not significant.(p = 0.282) No patient required permanent pacing. CPB duration, cross clamp times and intraoperative glucose levels, intensive care follow-up times and hospitalization times were found to be shorter in Group 2. Although the postoperative atrial fibrillation frequency was similar (p = 0.261), the time to return to sinus was lower in Group 2.(p = 0.001). CONCLUSION: The use of DN cardioplegia solution provides significant positive contributions to avoid arrhythmias compared to crystalloid blood cardioplegia. DN solution applied with this method may contribute to reducing the anxieties associated with its use in isolated coronary artery bypass surgery.
Subject(s)
Cardioplegic Solutions , Heart Arrest, Induced , Humans , Crystalloid Solutions , Heart Arrest, Induced/adverse effects , Cardioplegic Solutions/pharmacology , Troponin , Arrhythmias, Cardiac/prevention & control , Arrhythmias, Cardiac/etiology , Retrospective StudiesABSTRACT
PURPOSE: Maintaining hemodynamic stability during cardiac ablation under general anesthesia is challenging. Remimazolam, a novel ultrashort-acting benzodiazepine, is characterized by maintaining comparatively stable blood pressure and does not influence the cardiac conduction system, which renders it a reasonable choice for general anesthesia for cardiac ablation. We aimed to evaluate whether remimazolam is associated with a decreased incidence of intraoperative hypotension compared with desflurane. METHODS: In this single-centre, parallel-group, prospective, single-blind, randomized clinical trial, we randomized patients (1:1) into a remimazolam group (remimazolam-based total intravenous anesthesia) or desflurane group (propofol-induced and desflurane-maintained inhalational anesthesia) during cardiac ablation procedures for arrhythmia. The primary outcome was the incidence of intraoperative hypotensive events, defined as mean arterial pressure of < 60 mm Hg at any period. RESULTS: Overall, we enrolled 96 patients between 2 August 2022 and 19 May 2023 (47 and 49 patients in the remimazolam and desflurane groups, respectively). The remimazolam group showed a significantly lower incidence of hypotensive events (14/47, 30%) than the desflurane group (29/49, 59%; relative risk [RR], 0.5; 95% confidence interval [CI], 0.31 to 0.83; P = 0.004). Remimazolam was associated with a lower requirement for bolus or continuous vasopressor infusion than desflurane was (23/47, 49% vs 43/49, 88%; RR, 0.56; 95% CI, 0.41 to 0.76; P < 0.001). No between-group differences existed in the incidence of perioperative complications such as nausea, vomiting, oxygen desaturation, delayed emergence, or pain. CONCLUSIONS: Remimazolam was a viable option for general anesthesia for cardiac ablation. Remimazolam-based total intravenous anesthesia was associated with significantly fewer hypotensive events and vasopressor requirements than desflurane-based inhalational anesthesia was, without significantly more complications. STUDY REGISTRATION: ClinicalTrials.gov (NCT05486377); first submitted 1 August 2022.
RéSUMé: OBJECTIF: Le maintien de la stabilité hémodynamique lors d'une ablation cardiaque sous anesthésie générale est un défi. Le remimazolam, une nouvelle benzodiazépine à action ultra-courte, se caractérise par le maintien d'une tension artérielle relativement stable et son absence d'influence sur le système de conduction cardiaque, ce qui en fait un choix raisonnable pour l'anesthésie générale pour l'ablation cardiaque. Nous avons cherché à déterminer si le remimazolam est associé à une diminution de l'incidence d'hypotension peropératoire comparativement au desflurane. MéTHODE: Dans cette étude clinique randomisée, prospective, en simple aveugle, en groupes parallèles et monocentrique, nous avons randomisé des patient·es (1:1) dans un groupe remimazolam (anesthésie intraveineuse totale à base de remimazolam) et un groupe desflurane (anesthésie volatile induite par propofol et maintenue par desflurane) pendant des interventions d'ablation cardiaque pour arythmie. Le critère d'évaluation principal était l'incidence d'événements hypotensifs peropératoires, définis comme une tension artérielle moyenne de < 60 mm Hg à n'importe quelle période. RéSULTATS: Au total, nous avons recruté 96 patient·es entre le 2 août 2022 et le 19 mai 2023 (47 et 49 personnes dans les groupes remimazolam et desflurane, respectivement). Le groupe remimazolam a montré une incidence significativement plus faible d'événements hypotensifs (14/47, 30 %) que le groupe desflurane (29/49, 59 %; risque relatif [RR], 0,5; intervalle de confiance [IC] à 95 %, 0,31 à 0,83; P = 0,004). Le remimazolam a été associé à des besoins plus faibles de bolus ou de perfusion continue de vasopresseurs que le desflurane (23/47, 49 % vs 43/49, 88 %; RR, 0,56; IC 95 %, 0,41 à 0,76; P < 0,001). Il n'y avait pas de différences entre les groupes dans l'incidence des complications périopératoires telles que les nausées, les vomissements, la désaturation en oxygène, l'émergence retardée ou la douleur. CONCLUSION: Le remimazolam a constitué une option viable pour l'anesthésie générale en vue d'une ablation cardiaque. L'anesthésie intraveineuse totale à base de remimazolam a été associée à un nombre significativement plus faible d'événements d'hypotension et de besoins en vasopresseurs que l'anesthésie par inhalation à base de desflurane, sans complications significativement plus nombreuses. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT05486377); soumis pour la première fois le 1er août 2022.
Subject(s)
Anesthesia, General , Catheter Ablation , Desflurane , Hemodynamics , Hypotension , Humans , Male , Female , Middle Aged , Anesthesia, General/methods , Single-Blind Method , Prospective Studies , Aged , Desflurane/administration & dosage , Hemodynamics/drug effects , Hypotension/prevention & control , Hypotension/chemically induced , Catheter Ablation/methods , Benzodiazepines/administration & dosage , Propofol/administration & dosage , Propofol/adverse effects , Anesthetics, Inhalation/administration & dosage , Intraoperative Complications/prevention & control , Intraoperative Complications/epidemiology , Anesthetics, Intravenous/administration & dosage , Arrhythmias, Cardiac/prevention & control , AdultABSTRACT
Myocardial infarction (MI) causes cell death, disrupts electrical activity, triggers arrhythmia, and results in heart failure, whereby 50-60% of MI-associated deaths manifest as sudden cardiac deaths (SCD). The most effective therapy for SCD prevention is implantable cardioverter defibrillators (ICDs). However, ICDs contribute to adverse remodeling and disease progression and do not prevent arrhythmia. This work develops an injectable collagen-PEDOT:PSS (poly(3,4-ethylenedioxythiophene) polystyrene sulfonate) hydrogel that protects infarcted hearts against ventricular tachycardia (VT) and can be combined with human induced pluripotent stem cell (hiPSC)-cardiomyocytes to promote partial cardiac remuscularization. PEDOT:PSS improves collagen gel formation, micromorphology, and conductivity. hiPSC-cardiomyocytes in collagen-PEDOT:PSS hydrogels exhibit near-adult sarcomeric length, improved contractility, enhanced calcium handling, and conduction velocity. RNA-sequencing data indicate enhanced maturation and improved cell-matrix interactions. Injecting collagen-PEDOT:PSS hydrogels in infarcted mouse hearts decreases VT to the levels of healthy hearts. Collectively, collagen-PEDOT:PSS hydrogels offer a versatile platform for treating cardiac injuries.
Subject(s)
Arrhythmias, Cardiac , Collagen , Electric Conductivity , Hydrogels , Induced Pluripotent Stem Cells , Myocardial Infarction , Myocytes, Cardiac , Polystyrenes , Myocardial Infarction/pathology , Animals , Induced Pluripotent Stem Cells/cytology , Humans , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/cytology , Mice , Collagen/chemistry , Hydrogels/chemistry , Arrhythmias, Cardiac/prevention & control , Polystyrenes/chemistry , Polymers/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , ThiophenesABSTRACT
Aconitine is the main active component of Aconitum plants. Although aconitine has effects that include strengthening the heart, analgesia, anti-tumor, and immune-regulating effects, aconitine has both efficacy and toxicity, especially cardiotoxicity. Severe effects can include arrhythmia and cardiac arrest, which limits the clinical application of aconitine-containing traditional Chinese medicine. Ginsenoside Rb1(Rb1) is mainly found in plants, such as ginseng and Panax notoginseng, and has cardiovascular-protective and anti-arrhythmia effects. This study aimed to investigate the detoxifying effects of Rb1 on aconitine cardiotoxicity and the electrophysiological effect of Rb1 on aconitine-induced arrhythmia in rats. Pathological analysis, myocardial enzymatic indexes, and Western blotting were used to investigate the ameliorating effect of Rb1 on aconitine cardiotoxicity. Optical mapping was used to evaluate the effect of Rb1 on action potential and calcium signaling after aconitine-induced arrhythmia. Rb1 inhibited pathological damage caused by aconitine, decreased myocardial enzyme levels, and restored the balance of apoptotic protein expression by reducing the expression of Bax and cleaved caspase 3 and increasing the expression of Bcl-2, thereby reducing myocardial damage caused by aconitine. Rb1 also reduced the increase in heart rate caused by aconitine, accelerated action potential conduction and calcium signaling, and reduced the dispersion of action potential and calcium signal conduction. Rb1 reduced the cardiotoxicity of aconitine by attenuating aconitine-induced myocardial injury and inhibiting the aconitine-induced retardation of ventricular action potential and calcium signaling in rats.
Subject(s)
Aconitine , Calcium Signaling , Cardiotoxicity , Ginsenosides , Animals , Ginsenosides/pharmacology , Aconitine/analogs & derivatives , Cardiotoxicity/prevention & control , Rats , Calcium Signaling/drug effects , Male , Action Potentials/drug effects , Rats, Sprague-Dawley , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/prevention & control , Myocardium/metabolism , Myocardium/pathologyABSTRACT
BACKGROUND: Kawasaki disease (KD) is an acute febrile illness and systemic vasculitis often associated with cardiac sequelae, including arrhythmias. Abundant evidence indicates a central role for IL (interleukin)-1 and TNFα (tumor necrosis factor-alpha) signaling in the formation of arterial lesions in KD. We aimed to investigate the mechanisms underlying the development of electrophysiological abnormalities in a murine model of KD vasculitis. METHODS: Lactobacillus casei cell wall extract-induced KD vasculitis model was used to investigate the therapeutic efficacy of clinically relevant IL-1Ra (IL-1 receptor antagonist) and TNFα neutralization. Echocardiography, in vivo electrophysiology, whole-heart optical mapping, and imaging were performed. RESULTS: KD vasculitis was associated with impaired ejection fraction, increased ventricular tachycardia, prolonged repolarization, and slowed conduction velocity. Since our transcriptomic analysis of human patients showed elevated levels of both IL-1ß and TNFα, we asked whether either cytokine was linked to the development of myocardial dysfunction. Remarkably, only inhibition of IL-1 signaling by IL-1Ra but not TNFα neutralization was able to prevent changes in ejection fraction and arrhythmias, whereas both IL-1Ra and TNFα neutralization significantly improved vasculitis and heart vessel inflammation. The treatment of L casei cell wall extract-injected mice with IL-1Ra also restored conduction velocity and improved the organization of Cx43 (connexin 43) at the intercalated disk. In contrast, in mice with gain of function of the IL-1 signaling pathway, L casei cell wall extract induced spontaneous ventricular tachycardia and premature deaths. CONCLUSIONS: Our results characterize the electrophysiological abnormalities associated with L casei cell wall extract-induced KD and show that IL-1Ra is more effective in preventing KD-induced myocardial dysfunction and arrhythmias than anti-TNFα therapy. These findings support the advancement of clinical trials using IL-1Ra in patients with KD.
Subject(s)
Cardiomyopathies , Mucocutaneous Lymph Node Syndrome , Tachycardia, Ventricular , Vasculitis , Humans , Animals , Mice , Mucocutaneous Lymph Node Syndrome/complications , Mucocutaneous Lymph Node Syndrome/drug therapy , Interleukin 1 Receptor Antagonist Protein/pharmacology , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Tumor Necrosis Factor-alpha , Disease Models, Animal , Interleukin-1beta/metabolism , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/prevention & control , Tachycardia, Ventricular/prevention & control , Tachycardia, Ventricular/complicationsABSTRACT
Mast cells (MCs) are important intermediates between the nervous and immune systems. The cardiac autonomic nervous system (CANS) crucially modulates cardiac electrophysiology and arrhythmogenesis, but whether and how MC-CANS neuroimmune interaction influences arrhythmia remain unclear. Our clinical data showed a close relationship between serum levels of MC markers and CANS activity, and then we use mast cell stabilizers (MCSs) to alter this MC-CANS communication. MCSs, which are well-known anti-allergic agents, could reduce the risk of ventricular arrhythmia (VA) after myocardial infarction (MI). RNA-sequencing (RNA-seq) analysis to investigate the underlying mechanism by which MCSs could affect the left stellate ganglion (LSG), a key therapeutic target for modulating CANS, showed that the IL-6 and γ-aminobutyric acid (GABA)-ergic system may be involved in this process. Our findings demonstrated that MCSs reduce VA risk along with revealing the potential underlying antiarrhythmic mechanisms.
Subject(s)
Anti-Allergic Agents , Mast Cell Stabilizers , Humans , Neuroimmunomodulation , Arrhythmias, Cardiac/prevention & control , HeartSubject(s)
Benzhydryl Compounds , Cardiomyopathies , Chagas Cardiomyopathy , Glucosides , Tachycardia, Ventricular , Humans , Chagas Cardiomyopathy/diagnosis , Chagas Cardiomyopathy/drug therapy , Arrhythmias, Cardiac/diagnosis , Arrhythmias, Cardiac/drug therapy , Arrhythmias, Cardiac/prevention & controlABSTRACT
BACKGROUND: Our previous study showed that light-emitting diode modulation of the hypothalamic paraventricular nucleus (PVN), which is the control center of the sympathetic nervous system, might attenuate neuroinflammation in the PVN and prevent ventricular arrhythmias (VAs) after myocardial infarction (MI). Low-intensity focused ultrasound (LIFU) has deeper penetration than does light-emitting diode, while its effect on the PVN has not been reported. OBJECTIVE: This study aimed to explore the effect of LIFU modulation of the PVN on the inducibility of post-MI VAs. METHODS: Fifty-four Sprague-Dawley rats were randomly divided into acute control (n = 12, 22.22%), acute MI (AMI, n = 12, 22.22%), AMI + LIFU (n = 12, 22.22%), chronic control (n = 6, 11.11%), chronic MI (CMI, n = 6, 11.11%), and CMI + LIFU (n = 6, 11.11%) groups. MI was induced by left anterior artery ligation, and electrocardiographic recording for 0.5 hours after MI and programmed electrophysiological stimulation were used to test the vulnerability of VAs. Peripheral sympathetic neural activity was assessed by measuring left stellate ganglion neural activity. Finally, hearts and brains were extracted for Western blotting and histopathological analysis, respectively. RESULTS: Compared with the AMI group, AMI-induced VAs (P < .05) and left stellate ganglion neural activity (P < .05) were significantly attenuated in the AMI + LIFU group. In addition, LIFU resulted in a significant reduction of microglial activation in the PVN and expression of inflammatory cytokines in the peri-ischemic myocardium. In the CMI + LIFU group, there was no obvious tissue damage in the brain. CONCLUSION: LIFU modulation of the PVN may prevent the incidence of post-MI VAs by attenuating MI-induced sympathetic neural activation and inflammatory response.
Subject(s)
Myocardial Infarction , Paraventricular Hypothalamic Nucleus , Rats , Animals , Paraventricular Hypothalamic Nucleus/metabolism , Rats, Sprague-Dawley , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/prevention & control , HeartABSTRACT
Drug-induced cardiotoxicity is a primary concern in both drug development and clinical practice. Although the heart is not a common target for adverse drug reactions, some drugs still cause various adverse cardiac events, with sometimes severe consequences. Direct cardiac toxicity encompasses functional and structural changes of the cardiovascular system due to possible exposure to medicines. This phenomenon extends beyond cardiovascular drugs to include non-cardiovascular drugs including anticancer drugs such as tyrosine kinase inhibitors, anthracyclines and immune checkpoint inhibitors (ICIs), as well as various antipsychotics, venlafaxine, and even some antibiotics (such as macrolides). Cardiac ADRs comprise an array of effects, ranging from heart failure and myocardial ischemia to valvular disease, thrombosis, myocarditis, pericarditis, arrhythmias, and conduction abnormalities. The underlying mechanisms may include disturbances of ionic processes, induction of cellular damage via impaired mitochondrial function, and even hypercoagulability. To mitigate the impact of drug-induced cardiotoxicity, multi-stage evaluation guidelines have been established, following the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for in vitro and in vivo testing. Despite preclinical safeguards, post-marketing surveillance remains critical, as certain cardiotoxic drugs may escape initial scrutiny. Indeed, historical data show that cardiovascular ADRs contribute to almost 10% of market withdrawals. The impact of drug-induced cardiotoxicity on cardiac issues, particularly heart failure, is often underestimated, with incidence rates ranging from 11.0% to over 20.0%. We here comprehensively examine different patterns of drug-induced cardiotoxicity, highlighting current concerns and emerging pharmacovigilance signals. Understanding the underlying mechanisms and the associated risk factors is critical in order to promptly identify, effectively manage, and proactively prevent drug-induced cardiac adverse events. Collaborative efforts between physicians and cardiologists, coupled with thorough assessment and close monitoring, are essential to ensuring patient safety in the face of potential drug-induced cardiotoxicity.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Heart Diseases , Heart Failure , Humans , Cardiotoxicity/epidemiology , Cardiotoxicity/etiology , Heart Diseases/chemically induced , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/prevention & control , Drug-Related Side Effects and Adverse Reactions/epidemiology , Heart Failure/chemically induced , Heart Failure/epidemiology , Heart Failure/complicationsABSTRACT
AIMS: An automated method for determination of short-term variability (STV) of repolarization on intracardiac electrograms (STV-ARIauto) has previously been developed for arrhythmic risk monitoring by cardiac implantable devices, and has proved effective in predicting ventricular arrhythmias (VA) and guiding preventive high-rate pacing (HRP) in a canine model. Current study aimed to assess (i) STV-ARIauto in relation to VA occurrence and secondarily (ii-a) to confirm the predictive capacity of STV from the QT interval and (ii-b) explore the effect of HRP on arrhythmic outcomes in a porcine model of acute myocardial infarction (MI). METHODS AND RESULTS: Myocardial infarction was induced in 15 pigs. In 7/15 pigs, STV-QT was assessed at baseline, occlusion, 1â min before VA, and just before VA. Eight of the 15 pigs were additionally monitored with an electrogram catheter in the right ventricle, underwent echocardiography at baseline and reperfusion, and were randomized to paced or control group. Paced group received atrial pacing at 20â beatsâ perâ min faster than sinus rhythm 1â min after occlusion. Short-term variability increased prior to VA in both STV modalities. The percentage change in STV from baseline to successive timepoints correlated well between STV-QT and STV-ARIauto. High-rate pacing did not improve arrhythmic outcomes and was accompanied by a stronger decrease in ejection fraction. CONCLUSION: STV-ARIauto values increase before VA onset, alike STV-QT in a porcine model of MI, indicating imminent arrhythmias. This highlights the potential of automatic monitoring of arrhythmic risk by cardiac devices through STV-ARIauto and subsequently initiates preventive strategies. Continuous HRP during onset of acute MI did not improve arrhythmic outcomes.