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Journal of Clinical Medicine May 2024Adult patients with congenital heart disease have now surpassed the pediatric population due to advances in surgery and improved survival. One such complex congenital... (Review)
Review
Adult patients with congenital heart disease have now surpassed the pediatric population due to advances in surgery and improved survival. One such complex congenital heart disease seen in adult patients is the Fontan circulation. These patients have complex physiology and are at risk for several complications, including thrombosis of the Fontan pathway, pulmonary vascular disease, heart failure, atrial arrhythmias, atrioventricular valve regurgitation, and protein-losing enteropathy. This review discusses the commonly encountered phenotypes of Fontan circulatory failure and their contemporary management.
PubMed: 38892760
DOI: 10.3390/jcm13113049 -
International Journal of Molecular... Jun 2024Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton's tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a...
Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton's tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a next-generation BTKi, is associated with reduced atrial arrhythmia events. However, the role of ABR in ventricular arrhythmia (VA) has not been adequately evaluated. Our study aimed to investigate VA vulnerability and ventricular electrophysiology following chronic ABR therapy in male Sprague-Dawley rats utilizing epicardial optical mapping for ventricular voltage and Ca dynamics and VA induction by electrical stimulation in ex-vivo perfused hearts. Ventricular tissues were snap-frozen for protein analysis for sarcoplasmic Ca and metabolic regulatory proteins. The results show that both ABR and IBR treatments increased VA vulnerability, with ABR showing higher VA regularity index (RI). IBR, but not ABR, is associated with the abbreviation of action potential duration (APD) and APD alternans. Both IBR and ABR increased diastolic Ca leak and Ca alternans, reduced conduction velocity (CV), and increased CV dispersion. Decreased SERCA2a expression and AMPK phosphorylation were observed with both treatments. Our results suggest that ABR treatment also increases the risk of VA by inducing proarrhythmic changes in Ca signaling and membrane electrophysiology, as seen with IBR. However, the different impacts of these two BTKi on ventricular electrophysiology may contribute to differences in VA vulnerability and distinct VA characteristics.
Topics: Animals; Benzamides; Male; Rats; Rats, Sprague-Dawley; Agammaglobulinaemia Tyrosine Kinase; Arrhythmias, Cardiac; Piperidines; Action Potentials; Ventricular Remodeling; Protein Kinase Inhibitors; Pyrazines; Calcium; Adenine; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Heart Ventricles; Pyrimidines; Calcium Signaling; Pyrazoles; Tyrosine Kinase Inhibitors
PubMed: 38892396
DOI: 10.3390/ijms25116207 -
International Journal of Molecular... Jun 2024The sodium channel Na1.8, encoded by the gene, has recently emerged as a potential regulator of cardiac electrophysiology. We have previously shown that Na1.8...
The sodium channel Na1.8, encoded by the gene, has recently emerged as a potential regulator of cardiac electrophysiology. We have previously shown that Na1.8 contributes to arrhythmogenesis by inducing a persistent Na current (late Na current, I) in human atrial and ventricular cardiomyocytes (CM). We now aim to further investigate the contribution of Na1.8 to human ventricular arrhythmogenesis at the CM-specific level using pharmacological inhibition as well as a genetic knockout (KO) of in induced pluripotent stem cell CM (iPSC-CM). In functional voltage-clamp experiments, we demonstrate that I was significantly reduced in ventricular -KO iPSC-CM and in control CM after a specific pharmacological inhibition of Na1.8. In contrast, we did not find any effects on ventricular APD. The frequency of spontaneous sarcoplasmic reticulum Ca sparks and waves were reduced in KO iPSC-CM and control cells following the pharmacological inhibition of Na1.8. We further analyzed potential triggers of arrhythmias and found reduced delayed afterdepolarizations (DAD) in KO iPSC-CM and after the specific inhibition of Na1.8 in control cells. In conclusion, we show that Na1.8-induced I primarily impacts arrhythmogenesis at a subcellular level, with minimal effects on systolic cellular Ca release. The inhibition or knockout of Na1.8 diminishes proarrhythmic triggers in ventricular CM. In conjunction with our previously published results, this work confirms Na1.8 as a proarrhythmic target that may be useful in an anti-arrhythmic therapeutic strategy.
Topics: NAV1.8 Voltage-Gated Sodium Channel; Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Heart Ventricles; Arrhythmias, Cardiac; Action Potentials
PubMed: 38892333
DOI: 10.3390/ijms25116144 -
International Journal of Molecular... May 2024The high incidence of atrial fibrillation (AFib) following cardiac surgery (postoperative atrial fibrillation, POAF) relies on specific surgical features. However, in...
The high incidence of atrial fibrillation (AFib) following cardiac surgery (postoperative atrial fibrillation, POAF) relies on specific surgical features. However, in the setting of POAF, the role of the microbiome in the modulation of cardiac fibrosis is still not clear. This study aimed to analyze the effect of the microbiome and its main metabolic product (trimethylamine-N-oxide, TMAO) in the fibrosis of myocardial tissue, to investigate its role in POAF. Patients undergoing elective cardiac surgery with cardiopulmonary bypass, central atrio-caval cannulation and no history of AFib, were included. A fragment of the right atrium was analyzed for qualitative and mRNA-quantitative evaluation. A preoperative blood sample was analyzed with enzyme-linked immunosorbent assay (ELISA). A total of 100 patients have been included, with POAF occurring in 38%. Histologically, a higher degree of fibrosis, angiogenesis and inflammation has been observed in POAF. Quantitative evaluation showed increased mRNA expression of collagen-1, collagen-3, fibronectin, and transforming growth factor beta (TGFb) in the POAF group. ELISA analysis showed higher levels of TMAO, lipopolysaccharide and TGFb in POAF, with similar levels of sP-selectin and zonulin. TMAO ≥ 61.8 ng/mL (odds ratio, OR 2.88 [1.35-6.16], = 0.006), preoperative hemoglobin < 13.1 g/dL (OR 2.37 [1.07-5.24], = 0.033) and impaired right ventricular function (OR 2.38 [1.17-4.83], = 0.017) were independent predictors of POAF. Also, TMAO was significantly associated with POAF by means of increased fibrosis. Gut microbiome product TMAO is crucial for myocardial fibrosis, which is a key factor for POAF. Patients in preoperative sinus rhythm who will develop POAF have increased genetic expression of pro-fibrotic genes and enhanced fibrosis in histological staining. Elevated TMAO level (≥61.8 ng/mL) is an independent risk factor for POAF.
Topics: Humans; Atrial Fibrillation; Male; Female; Gastrointestinal Microbiome; Aged; Fibrosis; Middle Aged; Myocardium; Postoperative Complications; Methylamines
PubMed: 38892223
DOI: 10.3390/ijms25116037 -
International Journal of Molecular... May 2024Cardioembolic stroke accounts for over 20% of ischemic strokes and is associated with worse outcomes than other types of strokes. Atrial fibrillation (AF) is the most... (Review)
Review
Cardioembolic stroke accounts for over 20% of ischemic strokes and is associated with worse outcomes than other types of strokes. Atrial fibrillation (AF) is the most common risk factor for cardioembolic stroke. In this narrative review, we present an update about cardioembolic stroke mainly related to AF and atrial cardiopathy. Direct oral anticoagulants (DOACs) have revolutionized stroke prevention in patients with AF; however, their efficacy in preventing recurrent embolic stroke of unknown source remains uncertain. Various cardiac monitoring methods are used to detect AF, which is crucial for preventing stroke recurrence. DOACs are preferred over warfarin for AF-related stroke prevention; however, the timing of initiation after acute ischemic stroke is debated. Resuming anticoagulation after intracerebral hemorrhage in AF patients requires careful assessment of the risks. While catheter ablation may reduce the incidence of cardiovascular events, its effect on stroke prevention is unclear, especially in heart failure patients. Atrial cardiopathy is the emerging cause of embolic stroke of unknown source, which indicates atrial structural and functional disorders that can precede AF. Future research should focus on refining stroke risk prediction models, optimizing AF detection, understanding the roles of ablation and anticoagulation in stroke prevention, and establishing atrial cardiopathy as a therapeutic target, which could significantly reduce the burden of stroke.
Topics: Humans; Embolic Stroke; Atrial Fibrillation; Anticoagulants; Risk Factors
PubMed: 38891965
DOI: 10.3390/ijms25115777 -
International Journal of Molecular... May 2024The sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin is increasingly used in the treatment of diabetes and heart failure. Dapagliflozin has been...
The sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin is increasingly used in the treatment of diabetes and heart failure. Dapagliflozin has been associated with reduced incidence of atrial fibrillation (AF) in clinical trials. We hypothesized that the favorable antiarrhythmic outcome of dapagliflozin use may be caused in part by previously unrecognized effects on atrial repolarizing potassium (K) channels. This study was designed to assess direct pharmacological effects of dapagliflozin on cloned ion channels K11.1, K1.5, K4.3, K2.1, K2.1, K3.1, and K17.1, contributing to , , , , and K currents. Human channels coded by , , , , , , and were heterologously expressed in oocytes, and currents were recorded using the voltage clamp technique. Dapagliflozin (100 µM) reduced K11.1 and K1.5 currents, whereas K2.1, K2.1, and K17.1 currents were enhanced. The drug did not significantly affect peak current amplitudes of K4.3 or K3.1 K channels. Biophysical characterization did not reveal significant effects of dapagliflozin on current-voltage relationships of study channels. In conclusion, dapagliflozin exhibits direct functional interactions with human atrial K channels underlying , , , and currents. Substantial activation of K2.1 and K17.1 currents could contribute to the beneficial antiarrhythmic outcome associated with the drug. Indirect or chronic effects remain to be investigated in vivo.
Topics: Humans; Glucosides; Sodium-Glucose Transporter 2 Inhibitors; Benzhydryl Compounds; Animals; Xenopus laevis; Potassium Channels; Oocytes; Sodium-Glucose Transporter 2
PubMed: 38891889
DOI: 10.3390/ijms25115701 -
JCI Insight Jun 2024Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). The mechanisms underlying DM-associated AF are unclear. AF and DM are both related to...
Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). The mechanisms underlying DM-associated AF are unclear. AF and DM are both related to inflammation. We investigated whether DM-associated inflammation contributed to AF risk. Mice were fed with high fat diet to induce type II DM and were subjected to IL-1β antibodies, macrophage depletion by Clodronate liposomes, a mitochondrial antioxidant (mitoTEMPO), or a cardiac ryanodine receptor (RyR2) stabilizer (S107). All tests were performed at 36-38 weeks of age. DM mice presented with increased AF inducibility, enhanced mitochondrial reactive oxygen species (mitoROS) generation, and activated innate immunity in the atria as evidenced by enhanced monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, and IL-1β levels. Signs of aberrant RyR2 Ca2+ leak were observed in the atria of DM mice. IL-1β neutralization, macrophage depletion, mitoTEMPO, and S107 significantly ameliorated the AF vulnerability in DM mice. Atrial overexpression of MCP-1 increased AF occurrence in normal mice through the same mechanistic signaling cascade as observed in DM mice. In conclusion, macrophage-mediated IL-1β contributed to DM-associated AF risk through mitoROS modulation of RyR2 Ca2+ leak.
PubMed: 38889387
DOI: 10.1172/jci.insight.171102 -
European Heart Journal. Case Reports Apr 2024Atrial fibrillation is a common cardiac arrhythmia and often develops secondary to structural cardiac changes. Both the occurrence of atrial fibrillation and/or...
BACKGROUND
Atrial fibrillation is a common cardiac arrhythmia and often develops secondary to structural cardiac changes. Both the occurrence of atrial fibrillation and/or structural changes of the heart may lead to development of atrial cardiomyopathy and heart failure (HF). However, isolated atrial cardiomyopathy caused by focal atrial thickening is a rare condition, previously only described in case reports as a result of different aetiologies all linked to inflammation.
CASE SUMMARY
A patient with inflammatory-mediated atrial cardiomyopathy causing atrial fibrillation and acute decompensated HF presented as isolated left atrial wall thickening on transoesophageal echocardiography. The diagnosis was confirmed using multimodality imaging with transthoracic and transoesophageal echocardiography, cardiac magnetic resonance imaging, positron emissions tomography/computer tomography scanning and intracardiac echocardiography-guided endomyocardial biopsy. Despite no specific histological aetiology, the observed atrial cardiomyopathy might be associated with type 1 diabetes mellitus. The patient in the present case was successfully treated with prednisolone.
DISCUSSION
Diabetes mellitus is an important risk factor for developing atrial fibrillation and diabetic cardiomyopathy, due to reduced levels of anti-inflammatory and increased levels of proinflammatory cytokines causing cardiac inflammatory structural remodelling. The regression of the atrial thickening might be due to prednisolone's anti-inflammatory effects and thereby ability to suppress atrial remodelling and reduce the occurrence of atrial fibrillation. However, the effect of prednisolone might only affect the non-manifested inflammatory-mediated atrial remodelling. Due to the rare occurrence of isolated atrial cardiomyopathy a multiple imaging approach during the diagnostic process and follow-ups are essential to determine the aetiology and effect of the treatment.
PubMed: 38887777
DOI: 10.1093/ehjcr/ytae167 -
Frontiers in Cardiovascular Medicine 2024The prevalence of congenital heart disease (CHD) in adult patients has risen with advances in diagnostic and surgical techniques. Surgical modifications and hemodynamic... (Review)
Review
The prevalence of congenital heart disease (CHD) in adult patients has risen with advances in diagnostic and surgical techniques. Surgical modifications and hemodynamic changes increase the susceptibility to arrhythmias, impacting morbidity and mortality rates, with arrhythmias being the leading cause of hospitalizations and sudden deaths. Patients with CHD commonly experience both supraventricular and ventricular arrhythmias, with each CHD type associated with different arrhythmia patterns. Macroreentrant atrial tachycardias, particularly cavotricuspid isthmus-dependent flutter, are frequently reported. Ventricular arrhythmias, including monomorphic ventricular tachycardia, are prevalent, especially in patients with surgical scars. Pharmacological therapy involves antiarrhythmic and anticoagulant drugs, though data are limited with potential adverse effects. Catheter ablation is preferred, demanding meticulous procedural planning due to anatomical complexity and vascular access challenges. Combining imaging techniques with electroanatomic navigation enhances outcomes. However, risk stratification for sudden death remains challenging due to anatomical variability. This article practically reviews the most common tachyarrhythmias, treatment options, and clinical management strategies for these patients.
PubMed: 38887448
DOI: 10.3389/fcvm.2024.1395210 -
Scientific Reports Jun 2024Stroke is an acute cerebrovascular disease in which blood flow to the brain is suddenly disrupted, causing damage to nerve cells. It involves complex and diverse...
Stroke is an acute cerebrovascular disease in which blood flow to the brain is suddenly disrupted, causing damage to nerve cells. It involves complex and diverse pathophysiological processes and the treatment strategies are also diverse. The treatment for patients with stroke and atrial fibrillation (AF) is aimed at suppressing thrombus formation and migration. However, information regarding the protein networking involved in different thrombus formation pathways in patients with AF and stroke is insufficient. We performed protein profiling of patients with ischemic stroke with and without AF to investigate the mechanisms of thrombus formation and its pathophysiological association while providing helpful information for treating and managing patients with AF. These two groups were compared to identify the protein networks related to thrombus formation in AF. We observed that patients with ischemic stroke and AF had activated inflammatory responses induced by C-reactive protein, lipopolysaccharide-binding protein, and alpha-1-acid glycoprotein 1. In contrast, thyroid hormones were increased due to a decrease in transthyretin and retinol-binding protein 4 levels. The mechanism underlying enhanced cardiac activity, vasodilation, and the resulting thrombosis pathway were confirmed in AF. These findings will play an essential role in improving the prevention and treatment of AF-related stroke.
Topics: Humans; Atrial Fibrillation; Thrombosis; Male; Female; Aged; Middle Aged; Blood Proteins; Stroke; Ischemic Stroke; Protein Interaction Maps; Proteomics
PubMed: 38886511
DOI: 10.1038/s41598-024-64750-w