Search Results (18)

Background: The arrhythmogenic mechanism of idiopathic ventricular arrhythmias (VAs) from the outflow tracts (OTs) and adjacent anatomical structures has been described to be triggered activity. However, it is incompletely understood why this focal mechanism mainly originates from the OTs and what factors could precipitate it. The aim of this study was to further elucidate the arrhythmogenic mechanisms underlying focal ventricular arrhythmias originating from the outflow tracts. Methods: Six patients referred for catheter ablation of OT-related PVCs were included in this study. Programmed atrial stimulation at the interatrial septum or within the coronary sinus was performed. Pacing at the AV annuli was capable of evoking OT-PVCs with an ECG morphology identical to clinical PVCs by presumably capturing specific fibers within the network of nodal-type tissue of the AV junctional sleeves. Results: Based on the analysis of intracardiac electrograms, the observed PVCs could indeed be elicited as a result of prior atrial stimulation. Conclusions: Our findings suggest that unique pathways might exist between specific periannular atrial locations and the OTs, the activation of which could result in triggering PVCs from the presumed “exit site” of these pathways in the OTs. These findings might facilitate the development of a novel ablation strategy, which might also include the mapping of atrial locations, in order to identify and ablate the presumed “entry sites” of these special pathways. Full article

Objective: Direct oral anticoagulants (DOACs) are first-line therapy for stroke prevention for 1.4 million atrial fibrillation (AF) patients in the UK. However, the rates of DOAC dosing below evidence-based recommendations are estimated between 9% and 22%. This study explores specific patient and physician factors associated with prescribing inappropriate DOAC underdoses. Methods: DOAC-prescribing physicians within the UK completed both a clinical vignette survey, which contained 12 hypothetical patient profiles designed to replicate DOAC prescribing scenarios, and a physician survey to capture sociodemographic, clinical experience, and prescriber-related beliefs and motivations related to DOAC prescribing. Eight patient factors based on a literature search and an expert consultation process were varied within the vignettes. Associations between the prescribers’ dosing choices and patient factors were explored via multilevel logistic regression. The analysis is focused on the most frequently selected DOACs, apixaban and rivaroxaban, both of which have different dosing guidelines. Results: In all, 336 prescribers (69% male; 233/336) completed the survey, mostly general physicians (GPs) (45%) or cardiology specialists (36%) with a mean of 17.9 years’ experience. Most prescribers (73%; 244/336) inappropriately underdosed at least once; rates between GPs and specialists were nearly identical. Patient factors most strongly associated with apixaban inappropriate underdosing included a history of major bleeding and falls. For rivaroxaban, these were major bleeding and severe frailty. Only 32% (106/335) of prescribers reported DOAC dosing guidelines as the sole influence on their prescribing behaviour. Among prescribers who did not inappropriately underdose, greater prescribing confidence was aligned to increased perception of inappropriate underdose risk. Conclusions: Overall, patient factors such as major bleeding and severe frailty were found to be associated with inappropriate underdosing of apixaban and rivaroxaban. Furthermore, prescribers who were more confident in DOAC prescribing, and were more worried about the risk of stroke, were significantly less likely to inappropriately underdose. These findings suggest that all prescribers, regardless of speciality, may benefit from education and training to raise awareness of the risks associated with inappropriate DOAC underdosing. Full article

Abnormalities in G-protein-gated inwardly rectifying potassium (GIRK) channels have been implicated in diseased states of the cardiovascular system; however, the role of GIRK4 (Kir3.4) in cardiac physiology and pathophysiology has yet to be completely understood. Within the heart, the K_ACh channel, consisting of two GIRK1 and two GIRK4 subunits, plays a major role in modulating the parasympathetic nervous system’s influence on cardiac physiology. Being that GIRK4 is necessary for the functional K_ACh channel, KCNJ5, which encodes GIRK4, it presents as a therapeutic target for cardiovascular pathology. Human variants in KCNJ5 have been identified in familial hyperaldosteronism type III, long QT syndrome, atrial fibrillation, and sinus node dysfunction. Here, we explore the relevance of KCNJ5 in each of these diseases. Further, we address the limitations and complexities of discerning the role of KCNJ5 in cardiovascular pathophysiology, as identical human variants of KCNJ5 have been identified in several diseases with overlapping pathophysiology. Full article

Background: Magnesium (Mg) is often used to manage de novo atrial fibrillation (AF) in the emergency department (ED) and intensive care unit (ICU). Point of care measurement of ionized magnesium (iMg) allows a rapid identification of patients with impaired magnesium status, however, unlike ionized calcium, the interpretation of iMg is not entirely understood. Thus, we evaluated iMg reference values, correlation between iMg and plasmatic magnesium (pMg), and the impact of pH and albumin variations on iMg levels. Secondary objectives were to assess the incidence of hypomagnesemia in de novo AF. Methods: A total of 236 emergency department and intensive care unit patients with de novo AF, and 198 control patients were included. Reference values were determined in the control population. Correlation and concordance between iMg and pMg were studied using calcium (ionized and plasmatic) as a control in the whole study population. The impact of albumin and pH was assessed in the discordant iMg and pMg values. Lastly, we assessed the incidence of ionized hypomagnesemia (hypoMg) among de novo AF. Results: The reference range values established in our study for iMg were: 0.48–0.65 mmol/L (the manufacturers were: 0.45–0.60 mmol/L). A strong correlation was observed between pMg and iMg (r = 0.85), but, unlike for calcium values, there was no significant impact of pH and albumin in iMg/pMg interpretation. The incidence of hypoMg among de novo AF patients was 8.5% (12.7% using our ranges). When using our ranges, we found a significant link (p = 0.01) between hyopMg and hypokalemia. Conclusion: We highlight the need for more accurate reference range values of iMg. Furthermore, our results suggest that blood Mg content is not identical to that of calcium. The incidence of ionized hypomagnesemia among de novo AF patients in our study is 8.5%. Full article

Background: Pulsed Electric Field (PEF) ablation has been recently proposed to ablate cardiac ganglionic plexi (GP) aimed to treat atrial fibrillation. The effect of metal intracoronary stents in the vicinity of the ablation electrode has not been yet assessed. Methods: A 2D numerical model was developed accounting for the different tissues involved in PEF ablation with an irrigated ablation device. A coronary artery (with and without a metal intracoronary stent) was considered near the ablation source (0.25 and 1 mm separation). The 1000 V/cm threshold was used to estimate the ‘PEF-zone’. Results: The presence of the coronary artery (with or without stent) distorts the E-field distribution, creating hot spots (higher E-field values) in the front and rear of the artery, and cold spots (lower E-field values) on the sides of the artery. The value of the E-field inside the coronary artery is very low (~200 V/cm), and almost zero with a metal stent. Despite this distortion, the PEF-zone contour is almost identical with and without artery/stent, remaining almost completely confined within the fat layer in any case. The mentioned hot spots of E-field translate into a moderate temperature increase (<48 °C) in the area between the artery and electrode. These thermal side effects are similar for pulse intervals of 10 and 100 μs. Conclusions: The presence of a metal intracoronary stent near the ablation device during PEF ablation simply ‘amplifies’ the E-field distortion already caused by the presence of the vessel. This distortion may involve moderate heating (<48 °C) in the tissue between the artery and ablation electrode without associated thermal damage. Full article

Irreversible electroporation (IRE) ablation is a novel treatment option for localized prostate cancer. Here, we present a case of an abrupt and fatal arrhythmia during the IRE procedure in a prostate cancer patient with an implanted permanent pacemaker. A 78-year-old male patient with a pacemaker due to sick sinus syndrome and syncope was scheduled for IRE prostate ablation surgery under general anesthesia. He had a history of recovering from coronavirus disease 2019 (COVID-19) after having been vaccinated against it and recovered without sequalae. Pacemaker interrogation and reprogramming to asynchronous AOO mode was carried out before surgery, however, sinus pause occurred repeatedly during ablation pulse delivery. After the first sinus pause of 2.25 s there was a decrease in continuous arterial blood pressure (ABP). During the delivery of the second and third pulses, identical sinus pauses were observed due to failure to capture. However, the atrial-paced rhythm recovered instantly, and vital signs became acceptable. Although sinus pause recovered gradually, the duration thereof was increased by the delivery of more IRE pulses, with a subsequent abrupt decrease seen in blood pressure. The pacemaker was urgently reprogrammed to DOO mode, after which there were no further pacing failures and no hemodynamic adverse events. For patients with pacemakers, close cardiac monitoring in addition to the interrogation of the pacemaker during the electromagnetic interference (EMI) procedure is recommended, especially in the case of having a disease that may aggravate cardiac vulnerability, such as COVID-19. Full article

Background: Baseline impedance, radiofrequency current, and impedance drop during radiofrequency catheter ablation are thought to predict effective lesion formation. However, quantifying the contributions of local versus remote impedances provides insights into the limitations of indices using those parameters. Methods: An in silico model of left atrial radiofrequency catheter ablation was used based on human thoracic measurements and solved for (1) initial impedance (Z), (2) percentage of radiofrequency power delivered to the myocardium and blood (3) total radiofrequency current, (4) impedance drop during heating, and (5) lesion size after a 25 W–30 s ablation. Remote impedance was modeled by varying the mixing ratio between skeletal muscle and fat. Local impedance was modeled by varying insertion depth of the electrode (ID). Results: Increasing the remote impedance led to increased baseline impedance, lower system current delivery, and reduced lesion size. For ID = 0.5 mm, Z ranged from 115 to 132 Ω when fat percentage varied from 20 to 80%, resulting in a decrease in the RF current from 472 to 347 mA and a slight decrease in lesion size from 5.6 to 5.1 mm in depth, and from 9.2 to 8.0 mm in maximum width. In contrast, increasing the local impedance led to lower system current but larger lesions. For a 50% fat–muscle mixture, Z ranged from 118 to 138 Ω when ID varied from 0.3 to 1.9 mm, resulting in a decrease in the RF current from 463 to 443 mA and an increase in lesion size, from 5.2 up to 7.5 mm in depth, and from 8.4 up to 11.6 mm in maximum width. In cases of nearly identical Z but different contributions of local and remote impedance, markedly different lesions sizes were observed despite only small differences in RF current. Impedance drop better predicted lesion size (R² > 0.93) than RF current (R² < 0.1). Conclusions: Identical baseline impedances and observed RF currents can lead to markedly different lesion sizes with different relative contributions of local and remote impedances to the electrical circuit. These results provide mechanistic insights into the advantage of measuring local impedance and identifies potential limitations of indices incorporating baseline impedance or current to predict lesion quality. Full article

Heart rate is quite regular during sinus (normal) rhythm (SR) originating from the sinus node. In contrast, heart rate is usually irregular during atrial fibrillation (AF). Complete atrioventricular block with an escape rhythm, ventricular pacing, or ventricular tachycardia are the most common exceptions when heart rate may be regular in AF. Heart rate variability (HRV) is the variation in the duration of consecutive cardiac cycles (RR intervals). We investigated the utility of HRV parameters for automated detection of AF with machine learning (ML) classifiers. The minimum redundancy maximum relevance (MRMR) algorithm, one of the most effective algorithms for feature selection, helped select the HRV parameters (including five original), best suited for distinguishing AF from SR in a database of over 53,000 60 s separate electrocardiogram (ECG) segments cut from longer (up to 24 h) ECG recordings. HRV parameters entered the ML-based classifiers as features. Seven different, commonly used classifiers were trained with one to six HRV-based features with the highest scores resulting from the MRMR algorithm and tested using the 5-fold cross-validation and blindfold validation. The best ML classifier in the blindfold validation achieved an accuracy of 97.2% and diagnostic odds ratio of 1566. From all studied HRV features, the top three HRV parameters distinguishing AF from SR were: the percentage of successive RR intervals differing by at least 50 ms (pRR50), the ratio of standard deviations of points along and across the identity line of the Poincare plots, respectively (SD2/SD1), and coefficient of variation—standard deviation of RR intervals divided by their mean duration (CV). The proposed methodology and the presented results of the selection of HRV parameters have the potential to develop practical solutions and devices for automatic AF detection with minimal sets of simple HRV parameters. Using straightforward ML classifiers and the extremely small sets of simple HRV features, always with pRR50 included, the differentiation of AF from sinus rhythms in the 60 s ECGs is very effective. Full article

The existing electrocardiogram (ECG) biometrics do not perform well when ECG changes after the enrollment phase because the feature extraction is not able to relate ECG collected during enrollment and ECG collected during classification. In this research, we propose the sequence pair feature extractor, inspired by Bidirectional Encoder Representations from Transformers (BERT)’s sentence pair task, to obtain a dynamic representation of a pair of ECGs. We also propose using the self-attention mechanism of the transformer to draw an inter-identity relationship when performing ECG identification tasks. The model was trained once with datasets built from 10 ECG databases, and then, it was applied to six other ECG databases without retraining. We emphasize the significance of the time separation between enrollment and classification when presenting the results. The model scored 96.20%, 100.0%, 99.91%, 96.09%, 96.35%, and 98.10% identification accuracy on MIT-BIH Atrial Fibrillation Database (AFDB), Combined measurement of ECG, Breathing and Seismocardiograms (CEBSDB), MIT-BIH Normal Sinus Rhythm Database (NSRDB), MIT-BIH ST Change Database (STDB), ECG-ID Database (ECGIDDB), and PTB Diagnostic ECG Database (PTBDB), respectively, over a short time separation. The model scored 92.70% and 64.16% identification accuracy on ECGIDDB and PTBDB, respectively, over a long time separation, which is a significant improvement compared to state-of-the-art methods. Full article

Human pluripotent stem cell (hPSC)-derived cardiomyocytes have proven valuable for modeling disease and as a drug screening platform. Here, we depict an optimized protocol for the directed differentiation of hPSCs toward cardiomyocytes with an atrial identity by modulating the retinoic acid signaling cascade in spin embryoid bodies. The crucial steps of the protocol, including hPSC maintenance, embryoid body (EB) differentiation, the induction of cardiac mesoderm, direction toward the atrial phenotype, as well as molecular and functional characterization of the cardiomyocytes, are described. Atrial cardiomyocytes (AMs) can be generated within 14 days. Most importantly, we show that induction of the specific retinoic acid receptor alpha (RARα) increased the efficiency of atrial differentiation to 72% compared with 45% after modulating the retinoic acid (RA) pathway with all-trans RA (atRA). In contrast, the induction of RARβ signaling only had a minor impact on the efficiency of atrial differentiation (from about 45% to 50%). Similarly, the total yield of AM per EB of 5000 hPSCs was increased from 10,350 (2.07 per hPSC) to 16,120 (3.22 per hPSC) while selectively modulating RARα signaling. For further purification of the AMs, we describe a metabolic selection procedure that enhanced the AM percentage to more than 90% without compromising the AM yield (15,542 per EB, equal to 3.11 per hPSC) or functionality of the AMs as evaluated by RNAseq, immunostaining, and optical action potential measurement. Cardiomyocytes with distinct atrial and ventricular properties can be applied for selective pharmacology, such as the development of novel atrial-specific anti-arrhythmic agents, and disease modeling, including atrial fibrillation, which is the most common heart rhythm disorder. Moreover, fully characterized and defined cardiac subtype populations are of the utmost importance for potential cell-based therapeutic approaches. Full article

Background: Few data are available about brain natriuretic peptide (BNP) variation and left atrial remodeling after the left atrial appendage occlusion (LAAO) technique. Methods: Prospective study included all consecutive patients successfully implanted with an LAAO device. Contrast-enhanced cardiac computed tomography (CT) was performed before and 6 weeks after the procedure with reverse left atrial remodeling defined by an increase in LA volume >10%, together with blood sampling obtained before, 48 h after device implantation and at the first visit after discharge (30–45 days) for BNP measurement. Results: Among the 43 patients implanted with a complete dataset, mean end-diastolic LA volume was 139 ± 64 mL and 141 ± 62 mL at baseline and during follow-up (45 ± 15 days), respectively, showing no statistical difference (p = 0.45). No thrombus was seen on the atrial side of the device. Peridevice leaks (defined as presence of dye in the LAA beyond the device) were observed in 17 patients (40%) but were trivial or mild. Reverse atrial remodeling (RAR) at 6 weeks was observed in six patients (14%). Despite no difference in BNP levels on admission, median BNP levels at 48 h were slightly increased in RAR patients when compared with controls. During FU, BNP levels were strictly identical in both groups. These results were not modified even when each RAR case was matched with two controls on age, LVEF, creatinine levels and ACE inhibitors treatment to avoid potential confounders. Conclusion: Our study showed that despite the fact that the LAAO technique can induce left atrial remodeling measured by a CT scan, it does not seem to impact BNP levels on the follow-up. The results need to be transposed to clinical outcomes of this expanding population in future studies. Full article

Our ability to evaluate residual stroke risk despite anticoagulation in atrial fibrillation (AF) is currently lacking. The Calculator of Absolute Stroke Risk (CARS) has been proposed to predict 1-year absolute stroke risk in non-anticoagulated patients. We aimed to determine whether a modified CARS (mCARS) may be used to assess the residual stroke risk in anticoagulated AF patients from ‘real-world’ and ‘clinical trial’ cohorts. We studied patient-level data of anticoagulated AF patients from the real-world Murcia AF Project and AMADEUS clinical trial. Individual mCARS were estimated for each patient. None of the patients were treated with non-vitamin K antagonist oral anticoagulants. The predicted residual stroke risk was compared to actual stroke risk. 3503 patients were included (2205 [62.9%] clinical trial and 1298 [37.1%] real-world). There was wide variation of CARS for each category of CHA₂DS₂-VASc score in both cohorts. Average predicted residual stroke risk by mCARS (1.8 ± 1.8%) was identical to actual stroke risk (1.8% [95% CI, 1.3–2.4]) in the clinical trial, and broadly similar in the real-world (2.1 ± 1.9% vs. 2.4% [95% CI, 1.6–3.4]). AUCs of mCARS for prediction of stroke events in the clinical trial and real-world were 0.678 (95% CI, 0.598–0.758) and 0.712 [95% CI, 0.618–0.805], respectively. mCARS was able to refine stroke risk estimation for each point of the CHA₂DS₂-VASc score in both cohorts. Personalised residual 1-year absolute stroke risk in anticoagulated AF patients may be estimated using mCARS, thereby allowing an assessment of the absolute risk reduction of treatment and facilitating a patient-centred approach in the management of AF. Such identification of patients with high residual stroke risk could help target more aggressive interventions and follow-up. Full article

Cardiovascular development is a complex process that starts with the formation of symmetrically located precardiac mesodermal precursors soon after gastrulation and is completed with the formation of a four-chambered heart with distinct inlet and outlet connections. Multiple transcriptional inputs are required to provide adequate regional identity to the forming atrial and ventricular chambers as well as their flanking regions; i.e., inflow tract, atrioventricular canal, and outflow tract. In this context, regional chamber identity is widely governed by regional activation of distinct T-box family members. Over the last decade, novel layers of gene regulatory mechanisms have been discovered with the identification of non-coding RNAs. microRNAs represent the most well-studied subcategory among short non-coding RNAs. In this study, we sought to investigate the functional role of distinct microRNAs that are predicted to target T-box family members. Our data demonstrated a highly dynamic expression of distinct microRNAs and T-box family members during cardiogenesis, revealing a relatively large subset of complementary and similar microRNA–mRNA expression profiles. Over-expression analyses demonstrated that a given microRNA can distinctly regulate the same T-box family member in distinct cardiac regions and within distinct temporal frameworks, supporting the notion of indirect regulatory mechanisms, and dual luciferase assays on Tbx2, Tbx3 and Tbx5 3′ UTR further supported this notion. Overall, our data demonstrated a highly dynamic microRNA and T-box family members expression during cardiogenesis and supported the notion that such microRNAs indirectly regulate the T-box family members in a tissue- and time-dependent manner. Full article

Background: Antiarrhythmic drugs (AADs) are frequently initiated in patients with persistent atrial fibrillation (AF) prior to electrical cardioversion (ECV), achieving pharmacological cardioversion (PCV) in some cases. Little is known about the mode of cardioversion and the effect of the type of AAD used in the maintenance of sinus rhythm (SR). Methods: From three national surveys of patients with persistent AF referred for ECV, we selected those who were pre-treated with AADs (amiodarone or group Ic AADs). We analyzed the effect of the type of cardioversion (pharmacological vs. electrical) and the AAD used in the maintenance of SR at three months. Results: Among the 665 patients selected, 151 had a successful PCV prior to the planned ECV. In the remaining 514 patients, 460 had a successful ECV. A successful PCV was related to a higher rate of SR maintenance than a successful ECV (77.9% vs. 57.5%; p < 0.0001). After a successful PCV, the maintenance of SR was identical in those patients treated with amiodarone and those treated with group Ic AADs (77.4% vs. 77.5%; p = 0.99), whereas after a successful ECV, amiodarone was clearly superior to group Ic AADs (61.3% vs. 43.0%; p = 0.001). Considering patients with successful PCV and ECV together, PCV was an independent factor related to the maintenance of SR. Conclusions: In patients with persistent AF, successful PCV selects a subgroup with a high probability of maintenance of SR. With regard to drugs, amiodarone was superior to group Ic AADs in patients with ECV, whereas in PCV, no differences were observed. Full article

Proper development and function of the vertebrate heart is vital for embryonic and postnatal life. Many congenital heart defects in humans are associated with disruption of genes that direct the formation or maintenance of atrial and pacemaker cardiomyocytes at the venous pole of the heart. Zebrafish are an outstanding model for studying vertebrate cardiogenesis, due to the conservation of molecular mechanisms underlying early heart development, external development, and ease of genetic manipulation. Here, we discuss early developmental mechanisms that instruct appropriate formation of the venous pole in zebrafish embryos. We primarily focus on signals that determine atrial chamber size and the specialized pacemaker cells of the sinoatrial node through directing proper specification and differentiation, as well as contemporary insights into the plasticity and maintenance of cardiomyocyte identity in embryonic zebrafish hearts. Finally, we integrate how these insights into zebrafish cardiogenesis can serve as models for human atrial defects and arrhythmias. Full article