Arrhythmia Score Research Articles

Silent cerebral ischemic lesions in ablation-naïve patients with non-valvular atrial fibrillation: does the pulmonary vein anatomy matter?

Silent cerebral ischemic lesions (SCILs) detected by magnetic resonance imaging (MRI) can precede symptomatic stroke, the risk of which is increased five-fold in atrial fibrillation (AF) patients. In our study, we aimed to evaluate the initial incidence of SCILs in the population of patients referred for ablation due to symptomatic AF and to identify possible risk factors. A total of 110 patients, with a mean age (SD) of 59.9 (9.4) years, referred for ablation, were included in the study. In all patients, MRI was performed before the procedure to evaluate the incidence of SCILs in the ablation-naïve patients. MRI revealed preexisting SCIL in 81/110 patients (73.6%). Notably, SCILs were found in all patients with CHA₂DS₂-VASc score ≥ 4. In univariable analysis, age (p < 0.001), CHA₂DS₂-VASc score (p = 0.001), hypertension (p = 0.01), and anticoagulation duration (p = 0.023) were identified as significant risk factors for SCILs, while the presence of anatomical variants of left-sided common pulmonary veins trunk (LCPV) had negative prognostic value (p = 0.026). Multivariable logistic regression analysis identified age (p < 0.001) as the risk factor of preexisting SCILs, whereas the presence of LCPV trunk was associated with significantly lower (p = 0.005) SCILs incidence. Silent cerebral ischemic lesions detected in MRI are frequent in the population of patients with non-valvular AF. The incidence of SCILs is higher in patients with long history of arrhythmia and higher CHA₂DS₂-VASc score. The relationship between the anatomy of pulmonary veins and the incidence of SCILs needs further investigation.

Decreased ability to manage increases in reactive oxygen species may underlie susceptibility to arrhythmias in mice lacking Scn1b.

Scn1b plays essential roles in the heart, where it encodes β1-subunits that serve as modifiers of gene expression, cell surface channel activity, and cardiac conductivity. Reduced β1 function is linked to electrical instability in various diseases with cardiac manifestations and increased susceptibility to arrhythmias. Recently, we demonstrated that loss of Scn1b in mice leads to compromised mitochondria energetics and reactive oxygen species (ROS) production. In this study, we examined the link between increased ROS and arrhythmia susceptibility in Scn1b-/- mice. In addition, ROS-scavenging capacity can be overwhelmed during prolonged oxidative stress, increasing arrhythmia susceptibility. Therefore, we isolated whole hearts and cardiomyocytes from Scn1b-/- and Scn1b+/+ mice and subjected them to an oxidative challenge with diamide, a glutathione oxidant. Next, we analyzed gene expression and activity of antioxidant enzymes in Scn1b-/- hearts. Cells isolated from Scn1b-/- hearts died faster and displayed higher rates of ROS accumulation preceding cell death compared with those from Scn1b+/+. Furthermore, Scn1b-/- hearts showed higher arrhythmia scores and spent less time free of arrhythmia. Lastly, we found that protein expression and enzymatic activity of glutathione peroxidase is increased in Scn1b-/- hearts compared with wild type. Our results indicate that Scn1b-/- mice have decreased capability to manage ROS during prolonged oxidative stress. ROS accumulation is elevated and appears to overwhelm ROS scavenging through the glutathione system. This imbalance creates the potential for altered cell energetics that may underlie increased susceptibility to arrhythmias or other adverse cardiac outcomes.NEW & NOTEWORTHY Using an oxidative challenge, we demonstrated that isolated cells from Scn1b-/- mice are more susceptible to cell death and surges in reactive oxygen species accumulation. At the whole organ level, they were also more susceptible to the formation of cardiac arrhythmias. This may in part be due to changes to the glutathione antioxidant system.

Borneol promotes berberine-induced cardioprotection in a rat model of myocardial ischemia/reperfusion injury via inhibiting P-glycoprotein expression

Berberine is reported to protect the heart against ischemia/reperfusion (I/R) injury, although efficacy is limited by low bioavailability. This study aims to determine whether borneol, a classic guiding drug, can enhance the cardioprotection induced by berberine and to clarify the underlying mechanisms involving P-glycoprotein (P-gp) in the heart. Adult male Sprague Dawley rats were gavaged with berberine (200 mg/kg) with or without borneol (100 mg/kg) for 7 consecutive days. A rat model of myocardial I/R injury was established by 30 min left coronary artery occlusion followed with 120 min reperfusion. The arrhythmia score, cardiac enzyme content, and myocardial infarct size were determined following reperfusion. Heart tissues were collected for Western blot and immunofluorescence analyses to measure the protein expression levels of Bcl-2, Bax, and P-gp. The results showed that administration of berberine protected the heart against I/R injury, as demonstrated by lower arrhythmia scores, serum cTnI contents, myocardial infarct size, and cardiomyocytes apoptosis. Moreover, borneol substantially enhanced the cardioprotective effects of berberine. Western blot and immunofluorescence analyses showed that both berberine and I/R injury did not alter P-gp expression in heart. In contrast, borneol combined with berberine significantly reduced P-gp levels by 43.4% (P = 0.0240). Interestingly, treatment with borneol alone decreased P-gp levels, but did not protect against myocardial I/R injury. These findings suggest that borneol, as an adjuvant drug, improved the cardioprotective effects of berberine by inhibiting P-gp expression in heart. Borneol combined with berberine administration provides a new strategy to protect the heart against I/R injury.

β-Adrenergic receptor signalling pathway mediated antiarrhythmic activity of s-limonene in the rat heart.

S-Limonene (s-Lim) is a monocyclic monoterpene found in a variety of plants and has been shown to present antioxidant and cardioprotective activity in experimental models of myocardial infarction. The aim of this study was to evaluate the potential mechanism by which s-Lim exerts its antiarrhythmic effect, focusing on the blockade of β-adrenoceptor (β-AR) and its effects on various in vivo and in vitro parameters, including electrocardiogram (ECG) measurements, left ventricular developed pressure (LVDP), the β-adrenergic pathway, sarcomeric shortening and L-type calcium current (ICa,L). In isolated hearts, 10 μM of s-Lim did not alter the ECG profile or LVPD. s-Lim increased the heart rate corrected QT interval (QTc) (10.8%) at 50 μM and reduced heart rate at the concentrations of 30 (12.4%) and 50 μM (16.6%). s-Lim (10 μM) also inhibited the adrenergic response evoked by isoproterenol (ISO) (1 μM) reducing the increased of heart rate, LVDP and ECG changes. In ventricular cardiomyocyte, s-Lim antagonized the effect of dobutamine by preventing the increase of sarcomeric shortening, demonstrating a similar effect to atenolol (blocker β1-AR). In vivo, s-Lim antagonized the effect of ISO (agonists β1-AR), presenting a similar effect to propranolol (a non-selective blocker β-AR). In ventricular cardiomyocyte, s-Lim did not alter the voltage dependence for ICa,L activation or the ICa,L density. In addition, s-Lim did not affect changes in the ECG effect mediated by 5 μM forskolin (an activator of adenylate cyclase). In an in vivo caffeine/ISO-induced arrhythmia model, s-Lim (1 mg/kg) presented antiarrhythmic action verified by a reduced arrhythmia score, heart rate, and occurrence of ventricular premature beats and inappropriate sinus tachycardia. These findings indicate that the antiarrhythmic activity of s-Lim is related to blockade of β-AR in the heart.

Oxytocin Attenuates Sympathetic Innervation with Inhibition of Cardiac Mast Cell Degranulation in Rats after Myocardial Infarction.

Sympathetic hyperinnervation is the leading cause of fatal ventricular arrhythmia (VA) after myocardial infarction (MI). Cardiac mast cells cause arrhythmias directly through degranulation. However, the role and mechanism of mast cell degranulation in sympathetic remodeling remain unknown. We investigated the role of oxytocin (OT) in stabilizing cardiac mast cells and improving sympathetic innervation in rats. MI was induced by coronary artery ligation. Western blotting, immunofluorescence, and toluidine staining of mast cells were performed to determine the expression and location of target protein. Mast cells accumulated significantly in peri-infarcted tissues and were present in a degranulated state. They expressed OT receptor (OTR), and OT infusion reduced the number of degranulated cardiac mast cells post-MI. Sympathetic hyperinnervation was attenuated as assessed by immunofluorescence for tyrosine hydroxylase (TH). Seven days post-MI, the arrhythmia score of programmed electrical stimulation was higher in vehicle-treated rats with MI than in rats treated with OT. An in vitro study showed that OT stabilized mast cells via the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Further in vivo studies on OTR-deficient mice showed worsening mast cell degranulation and worsening sympathetic innervation. OT pretreatment inhibited cardiac mast cell degranulation post-MI and prevented sympathetic hyperinnervation, along with mast cell stabilization via the PI3K/Akt pathway. SIGNIFICANCE STATEMENT: This is the first study to elucidate the role and mechanism of oxytocin (OT) in inflammatory-sympathetic communication mediated sympathetic hyperinnervation after myocardial infarction (MI), providing new approaches to prevent fatal arrhythmias.

Testing Machine Learning Models to Predict Postoperative Ileus after Colorectal Surgery.

Background: Postoperative ileus (POI) is a common complication after colorectal surgery, leading to increased hospital stay and costs. This study aimed to explore patient comorbidities that contribute to the development of POI in the colorectal surgical population and compare machine learning (ML) model accuracy to existing risk instruments. Study Design: In a retrospective study, data were collected on 316 adult patients who underwent colorectal surgery from January 2020 to December 2021. The study excluded patients undergoing multi-visceral resections, re-operations, or combined primary and metastatic resections. Patients lacking follow-up within 90 days after surgery were also excluded. Eight different ML models were trained and cross-validated using 29 patient comorbidities and four comorbidity risk indices (ASA Status, NSQIP, CCI, and ECI). Results: The study found that 6.33% of patients experienced POI. Age, BMI, gender, kidney disease, anemia, arrhythmia, rheumatoid arthritis, and NSQIP score were identified as significant predictors of POI. The ML models with the greatest accuracy were AdaBoost tuned with grid search (94.2%) and XG Boost tuned with grid search (85.2%). Conclusions: This study suggests that ML models can predict the risk of POI with high accuracy and may offer a new frontier in early detection and intervention for postoperative outcome optimization. ML models can greatly improve the prediction and prevention of POI in colorectal surgery patients, which can lead to improved patient outcomes and reduced healthcare costs. Further research is required to validate and assess the replicability of these results.

Intrathecal Anesthesia Prevents Ventricular Arrhythmias in Rats with Myocardial Ischemia/Reperfusion

Introduction: Ventricular arrhythmia is commonly provoked by acute cardiac ischemia through sympathetic exaggeration and is often resistant to anti-arrhythmic therapies. Thoracic epidural anesthesia has been reported to terminate fatal ventricular arrhythmia; however, its underlying mechanism is unknown. Methods: Rats were randomly divided into four groups: sham, sham plus bupivacaine, ischemia/reperfusion (IR), and IR plus bupivacaine groups. Bupivacaine (1 mg/mL, 0.05 mL/100 g body weight) was injected intrathecally into the L5–L6 intervertebral space prior to establishing a myocardial IR rat model. Thereafter, cardiac arrhythmia, cardiac function, myocardial injury, and electrical activities of the heart and spinal cord were evaluated. Results: Intrathecal bupivacaine inhibited spinal neural activity, improved heart rate variability, reduced ventricular arrhythmia score, and ameliorated cardiac dysfunction in IR rats. Furthermore, intrathecal bupivacaine attenuated cardiac injury and myocardial apoptosis and regulated cardiomyocyte autophagy and connexin-43 distribution during myocardial IR. Conclusion: Our results indicate that intrathecal bupivacaine blunts spinal neural activity to prevent cardiac arrhythmia and dysfunction induced by IR and that this anti-arrhythmic activity may be associated with regulation of autonomic balance, myocardial apoptosis and autophagy, and cardiac gap junction function.

Effect of electroacupuncture at Neiguan (PC6) at different time points on myocardial ischemia reperfusion arrhythmia in rats.

To observe the effects of electroacupuncture at Neiguan (PC6) at different time points on reperfusion arrhythmia (RA) after myocardial ischemia and reperfusion in rats, and to investigate the correlation of this protective effect with nerve growth factor (NGF), tyrosine kinase A (TrkA), tyrosine hydroxylase (TH), and norepinephrine (NE). METHODS：A total of 72 Sprague-Dawley male rats were randomly divided into six groups (n = 12 rats/group): normal group (Norm), sham operation group (Sham), ischemia reperfusion group (I/R), pre-ischemic electroacupuncture group (EAI), pre-reperfusion electroacupuncture group (EAII), post-reperfusion electroacupuncture group (EAIII). The myocardial ischemia-reperfusion injury (MIRI) model was induced by occlusion of left anterior descending coronary artery for 20 min followed by reperfusion for 40 min in rats. With no intervention in the Norm group and only threading without ligation in the Sham group. Electroacupuncture pre-treatment at 20 min/d for 7 d before ligation in the EAⅠ group, 20 min of electroacupuncture before reperfusion in the EAII group and 20 min of electroacupuncture after reperfusion in the EAIII group. The electrocardiogram (ECG) of each group was recorded throughout the whole process, and the success of the MIRI model was determined based on the changs of J-point and T-wave in the ECG. The arrhythmia score was used to record premature ventricular contractions, ventricular tachycardia and ventricular fibrillation during the reperfusion period to assess the reperfusion induced arrhythmias. The expression levels of NGF, TrkA, TH protein were measured by Western blot. Moreover, the expression levels of plasma and myocardial NE levels were detected by enzyme linked immunosorbent assay. The differences between Norm group and Sham group were not statistically significant in all indexes. Arrhythmia score, myocardial NGF, TrkA, TH, and NE expression were significantly higher in the I/R group compared with the Sham group. Arrhythmia score, myocardial NGF, TrkA, TH, and NE expression were significantly lower in each EA group compared with the I/R group. Electroacupuncture at Neiguan (PC6) at different time points can reduce the incidence and severity of reperfusion arrhythmias in rats. This protective effect is related to electroacupuncture regulating NGF, TrkA, TH, NE expression and reducing sympathetic hyperactivation.

Electrophysiological Characteristics and Ablation Outcomes in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia.

Catheter ablation of premature ventricular contractions (PVCs) that trigger polymorphic ventricular tachycardia (PVT) or ventricular fibrillation has been reported as a novel therapy to reduce the syncope events in patients with catecholaminergic PVT, whereas the long-term ablation outcome and its value in improving exercise-induced ventricular arrhythmias remain unclear. Fourteen consecutive selected patients with catecholaminergic PVT (mean±SD age, 16±6 years; 43% male patients) treated with maximum β-blockers with no possibility of adding flecainide were prospectively enrolled for catheter ablation. The primary end point was syncope recurrence, and the secondary end point was the reduction of the ventricular arrhythmia score during exercise testing. Twenty-six PVT/ventricular fibrillation-triggering PVCs were identified for ablation. The trigger beats arose from the left ventricle in 50% of the cases and from both ventricles in 36% of the cases. Purkinje potentials were observed at 27% of the targets. After a mean follow-up of 49 months after ablation, 8 (57%) patients were free from syncope recurrence. Ablation of trigger beat significantly reduced the syncope frequency (mean±SD, 4.3±1.6 to 0.5±0.8 events per year; P<0.001) and improved the ventricular arrhythmia scores at the 3-month (5 [range, 3-6] to 1.5 [range, 0-5]; P=0.002) and 12-month (5 [range, 3-6] to 2 [range, 0-5]; P=0.014) follow-ups. The induction of nontriggering PVCs postablation was closely associated with syncope recurrence (hazard ratio, 6.8 [95% CI, 1.3-35.5]; P=0.026). Catheter ablation of PVT/ventricular fibrillation-triggering PVCs in patients with catecholaminergic PVT who cannot receive flecainide treatment seems to be a safe and feasible adjunctive treatment that may reduce the syncope burden and improve exercise-related ventricular arrhythmias. Induction of nontriggering PVCs after ablation is associated with a higher risk of syncope recurrence.

External validation of survival predicting score in repaired tetralogy of Fallot: an opportunity to improve

Abstract Introduction In recent years, integrating both better diagnosis and treatment allowed most adults with repaired tetralogy of Fallot (rTOF) to expect a longer life expectancy. However, a minority is at higher risk for premature cardiovascular death. Recently, 2 scores identified the subgroup of rTOF patients (pts) who are at high annual risk of death and ventricular arrhytmias (VA). We aimed to implement both in our population. Methods Retrospective single center review was done on rTOF pts who undergone cardiovascular magnetic resonance with gadolinium, blood sampling for B-type natriuretic peptide (BNP), echocardiography and cardiopulmonary exercise testing. The risk scores were calculated with weighted independent predictors, namely presence of late gadolinium enhancement in left ventricle (LV) and right ventricle (RV), akinetic RV outflow length, LV and RV ejection fraction (EF), RV systolic pressure, peak oxygen uptake (pVO2), BNP, atrial arrythmias and age. Low mortality risk was defined as 0-20 points, intermediate as 21-50 and high ≥51. In terms of VA prediction, low risk was defined as 0-20 points, intermediate as 21-39 and high as ≥51. Results From a total of 240 rTOF pts, 61 (56% male, mean age 34±9 years) had all the necessary data. RV dysfunction was present in 52.5%, RV systolic pressure was high in 12 and LVEF≤35% in 18% pts. BNP level was elevated in 27 and pVO2≤17mL/kg/m2 in 14.8% pts. The mean mortality risk score was 15.1±11.2, being that 68.9% had a lower and 31.1% an intermediate risk. Regarding VA score, the mean was 14.7±10.8, where the majority (80.3%) were in lower risk. 29.5% had a sustain atrial arrhythmia (mainly atrial fibrillation) and 14.8% a VA. There were 3 cardiac related deaths (4.9%). Analysis of time to event data showed that mortality and VA scores were not predictors of overall mortality (M) or VA events, respectively. However, considering 1-year M, LVEF≤35% (p= 0.002), RVEF≤35% (p=0.002), pVO2≤17mL/kg/m2 (p&amp;lt;0.001), and both scores: M (p=0.013) and VA (p&amp;lt;0.001) were predictors of that endpoint. In multivariate analysis, VA risk score (p=0.035) and low pVO2 (p= 0.006) were independent 1-year M predictors. Conclusion In our population, ventricular arrhythmia score and low peak oxygen uptake were independent predictors of 1-year mortality. However, there is probably a selection bias. Since the scores were recently proposed, patients were not recruited prospectively, many ended up not having all the needed or recent data, thus were not included. There is the need to validate and improve available scores to truly assess the risk of mortality and arrhythmias, as well as defined protocols and longer follow-up for this purpose.

Thoracic Dorsal Root Ganglion Application of Resiniferatoxin Reduces Myocardial Ischemia-Induced Ventricular Arrhythmias.

A myocardial ischemia/reperfusion (IR) injury activates the transient receptor potential vanilloid 1 (TRPV1) dorsal root ganglion (DRG) neurons. The activation of TRPV1 DRG neurons triggers the spinal dorsal horn and the sympathetic preganglionic neurons in the spinal intermediolateral column, which results in sympathoexcitation. In this study, we hypothesize that the selective epidural administration of resiniferatoxin (RTX) to DRGs may provide cardioprotection against ventricular arrhythmias by inhibiting afferent neurotransmission during IR injury. Yorkshire pigs (n = 21) were assigned to either the sham, IR, or IR + RTX group. A laminectomy and sternotomy were performed on the anesthetized animals to expose the left T2-T4 spinal dorsal root and the heart for IR intervention, respectively. RTX (50 μg) was administered to the DRGs in the IR + RTX group. The activation recovery interval (ARI) was measured as a surrogate for the action potential duration (APD). Arrhythmia risk was investigated by assessing the dispersion of repolarization (DOR), a marker of arrhythmogenicity, and measuring the arrhythmia score and the number of non-sustained ventricular tachycardias (VTs). TRPV1 and calcitonin gene-related peptide (CGRP) expressions in DRGs and CGRP expression in the spinal cord were assessed using immunohistochemistry. The RTX mitigated IR-induced ARI shortening (-105 ms ± 13 ms in IR vs. -65 ms ± 11 ms in IR + RTX, p = 0.028) and DOR augmentation (7093 ms2 ± 701 ms2 in IR vs. 3788 ms2 ± 1161 ms2 in IR + RTX, p = 0.020). The arrhythmia score and VT episodes during an IR were decreased by RTX (arrhythmia score: 8.01 ± 1.44 in IR vs. 3.70 ± 0.81 in IR + RTX, p = 0.037. number of VT episodes: 12.00 ± 3.29 in IR vs. 0.57 ± 0.3 in IR + RTX, p = 0.002). The CGRP expression in the DRGs and spinal cord was decreased by RTX (DRGs: 6.8% ± 1.3% in IR vs. 0.6% ± 0.2% in IR + RTX, p < 0.001. Spinal cord: 12.0% ± 2.6% in IR vs. 4.5% ± 0.8% in IR + RTX, p = 0.047). The administration of RTX locally to thoracic DRGs reduces ventricular arrhythmia in a porcine model of IR, likely by inhibiting spinal afferent hyperactivity in the cardio-spinal sympathetic pathways.

Non-intubated versus intubated video-assisted thoracoscopic lobectomy for lung cancer patients

IntroductionVideo-assisted thoracoscopic surgery (VATS) lobectomy has been shown to be a standard treatment for lung cancer patient due to less pain, post-operative complication and faster recovery. In recent years, Non-intubated video-assisted thoracoscopic surgery (NIVATS) is become an alternative approach for various types of thoracic surgery with a benefit on fewer complication from mechanical ventilation. Out study is aimed to study outcome compare between NIVATS lobectomy and to general anesthetic video assisted thoracoscopic surgery (GAVATS) lobectomy. MethodsThis is a retrospective cohort study conduct in Vajira hospital, Navamindradhiraj University, Bangkok, Thailand between January 2019 to September 2022.152 lung cancer patients underwent lobectomy. However, lung cancer patients whom needed to convert to GAVATS, open thoracotomy or emergency surgery were excluded from this study. In this study, we compare lung patients whom underwent NIVATS lobectomy and those whom underwent GAVATS lobectomy. These two groups are compared in term of pre-, intra- and post-operative outcomes. The inverse-probability weighting propensity score is used to identify the treatment effects of NIVATS. ResultsIn total, there are 132 cases patients including in this analysis. There are 54 and 78 patients in the NIVATS and GAVATS respectively. Intra-operative outcome, induction and operative time are lower in the NIVATS lobectomy group (25 vs 30 min, p < 0.001 and 90 vs 120 min, p = 0.003). There is no difference regarding number of node resection, station of lymph node dissection, arrhythmia, postoperative complications, and pain visual analogue score (VAS) in both groups. Postoperative outcome, length of hospital stay is shorter in NIVATS lobectomy group (4 vs 5 days, p < 0.001). There is no patient which needed to convert from NIVATS to GAVATS. The treatment-effect analyzed by using inverse-probability weighting propensity score has shown benefits of NIVATS in terms of shorter hospital stays (coefficient −2.31, 95%CI -3.65 to −0.97, p = 0.001), and shorter chest tube duration (coefficient −1.59, 95%CI -2.93 to −0.26, p = 0.019). ConclusionNIVATS lobectomy could be an alternative approach for lung cancer patients with benefits of lesser in hospital stays and duration of chest tube.

Naringin improves post-ischemic myocardial injury by activation of KATP channels

Naringin (NRG) is a flavonoid with recognized cardioprotective effects. Then, it was investigated the cardioprotective mechanisms of NRG against ischemia-reperfusion (I/R) injury. The rats were pretreated for 7 days (v.o.) with NRG (25 mg/kg) or n-acetylcysteine (NAC, 100 mg/kg) and their isolated hearts were subjected to global ischemia (30 min) and reperfusion (60 min). Furthermore, isolated hearts were perfused with 5 μM NRG in the presence of 10 μM glibenclamide (GLI) and subjected to I/R protocol. In healthy ventricular cardiomyocyte, it was evaluated the acute effect of 5 μM NRG on the GLI sensitive current. The results showed that NRG pretreatment restored the cardiac function and electrocardiogram (ECG) alterations induced by I/R injury, decreasing arrhythmia scores and the occurrence of severe arrhythmias. Lactate dehydrogenase and infarct area were decreased while superoxide dismutase (SOD), catalase and citrate synthase activities increased. Expression of SOD CuZn and SOD Mn not was altered. NRG treatment decreased reactive oxygen species (ROS) generation and lipid peroxidation without alter sulfhydryl groups and protein carbonylation. Also, NRG (5 μM) increased the glibenclamide sensitive current in isolated cardiomyocytes. In isolated heart, the cardioprotection of NRG was significantly reduced by GLI. Furthermore, NRG promoted downregulation of Bax expression and Bax/Bcl-2. Histopathological analysis showed that NRG decreased cell edema, cardiomyocytes and nucleus diameter. Thus, NRG has a cardioprotective effect against cardiac I/R injury which is mediated by its antioxidant and antiapoptotic actions and KATP channels activation.

PO-03-157 ACTIVITY RESTRICTION IN PEDIATRIC CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA: DOES IT MATTER WHAT THE DOCTOR SAYS?

Catecholaminergic polymorphic Ventricular Tachycardia (CPVT) is a rare inherited arrhythmia disorder characterized by adrenergic-induced polymorphic ventricular tachycardia (VT). Physical activity (PA) restriction was once a mainstay of therapy. Although an individualized, shared decision approach to PA is recommended, the amount activity considered safe remains unknown. To describe 1) the association between PA levels and ventricular arrhythmia scores and 2) the PA levels in relation to Canadian PA guidelines and physician PA recommendations. Patients 8-18 years with CPVT were prospectively recruited from the International Pediatric CPVT Registry. PA levels were assessed via an Actigraph accelerometer (GT3X) worn for ≥ 10-hours a day for 7-days. Ventricular arrhythmia score was ascertained from treadmill tests (to volitional fatigue) by an established scale (1=no ectopy or premature ventricular complexes (PVCs), 2=bigeminy, 3=couplets, 4=non-sustained VT). The association between ventricular arrhythmia and PA metrics were controlled for medication doses. A total of 26 pediatric CPVT patients (median age 14 (IQR 11-17) years; 46% females) were included. Nine (35%) patients were on BB monotherapy, 15 (58%) BB and flecainide and 2 (8%) were on no medication. Of those on medication, 3 (12%) underwent left cardiac sympathetic denervation. Median ventricular arrhythmia score among all patients was 2 (IQR 1-2); 11 (42%) had no ectopy or isolated PVCs on treadmill. Moderate-to-vigorous PA (odds ratio: 0.98, 95% CI: 0.95-1.0, p=0.31) was not associated with ventricular arrhythmia scores after adjusting for medication. Median moderate-to-vigorous PA was 44 (IQR 29-59) min/day and only 5 (19%) patients met PA guidelines (≥60 min/day in healthy children). Adolescents were less active than younger children (rho=-0.44, p=0.03), and moderate-to-vigorous PA did not differ based on sex (p=0.18). Physician PA recommendation ranged from no restrictions in 14 (54%) to partial PA restrictions (no competitive, team sport and/or endurance PA) in 12 (46%) patients. Ventricular arrhythmia scores (Figure 1; p=0.42) and moderate-to-vigorous PA (p=0.41) did not differ based on physician PA restrictions. There was no association between amount of PA and clinical ventricular arrhythmia scores in this cohort of predominantly treated CPVT children. Only a fifth of patients met PA guidelines irrespective of physician recommendations, and a large proportion continue to be restricted from PA.

The Acute Effects Of ATP-Sensitive Potassium Channel Opener (Pinacidil) And Blocker (Glimepride) On the Ischemia or Reperfusion-Induced Arrhythmias

Introduction: Myocardial ischemia due to coronary obstruction and reperfusion due to the opening of the coronary vessel occurring in the acute stage of myocardial infarction leads to lethal arrhythmia and sudden death in humans. That is why pharmacological drug research to decrease these arrhythmias have been researched intensively. In this study, the effect of acute administration of pinacidil and glimepride, on ischemia or reperfusion-induced arrhythmia was aimed to be researched. Methods: Two groups were produced; In the first group, only ischemia was produced by the ligation of the left coronary artery in 20 minutes, and in the second group 6 minutes of ischemia by the ligation of the artery and the subsequent 15 minutes of reperfusion were produced by the opening of the occluded artery. Drugs were administered intravenously at 2 minutes of ischemia in the first group and just following the reperfusion in the second group. The ECG and blood pressure were recorded during ischemia and reperfusion. The type, duration, incidence of arrhythmia, heart rate, blood pressure, and the death rate from the recording were determined. All data were first compared by one-way ANOVA. Then, the drug groups with their control, and control and drug groups with each other were compared by a one-tailed student t-test. The incidence of arrhythmia and the death rate between groups was compared by the Ki square test. Results: Pinacidil significantly decreased the arrhythmia score both in the ischemia and reperfusion period but glimepiride was not effective when they were given intravenously in the acute stage of ischemia or reperfusion. Discussion and Conclusion: This study suggests that pinacidil might be a candidate for drugs that can be used to decrease arrhythmia in the acute stage of myocardial infarction but more study is needed to reveal the antiarrhythmic or proarrhythmic effect of glimepride in the acute stage of myocardial infarction.

Establishment of a new arrhythmia model in SD rats induced by isoproterenol

Background The main purpose of this study was to establish an ideal arrhythmia model using isoproterenol and explore its mechanism. Methods Fifty healthy male SD rats were randomly divided into the following groups: control (CON), subcutaneous injection (SC; 5 mg/kg ISO for 2 consecutive days), intraperitoneal injection (IP; ISO 5 mg/kg for 2 consecutive days), 2 + 1 (5 mg/kg ISO by SC for 2 consecutive days and then 3 mg/kg ISO by IP for 1 day), and 6 + 1 (5 mg/kg ISO by SC for 6 consecutive days and then 3 mg/kg ISO by IP for 1 day). Electrocardiograms (ECGs) were recorded using a BL-420F system, and the pathological changes in myocardial tissue were observed by HE and Masson staining. The serum cTnI, TNF-α, IL-6, and IL-1β levels were detected by ELISA, and serum CK, LDH and oxidative stress-related indicators were detected with an automatic biochemical analyser. Results The cardiomyocytes of the rats belonging to the CON group were normal, whereas those of the rats in the other groups, particularly the 6 + 1 group, showed signs of disorder, unclear borders, and lysis and necrosis. The incidence of arrhythmia, arrhythmia score, and levels of serum myocardial enzymes, troponin, and some inflammatory factors were higher in the 2 + 1 and 6 + 1 groups than in the single injection group (p < 0.01 or p < 0.05). The indicator levels found for the 6 + 1 group were generally higher than those found for the 2 + 1 group (p < 0.01), and the 6 + 1 group exhibited a lower SOD level and higher MDA and NO levels compared with the CON group (p < 0.01 or p < 0.05). Conclusion The combined mode of ISO injection (SC with IP) was more likely to induce arrhythmia than a single ISO injection. The “6 + 1” method of ISO injection can establish a more stable arrhythmia model and cardiomyocyte damage induced by oxidative stress and inflammation was an important mechanism.

PyHeart4Fish: Chamber-specific heart phenotype quantification of zebrafish in high-content screens.

Cardiovascular diseases (CVDs) are the leading cause of death. Of CVDs, congenital heart diseases are the most common congenital defects, with a prevalence of 1 in 100 live births. Despite the widespread knowledge that prenatal and postnatal drug exposure can lead to congenital abnormalities, the developmental toxicity of many FDA-approved drugs is rarely investigated. Therefore, to improve our understanding of drug side effects, we performed a high-content drug screen of 1,280 compounds using zebrafish as a model for cardiovascular analyses. Zebrafish are a well-established model for CVDs and developmental toxicity. However, flexible open-access tools to quantify cardiac phenotypes are lacking. Here, we provide pyHeart4Fish, a novel Python-based, platform-independent tool with a graphical user interface for automated quantification of cardiac chamber-specific parameters, such as heart rate (HR), contractility, arrhythmia score, and conduction score. In our study, about 10.5% of the tested drugs significantly affected HR at a concentration of 20µM in zebrafish embryos at 2days post-fertilization. Further, we provide insights into the effects of 13 compounds on the developing embryo, including the teratogenic effects of the steroid pregnenolone. In addition, analysis with pyHeart4Fish revealed multiple contractility defects induced by seven compounds. We also found implications for arrhythmias, such as atrioventricular block caused by chloropyramine HCl, as well as (R)-duloxetine HCl-induced atrial flutter. Taken together, our study presents a novel open-access tool for heart analysis and new data on potentially cardiotoxic compounds.

IKs Activator ML277 Mildly Affects Repolarization and Arrhythmic Outcome in the CAVB Dog Model

Long QT syndrome type 1 with affected IKs is associated with a high risk for developing Torsade de Pointes (TdP) arrhythmias and eventually sudden cardiac death. Therefore, it is of high interest to explore drugs that target IKs as antiarrhythmics. We examined the antiarrhythmic effect of IKs channel activator ML277 in the chronic atrioventricular block (CAVB) dog model. TdP arrhythmia sensitivity was tested in anesthetized mongrel dogs (n = 7) with CAVB in series: (1) induction experiment at 4 ± 2 weeks CAVB: TdP arrhythmias were induced with our standardized protocol using dofetilide (0.025 mg/kg), and (2) prevention experiment at 10 ± 2 weeks CAVB: the antiarrhythmic effect of ML277 (0.6-1.0 mg/kg) was tested by infusion for 5 min preceding dofetilide. ML277: (1) temporarily prevented repolarization prolongation induced by dofetilide (QTc: 538 ± 65 ms at induction vs. 393 ± 18 ms at prevention, p < 0.05), (2) delayed the occurrence of the first arrhythmic event upon dofetilide (from 129 ± 28 s to 180 ± 51 s, p < 0.05), and (3) decreased the arrhythmic outcome with a significant reduction in the number of TdP arrhythmias, TdP score, arrhythmia score and total arrhythmic events (from 669 ± 132 to 401 ± 228, p < 0.05). IKs channel activation by ML277 temporarily suppressed QT interval prolongation, delayed the occurrence of the first arrhythmic event and reduced the arrhythmic outcome in the CAVB dog model.

A comparative study between angiotensin receptor neprilysin inhibitor (thiorphan/irbesartan) with each of nitrate and carvedilol in a rat model of myocardial ischemic reperfusion injury.

The combined angiotensin receptor neprilysin inhibitor is a promising cardioprotective pharmacological agent. This study investigated the beneficial effects of thiorphan (TH)/irbesartan (IRB), in myocardial ischemia-reperfusion (IR) injury, compared to each of nitroglycerin and carvedilol. Male Wistar rats were divided into five groups (10 rats/group): Sham, untreated I/R, TH/IRB + IR (0.1/10mg/kg), nitroglycerin + IR (0.2mg/kg), and carvedilol + IR (10mg/kg). Mean arterial blood pressure, cardiac functions and arrhythmia incidence, duration and score were assessed. Cardiac levels of creatine kinase-MB (CK-MB), oxidative stress, endothelin-1, ATP, Na+ /K+ ATPase pump activity and mitochondria complexes activities were measured. Histopathological examination, Bcl/Bax immunohistochemistry studies and electron microscopy examination of left ventricle were performed. TH/IRB preserved the cardiac functions and mitochondrial complexes activities, mitigated cardiac damage, reduced oxidative stress and arrhythmia severity, improved the histopathological changes and decreased cardiac apoptosis. TH/IRB showed a comparable effect to each of nitroglycerin and carvedilol in alleviating the IR injury consequences. TH/IRB showed significant preservation of mitochondrial complexes activity I and II compared to nitroglycerin. TH/IRB significantly increased LVdP/dtmax and decreased oxidative stress, cardiac damage and endothelin-1 along with increasing the ATP content, Na+ /K+ ATPase pump activity and mitochondrial complexes activity when compared to carvedilol. TH/IRB showed a cardioprotective effect in reducing IR injury that is comparable to each of nitroglycerin and carvedilol that could be explained in part by its ability to preserve mitochondrial function, increase ATP, decrease oxidative stress as well as endothelin 1.

Dietary Canola Oil Modifies Myocardial Fatty Acids and Inhibits Cardiac Arrhythmias in Rats

Previous research showed that dietary fish oil was potently antiarrhythmic in rats but olive oil was not. This study was designed to test the hypothesis that canola oil, another major dietary source of oleic acid additionally containing the (n-3) polyunsaturated fatty acid α-linolenic acid [18:3(n-3)], can reduce vulnerability to cardiac arrhythmia in rats. Rats were randomly assigned to one of four experimental diet groups for 12 wk. The fat source in the diets was 12% olive (63% oleic acid), canola (55% oleic, 8% α-linolenic acid), soybean [50% linoleic 18:2(n-6), 7% α-linolenic acid] or sunflower seed oil (64% linoleic acid). Arrhythmias were induced by coronary artery occlusion and reperfusion. Incidence of ventricular fibrillation, mortality and arrhythmia score during reperfusion were significantly lower in rats fed the diet containing canola oil than in those fed the olive oil diet. No difference in the severity of arrhythmias was seen in groups fed diets containing soybean or sunflower seed oils. Analysis of myocardial phospholipid fatty acids showed that consumption of canola oil decreased the ratio of (n-6)/(n-3) polyunsaturated fatty acids relative to the other diets, as does dietary fish oil. These results suggest that regular substitution of canola oil for other dietary lipid sources may assist in reducing the likelihood of a transient ischemic event leading to life-threatening cardiac arrhythmias, but the effectiveness of α-linolenic acid is reduced by high levels of linoleic acid.