Fatal Arrhythmias Research Articles

QTNet: Deep Learning for Estimating QT Intervals Using a Single Lead ECG.

QT prolongation often leads to fatal arrhythmia and sudden cardiac death. Antiarrhythmic drugs can increase the risk of QT prolongation and therefore require strict post-administration monitoring and dosage control. Measurement of the QT interval from the 12-lead electrocardiogram (ECG) by a trained expert, in a clinical setting, is the accepted method for tracking QT prolongation. Recent advances in wearable ECG technology, however, raise the possibility of automated out-of-hospital QT tracking. Applications of Deep Learning (DL) - a subfield within Machine Learning - in ECG analysis holds the promise of automation for a variety of classification and regression tasks. In this work, we propose a residual neural network, QTNet, for the regression of QT intervals from a single lead (Lead-I) ECG. QTNet is trained in a supervised manner on a large ECG dataset from a U.S. hospital. We demonstrate the robustness and generalizability of QTNet on four test-sets; one from the same hospital, one from another U.S. hospital, and two public datasets. Over all four datasets, the mean absolute error (MAE) in the estimated QT interval ranges between 9ms and 15.8ms. Pearson correlation coefficients vary between 0.899 and 0.914. By contrast, QT interval estimation on these datasets with a standard method for automated ECG analysis (NeuroKit2) yields MAEs between 22.29ms and 90.79ms, and Pearson correlation coefficients 0.345 and 0.620. These results demonstrate the utility of QTNet across distinct datasets and patient populations, thereby highlighting the potential utility of DL models for ubiquitous QT tracking.Clinical Relevance- QTNet can be applied to inpatient or ambulatory Lead-I ECG signals to track QT intervals. The method facilitates ambulatory monitoring of patients at risk of QT prolongation.

Sudden cardiac death of a 16-year-old boy with Wolff-Parkinson-White syndrome and hypertrophic cardiomyopathy

AbstractIn Europe, 350,000 people die suddenly and unexpectedly every year. The majority of sudden deaths are caused by cardiac alterations and known as sudden cardiac death (SCD). The interpretation of medicolegal findings is especially difficult in those SCDs where there is no morphological correlate and no antemortem electrocardiograms or relevant medical history are available. The Wolff-Parkinson-White (WPW) syndrome, in which an accessory electrical conduction pathway exists between the atrium and the ventricle in addition to the physiological conduction system, is mostly a benign disease of the heart, which may lead to cardiac arrhythmia. A 16-year-old boy with a known history of WPW syndrome since the second year of life had consumed alcohol before death and was found sitting on the toilet fully dressed. The autopsy performed on the deceased 3 days postmortem showed a marked mass increase of the heart with left ventricular concentric hypertrophy and macroscopic signs of cardiomyopathy. In the microscopic examination, the right and left ventricles and the atria were found to have a regular structure with normal vessels. Hematoxylin-eosin (HE) and elastica-van-Gieson (EvG) staining disclosed a thin accessory muscle bridge connecting the left atrium with the left ventricle as a possible morphological correlate of a fatal cardiac arrhythmia.

Wearable defibrillator use in patients with high risk of sudden cardiac death: a brief report from a single center

Devices such as implantable cardioverter defibrillators (ICDs) and wearable cardioverter defibrillators (WCDs) have opened up new paths in the treatment of Sudden Cardiac Death. Guidelines advocate ICD placement for primary prevention after at least three months of optimal medical therapy following the first diagnosis of heart failure with reduced FE from any cause, and at least 40 days after an acute myocardial infarction with FE 35% notwithstanding medication. In these and other cases documented in the guidelines, the use of a wearable defibrillator (WCD), a noninvasive device that guards against malignant arrhythmias while waiting for arrhythmic risk to be defined and medication therapy to be optimized, may be considered. In our Cardiology/Utic Department, we treated 26 patients with a preliminary indication for ICD implantation: the use of the WCD allowed us to swiftly put them in clinical safety, avoiding potentially fatal arrhythmias while waiting for pharmacological therapy to be optimized. At the end of the periodic follow-up, FE had normalized in ten patients, allowing them to avoid ICD. Only 10 of the 26 participants with WCD had a proven indication for final implantation. There were no fatalities or problems in any of the patients.

Value of next-generation sequencing in inherited arrhythmia syndromes

BackgroundGenetic studies are clinically recommended in some cases of inherited arrhythmia syndromes. Next-generation sequencing (NGS) would be helpful because of its high analytical throughput and relative speed. This study aimed to assess the mutation-detection yield obtained by NGS compared with conventional Sanger sequencing method.MethodsPatients with aborted sudden cardiac death and their families who underwent gene sequencing tests for inherited arrhythmia syndromes were retrospectively and enrolled in this study from 2017 to 2022 at Chonnam National University Hospital. We evaluated NGS study results of 17 patients (NGS group) and Sanger study results of 19 patients (Sanger group).Results64.7% of NGS and 94.7% of Sanger group were probands. Type 1 Brugada pattern ECG was more frequent in NGS group (64.7% vs. 21.1%; p = 0.007). BrS was the most common disorder in NGS group (76.5%), and idiopathic ventricular fibrillation was the most common one in Sanger group (63.2%). Mutations with uncertain significance were the most common ones in NGS group (89.5%), and pathogenic or likely pathogenic mutations were the most common ones in Sanger group (45.7%). When positive yield was defined as the ratio of pathogenic or likely pathogenic mutations that were detected by sequencing, the yields were 10.5% and 45.7% in NGS and Sanger groups, respectively. The NGS arrhythmia panel did not cover two inherited arrhythmia-related mutations (RYR1, APOA5) that were detected by the Sanger method. The extended NGS arrhythmia panel was able to detect 84.8% of inherited arrhythmia-related mutations that were detected in Sanger group.ConclusionsNGS study has some limitations in obtaining the full genetic data of probands. Well-designed NGS panels are needed to increase the efficiency of the NGS study. With the well-designed panels, large-scale gene sequencing can efficiently and rapidly be applied in real clinical practices, especially in inherited fatal arrhythmia syndromes that have a high detection yield in genetic analyses.

Temporal change in repolarization parameters after surgical correction of valvular heart diseases.

Ventricular tachyarrhythmia is a potentially fatal outcome of cardiac surgery. Abrupt changes in the hemodynamics after surgical correction of valvular heart disease (VHD) can lead to alterations in ventricular repolarization. We compared the difference between temporal changes in repolarization parameters after correction of left-sided VHD. We retrospectively analyzed the electrograms of patients who underwent surgical correction of isolated VHD between 2006 and 2015 at Asan Medical Center, including mitral stenosis (MS), mitral regurgitation (MR), aortic stenosis (AS), and aortic regurgitation (AR). Ventricular repolarization parameters were measured at pre-specified time intervals after index surgery using a custom-made ECG analysis program. We compared repolarization parameters, including QT and corrected QT intervals, T peak-to-end interval, and corrected T peak-to-end interval. Analysis of 8265 ECGs from 2110 patients (266 MS, 1059 MR, 421 AS, and 364 AR) was performed. Patients with AS were characterized by older age and more comorbidities than other VHDs. The corrected QT interval showed a peak value immediately after surgery and decreased thereafter in the AS groups. However, a gradual increase over 1month after surgery in AR, MS, and MR groups was observed. The corrected T peak-to-end interval increased in the MS and MR groups and was unchanged in the AS and AR groups. The repolarization parameters of surgery changed dynamically after left-sided valvular surgery. Understanding differential temporal change of repolarization parameters according to the type of VHD would help clinicians avoid fatal arrhythmias related to the repolarization changes.

Anamorelin in Japanese patients with cancer cachexia: an update.

Anamorelin was approved for production and marketing in Japan on 22 January 2021 for cancer cachexia in non-small-cell lung cancer, gastric cancer, pancreatic cancer, and colorectal cancer. The authors describe the updates of anamorelin for cancer cachexia in Japan. Recent evidence showed that anamorelin improved lean body mass, body weight, and appetite in patients with cancer cachexia in clinical practice. Anamorelin does not increase body weight in the severe-weight-loss group in cachectic patients with pancreatic cancer. Several case reports showed that anamorelin can cause cardiac adverse drug reactions. Among the cardiac adverse reactions, fatal arrhythmias should be monitored carefully even if it is the first dose. Anamorelin combined with nutrition, physical activity, and exercise may be more useful than anamorelin alone for treating cancer cachexia. An interim analysis from post-marketing all-case surveillance was performed; however, details have not yet been published. When anamorelin cannot be used for cancer cachexia, Kampo medicines can be considered as an option. Anamorelin has changed the clinical practice of cancer cachexia in Japan. The authors hope that anamorelin is available for other disease-related cachexia along with appropriate multidisciplinary interventions.

144-OR: Norepinephrine Mediates Severe Hypoglycemia–Induced Fatal Heart Block in Rats

Severe hypoglycemia can lead to fatal cardiac arrhythmias, specifically 3rd degree heart block. During hypoglycemia, the brain senses low glucose and activates the sympathetic nervous system leading to epinephrine and norepinephrine secretion. It is hypothesized that norepinephrine increases severe hypoglycemia induced fatal cardiac arrhythmias. To test this hypothesis, nondiabetic Sprague Dawley rats underwent hyperinsulinemic/severe hypoglycemic (10-15 mg/dl) clamps for 3 hours with continuous electrocardiogram recording. Rats were continuously infused with either 1) brain norepinephrine (ICV; n =15), 2) brain control (ICV aCSF; n = 11), 3) IV norepinephrine nerve terminal blocker (reserpine; n = 7), or 4) IV control (DMSO/saline; n = 6). Severe hypoglycemia induced mortality was increased to 40% with brain norepinephrine infusion compared to 27% in aCSF. Similarly, heart block was increased to 40% with brain norepinephrine infusion compared to 25% in aCSF (p < 0.05). Blockade of norepinephrine completely prevented mortality and heart block during severe hypoglycemia compared to 17% and 25% (p < 0.05), respectively, in controls. In summary, norepinephrine increases while blockade of norepinephrine prevents fatal heart block during severe hypoglycemia. Drugs that target norepinephrine action may have therapeutic potential in people with diabetes at risk for severe hypoglycemia. Disclosure E.H. Nuibe: None. M. Chambers: None. C.M. Reno-Bernstein: None. Funding National Institutes of Health (1R56HL160835-01); University of Utah

Diagnostic and prognostic value of right ventricle uptake at 99m-PYP scintigraphy in patients with ATTR cardiac amyloidosis

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Pfizer. Introduction Bone-seeking tracers scintigraphy has assumed a central role in the diagnosis of Amyloid Transthyretin Cardiac Amyloidosis (ATTR-CA) since it is currently the only non-invasive imaging method capable of accurately diagnosing ATTR-CA. It is well known that right ventricle (RV) involvement is associated with poor clinical prognosis in patients with heart failure. Non-invasive imaging methods such as echocardiography and cardiac magnetic resonance have shown that RV involvement is common and related to poor outcomes. However, there is a paucity of data regarding scintigraphy in such a particular group of ATTR - CA patients. Purpose The present study was primarily designed to evaluate the diagnostic and incremental prognostic value of RV uptake of technetium-99m (99mTc) pyrophosphate (PYP) scintigraphy in ATTR-CA patients. Methods This is a prospective, observational, longitudinal study to evaluate clinical, laboratory and data obtained from non-invasive imaging methods for a period of 24 months. Only patients with a diagnosis of ATTR-CA suggested by scintigraphy and after ruling out monoclonal gammopathies were selected. Patients underwent 99mTc-PYP-scintigraphy and myocardial uptake was confirmed on planar images and SPECT/CT according to Perugini visual score. The primary outcome was a composite of cardiovascular death due to worsening of heart failure or fatal arrhythmia, atrial fibrillation and stroke. Results Ten subjects were included from August 2020 to October 2022. Median age of 72 years, all male and 5 (50%) African American. 8 (80%) patients had hereditary ATTR-CA and 2 (20%) ATTR-CA wild type. 5 (50%) had mild renal dysfunction and NYHA Class II or III was observed in 90% of the patients. Median levels of NT-pro-BNP and troponin were 1688,77 pg/ml (100–4545) and 0,084 ng/ml (0,064–0,123), respectively. Median Left Ventricle Ejection Fraction was 39,5 ± 7,86 (Simpson's) and median interventricular septum thickness was 16,1 ± 2,56 mm. Regarding scintigraphy results bi-ventricular (BIV) uptake was observed in 7 patients (70%). All patients had a grade 3 of Perugini score on left ventricle (LV) and the most common pattern of uptake was homogeneous and diffuse (70%). In patients with BIV the grade of Perugini score observed in RV was 57% (grade 3), 29% (grade 2) and 14% (grade 1) and the most common pattern of uptake was also homogeneous and diffuse (57%). Apex and mid-apex uptake was observed in 14% and 29% of patients, respectively. Three patients died during follow-up due to worsening of heart failure and cardiogenic shock: two in the group with BIV uptake and one in the group without right ventricle uptake at 99m-Tc-PYP scintigraphy. No statically significant difference was observed in the survival curve during follow up. Conclusions The prevalence of bi-ventriclular uptake on 99m-Tc-PYP- scintigraphy was high but was not related to a poor outcome of patients with ATTR-CA in our study.

Anesthesia in patients with Brugada syndrome: two case reports

BackgroundBrugada syndrome is a rare disease. It causes sudden cardiac arrest, which is a serious life-threatening event. Sudden cardiac death mostly results from coronary artery disease. However, patients with Brugada syndrome show normal cardiac anatomy and no evidence of ischemia or electrolyte imbalance. Anesthesia in patients with Brugada syndrome is challenging due to its unpredictable nature, and is worth our attention.Case presentationWe report two cases of Brugada syndrome during anesthesia. In case one, a 31-year-old Filipino laborer was scheduled for laparoscopic appendectomy. The patient denied any preexisting cardiac disease. The preoperative vital signs were stable, with mild fever of 37.9 °C. The operation was smooth. During the emergence period, the patient suffered from sudden onset of ventricular tachycardia. After resuscitation, the cardiac rhythm returned to normal. Later, he was confirmed to have a genetic trait of Brugada syndrome. In case two, a young Taiwanese patient with pre-diagnosed Brugada syndrome underwent an operation. The perioperative precautions were taken to prevent the occurrence of ventricular arrhythmia. The surgery was uneventful.ConclusionsBrugada syndrome, although rare, has the highest incidence in South East Asian healthy young males. It brings attention to possible fatal cardiac arrhythmia in this population. Careful preoperative evaluation and perioperative management can help reduce the harmful outcome of the disease and prevent any untoward events.

Aconite Toxicity Presenting as Electrical Storm: A Diagnostic and Therapeutic Challenge

Aconite is a plant with deceptively beautiful flowers that contain a deadly cardiotoxin. Aconite toxicity presents with often fatal ventricular arrhythmias that are refractory to conventional antiarrhythmic medications. An electrical storm (ES) is an acute cardiac emergency that carries a high mortality. We report one such case of acute aconite toxicity presenting with ES that was managed successfully with hemodynamic support, overdrive pacing, and charcoal hemoperfusion with high-flux ultrafiltration.

Serial electrocardiogram recordings revealed a high prevalence of QT interval prolongation in patients with tuberculosis receiving fluoroquinolones

Fluoroquinolones, crucial components of treatment regimens for drug-resistant tuberculosis (TB), are associated with QT interval prolongation and risks of fatal cardiac arrhythmias. However, few studies have explored dynamic changes in the QT interval in patients receiving QT-prolonging agents. This prospective cohort study recruited hospitalized patients with TB who received fluoroquinolones. The study investigated the variability of the QT interval by using serial electrocardiograms (ECGs) recorded four times daily. This study analyzed the accuracy of intermittent and single-lead ECG monitoring in detecting QT interval prolongation. This study included 32 patients. The mean age was 68.6±13.2 years. The results revealed mild-to-moderate and severe QT interval prolongation in 13 (41%) and 5 (16%) patients, respectively. The incremental yields in sensitivity of one to four daily ECG recordings were 61.0%, 26.1%, 5.6%, and 7.3% in detecting mild-to-moderate QT interval prolongation, and 66.7%, 20.0%, 6.7%, and 6.7% in detecting severe QT interval prolongation. The sensitivity levels of lead II and V5 ECGs in detecting mild-to-moderate and severe QT interval prolongation exceeded 80%, and their specificity levels exceeded 95%. This study revealed a high prevalence of QT interval prolongation in older patients with TB who receive fluoroquinolones, particularly those with multiple cardiovascular risk factors. Sparsely intermittent ECG monitoring, the prevailing strategy in active drug safety monitoring programs, is inadequate owing to multifactorial and circadian QT interval variability. Additional studies performing serial ECG monitoring are warranted to enhance the understanding of dynamic QT interval changes in patients receiving QT-prolonging anti-TB agents.

Empagliflozin reduces arrhythmogenic effects in rat neonatal and human iPSC-derived cardiomyocytes and improves cytosolic calcium handling at least partially independent of NHE1

The antidiabetic agent class of sodium-glucose cotransporter 2 (SGLT2) inhibitors confer unprecedented cardiovascular benefits beyond glycemic control, including reducing the risk of fatal ventricular arrhythmias. However, the impact of SGLT2 inhibitors on the electrophysiological properties of cardiomyocytes exposed to stimuli other than hyperglycemia remains elusive. This investigation tested the hypothesis that the SGLT2 inhibitor empagliflozin (EMPA) affects cardiomyocyte electrical activity under hypoxic conditions. Rat neonatal and human induced pluripotent stem cell (iPSC)-derived cardiomyocytes incubated or not with the hypoxia-mimetic agent CoCl2 were treated with EMPA (1 μM) or vehicle for 24 h. Action potential records obtained using intracellular microelectrodes demonstrated that EMPA reduced the action potential duration at 30%, 50%, and 90% repolarization and arrhythmogenic events in rat and human cardiomyocytes under normoxia and hypoxia. Analysis of Ca2+ transients using Fura-2-AM and contractility kinetics showed that EMPA increased Ca2+ transient amplitude and decreased the half-time to recover Ca2+ transients and relaxation time in rat neonatal cardiomyocytes. We also observed that the combination of EMPA with the Na+/H+ exchanger isoform 1 (NHE1) inhibitor cariporide (10 µM) exerted a more pronounced effect on Ca2+ transients and contractility than either EMPA or cariporide alone. Besides, EMPA, but not cariporide, increased phospholamban phosphorylation at serine 16. Collectively, our data reveal that EMPA reduces arrhythmogenic events, decreases the action potential duration in rat neonatal and human cardiomyocytes under normoxic or hypoxic conditions, and improves cytosolic calcium handling at least partially independent of NHE1. Moreover, we provided further evidence that SGLT2 inhibitor-mediated cardioprotection may be partly attributed to its cardiomyocyte electrophysiological effects.

Advanced imaging in an adult dog with anomalous origin of the left coronary artery from the pulmonary artery and extensive collateral coronary circulation

A three-year-old, spayed female, Bichon Frise was diagnosed with an anomalous origin of the left coronary artery from the pulmonary artery, a rare congenital coronary artery defect which has only been reported in two other dogs. Echocardiography was initially performed, though the final diagnosis was made with angiography and computed tomography angiography. An extensive network of collateral coronary circulation allowed for communication between the dilated, tortuous right coronary artery, and the anomalous left coronary artery. Though collateral circulation likely prolonged the patient's life, it is suspected that coronary steal phenomenon and chronic myocardial ischemia ultimately led to fatal ventricular arrhythmias. The dog died suddenly at the age of six, three years after initial diagnosis.

Temporal changes of QT dispersion in patients with acute ischemic stroke

Aim: Ischemic stroke is a significant cause of morbidity and mortality and can lead to fatal arrhythmias even in the absence of underlying cardiac pathology. The objective of this study was to investigate the impact of acute ischemic stroke on QT dispersion and its temporal changes over time. Methods: A total of 124 patients with acute ischemic stroke who did not receive any reperfusion treatment were included in the study. Corrected QT dispersion (QTcd) values were obtained from 12-lead surface electrocardiograms taken within the first 12 hours and after 48 hours of stroke onset. These values were compared with those of 93 age and sex-matched control subjects. The effects of diabetes and lesion lateralization on QT dispersion were also analyzed. Stroke patients whose lesions were clearly localized to either the right or left hemisphere were divided into two subgroups. The change in QT dispersion overtime during the follow-up period was also determined. Results: The study included 124 patients with acute ischemic stroke (54 females and 70 males) with a mean age of 67±11 years, as well as a control group of 93 subjects (49 females and 44 males) with a mean age of 69±8 years. The QTcd values of the stroke group were significantly longer than the control group in the first 12 hours of symptom onset. However, after 48 hours, the QTcd values of the stroke group decreased and the difference between the two groups was not statistically significant. The presence of diabetes mellitus caused a more significant increase in QT dispersion, and after 48 hours, the QTcd values of diabetic stroke patients were still significantly longer. The QTcd values of patients with left hemispheric lesions were significantly longer than those of patients with right hemispheric lesions, and this difference persisted after 48 hours. Conclusion: This study found that QT dispersion increases during the first few hours of ischemic stroke and decreases during the treatment period. This increase is more obvious and lasts longer in stroke patients with diabetes and left hemispheric lesions. The results suggest that QT dispersion may be a useful prognostic indicator for patients with acute ischemic stroke.

P264 THE RELATIONSHIP BETWEEN MEAN DAILY HEART RATE AND THE INCIDENCE OF CARDIAC ARRHYTHMIAS IN PATIENTS WITH WEARABLE CARDIAC DEFIBRILLATOR

Abstract Background The wearable defibrillator (WCD) is a useful device to prevent sudden cardiac death (SCD) due to fatal arrhythmias in patients in which an implantable cardioverter defibrillator (ICD) is not currently indicated. Measurement of mean daily heart rate and related variability (HRV) has proved to be useful in identifying patients at increased arrhythmic risk of SCD and in patients with chronic heart failure (CHF), although the specificity and predictive accuracy of fatal arrhythmic events is still relatively limited. We analyzed the mean HR of patients with WCD to determine their impact on the incidence of fatal and non–fatal arrhythmic events. Methods We enrolled 7 patients with WCD and optimal medical therapy by monitoring daily HR and variability over a 30– 90 day follow–up. Monitoring was performed remotely, analyzing both trends acquired by the devices, daily ECG recordings, and telephone surveillance. Results Men constituted 71.4% of the population, with a mean age of 69.1±10.3 yrs, and an ejection fraction of 30.7%±8.7. The devices were worn for 36±24 days, with a daily adherence of 23.8±0.23 hrs. The trend in mean HR showed a progressive, although non–significant reduction (77.5±10.2 bpm vs 66.5±11.9 bpm p=0.08). No fatal arrhythmic events were recorded during monitoring. Two non–fatal arrhythmic events were recorded from patient discharge. Conclusions Mean daily HR is a predictor of cardiac death, independent of other risk factors in patients with cardiovascular disease. Although the small sample size doesn‘t provide a convincing correlation, it is conceivable that reducing mean HR may contribute to a decrease in fatal cardiac arrhythmias. Further studies are needed to confirm these insights.

P324 LEFT VENTRICULAR ISOLATED CARDIOMYOPATHY OR DILATED CARDIOMYOPATHY: THE ROLE OF GENETIC ANALYSIS

Abstract Introduction arrhytmogenic cardiomyopathy (ACM) is a genetic heart muscle disease caracterized by substitution of the ventricular myocardium with fibrofatty tissue. The disease was originally termed “arrhytmogenic right ventricular (dysplasia)/cardiomyopathy” to define a condition which distinctively affected the right ventricle and predisposed to fatal ventricular arrhythmias. New insights led to comprehending that the left ventricle is also frequently affected. Clinical case 62 yo, male, no cardiovascular risk factors, positive history for frequent ventricular premature beats treated with Sotalol 40 mg twice a day. No other previous cardiological events. Accesses the ER with suddenly occured dyspnea for minimal exertion, without palpitation, chest discomfort or loss of consciousness. EKG: synus rhythm, low voltages, negative V4–V6 T waves, fragmented QRS. Blood testing: TnI 0,532 ng/ml (n.v. 0–0.034) NTproBNP 3840. Echocardiography: dilated left ventricle. 20% EF due to infero–lateral wall akynesia. Coronary angiography was performed and showed no coronary stenosis. Considered the frequent NSVTs showed by the telemetry, he was admitted to ICU and treated with Amiodarone, Atenolol 100 mg, Sacubistril/Valsartan 24/26 mg, diuretic therapy showing good control of major arrhytmic events. To evaluate characterize heart tissue, a magnetic resonance was performed, which showed: scalloping of the mid and apical left ventricular lateral wall, with fibrofatty substitution. Subepicardial, mid–wall and transmural LGE of the LV anterior, lateral and inferior walls. No RV abnormalities. Considered the reduced EF and the presence of arrhytmic substratum, an ICD was implanted. Finally, a genetic evaluation was discussed with the patient, but was declined. Discussion in patients presenting with typical LV abnormalities, without RV involvement, the phenotipic Padua criterias are not enough for a certain diagnosis. This is because of the phenotipic overlap between ACM and other diseases, such as dilated cardiomyopathy, myocarditis and cardiac sarcoidosis. In the presence of LV involvement, consistent with ACM, the evidence of a pathogenetic mutation is key for the diagnosis.

P259 S–ICD OFFERS A POTENTIAL SYNERGISTIC THERAPY FOR HEART FAILURE PATIENTS WITH AN INDICATION FOR ICD IMPLANTATION AND CANDIDATES FOR CCM IMPLANTATION

Abstract CCM (cardiac contractility modulation) is a very promising therapy in heart failure patients as it allows, by increasing intracellular calcium handling, an improvement in cardiac contractility, ejection fraction, and patient quality of life. It delivers high–energy (7.5 V) and long–duration (about 20 milliseconds) pulses in absolute refractory period through the use of two leads on the right ventricular septum. It is indicated in patients with narrow QRS (< 130 msec) and ejection fraction between 25 and 45%. Therefore, a large proportion of patients suitable for CCM therapy also have an indication for ICD implantation. The coexistence of an ICD (single–chamber or dual–chamber) and CCM presupposes the presence of 3 leads in the right ventricle and possibly a catheter in the right atrium if a dual–chamber ICD is used. The presence of numerous leads increases the risk of infection, mechanical complications, and damage on the leads. In view of the above, the strategy we propose in patients with concomitant indication for ICD and CCM is the use of the subcutaneous defibrillator (S–ICD) in patients with potential indication for CCM, narrow QRS, no pacing indication, and ejection fraction <35%, thus limiting the number of leads and the risk of complications. In our center, we have started using this strategy with excellent clinical results and in the absence of complications. One of the cases treated with this strategy is a 60–year–old patient with nonischemic dilated myocardiopathy, ejection fraction 34%, QRS < 130 msec, NYHA class III, despite therapy with beta blockers, ARNI, SGLT2–i, MRA at the maximum dose. The patient, also considering the potential future need for CCM implantation, underwent S–ICD implantation. After 3 months, NYHA class III with reduced quality of life persisted (MLHFQ 82). Therefore, the patient successfully underwent CCM implantation, with marked improvement in symptoms (MLHFQ 71) and ejection fraction (43%) 3 months later. This strategy avoided the placement of additional leads in the right ventricle while ensuring protection from potentially fatal arrhythmias and improvement in contractile function and symptoms. We suggest the use of the subcutaneous defibrillator (S–ICD) in all patients in whom there might be an indication for the use of CCM and no need for pacing, ensuring maximum efficacy and reducing the risk of infection and leads related complications.

Prediction of Kv11.1 potassium channel PAS-domain variants trafficking via machine learning

Congenital long QT syndrome (LQTS) is characterized by a prolonged QT-interval on an electrocardiogram (ECG). An abnormal prolongation in the QT-interval increases the risk for fatal arrhythmias. Genetic variants in several different cardiac ion channel genes, including KCNH2, are known to cause LQTS. Here, we evaluated whether structure-based molecular dynamics (MD) simulations and machine learning (ML) could improve the identification of missense variants in LQTS-linked genes. To do this, we investigated KCNH2 missense variants in the Kv11.1 channel protein shown to have wild type (WT) like or class II (trafficking-deficient) phenotypes in vitro. We focused on KCNH2 missense variants that disrupt normal Kv11.1 channel protein trafficking, as it is the most common phenotype for LQTS-associated variants. Specifically, we used computational techniques to correlate structural and dynamic changes in the Kv11.1 channel protein PAS domain (PASD) with Kv11.1 channel protein trafficking phenotypes. These simulations unveiled several molecular features, including the numbers of hydrating waters and hydrogen bonding pairs, as well as folding free energy scores, that are predictive of trafficking. We then used statistical and machine learning (ML) (Decision tree (DT), Random forest (RF), and Support vector machine (SVM)) techniques to classify variants using these simulation-derived features. Together with bioinformatics data, such as sequence conservation and folding energies, we were able to predict with reasonable accuracy (≈75%) which KCNH2 variants do not traffic normally. We conclude that structure-based simulations of KCNH2 variants localized to the Kv11.1 channel PASD led to an improvement in classification accuracy. Therefore, this approach should be considered to complement the classification of variant of unknown significance (VUS) in the Kv11.1 channel PASD.

Potential favorable action of sodium-glucose cotransporter-2 inhibitors on sudden cardiac death: a brief overview.

The primary pharmacological action of sodium-glucose co-transporter 2 (SGLT2) inhibitors is to inhibit the reabsorption of glucose and sodium ions from the proximal tubules of the kidney and to promote urinary glucose excretion. Notably, several clinical trials have recently demonstrated potent protective effects of SGLT2 inhibitors in patients with heart failure (HF) or chronic kidney disease (CKD), regardless of the presence or absence of diabetes. However, the impact of SGLT2 inhibitors on sudden cardiac death (SCD) or fatal ventricular arrhythmias (VAs), the pathophysiology of which is partly similar to that of HF and CKD, remains undetermined. The cardiorenal protective effects of SGLT2 inhibitors have been reported to include hemodynamic improvement, reverse remodeling of the failing heart, amelioration of sympathetic hyperactivity, correction of anemia and impaired iron metabolism, antioxidative effects, correction of serum electrolyte abnormalities, and antifibrotic effects, which may lead to prevent SCD and/or VAs. Recently, as possible direct cardiac effects of SGLT2 inhibitors, not only inhibition of Na+/H+ exchanger (NHE) activity, but also suppression of late Na+ current have been focused on. In addition to the indirect cardioprotective mechanisms of SGLT2 inhibitors, suppression of aberrantly increased late Na+ current may contribute to preventing SCD and/or VAs via restoration of the prolonged repolarization phase in the failing heart. This review summarizes the results of previous clinical trials of SGLT2 inhibitors for prevention of SCD, their impact on the indices of electrocardiogram, and the possible molecular mechanisms of their anti-arrhythmic effects.

Association of sotalol versus atenolol therapy with survival in dogs with severe subaortic stenosis

Introduction/objectivesDogs with severe subaortic stenosis (SAS) are at risk of dying suddenly from fatal arrhythmias. Survival is not improved when treated with pure beta-adrenergic receptor (β)-blockers; however, the effect of other antiarrhythmic drugs on survival is unknown. Sotalol is both a β-blocker and a class III antiarrhythmic drug; the combination of these differing mechanisms may provide benefit to dogs with severe SAS. The primary objective of this study was to compare survival in dogs with severe SAS that were treated with either sotalol or atenolol. The secondary objective was to evaluate the effect of pressure gradient (PG), age, breed, and aortic regurgitation on survival. AnimalsForty-three client-owned dogs. Materials and methodsRetrospective cohort study. Medical records of dogs diagnosed with severe SAS (PG ≥ 80 mmHg) between 2003 and 2020 were reviewed. ResultsNo statistical difference was identified in survival time between dogs treated with sotalol (n=14) and those treated with atenolol (n=29) when evaluating all-cause mortality (p=0.172) or cardiac-related mortality (p=0.157). Of the dogs that died suddenly, survival time was significantly shorter in dogs treated with sotalol compared to those treated with atenolol (p=0.046). Multivariable analysis showed that PG (p=0.002) and treatment with sotalol (p=0.050) negatively influenced survival in the dogs that died suddenly. ConclusionsSotalol did not have a significant effect on survival overall but may increase the risk of sudden death in dogs with severe SAS compared to atenolol.