Increase In QRS Duration Research Articles

Twelve-lead electrocardiography-based artificial intelligence predicts the upcoming future of patients with heart failure with mildly reduced ejection fraction

Abstract Background Heart failure with mildly reduced ejection fraction (HFmrEF) has emerged as the predominant subtype of heart failure (HF), but there is a paucity of data for identifying it using artificial intelligence (AI) based electrocardiogram (ECG). Purpose This study aimed to develop artificial intelligence (AI)-ECG to identify and predict the prognosis of patients with HFmrEF. Methods We collected 104,336 12-lead electrocardiography (ECG) datasets from April 2009 to December 2021 in a tertiary center. The AI-ECG encompasses a novel model that combines an automatic labelling preprocessing method with a transformer architecture incorporating a triplet loss for HFmrEF analysis. Results The receiver operating characteristic analyses revealed that the area under the curve of AI-ECG for identifying all types of HF were acceptable (0.87, 95% confidence interval [CI]: 0.86-0.89), but that for identifying those with HFmrEF was relatively lower (0.83, 95% CI: 0.78-0.86) than those with HF with reduced ejection fraction (HFrEF) (0.89, 95% CI: 0.85-0.82) and those with normal ejection fraction (EF) (0.87, 95% CI: 0.85-0.89). The analysis of ECG features showed significant increases in QRS duration (p=0.001), QT interval (p=0.045), and corrected QT interval (p=0.041) with increasing ‘Severity by Euclidean distance’. Following the predictability analysis with another group of 1,134 patients for improvements of follow-up EF in HFmrEF, the patients were grouped into three clusters based on the AI- Euclidean distance; Cluster 1 had the most severe cases and poorer outcomes than Clusters 2 (p<0.001) and 3 (p<0.001). Conclusion AI-ECG presents an innovative approach for the prognostic stratification of cardiac contractility in patients with HFmrEF. By using AI-ECG, patients with HFmrEF will be able to predict upcoming disease progression.

Multi-modal characterisation of early-stage, subclinical cardiac deterioration in patients with type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is a major risk factor for heart failure with preserved ejection fraction and cardiac arrhythmias. Precursors of these complications, such as diabetic cardiomyopathy, remain incompletely understood and underdiagnosed. Detection of early signs of cardiac deterioration in T2DM patients is critical for prevention. Our goal is to quantify T2DM-driven abnormalities in ECG and cardiac imaging biomarkers leading to cardiovascular disease. We quantified ECG and cardiac magnetic resonance imaging biomarkers in two matched cohorts of 1781 UK Biobank participants, with and without T2DM, and no diagnosed cardiovascular disease at the time of assessment. We performed a pair-matched cross-sectional study to compare cardiac biomarkers in both cohorts, and examined the association between T2DM and these biomarkers. We built multivariate multiple linear regression models sequentially adjusted for socio-demographic, lifestyle, and clinical covariates. Participants with T2DM had a higher resting heart rate (66 vs. 61 beats per minute, p < 0.001), longer QTc interval (424 vs. 420ms, p < 0.001), reduced T wave amplitude (0.33 vs. 0.37mV, p < 0.001), lower stroke volume (72 vs. 78ml, p < 0.001) and thicker left ventricular wall (6.1 vs. 5.9mm, p < 0.001) despite a decreased Sokolow-Lyon index (19.1 vs. 20.2mm, p < 0.001). T2DM was independently associated with higher heart rate (beta = 3.11, 95% CI = [2.11,4.10], p < 0.001), lower stroke volume (beta = -4.11, 95% CI = [-6.03, -2.19], p < 0.001) and higher left ventricular wall thickness (beta = 0.133, 95% CI = [0.081,0.186], p < 0.001). Trends were consistent in subgroups of different sex, age and body mass index. Fewer significant differences were observed in participants of non-white ethnic background. QRS duration and Sokolow-Lyon index showed a positive association with the development of cardiovascular disease in cohorts with and without T2DM, respectively. A higher left ventricular mass and wall thickness were associated with cardiovascular outcomes in both groups. T2DM prior to cardiovascular disease was linked with a higher heart rate, QTc prolongation, T wave amplitude reduction, as well as lower stroke volume and increased left ventricular wall thickness. Increased QRS duration and left ventricular wall thickness and mass were most strongly associated with future cardiovascular disease. Although subclinical, these changes may indicate the presence of autonomic dysfunction and diabetic cardiomyopathy.

Twelve-lead electrocardiography-based artificial intelligence predicts the upcoming future of patients with heart failure with mildly reduced ejection fraction

Abstract Background Heart failure with mildly reduced ejection fraction (HFmrEF) has emerged as the predominant subtype of heart failure (HF), but there is a paucity of data for identifying it using artificial intelligence (AI) based electrocardiogram (ECG). Purpose This study aimed to develop artificial intelligence (AI)-ECG to identify and predict the prognosis of patients with HFmrEF. Methods We collected 104,336 12-lead electrocardiography (ECG) datasets from April 2009 to December 2021 in a tertiary center. The AI-ECG encompasses a novel model that combines an automatic labelling preprocessing method with a transformer architecture incorporating a triplet loss for HFmrEF analysis. Results The receiver operating characteristic analyses revealed that the area under the curve of AI-ECG for identifying all types of HF were acceptable (0.87, 95% confidence interval [CI]: 0.86-0.89), but that for identifying those with HFmrEF was relatively lower (0.83, 95% CI: 0.78-0.86) than those with HF with reduced ejection fraction (HFrEF) (0.89, 95% CI: 0.85-0.82) and those with normal ejection fraction (EF) (0.87, 95% CI: 0.85-0.89). The analysis of ECG features showed significant increases in QRS duration (p=0.001), QT interval (p=0.045), and corrected QT interval (p=0.041) with increasing ‘Severity by Euclidean distance’. Following the predictability analysis with another group of 1,134 patients for improvements of follow-up EF in HFmrEF, the patients were grouped into three clusters based on the AI- Euclidean distance; Cluster 1 had the most severe cases and poorer outcomes than Clusters 2 (p&amp;lt;0.001) and 3 (p&amp;lt;0.001). Conclusion AI-ECG presents an innovative approach for the prognostic stratification of cardiac contractility in patients with HFmrEF. By using AI-ECG, patients with HFmrEF will be able to predict upcoming disease progression.

Protection by L-arginine against Epinephrine-induced Arrhythmia and Cardiotoxicity

Nitric oxide is important in control of coronary blood flow, cardiomyocyte contractility, cardiac rhythm, and thrombogenicity. We aimed to investigate the effect of the nitric oxide precursor L-arginine on cardiac arrhythmia and myocardial injury induced by epinephrine in male Sprague-Dawley rats. The possible modulation of L-arginine effects by methylene blue (MethyB), a nitric oxide synthase inhibitor was also examined. Cardiac arrhythmia was induced with 10μg/kg epinephrine given intravenously (i.v.). L-arginine (200mg/kg) or L-arginine and MethyB (100mg/kg) were intraperitoneally (i.p.) administered prior to i.v. epinephrine. Other groups received i.p. saline, only L-arginine or only MethyB (100mg/kg). Results showed that compared with the saline control, epinephrine caused a significant bradycardia (188.7±24.4 vs. 405.6±1.19beats/min), increased QRS duration (0.039±0.006 vs. 0.0185±0.0001s), decreased R wave amplitude (0.18±0.01 vs. 0.23±0.011mv), and ventricular extrasystoles. L-arginine alone showed no significant effect on heart rate (380.8±10.0 vs. 405.6±1.19beats/min) but increased QRS duration (0.029±0.0002 vs. 0.0185±0.0001s), and R wave amplitude (0.47±0.01 vs. 0.23±0.011mv). L-arginine given prior to epinephrine prevented bradycardia, shortened the duration of arrhythmia and decreased the number of extrasystoles. The administration of L-arginine and MethyB almost completely suppressed epinephrine-induced ventricular arrhythmias. Epinephrine caused severe degeneration of muscle fibres, widening of intercellular spaces, cellular infiltrations and interstitial haemorrhage. L-arginine markedly attenuated, while L-arginine/MethyB completely prevented these changes. It is concluded that L-arginine protects against cardiac arrhythmias and cardiac tissue damage caused by epinephrine.

The role of MAPRE2 and microtubules in Brugada syndrome pathogenesis

Abstract Background Brugada syndrome (BrS) is associated with loss-of-function variants in SCN5A (encoding NaV1.5), which are found in only ∼20% of patients. Recent genome-wide association studies identified a novel locus within an intron of MAPRE2 (encoding microtubule end-binding protein 2, EB2), implicating microtubule (MT) involvement in BrS. Purpose To understand the role of MAPRE2 and MT in BrS pathogenesis. Methods A mapre2 knock-out (KO) zebrafish model was generated using CRISPR/Cas9 and validated by western blot. Larval hearts at 5 day-post-fertilization (dpf) were isolated for voltage mapping and immunohistochemistry with confocal imaging. Morpholino targeting mapre2 or ttl (encoding tubulin tyrosine ligase) were injected into zebrafish embryos at the one-cell stage. A transgenic zebrafish line with cdh2 (encoding N-cadherin) tandem fluorescent timer (tFT) was used to study adherens junction. MT plus-end tracking experiments were performed in iPSC-derived cardiomyocytes (CM) with MAPRE2 knockdown (KD) using siRNA. ECG was recorded in adult fish. Results Voltage mapping of larval hearts (14 WTs vs. 19 KOs) showed a significant decrease in ventricular conduction velocity (17.4±1.5 vs. 13.4±0.8 mm/s; p&amp;lt;0.05) and action potential upstroke velocity (Vmax; 86.1±3.6 vs. 73.9±3.2 1/s; p&amp;lt;0.05), suggesting loss of cardiac NaV function. Correspondingly, ECG of adult fish (11 WTs vs. 10 KOs) showed a significant increase in QRS duration (27.8±0.5 vs. 32.3±0.7 ms; p&amp;lt;0.0001). Confocal imaging of KO hearts showed disorganized adherens junction based on N-cadherin staining. Similarly, morpholino KD of mapre2 in the cdh2 tFT line showed ∼40% mislocalization of mature N-cadherin relative to ZO-1 staining in larval ventricles (8 KDs vs 9 control hearts; p&amp;lt;0.05), suggesting disruption of adherens junction. In terms of MT, immunohistochemistry showed a 23% decrease of detyrosinated tubulin relative to total alpha tubulin in KO hearts (16 vs. 8 WT hearts; p&amp;lt;0.01). MAPRE2 KD in iPSC-CM (337 control vs. 285 KD MT in 4 sets of cells) showed an increase in MT velocity (7.9±0.2 vs. 8.8±0.2 µm/min; p&amp;lt;0.001), distance (5.8±0.2 vs. 7.1±0.2 µm; p&amp;lt;0.0001), and duration (46.2±1.4 vs. 52.2±1.6 s; p&amp;lt;0.001), suggesting changes to MT dynamics. Finally, morpholino KD of ttl in mapre2 KO embryos restored the fraction of detyrosinated tubulin (46% increase; 16 controls vs. 16 KDs; p&amp;lt;0.01) as well as Vmax (74.3±3.0 vs. 88.3±2.1 1/s; 13 controls vs. 9 KDs; p&amp;lt;0.01) to WT levels. Conclusion Genetic ablation of mapre2 led to a decrease in cardiac NaV function, a hallmark of BrS. This is associated with disruption of adherens junction, a decrease of detyrosinated tubulin as a marker of MT stability, and changes in MT dynamics. Restoration of detyrosinated tubulin fraction with ttl KD led to a rescue of NaV function in zebrafish larval hearts. Taken together, MAPRE2 loss-of-function may contribute to BrS pathogenesis by disruption of adherens junction via changes in MT dynamics.

Monitoring the electrophysiological effects of hydroquinidine non-invasively in patients with Brugada syndrome

Abstract Background Quinidine and it’s derivative hydroquinidine are the only drugs shown to reduce arrhythmic events in patients with Brugada syndrome (BrS). There is currently no standardised approach to monitoring the effect of pharmacotherapy in BrS to guide dosing and evaluate an individual’s response to therapy. Purpose To investigate if the electrophysiological effects of Hydroquinidine can be detected on non-invasive testing and identify parameters that may be used to study a non-invasive strategy for monitoring pharmacotherapy in BrS. Methods Patients with a diagnosis of BrS underwent multimodality non-invasive assessment with electrocardiogram (ECG), signal averaged ECG, 24 hour 12-lead Holter monitor and electrocardiographic imaging (ECGi – a method of non-invasive electroanatomical mapping), at baseline and "on treatment" with hydroquinidine (300mg BD) therapy. A medication survey was used to recorded adverse drug reactions and serum hydroquinidine levels were determined using liquid chromatography mass spectrometry. Results Twelve patients with BrS (11 male, mean age 47.6±10.9 years) with spontaneous type 1 BrS pattern or drug inducible type 1 BrS pattern and resuscitated cardiac arrest participated in the study. The mean Shanghai score was 4.6±1.4 and two patients had disease-causing SCN5A variants. During hydroquinidine therapy, there was a significant increase in QRS duration (110.7msec vs 117.8msec, p=0.004) and in mean activation time in the area of late activation in the right ventricular outflow tract (RVOT, 90.9ms to 97.7ms, p=0.020). In nine (75%) patients, the area of late activation (defined as &amp;gt;80ms after initial activation) in the RVOT also increased with hydroquinidine. Repolarisation parameters were also affected by hydroquinidine with an increase in QT interval corrected for heart rate (369.5msec vs 434.8msec, p&amp;lt;0.0001) and T-wave width (232.8msec to 271.2msec p=0.003) and a significant reduction in T-wave amplitude (0.4mV to 0.2mV p=0.001) on treatment. The reduction in T-wave amplitude precluded computation of repolarisation time in the RVOT by ECGi on treatment. No difference in the burden of type 1 BrS ECG pattern over 24 hours was seen on 12-lead Holter monitor between baseline and on treatment assessment. No significant difference in serum hydroquinidine level was detected between those who experienced side effects and those who did not (2.9µmol vs 3.1µmol, p=0.790). Conclusion Hydroquinidine affects both ventricular activation and repolarisation in patients with BrS and these effects can be detected non-invasively. Further work is required to determine clinical significance of these observed effects and investigate the feasibility of non-invasive monitoring strategy of pharmacotherapy in BrS.ECGi activation maps

The Effects of Nitric Oxide Synthase Inhibition on Epinephrine-Induced Arrhythmia and Myocardial Damage

We have recently reported that methylene blue (MethyB) was able to inhibit epinephrine-induced arrhythmias and cardiac muscle injury. In this study, we investigated the effect of nitric oxide synthase inhibition by NG-nitro-L-arginine methyl ester (L-NAME) on cardiac arrhythmias, and myocardial damage induced by epinephrine in rats. Whether nitric oxide inhibition would affect the antiarrhythmic and cardiac protective actions of MethyB was also examined. L-NAME (40 mg/kg), L-arginine (200 mg/kg) + L-NAME, or MethyB (100 mg/kg) + L-NAME were given intraperitoneally (i.p.). Cardiac arrhythmia was then induced with intravenous (i.v.) injection of 10 μg/kg epinephrine. Results showed that epinephrine injection caused marked bradycardia (221.0 ± 1.37 vs. 409.4 ± 3.18 beats/min), shortened QTc interval (0.096 ± 0.0093 vs. 0.177 ± 0.0008 s), increased QRS duration (0.040 ± 0.0035 vs. 0.0185 ± 0.0002 s), decreased R wave amplitude (0.176 ± 0.0051 vs. 0.21 ± 0.0009 mv), ST segment height (-0.026 ± 0.007 vs. -0.002 ± 0.0005 mv), and induced ventricular extrasystoles. L-NAME given to untreated control rats resulted in a decrease in heart rate (288.2 ± 0.88 vs. 409.4 ± 3.18 beats/min), and increased R wave amplitude (0.436 ± 0.004 vs. 0.21 ± 0.0009 mv) compared to controls. L-NAME did not cause extrasystoles in untreated control rats but significantly increased the number of extrasystoles and duration of arrhythmia in the epinephrine-treated group. The administration of L-arginine (200 mg/kg, i.p.) to epinephrine plus L-NAME-treated rats resulted in increased heart rate and markedly decreased the number of extrasystoles and duration of arrhythmia. Methylene blue given at 100 mg/kg to rats treated with epinephrine and L-NAME caused a marked increase in heart rate. It also normalized QRS duration, prevented ST segment depression, markedly suppressed ventricular extrasystoles, and decreased the duration of arrhythmia compared with either epinephrine or L-NAME plus epinephrine-treated groups. Epinephrine injection caused disorganization, and necrosis of cardiac cells, interstitial hemorrhage, and cellular infiltrations. These changes were markedly improved by treatment with either L-NAME or L-NAME/MethyB. These results suggest that (i) inhibiting nitric oxide synthase by L-NAME increases epinephrine-induced arrhythmia which is inhibited by L-arginine or MethyB; (ii) either L-NAME alone or in combination with MethyB prevented cardiac muscle injury induced by epinephrine; (iii) L-NAME did not prevent the cardiac protective and antiarrhythmic actions of MethyB.

Left ventricular lead implantation failure in an unselected nationwide cohort

Left ventricular (LV) lead implantation is often the most challenging aspect of cardiac resynchronization therapy (CRT) procedures; early studies reported implant failure rates in ∼10% of cases. The purpose of this study was to define rates, reasons for, and factors independently associated with LV lead implant failure. We studied patients with left bundle branch block and ejection fraction ≤ 35% who underwent planned de novo transvenous CRT implantation (2010-2016) and were reported to the National Cardiovascular Data Registry ICD Registry. Independent predictors of LV lead implant failure were determined using logistic regression; age, sex, and variables with a univariate P value of <.15 were considered for inclusion in the model. Of the 111,802 patients who underwent a planned CRT procedure, 3.6% of patients (n = 3979) had LV lead implant failure. Reasons for implant failure included venous access (7.5%), coronary sinus access (64.3%), tributary vein access (13.5%), coronary sinus dissection (7.6%), unacceptable threshold (4.4%), and diaphragmatic stimulation (1.7%). Significant independent predictors of LV lead implant failure included younger age (odds ratio [OR] 1.01; 95% confidence interval [CI] 0.1.01-1.02), female sex (OR 1.38; 95% CI 1.29-1.47), black race (vs white, OR 1.44; 95% CI 1.32-1.57), Hispanic ethnicity (OR 1.23; 95% CI 1.08-1.40), QRS duration (OR 1.055 per 10 ms; 95% CI 1.038-1.072 per 10 ms), obstructive sleep apnea (OR 1.14; 95% CI 1.04-1.24), and implant by a physician without specialized training (vs electrophysiology trained, OR 1.53; 95% CI 1.34-1.76). LV lead implant failure is uncommon in the current era and is most commonly due to coronary sinus access failure. Predictors of LV lead implant failure included younger age, female sex, black race, Hispanic ethnicity, increased QRS duration, sleep apnea, and absence of electrophysiology training.

Relationship between parameters of myocardial electrical remodeling and parameters of contractile function, deformation and myocardium work in patients with chronic heart failure with low left ventricular ejection fraction and atrial fibrillation.

Aim To compare electrocardiographic parameters and characteristics of myocardial contractility by echocardiography data in patients with chronic heart failure (CHF) with low left ventricular ejection fraction (LV EF) and atrial fibrillation (AF).Material and methods The study included 66 patients with CHF and LV EF ≤40%. Electrocardiography was used to assess the QRS complex duration, QRS fragmentation, frontal QRS-T angle (fQRS-Ta), and 3D vectorcardiographic parameters, including the planarity of QRS loop, and the spatial QRS-T angle (sQRS-Ta). Echocardiography assessed LV EF, global longitudinal strain (GLS), global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE).Results Statistically significant correlations between electrocardiographic parameters and LV EF were not found. The presence of QRS fragmentation was associated with impaired GLS, higher GWW values, and lower GWE. A number of weak but significant correlations was observed: GLS worsened with increasing QRS duration, fQRS-Ta, and sQRS-Ta and decreasing QRS planarity index; GWW increased with increasing QRS duration; GWI, GCW, and GWE decreased as the QRS planarity index decreased. GWI decreased with increasing sQRS-Ta; GCW decreased with increasing fQRS-Ta and sQRS-Ta; GWE decreased with increasing QRS duration, fQRS-Ta and sQRS-Ta.Conclusion Correlations were found between indicators of myocardial electrical remodeling and parameters of myocardial contractility, strain, and performance in CHF patients with low LV EF and AF. Further study of these parameters may be promising for assessing the severity of changes in myocardial structure and function in patients with various cardiovascular pathologies.

Electrophysiologic effects of left bundle branch area pacing: comparing left ventricular septal pacing and left bundle branch pacing

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Medtronic Background Left bundle branch area pacing(LBBAP) has been introduced as a more physiological pacing alternative to anti-bradycardia pacing and as an alternative to biventricular pacing in cardiac resynchronization therapy (CRT). LBBAP is the common denominator of left ventricular septal pacing(LVSP) and left bundle branch pacing(LBBP). In LVSP, there is only capture of the myocardium on the left side of the interventricular septum, whereas in LBBP there is additional capture of the left bundle branch(LBB) and subsequent Purkinje fibers. Purpose To investigate the electrophysiological differences between LBBP and LVSP. Methods Patients with a permanent pacemaker indication due to bradycardia or heart failure according to current guidelines were included and underwent LBBAP implantation. At baseline and during implantation, electrical activation parameters were recorded pacing at different sites (Right ventricle, LVSP and LBBP), using the standard 12-lead ECG and the ECG BELT. Electrophysiologic measures included: QRS duration, QRSarea calculated from the vectorcardiogram after conversion from the ECG using the Kors matrix, and standard deviation of activation time(SDAT) measured through the ECG BELT. Both QRS area and SDAT are known markers of ventricular dyssynchrony. Results 28 patients (17 male), with an age of 67±7 yrs underwent LBBAP. 21(75%) had a pacing indication for bradycardia with a baseline narrow QRS and 7(25%) for heart failure with a baseline LBBB. In 17 patients (61%) LBB capture was achieved. The remaining patients were treated with LVSP. In patients with baseline narrow QRS, both LVSP and LBBP showed a significant increase in QRS duration(p&amp;lt;0.001, p&amp;lt;0.001 resp.), without a significant difference in QRS duration between LVSP and LBBP(fig. 1 A). There was no significant difference in SDAT between LVSP and LBBP compared to baseline narrow QRS, and a significant SDAT reduction in patients with underlying LBBB (p=0.005, p&amp;lt;0.001 resp.) Furthermore, there was no significant SDAT difference between LVSP and LBBP(fig. 1 B). LVSP showed a small but significant increase in QRSarea compared to baseline narrow QRS (p=0.011) where LBBP showed no difference compared to baseline narrow QRS. Compared to baseline LBBB both LVSP and LBBP showed a significant QRSarea reduction (p=0.003, p&amp;lt;0.001 resp.). Moreover, there was a small but significant reduction in QRSarea when LBBP was achieved over LVSP(p=0.044) (fig. 1 C). Conclusion LVSP and LBBP showed a similar effect on ventricular synchrony in terms of SDAT, with levels of synchrony comparable to normal physiologic activation. Left bundle branch capture resulted in a small, but significant improvement in QRSarea over LVSP. Fig. 1 Relative changes in QRS duration(A), SDAT (B) and QRS area (C) compared to baseline narrow QRS (bradypacing) and baseline heart failure with LBBB. *p&amp;lt;0.05 compared to baseline, **p&amp;lt;0.05 for bradypacing and heart failure with LBBB combined.

Immune checkpoint inhibitor myocarditis with complete heart block: a case series

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction Immune checkpoint inhibitor (ICI) myocarditis is a life-threatening condition characterized by lymphocytic myocardial infiltration[1]. Complete heart block (CHB) occurs in 15% of cases and is often fatal[2-4]. The nature and optimal management of this often-malignant condition is poorly understood[5]. Purpose This case series assesses prognostic factors associated with survival at 90 days among people with ICI myocarditis and CHB. Methods The electronic patient record system was used to identify patients admitted with ICI myocarditis. A two-physician review was used to assess the presence of ICI-associated CHB. Wilcoxon rank sum and Spearman’s rank correlation were used for categorical and quantitative variables respectively. Data was analysed using STATA/IC 16.1. The primary outcome was person-day survival 90 days after presenting symptom onset. Results Six patients were included in the final analysis. Mean survival was 47 person days. All had metastatic disease and presented 15 to 32 days after the first ICI infusion. All had muscle weakness. Other common self-symptoms were shortness of breath (4), blurred vision (4), double vision (3), collapse (3), and leg swelling (1). Proximal myopathy (2), fatigable myopathy (1), ptosis (3), and peripheral oedema (1) were present on examination. Raised troponin T and white blood cell count (WBC) were associated with 90-day survival (see Table 1). Nt-pro BNP, AST, and CK levels were raised in all patients. Two patients were tested for anti-striated muscle antibody titres, and both were strongly positive. Increase in QRS duration compared to baseline ECG was associated with lower survival at 90 days. Only one patient had CHB on admission. Steroid dose, IVIG, and plasmapheresis weren’t associated with survival. One patient declined device therapy. One declined permanent pacemaker (PPM) after insertion of transvenous pacemaker (TVP). Both died within 2 weeks. Three people underwent insertion of a transvenous pacemaker (TVP) followed by PPM insertion (table 2). All three eventually died within 100 days. One person received isoproterenol and immunosuppression as a bridge to PPM and survived. One patient was managed initially with TVP but subsequently declined PPM insertion. TVP removal resulted in CHB recurrence, and they died shortly after discharge. One person declined device therapy and died while receiving comfort care. Lead malfunction was frequent. One patient experienced bradycardia arrest with failure of a TVP lead to capture, while another experienced lead dislodgement. Conclusion CHB secondary to ICI is often fatal. It should be considered in patients presenting with symptoms of myositis, raised troponin and increased QRS duration. Despite a small sample size, this study identifies several prognostic factors which can guide both patients and physicians with decision-making. Larger studies are needed to better understand the role of device therapy in this population.

PO-02-153 THE ROLE OF MAPRE2 AND MICROTUBULES IN CARDIAC ELECTROPHYSIOLOGY AND BRUGADA SYNDROME

Brugada syndrome (BrS) is associated with loss-of-function variants in SCN5A (encoding NaV1.5), yet these are only found in ∼20% of probands. Recent genome-wide association studies identified a novel locus within an intron of MAPRE2 (encoding microtubule end-binding protein 2, EB2), which implicates microtubule (MT) involvement in BrS. To understand the role of MAPRE2 and MT in cardiac electrophysiology and BrS pathogenesis. Using CRISPR/Cas9, a mapre2 knock-out (KO) mutant was generated in zebrafish and validated by western blot. Morpholino targeting ttl (encoding tubulin tyrosine ligase) was injected into zebrafish embryos at the one-cell stage. Larval hearts at 5 day-post-fertilization (dpf) were isolated for voltage mapping and immunohistochemistry. MT plus-end tracking experiments were performed in iPSC-derived cardiomyocytes with MAPRE2 knockdown (KD) using siRNA. ECG was recorded in adult fish. Voltage mapping of larval hearts (14 WTs vs. 19 KOs) showed a significant decrease in ventricular conduction velocity (17.4±1.5 vs. 13.4±0.8 mm/s; p<0.05) and action potential upstroke velocity (Vmax; 86.1±3.6 vs. 73.9±3.2 1/s; p<0.05), suggesting loss of cardiac NaV function. Correspondingly, ECG of adult fish (11 WTs vs. 10 KOs) showed a significant increase in QRS duration (27.8±0.5 vs. 32.3±0.7 ms; p<0.0001). Immunohistochemistry showed a 23% decrease of detyrosinated (glu) tubulin relative to total alpha tubulin in KO hearts (16 vs. 8 WT hearts; p<0.01). MT plus-end tracking experiments (337 control vs. 285 KD MT in 4 sets of cells) showed an increase in MT velocity (7.9±0.2 vs. 8.8±0.2 μm/min; p<0.001), distance (5.8±0.2 vs. 7.1±0.2 μm; p<0.0001), and duration (46.2±1.4 vs. 52.2±1.6 s; p<0.001) with MAPRE2 KD, suggesting changes to MT dynamics. Finally, morpholino KD of ttl in mapre2 KO embryos restored the fraction of glu-tubulin (46% increase; 16 controls vs. 16 ttl KDs; p<0.01) and Vmax (74.3±3.0 vs. 88.3±2.1 1/s; 13 controls vs. 9 KDs; p<0.01) to WT levels. Genetic ablation of mapre2 led to a decrease in NaV function, a hallmark of BrS. This is associated with a decrease in glu-tubulin as a marker of MT stability and changes in MT dynamics. Restoration of glu-tubulin fraction with ttl KD led to a rescue of NaV function in zebrafish larval hearts. Taken together, MAPRE2 loss-of-function may contribute to BrS pathogenesis via a novel paradigm of disrupting MT stability and dynamics.

Ectopic Purkinje fibers recruitment leads to permanent structural and functional conductive defects following myocardial infarction in newborn mice

The Purkinje network (PN) is the most distal part of the cardiac conduction system and ensures fast conduction of the electrical impulse through the ventricles. Despite its small volume in the heart, the PN has a disproportionally high pathogenic role. Indeed, defects in PN architecture or electrophysiology trigger conduction blocks and/or ventricular arrythmia associated with poor clinical outcomes. Purkinje fibers (PF) are specialized cardiomyocytes with a low proliferative capacity and are recruited from bipotent cardiomyocyte progenitors throughout development up to the neonatal period. Late PF recruitment is dependent on maximal levels of the transcription factor Nkx2-5. A decade ago, a neonatal regenerative window was identified in mice following myocardial infarction (MI). While damaged contractile myocardium regenerates within weeks, neither PN structure nor function has been investigated in this context. This study aims to determine whether the PN is capable of regeneration in the neonatal period, and whether PN maturation is compromised in the regenerating context. Neonatal MI was performed by permanent ligation of the left coronary artery on one-day-old mice. PN structure and function were characterized by histology and electrocardiogram. PF recruitment was investigated by clonal analysis in wildtype and Nkx2-5 haploinsufficent mice. Damage caused by the MI to the PN is spatially restricted and PFs are not replaced after regeneration, leaving a gap in the network. Surprisingly, we also observed PN hyperplasia (Fig. 1A) in regions that were not directly affected by the MI, attesting to abnormal PN maturation in the context of regeneration. At the cellular level, ectopic PFs have abnormal shapes and gap junction content. Consistently, ventricular conduction was slowed, shown by an increased QRS duration (Fig. 1B). Nkx2-5± mice, which are incompetent for late PF recruitment, do not develop MI-induced hyperplasia. Together with clonal analysis, this indicates that the hyperplastic PN in WT mice arises from ectopic PF recruitment during regeneration. Our study reveals the incapacity of the PN to regenerate after direct damage. We also uncover an extended window of PF recruitment following MI, which leads to permanent structural defects and impaired electrical conduction.

Cardioprotection by methylene Blue Against Epinephrine-Induced Cardiac Arrhythmias and Myocardial Injury

Methylene blue is used in the treatment of vasoplegic syndrome after cardiac surgery, anaphylaxis, and septic shock refractory to epinephrine and fluid resuscitation. In this study, we investigated the potential protective effect of methylene blue on the development of cardiac arrhythmias after injection of epinephrine in rats. Methylene blue was given intraperitoneally at doses of 50 or 100 mg/kg. Cardiac arrhythmia was then induced with 10 μg/kg of epinephrine intravenously. In untreated, control rats, epinephrine caused bradycardia (96.48 ± 1.06 vs. 365.03 ± 0.68 beats/min), increased PR interval (0.54 ± 0.04 vs. 0.039 ± 0.004), RR interval (0.64 ± 0.003 vs. 0.16 ± 0.004 sec), shortened QTc interval (0.067 ± 0.05 vs. 0.1 ± 0.004 sec), increased QRS duration (0.048 ± 0.005 vs. 0.028 ± 0.002 sec), decreased R wave amplitude (0.3 ± 0.03 vs. 0.49 ± 0.04 mv), decreased the height of the ST segment (-0.0696 ± 0.004 vs. -0.0054 ± 0.003 mv), and caused ventricular extrasystoles (7.92 ± 0.56 vs. 0.5 ± 0.5). Methylene blue given at 50 or 100 mg/kg increased the heart rate, decreased RR interval, QRS duration and the drop in the ST height, increased duration of QTc interval and R wave amplitude and decreased the number of extrasystoles. The histological study showed that methylene blue protected against myocardial structural disorganization, cellular damage, necrosis, and haemorrhage between muscle fibres induced by epinephrine injection. We conclude that methylene blue dose-dependently prevented epinephrine-induced arrhythmias and cardiac muscle injury.

The Brugada syndrome: risk stratification.

Thirty years after its first description, the knowledge regarding Brugada syndrome has greatly increased. Spontaneous type 1 ECG pattern (BrECG) is a well-defined prognostic marker in asymptomatic patients and is associated with a double risk of arrhythmic events during follow-up as compared to drug-induced ECG pattern. Due to the extreme variability of the ECG pattern over time, the spontaneous type 1 BrECG must be carefully sought, not only through periodic ECGs but especially with repeated 12-lead 24-h Holter monitoring, with V1 and V2 electrodes placed also on the second and third intercostal space, in order to explore the right ventricular outflow tract. 12-lead 24-h Holter should also be performed in all the patients with a dubious BrECG pattern even before the drug challenge with sodium channel blockers, which carries a low but definite risk of complications. In addition to spontaneous type 1, other electrocardiographic markers of increased arrhythmic risk have been described, such as first-degree AV block, QRS fragmentation, S wave in lead I and II, and increased QRS duration. The electrophysiological study in asymptomatic patients with a spontaneous ECG Brugada pattern is still under jury and further studies need to clarify its precise role.

Effect of Spironolactone on QRS Duration in Patients at Risk for Heart Failure (from the HOMAGE Trial)

The QRS duration can be easily obtained from a 12-lead electrocardiogram. Increased QRS duration reflects greater ventricular activation times and often ventricular dyssynchrony. Dyssynchrony causes an impairment of the global cardiac function and adversely affects the prognosis of patients with heart failure (HF). Little is known about the impact of pharmacologic therapies on the QRS duration, particularly for patients with presymptomatic HF with a preserved left ventricular (LV) ejection fraction (i.e., stage B HF with preserved ejection fraction [HFpEF]). The HOMAGE (Heart OMics in AGEing) trial enrolled patients at risk factors for developing HF and assigned them to receive either spironolactone or the usual care for approximately 9months in a randomized manner. This analysis reports the effect of spironolactone on the QRS duration. A total of 525 patients was included in the analysis. The median (percentile25-75) QRS duration at baseline was 92 (84 to 106) ms. Spironolactone reduced the QRS duration at month 9 by -2.8, 95% confidence interval -4.6 to -1.0 ms, p=0.003. No significant associations were found between month 9 changes in the QRS duration and corresponding changes in the LV ejection fraction, LV mass, LV end-diastolic volume, blood pressure, N-terminal pro-brain natriuretic peptide, and procollagen type I carboxy-terminal propeptide (all p >0.05). This analysis shows that for patients with stage B HFpEF, therapy with spironolactone for 9months shortened the QRS duration, an effect that was not associated with reductions in LV mass or volume, supporting the hypothesis that spironolactone has direct beneficial effects to improve myocardial electrical activation in patients with stage B HFpEF.

Dapagliflozin May Protect Against Doxorubicin-Induced Cardiotoxicity.

Doxorubicin is a widely used agent in the treatment of cancer, but the cardiotoxicity associated with this drug limits its potential for use. The cardioprotective effects of dapagliflozin, an antidiabetic drug, have the potential to counteract the cardiotoxic effect of doxorubicin therapy. In our study, we aimed to investigate the protective effect of dapagliflozin from possible doxorubicin-induced cardiotoxicity. A total of 40 male Wistar albino rats were divided into 4 groups consisting of 10 each (control = 10, dapagliflozin = 10, doxorubicin = 10, doxorubicin + dapagliflozin = 10). Meanwhile, doxorubicin and doxorubicin + dapagliflozin groups received a total dose of 15 mg/kg doxorubicin intraperitoneally, dapagliflozin and doxorubicin + dapagliflozin groups were gavaged daily with 10 mg/kg dapagliflozin. At the sixth week of the study, rats were examined by echocardiography and electrocardiogram. Furthermore, histopathological method was used to evaluate the level of cardiotoxicity. Ejection fraction decreased by 15% in the doxorubicin group, and this reduction in ejection fraction was alleviated in the doxorubicin + dapagliflozin group. In addition, a 65% increase in QRS duration was observed in the group given doxorubicin, while an increase of 7% was observed in doxorubicin + dapagliflozin group. Corrected QT duration increased by 12% in the doxorubicin group, compared to 2% in doxorubicin + dapagliflozin group. Meanwhile, sarco-myolysis, inflammatory cell infiltration, and necrotic changes were examined heavily in doxorubicin group, they were minimal in doxorubicin + dapagliflozin group. Our study showed that dapagliflozin has the potential to reduce the effects of doxorubicin-induced cardiotoxicity.

Subtle QRS changes are associated with reduced ejection fraction, diastolic dysfunction, and heart failure development and therapy responsiveness: Applications for artificial intelligence to ECG

Since the last century, the electrocardiogram (ECG) remains the non-invasive test, that is, most easily accessible, feasible, and inexpensive for cardiology assessment. In past years, many novel ECG indexes and patterns have been published that allow for a more advanced evaluation of what is currently being done, especially based on subtle QRS changes and patterns. The objective of the study was to provide an update on the evidence and clinical applications of these ECG subtle QRS changes and patterns associated with heart disease. Through the literature review, we will highlight the subtle QRS changes and patterns associated with heart disease, mainly focusing on QRS duration, voltage, morphology, axis, and QT interval. Small increases in QRS duration are associated with a reduction in left ventricular ejection fraction (EF), increased cardiac chamber dimensions, and risk for incident heart failure (HF). Moreover, fragmentation of the QRS complex is associated with myocardial fibrosis and is a substrate for developing arrhythmic events. Besides, low amplitude QRS voltage is associated with congestive HF, and an increase in the voltage of the QRS complexes is associated with the effectiveness of diuresis treatment. Furthermore, small increases in QT interval are associated with diastolic dysfunction due to impaired sarcoplasmic reticulum calcium handling as occurs in myocardial ischemia, hypertension, or diabetes. On the other hand, in patients with left ventricular dysfunction, the QRS area is associated with clinical and echocardiographic response to cardiac resynchronization therapy regardless of the type of bundle branch block. In addition, subtle ECG changes and patterns in the left bundle branch block are associated with concomitant right ventricular dilation, mostly based on the QRS axis and voltage. Notwithstanding, to identify these subtle changes in QRS require exact manual measurements that can take time. In this regard, applying artificial intelligence (AI) to the ECG can make a quicker and more complete assessment, as well as provide a low cost when applied to large populations. We provided an update on the evidence and clinical applications of these subtle QRS changes and patterns associated with diastolic dysfunction, reduced EF, and HF development and therapy responsiveness, as well as their applications for AI to ECG.

Association between Empagliflozin Use and Electrocardiographic Changes.

Empagliflozin, a sodium-glucose transporter 2 inhibitor, has been shown to bind to late sodium channels in mice cardiomyocytes. We sought to investigate the electrocardiographic (ECG) features associated with empagliflozin use in patients with diabetes mellitus. We compared ECG features of 101 patients before and after initiation of empagliflozin and found that empagliflozin was associated with a significant increase in QRS duration among diabetes patients with heart failure.

Bradyarrhythmias detected by extended rhythm recording in patients undergoing transcatheter aortic valve replacement (Brady-TAVR Study).

Bradyarrhythmias leading to permanent pacemaker (PPM) implantation continue to be a complication after transcatheter aortic valve replacement (TAVR). The purpose of this study was to assess the prevalence of bradyarrhythmias using an electrocardiographic (ECG) extended rhythm recording in patients pre- and post-TAVR and whether they can predict the need for PPM. This was a prospective single-center study in patients undergoing TAVR. Patients received an ECG patch for 2 weeks pre-, immediately post-, and 2-3 months post-TAVR. Caring physicians were blinded to the results of the patch except when predefined urgent arrhythmias were detected. The main outcome was the need for PPM implantation after TAVR. We enrolled 110 patients, of whom 96 underwent TAVR and were included in the final analysis. Bradyarrhythmias, defined as a pause of 3 seconds or more, occurred in 5.2%, 12.7%, and 7% of patients pre-, immediately post-, and 2-3 months post-TAVR, respectively. PPM implantation occurred in 12 patients (12.5%), of whom 9 (9.4%) underwent implantation during their index hospitalization while 3 (3.1%) required implantation postdischarge for indications other than heart block. No patients required PPM after receiving an ECG patch 2-3 months post-TAVR. Significant baseline predictors for the need for PPM included the presence of right bundle branch block and increased QRS duration. Bradyarrhythmias detected by the ECG patch did not predict the need for PPM at either the index hospitalization or the follow-up period. Bradyarrhythmias are common and can be detected with extended ECG monitoring before and after TAVR; however, in our study they did not predict the need for PPM after TAVR (ClinicalTrials.gov identifier: NCT03180073).