Prolonged QRS Research Articles

Right ventricular dilatation and systolic dysfunction and relationship to QRS duration in patients with left bundle branch block and cardiomyopathy.

Marked QRS widening in patients with left bundle branch block (LBBB) may reduce efficacy of cardiac resynchronization therapy (CRT). We hypothesized that extreme QRS prolongation may accompany right ventricular (RV) dilatation/systolic dysfunction (RVD/RVsD) as well as left ventricular dilatation/systolic dysfunction (LVD/LVsD). We assessed rates of both ventricular dilatation and systolic dysfunction according to widening of QRS duration (QRSd) in 100 consecutive cardiomyopathy patients with true LBBB (QRSd≥130ms in female or ≥140ms in male, QS or rS in leads V1/V2, and mid-QRS notching/slurring in ≥2 contiguous leads of I, aVL, and V1/V2/V5/V6). Ventricular dimensions and function were measured by cardiac magnetic resonance imaging. There was a trend toward an increase in the prevalence of LVD (13%, 20%, and 90%), LVsD (67%, 77%, and 90%), RVD (23%, 27%, and 50%), RVsD (27%, 27%, and 40%), RVD plus RVsD (13%, 17%, and 40%), or RVD/RVsD (37%, 37%, and 50%) according to the degree of QRS prolongation (<150ms, n=30; 150-180ms, n=60; and ≥180ms, n=10). Similarly, patients in the highest quartile of QRSd (QRSd≥168ms, n=26) showed greater rates of RVD (23% vs. 44%, p=.069), RVsD (22% vs. 48%, p=.032), RVD plus RVsD (10% vs. 30%, p=.040), or RVD/RVsD (33% vs. 57%, p=.050) compared to those in the remaining quartiles (n=74). QRSd≥180ms was identified as an independent predictor for the presence of RVD plus RVsD. The rates of RVD and/or RVsD increased with QRS widening, particularly when QRSd exceeded 180ms. This may diminish anticipated CRT response rates in cardiomyopathy patients with LBBB.

Assessment of echocardiographic left ventricular dimensions with several clinical findings among healthy people

Background: The echocardiographic measurement of left ventricular dimensions and the changes of left ventricular dimensions may be important to assess cardiac as well as the cardiovascular conditions of patients. On the other hand, the QRS duration signifies the time for ventricular depolarization. Aim of the study: The aim of this study was to assess the echocardiographic left ventricular dimensions with several clinical findings among healthy people. Methods: This was an observational cross-sectional study which was conducted in the Department of Cardiology, University Cardiac Centre, Bangabandhu Sheikh Mujib Medical University, Dhaka over a period of 2 years from July 2008 to June 2010. In total 92 apparently healthy people without heart failure (HF) or myocardial infarction (MI) were included as the study population. Among them, 22 were in Referent (QRS duration &lt;100 ms), 40 in Incomplete BBB (QRS duration 100 – 119), and 30 in Complete BBB (≥ 120 ms) groups. Proper written consent was taken from all the participants and this study was approved by the ethical committee of the mentioned university. All data were processed, analyzed, and disseminated by MS Office and SPSS version as per need. Results: In this study, the left ventricular (LV) mass, left ventricular diastolic dimension, septal wall thickness, posterior wall thickness and left atrial size were significantly higher in complete BBB group than those in referent and incomplete BBB group (143.0 ± 30.2 vs. 182.6 ± 37.9 vs. 222.0 ± 61.0, p &lt; 0.001; 4.6 ± 0.3 vs. 4.9 ± 0.3 vs. 5.2±0.4, p&lt; 0.001; 0.9±0.1 vs. 1.0 ± 0.1 vs. 1.1± 0.1, p&lt;0.001; 0.9 ± 0.1 vs. 1.0 ± 0.1 vs. 1.1± 0.1, p&lt;0.001; and 3.3 ± 0.3 vs. 3.6±0.3 vs. 3.7±0.3, p&lt;0.001 respectively). However, fractional shortening and left ventricular ejection fraction were found to decrease significantly with the increase in QRS duration (p &lt; 0.001 and p &lt; 0.001 respectively). In this study the QRS duration was observed to be linearly correlated with LV mass, LV diastolic dimension, septal wall thickness, posterior wall thickness and left atrial size (r=0.577, p&lt;0.001; r=0.480, p&lt;0.001; r=0.583, p&lt;0.001; r=0.521, p&lt; 0.001 and r= 0.418, p&lt;0.001 respectively).&nbsp; However, QRS duration was found to maintain a negative correlation with fractional shortening and LVEF (r =- 0.637, p&lt;0.001 and r =- 0.701, p&lt;0.001 respectively). Conclusion: The present study revealed that longer electrocardiographic QRS duration was correlated with the increase in LV mass, LV diastolic dimensions, septal wall thickness, posterior wall thickness, and left atrial size. The association was most striking in individuals with complete BBB compared with a normal QRS duration. Meanwhile, the presence of prolonged QRS in a patient’s ECG can serve as a bedside clue to the presence of decreased fractional shortening and left ventricular ejection fraction.

Abstract P356: Dual Dysfunction Of Kir2.1 Underlies Conduction And Excitation-contraction Coupling Defects Promoting Arrhythmias In A Mouse Model Of Andersen-tawil Syndrome Type 1

Background: Andersen-Tawil syndrome type 1 (ATS1), caused by trafficking deficient mutations in the gene KCNJ2 coding the inward rectifier K + channel Kir2.1, is associated with life-threatening arrhythmias, which in some patients resemble catecholaminergic polymorphic ventricular tachycardia (CPVT), but the mechanisms are poorly understood. We tested the hypothesis that dysfunction of two different populations of mutant Kir2.1 channels, one at the sarcolemma, and the other at the sarcoplasmic reticulum (SR) membrane, directly alters conduction and intracellular calcium dynamics, respectively, to promote the ATS1 phenotype and arrhythmias that resemble CPVT. Methods: We generated a new mouse model of ATS1 by a single i.v. injection of cardiac specific adeno-associated viral (AAV) transduction with Kir2.1 Δ314-315 . In-vivo and cellular, structural and functional analyses of the model were carried out by electrocardiogram (ECG), magnetic resonance imaging (MRI), intracardiac stimulation, patch-clamping, membrane fractionation, western blot, immunolocalization and live calcium imaging. Results: Our mouse model carrying mutant Kir2.1 Δ314-315 recapitulated the ATS1 phenotype without modifying ventricular function. On ECG, Kir2.1 Δ314-315 mice had prolonged PR, QRS and QT intervals and occasional U waves. They showed significantly slower conduction velocities than wildtype mice in response to flecaidine-induced Na + -channel blockade, additional QT prolongation in response to isoproterenol, and increased vulnerability to cardiac fibrillation. Cardiomyocytes from Kir2.1 Δ314-315 mice had significantly reduced inward rectifier K + and Na + inward currents, depolarized resting membrane potential and prolonged action potential duration. Immunolocalization in wildtype cardiomyocytes and skeletal muscle cells revealed a novel SR microdomain of functional Kir2.1 channels contributing to intracellular Ca 2+ homeostasis. Kir2.1 Δ314-315 cardiomyocytes showed defects in SR Kir2.1 localization and function, which contributed to abnormal spontaneous Ca 2+ release events. Conclusions: Cardiac-specific AAV transduction with Kir2.1 Δ314-315 in mice recapitulates the ATS1 phenotype by disrupting localization and function of Kir2.1 channels at the SR, and the Kir2.1-Na V 1.5 channelosome at the sarcolemma. These results reveal a novel dual mechanism of arrhythmogenesis in ATS1 involving defects in Kir2.1 channel trafficking and function at two different microdomains. They also provide the first demonstration at the molecular level of the mechanism underlying the overlap between ATS1 and CPVT associated with defects in intracellular calcium homeostasis.

Abstract P361: Reduced Cardiac Tmem65 In Mouse Hearts Results In Intercalated Disc Defects And Eventual Dilated Cardiomyopathy With Cardiac Fibrosis

The intercalated disc (ICD) is unique membrane structure that is indispensable to normal heart function. However, its structural organization is not well understood. Previously, we showed that the ICD-bound transmembrane protein 65 (Tmem65) was required for connexin 43 (Cx43) localization in cultured mouse neonatal cardiomyocytes. Here, we investigated the role of Tmem65 in ICD organization in vivo . A mouse model was established by injecting CD1 mouse pups (3-7 days after birth) with recombinant adeno-associated virus 9 (rAAV9) harboring Tmem65 (or scrambled) shRNA. Quantitative polymerase chain reaction (qPCR) and immunoblots confirmed greater than 85% reduction in Tmem65 expression (7.1±0.7% remained for Tmem65 proteins; 14.4±2.5% remained for Tmem65 transcripts, n =4) in mouse ventricles compared to control hearts. Tmem65 knockdown (KD) mice exhibited heart failure-like symptoms as early as 3 weeks post viral administration. Specifically, Tmem65 KD mice developed eccentric hypertrophic cardiomyopathy in 3 weeks and dilated cardiomyopathy with severe cardiac fibrosis in 7 weeks, as confirmed by H&amp;E and Masson’s Trichrome staining. Echocardiography and electrocardiography, respectively, showed depressed hemodynamics (19.27±1.46ml/min for cardiac output in control hearts vs. 6.63±0.52ml/min for Tmem65 KD hearts, n =6) and impaired conduction, including prolonged PR (22.7±1.85ms in control hearts vs. 28.89±3.85ms in Tmem65 KD hearts, n≥8), QRS intervals (10.47±0.42ms in control hearts vs. 16.35±0.36ms in Tmem65 KD hearts, n≥8), and slowed heart rate (415±10bpm in control hearts vs. 347±16bpm in Tmem65 KD hearts, n≥8) in Tmem65 KD mouse hearts. Immunoprecipitation and super-resolution microscopy confirmed the physical interaction and localization between Tmem65 and voltage-gated sodium channel β subunit (β1) at the ICD and this interaction was evidently required for the establishment of perinexal nanodomains and voltage-gated sodium channel 1.5 (NaV1.5) localization to the ICD. Disrupting Tmem65 function, thus, impaired perinexal structure, reduced conduction velocity, and ultimately resulted in cardiomyopathy in vivo .

Left ventricular activation time and pattern are preserved with both selective and nonselective His bundle pacing.

BackgroundHis bundle pacing (HBP) can be achieved in 2 ways: selective HBP (S-HBP), where the His bundle is captured alone, and nonselective HBP (NS-HBP), where local myocardium is also captured, resulting a pre-excited electrocardiogram appearance.ObjectiveWe assessed the impact of this ventricular pre-excitation on left and right ventricular dyssynchrony.MethodsWe recruited patients who displayed both S-HBP and NS-HBP. We performed noninvasive epicardial electrical mapping for left and right ventricular activation time (LVAT and RVAT) and pattern.ResultsTwenty patients were recruited. In the primary analysis, the mean within-patient change in LVAT from S-HBP to NS-HBP was -5.5 ms (95% confidence interval: -0.6 to -10.4, noninferiority P < .0001). NS-HBP did not prolong RVAT (4.3 ms, -4.0 to 12.8, P = .296) but did prolong QRS duration (QRSd, 22.1 ms, 11.8 to 32.4, P = .0003). In patients with narrow intrinsic QRS (n = 6), NS-HBP preserved LVAT (-2.9 ms, -9.7 to 4.0, P = .331) but prolonged QRS duration (31.4 ms, 22.0 to 40.7, P = .0003) and mean RVAT (16.8 ms, -5.3 to 38.9, P = .108) compared to S-HBP. Activation pattern of the left ventricular surface was unchanged between S-HBP and NS-HBP, but NS-HBP produced early basal right ventricular activation that was not seen in S-HBP.ConclusionCompared to S-HBP, local myocardial capture during NS-HBP produces pre-excitation of the basal right ventricle resulting in QRS duration prolongation. However, NS-HBP preserves the left ventricular activation time and pattern of S-HBP. Left ventricular dyssynchrony is not an important factor when choosing between S-HBP and NS-HBP in most patients.

Electrocardiographic manifestations of COVID-19: Effect on cardiac activation and repolarization.

BackgroundProlonged QT intervals are reported in patients with COVID-19. Additionally, virus particles in heart tissue and abnormal troponin levels have been reported. Consequently, we hypothesize that cardiac electrophysiologic abnormalities may be associated with COVID-19.MethodsThis is a retrospective study between March 15th, 2020 and May 30th, 2020 of 828 patients with COVID-19 and baseline ECG. Corrected QT (QTc) and QRS intervals were measured from ECGs performed prior to intervention or administration of QT prolonging drugs. QTc and QRS intervals were evaluated as a function of disease severity (patients admitted versus discharged; inpatients admitted to medical unit vs ICU) and cardiac involvement (troponin elevation >0.03 ng/ml, elevated B-natriuretic peptide (BNP) or NT pro-BNP >500 pg/ml). Multivariable analysis was used to test for significance. Odds ratios for predictors of disease severity and mortality were generated.FindingsBaseline QTc of inpatients was prolonged compared to patients discharged (450.1±30.2 versus 423.4±21.7 msec, p<0.0001) and relative to a control group of patients with influenza (p=0.006). Inpatients with abnormal cardiac biomarkers had prolonged QTc and QRS compared to those with normal levels (troponin - QTc: 460.9±34.6 versus 445.3±26.6 msec, p<0.0001, QRS: 98.7±24.6 vs 90.5±16.9 msec, p<0.0001; BNP - QTc: 465.9±33.0 versus 446.0±26.2 msec, p<0.0001, QRS: 103.6±25.3 versus 90.6±17.6 msec, p<0.0001). Findings were confirmed with multivariable analysis (all p<0.05). QTc prolongation independently predicted mortality (8.3% increase in mortality for every 10 msec increase in QTc; OR 1.083, CI [1.002, 1.171], p=0.04).InterpretationQRS and QTc intervals are early markers for COVID-19 disease progression and mortality. ECG, a readily accessible tool, identifies cardiac involvement and may be used to predict disease course.FundingSt. Francis Foundation.

Electrocardiographic findings in true acute left main coronary total occlusion a subanalisys from ATOLMA registry

IntroductionAcute total occlusion of the left main coronary artery (ATOLMA) usually leads to a catastrophic presentation. Prediction of ATOLMA by electrocardiogram (ECG) may contribute to early detection and reperfusion. Limited data have been reported previously. This study aims to identify the admission 12‑leads ECG features that can predict the presence of ATOLMA and in-Hospital mortality in these patients. MethodsThe admission ECGs findings in 24 patients from the previously reported ATOLMA multicenter registry were compared to the ECGs findings in 15 patients with an acute subtotal occlusion of the left main (ASOLMA) and to 15 patients with anterior ST-elevation myocardial infarction of the proximal left anterior descending (LADp-STEMI). ResultsSome ECG features at presentation can predict an ATOLMA: QRS left axis deviation (−61.17 ± 9 degrees); ST-segment elevation in aVL (1.9 ± 0.65 mm); absence of ST-segment elevation in V1 (0.0 ± 0.6 mm); bifascicular block (58%); fragmented QRS (62.5%); prolongation of QTc interval (465 ± 19 ms) and of QRS interval (136 ± 12 mm). The multivariate analysis found that the independent predictors to distinguish ATOLMA from ASOLMA were aVL ST-segment deviation (OR 5.6(95% CI 1.5–21), p = 0.01) and absence of V1 ST-segment elevation (OR 27(95% CI 1.4–52), p = 0.01); and from LADp-STEMI was QRS width (OR 1.1(95% CI 1.02–1.2), p = 0.02). Fragmented QRS was the only independent predictor of in-hospital mortality in ATOLMA (OR 0.125(95% CI 0.01–0.81), p = 0.03). ConclusionsaVL ST-segment elevation, the absence of V1 ST-segment elevation, left axis deviation, the presence of bifascicular block, and prolongation of QRS and QTc interval are predictors of ATOLMA. Fragmented QRS predicts in-hospital mortality in ATOLMA.

B-PO01-101 COMPARISON OF RIGHT VENTRICULAR, DEEP SEPTAL, AND BIVENTRICULAR PACING

Left septal pacing results in comparable electrical activation and hemodynamics to LBB, His bundle, or biventricular (BIV) pacing. This study compared acute electrogram and echocardiographic parameters between right ventricular (RV), deep septal, and BIV pacing. Deep septal pacing was performed by advancing an active fixation lead across the septum guided by QRS duration and morphology. RV, deep septal, and BIV pacing were compared with respect to QRS, left ventricular activation time as measured from stimulus to the latest peak of V5 or V6 (LVAT), LV ejection fraction (LVEF), and global longitudinal strain (GLS). In a subset of patients with adequate quality electrograms, paced vectorcardiographic ECG area was also compared. The study cohort had 35 patients (34% female, 79±9 years, 64% nonischemic cardiomyopathy, baseline QRS 167 ± 28ms, LVEF 30 ± 9%, LV end diastolic dimension 5.4 ± 0.9 cm). The deep septal pacing threshold was 0.6±0.2 mV and 0.6 ms. Paced QRS duration was 179± 23 ms with RV pacing, 135 ± 21 ms with deep septal pacing and 144 ±15 ms with BIV pacing (p<0.01, 0.2 for deep septal vs. BIV). LVAT was 101±20 ms with RV pacing, 78 ± 15 ms with deep septal pacing, and 80 ± 18 ms with BIV pacing (p<0.01, p=0.9 for deep septal vs. BIV). LVEF and GLS were 29 ± 9% and 9±4% with RV pacing, 36 ± 10% and 10 ± 4% with deep septal pacing, and 35 ± 10% and 10 ± 3% with biventricular pacing respectively (p=0.01) In a subset of patients (n=22) QRS area was 62 ± 27 ms*mV with deep septal pacing and 69 ± 32 ms*mV with BIV (p=0.3). In patients with QRS prolongation, deep septal and BIV pacing result in similar acute electrical and echocardiographic left ventricular activation.

B-PO02-191 THE LV LEAD PLACEMENT FOR CARDIAC RESYNCHRONIZATION THERAPY (CRT) BY THE FEMORAL VEIN CORONARY SINUS (CS) CANNULATION: A TECHNICAL EXTENSION

CRT is a mainstay of treatment in refractory dilated cardiomyopathy in chronic systolic heart failure and prolonged QRS duration of more than120 ms. The limiting factor for successful CRT is the CS cannulation for LV lead placement. The study aimed to assess if the femoral vein CS cannulation facilitated LV lead placement for the CRT after failed cannulation from the intended site. The study included 39 patients (17 Female) and severe non-ischemic cardiomyopathy (Table1). The left pectoral region was the preferred site for implantation. Initially, anterograde CS cannulation was attempted from the intended site. In anterograde success (48.7%), the CS cannulation was under 10 minutes. In anterograde failure (51.28%), time was over 10 minutes. The CS was cannulated doubly, initially from the right femoral vein using a steerable decapolar EP catheter. This facilitated subsequent CS cannulation and LV lead placement from the intended site. The time duration among the 19 anterograde success cases: mean = 7.2 minutes, median = 7.0 minutes, interquartile range is [6.0, 8.0]. The total duration (Table1) for LV lead placement was 42.4 ± 2.0 minutes in anterograde success, and in femoral vein facilitated (anterograde failure) technique was 37.7 ± 2.1, P<0.0001. The multivariable logistic regression model shows, age is positively associated with anterograde failure (OR and 95% CI: 1.23 (1.08, 1.40), while sodium level is negatively related to anterograde failure (OR and 95% CI: 0.37 (0.17, 0.81). The CS cannulation from the femoral vein is a possibility. CRT failure rate and fluoroscopy duration can be reduced by this method.

A Case Report of Tachycardia-Dependent Right Bundle Branch Block During Cardiac Resynchronization Therapy

Cardiac resynchronization therapy (CRT) has been shown to improve symptoms and mortality in a suitably selected population with systolic heart failure and prolonged QRS duration. Various factors have been reported to be associated with poor response to CRT. A 67-year-old man with CRT implantation experienced response, nonresponse, and response in turn. The new-onset right tachycardia-dependent bundle branch block was considered to be an exclusive cause. More attention should be paid to the possible changes of paced-QRS morphology, resulting from tachycardia-dependent aberrancy during CRT, ensuring a high percentage of effective biventricular pacing.

Correlation Between Fragmented QRS and Ventricular Function from Cardiac Magnetic Resonance in Patients with Repaired Tetralogy of Fallot.

Fragmented QRS is an abnormal sign in an ECG resulting from ventricular dyssynchrony. The presence of fragmented QRS (fQRS) is related to mortality in patients with repaired tetralogy of Fallot (rTOF). This study aimed to analyze the correlations between fQRS and ventricular function parameters from cardiac magnetic resonance (CMR) images. A total of 54 patients with rTOF or repaired DORV, TOF type who had been investigated by CMR at Songklanagarind Hospital from January 2012 to August 2019 were retrospectively reviewed. Most of the patients (47 patients, 87%) were diagnosed with TOF and most of these (57.4%) were treated with a transannular patch (TAP) on the right ventricular outflow tract (RVOT). Forty-four patients (81%) had fQRS. The median time interval between EKG and CMR was 4.2months (IQR 1.1, 6.9). Patients with fQRS had significantly higher RVEDVi (145.6 [IQR 121.1, 173.1) vs. 115.9 [IQR 96.2, 146.9] mL/m2, p = 0.037), higher RVESVi (82.5 [IQR 62.9, 100.8] vs. 58.6 [IQR 46, 77.2] mL/m2, p = 0.032) and higher RVEDV/LVEDV ratio [1.6 (IQR 1.4, 1.9) vs. 1.4 (IQR 1.3, 1.5), p = 0.026]. The extent of fQRS was significantly associated with an increase in RVEDVi (r = 0.39, p = 0.004) and RVESVi (r = 0.45, p < 0.001) but a decrease in RVEF (r = - 0.37, p = 0.006). Fragmented QRS had higher sensitivity and lower specificity than prolonged QRS duration (≥ 160ms) to predict all of the parameters indicating pulmonary valve replacement (PVR). Patients with rTOF who had fQRS were significantly associated with RV dilatation. The extent of fQRS had only low to moderate correlation with right ventricular parameters (RVEDVi, RVESVi and RVEF). Fragmented QRS could be used for early detection of RV dilatation and the need for PVR in patients with rTOF.

Structural heart disease, not the right ventricular pacing site, determines the QRS duration during right ventricular pacing.

Right ventricular (RV) pacing causes changes in the heart's electrical and mechanical activation patterns. The QRS duration is a useful surrogate marker of electrical dyssynchrony; a longer QRS duration during RV pacing indicates poor prognosis. However, the mechanisms underlying a longer QRS duration during RV pacing remain unclear; hence, we investigated factors predicting QRS prolongation during RV pacing. We enrolled 211 patients who underwent catheter ablation for supraventricular tachyarrhythmia and showed no bundle branch block. Three-dimensional mapping for the QRS duration during RV pacing from the RV outflow to RV apex was performed, and differences in the QRS duration were analyzed. The predisposing factors causing QRS > 160ms during RV apical pacing were also analyzed. The QRS durations at baseline and during RV pacing from the RV outflow and at the RV apex were 85.0 ± 7.5ms, 163.7 ± 17.1ms, and 156.2 ± 16.1ms, respectively. With respect to the QRS duration, there was a significant correlation between RV outflow and RV apical pacing (r = 0.658, p < 0.001). Difference in the QRS duration between the RV outflow and RV apex in each patient was only 12.5 ± 10.4ms. Logistic multivariable regression analysis identified baseline QRS duration [odds ratio (OR) 1.24, 95% confidence interval (CI) 1.15-1.33, p < 0.01], interventricular septum thickness (OR 1.20, 95% CI 1.02-1.40, p = 0.025), left atrial diameter (OR 1.08, 95% CI 1.01-1.16, p = 0.024), and E/e' (OR 1.23, 95% CI 1.12-1.35, p < 0.01) as significant predictors of QRS prolongation during RV apical pacing. The QRS duration during RV pacing largely depends not on the pacing site, but on the underlying structural heart diseases.

Mechanism of angiotensin receptor-neprilysin inhibitor in suppression of ventricular arrhythmia

BackgroundThe mechanisms underlying angiotensin receptor-neprilysin inhibitor (ARNi) suppression of ventricular arrhythmia (VA) are unclear. This study aimed to investigate the mechanism of ARNi-related suppression of VA in a heart failure (HF) model. MethodsNew Zealand white rabbits (n = 6 per group) were assigned to normal, HF [4 weeks of left ascending artery (LAD) ligation], angiotensin receptor blocker (ARB, valsartan at 27 mg/kg/day for 3 weeks after 1 week of LAD ligation), and ARNi (sacubitril at 34 mg/kg/day and valsartan at 27 mg/kg/day for 3 weeks after 1 week of LAD ligation) groups. Experiments involving echocardiogram, optical mapping, histological of trichrome stain and immunostain, and flow cytometry were performed. ResultsHF group had larger left ventricular (LV) internal dimensions in diastole and systole, and lower LV ejection fraction and fractional shortening than normal, ARB, and ARNi groups. HF group had a prolonged action potential duration (APD) and decreased conduction velocity (CV), which was mitigated in ARB and ARNi groups. HF group had a prolonged QRS duration, QT and QTc intervals, which was reversed in ARB and ARNi groups. HF group had a steeper maximum slope of APD restitutions, which was attenuated in normal, ARB, and ARNi groups. HF group had increased number of phase singularities (PSs) and VA inducibility than normal, ARB, and ARNi groups. A higher content of fibrosis was found in HF group than that in normal, ARB, and ARNi groups. Compared to ARB group, ARNi had a lower context of fibrosis. HF group had more peripheral blood CD4+ and CD8+ cells count than normal, ARB, and ARNi group. ConclusionsIn a rabbit model of ischemic HF, ventricular arrhythmogenesis could be suppressed by ARNi treatment. This appears to be mediated by reversing changes in the APD, CV, maximum slope of the APDR, PSs, fibrosis, and inflammation.

Fibrosis biomarkers as a predictive tool for clinical outcome in PLNR14Del patients

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Netherlands Cardio Vascular Research Initiative (CVON): the Dutch heart foundation Background Mutations in phospholamban (PLN, most often PLNR14Del), a protein that regulates Ca2+ homeostasis in cardiomyocytes, are found in patients diagnosed with arrhythmogenic (ACM) and dilated cardiomyopathy (DCM). Fibrosis formation in the heart is one of the hallmarks in PLN patients, which compromises cardiac contractility and predisposes to arrhythmogenicity. Collagen type I is the most abundant type of collagen in the heart (85%). During continuous collagen synthesis propeptides, like procollagen type I carboxy-terminal propeptide (PICP) and during collagen breakdown, C-terminal telopeptide collagen type I (ICTP), are released into the circulation. Clinically, detection of fibrosis occurs via echo or MRI, however difficulties arise when patchy fibrosis has to be detected. Purpose To investigate if PICP and ICTP levels in blood are useful predictive biomarkers for clinical outcome in PLN patients. Methods 78 serum and EDTA blood samples were collected on the same day from ACM diagnosed (n = 12), DCM diagnosed (n = 14) or non-classified (n = 52) PLN patients. PICP levels were measured with an ELISA assay and ICTP with a RIA. Clinical data were subtracted two years around blood collection from Redcap, a Dutch database with medical records from PLN patients. Data were not normally distributed, so Spearman’s correlation coefficient and Mann-Whitney test were used. Results Gender, age and PICP/ICTP ratios were similarly distributed between the subgroups. First, we checked if clinical data subtracted two years around blood collection provided reliable results regarding clinical outcome. Patients who underwent clinical testing 5.5 weeks around blood collection revealed that clinical data were in line with the best-fitted line of the linear regression and therefore provide reliable results. Next, the potential correlation of fibrosis biomarkers with electrical parameters was assessed. Increased PICP/ICTP ratios suggest a higher collagen deposition. Although there was no correlation with prolonged QRS duration (Rs 0.13, n = 62, ns), subgroup analysis showed a significant weak correlation for non-classified patients (Rs 0.32, n = 38, p = 0.05). No significant correlation was found for ACM or DCM patients; however, groups were rather small. PICP/ICTP ratio was significantly higher in patients with T wave inversion and premature ventricular contractions (PVCs) during an exercise tolerance test. A weak inverted correlation was found with left ventricular ejection fraction and PICP/ICTP (Rs -0.28, n = 23, ns), while moderate correlations between the ratio and end diastolic volume, and end systolic volume exist (both Rs 0.40, n = 23, p = 0.06). Conclusion High PICP/ICTP ratios correlate with clinical outcome in PLN patients, such as T wave inversion and PVCs. However, the size and heterogeneity of the patient group resulted in weak to moderate correlation coefficients and might therefore currently precludes to use PICP and ICTP levels as biomarker.

Non-selective and selective His bundle pacing both preserve left ventricular activation time and pattern

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): British Heart Foundation Background: His bundle pacing can be achieved in two ways selective His bundle pacing, where the His bundle is captured alone, and non-selective His bundle pacing, where local myocardium is also captured resulting a pre-excited ECG appearance. We assessed the impact of this ventricular pre-excitation on left and right ventricular dys-synchrony. Methods We recruited patients who displayed both selective and non-selective His bundle pacing. We performed non-invasive epicardial electrical mapping to determine left and right ventricular activation times and patterns. Results In the primary analysis (n = 20, all patients), non-selective His bundle pacing did not prolong LVAT compared to select His bundle pacing by a pre-specified non-inferiority margin of 10ms (LVAT prolongation: -5.5ms, 95% confidence interval (CI): -0.6 to -10.4, non-inferiority p &amp;lt; 0.0001). Non-selective His bundle pacing did not prolong right ventricular activation time (4.3ms, 95%CI: -4.0 to 12.8, p = 0.296) but did prolong QRS duration (22.1ms, 95%CI: 11.8 to 32.4, p = 0.0003). In patients with narrow intrinsic QRS (n = 6), non-selective His bundle pacing preserved left ventricular activation time (-2.9ms, 95%CI: -9.7 to 4.0, p = 0.331) but prolonged QRS duration (31.4ms, 95%CI: 22.0 to 40.7, p = 0.0003) and mean right ventricular activation time (16.8ms, 95%CI: -5.3 to 38.9, p = 0.108) compared to selective His bundle pacing. Activation pattern of the left ventricular surface was unchanged between selective and non-selective His bundle pacing. Non-selective His bundle pacing produced early basal right ventricular activation, which was not observed with selective His bundle pacing. Conclusions Compared to selective His bundle pacing, local myocardial capture during non-selective His bundle pacing produces right ventricular pre-excitation resulting in prolongation of QRS duration. However, non-selective His bundle pacing preserves the left ventricular activation time and pattern of selective His bundle pacing. When choosing between selective and non-selective His bundle pacing, left ventricular dyssynchrony is not an important factor. Abstract Figure: Selective vs Non-Selective HBP

Compensatory depression of arterial pressure and reversal of ECG abnormalities by Annona muricata and Curcuma longa in hypertensive Wistar rats.

Increasing hypertension incidence in Sub-Sahara Africa and the current cost of management of the metabolic disorder has necessitated research on medicinal plants employed in African Traditional Medicine for hypertension. Thus, this study evaluated antihypertensive effect of Annona muricata leaves or Curcuma longa rhizomes in experimentally-induced hypertensive male Wistar rats (n=70) which were unilaterally nephrectomized and daily loaded with 1% salt. Cardiovascular and haematological changes, as well as urinalysis were determined. Rats were uninephrectomized and NaCl (1%) included in drinking water for 42days. Extract-treated hypertensive rats were compared to normotensive, untreated hypertensive and hypertensive rats treated with lisinopril (5mg/70kg) or hydrochlorothiazide (12.5mg/70kg). A.muricata extract or C.longa extract were administered at 100, 200 or 400mg/kg. Blood pressure (systolic, diastolic and mean arterial) and electrocardiogram was measured on day 41. Twenty-four-hour urine samples were collected from day 42. Blood samples were collected on day 43 for haematology (PCV, red cell indices, WBC and its differentials, and platelets). A.muricata or C.longa extracts caused a decline in elevated blood pressure of hypertensive rats. Heart rate and QT segment reduction coupled with prolonged QRS duration were reversed in extract-treated rats, with significant increases in hemogram parameters indicating increased blood viscosity. Also, leukocyturia, proteinuria and ketonuria with increased urine alkalinity, urobilinogen and specific gravity which are classical indicators of poor prognostic outcomes in hypertension were reversed in extract-treated rats. In conclusion, A.muricata and C.longa have cardioprotective effect with reversal of derangements in haemogram and urinalysis associated with hypertension.

"Second line medications" for supraventricular arrhythmias in children: In-hospital efficacy and adverse events during treatment initiation of sotalol and flecainide.

Sotalol and flecainide are used as second line agents in children for the treatment of supraventricular arrhythmias (SA) refractory to anti-beta adrenergic antiarrhythmics or digoxin. Efficacy and adverse events in this cohort have not been well described. Here, we report our institutional experience of second line treatment initiation for SA in children. Utilizing an institutional database, 247 patients initiated on sotalol and 81 patients initiated on flecainide were identified. Congenital heart disease (CHD) was present in 40% of patients. Arrhythmia-free discharge on single or dual agent therapy (in combination with other antiarrhythmics) was 87% for sotalol and 91% for flecainide. Neither age, sex, dosing, presence of CHD nor arrhythmia subtype were associated with alterations in in-hospital efficacy. Compared to baseline, QTc intervals in sotalol patients (436 [416-452 ms] vs. 415 [400-431 ms], p < .01) and QRS intervals in flecainide patients (75 [68-88 ms] vs. 62 [56-71 ms], p < .01) were prolonged. Dose reduction or discontinuation due to QRS prolongation occurred in 9% of patients on flecainide. QTc prolongation resulting in dose reduction/discontinuation of sotalol was encountered in 9 patients (4%) and death with documented torsade de pointes in 2 patients (1%), with 9 of 11 patients having underlying CHD. In children requiring second line agents for treatment of SA, both sotalol and flecainide appear to be highly efficacious. Although predominantly safe in otherwise healthy patients, electrocardiogram changes can occur and children with underlying cardiac disease may have an increased risk of adverse events and rhythm-related side effects during initiation.

Post hoc assessment of the relationship among coronary stenosis, electrocardiography, and ventricular function in patients with heart disease.

Cardiovascular diseases including cardiac arrhythmias lead to fatal events in patients with coronary artery disease; however, clinical associations from echocardiography, electrocardiography (ECG), and biomarkers remain unknown. We sought to identify the factors that may be related to elevated QRS intervals in patients with risk for coronary artery disease. In this study, we performed analysis of clinical data from 503 patients divided into two groups, i.e., patients with either <50% coronary artery stenosis or >50% coronary artery stenosis. We further examined patients with elevated ECG parameters such as QRS> 100ms and QTc> 440ms. Patients with >50% coronary artery stenosis exhibited significant increases in age, triglycerides, and troponin levels. Further, ECG parameters demonstrated increased QRS and QTc durations, while echocardiographic parameters highlighted a decrease in ejection fraction (EF) and fractional shortening (FS). Patients with QTc> 440ms exhibited increased brain natriuretic peptide and creatinine levels with a decrease in estimated glomerular filtration rate clearance rates. Patients with QRS> 100ms had greater left ventricular (LV) mass and LV internal diameter in systole and diastole. Multimodal logistic regression showed significant relation between QTc, age, and creatinine. These findings suggest that patients with significant coronary stenosis may have lower EF and FS with prolonged QRS intervals, demonstrating greater risk for arrhythmic events.

Mutation of the Cardiac Sodium Channel Nav1.5 Leads to Sex Specific Arrhythmias

Introduction Cardiac Nav1.5 sodium channels, encoded by the SCN5A gene, are responsible for initiating the electrical action potential in the heart, resulting in coordinated muscular contraction. Channelopathies caused by mutations in Nav1.5 occur in 1/2500 individuals and lead to arrhythmic diseases, such as long QT syndrome, and cardiomyopathies1,2. Males with Nav1.5 mutations are at a higher risk for sudden cardiac arrest, indicative of an innate protection in females through an unknown mechanism. The gain of function Arg222Gln mutation affects the voltage sensing segment of Nav1.5, creating an aberrant pore leading to arrhythmia-inducing membrane ion leaks3. We sought to determine the sex-specific effects of this clinically relevant mutation, attempting to undercover the protective mechanisms present in females. Methods The Arg222Gln mutation was knocked into exon 6 of the mouse SCN5A gene to generate viable animals that phenocopy the human disease. Three-lead electrocardiograms (ECG) from adult male and female animals were recorded under anesthesia, including wild-type (WT) controls. Isoproterenol (β-adrenoreceptor agonist) was injected to examine electrophysiological changes under acute stress. Baseline echocardiograms were collected at four months and after 30 days of transverse aortic constriction (TAC). Differentially expressed genes from whole heart lysate were measured by chip-based analysis after TAC . Protein levels were quantified using Western blot and ELISA. Results ECG measurements revealed a prolonged QTc (0.064ms±0.006) and QRS interval (0.011ms±0.0003) in mutant males compared to WT males (0.036ms±0.008 and 0.0085ms±0.0004 respectively) (P<0.05). Mutant males had an observable sinus arrhythmia at baseline (RMSSD of beat to beat intervals of 4.60 vs 0.79 in WT males, P<0.05), whereas mutant and wild-type females had no evidence of adverse changes to the beating rhythm. The ejection fraction (EF) of mutant males decreased by 40%±9.9% 4 weeks post-TAC, whereas no significant changes in EF were observed in all other groups. We found that transcript and protein levels of pyruvate dehydrogenase kinase-4, which reduces pyruvate dehydrogenase (PDH) activity through phosphorylation, were 6-fold higher in mutant males compared to WT males (P<0.05), whereas no differences were observed between females. Despite this, phospho-PDH levels were lower and PDH activity higher in mutant males compared to WT males (P<0.01), with no differences between the female groups. Conclusion We found functional, electrophysiological, and metabolic enzyme abnormalities in male mice harboring the Arg222Gln Nav1.5 mutation. These differences did not exist in the female mutant mice. Our data illustrate a strong sex-specific phenotype, and suggest that metabolic alterations through increased PDH activity provide a protective mechanism against the arrhythmia and heart failure produced by Nav1.5-related cation leak. Further experiments will seek to determine if sex hormones alone can induce a protective effect in the context of the Arg222Gln mutation. 1Priori et al., NEJM, 2003 2Veerman et al., Gene, 2015 3Moreau et al., J Gen Physio, 2015

Inversion of T Waves on Admission is Associated with Mortality in Spontaneous Intracerebral Hemorrhage

IntroductionCardiac dysfunction directly caused by spontaneous intracerebral hemorrhage (ICH) is a poorly understood phenomenon, and its impact on outcome is still uncertain. The aim of this study is to investigate the relationship between electrocardiographic (EKG) abnormalities and mortality in ICH. MethodsThis is a retrospective study analyzing EKG patterns on admission in patients admitted with ICH at a tertiary care center over an eight-year period. For each patient, demographics, medical history, clinical presentation, EKG on admission and during hospitalization, and head CT at presentation were reviewed. Mortality was noted. ResultsA total of 301 ICH patients were included in the study. The most prevalent EKG abnormalities were QTc prolongation in 56% of patients (n = 168) followed by inversion of T waves (TWI) in 37% of patients (n = 110). QTc prolongation was associated with ganglionic location (p = 0.03) and intraventricular hemorrhage (IVH) (p = 0.01), TWIs were associated with ganglionic location (p = 0.02), and PR prolongation was associated with IVH (p = 0.01), while QRS prolongation was associated with lobar location (p < 0.01). Volume of ICH, hemispheric laterality, and involvement of insular cortex were not correlated with specific EKG patterns. In a logistic regression model, after correcting for ICH severity and prior cardiac history, presence of TWI was independently associated with mortality (OR: 3.04, CI:1.6–5.8, p < 0.01). Adding TWI to ICH score improved its prognostic accuracy (AUC 0.81, p = 0.04). Disappearance of TWI during hospitalization did not translate into improvement of survival (p = 0.5). ConclusionPresence of TWI on admission is an independent and unmodifiable factor associated with mortality in ICH. Further research is needed to elucidate the pathophysiologic mechanisms underlying electrocardiographic changes after primary intracerebral hemorrhage.