Electrophysiological Substrate Research Articles

221 Impact of Liver Transplantation on QT Interval in Patients With Cirrhosis

Prolongation of the corrected QT-interval (QTc) is the electrophysiological hallmark of cirrhotic cardiomyopathy. However, it is unclear whether liver transplantation (LT) and associated reversal of the cirrhotic milieu affects QTc. We sought to examine whether liver transplantation had any effect on a patient’s corrected QT-interval. Consecutive adult inpatients undergoing LT between 2010-2017 at a state-wide liver transplant centre in Melbourne, Australia were included in this study. The preoperative, immediate postoperative (day 1 post-LT) and follow-up (median 6 months post-LT) QT-intervals were manually measured by a cardiologist blinded to the clinical outcomes. QTc was calculated using the Bazett formula (QT interval/√RR interval). A QTc ≥440msec in either sex was considered prolonged in liver cirrhosis. Overall, 600 ECGs among 300 patients (mean age 57±10 years) undergoing LT were assessed. 171 (57%) patients pre-LT had a QTc ≥440msec and 16 (5.2%) patients had a QTc ≥500msec. ECG at long-term follow-up (median 6 months), revealed significant reduction in QTc (451±30±429±30msec; p<0.001). Following LT, only 62 (20.6%) of patients had QTc ≥440msec. Over half of patients undergoing LT had a prolonged QT interval. LT led to normalisation of QTc in the majority of individuals within 6 months. This suggests that LT can lead to a reversal of the underlying electrophysiological substrate that characterises cirrhotic cardiomyopathy.

Cardiomyocyte-Specific STIM1 (Stromal Interaction Molecule 1) Depletion in the Adult Heart Promotes the Development of Arrhythmogenic Discordant Alternans.

STIM1 (stromal interaction molecule 1) is a calcium (Ca2+) sensor that regulates cardiac hypertrophy by triggering store-operated Ca2+ entry. Because STIM1 binding to phospholamban increases sarcoplasmic reticulum Ca2+ load independent of store-operated Ca2+ entry, we hypothesized that it controls electrophysiological function and arrhythmias in the adult heart. Inducible myocyte-restricted STIM1-KD (STIM1 knockdown) was achieved in adult mice using an αMHC (α-myosin heavy chain)-MerCreMer system. Mechanical and electrophysiological properties were examined using echocardiography in vivo and optical action potential (AP) mapping ex vivo in tamoxifen-induced STIM1flox/flox-Cretg/- (STIM1-KD) and littermate controls for STIM1flox/flox (referred to as STIM1-Ctl) and for Cretg/- without STIM deletion (referred to as Cre-Ctl). STIM1-KD mice (N=23) exhibited poor survival compared with STIM1-Ctl (N=22) and Cre-Ctl (N=11) with >50% mortality after only 8-days of cardiomyocyte-restricted STIM1-KD. STIM1-KD but not STIM1-Ctl or Cre-Ctl hearts exhibited a proclivity for arrhythmic behavior, ranging from frequent ectopy to pacing-induced ventricular tachycardia/ventricular fibrillation (VT/VF). Examination of the electrophysiological substrate revealed decreased conduction velocity and increased AP duration (APD) heterogeneity in STIM1-KD. These features, however, were comparable in VT/VF(+) and VT/VF(-) hearts. We also uncovered a marked increase in the magnitude of APD alternans during rapid pacing, and the emergence of a spatially discordant alternans profile in STIM1-KD hearts. Unlike conduction velocity slowing and APD heterogeneity, the magnitude of APD alternans was greater (by 80%, P<0.05) in VT/VF(+) versus VT/VF(-) STIM1-KD hearts. Detailed phase mapping during the initial beats of VT/VF identified one or more rotors that were localized along the nodal line separating out-of-phase alternans regions. In an adult murine model with inducible and myocyte-specific STIM1 depletion, we demonstrate for the first time the regulation of spatially discordant alternans by STIM1. Early mortality in STIM1-KD mice is likely related to enhanced susceptibility to VT/VF secondary to discordant APD alternans.

Nkx2.5 insufficiency leads to atrial electrical remodeling through Wnt signaling in HL-1 cells.

Homeobox protein Nxk-2.5 (Nkx2.5) is a homeobox transcription factor that promotes chamber-like myocardial gene expression. Data from a previous genome-wide association study suggested that Nkx2.5 may be associated with the genetic variation that underlies atrial fibrillation (AF). Nkx2.5 loss of function has been demonstrated to be associated with an increasing susceptibility of familial AF. Therefore, the aim of the present study was to investigate the effect of Nkx2.5 loss of function on electrophysiological substrates in HL-1 cells. To the best of our knowledge, the results demonstrated for the first time that Nkx2.5 expression was significantly decreased in a rat model exhibiting AF. The effect of silencing Nkx2.5 was assessed following transfection with adenoviral vectors with specific NKX2.5-shRNA. The effect of Nkx2.5 silencing on potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4), gap junction alpha-5 protein (Cx40), calcium handling proteins and protein Wnt-11 (Wnt11) expression levels was also assessed in HL-1 cells. The results revealed that Nkx2.5 silencing increased HCN4 expression, decreased Cx40 expression and disrupted the expression of calcium handling proteins. Additionally, Wnt11 signal protein expression was decreased following Nkx2.5 silencing. The results of the present study demonstrated that Nkx2.5 served as a transcriptional regulator of the electrophysiological substrates associated with AF.

P5690Comparison of two methods to navigate the stereotactic body radiotherapy ablation for ventricular tachycardia, the invasive electrophysiological study and substrate identification

Abstract Purpose To compare two methods used for identifying the arrhythmogenic substrate - invasive electrophysiological study versus PET-CT scar identification. The substrate is then targeted by stereotactic body radiotherapy (SBRT) in patients with previously unsuccessful radiofrequency catheter ablation. Methodology Patients with ischemic cardiomyopathy, LVEF less than 40% and unsuccessful conventional treatment resulting in recurring ventricular tachycardias, were divided into two groups with different methods of obtaining arrhythmogenic substrate. In the group A, invasive electrophysiological mapping was used, while in the group B, scar identification by PET-CT was done, enhanced with non-invasive body surface ecg mapping of all inducible ventricular tachycardias. This target obtained was then attacked with SBRT. We compared the size of the planned target volume (PVT), the SBRT duration, the calculated dose for the esophagus, stomach and lung and the incidence of acute complications. Cohort description Patients in group A were recruited from April 2014 to December 2018, patients in group B from June to December 2018. Group A (8 patients) – mean age 66, NYHA class 2.4, LVEF 29,4%. Group B (6 patients) – mean age 71, NYHA class 2.1, LVEF 25,2%. All patients were men. Results There was a statistically significant difference in PTV – Group A (mean 24.1ml, SD = 3,9), Group B (mean 76.0ml, SD 14.1), p&lt;0,001 (two-sample t-test). There was no difference in the calculated secondary radiation doses acquired by surrounding organs. The most frequent adverse event was acute anorexia, occurring in 4 patients from Group A and in 2 patients from Group B. The anorexia subsided in one week time. One patient from Group B suffered from esophageal ulcer, which developed 6 months after the therapy. Conclusion Using invasive electrophysiology mapping to identify arrhythmogenic substrate for SBRT yields significantly smaller volume of targeted tissue. Despite this finding, we did not find any difference neither in radiation dose delivered to the surrounding organs, nor in the radiation duration.

Noninvasive Mapping of the Electrophysiological Substrate in Cardiac Amyloidosis and Its Relationship to Structural Abnormalities.

BackgroundThe relationship between structural pathology and electrophysiological substrate in cardiac amyloidosis is unclear. Differences between light‐chain (AL) and transthyretin (ATTR) cardiac amyloidosis may have prognostic implications.Methods and Results ECG imaging and cardiac magnetic resonance studies were conducted in 21 cardiac amyloidosis patients (11 AL and 10 ATTR). Healthy volunteers were included as controls. With respect to ATTR, AL patients had lower amyloid volume (51.0/37.7 versus 73.7/16.4 mL, P=0.04), lower myocardial cell volume (42.6/19.1 versus 58.5/17.2 mL, P=0.021), and higher T1 (1172/64 versus 1109/80 ms, P=0.022) and T2 (53.4/2.9 versus 50.0/3.1 ms, P=0.003). ECG imaging revealed differences between cardiac amyloidosis and control patients in virtually all conduction‐repolarization parameters. With respect to ATTR, AL patients had lower epicardial signal amplitude (1.07/0.46 versus 1.83/1.26 mV, P=0.026), greater epicardial signal fractionation (P=0.019), and slightly higher dispersion of repolarization (187.6/65 versus 158.3/40 ms, P=0.062). No significant difference between AL and ATTR patients was found using the standard 12‐lead ECG. T1 correlated with epicardial signal amplitude (cc=−0.78), and extracellular volume with epicardial signal fractionation (cc=0.48) and repolarization time (cc=0.43). Univariate models based on single features from both cardiac magnetic resonance and ECG imaging classified AL and ATTR patients with an accuracy of 70% to 80%.ConclusionsIn this exploratory study cardiac amyloidosis was associated with ventricular conduction and repolarization abnormalities, which were more pronounced in AL than in ATTR. Combined ECG imaging–cardiac magnetic resonance analysis supports the hypothesis that additional mechanisms beyond infiltration may contribute to myocardial damage in AL amyloidosis. Further studies are needed to assess the clinical impact of this approach.

Abstract 239: Selective Right-sided Electrical Remodeling In A Pure Model Of Pulmonary Hypertension Promotes Micro-reentrant Arrhythmias

Background: Pulmonary arterial hypertension (PAH) is characterized by elevated mean PA pressures that increase right ventricular (RV) afterload, leading to RV failure. Whereas structural and mechanical decompensation in PAH are well established, the extent of electrophysiological (EP) remodeling and arrhythmia propensity are far less clear. This is, in large part, because PAH-related EP properties have been exclusively studied in the monocrotaline (MCT) model, which is confounded by major extra-pulmonary toxicities, including liver failure and direct myocardial damage. To address this knowledge gap, we performed a comprehensive evaluation of the EP substrate, including arrhythmia dynamics, in a new pure model of PAH. Methods: Sprague Dawley rats underwent surgical left pneumonectomy followed by injection of the VEGF inhibitor Sugen 5416 (S/P), or underwent no intervention (CTRL). 5 wks later, rats were euthanized for high-resolution optical action potential (AP) mapping studies in ex vivo perfused hearts. Results: 6/6 S/P vs 0/5 CTRL hearts were prone to pacing-induced VT (P&lt;.05). Underlying this differential susceptibility was disproportionate RV sided prolongation of AP duration in S/P. This, in turn, promoted the formation of right-sided AP alternans at physiological rates in S/P but not CTRL. Correspondingly, KCND2 mRNA transcripts were downregulated by 80X in the RV of S/P relative to CTRL. While propagation was impaired at all rates in S/P, the most profound decrease in conduction velocity (53%) was always observed immediately prior to VT initiation. Nav1.5 and Cx43 mRNA expression were not altered in S/P. In contrast Col1a1, Col3a1, and fibronectin transcripts were upregulated implicating fibrosis in impaired conduction. The average wavelength was significantly decreased in S/P relative to CTRL (P&lt;.05). Once generated, VT was sustained by multiple microreentrant circuits likely facilitated by the short wavelengths. Conclusion: In this pure model of PAH, we document highly selective RV-sided EP remodeling that facilitates the initiation of multi-wavelet micro-reentry underlying VT. The S/P model represents a severe form of PAH that allows the study of EP properties without the confounding influence of extra-pulmonary toxicity.

Relief Following Chronic Stress Augments Spreading Depolarization Susceptibility in Familial Hemiplegic Migraine Mice

Cortical spreading depolarization (CSD) is the electrophysiological substrate of migraine aura, and a putative trigger of trigeminovascular activation and migraine headache. Many migraineurs report stress or relief after a stress triggers an attack. We tested whether various stress conditions might modulate CSD susceptibility and whether this is dependent on genetic factors. Male and female wild type and familial hemiplegic migraine type1 (FHM1) knock-in mice heterozygous for the S218L missense mutation were subjected to acute or chronic stress, or chronic stress followed by relief (36 h). Acute stress was induced by restraint and exposure to bright light and white noise (3 h). Chronic stress was induced for 28 days by two cycles of repeated exposure of mice to a rat (7 days), physical restraint (3 days), and forced swimming (3 days). Electrical CSD threshold and KCl-induced (300 mM) CSD frequency were determined in occipital cortex in vivo at the end of each protocol. Relief after chronic stress reduced the electrical CSD threshold and increased the frequency of KCl-induced CSDs in FHM1 mutants only. Acute or chronic stress without relief did not affect CSD susceptibility in either strain. Stress status did not affect CSD propagation speed, duration or amplitude. In summary, relief after chronic stress, but not acute or chronic stress alone, augments CSD in genetically susceptible mice. Therefore, enhanced CSD susceptibility may explain why, in certain patients, migraine attacks typically occur during a period of stress relief such as weekends or holidays.

Evaluation of a real-time magnetic resonance imaging-guided electrophysiology system for structural and electrophysiological ventricular tachycardia substrate assessment.

AimsPotential advantages of real-time magnetic resonance imaging (MRI)-guided electrophysiology (MR-EP) include contemporaneous three-dimensional substrate assessment at the time of intervention, improved procedural guidance, and ablation lesion assessment. We evaluated a novel real-time MR-EP system to perform endocardial voltage mapping and assessment of delayed conduction in a porcine ischaemia–reperfusion model.Methods and resultsSites of low voltage and slow conduction identified using the system were registered and compared to regions of late gadolinium enhancement (LGE) on MRI. The Sorensen–Dice similarity coefficient (DSC) between LGE scar maps and voltage maps was computed on a nodal basis. A total of 445 electrograms were recorded in sinus rhythm (range: 30–186) using the MR-EP system including 138 electrograms from LGE regions. Pacing captured at 103 sites; 47 (45.6%) sites had a stimulus-to-QRS (S-QRS) delay of ≥40 ms. Using conventional (0.5–1.5 mV) bipolar voltage thresholds, the sensitivity and specificity of voltage mapping using the MR-EP system to identify MR-derived LGE was 57% and 96%, respectively. Voltage mapping had a better predictive ability in detecting LGE compared to S-QRS measurements using this system (area under curve: 0.907 vs. 0.840). Using an electrical threshold of 1.5 mV to define abnormal myocardium, the total DSC, scar DSC, and normal myocardium DSC between voltage maps and LGE scar maps was 79.0 ± 6.0%, 35.0 ± 10.1%, and 90.4 ± 8.6%, respectively.ConclusionLow-voltage zones and regions of delayed conduction determined using a real-time MR-EP system are moderately associated with LGE areas identified on MRI.

Changes in atrial electrophysiological and structural substrate and their relationship to histology in a long-term chronic canine atrial fibrillation model.

Atrial fibrillation (AF) is related to numerous electrophysiological changes; however, the extent of structural and electrophysiological remodeling with long-term AF is not well characterized. Dogs (n=6) were implanted with a neurostimulator in the right atrium (AF group). No implantation was done in the Control group (n=3). Electroanatomical mapping was done prior to and following more than 6 months of AF. Magnetic resonance imaging was also done to assess structural remodeling. Animals were euthanized and tissue samples were acquired for histological analysis. A significant increase was seen in the left atrial (LA) volume among all AF animals (22.25 ± 12.60 cm3 vs 34.00 ± 12.23 cm3 , P=.01). Also, mean bipolar amplitude in the LA significantly decreased from 5.96 ± 2.17mV at baseline to 3.23 ± 1.51mV (P<.01) after chronic AF. Those significant changes occurred in each anterior, lateral, posterior, septal, and roof regions as well. Additionally, the dominant frequency (DF) in the LA increased from 7.02 ± 0.37Hz to 10.12 ± 0.28Hz at chronic AF (P<.01). Moreover, the percentage of fibrosis in chronic AF animals was significantly larger than that of control animals in each location (P<.01). Canine chronic AF is accompanied by a significant decrease in intracardiac bipolar amplitudes. These decreased electrogram amplitude values are still higher than traditional cut-off values used for diseased myocardial tissue. Despite these "normal" bipolar amplitudes, there is a significant increase in DF and tissue fibrosis.

Electrophysiologic and molecular mechanisms of a frameshift NPPA mutation linked with familial atrial fibrillation

A frameshift (fs) mutation in the natriuretic peptide precursor A (NPPA) gene, encoding a mutant atrial natriuretic peptide (Mut-ANP), has been linked with familial atrial fibrillation (AF) but the underlying mechanisms by which the mutation causes AF remain unclear. We engineered 2 transgenic (TG) mouse lines expressing the wild-type (WT)-NPPA gene (H-WT-NPPA) and the human fs-Mut-NPPA gene (H-fsMut-NPPA) to test the hypothesis that mice overexpressing the human NPPA mutation are more susceptible to AF and elucidate the underlying electrophysiologic and molecular mechanisms. Transthoracic echocardiography and surface electrocardiography (ECG) were performed in H-fsMut-NPPA, H-WT-NPPA, and Non-TG mice. Invasive electrophysiology, immunohistochemistry, Western blotting and patch clamping of membrane potentials were performed. To examine the role of the Mut-ANP in ion channel remodeling, we measured plasma cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity in the 3 groups of mice. In H-fsMut-NPPA mice mean arterial pressure (MAP) was reduced when compared to H-WT-NPPA and Non-TG mice. Furthermore, injection of synthetic fs-Mut-ANP lowered the MAP in H-WT-NPPA and Non-TG mice while synthetic WT-ANP had no effect on MAP in the 3 groups of mice. ECG characterization revealed significantly prolonged QRS duration in H-fsMut-NPPA mice when compared to the other two groups. Trans-Esophageal (TE) atrial pacing of H-fsMut-NPPA mice showed increased AF burden and AF episodes when compared with H-WT-NPPA or Non-TG mice. The cardiac Na+ (NaV1.5) and Ca2+ (CaV1.2/CaV1.3) channel expression and currents (INa, ICaL) and action potential durations (APD90/APD50/APD20) were significantly reduced in H-fsMut-NPPA mice while the rectifier K+ channel current (IKs) was markedly increased when compared to the other 2 groups of mice. In addition, plasma cGMP levels were only increased in H-fsMut-NPPA mice with a corresponding reduction in plasma cAMP levels and PKA activity. In summary, we showed that mice overexpressing an AF-linked NPPA mutation are more prone to develop AF and this risk is mediated in part by remodeling of the cardiac Na+, Ca2+ and K+ channels creating an electrophysiologic substrate for reentrant AF.

Non-paroxysmal atrial fibrillation mapping: characterization of the electrophysiological substrate using a novel integrated mapping technique.

Clinical outcomes after radiofrequency catheter ablation (RFCA) remain suboptimal in the treatment of non-paroxysmal atrial fibrillation (AF). Electrophysiological mapping may improve understanding of the underlying mechanisms. To describe the arrhythmia substrate in patients with persistent (Pers) and long-standing persistent (LSPers) AF, undergoing RFCA, using an integrated mechanism mapping technique. Patients underwent high-density electroanatomical mapping before and after catheter ablation. Integrated maps characterized electrogram (EGM) cycle length (CL) in regions with repetitive-regular (RR) activations, stable wavefront propagation, fragmentation, and peak-to-peak bipolar voltage. Among 83 patients (72% male, 60 ± 11 years old), RR activations were identified in 376 regions (mean CL 180 ± 31 ms). PersAF patients (n = 43) showed more RR sites per patient (5.3 ± 2.4 vs. 3.7 ± 2.1, P = 0.002) with faster CL (166 ± 29 vs. 190 ± 29 ms; P < 0.001) and smaller surface area of fragmented EGMs (15 ± 14% vs. 27 ± 17%, P < 0.001) compared with LSPersAF. The post-ablation map in 50 patients remaining in AF, documented reduction of the RR activities per patient (1.5 ± 0.7 vs. 3.7 ± 1.4, P < 0.001) and area of fragmentation (22 ± 17% vs. 8 ± 9%, P < 0.001). Atrial fibrillation termination during ablation occurred at RR sites (0.48 ± 0.24 mV; 170.5 ± 20.2 ms CL) in 31/33 patients (94%). At the latest follow-up, arrhythmia freedom was higher among patients receiving ablation >75% of RR sites (Q4 82.6%, Q3 63.1%, Q2 35.1%, and Q1 0%; P < 0.001). The integrated mapping technique allowed characterization of multiple arrhythmic substrates in non-paroxysmal AF patients. This technique might serve as tool for a substrate-targeted ablation approach.

Application of nonlinear methods to discriminate fractionated electrograms in paroxysmal versus persistent atrial fibrillation

Background and ObjectiveComplex fractionated atrial electrograms (CFAE) may contain information concerning the electrophysiological substrate of atrial fibrillation (AF); therefore they are of interest to guide catheter ablation treatment of AF. Electrogram signals are shaped by activation events, which are dynamical in nature. This makes it difficult to establish those signal properties that can provide insight into the ablation site location. Nonlinear measures may improve information. To test this hypothesis, we used nonlinear measures to analyze CFAE. MethodsCFAE from several atrial sites, recorded for a duration of 16 s, were acquired from 10 patients with persistent and 9 patients with paroxysmal AF. These signals were appraised using non-overlapping windows of 1-, 2- and 4-s durations. The resulting data sets were analyzed with Recurrence Plots (RP) and Recurrence Quantification Analysis (RQA). The data was also quantified via entropy measures. ResultsRQA exhibited unique plots for persistent versus paroxysmal AF. Similar patterns were observed to be repeated throughout the RPs. Trends were consistent for signal segments of 1 and 2 s as well as 4 s in duration. This was suggestive that the underlying signal generation process is also repetitive, and that repetitiveness can be detected even in 1-s sequences. The results also showed that most entropy metrics exhibited higher measurement values (closer to equilibrium) for persistent AF data. It was also found that Determinism (DET), Trapping Time (TT), and Modified Multiscale Entropy (MMSE), extracted from signals that were acquired from locations at the posterior atrial free wall, are highly discriminative of persistent versus paroxysmal AF data. ConclusionsShort data sequences are sufficient to provide information to discern persistent versus paroxysmal AF data with a significant difference, and can be useful to detect repeating patterns of atrial activation.

QT Assessment in Early Drug Development: The Long and the Short of It.

The QT interval occupies a pivotal role in drug development as a surface biomarker of ventricular repolarization. The electrophysiologic substrate for QT prolongation coupled with reports of non-cardiac drugs producing lethal arrhythmias captured worldwide attention from government regulators eventuating in a series of guidance documents that require virtually all new chemical compounds to undergo rigorous preclinical and clinical testing to profile their QT liability. While prolongation or shortening of the QT interval may herald the appearance of serious cardiac arrhythmias, the positive predictive value of an abnormal QT measurement for these arrhythmias is modest, especially in the absence of confounding clinical features or a congenital predisposition that increases the risk of syncope and sudden death. Consequently, there has been a paradigm shift to assess a compound’s cardiac risk of arrhythmias centered on a mechanistic approach to arrhythmogenesis rather than focusing solely on the QT interval. This entails both robust preclinical and clinical assays along with the emergence of concentration QT modeling as a primary analysis tool to determine whether delayed ventricular repolarization is present. The purpose of this review is to provide a comprehensive understanding of the QT interval and highlight its central role in early drug development.

Evolution of post–pulmonary vein isolation atrial fibrillation inducibility at redo ablation: Electrophysiological evidence of extra–pulmonary vein substrate progression

The electrophysiological substrate underlying atrial fibrillation (AF) progression remains difficult to identify. The goals of this study were to study the evolution of post-pulmonary vein isolation (PVI) AF inducibility (AFI) after AF ablation and to compare patients with organized atrial tachycardia recurrence (OATr) versus those with paroxysmal or persistent AF recurrence. We studied 99 patients who underwent de novo AF ablation (p1) and redo ablation (p2) for AF recurrence (AFr) or OATr. Stepwise AF ablation was performed at p1 and p2: (1) PVI, (2) coronary sinus defragmentation, and (3) left atrial (LA) defragmentation. Burst pacing followed each step, with AFI defined as sustained AF >5 minutes, triggering the next step. Patients with OATr underwent OAT ablation and inducibility testing post-redo PVI. Inducibility progression (IP) was defined as AFI at further steps of p2 compared to p1. Among patients with AFr, 34 of 72 patients (47%) exhibited post-PVI IP vs 2 of 27 (7.4%) patients with OATr (P = .0002). Stratification for persistent AF/paroxysmal AF/OATr showed a consistent association between recurrence phenotype and IP. Pulmonary vein (PV) reconnection incidence was 90%, without association with recurrence type or IP. LA volume was larger in patients with IP than in those without IP (86.7 ± 25.3 mL vs 72.0 ± 28.9 mL; P=.001). Right atrial dimensions increased between p1 and p2 in patients with IP vs no IP and in patients with AFr vs OATr. Patients with AFr after first ablation exhibit IP more frequently at redo ablation than do patients with OATr. IP correlates with more advanced AFr type, larger LA volumes, and progressive right atrial enlargement. PV reconnection is not associated with AFr. Changes in post-PVI AFI may accurately indicate progression of extra-PV AF-maintaining substrate.

Cardiac Electrical Vulnerability after Acute Myocardial Infarction Associated with Respiratory Infections

Heart rate variability and the presence of late potentials are independent predictor factors for cardiac death and electrical vulnerability of the ischemic myocardium, especially after myocardial infarction(MI). Respiratory infection are known to be associated with MI both through direct action of the pathogen and by altering the hemodynamic status, through tachycardia and a rise in myocardial oxigen demand. Our paper wants to highlight that respiratory infection during subacute and late recovery phase of myocardial infarction can aggravate the electrical vulnerability of the myocardium and increases the arrhythmic risk. We analysed heart rate variability and the presence of late potentials on signal-averaged ECG in patients who developed acute respiratory infection after MI. All parameters of heart rate variability were signifficantly decreased in our target group. Incidence of late potentials did not differ between the two groups, meaning that the electrophysiological substrate of arrhythmias was not influenced by respiratory infection. Ventricular arrhythmias were more severe and frequent in the infection group. Respiratory infectious disease in early and late recovery phase after acute myocardial infarction, increases the risk of life threatening arrhythmias. It must be emphasized the need to consider prevention and early treatment of respiratory viral or bacterial infections, particularly in patients with cardiac ischemic disease.

Global Electrical Heterogeneity: Mechanisms and Clinical Significance.

This review summarizes recent findings and discusses a clinical significance of a vectorcardiographic (VCG) Global electrical heterogeneity (GEH). GEH concept is based on the concept of the spatial ventricular gradient (SVG), which is a global measure of the dispersion of total recovery time. We quantify GEH by measuring five features of the SVG vector (SVG magnitude, direction (azimuth and elevation), a scalar value, and spatial QRS-T angle) on orthogonal XYZ ECG. In analysis of more than 20,000 adults we showed that GEH is independently associated with sudden cardiac death (SCD) after adjustment for demographics, cardiovascular disease (time-updated incident non-fatal cardiovascular events [coronary heart disease, heart failure, stroke, atrial fibrillation, use of beta-blockers], and known risk factors [cholesterol, triglycerides, physical activity index, smoking, diabetes, obesity, hypertension, anti-hypertensive medications, creatinine, alcohol intake, left ventricular ejection fraction, and time-updated ECG metrics (heart rate, QTc, QRS duration, ECG-left ventricular hypertrophy, bundle branch block or interventricular conduction delay)]. This finding suggests that GEH represents an independent electrophysiological substrate of SCD.

Intra-tracheal gene delivery of aerosolized SERCA2a to the lung suppresses ventricular arrhythmias in a model of pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) results in right ventricular (RV) failure, electro-mechanical dysfunction and heightened risk of sudden cardiac death (SCD), although exact mechanisms and predisposing factors remain unclear. Because impaired chronotropic response to exercise is a strong predictor of early mortality in patients with PAH, we hypothesized that progressive elevation in heart rate can unmask ventricular tachyarrhythmias (VT) in a rodent model of monocrotaline (MCT)-induced PAH. We further hypothesized that intra-tracheal gene delivery of aerosolized AAV1.SERCA2a (AAV1.S2a), an approach which improves pulmonary vascular remodeling in PAH, can suppress VT in this model. ObjectiveTo determine the efficacy of pulmonary AAV1.S2a in reversing electrophysiological (EP) remodeling and suppressing VT in PAH. MethodsMale rats received subcutaneous injection of MCT (60 mg/kg) leading to advanced PAH. Three weeks following MCT, rats underwent intra-tracheal delivery of aerosolized AAV1.S2a (MCT + S2a, N = 8) or saline (MCT, N = 9). Age-matched rats served as controls (CTRL, N = 7). The EP substrate and risk of VT were determined using high-resolution optical action potential (AP) mapping ex vivo. The expression levels of key ion channel subunits, fibrosis markers and hypertrophy indices were measured by RT-PCR and histochemical analyses. ResultsOver 80% of MCT but none of the CTRL hearts were prone to sustained VT by rapid pacing (P < .01). Aerosolized gene delivery of AAV1.S2a to the lung suppressed the incidence of VT to <15% (P < .05). Investigation of the EP substrate revealed marked prolongation of AP duration (APD), increased APD heterogeneity, a reversal in the trans-epicardial APD gradient, and marked conduction slowing in untreated MCT compared to CTRL hearts. These myocardial EP changes coincided with major remodeling in the expression of K and Ca channel subunits, decreased expression of Cx43 and increased expression of pro-fibrotic and pro-hypertrophic markers. Intra-tracheal gene delivery of aerosolized AAV1 carrying S2a but not luciferase resulted in selective upregulation of the human isoform of SERCA2a in the lung but not the heart. This pulmonary intervention, in turn, ameliorated MCT-induced APD prolongation, reversed spatial APD heterogeneity, normalized myocardial conduction, and suppressed the incidence of pacing-induced VT. Comparison of the minimal conduction velocity (CV) generated at the fastest pacing rate before onset of VT or at the end of the protocol revealed significantly lower values in untreated compared to AAV1.S2a treated PAH and CTRL hearts. Reversal of EP remodeling by pulmonary AAV1.S2a gene delivery was accompanied by restored expression of key ion channel transcripts. Restored expression of Cx43 and collagen but not the pore-forming Na channel subunit Nav1.5 likely ameliorated VT by improving CV at rapid rates in PAH. ConclusionAerosolized AAV1.S2a gene delivery selectively to the lungs ameliorates myocardial EP remodeling and VT susceptibility at rapid heart rates. Our findings highlight for the first time the utility of a non-cardiac gene therapy approach for arrhythmia suppression.

Electroanatomical Remodeling oftheAtria in Obesity: Impact of Adjacent Epicardial Fat.

The aims of the study were to characterize: 1) electrical and electroanatomical remodeling in patients with atrial fibrillation (AF) with obesity; and 2) the impact of epicardial fat depots on adjacent atrial tissue. Obesity is associated with an increased risk of AF. A total of 115 patients with AF who underwent AF ablation were screened. After exclusion, 26 patients were divided into 2 groups (obese: body mass index [BMI]≥27 kg/m2 and reference: BMI<27 kg/m2). They underwent cardiac magnetic resonance (CMR) imaging and electroanatomic mapping of the left atrium (LA) in sinus rhythm before AF ablation. Atrial and ventricular epicardial adipose tissue (EAT) were assessed by CMR. The following electrophysiological parameters were assessed: global and regional voltage, conduction velocity (CV), electrogram fractionation, and CV heterogeneity. In addition, the regional relationship between LA EAT depots and the electrophysiological substrate was evaluated. The BMIs of the obese and reference groups were 30.2 ± 2.6 and 25.2 ± 1.3 kg/m2, respectively (p< 0.001). There was no difference in the left ventricular ejection fraction and a nonsignificant increase in LA size with obesity. Obesity was associated with increase in all measures of EAT (p< 0.05), with a predominant distribution adjacent to the posterior LA and the atrioventricular groove. Obesity was associated with reduced global CV (0.86 ± 0.31 m/s vs. 1.26 ± 0.29 m/s; p< 0.001), with a nonsignificant increase in conduction heterogeneity (p= 0.10), increased fractionation (54 ± 17% vs. 25 ± 10%; p< 0.001), and regional alteration in voltage (p< 0.001). Although the global LA voltage was preserved, there was greater voltage heterogeneity (p= 0.001) and increased low-voltage areas (13.9% vs. 3.4%; p< 0.001) in the obese group compared with the reference group. The low voltage areas were predominantly seen in the posterior and/or inferior LA, which was similar to location of EAT on CMR imaging. Among various measures of obesity, LA EAT volume correlated best with posterior LA fractionation (r2= 0.55 for LA EAT volume vs. r2= 0.36 for BMI) and CV (r2= 0.31 for LA EAT volume vs. r2= 0.22 for BMI). Obesity is associated with electroanatomical remodeling of the atria, with areas of low voltage, conduction slowing, and greater fractionation of electrograms. These changes were more pronounced in regions adjacent to epicardial fat depots, which suggested a role for fat depots in the development of the AF substrate.

Epicardial ventricular tachycardia in ischemic cardiomyopathy: Prevalence, electrophysiological characteristics, and long-term ablation outcomes.

The characteristics of the epicardial (EPI) substrate responsible for ventricular tachycardia (VT) in ischemic cardiomyopathy (ICM) are undefined, and data on the long-term outcomes of EPI catheter ablation limited. We evaluated the prevalence, electrophysiologic features, and outcomes of catheter ablation of EPI VT in ICM. From December 2010 to June 2013, a total of 13 of 93 (14%) patients with ICM underwent catheter ablation at our institution and had conclusive evidence of critical EPI substrate demonstrated to participatein VT with activation, entrainment and/or pace mapping during sinus rhythm (two other patients underwent EPI mapping but had no optimal ablation targets). The electrophysiologic substrate characteristics and activation/entrainment mapping data were compared with a reference group of ICM patients without evidence of critical EPI substrate (N = 44), defined as a complete procedural success (noninducibility of any VT at programmed stimulation) after endocardial (ENDO)-only ablation. Patients with failed EPI access (N = 2) or history of cardiac surgery (N = 92) were excluded from the study. All 13 patients had evidence of abnormal EPI substrate with fractionated/late/split electrograms and low-bipolar voltage areas. The critical VT ablation sites were all located within the EPI bipolar "dense" scar (<1.0 mV) opposite the ENDO bipolar scar in 77% of cases and extending beyond the ENDO bipolar scar (within the ENDO unipolar low-voltage area) in the remaining patients. Compared with the reference ENDO-only group, patients with EPI VT had a smaller ENDO bipolar scar area, 54.0 (37.1-84) vs 86.7 (55.6-112) cm2 ; P = 0.0159, with a similar extent of ENDO unipolar low voltage. No other substrate characteristics or location differed between the two groups. After 35.2 ± 24.2 months of follow-up, VT-free survival was 73% in patients with EPI VT compared with 66% in the ENDO-only group (log-rank P = 0.56). The presence of the critical EPI substrate responsible for VT can be demonstrated in at least 14% of patients with ICM. The majority of EPI critical ablation sites are distributed oppositethe ENDO bipolar scar area and catheter ablation is effective in achieving long-term arrhythmia control.

Electrophysiologic Substrate, Safety, Procedural Approaches, and Outcomes of Catheter Ablation for Ventricular Tachycardia in Patients After Aortic Valve Replacement

This study sought to investigate the substrate, procedural strategies, safety, and outcomes of catheter ablation (CA) for ventricular tachycardia (VT) in patients with aortic valve replacement (AVR). VT ablation in patients with AVR is challenging, particularly when mapping and ablation in the periaortic region are necessary. We identified consecutive patients with mechanical, bioprosthetic, and transcatheter AVR who underwent CA for VT refractory to antiarrhythmic drugs and analyzed VT substrate, approach to LV access, complications, and long-term outcomes. Overall, 29 patients (87% men, mean age 67.9 ± 9.8 years, left ventricular ejection fraction 39 ± 10%) with prior AVR (13 mechanical, 15 bioprosthetic, 1 transcatheter AVR) underwent 40 ablations from 2004 to 2016. Left-sided mapping/CA was performed in 27 patients (36 procedures). Access was retrograde aortic in 11 procedures (all bioprosthetic), transseptal in 24 (13 mechanical; 10 bioprosthetic; 1 transcatheter AVR), or transventricular septal in 1. Periaortic bipolar or unipolar scar was detected in all 24 patients in whom detailed periaortic mapping was performed. Clinical VT circuit(s) involved the periaortic region in 10 patients (34%), 2 (7%) had bundle branch re-entry VT, and 17 (59%) had substrate unrelated to AVR. There were 2 major complications (both related to vascular access). Only 2 patients (9.1%) had VT recurrence. Over median follow-up of 12.8 months, 11 patients died (none as a result of recurrent VT). Whereas most patients undergoing CA for VT after AVR had VT from substrate unrelated to AVR, periaortic scar is universally present and bundle branch re-entry can be the VT mechanism. CA can be safely performed with excellent long-term VT elimination.