Ventricular Epicardial Action Research Articles

Pilot study to evaluate left-to-right ventricular offset in biventricular pacing-comparison of electrocardiographic imaging and ECG.

Biventricular pacing (BiVp) improves outcomes in systolic heart failure patients with electrical dyssynchrony. BiVp is delivered from epicardial left ventricular (LV) and endocardial right ventricular (RV) electrodes. Acute electrical activation changes with different LV-RV stimulation offsets can help guide individually optimized BiVp programming. We sought to study the BiVp ventricular activation with different LV-RV offsets and compare with 12-lead ECG. In five patients with BiVp (63 ± 17-year-old, 80% male, LV ejection fraction 27 ± 6%), we evaluated acute ventricular epicardial activation, varying LV-RV offsets in 20 ms increments from -40 to 80 ms, using electrocardiographic imaging (ECGI) to obtain absolute ventricular electrical uncoupling (VEUabs, absolute difference in average LV and average RV activation time) and total activation time (TAT). For each patient, we calculated the correlation between ECGI and corresponding ECG (3D-QRS-area and QRS duration) with different LV-RV offsets. The LV-RV offset to attain minimum VEUabs in individual patients ranged 20-60 ms. In all patients, a larger LV-RV offset was required to achieve minimum VEUabs (36 ± 17 ms) or 3D-QRS-area (40 ± 14 ms) than that for minimum TAT (-4 ± 9 ms) or QRS duration (-8 ± 11 ms). In individual patients, 3D-QRS-area correlated with VEUabs (r 0.65 ± 0.24) and QRS duration correlated with TAT (r 0.95 ± 0.02). Minimum VEUabs and minimum 3D-QRS-area were obtained by LV-RV offset within 20 ms of each other in all five patients. LV-RV electrical uncoupling, as assessed by ECGI, can be minimized by optimizing LV-RV stimulation offset. 3D-QRS-area is a surrogate to identify LV-RV offset that minimizes LV-RV uncoupling.

Ultra-high-frequency ECG volumetric and negative derivative epicardial ventricular electrical activation pattern

From precordial ECG leads, the conventional determination of the negative derivative of the QRS complex (ND-ECG) assesses epicardial activation. Recently we showed that ultra-high-frequency electrocardiography (UHF-ECG) determines the activation of a larger volume of the ventricular wall. We aimed to combine these two methods to investigate the potential of volumetric and epicardial ventricular activation assessment and thereby determine the transmural activation sequence. We retrospectively analyzed 390 ECG records divided into three groups-healthy subjects with normal ECG, left bundle branch block (LBBB), and right bundle branch block (RBBB) patients. Then we created UHF-ECG and ND-ECG-derived depolarization maps and computed interventricular electrical dyssynchrony. Characteristic spatio-temporal differences were found between the volumetric UHF-ECG activation patterns and epicardial ND-ECG in the Normal, LBBB, and RBBB groups, despite the overall high correlations between both methods. Interventricular electrical dyssynchrony values assessed by the ND-ECG were consistently larger than values computed by the UHF-ECG method. Noninvasively obtained UHF-ECG and ND-ECG analyses describe different ventricular dyssynchrony and the general course of ventricular depolarization. Combining both methods based on standard 12-lead ECG electrode positions allows for a more detailed analysis of volumetric and epicardial ventricular electrical activation, including the assessment of the depolarization wave direction propagation in ventricles.

Attenuation of stretch-induced arrhythmias following chemical ablation of Purkinje fibres, in isolated rabbit hearts.

Purkinje fibres (PFs) play an important role in some ventricular arrhythmias and acute ventricular stretch can evoke mechanically-induced arrhythmias. We tested whether Purkinje fibres, play a role in these arrhythmias. Pseudo-ECGs were recorded in isolated, Langendorff-perfused, rabbit hearts in which the left ventricular endocardial surface was also irrigated with Tyrode, via an indwelling catheter placed in the left ventricular lumen. The number and period of ectopic activations was measured during left ventricular lumen inflation via an indwelling fluid-filled balloon (500μL added over 2s and maintained for 15s in total). Mechanically-induced arrhythmias occurred in 70% of balloon inflations: they were maximal in the first 5s and ceased within 15s. Brief, (10s) irrigation of the left ventricular lumen with Lugol solution (IK/I2), via the indwelling catheter, reduced inflation-induced ectopics by 98% (p < 0.05). Ablation of endocardial PFs by Lugol was confirmed by Triphenyltetrazolium Chloride staining. Optical mapping revealed the left ventricular epicardial activation patterns of ectopics could have PF-mediated and focal sources. In silico modelling predicted ectopic sources originating in the endocardial region propagate to and through the Purkinje fibres network. Acute distention-induced ectopics are multi-focal, their attenuation by Lugol, their activation patterns and in silico modelling indicate a participation of Purkinje fibres in these arrhythmias.

Bariatric surgery reverses ventricular repolarisation heterogeneity in obesity: mechanistic insights into fat-related arrhythmic risk

Abstract Background Obesity is a growing global health problem that confers higher risks of atrial arrhythmias and sudden cardiac death. Despite this, the proarrhythmic substrate in obesity and its reversibility with weight loss has not been studied in-depth. Purpose To characterise the proarrhythmic substrate in obese patients, and its reversibility with bariatric surgery, using electrocardiographic imaging (ECGi). Methods ECGi was performed in 16 obese patients pre-bariatric surgery (PreSurg; mean age 43±12 years, 13 female) and 16 age- and sex-matched non-obese (lean) individuals (42±11 years). 12 of the 16 obese patients also underwent ECGi after bariatric surgery (PostSurg). Over 2000 atrial and ventricular epicardial electrograms were computed using high density body surface mapping (256-lead ECG) and heart-torso geometries from cardiac magnetic resonance imaging, by solving the inverse problem of electrocardiography. Local atrial and ventricular epicardial activation times (AT) were calculated as the steepest downslope of their respective activation complexes, and local ventricular repolarisation times (RT) as the steepest upslope of the T-wave. Atrial activation gradients (ATG) and ventricular repolarisation gradients (RTG) were calculated as the maximum difference within 10 mm radius divided by the corresponding distance. Results Body mass index was greater in PreSurg vs lean (46.7±5.5 vs 22.8±2.6 kg/m2, p&amp;lt;0.0001) and decreased with surgery (PostSurg 36.8±6.5 kg/m2, p&amp;lt;0.0001). Epicardial adipose tissue (EAT) was greater in PreSurg vs lean (83±56 vs 28±13 ml, p&amp;lt;0.0001) and decreased post-surgery (PostSurg 69±45 ml, p=0.0010). Total atrial AT was prolonged in PreSurg vs lean (62±15 vs 46±12 ms, p=0.0028), which persisted post-surgery (PostSurg 67±15 ms, p=0.86). Atrial ATG were also greater in PreSurg vs lean (26±11 vs 14±8 ms, p=0.0007) and did not change with weight loss (PostSurg 25±12, p=0.44). Ventricular RTG were greater in PreSurg vs lean (26±11 vs 15±7 ms/mm, p=0.0024) and decreased with weight loss (PostSurg 19±8, p=0.0009). Ventricular RTG were similar between PostSurg and lean (p=0.20). EAT from lean and PreSurg individuals correlated with atrial ATG (r=0.36, p=0.044) and ventricular RTG (r=0.54, p=0.0014). Ventricular AT were similar between lean (31±6 ms), PreSurg (34±5 ms) and PostSurg (35±9 ms); all p&amp;gt;0.05. Conclusion Steep ventricular repolarisation gradients and prolonged atrial activation contribute to the proarrhythmic substrate in obesity. Ventricular repolarisation gradients correlate with epicardial adiposity and both regress post-bariatric surgery. By contrast, atrial activation remains prolonged after weight loss. These results provide mechanistic insights into obesity-related arrhythmic risks and their reversibility with weight loss following bariatric surgery. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): British Heart FoundationNational Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC).

Myocardial development in crocodylians.

Recent reports confirmed the notion that there exists a rudimentary cardiac conduction system (CCS) in the crocodylian heart, and development of its ventricular part is linked to septation. We thus analyzed myocardial development with the emphasis on the CCS components and vascularization in two different crocodylian species. Using optical mapping and HNK-1 immunostaining, pacemaker activity was localized to the right-sided sinus venosus. The atrioventricular conduction was restricted to dorsal part of the atrioventricular canal. Within the ventricle, the impulse was propagated from base-to-apex initially by the trabeculae, later by the ventricular septum, in which strands of HNK-1 positivity were temporarily observed. Completion of ventricular septation correlated with transition of ventricular epicardial activation pattern to mature apex-to-base direction from two periapical foci. Despite a gradual thickening of the ventricular wall, no morphological differentiation of the Purkinje network was observed. Thin-walled coronary vessels with endothelium positive for QH1 obtained a smooth muscle coat after septation. Intramyocardial vessels were abundant especially in the rapidly thickening left ventricular wall. Most of the CCS components present in the homeiotherm hearts can be identified in the developing crocodylian heart, with a notable exception of the Purkinje network distinct from the trabeculae carneae.

Body Surface Mapping system - a potential diagnostic tool for unmasking delayed right ventricular epicardial activation in ARVC patients and phenotype-negative gene-carriers

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Selanders stiftelsen Background Life-threatening ventricular arrhythmias can occur at any stages of ARVC – the detection of early manifestations of the disease may have prognostic implications. Purpose The purpose was to explore the usefulness of a 252-leads noninvasive Body Surface Mapping (BSM) system for the detection of delayed epicardial activation in ARVC patients and phenotype-negative gene-carriers (GC). Methods Twelve patients with ARVC, 20 GC and 8 genotype and phenotype negative family members served as controls (C) were included. 12-lead ECG, signal-averaged-electrocardiogram, echocardiography, 252-lead BSM recordings and thoracic CT scan were performed in all subjects. The noninvasively reconstructed epicardial signals of the right ventricle (RV) were analysed using the Activation Time Editing tool of the BSM system. Local depolarisation was defined as the steepest negative dV/dt of the local epicardial signal. The time from the start of RV epicardial signals to the earliest local depolarisation (ELD) and to the latest local depolarisation (LLD), were measured for the whole RV and separately for the anterior free wall (AW) and inferior wall (IW). The duration of the activation, defined as LLD-ELD, was calculated for AW, IW and the whole RV. Results The ELDs was similar in all study groups whereas the LLD in the IW and whole RV was significantly longer among ARVC patients compared to C. Although the activation durations in the AW and IW did not differ between the groups, the activation duration of the whole RV was significantly longer in ARVC patients. A LLD cut off of 81ms in RV and an activation duration cut off of 49msec in RV discriminated ARVC patients from C with highest sensitivity and specificity. Based on these cut-offs, 35% of GC group had longer LLD times and 70 % had longer activation duration (figure 1). Conclusions ARVC patients as well as the majority of GC demonstrated prolonged LLD and/or activation duration times in RV compared to C, suggesting that the 252-leads noninvasive BSM system may be a useful tool for early detection of delayed RV epicardial activations. Larger studies are required to confirm our results.

Bariatric surgery reduces ventricular repolarisation gradients in obese patients - results from an electrocardiographic imaging study

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): National Institute for Health Research (NIHR) British Heart Foundation Background Obesity confers higher risks of atrial arrhythmias and is associated with abnormal ventricular repolarisation. Despite this, the proarrhythmic substrate in obesity and its reversibility with weight loss has not been studied in-depth. Purpose To characterise the proarrhythmic substrate in obese patients, and its reversibility with bariatric surgery, using electrocardiographic imaging (ECGi). Methods ECGi was performed in 8 obese patients before (PreOb) and after (PostOb) bariatric surgery (mean age 39+/-11years, 7 female), and in 8 age- and sex-matched non-obese controls (NOb) (40+/-11 years). ECGi recordings were made at rest, on exercise, and during recovery from exercise. For ECGi analysis, &amp;gt;2000 atrial and ventricular epicardial electrograms were calculated from body surface potential recordings from 256 sites and information from cardiac magnetic resonance imaging, by solving the inverse problem. Local atrial and ventricular epicardial activation times (AT) were calculated as the steepest downslope of their respective activation complexes, and local ventricular repolarisation times (RT) as the steepest upslope of the T-wave. Atrial activation gradients (ATG) and ventricular repolarisation gradients (RTG) were calculated as the maximum difference within 10mm radius divided by the corresponding Euclidean distance. Results BMI was greater in PreOb vs NOb (46.6+/-4.8 vs 23.8+/-2.6kg/m2, p&amp;lt;0.0001) and decreased with surgery (PostOb 35.3+/-4.2kg/m2, p&amp;lt;0.0001). Total atrial AT was prolonged in PreOb vs NOb (68+/-12 vs 45+/-10ms, p=0.016) and did not change post-surgery (PreOb vs PostOb: 68+/-12 vs 67+/-16ms, p=0.81). Atrial ATG were also greater in PreOb vs NOb: max 254+/-111 vs 106+/-58ms, p=0.035; mean 24+/-6 vs 12+/-6ms, p=0.0087) and did not change with weight loss (PreOb vs PostOb: max 254+/-111 vs 222+/-69ms/mm, p=0.61; mean 24+/-6 vs 21+/-7ms/mm, p=0.52). Ventricular RTG were greater in PreOb vs NOb (max: 287+/-73 vs 131+/-89ms/mm, p=0.012; mean: 33+/-10 vs 17+/-9ms/mm, p=0.0052). Ventricular RTG decreased with weight loss (PreOb vs PostOb: max 287+/-73 vs 151+/-54ms/mm, p=0.0070; mean: 33+/-10 vs 21+/-8ms/mm, p=0.018), and were similar between PostOb and NOb (max, p=0.81; mean p=0.58). Ventricular AT and RT were non-different in NOb, PreOb and PostOb. Conclusion Obesity is associated with pro-arrhythmic electrophysiological remodelling, including steeper ventricular repolarisation gradients and slower atrial activation. At 6 months post-bariatric surgery, there was a reduction in ventricular repolarisation gradients though atrial conduction abnormalities persisted. These findings provide a mechanistic insight into obesity-related arrhythmic risks and its potential reversibility with weight loss surgery.

Modeling the His-Purkinje Effect in Non-invasive Estimation of Endocardial and Epicardial Ventricular Activation

Inverse electrocardiography (iECG) estimates epi- and endocardial electrical activity from body surface potentials maps (BSPM). In individuals at risk for cardiomyopathy, non-invasive estimation of normal ventricular activation may provide valuable information to aid risk stratification to prevent sudden cardiac death. However, multiple simultaneous activation wavefronts initiated by the His-Purkinje system, severely complicate iECG. To improve the estimation of normal ventricular activation, the iECG method should accurately mimic the effect of the His-Purkinje system, which is not taken into account in the previously published multi-focal iECG. Therefore, we introduce the novel multi-wave iECG method and report on its performance. Multi-wave iECG and multi-focal iECG were tested in four patients undergoing invasive electro-anatomical mapping during normal ventricular activation. In each subject, 67-electrode BSPM were recorded and used as input for both iECG methods. The iECG and invasive local activation timing (LAT) maps were compared. Median epicardial inter-map correlation coefficient (CC) between invasive LAT maps and estimated multi-wave iECG versus multi-focal iECG was 0.61 versus 0.31. Endocardial inter-map CC was 0.54 respectively 0.22. Modeling the His-Purkinje system resulted in a physiologically realistic and robust non-invasive estimation of normal ventricular activation, which might enable the early detection of cardiac disease during normal sinus rhythm.

Comparing Non-invasive Inverse Electrocardiography With Invasive Endocardial and Epicardial Electroanatomical Mapping During Sinus Rhythm.

This study presents a novel non-invasive equivalent dipole layer (EDL) based inverse electrocardiography (iECG) technique which estimates both endocardial and epicardial ventricular activation sequences. We aimed to quantitatively compare our iECG approach with invasive electro-anatomical mapping (EAM) during sinus rhythm with the objective of enabling functional substrate imaging and sudden cardiac death risk stratification in patients with cardiomyopathy. Thirteen patients (77% males, 48 ± 20 years old) referred for endocardial and epicardial EAM underwent 67-electrode body surface potential mapping and CT imaging. The EDL-based iECG approach was improved by mimicking the effects of the His-Purkinje system on ventricular activation. EAM local activation timing (LAT) maps were compared with iECG-LAT maps using absolute differences and Pearson’s correlation coefficient, reported as mean ± standard deviation [95% confidence interval]. The correlation coefficient between iECG-LAT maps and EAM was 0.54 ± 0.19 [0.49–0.59] for epicardial activation, 0.50 ± 0.27 [0.41–0.58] for right ventricular endocardial activation and 0.44 ± 0.29 [0.32–0.56] for left ventricular endocardial activation. The absolute difference in timing between iECG maps and EAM was 17.4 ± 7.2 ms for epicardial maps, 19.5 ± 7.7 ms for right ventricular endocardial maps, 27.9 ± 8.7 ms for left ventricular endocardial maps. The absolute distance between right ventricular endocardial breakthrough sites was 30 ± 16 mm and 31 ± 17 mm for the left ventricle. The absolute distance for latest epicardial activation was median 12.8 [IQR: 2.9–29.3] mm. This first in-human quantitative comparison of iECG and invasive LAT-maps on both the endocardial and epicardial surface during sinus rhythm showed improved agreement, although with considerable absolute difference and moderate correlation coefficient. Non-invasive iECG requires further refinements to facilitate clinical implementation and risk stratification.

9-05: Both Selective And Non-Selective His Pacing Preserve Left Ventricle Activation

Purpose: His pacing provides physiological pacing by preserving ventricular activation via the His-Purkinjie system. The characteristics of selective and non-selective His capture have not been well established. Methods: The CardioInsight ECVUE(TM) system uses a 252-electrode vest to non-invasively map epicardial electrical activity from the entire myocardium in single beat. Vests were applied to four patients with heart failure undergoing His pacing. Mapping of ventricular activation was performed during selective and non-selective His pacing (as determined by the 12 lead surface ECG and intra-cardiac His signal) as well as during intrinsic ventricular activation. Results: Non-Selective His pacing resulted in early activation in the mid and basal right ventricle (RV), but subsequent RV activation matched that occurring during intrinsic activation. The epicardial ventricular activation pattern of selective His pacing was the same as activation observed during un-paced sinus rhythm. The left ventricular activation pattern observed with non-selective His pacing was identical to that seen during selective His pacing and intrinsic activation. Figure 1 depicts the activation maps derived from one patient with ischaemic cardiomyopathy (Ejection Fraction 35%) with a prolonged PR interval of 280ms but a normal QRS duration of 114ms. Left ventricular total activation time (LVTAT) did not differ significantly with non-selective His pacing compared to selective His pacing or intrinsic activation, mean change in LVTAT -0.8ms and -8ms, respectively, p = 0.8 & 0.4 in paired t-tests.

The Effect of Diabetes Mellitus on the Ventricular Epicardial Activation and Repolarization in Mice

Cardiac repolarization is prolonged in diabetes mellitus (DM), however the distribution of repolarization durations in diabetic hearts is unknown. We estimated the ventricular repolarization pattern and its relation to the ECG phenomena in diabetic mice. Potential mapping was performed on the anterior ventricular surface in healthy (n=18) and alloxan-induced diabetic (n=12) mice with the 64-electrode array. Activation times, end of repolarization times, and activation-recovery intervals (ARIs) were recorded along with limb lead ECGs. ARIs were shorter in the left as compared to right ventricular leads (P<0.05). The global dispersion of repolarization, interventricular and apicobasal repolarization gradients were greater in DM than in healthy animals (P<0.03). The increased dispersion of repolarization and apicobasal repolarization gradient in DM correlated with the prolonged QTc and Tpeak-Tend intervals, respectively. The increased ventricular repolarization heterogeneity corresponded to the electrocardiographic markers was demonstrated in DM.

Frequency distribution analysis of activation times and regional fibrosis in murine Scn5a+/− hearts: The effects of ageing and sex

Both Brugada Syndrome (BrS) and progressive cardiac conduction defect (PCCD) are associated respectively with diffuse and discrete alterations in conduction pathways affected by ageing and sex. This study assessed for contributions of such processes to the mechanism of conduction changes in Scn5a+/− and WT hearts stratified by age (3 and 12 months) and sex. In vivo electrocardiographic chest-lead assessment demonstrated greater incidences of bundle branch block in all Scn5a+/− mice compared to WT. Frequency analysis of right ventricular (RV) epicardial activation obtained from a 64-channel multi-electrode array demonstrated greater prominence of late conducting components in Scn5a+/− compared to WT male, and in male compared to female Scn5a+/− following stratification by genotype and sex. Similar differences were observed between old male Scn5a+/− and young male Scn5a+/−, old female Scn5a+/−, and old male WT, following stratification by genotype, age and sex. These findings directly correlated with histomorphometric assessment of regional fibrosis in both septa and free walls preferentially involving the RV. We demonstrate complex alterations in conduction distributions suggesting a conversion of normal to slow-conducting tissue, modulated by ageing and sex, coupled with fibrosis in Scn5a+/− hearts. These features suggest an overlap between pathophysiological processes related to BrS and PCCD in Scn5a+/− hearts.

Single-Beat Noninvasive Imaging of Ventricular Endocardial and Epicardial Activation in Patients Undergoing CRT

BackgroundLittle is known about the effect of cardiac resynchronization therapy (CRT) on endo- and epicardial ventricular activation. Noninvasive imaging of cardiac electrophysiology (NICE) is a novel imaging tool for visualization of both epi- and endocardial ventricular electrical activation.Methodology/Principal FindingsNICE was performed in ten patients with congestive heart failure (CHF) undergoing CRT and in ten patients without structural heart disease (control group). NICE is a fusion of data from high-resolution ECG mapping with a model of the patient's individual cardiothoracic anatomy created from magnetic resonance imaging. Beat-to-beat endocardial and epicardial ventricular activation sequences were computed during native rhythm as well as during ventricular pacing using a bidomain theory-based heart model to solve the related inverse problem. During right ventricular (RV) pacing control patients showed a deterioration of the ventricular activation sequence similar to the intrinsic activation pattern of CHF patients. Left ventricular propagation velocities were significantly decreased in CHF patients as compared to the control group (1.6±0.4 versus 2.1±0.5 m/sec; p<0.05). CHF patients showed right-to-left septal activation with the latest activation epicardially in the lateral wall of the left ventricle. Biventricular pacing resulted in a resynchronization of the ventricular activation sequence and in a marked decrease of total LV activation duration as compared to intrinsic conduction and RV pacing (129±16 versus 157±28 and 173±25 ms; both p<0.05).Conclusions/SignificanceEndocardial and epicardial ventricular activation can be visualized noninvasively by NICE. Identification of individual ventricular activation properties may help identify responders to CRT and to further improve response to CRT by facilitating a patient-specific lead placement and device programming.

Idiopathic premature ventricular contractions successfully ablated from the epicardial right ventricular outflow tract

A case of idiopathic premature ventricular contractions successfully ablated from the epicardial right ventricular outflow tract (RVOT) via the subxiphoid pericardial approach was described. The sites with earliest endocardial and epicardial ventricular activation were located adjacent to each other in the RVOT and at both sites, double potentials were recorded. Coronary angiography was helpful for identifying the ablation site.

Heterogeneous Connexin43 distribution in heart failure is associated with dispersed conduction and enhanced susceptibility to ventricular arrhythmias

Sudden arrhythmogenic cardiac death is a major cause of mortality in patients with congestive heart failure (CHF). To investigate determinants of the increased arrhythmogenic susceptibility, we studied cardiac remodelling and arrhythmogenicity in CHF patients and in a mouse model of chronic pressure overload. Clinical and (immuno)histological data of myocardial biopsies from CHF patients with (VT+) and without (VT-) documented ventricular arrhythmia were compared with controls. In CHF patients, ejection fraction was decreased and QRS duration was increased. Cell size and interstitial fibrosis were increased, but Connexin43 (Cx43) levels, the most abundant gap junction in ventricular myocardium, were unchanged. No differences were found between VT+ and VT- patients, except for the distribution pattern of Cx43, which was significantly more heterogeneous in VT+. Mice were subjected to transverse aortic constriction (TAC) or sham operated. At 16 weeks, cardiac function was determined by echocardiography and epicardial ventricular activation mapping was performed. Transverse aortic constriction mice had decreased fractional shortening and prolonged QRS duration. Right ventricular conduction velocity was reduced, and polymorphic VTs were induced in 44% TAC and 0% sham mice. Interstitial fibrosis was increased and Cx43 quantity was unchanged in TAC mice with and without arrhythmias. Similar to CHF patients, heterogeneous Cx43 distribution was significantly associated with arrhythmias in TAC mice and with spatial heterogeneity of impulse conduction. Heterogeneous Cx43 expression during CHF is associated with dispersed impulse conduction and may underlie enhanced susceptibility to ventricular tachyarrhythmias.

Reduction of fibrosis-related arrhythmias by chronic renin-angiotensin-aldosterone system inhibitors in an aged mouse model

Myocardial fibrosis increases arrhythmia vulnerability of the diseased heart. The renin-angiotensin-aldosterone system (RAAS) governs myocardial collagen synthesis. We hypothesized that reducing cardiac fibrosis by chronic RAAS inhibition would result in reduced arrhythmia vulnerability of the senescent mouse heart. Wild-type mice (52 wk old) were treated for 36 wk: 1) untreated control (C); 2) eplerenone (E); 3) losartan (L); and 4) cotreatment with eplerenone and losartan (EL). Ventricular epicardial activation mapping was performed on Langendorff-perfused hearts. Arrhythmia inducibility was tested by one to three premature stimuli and burst pacing. Longitudinal and transverse conduction velocity and dispersion of conduction were determined during pacing at a basic cycle length of 150 ms. Sirius red staining (collagen) was performed. As a result, in the RV of mice in the E, L, and EL groups, transverse conduction velocity was significantly increased and anisotropic ratio was significantly decreased compared with those values of mice in the C group. Anisotropic reentrant arrhythmias were induced in 52% of untreated mice and significantly reduced to 22%, 26%, and 16% in the E, L, and EL groups, respectively. Interstitial fibrosis was significantly decreased in both the RV and LV of all treated groups. Scattered patches of replacement fibrosis were found in 90% of untreated hearts, which were significantly reduced in the E, L, and EL groups. A strong correlation between the abundance of patchy fibrosis and arrhythmia inducibility was found. In conclusion, chronic RAAS inhibition limited aging-related interstitial fibrosis. The lower arrhythmogeneity of treated mice was directly correlated to the reduced amount of patchy fibrosis.

Differences in distribution of fibrosis in the ventricles underlie dominant arrhythmia vulnerability of the right ventricle in senescent mice.

Mutations that are supposed to affect right (RV) and left ventricular (LV) electrophysiology equally, often reveal dominant conduction slowing and arrhythmia vulnerability in RV. In this study we investigated the mechanism of dominant arrhythmia vulnerability of RV in senescent mice. We performed epicardial ventricular activation mapping on adult and senescent Langendorff perfused hearts. Longitudinal and transversal conduction velocity, as well as arrhythmia inducibility were determined. Subsequently, hearts were processed for immunohisto-chemistry and Picro Sirius Red staining. Senescent mice revealed decreased conduction velocity, increased aniso-tropic ratio and reduced excitation wavelength in RV, but not in LV. Arrhythmias were mainly induced in RV of senescent hearts. No arrhythmias were induced in adult hearts. Immunohistochemistry revealed that the amount of Connexin 43 and cardiac sodium channel Nav1 .5 were equally decreased, and that collagen content was equally increased in senescent RV and LV. However, patches of replacement fibrosis were found throughout the RV wall, but only in the sub-endocardium and mid-myocardium of LV. The study shows that the dominant arrhythmia vulnerability in RV of senescent mice is caused by the distribution of replacement fibrosis which involves the entire RV but only part of the LV. (Neth Heart J 2008;16:356-8.).

In calcineurin-induced cardiac hypertrophy expression of Nav1.5, Cx40 and Cx43 is reduced by different mechanisms

Alterations in expression levels of Nav1.5, Cx43 and Cx40 have been frequently reported in cardiac disease and are associated with the development of arrhythmias, but little is known about the underlying molecular mechanisms. In this study we investigated electrical conduction and expression of Nav1.5, Cx43 and Cx40 in hearts of transgenic mice overexpressing a constitutively active form of calcineurin (MHC-CnA). ECG recordings showed that atrial, atrioventricular and ventricular activation were significantly prolonged in MHC-CnA hearts as compared to wildtype (WT) littermates. Epicardial activation and arrhythmia susceptibility analysis revealed increased ventricular activation thresholds and arrhythmia vulnerability. Moreover, epicardial ventricular activation patterns in MHC-CnA mice were highly discontinuous with multiple areas of block. These impaired conduction properties were associated with severe reductions in Nav1.5, Cx43 and Cx40 protein expression in MHC-CnA hearts as visualized by immunohistochemistry and immunoblotting. Real-time RT-PCR demonstrated that the decreased protein levels for Nav1.5 and Cx40, but not for Cx43, were accompanied by corresponding reductions at the RNA level. Cx43 RNA isoform analysis indicated that the reduction in Cx43 protein expression is caused by a post-transcriptional mechanism rather than by RNA isoform switching. In contrast, RNA isoform analysis for Cx40 and Nav1.5 provided additional evidence that in calcineurin-induced hypertrophy the downregulation of these proteins originates at the transcriptional level. These results provide the molecular rationale for Nav1.5, Cx43 and Cx40 downregulation in this model of hypertrophy and failure and the development of the pro-arrhythmic substrate.

Left Ventricular Epicardial Activation Increases Transmural Dispersion of Repolarization in Healthy, Long QT, and Dilated Cardiomyopathy Dogs

Benefits of cardiac resynchronization therapy (CRT) are well established. However, less is understood concerning its effects on myocardial repolarization and the potential proarrhythmic risk. Healthy dogs (n = 8) were compared to a long QT interval (LQT) model (n = 8, induced by cesium chloride, CsCl) and a dilated cardiomyopathy with congestive heart failure (DCM-CHF, induced by rapid ventricular pacing, n = 5). Monophasic action potential (MAP) recordings were obtained from the subendocardium, midmyocardium, subepicardium, and the transmural dispersion of repolarization (TDR) was calculated. The QT interval and the interval from the peak to the end of the T wave (T(p-e)) were measured. All these characteristics were compared during left ventricular epicardial (LV-Epi), right ventricular endocardial (RV-Endo), and biventricular (Bi-V) pacing. In healthy dogs, TDR prolonged to 37.54 ms for Bi-V pacing and to 47.16 ms for LV-Epi pacing as compared to 26.75 ms for RV-Endo pacing (P < 0.001), which was parallel to an augmentation in T(p-e) interval (Bi-V pacing, 64.29 ms; LV-Epi pacing, 57.89 ms; RV-Endo pacing, 50.29 ms; P < 0.01). During CsCl exposure, Bi-V and LV-Epi pacing prolonged MAPD, TDR, and T(p-e) interval as compared to RV-Endo pacing. The midmyocardial MAPD (276.30 ms vs 257.35 ms, P < 0.0001) and TDR (33.80 ms vs 27.58 ms, P=0.002) were significantly longer in DCM-CHF dogs than those in healthy dogs. LV-Epi and Bi-V pacing further prolonged the MAPD and TDR in this model. LV-Epi and Bi-V pacing result in prolongation of ventricular repolarization time, and increase of TDR accounted for a parallel augmentation of the T(p-e) interval, which provides evidence that T(p-e) interval accurately represents TDR. These effects are magnified in the LQT and DCM-CHF canine models in addition to their intrinsic transmural heterogeneity in the intact heart. This mechanism may contribute to the development of malignant ventricular arrhythmias, such as torsades de pointes (TdP) in congestive heart failure (CHF) patients treated with CRT.

Pathophysiological mechanisms of Brugada syndrome: Depolarization disorder, repolarization disorder, or more?

After its recognition as a distinct clinical entity, Brugada syndrome is increasingly recognized worldwide as an important cause of sudden cardiac death. Brugada syndrome exhibits autosomal dominant inheritance with SCN5A, which encodes the cardiac sodium channel, as the only gene with a proven involvement in 20-30% of patients. Its signature feature is ST segment elevation in right precordial ECG leads and predisposition to malignant ventricular tachyarrhythmias. The pathophysiological mechanism of ST elevation and ventricular tachyarrhythmia, two phenomena strongly related, is controversial. Here, we review clinical and experimental studies as they provide evidence to support or disprove the two hypotheses on the mechanism of Brugada syndrome that currently receive the widest support: (1) nonuniform abbreviation of right ventricular epicardial action potentials ("repolarization disorder"), (2) conduction delay in the right ventricular outflow tract ("depolarization disorder"). We also propose a schematic representation of the depolarization disorder hypothesis. Moreover, we review recent evidence to suggest that other derangements may also contribute to the pathophysiology of Brugada syndrome, in particular, right ventricular structural derangements. In reviewing these studies, we conclude that, similar to most diseases, it is likely that Brugada syndrome is not fully explained by one single mechanism. Rather than adhering to the notion that Brugada syndrome is a monofactorial disease, we should aim for clarification of the contribution of various pathophysiological mechanisms in individual Brugada syndrome patients and tailor therapy considering each of these mechanisms.