Activation-recovery Interval Dispersion Research Articles

Non-invasive electrocardiographic assessment of arrhythmic risk in ischaemic cardiomyopathy patients undergoing revasularisation

Abstract Background Ventricular arrhythmias are a leading cause of death in patients with ischaemic cardiomyopathy (ICM). Ischaemia is thought to increase arrhythmic risk and coronary revascularisation is frequently undertaken to reduce this risk, although the recent REVIVED-BCIS2 trial did not show a difference in the incidence of death, device therapies or sustained arrhythmias in patients assigned to have percutaneous coronary intervention (PCI) compared to optimal medical therapy alone(1). Purpose We assessed the mechanistic effects of revascularisation on arrhythmic risk in patients with ICM using non-invasive electrocardiographic imaging (ECGi). Methods Patients were eligible if they had a left ventricular ejection fraction (LVEF) <40%, extensive coronary disease (BCIS Jeopardy Score≥6) and were scheduled to undergo revascularisation with coronary artery bypass grafting or PCI. ECGi assessment was performed using a 252-electrode vest with anatomical co-registration using a CT thorax. Patients underwent stress perfusion cardiac magnetic resonance (CMR) imaging; both ECGi and CMR were conducted at baseline and 3 months post revascularisation(Figure 1). The primary outcome measure was dispersion of repolarisation measured using global activation recovery interval (ARI) dispersion. Secondary outcome measures included repolarisation time (RT) dispersion, mean ARI and LV ARI dispersion. We also assessed the relationship between ARI dispersion, revascularisation and left ventricular scar burden. Data are presented as mean ± SD or median [IQR]. Results Thirty patients were recruited between 2020-2023; age 67±11 years, 90% male, BMI 28±5 and baseline LVEF was 29±8%. Twelve patients underwent CABG, 18 (60%) had PCI. The BCIS jeopardy score was 10 [9-11] at enrolment and decreased to 2 [0-4] after revascularisation. The LV scar burden at baseline was 15.1±6.5% and the change at 3 months was -0.5±5% (p=0.70). ARI dispersion and LV ARI dispersion were correlated with LV scar burden (r=0.62,p=0.01 and 0.71,p=0.002 respectively). No differences were seen in ARI dispersion (44.5 vs 44.1, p=0.86) or secondary outcome measures before and after revascularisation (RT dispersion: 45.5 vs 44.7, p=0.49; Mean ARI: 281.3 vs 282.6, p=0.74; ARI dispersion: 44.5 vs 44.1, p=0.86; LV ARI dispersion: 38.4 vs 36.7, p=0.39)(Figure 2). The LVEF change on CMR at 3 months was +6.9±10%; no relationship was seen between change in LVEF and ARI dispersion. Conclusion Arrhythmic risk assessed by non-invasive ECGi was not altered by coronary revascularisation. LV ARI dispersion was highly correlated with scar burden, which is not altered by revascularisation. Future work includes analysis of perfusion data. Our results support the findings of the REVIVED arrhythmia study that revascularisation does not reduce arrhythmic risk in patients with ICM(1). ECGi derived LV ARI dispersion correlates with scar and may represent a non-invasive arrhythmic risk assessment tool.Figure 1Figure 2

Left bundle branch area pacing reduces epicardial dispersion of repolarization compared with biventricular cardiac resynchronization therapy

Biventricular endocardial pacing (BiV-endo) and left bundle branch area pacing (LBBAP) are novel methods of delivering cardiac resynchronization therapy. These techniques are associated with improved activation times and acute hemodynamic response compared with conventional biventricular epicardial pacing (BiV-epi); however, the effects on repolarization and arrhythmic risk are unknown. The purpose of this study was to compare the effects of temporary BiV-epi, BiV-endo, and LBBAP on epicardial left ventricular (LV) repolarization using electrocardiographic imaging (ECGi). Eleven patients indicated for cardiac resynchronization therapy underwent a temporary pacing protocol with ECGi. BiV-endo was delivered via endocardial stimulation of the LV lateral wall. LBBAP was delivered by pacing the LV septum. Epicardial LV repolarization time (LVRT-95; time taken for 95% of the LV to repolarize), LV RT dispersion, mean LV activation recovery interval (ARI), LV ARI dispersion, and RT gradients were calculated. The protocol was completed in 10 patients. During LBBAP, there were significant reductions in LVRT-95 (94.9 ± 17.4 ms vs 125.0 ± 29.4 ms; P=.03) and LV RT dispersion (29.4 ± 6.3 ms vs 40.8 ± 11.4 ms; P = .015) compared with BiV-epi. In contrast, there were no significant differences between baseline, BiV-epi, or BiV-endo. There was a nonsignificant reduction in mean RT gradients between LBBAP and baseline rhythm (0.74 ± 0.22 ms/mm vs 1.01 ± 0.31 ms/mm; P = .07). There were no significant differences in mean LV ARI or LV ARI dispersion between groups. Temporary LBBAP reduces epicardial dispersion of repolarization compared with conventional BiV-epi. Further study is required to determine whether these repolarization changes on ECGi translate into a reduced risk of ventricular arrhythmia in clinical practice.

Conduction Velocity Dispersion Predicts Postinfarct Ventricular Tachycardia Circuit Sites and Associates With Lipomatous Metaplasia

BackgroundRegional myocardial conduction velocity (CV) dispersion has not been studied in postinfarct patients with ventricular tachycardia (VT). ObjectivesThis study sought to compare the following: 1) the association of CV dispersion vs repolarization dispersion with VT circuit sites; and 2) myocardial lipomatous metaplasia (LM) vs fibrosis as the anatomic substrate for CV dispersion. MethodsAmong 33 postinfarct patients with VT, we characterized dense and border zone infarct tissue by late gadolinium enhancement cardiac magnetic resonance, and LM by computed tomography, with both images registered with electroanatomic maps. Activation recovery interval (ARI) was the time interval from the minimum derivative within the QRS complex to the maximum derivative within the T-wave on unipolar electrograms. CV at each EAM point was the mean CV between that point and 5 adjacent points along the activation wave front. CV and ARI dispersion were the coefficient of variation (CoV) of CV and ARI per American Heart Association (AHA) segment, respectively. ResultsRegional CV dispersion exhibited a much larger range than ARI dispersion, with median 0.65 vs 0.24; P < 0.001. CV dispersion was a more robust predictor of the number of critical VT sites per AHA segment than ARI dispersion. Regional LM area was more strongly associated with CV dispersion than fibrosis area. LM area was larger (median 0.44 vs 0.20 cm2; P < 0.001) in AHA segments with mean CV <36 cm/s and CoV_CV >0.65 than those with mean CV <36 cm/s and CoV_CV <0.65. ConclusionsRegional CV dispersion more strongly predicts VT circuit sites than repolarization dispersion, and LM is a critical substrate for CV dispersion.

Lipomatous metaplasia prolongs repolarization and increases repolarization dispersion within post-infarct ventricular tachycardia circuit cites.

Post-infarct myocardium contains viable corridors traversing scar or lipomatous metaplasia (LM). Ventricular tachycardia (VT) circuitry has been separately reported to associate with corridors that traverse LM and with repolarization heterogeneity. We examined the association of corridor activation recovery interval (ARI) and ARI dispersion with surrounding tissue type. The cohort included 33 post-infarct patients from the prospective Intra-Myocardial Fat Deposition and Ventricular Tachycardia in Cardiomyopathy (INFINITY) study. We co-registered scar and corridors from late gadolinium enhanced magnetic resonance, and LM from computed tomography with intracardiac electrogram locations. Activation recovery interval was calculated during sinus or ventricular pacing, as the time interval from the minimum derivative within the QRS to the maximum derivative within the T-wave on unipolar electrograms. Regional ARI dispersion was defined as the standard deviation (SD) of ARI per AHA segment (ARISD). Lipomatous metaplasia exhibited higher ARI than scar [325 (interquartile range 270-392) vs. 313 (255-374), P < 0.001]. Corridors critical to VT re-entry were more likely to traverse through or near LM and displayed prolonged ARI compared with non-critical corridors [355 (319-397) vs. 302 (279-333) ms, P < 0.001]. ARISD was more closely associated with LM than with scar (likelihood ratio χ2 50 vs. 12, and 4.2-unit vs. 0.9-unit increase in 0.01*Log(ARISD) per 1 cm2 increase per AHA segment). Additionally, LM and scar exhibited interaction (P < 0.001) in their association with ARISD. Lipomatous metaplasia is closely associated with prolonged local action potential duration of corridors and ARI dispersion, which may facilitate the propensity of VT circuit re-entry.

Abstract 12655: Lipomatous Metaplasia in Chronic Infarcts is Associated With Prolonged Activation Recovery Interval Within Ventricular Tachycardia Corridors

Introduction: We studied the association of infarct scar versus lipomatous metaplasia (LM) with the activation recovery interval (ARI) in putative ventricular tachycardia (VT) corridors traversing the infarct zone. Methods: The cohort included 32 patients from the prospective Intra-Myocardial Fat Deposition and Ventricular Tachycardia in Ischemic Cardiomyopathy (INFINITY) study. We defined myocardial scar, border zone (BZ) and potential viable corridors through infarct by late gadolinium enhancement (LGE)-cardiac magnetic resonance (CMR), and LM by computed tomography (CT). The images were registered with electroanatomic maps wherein the ARI of each point (1,530 within LM, 4,946 within scar) was calculated using a custom Python code as the time interval from the minimum derivative within the QRS to the maximum derivative within the T wave. ARI dispersion was defined as the standard deviation (SD) of ARI per AHA segment. Multilevel random effects linear regression models, clustered by patient, were used to evaluate the association between ARI (or ARI dispersion) with tissue types. Results: LM exhibited higher myocardial ARI than normal myocardium, BZ, scar [regression coefficient: 35.5 vs. 0, 11.4, and 25.4, P &lt;0.001]. Of 100 corridors computed from LGE-CMR and electrophysiologically confirmed to participate in VT reentry, 97 traversed through or near LM, and displayed prolonged ARI compared to 123 non-critical corridors distant from LM [356 (319, 396) vs. 283 (266, 316) ms, P &lt;0.001, Figure 1]. The association of LM with Log(ARI SD ) was more robust than that of scar (likelihood ratio χ 2 47.5 vs. 23.4, and 5.9% vs. 1.6% increase in Log(ARI SD ) /1 cm 2 increase per AHA segment, respectively). Additionally, LM and scar exhibited interaction (p&lt;0.001) in their association with Log(ARI SD ). Conclusion: LM is closely associated with prolonged local action potential duration of corridors and ARI dispersion, which may facilitate the propensity of VT circuit reentry.

Dispersion of repolarization increases after cardiac resynchronization therapy in patients who do not undergo left ventricular reverse remodelling

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Wellcome/EPSRC Centre for Medical Engineering CardioInsight Inc. Background The effect of CRT on dispersion of repolarization and arrhythmic risk is unclear. LV epicardial pacing has been associated with increased dispersion of repolarization, which may be due to altered activation and repolarization sequence. However, while CRT-induced ventricular arrhythmias have been reported, evidence from large clinical trials suggest CRT has a favourable effect on arrhythmic risk, with a lower incidence of arrhythmia in patients who undergo LV reverse remodelling. Purpose To investigate the effect of CRT and LV reverse remodelling on dispersion of repolarization using electrocardiographic imaging (ECGi). Methods 11 patients with heart failure and electrical dyssynchrony underwent ECGi after CRT implant and again at 6 months. Reconstructed epicardial electrograms were used to create maps of activation recovery intervals (ARI), an accepted surrogate for action potential duration, which were corrected for heart rate. LV ARI dispersion was calculated as the standard deviation of ARI across the LV epicardium. The methodology is summarized in figure 1. Results Mean age at implant was 74±10 years and 82% of patients were male. 64% had ischaemic aetiology of heart failure, and mean LV ejection fraction was 29±10%. 64% of patients had underlying LBBB, 28% had an RV-paced rhythm and 9% had RBBB. 8 patients had a ≥15% reduction in LV end-systolic volume (LVESV) with CRT at 6 months (volumetric responders). Example ARI maps for 1 patient are shown in figure 2A. There was a significant increase in LV ARI dispersion at 6 months compared to baseline (36.4±7.2ms vs 28.2±7.7ms; P=0.03) [Fig 2B]. In a multiple linear regression analysis, volumetric response was an independent predictor of relative change in LV ARI dispersion from baseline to 6 months (P=0.04). In a sub-analysis, for volumetric responders there was no significant difference in LV ARI dispersion between baseline and CRT at 6 months (36.4 ±6.1 vs 30.1±7.8 ms; P=0.1). In comparison, in volumetric non-responders there was a significant increase in LV ARI dispersion (38.3±1.2 vs 22.6±2.6 ms; P=0.01). The relative change in LV ARI dispersion from baseline to CRT 6-months was greater for volumetric non-responders compared to volumetric responders (70.7 ±21.3% vs 27.0 ±35.4%; P=0.04) [Fig 2C]. There was a moderate negative correlation between relative change in LV ARI dispersion and relative reduction in LVESV (R=-0.5), however this did not meet statistical significance (P=0.12) [Fig 2D]. Conclusion CRT increases dispersion of repolarization at 6 months. However, this potentially arrhythmogenic effect of epicardial pacing was only observed in CRT non-responders, which is in keeping with previous evidence that LV reverse remodelling reduces risk of ventricular arrhythmia.

His resynchronization therapy produces more physiological ventricular repolarisation compared with biventricular pacing

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation BACKGROUND Biventricular pacing (BVP) is known to shorten activation time in patients with heart failure and left bundle branch block (LBBB) but its effects on repolarisation are not well studied. His bundle pacing (HBP) can correct LBBB to deliver cardiac resynchronization therapy (HBP-CRT), producing more physiological ventricular activation time and pattern than BVP. It is not known whether this translates to more physiological repolarisation, and if so whether the effect is mediated through its effects on activation. PURPOSE We measured the effects of HBP-CRT and BVP on left ventricular repolarisation using non-invasive epicardial mapping (ECGI). METHODS Patients were recruited in two groups. 1) Patients scheduled for clinically indicated BVP procedures for heart failure with LBBB, 2) Individuals with narrow QRS, normal ventricular function and intact conduction systems. Using non-invasive electrocardiographic imaging, we identified patients with LBBB in whom HBP shortened ECGI-derived left ventricular (LV) activation time by &amp;gt;10ms. We compared the effects of HBP and BVP on ECGI-derived dispersion of LV repolarisation times and activation-recovery intervals (a surrogate for action potential duration). RESULTS 21 patients in whom HBP shortened LV activation time by &amp;gt;10ms and an equal number of individuals with narrow intrinsic QRS were recruited. LV repolarisation dispersion was reduced by HBP-CRT (-42.0 ms, 95% confidence interval (CI): -52.3 to -31.7 ms, p &amp;lt;0.001) but not by BVP (11.9 ms, 95% CI: -6.24 to 30.1 ms, p = 0.182). The mean within-patient change in LV repolarisation dispersion from BVP to HBP-CRT was -56.5 ms (95% CI: -70.5 to -42.5 ms, p &amp;lt; 0.001). LV repolarisation dispersion with HBP-CRT was not different from individuals with narrow intrinsic QRS (2.75 ms, 95% CI: -16.2 to 21.7 ms, p = 0.981). The magnitude of reduction in LV repolarisation dispersion with HBP-CRT from intrinsic LBBB appeared similar to the magnitude of LV activation time shortening (-54.9 ms, 95% CI: -68.2 to -41.6 ms, p &amp;lt; 0.001). However, LV activation-recovery interval dispersion was also reduced by HBP-CRT (-44.3 ms, 95% CI: -69.2 to -19.3 ms, p &amp;lt; 0.001). Repolarisation mapping demonstrated normalisation of repolarisation pattern by HBP-CRT. CONCLUSIONS HBP-CRT can normalise repolarisation dispersion, producing more physiological repolarisation compared with BVP, which does not resolve the repolarisation abnormality of LBBB. HBP-CRT improves repolarisation through both activation resynchronization and modulation of action-potential duration. If these acute results translate to longer term outcomes, HBP-CRT may reduce the risk of ventricular arrhythmias in heart failure with LBBB to a greater extent than BVP. Abstract Figure. Epicardial Repolarisation Maps

Effects of Hypoxia and Acidosis on Cardiac Electrophysiology and Hemodynamics. Is NHE-Inhibition by Cariporide Still Advantageous?

Hypoxia often leads to severe cardiac malfunctions. It is assumed that intracellular calcium overload is -inter alia- responsible for left ventricular (LV) deterioration. Inhibition of the sodium-proton exchanger (NHE), which finally inhibits/slows calcium overload, may ameliorate cardiac function. Our aim was to evaluate cariporide, an inhibitor of NHE1 in a Langendorff-perfused heart model. To discriminate a potentially different impact of extracellular acidosis and hypoxia we examined 48 Chinchilla Bastard rabbits divided into 8 experimental groups: control group (pH = 7.4, O2 = 100%) without or with cariporide (1 μM), acidosis group (pH = 7.0, O2 = 100%) without or with cariporide (1 μM), hypoxia group (pH = 7.4, O2 = 40%) without or with cariporide (1 μM) and hypoxia+acidosis group (pH = 7.0, O2 = 40%) without or with cariporide (1 μM). Hearts were subjected to acidotic/hypoxic conditions for 90 min followed by 60 min of reperfusion. Hypoxia and hypoxia+acidosis led to a severe deterioration of LV function with a decrease in LV pressure by about 70% and an increase of end-diastolic pressure from 6.7 ± 0.6 to 36.8 ± 5.4 (hypoxia) or from 7.0 ± 0.2 to 18.6 ± 4.1 (hypoxia+acidosis). Moreover, maximum contraction velocity decreased from about 1,800 mmHg/s to 600 mmHg/s during hypoxia ± acidosis and maximum relaxation velocity deteriorated from −1,500 mmHg/s to about −600 mmHg/s. During reperfusion hearts subjected to hypoxia+acidosis recovered faster than hearts subjected to hypoxia alone, reaching control levels after 5 min of reperfusion. Electrophysiologic analysis revealed an 1.2 fold increase in both dispersion of activation-recovery interval and in total activation time in the hypoxia ± acidosis group. Cariporide application significantly improved LV hemodynamics and electrophysiology in the hypoxia group but not in the group subjected to hypoxia+acidosis. Immunohistologic analysis of cardiac specimen revealed a significant increase of factors involved in hypoxia/reperfusion injury like nitrotyrosine and poly-ADP-ribose as well as apoptosis-inducing factors like AIF or cleaved-caspase 3 in LV after hypoxia ± acidosis. ATP was reduced by hypoxia but not by acidosis. Again, cariporide mitigated these processes only in the hypoxia alone group, but not in the group with additional acidosis. Acidosis without hypoxia only marginally disturbed LV function and electrophysiology, and was not affected by cariporide. Thus, our study demonstrated that several detrimental effects of hypoxia were mitigated or abrogated by acidosis and that NHE-inhibition improved only hypoxia-induced cardiac dysfunction.

Non-invasive electrocardiographic imaging in patients with idiopathic premature ventricular contractions from the right ventricular outflow tract: New insights into arrhythmia substrate

AimsThe aim of this study was to use non-invasive electrocardiographic imaging (ECGI) to study the electrophysiological properties of right ventricular outflow tract (RVOT) in patients with frequent premature ventricular contractions (PVCs) from the RVOT and in controls. MethodsECGI is a combined application of body surface electrocardiograms and computed tomography or magnetic resonance imaging data. Unipolar electrograms are reconstructed on the epicardial and endocardial surfaces. Activation time (AT) was defined as the time of maximal negative slope of the electrogram (EGM) during QRS, recovery time (RT) as the time of maximal positive slope of the EGM during T wave, Activation recovery interval (ARI) was defined as the difference between RT and AT. ARI dispersion (Δ ARI) and RT dispersion (Δ RT) were calculated as the difference between maximal and minimal ARI and RT respectively. We evaluated those parameters in patients with frequent PVCs from the RVOT, defined as >10.000 per 24 h, and in a control group. ResultsWe studied 7 patients with frequent RVOT PVCs and 17 controls. Patients with PVCs from the RVOT had shorter median RT than controls, in the endocardium and in the epicardium, respectively 380 (239–397) vs 414 (372–448) ms, p = 0.047 and 275 (236–301) vs 330 (263–418) ms, p = 0.047. The dispersion of ARI and of RT in the epicardium was higher than in controls, Δ ARI of 145 (68–216) vs 17 (3–48) ms, p = 0.001 and Δ RT of 201 (160–235) vs 115 (65–177), p = 0.019. ConclusionIn this group of patients we found a shorter median RT in the endocardium and in the epicardium of the RVOT and a higher dispersion of the ARI and RT across the epicardium in patients with PVCs from the RVOT when comparing to controls.

Repolarization abnormalities unmasked with exercise in sudden cardiac death survivors with structurally normal hearts.

Models of cardiac arrhythmogenesis predict that nonuniformity in repolarization and/or depolarization promotes ventricular fibrillation and is modulated by autonomic tone, but this is difficult to evaluate in patients. We hypothesize that such spatial heterogeneities would be detected by noninvasive ECG imaging (ECGi) in sudden cardiac death (SCD) survivors with structurally normal hearts under physiological stress. ECGi was applied to 11 SCD survivors, 10 low-risk Brugada syndrome patients (BrS), and 10 controls undergoing exercise treadmill testing. ECGi provides whole heart activation maps and>1,200 unipolar electrograms over the ventricular surface from which global dispersion of activation recovery interval (ARI) and regional delay in conduction were determined. These were used as surrogates for spatial heterogeneities in repolarization and depolarization. Surface ECG markers of dispersion (QT and Tpeak-end intervals) were also calculated for all patients for comparison. Following exertion, the SCD group demonstrated the largest increase in ARI dispersion compared to BrS and control groups (13 ± 8ms vs. 4 ± 7ms vs. 4 ± 5ms; P=0.009), with baseline dispersion being similar in all groups. In comparison, surface ECG markers of dispersion of repolarization were unable to discriminate between the groups at baseline or following exertion. Spatial heterogeneities in conduction were also present following exercise but were not significantly different between SCD survivors and the other groups. Increased dispersion of repolarization is apparent during physiological stress in SCD survivors and is detectable with ECGi but not with standard ECG parameters. The electrophysiological substrate revealed by ECGi could be the basis of alternative risk-stratification techniques.

Antifibrillatory effects of renal denervation on ventricular fibrillation in a canine model of pacing-induced heart failure.

What is the central question of this study? In the present study, we investigated the effects of renal denervation on the vulnerability to ventricular fibrillation and the ventricular electrical properties in a rapid pacing-induced heart failure canine model. What is the main finding and its importance? Renal denervation significantly attenuated the process of heart failure and improved left ventricular systolic dysfunction, stabilized ventricular electrophysiological properties and decreased the vulnerability of the heart to ventricular fibrillation during heart failure. Thus, renal denervation can attenuate ventricular electrical remodelling and exert a potential antifibrillatory action in a pacing-induced heart failure canine model. In this study, we investigated the effects of renal denervation (RDN) on the vulnerability to ventricular fibrillation (VF) and the ventricular electrical properties in a canine model of pacing-induced heart failure (HF). Eighteen beagles were divided into the following three groups: control (n=6), HF (n=6) and HF+RDN (n=6). Heart failure was induced by rapid right ventricular pacing. Renal denervation was performed simultaneously with the pacemaker implantation in the HF+RDN group. A 64-unipolar basket catheter was used to perform global endocardial mapping of the left ventricle. The restitution properties and dispersion of refractoriness were estimated from the activation recovery intervals (ARIs) by a pacing protocol. The VF threshold (VFT) was defined as the maximal pacing cycle length required to induce VF using a specific pacing protocol. The defibrillation threshold (DFT) was measured by an up-down algorithm. Renal denervation partly restored left ventricular systolic function and attenuated the process of HF. Compared with the control group, the VFT in the HF group was decreased by 27% (106±8.0 versus 135±10ms, P<0.01). However, RDN increased the VFT by 13% (135±10 versus 118±7.5ms, P<0.05) and decreased the DFT by 27% (30±6.3 versus 21.8±4.7J, P<0.05) in the treated hearts compared with the failing hearts. Renal denervation significantly flattened the ventricular ARI restitution curve by 15% (1.48±0.2 versus 1.26±0.11, P<0.05) and decreased the dispersion of ARI by 25% (0.08±0.02 versus 0.06±0.01, P<0.01) in the treated group compared with the HF group. The findings of this study suggest that RDN can attenuate ventricular electrical remodelling and exert a potential antifibrillatory action on VF in a canine model of pacing-induced HF.

Normal 123 I-MIBG uptake areas may be associated with hyperinnervation and arrhythmia risk in phenol model rabbit hearts.

Iodine-123 metaiodobenzylguanidine (123 I-MIBG) is useful for detecting sympathetic innervation in the heart, and has been closely associated with fatal arrhythmias. However, such imaging is typically calibrated to the area of highest uptake and thus is unable to identify areas of hyperinnervation. We hypothesized that normal 123 I-MIBG uptake regions in the denervated heart would demonstrate nerve sprouting and correlate with the potential for arrhythmogenesis. Twenty New Zealand white rabbits treated with phenol or sham were prepared under anesthesia. Sympathetic innervation was quantified using autoradiography and immunostaining 4weeks after phenol application, and electrophysiological study was performed. 123 I-MIBG revealed maximal local differences in isotope uptake in the border zone between areas with attenuated and abundant MIBG compared with that seen between adjacent regions within the lowest uptake areas. On immunostaining, heterogeneous and decreased expressions of growth-associated protein 43 signal were observed in the MIBG-attenuated areas; however, abundant signals were recognized in the MIBG-abundant areas. Upregulation of the tyrosine hydroxylase signal was observed at the part of the MIBG-abundant area. In electrophysiological study, the dispersion of activation recovery interval (ARI) was increased in the phenol-applied areas by norepinephrine infusion. Stellate stimulation exacerbated the ARI dispersion in both the phenol-applied and nonapplied areas, and was associated with increased inducibility of ventricular tachycardia and ventricular fibrillation. The presence of hyperinnervation in the nondenervated regions of denervated rabbit hearts suggests that heterogeneous neural remodeling occurs in regions with seemingly normal 123 I-MIBG uptake and contributes to electrical instability.

The relationship between repolarization parameters and serum electrolyte levels in patients with J wave syndromes.

Intravenous administration of magnesium (Mg(2+)) is effective for polymorphic ventricular tachycardia via homogenization of transmural ventricular repolarization. Mg(2+) likely plays some role in the heterogeneity of repolarization in J wave syndromes. To investigate the relationship between the repolarization parameters and serum Mg(2+), potassium (K(+)), and calcium (Ca(2+)) levels in J wave syndromes. Thirteen J-wave syndrome patients (Brugada and early repolarization [ER] syndromes), with documented episodes of ventricular fibrillation (VF), and 13 ER pattern (ERP) or Brugada type ECG patients were enrolled (25 males, mean age 48 ± 15 years). The 12-lead ECG-derived parameters including the QT, QT dispersion (QTd), Tpeak-Tend (Tp-e) interval, Tp-e dispersion (Tp-ed), Tp-e/QT ratio, and activation recovery interval (ARI) dispersion were calculated; the correlations between these parameters and electrolytes including Mg(2+), K(+), and Ca(2+) were analyzed. Although there was no association between serum K(+) or Ca(2+) and QTd, there was a strong negative correlation between serum Mg(2+) and QTd in J wave syndrome patients with a history of VF (r = -0.715, p = 0.006). Also, there was a tendency for a negative correlation between Mg(2+) and Tp-ed or ARI dispersion in J wave syndrome patients with a history of VF (r = -0.513, p = 0.072 and r = -0.53, p = 0.063, respectively). On the other hand, in 13 patients with a Brugada type ECG or ERP, no correlation was observed between serum Mg(2+) and the QTd, Tp-ed or ARI dispersion. Serum Mg(2+) may play an important role in the cardiac repolarization process in J wave syndromes.

Functional differences between junctional and extrajunctional adrenergic receptor activation in mammalian ventricle

Increased cardiac sympathetic activation worsens dispersion of repolarization and is proarrhythmic. The functional differences between intrinsic nerve stimulation and adrenergic receptor activation remain incompletely understood. This study was undertaken to determine the functional differences between efferent cardiac sympathetic nerve stimulation and direct adrenergic receptor activation in porcine ventricles. Female Yorkshire pigs (n = 13) underwent surgical exposure of the heart and stellate ganglia. A 56-electrode sock was placed over the ventricles to record epicardial electrograms. Animals underwent bilateral sympathetic stimulation (BSS) (n = 8) or norepinephrine (NE) administration (n = 5). Activation recovery intervals (ARIs) were measured at each electrode before and during BSS or NE. The degree of ARI shortening during BSS or NE administration was used as a measure of functional nerve or adrenergic receptor density. During BSS, ARI shortening was nonuniform across the epicardium (F value 9.62, P = 0.003), with ARI shortening greatest in the mid-basal lateral right ventricle and least in the midposterior left ventricle (LV) (mean normalized values: 0.9 ± 0.08 vs. 0.56 ± 0.08; P = 0.03). NE administration resulted in greater ARI shortening in the LV apex than basal segments [0.91 ± 0.04 vs. 0.63 ± 0.05 (averaged basal segments); P = 0.003]. Dispersion of ARIs increased in 50% and 60% of the subjects undergoing BSS and NE, respectively, but decreased in the others. There is nonuniform response to cardiac sympathetic activation of both porcine ventricles, which is not fully explained by adrenergic receptor density. Different pools of adrenergic receptors may mediate the cardiac electrophysiological effects of efferent sympathetic nerve activity and circulating catecholamines.

The effect of pinacidil on postshock activation and ventricular defibrillation threshold in canine hearts

To determine the postshock activation patterns with both successful and failed shocks in a canine model of ventricular fibrillation, and whether piniacidil, an early after-depolarization (EAD) inhibitor, altered the defibrillation threshold (DFT) and postshock activation patterns. In 6 beagles, a basket catheter with 64 unipolar electrodes was placed in the LV for global endocardial mapping, a monophasic action potential catheter was inserted into the LV apex, and a catheter with the negative electrode in the right ventricle and the positive electrode in the superior vena cava was inserted for defibrillation. The DFT, 90% action potential duration (APD(90)) and activation recovery interval (ARI) were evaluated before and after pinacidil administration (loading dosage 0.5 mg/kg and maintenance dosage 0.5 mg·kg(-1)·h(-1), iv). Electrical heterogeneities were defined with the dispersion of ARI. After successful and failed shocks with near-DFT strength, the earliest postshock activation patterns (focal or nonfocal endocardial activation), interval and location were detected. Pinacidil significantly decreased APD(90) (from 178±16 ms to 168±18 ms) and ARI from (152±10 ms to 143±10 ms) at pacing cycle length of 300 ms. The drug significantly increased VF activation rate (from 10.0±1.9 Hz to 10.8±2.0 Hz). The drug did not affect the dispersion of ARI, neither it changed DFT (baseline: 480±110 V; pinacidil: 425±55 V, P>0.05). The earliest postshock activation arose locally on the LV apical endocardium before and after the drug treatment. Pinacidil significantly prolonged the postshock cycle length of cycles 2 to 5 for the successful episodes but not for the failed episodes. Pinacidil increases the postshock cycle length suggesting that EAD may play a role in postshock activation, while it fails to alter DFT suggesting that EAD produced by shock does not determine a defibrillation success or failure.

Desipramine prevents cardiac gap junction uncoupling

Uncoupling of cardiac gap junction channels is an important arrhythmogenic mechanism in ischemia/reperfusion. Antiarrhythmic peptide AAP10 (H-Gly-Ala-Gly-Hyp-Pro-Tyr-CONH(2)) has been shown to prevent acidosis-induced uncoupling and ischemia-related increase in dispersion. Previous structure-effect investigations and subsequent computer modeling studies indicated that the tricyclic antidepressant desipramine may exert similar effects as AAP10. We assessed the binding of (14)C-AAP10 to membranes of rabbit cardiac ventricles and its displacement with desipramine in a classical radioligand binding and competition study. Gap junction currents were measured between isolated pairs of human atrial cardiomyocytes under normal and acidotic (pH 6.3) conditions with or without 1μmol/l desipramine using dual whole-cell voltage clamp. The effect of 1μmol/l desipramine was assessed in isolated rabbit hearts (Langendorff technique) undergoing local ischemia by coronary occlusion with 256-channel electrophysiological mapping and subsequent analysis of connexin43 (Cx43) expression, phosphorylation (Western blot), and subcellular localization (immunohistology). We found saturable (14)C-AAP10 binding to cardiac membranes (K (D), 0.29 ± 0.11nmol/l; B (max), 42.5 ± 7.2 pmol/mg) which could be displaced by desipramine with a K (D.High) = 0.14μmol/l and a K (D.Low) = 22μmol/l. Acidosis reduced the gap junction conductance in human cardiomyocyte pairs from 24.1 ± 4.7 to 11.5 ± 2.5 nS, which could be significantly reversed by desipramine (26.6 ± 4.8 nS). In isolated hearts, ischemia resulted in significantly increased dispersion of activation-recovery intervals, loss of membrane Cx43, and dephosphorylation of Cx43, which all could be prevented by desipramine. Desipramine seems to prevent the uncoupling of cardiac gap junctions and ischemia-related increase in dispersion.

Doxorubicin-induced Changes of Ventricular Repolarization Heterogeneity: Results of a Chronic Rat Study

Anthracycline chemotherapy produces cardiac repolarization abnormalities and arrhythmias because of cardiac toxicity of drugs. Ventricular arrhythmogenesis is attributable to increase in repolarization heterogeneity that is characterized by spatial dispersion of repolarization. The purpose of this work was to study the delayed effects of doxorubicin, the most frequently used anthracycline, on repolarization heterogeneity of the ventricular epicardium. Doxorubicin was administered to rats in a cumulative dose of 15 mg/kg (six equal intraperitoneal injections over a period of 2 weeks). Six weeks after the last injection, electrophysiological mapping of the ventricular epicardium was performed by sequential superimposition of a 64-electrode array on the left ventricular base, left ventricular apex, right ventricular base, and right ventricular apex. Activation-recovery intervals (ARIs) were measured. In doxorubicin-treated rats, ARIs were inhomogeneously prolonged, the overall ARI dispersion and local ARI dispersions were increased, and the interregional differences in ARI dispersion were decreased. These data demonstrate that doxorubicin-induced inhomogeneous prolongation of repolarization of the ventricular epicardium results in increasing heterogeneity of ventricular repolarization because of increasing intraregional heterogeneity while interregional differences are lost. Repolarization of the right ventricle is more sensitive to doxorubicin than that of the left one.

Nifekalant Enlarged the Transmural Activation–Recovery Interval Difference as Well as the Peak‐to‐End Interval on Surface ECG in a Patient with Short‐QT Syndrome

A 38-year-old woman with type 1 short-QT syndrome (SQTS) was referred to our hospital. Her ECG showed short QT/QTc interval and peaked T wave. Activation-recovery intervals (ARIs) were calculated from the intracardiac endocardial and epicardial electrode catheters placed in the left ventricle (LV). Intravenous administration of nifekalant prolonged effective refractory period at multiple ventricular sites as well as the QT/QTc interval (from 260/300 to 364/419 ms) on the surface ECG. Nifekalant also enlarged the transmural ARI dispersion of the ventricular repolarization, which was measured by the difference between the longest endocardial ARI and the shortest epicardial ARI during atrial pacing at 90 bpm, from 73 to 103-105 ms. These values corresponded to the intervals between the peak and end of the T wave on the surface ECG. Nifekalant-induced QT interval prolongation on the surface ECG may not indicate attenuation of the arrhythmogenic potential in the heart of SQTS patients.

Sympathetic innervation of the anterior left ventricular wall by the right and left stellate ganglia

The sympathetic nervous system is thought to play a role in the genesis of ventricular tachyarrhythmias (VT). Left and added right cardiac sympathectomy have been shown to reduce the burden of arrhythmias in the setting of a VT storm. However, the contribution of the right stellate ganglion (RSG) and the left stellate ganglion (LSG) to the innervation of the anterior left ventricular (LV) wall is not well understood. To evaluate the innervation of the anterior LV wall by the LSG and the RSG. The heart and stellate ganglia were exposed via sternotomy in pigs with normal hearts (n = 8). A 20-electrode catheter was placed on the anterior LV wall to record activation recovery interval (ARI), a surrogate measure of action potential duration. A microdialysis catheter was inserted in a similar location to sample interstitial norepinephrine (NE) content. ARI and NE measurements were recorded at baseline and during LSG and RSG stimulation. LSG stimulation shortened ARI by 17.1% ± 10.5% (mean ± standard error), while RSG stimulation shortened ARI by 42.1% ± 15.7%, P = .04 (LSG vs RSG). LSG stimulation increased interstitial NE levels by 200% ± 65%, while RSG stimulation increased the NE content by 260% ± 40% (P = .012). LSG stimulation increased dispersion in ARI from 376.0 ± 83.7 ms(2) to 1242.5 ± 566 ms(2) (P = .03) and caused ventricular fibrillation in 2 pigs. During RSG stimulation, dispersion increased from 419 ± 65.8 to 474.8 ± 81 ms(2) (P = .4). Both the LSG and the RSG provide significant innervation to the anterior LV wall as demonstrated by both ARI shortening and NE concentrations. LSG stimulation significantly increases ARI dispersion. This study provides mechanistic insight into the beneficial effects of left sympathectomy and the additional role of right sympathectomy in reducing arrhythmias in patients with anterior myocardial scars and VT storm.

Sympathetic stimulation increases dispersion of repolarization in humans with myocardial infarction

The sympathetic nervous system is thought to play a key role in genesis and maintenance of ventricular arrhythmias. The myocardial effect of sympathetic stimulation on myocardial repolarization in humans is poorly understood. The purpose of this study was to evaluate the effects of direct and reflex sympathetic stimulation on ventricular repolarization in patients with postinfarct cardiomyopathy (ICM). The effects of direct sympathetic stimulation were assessed using isoproterenol, while those of reflex sympathetic stimulation were assessed with nitroprusside infusion in ICM patients (n = 5). Five patients without cardiomyopathy were also studied. Local repolarization was measured from intracardiac electrograms that were used to calculate the activation recovery interval (ARI), a surrogate of action potential duration. Isoproterenol significantly increased heterogeneity in repolarization in patients with ICM; the decrease in ARI from baseline was 72.9 ± 9.1 ms in more viable regions, 64.5 ± 8.9 ms in the scar, and 54.9 ± 9.1 ms in border zones (P = 0.0002 and 0.014 comparing normal and scar to border zones, respectively). In response to nitroprusside, the ARI at the border zones decreased significantly more than either scar or surrounding viable myocardium, which showed an increase in ARI (P = 0.014 and 0.08 comparing normal tissue and scar to border zones, respectively). Furthermore, isoproterenol increased ARI dispersion by 70%, while nitroprusside increased ARI dispersion by 230% when ICM patients were compared to those with structurally normal hearts (P = 0.0015 and P < 0.001, respectively). In humans, both direct and reflex sympathetic stimulations increase regional differences in repolarization. The normal tissue surrounding the scar appears denervated. Dispersion of ARI in response to sympathetic stimulation is significantly increased in patients with ICM.