Introduction: Since traditional methods of mapping fail to reveal localized AF drivers, it is une... more Introduction: Since traditional methods of mapping fail to reveal localized AF drivers, it is unexplained how ablation of limited areas guided by phase mapping can terminate persistent AF. We hypothesised that structural remodelling (LA size, raised BMI and high CHADSVASc) may reconcile traditional and phase mapping of AF. Methods: We recruited 60 patients at 5 international centers in whom persistent AF terminated by localized ablation (area Results: Each patient had AF termination (52% to sinus) by localized ablation, in whom we analyzed 550 activation (isochronal) maps. Unexpectedly, rotational sources were found by activation mapping, confirming phase maps in 15/60 (25%) cases (Figure A). Remaining cases had partial (45%) or no (30%) agreement (p 3 but not LA size or AF duration (table). Discussion: For the first time, this international study reveals rotational drivers of persistent AF by traditional mapping, focused at sites of known AF termination rather than arbitrary regions. However, traditional mapping was less sensitive than phase mapping for AF drivers, due to the impact of BMI and CHADSVASc substrates on electrograms. These data highlight the role of mapping technique in AF to guide ablation.
Arrhythmia & electrophysiology review, May 21, 2022
Anatomically based pulmonary vein isolation (PVI) is the cornerstone of ablation, yet continues t... more Anatomically based pulmonary vein isolation (PVI) is the cornerstone of ablation, yet continues to achieve success rates of 55-75% at 12-18 months in randomised trials, depending on the population, which falls over time. 1 Notably, there has been little benefit from adding several anatomical ablation strategies targeting the posterior wall, the mitral isthmus, left atrial roof or other linear lesions. 2-5 Studies that add isolation of the left atrial appendage are ongoing. 6 A dominant alternative viewpoint is that patients with AF likely differ in the anatomical locations for their mechanisms, underscoring the need to optimise AF mapping. This viewpoint is tempered by the reality that mapping systems to date have yielded divergent data, varying outcomes in different clinical series and complex mathematical approaches that are difficult to validate by clinical observation. 7 In contrast, PVI and anatomical ablation lines are relatively straightforward to confirm clinically. This review critically evaluates the bench-to-bedside evidence that localised regions of interest perpetuate AF, and describes clinical approaches used to identify these regions for ablation. 8,9 We will attempt to address why the localised source hypothesis may be more important to some patients than others. 10-15 We will intersperse our descriptions with thoughts on future directions to address challenges that we believe must be overcome to truly advance the field. Mechanisms that Sustain Human AF Once AF has been initiated by triggers from the pulmonary veins or other sites, its disorganised wavefronts must be continuously replenished for AF to sustain. 16 Two mechanisms are proposed. In one model, disorganised activity self-sustains because new wavelets are generated across atrial tissue over time. Computer simulations reveal that such wavelets can be generated by unstable spiral waves and wavebreak. 17,18 Collision from repetitive foci in multiple spatial locations can also destabilise wave propagation, again producing new wavelets. 19 This hypothesis does not require preferred regions of interest (Figure 1A), and effective therapy would require large-scale debulking of the atrium. In the second major model, preferred regions of interest are central to perpetuating AF. Such regions may represent localised rotational or focal sources, other electrical features such as repetitive activation patterns, or structural regions of fibrosis or tissue anisotropy that replenish disordered wavefronts and can thus be termed 'drivers' (Figures 1B, 1C and 1D). Localised rotational or focal sources are a well-described mechanism for replenishing AF wavelets. Rotational circuits were first described in animal models of ventricular and AF in seminal work by Jalife and others in the 1990s. 9 Classically, a rotor is defined as re-entry around an unexcited yet excitable core, activating too rapidly for surrounding tissue to keep up and resulting in disordered waves ('fibrillatory conduction'). This has been shown in multiple animal studies using optical mapping and contact mapping and more recently in human atria during AF (Figures 1B and 1C). 9 These features have been reported in patients by many techniques, and ablation at these localised sites alone may terminate AF (Figure 1D). 8,20 The field has been confused by argument on the definitions of a rotor, yet this argument has little practical significance at the spatial resolution of clinical mapping. We use the terms rotational activation, localised re-entry and rotor interchangeably, leaving ultimate adjudication on this issue to
Introduction: Mechanisms for persistent AF are unclear. On the basis that sites where ablation te... more Introduction: Mechanisms for persistent AF are unclear. On the basis that sites where ablation terminates persistent AF may have mechanistic relevance, we performed the first systematic mapping of ...
Drivers are increasingly studied ablation targets for atrial fibrillation (AF). However, results ... more Drivers are increasingly studied ablation targets for atrial fibrillation (AF). However, results from ablation remain controversial. First, outcomes vary between centers and patients. Second, it is unclear how best to perform driver ablation. Third, there is a lack of practical guidance on how to identify critical from secondary sites using different AF mapping methods. This article addresses each of these issues.
Introduction: Ventricular tachycardia (VT) associated with a primary cardiac tumor is extremely r... more Introduction: Ventricular tachycardia (VT) associated with a primary cardiac tumor is extremely rare; however, this VT occurs in young patients and can be lethal. Complete resection of a tumor was reported to be effective in a treatment of this VT although the mechanism of this VT is still unknown and treatment methods in patients with an unresectable tumor are not determined. Purpose: The purposes of this study were to clarify the mechanism of the cardiac tumor-related VT (CT-VT) and to establish a therapeutic strategy for this VT. Methods: Among 24 patients with a non-ischemic VT cured by the surgical treatment in our institute, four patients (20±15 years, 3 males) were identified with CT-VT (fibroma in 2, lipoma in 1, and hemangioma in 1 patient). An electrophysiological study with electroanatomical mapping was performed during the openheart surgery and the resected cardiac tumor was examined histopathologically. Results: All four patients developed repetitive forms of monomorphic VTs, which were reproducibly induced by programmed ventricular stimulation and terminated by burst pacing. These VTs exhibited a right bundle branch block QRS morphology (QRS duration, 160±28 ms) with a pseudo-delta wave (75±10 ms) at a cycle length of 330±86 ms. Intraoperative electroanatomical mapping showed a radially spreading activation pattern originating from the epicardial border of the tumor, where fractionated and late potentials were detected during sinus rhythm. Histopathological studies of the sections from this border area revealed tumor infiltration to the surrounding myocardium and myocardial cell disorganization exhibiting myocardial disarray. In 2 patients in whom the cardiac tumor was completely resected, cryoablation was added to the resection line. In the remaining 2 patients in whom complete resection of the tumor was unfeasible, encircling cryoablation to entirely isolate the unresectable tumor was effective in suppressing their VTs. Conclusions: The mechanism of CT-VT is reentry localized at the border of the tumor. Myocardial disarray associated with infiltration of the cardiac tumor may be a substrate of this VT. Encircling cryoablation along the border of the tumor may be a therapeutic option for an unresectable CT-VT.
nisms remain to be fully elucidated. We examined the relationship between EAT and atrial myocardi... more nisms remain to be fully elucidated. We examined the relationship between EAT and atrial myocardium on the histological and biochemical properties. Methods: Human Left atrial appendage (LAA) samples were obtained during routine cardiac surgery (AF group, n=45). The excised LAA specimens were used for histological analysis and measurement of various proteins concentrations. As controls, human LAAs were obtained from autopsy heart (No AF group, n=12) and used for histological analysis. Results: Infiltration of the subepicardial area by adipose tissue was commonly observed in human LAA sections. In sections of human LAA samples, EATpercentage of sections were significantly higher in AF group (no AF: 8.8±5.6% vs. AF: 15.8±11.2%, p=0.041). Focusing on EAT area, characteristic fibrotic remodeling of EAT were observed significantly higher in AF group (no AF: 12.9±10.9% vs. AF: 36.4±38.9%, p=0.0446). In addition, there were significant positive correlation between EAT-fibrosis and myocardial fibrosis. In AF group, we confirmed that there was a positive correlation between EAT-fibrosis and the number of M1 macrophages in EAT, as determined by immunohistochemical staining against CD11c. Protein concentration analysis in AF group demonstrated that the contents of various inflammatory cytokines (eg, IL-1β, IL-6, IL-8, MIP-1α, MIP-1β, VEGF, MCP-1, and TNF-α) and MMPs in EAT were positively correlated with the collagen protein content in atrial myocardium. Interestingly, serum levels of various inflammatory cytokines were not related with the collagen protein content in atrial myocardium. These results indicate that local inflammatory burden between EAT and atrial myocardium could be more effective than systemic inflammation for atrial myocardial fibrosis. Furthermore, we confirmed that the protein content of angiopoietin-like protein 2 (Angptl2) in EAT, not in serum, were positively correlated with the protein content of various inflammatory cytokines, MMPs in EAT and the collagen protein content in atrial myocardium. In addition, the high levels of Angptl2 content in EAT were related with the high levels of Hif-1α, phospho-IκBα, and phospho-p38 MAPK/p38 MAPK content in EAT by western blotting. These data suggest that hypoxia may increase EAT-secreted Angptl2, and which may regulate the protein levels of pro-inflammatory cytokines and pro-fibrotic enzymes. Conclusions: Overall, infiltration of EAT and fibrotic remodeling of EAT are highly associated with myocardial inflammatory fibrosis as a substrate of AF. The qualitative alteration of EAT such as abundance of inflammatory cytokines and fibrotic remodeling which induced by EAT-secreted Angptl2 may be involved in atrial fibrosis. 978 | BENCH Characterization of the novel mutant A78T-HERG from a long QT syndrome type2 patient: Instability of the mutant protein and stabilization by heat shock protein family and heat shock factor-1
Best Posters in hypertension basic research / Best Posters in in atrial fibrillation screening-Ma... more Best Posters in hypertension basic research / Best Posters in in atrial fibrillation screening-Management and prognosis 1273 addition, they may be involved in the pathophysiology of in hypertensive heart disease and may be promising therapeutic targets.
Background: Ablation of complex arrhythmias increasingly focuses on efficiency and reduced fluoro... more Background: Ablation of complex arrhythmias increasingly focuses on efficiency and reduced fluoroscopic exposure for patients and operators. This may be challenging for new techniques such as FIRM guidance. Purpose: We tested the feasibility of a minimal fluoroscopic approach during FIRM guided ablation, which has the challenges of requiring optimal basket placement, contact, and precise ablation targeting. Methods: In a propensity-matched case-control design, we compared 36 patients (from a total of 312) who underwent FIRM-guided (FIRM þ PVI) ablation on a standard or minimal fluoroscopy protocol. Seventeen (67.4610.0, 70.4% male, 11 persistent AF) underwent minimal fluoroscopy performed by an operator new to FIRM (3 case lead-in). Nineteen controls (68.968.1, 68.4% male, 14 persistent AF) were propensity matched from 295 cases of FIRM-guided ablation with routine fluoroscopy at our Institution, using logistic regression. In each limb, ablation comprised FIRM plus PVI, aided by intra-cardiac echocardiography for catheter positioning. For patients with minimal fluoroscopy, mapping, catheter placement, basket placement and ablation were guided entirely by EA mapping and ICE. Results: Panel A shows FIRM and PVI lesions delivered using minimal fluoroscopy (total 2.2 minutes) in a 64-year-old male with paroxysmal AF. Panel B shows how this protocol reduced fluoroscopy time to a total of 262 minutes versus 41616 minutes (p<0.001), and trended to reduce procedure time (p¼0.10) with no difference in complications. Conclusion: A minimal fluoroscopic approach to FIRM guided ablation is feasible, despite the challenges of optimal basket placement and precise ablation targeting, and poses no apparent safety concerns. Long-term outcomes from this approach require further study.
Atrial fibrillation is considered a model disease of trigger and substrate, with atrial electrica... more Atrial fibrillation is considered a model disease of trigger and substrate, with atrial electrical remodeling a key substrate factor for perpetuation of AF. Work conducted with human monophasic action potential (MAP) and continuous multipolar recordings has advanced our current understanding of atrial electrical properties and the transitions between physiologic activation of the atria and AF. Electrical heterogeneity seen during AF manifests as rate maladaptation, alternans, and higher-level oscillations in atrial action potential duration and shape. Defining these putative mechanisms for AF have been used to identify novel clinical phenotypes and may be used to guide therapy.
Introduction: Since traditional methods of mapping fail to reveal localized AF drivers, it is une... more Introduction: Since traditional methods of mapping fail to reveal localized AF drivers, it is unexplained how ablation of limited areas guided by phase mapping can terminate persistent AF. We hypothesised that structural remodelling (LA size, raised BMI and high CHADSVASc) may reconcile traditional and phase mapping of AF. Methods: We recruited 60 patients at 5 international centers in whom persistent AF terminated by localized ablation (area Results: Each patient had AF termination (52% to sinus) by localized ablation, in whom we analyzed 550 activation (isochronal) maps. Unexpectedly, rotational sources were found by activation mapping, confirming phase maps in 15/60 (25%) cases (Figure A). Remaining cases had partial (45%) or no (30%) agreement (p 3 but not LA size or AF duration (table). Discussion: For the first time, this international study reveals rotational drivers of persistent AF by traditional mapping, focused at sites of known AF termination rather than arbitrary regions. However, traditional mapping was less sensitive than phase mapping for AF drivers, due to the impact of BMI and CHADSVASc substrates on electrograms. These data highlight the role of mapping technique in AF to guide ablation.
Arrhythmia & electrophysiology review, May 21, 2022
Anatomically based pulmonary vein isolation (PVI) is the cornerstone of ablation, yet continues t... more Anatomically based pulmonary vein isolation (PVI) is the cornerstone of ablation, yet continues to achieve success rates of 55-75% at 12-18 months in randomised trials, depending on the population, which falls over time. 1 Notably, there has been little benefit from adding several anatomical ablation strategies targeting the posterior wall, the mitral isthmus, left atrial roof or other linear lesions. 2-5 Studies that add isolation of the left atrial appendage are ongoing. 6 A dominant alternative viewpoint is that patients with AF likely differ in the anatomical locations for their mechanisms, underscoring the need to optimise AF mapping. This viewpoint is tempered by the reality that mapping systems to date have yielded divergent data, varying outcomes in different clinical series and complex mathematical approaches that are difficult to validate by clinical observation. 7 In contrast, PVI and anatomical ablation lines are relatively straightforward to confirm clinically. This review critically evaluates the bench-to-bedside evidence that localised regions of interest perpetuate AF, and describes clinical approaches used to identify these regions for ablation. 8,9 We will attempt to address why the localised source hypothesis may be more important to some patients than others. 10-15 We will intersperse our descriptions with thoughts on future directions to address challenges that we believe must be overcome to truly advance the field. Mechanisms that Sustain Human AF Once AF has been initiated by triggers from the pulmonary veins or other sites, its disorganised wavefronts must be continuously replenished for AF to sustain. 16 Two mechanisms are proposed. In one model, disorganised activity self-sustains because new wavelets are generated across atrial tissue over time. Computer simulations reveal that such wavelets can be generated by unstable spiral waves and wavebreak. 17,18 Collision from repetitive foci in multiple spatial locations can also destabilise wave propagation, again producing new wavelets. 19 This hypothesis does not require preferred regions of interest (Figure 1A), and effective therapy would require large-scale debulking of the atrium. In the second major model, preferred regions of interest are central to perpetuating AF. Such regions may represent localised rotational or focal sources, other electrical features such as repetitive activation patterns, or structural regions of fibrosis or tissue anisotropy that replenish disordered wavefronts and can thus be termed 'drivers' (Figures 1B, 1C and 1D). Localised rotational or focal sources are a well-described mechanism for replenishing AF wavelets. Rotational circuits were first described in animal models of ventricular and AF in seminal work by Jalife and others in the 1990s. 9 Classically, a rotor is defined as re-entry around an unexcited yet excitable core, activating too rapidly for surrounding tissue to keep up and resulting in disordered waves ('fibrillatory conduction'). This has been shown in multiple animal studies using optical mapping and contact mapping and more recently in human atria during AF (Figures 1B and 1C). 9 These features have been reported in patients by many techniques, and ablation at these localised sites alone may terminate AF (Figure 1D). 8,20 The field has been confused by argument on the definitions of a rotor, yet this argument has little practical significance at the spatial resolution of clinical mapping. We use the terms rotational activation, localised re-entry and rotor interchangeably, leaving ultimate adjudication on this issue to
Introduction: Mechanisms for persistent AF are unclear. On the basis that sites where ablation te... more Introduction: Mechanisms for persistent AF are unclear. On the basis that sites where ablation terminates persistent AF may have mechanistic relevance, we performed the first systematic mapping of ...
Drivers are increasingly studied ablation targets for atrial fibrillation (AF). However, results ... more Drivers are increasingly studied ablation targets for atrial fibrillation (AF). However, results from ablation remain controversial. First, outcomes vary between centers and patients. Second, it is unclear how best to perform driver ablation. Third, there is a lack of practical guidance on how to identify critical from secondary sites using different AF mapping methods. This article addresses each of these issues.
Introduction: Ventricular tachycardia (VT) associated with a primary cardiac tumor is extremely r... more Introduction: Ventricular tachycardia (VT) associated with a primary cardiac tumor is extremely rare; however, this VT occurs in young patients and can be lethal. Complete resection of a tumor was reported to be effective in a treatment of this VT although the mechanism of this VT is still unknown and treatment methods in patients with an unresectable tumor are not determined. Purpose: The purposes of this study were to clarify the mechanism of the cardiac tumor-related VT (CT-VT) and to establish a therapeutic strategy for this VT. Methods: Among 24 patients with a non-ischemic VT cured by the surgical treatment in our institute, four patients (20±15 years, 3 males) were identified with CT-VT (fibroma in 2, lipoma in 1, and hemangioma in 1 patient). An electrophysiological study with electroanatomical mapping was performed during the openheart surgery and the resected cardiac tumor was examined histopathologically. Results: All four patients developed repetitive forms of monomorphic VTs, which were reproducibly induced by programmed ventricular stimulation and terminated by burst pacing. These VTs exhibited a right bundle branch block QRS morphology (QRS duration, 160±28 ms) with a pseudo-delta wave (75±10 ms) at a cycle length of 330±86 ms. Intraoperative electroanatomical mapping showed a radially spreading activation pattern originating from the epicardial border of the tumor, where fractionated and late potentials were detected during sinus rhythm. Histopathological studies of the sections from this border area revealed tumor infiltration to the surrounding myocardium and myocardial cell disorganization exhibiting myocardial disarray. In 2 patients in whom the cardiac tumor was completely resected, cryoablation was added to the resection line. In the remaining 2 patients in whom complete resection of the tumor was unfeasible, encircling cryoablation to entirely isolate the unresectable tumor was effective in suppressing their VTs. Conclusions: The mechanism of CT-VT is reentry localized at the border of the tumor. Myocardial disarray associated with infiltration of the cardiac tumor may be a substrate of this VT. Encircling cryoablation along the border of the tumor may be a therapeutic option for an unresectable CT-VT.
nisms remain to be fully elucidated. We examined the relationship between EAT and atrial myocardi... more nisms remain to be fully elucidated. We examined the relationship between EAT and atrial myocardium on the histological and biochemical properties. Methods: Human Left atrial appendage (LAA) samples were obtained during routine cardiac surgery (AF group, n=45). The excised LAA specimens were used for histological analysis and measurement of various proteins concentrations. As controls, human LAAs were obtained from autopsy heart (No AF group, n=12) and used for histological analysis. Results: Infiltration of the subepicardial area by adipose tissue was commonly observed in human LAA sections. In sections of human LAA samples, EATpercentage of sections were significantly higher in AF group (no AF: 8.8±5.6% vs. AF: 15.8±11.2%, p=0.041). Focusing on EAT area, characteristic fibrotic remodeling of EAT were observed significantly higher in AF group (no AF: 12.9±10.9% vs. AF: 36.4±38.9%, p=0.0446). In addition, there were significant positive correlation between EAT-fibrosis and myocardial fibrosis. In AF group, we confirmed that there was a positive correlation between EAT-fibrosis and the number of M1 macrophages in EAT, as determined by immunohistochemical staining against CD11c. Protein concentration analysis in AF group demonstrated that the contents of various inflammatory cytokines (eg, IL-1β, IL-6, IL-8, MIP-1α, MIP-1β, VEGF, MCP-1, and TNF-α) and MMPs in EAT were positively correlated with the collagen protein content in atrial myocardium. Interestingly, serum levels of various inflammatory cytokines were not related with the collagen protein content in atrial myocardium. These results indicate that local inflammatory burden between EAT and atrial myocardium could be more effective than systemic inflammation for atrial myocardial fibrosis. Furthermore, we confirmed that the protein content of angiopoietin-like protein 2 (Angptl2) in EAT, not in serum, were positively correlated with the protein content of various inflammatory cytokines, MMPs in EAT and the collagen protein content in atrial myocardium. In addition, the high levels of Angptl2 content in EAT were related with the high levels of Hif-1α, phospho-IκBα, and phospho-p38 MAPK/p38 MAPK content in EAT by western blotting. These data suggest that hypoxia may increase EAT-secreted Angptl2, and which may regulate the protein levels of pro-inflammatory cytokines and pro-fibrotic enzymes. Conclusions: Overall, infiltration of EAT and fibrotic remodeling of EAT are highly associated with myocardial inflammatory fibrosis as a substrate of AF. The qualitative alteration of EAT such as abundance of inflammatory cytokines and fibrotic remodeling which induced by EAT-secreted Angptl2 may be involved in atrial fibrosis. 978 | BENCH Characterization of the novel mutant A78T-HERG from a long QT syndrome type2 patient: Instability of the mutant protein and stabilization by heat shock protein family and heat shock factor-1
Best Posters in hypertension basic research / Best Posters in in atrial fibrillation screening-Ma... more Best Posters in hypertension basic research / Best Posters in in atrial fibrillation screening-Management and prognosis 1273 addition, they may be involved in the pathophysiology of in hypertensive heart disease and may be promising therapeutic targets.
Background: Ablation of complex arrhythmias increasingly focuses on efficiency and reduced fluoro... more Background: Ablation of complex arrhythmias increasingly focuses on efficiency and reduced fluoroscopic exposure for patients and operators. This may be challenging for new techniques such as FIRM guidance. Purpose: We tested the feasibility of a minimal fluoroscopic approach during FIRM guided ablation, which has the challenges of requiring optimal basket placement, contact, and precise ablation targeting. Methods: In a propensity-matched case-control design, we compared 36 patients (from a total of 312) who underwent FIRM-guided (FIRM þ PVI) ablation on a standard or minimal fluoroscopy protocol. Seventeen (67.4610.0, 70.4% male, 11 persistent AF) underwent minimal fluoroscopy performed by an operator new to FIRM (3 case lead-in). Nineteen controls (68.968.1, 68.4% male, 14 persistent AF) were propensity matched from 295 cases of FIRM-guided ablation with routine fluoroscopy at our Institution, using logistic regression. In each limb, ablation comprised FIRM plus PVI, aided by intra-cardiac echocardiography for catheter positioning. For patients with minimal fluoroscopy, mapping, catheter placement, basket placement and ablation were guided entirely by EA mapping and ICE. Results: Panel A shows FIRM and PVI lesions delivered using minimal fluoroscopy (total 2.2 minutes) in a 64-year-old male with paroxysmal AF. Panel B shows how this protocol reduced fluoroscopy time to a total of 262 minutes versus 41616 minutes (p<0.001), and trended to reduce procedure time (p¼0.10) with no difference in complications. Conclusion: A minimal fluoroscopic approach to FIRM guided ablation is feasible, despite the challenges of optimal basket placement and precise ablation targeting, and poses no apparent safety concerns. Long-term outcomes from this approach require further study.
Atrial fibrillation is considered a model disease of trigger and substrate, with atrial electrica... more Atrial fibrillation is considered a model disease of trigger and substrate, with atrial electrical remodeling a key substrate factor for perpetuation of AF. Work conducted with human monophasic action potential (MAP) and continuous multipolar recordings has advanced our current understanding of atrial electrical properties and the transitions between physiologic activation of the atria and AF. Electrical heterogeneity seen during AF manifests as rate maladaptation, alternans, and higher-level oscillations in atrial action potential duration and shape. Defining these putative mechanisms for AF have been used to identify novel clinical phenotypes and may be used to guide therapy.
The spontaneously hypertensive rat (SHR) is a well-characterised model for studies of hypertensio... more The spontaneously hypertensive rat (SHR) is a well-characterised model for studies of hypertension and atrial arrhythmias but little is known about the electrophysiological properties of the left ventricle (LV) and their relation with ventricular arrhythmias in the development of this disease. To investigate the mechanisms behind electrophysiological abnormalities in the LV we used myocardial slices which allow the investigation of functional and structural properties in the same tissue location. Myocardial slices (300mm thick) were prepared from young (3months) and old (20months) SHR and age-matched control LVs. Slices were point-stimulated and analysed using a multi-electrode array system; longitudinal conduction velocity (CVL) was measured. CVL was unchanged between the young and old control groups. However, CVL was significantly reduced in the old SHR group compared to the corresponding age-matched control and young SHR groups (20months: 27+2 cm/s, n=29 slices/3 hearts vs control 39+4 cm/s, n=22 slices/4hearts and 3months: 37+3 cm/s, n=18 slices/3 hearts; p,0.05). In support of the slower CVL found in the aged group, western blotting analysis revealed a reduction in the expression of the gap junctional protein connexin43 in the old SHR when compared to age-matched control (in arbitrary units; control: 2+0.2,n=8slices /4hearts SHR:1.2+0.1,n=6slices/3hearts; p,0.01). These findings suggest that LV electrophysiological abnormalities are a result of disease progression as opposed to age-related changes. Cardiovascular Research Supplements (2014) 103, S57-S94
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