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  • 1
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    Drug-Induced Torsade de Pointes Arrhythmias in the Chronic AV Block Dog Are Perpetuated by Focal Activity
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Circulation: Arrhythmia and Electrophysiology Vol. 4, No. 4 ( 2011-08), p. 566-576
    Details
    In: Circulation: Arrhythmia and Electrophysiology, Ovid Technologies (Wolters Kluwer Health), Vol. 4, No. 4 ( 2011-08), p. 566-576
    Abstract: The electrically remodeled canine heart after chronic AV block (CAVB) has a high susceptibility for drug-induced torsade de pointes (TdP) arrhythmias. Although focal mechanisms have been considered for initiation, there is still controversy about whether reentry is the dominant mechanism for perpetuation of TdP. In this animal model with known nonuniform prolongation of repolarization, the mechanism of perpetuation of TdP arrhythmia was explored. Methods and Results— Seventeen TdP-sensitive CAVB and 10 sinus rhythm (SR) dogs were studied. In 6 animals, 66 needle electrodes were evenly distributed transmurally to record 240 unipolar local electrograms simultaneously. Activation times and activation recovery intervals were determined before and during ibutilide-induced TdP. In 12 CAVB and 9 SR dogs, left ventricular (LV) and right ventricular (RV) epicardial electrograms were recorded with a 208-point multiterminal grid electrode allowing conduction velocity (CV) and ventricular effective refractory period (VERP) measurements. Biopsy specimens were processed for connexin43 (Cx43) expression and collagen content. Ventricular myocytes were isolated to determine sodium current ( I Na ) density and cell dimensions. Computer simulations were used to assess the effects of changes therein. In CAVB, VERP and ARI were increased, whereas CV was unaltered in LV. Transversal but not longitudinal CV was increased in RV. I Na was reduced by 37% in LV but unaltered in RV. LV and RV cell size were increased, but collagen and Cx43 content remained unchanged. Simulations showed increase in CV of RV as a consequence of increased cell size at normal I Na . Ibutilide increased ARI, ERP, and maximal transmural dispersion of ERP (45±25 to 120±65 ms; P 〈 0.05). Twenty-eight of 47 episodes of self-terminating TdP (43±72 beats) were analyzed. The majority ( 〉 90%) of beats were focal; reentry was observed only occasionally. Conclusions— Focal activity is the dominant mechanism involved in perpetuation of ibutilide-induced TdP in CAVB dogs based on detailed 3D mapping. This conclusion is in line with unaltered conduction and documented increase in VERP.
    Type of Medium: Online Resource
    ISSN: 1941-3149 , 1941-3084
    URL: Article
    DOI: 10.1161/CIRCEP.110.958991
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
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  • 2
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    Reduced Cx43 Expression Triggers Increased Fibrosis Due to Enhanced Fibroblast Activity
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Circulation: Arrhythmia and Electrophysiology Vol. 5, No. 2 ( 2012-04), p. 380-390
    Details
    In: Circulation: Arrhythmia and Electrophysiology, Ovid Technologies (Wolters Kluwer Health), Vol. 5, No. 2 ( 2012-04), p. 380-390
    Abstract: Arrhythmogenic ventricular remodeling is hallmarked by both reduced gap junction expression and increased collagen deposition. We hypothesized that reduced connexin43 (Cx43) expression is responsible for enhanced fibrosis in the remodeled heart, resulting in an arrhythmogenic substrate. Therefore, we investigated the effect of normal or reduced Cx43 expression on the formation of fibrosis in a physiological (aging) and pathophysiological (transverse aortic constriction [TAC]) mouse model. Methods and Results— The Cx43 fl/fl and Cx43 CreER(T)/fl mice were aged 18 to 21 months or, at the age of 3 months, either TAC or sham operated and euthanized after 16 weeks. Epicardial activation mapping of the right and left ventricles was performed on Langendorff perfused hearts. Sustained ventricular arrhythmias were induced in 0 of 11 aged Cx43 fl/fl and 10 of 15 Cx43 Cre-ER(T)/fl mice ( P 〈 0.01). Cx43 expression was reduced by half in aged Cx43 CreER(T)/fl compared with aged Cx43 fl/fl mice, whereas collagen deposition was significantly increased from 1.1±0.2% to 7.4±1.3%. Aged Cx43 CreER(T)/fl mice with arrhythmias had significantly higher levels of fibrosis and conduction heterogeneity than aged Cx43 CreER(T)/fl mice without arrhythmias. The TAC operation significantly increased fibrosis in control compared with sham (4.0±1.2% versus 0.4±0.06%), but this increase was significantly higher in Cx43 CreER(T)/fl mice (10.8±1.4%). Discoidin domain receptor 2 expression was unchanged, but procollagen peptide I and III expression and collagen type 1α2 mRNA levels were higher in TAC–operated Cx43HZ mice. Conclusions— Reduced cellular coupling results in more excessive collagen deposition during aging or pressure overload in mice due to enhanced fibroblast activity, leading to increased conduction in homogeneity and proarrhythmia.
    Type of Medium: Online Resource
    ISSN: 1941-3149 , 1941-3084
    URL: Article
    DOI: 10.1161/CIRCEP.111.966580
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
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  • 3
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    Online Resource
    Discontinuous Conduction in Mouse Bundle Branches Is Caused by Bundle-Branch Architecture
    Ovid Technologies (Wolters Kluwer Health) ; 2005
    In:  Circulation Vol. 112, No. 15 ( 2005-10-11), p. 2235-2244
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 112, No. 15 ( 2005-10-11), p. 2235-2244
    Abstract: Background— Recordings of the electrical activity of mouse bundle branches (BBs) suggest reduced conduction velocity (CV) in the midseptal compared with the proximal part of the BB. The present study was performed to elucidate the mechanism responsible for this slowing of conduction. Methods and Results— Hearts of 16 mice were isolated and Langendorff perfused. After the right and left ventricular free walls were removed, the extracellular activity of the BB was mapped with a 247-point electrode. Premature stimulation was used to estimate CV restitution in the BBs. Expression/distribution of connexin40 (Cx40), Cx43, and Cx45 was determined. Morphology of the conduction system was assessed by whole-mount acetylcholine esterase staining and in Cx40 +/KI-GFP hearts. Effective CV in the midseptal part of the left and right BBs was reduced by 50% compared with the proximal BB. CV restitution in the proximal and midseptal parts of the BBs was similar. Myocytes labeled positive for Cx40 and Cx45 in the entire BB. Cx43 colocalized with Cx40 and Cx45 only in the very distal BB. Subcellular distribution of gap junctions differed between proximal and distal BBs. Geometry of the midseptal and distal BBs revealed on both sides a profuse network of interlacing fibers, whereas the proximal BB consisted of a single (right BB) or multiple (left BB) parallel fibers. Conclusions— Comparison of connexin expression/distribution, geometry of the BBs, and CV characteristics suggests that increased path length for activation resulting from BB geometry is responsible for the apparently reduced CV in the midseptal BB of the mouse heart.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.105.547893
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2005
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  • 4
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    Mouse Model of SCN5A -Linked Hereditary Lenègre’s Disease : Age-Related Conduction Slowing and Myocardial Fibrosis
    Ovid Technologies (Wolters Kluwer Health) ; 2005
    In:  Circulation Vol. 111, No. 14 ( 2005-04-12), p. 1738-1746
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 111, No. 14 ( 2005-04-12), p. 1738-1746
    Abstract: Background— We have previously linked hereditary progressive cardiac conduction defect (hereditary Lenègre’s disease) to a loss-of-function mutation in the gene encoding the main cardiac Na + channel, SCN5A . In the present study, we investigated heterozygous Scn5a -knockout mice ( Scn5a +/− mice) as a model for hereditary Lenègre’s disease. Methods and Results— In Scn5a +/− mice, surface ECG recordings showed age-related lengthening of the P-wave and PR- and QRS-interval duration, coinciding with previous observations in patients with Lenègre’s disease. Old but not young Scn5a +/− mice showed extensive fibrosis of their ventricular myocardium, a feature not seen in wild-type animals. In old Scn5a +/− mice, fibrosis was accompanied by heterogeneous expression of connexin 43 and upregulation of hypertrophic markers, including β-MHC and skeletal α-actin. Global connexin 43 expression as assessed with Western blots was similar to wild-type mice. Decreased connexin 40 expression was seen in the atria. Using pangenomic microarrays and real-time PCR, we identified in Scn5a +/− mice an age-related upregulation of genes encoding Atf3 and Egr1 transcription factors. Echocardiography and hemodynamic investigations demonstrated conserved cardiac function with aging and lack of ventricular hypertrophy. Conclusions— We conclude that Scn5a +/− mice convincingly recapitulate the Lenègre’s disease phenotype, including progressive impairment with aging of atrial and ventricular conduction associated with myocardial rearrangements and fibrosis. Our work provides the first demonstration that a monogenic ion channel defect can progressively lead to myocardial structural anomalies.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/01.CIR.0000160853.19867.61
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2005
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  • 5
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    SERCA2a Protein Levels Are Unaltered in Human Heart Failure
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Circulation Vol. 148, No. 7 ( 2023-08-15), p. 613-616
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 148, No. 7 ( 2023-08-15), p. 613-616
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.123.064513
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
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  • 6
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    Impaired Impulse Propagation in Scn5a -Knockout Mice : Combined Contribution of Excitability, Connexin Expression, and Tissue Architecture in Relation to Aging
    Ovid Technologies (Wolters Kluwer Health) ; 2005
    In:  Circulation Vol. 112, No. 13 ( 2005-09-27), p. 1927-1935
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 112, No. 13 ( 2005-09-27), p. 1927-1935
    Abstract: Background— The SCN5A sodium channel is a major determinant for cardiac impulse propagation. We used epicardial mapping of the atria, ventricles, and septae to investigate conduction velocity (CV) in Scn5a heterozygous young and old mice. Methods and Results— Mice were divided into 4 groups: (1) young (3 to 4 months) wild-type littermates (WT); (2) young heterozygous Scn5a -knockout mice (HZ); (3) old (12 to 17 months) WT; and (4) old HZ. In young HZ hearts, CV in the right but not the left ventricle was reduced in agreement with a rightward rotation in the QRS axes; fibrosis was virtually absent in both ventricles, and the pattern of connexin43 (Cx43) expression was similar to that of WT mice. In old WT animals, the right ventricle transversal CV was slightly reduced and was associated with interstitial fibrosis. In old HZ hearts, right and left ventricle CVs were severely reduced both in the transversal and longitudinal direction; multiple areas of severe reactive fibrosis invaded the myocardium, accompanied by markedly altered Cx43 expression. The right and left bundle-branch CVs were comparable to those of WT animals. The atria showed only mild fibrosis, with heterogeneously disturbed Cx40 and Cx43 expression. Conclusions— A 50% reduction in Scn5a expression alone or age-related interstitial fibrosis only slightly affects conduction. In aged HZ mice, reduced Scn5a expression is accompanied by the presence of reactive fibrosis and disarrangement of gap junctions, which results in profound conduction impairment.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.105.539072
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2005
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  • 7
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    Combined Na + /Ca 2+ Exchanger and L-Type Calcium Channel Block as a Potential Strategy to Suppress Arrhythmias and Maintain Ventricular Function
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Circulation: Arrhythmia and Electrophysiology Vol. 6, No. 2 ( 2013-04), p. 371-379
    Details
    In: Circulation: Arrhythmia and Electrophysiology, Ovid Technologies (Wolters Kluwer Health), Vol. 6, No. 2 ( 2013-04), p. 371-379
    Abstract: L-type calcium channel (LTCC) and Na + /Ca 2+ exchanger (NCX) have been implicated in repolarization-dependent arrhythmias, but also modulate calcium and contractility. Although LTCC inhibition is negative inotropic, NCX inhibition has the opposite effect. Combined block may, therefore, offer an advantage for hemodynamics and antiarrhythmic efficiency, particularly in diseased hearts. In a model of proarrhythmia, the dog with chronic atrioventricular block, we investigated whether combined inhibition of NCX and LTCC with SEA-0400 is effective against dofetilide-induced torsade de pointes arrhythmias (TdP), while maintaining calcium homeostasis and hemodynamics. Methods and Results— Left ventricular pressure (LVP) and ECG were monitored during infusion of SEA-0400 and verapamil in anesthetized dogs. Different doses were tested against dofetilide-induced TdP in chronic atrioventricular block dogs. In ventricular myocytes, effects of SEA-0400 were tested on action potentials, calcium transients, and early afterdepolarizations. In cardiomyocytes, SEA-0400 (1 μmol/L) blocked 66±3% of outward NCX, 50±2% of inward NCX, and 33±9% of LTCC current. SEA-0400 had no effect on systolic calcium, but slowed relaxation, despite action potential shortening, and increased diastolic calcium. SEA-0400 stabilized dofetilide-induced lability of repolarization and suppressed early afterdepolarizations. In vivo, SEA-0400 (0.4 and 0.8 mg/kg) had no effect on left ventricular pressure and suppressed dofetilide-induced TdPs dose dependently. Verapamil (0.3 mg/kg) also inhibited TdP, but caused a 15±8% drop of left ventricular pressure. A lower dose of verapamil without effects on left ventricular pressure (0.06 mg/kg) was not antiarrhythmic. Conclusions— In chronic atrioventricular block dogs, SEA-0400 treatment is effective against TdP. Unlike specific inhibition of LTCC, combined NCX and LTCC inhibition has no negative effects on cardiac hemodynamics.
    Type of Medium: Online Resource
    ISSN: 1941-3149 , 1941-3084
    URL: Article
    DOI: 10.1161/CIRCEP.113.000322
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
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  • 8
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    Defective Cx40 Maintains Cx37 Expression but Intact Cx40 Is Crucial for Conducted Dilations Irrespective of Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Hypertension Vol. 60, No. 6 ( 2012-12), p. 1422-1429
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 60, No. 6 ( 2012-12), p. 1422-1429
    Abstract: The gap junction channel protein connexin40 (Cx40) is crucial in vascular and renal physiology, because Cx40-deficient mice exhibit impaired conduction of endothelium-dependent dilations and pronounced hypertension. The latter precludes mechanistic insights into the role of endothelial Cx40, because long-lasting hypertension itself may affect conduction and Cx expression. We aimed to identify endothelial Cx40 functions, their dependency on the conductive capability, and to separate these from hypertension-related alterations. We assessed conduction and Cx expression in mice with cell type–specific deletion of Cx40 and in mice expressing a defective Cx40 (Cx40A96S) identified in humans, which forms nonconducting gap junction channels. Confined arteriolar stimulation with acetylcholine or bradykinin elicited local dilations that conducted upstream without attenuation of the amplitude for distances up to 1.2-mm in controls with a floxed Cx40 gene (Cx40 fl/fl ). Conducted responses in hypertensive animals devoid of Cx40 in renin-producing cells were unaltered but remote dilations were reduced in normotensive animals deficient for Cx40 in endothelial cells (Cx40 fl/fl :Tie2-Cre). Surprisingly, Cx37 expression was undetectable by immunostaining in arteriolar endothelium only in Cx40 fl/fl :Tie2-Cre; however, transcriptional activity of Cx37 in the cremaster was comparable with Cx40 fl/fl controls. Cx40A96S mice were hypertensive with preserved expression of Cx40 and Cx37. Nevertheless, conducted responses were blunted. We conclude that endothelial Cx40 is necessary to support conducted dilations initiated by endothelial agonists and to locate Cx37 into the plasma membrane. These functions are unaltered by long-lasting hypertension. In the presence of a nonconducting Cx40, Cx37 is present but cannot support the conduction highlighting the importance of endothelial Cx40.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.112.201194
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
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  • 9
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    Larger Cell Size in Rabbits With Heart Failure Increases Myocardial Conduction Velocity and QRS Duration
    Ovid Technologies (Wolters Kluwer Health) ; 2006
    In:  Circulation Vol. 113, No. 6 ( 2006-02-14), p. 806-813
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 113, No. 6 ( 2006-02-14), p. 806-813
    Abstract: Background— Patients with heart failure (HF) have an increased QRS duration, usually attributed to decreased conduction velocity (CV) due to ionic remodeling but which may alternatively result from increased heart size or cellular uncoupling. We investigated the relationship between QRS width, heart size, intercellular coupling, and CV in a rabbit model of moderate HF and in computer simulations. Methods and Results— HF was induced by pressure-volume overload. Heart weight (21.1±0.5 versus 10.2±0.4 g, mean±SEM; P 〈 0.01) and QRS duration (58±1 versus 50±1 ms; P 〈 0.01) were increased in HF versus control. Longitudinal CV (θ L ; 79±2 versus 67±4 cm/s; P 〈 0.01) and transversal subepicardial CV (θ T ; 43±2 versus 37±2 cm/s; P 〈 0.05) were higher in HF than in controls. Transmural CV (θ TM ) was unchanged (25±2 versus 24±1 cm/s; P =NS). Patch-clamp experiments demonstrated that sodium current was unchanged in HF versus control. Immunohistochemical experiments revealed that connexin43 content was reduced in midmyocardium but unchanged in subepicardium. Myocyte dimensions were increased in HF by ≈30%. Simulated strands of mammalian ventricular cells (Luo-Rudy dynamic model) revealed increased θ L and θ T with increased myocyte size; however, increased CV could not compensate for increased strand size of longitudinally coupled cells, and consequently, total activation time was longer. Conclusions— Increased myocyte size combined with the observed expression pattern of connexin43 yields increased θ L and θ T and unchanged θ TM in our nonischemic model of HF. A hypertrophied left ventricle together with insufficiently increased θ L and unaltered θ TM results in a prolonged QRS duration.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.105.565804
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2006
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