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Biomedical subjects

Nicholas S Peters

Publications and source records attributed to Nicholas S Peters.

At least 19 recordsLinked to original sources
PubMed2006

The effects of carbenoxolone on human myocardial conduction: a tool to investigate the role of gap junctional uncoupling in human arrhythmogenesis.

OBJECTIVES: This study assessed the effects of carbenoxolone on human myocardial conduction and refractoriness. BACKGROUND: Carbenoxolone, an antipeptic ulcer drug, has been shown to reduce gap junctional coupling without affecting cellular ion channels. Gap junctions (GJ) are considered to be determinants of cardiac action potential propagation. The effects of GJ uncoupling in the human heart are unknown. METHODS: Right atrial (RA) and ventricular (RV) activation mapping (Carto, Biosense Webster Inc., Diamond Bar, California) was performed during sinus rhythm. Right atrial and RV wavefront propagation velocity (WPV), specifically in the direction of propagation, was determined from these maps using a triangulation method. Refractoriness at multiple RA and RV sites, sinus rhythm cycle length, and AH, PR, QRS, and QT intervals were measured. The protocol was repeated 1 h after oral administration of 100 mg of carbenoxolone. RESULTS: In 11 patients, WPV was reduced from 79.6 +/- 13.3 cm/s to 57.2 +/- 9.1 cm/s (-27.1 +/- 12.8%, p < 0.001) in RA and from 98.7 +/- 19.8 cm/s to 76.5 +/- 21.7 cm/s (-22.7 +/- 14.1%, p < 0.01) in RV after carbenoxolone. Conduction slowing was more marked in 6 older patients with ischemic heart disease compared with younger subjects with normal hearts (RA -35.1 +/- 5.5% vs. -17.5 +/- 12.7%, p = 0.03; RV -33.8 +/- 5.1% vs. -9.3 +/- 7.7%, p < 0.001). Refractoriness and electrocardiogram parameters remained unchanged. CONCLUSIONS: Carbenoxolone causes a 27% reduction in human RA WPV and 23% in the RV without affecting refractoriness. The slowing of myocardial conduction by carbenoxolone demonstrates the significance of GJ in regulating human myocardial conduction and provides a tool for investigating the effects of GJ uncoupling on human arrhythmogenesis.

Action Potentials↗
PubMed2006

Heterogeneous gap junction remodeling in reentrant circuits in the epicardial border zone of the healing canine infarct.

BACKGROUND: The epicardial border zone (EBZ) of surviving myocytes in the healing, 4- to 5-day-old canine infarct is an arrhythmogenic substrate characterized by both structural and functional remodeling of Cx43. Unknown is whether the remodeling of gap junction conductance is heterogeneous in the EBZ like that of sarcolemmal ion channel remodeling and how remodeling of the gap junction influences conduction and anisotropy. METHODS AND RESULTS: Ventricular tachycardia was initiated by programmed stimulation in healing canine infarcted hearts. Reentrant circuits were mapped and the central common pathway (CCP) and outer pathway (OP) regions localized. Epimyocardium removed from the CCP was disaggregated to generate myocyte pairs for conductance measurements. Cx43 distribution was determined by immunofluorescent confocal microscopy. While transverse coupling (gap junction conductance) was markedly decreased in OP cells, CCP cells with lateralized Cx43 gap junctions showed normal conductance. Longitudinal coupling in both OP and CCP was no different than normal. Consistent with conductance measurements, the anisotropic ratio in the CCP was similar to that of normal tissue. In the OP it was increased. Despite normal longitudinal and transverse conductance and anisotropic ratio, longitudinal and transverse conduction velocities were decreased in the CCP with respect to normal epicardium, possibly as a result of the remodeling of sarcolemmal ion channels in this region. CONCLUSIONS: Gap junction conductance and distribution is heterogeneous in different regions of reentrant circuits. Lateralization of Cx43 gap junctions in CCP of reentrant circuits is associated with normal transverse conductance between cell pairs. In contrast, absence of lateralization in OP is associated with reduced transverse conductance. Despite normal anisotropic ratio, conduction velocity in CCP region remains slower than normal. This suggests that the effects of Cx43 remodeling in the infarcted heart should be interpreted in conjunction with other types of remodeling occurring in the EBZ (i.e. sarcolemmal ion channels).

Animals↗
PubMed2006

Overexpression of connexin 43 using a retroviral vector improves electrical coupling of skeletal myoblasts with cardiac myocytes in vitro.

BACKGROUND: Organ transplantation is presently often the only available option to repair a damaged heart. As heart donors are scarce, engineering of cardiac grafts from autologous skeletal myoblasts is a promising novel therapeutic strategy. The functionality of skeletal muscle cells in the heart milieu is, however, limited because of their inability to integrate electrically and mechanically into the myocardium. Therefore, in pursuit of improved cardiac integration of skeletal muscle grafts we sought to modify primary skeletal myoblasts by overexpression of the main gap-junctional protein connexin 43 and to study electrical coupling of connexin 43 overexpressing myoblasts to cardiac myocytes in vitro. METHODS: To create an efficient means for overexpression of connexin 43 in skeletal myoblasts we constructed a bicistronic retroviral vector MLV-CX43-EGFP expressing the human connexin 43 cDNA and the marker EGFP gene. This vector was employed to transduce primary rat skeletal myoblasts in optimised conditions involving a concomitant use of the retrovirus immobilising protein RetroNectin and the polycation transduction enhancer Transfectam. The EGFP-positive transduced cells were then enriched by flow cytometry. RESULTS: More than four-fold overexpression of connexin 43 in the transduced skeletal myoblasts, compared with non-transduced cells, was shown by Western blotting. Functionality of the overexpressed connexin 43 was demonstrated by microinjection of a fluorescent dye showing enhanced gap-junctional intercellular transfer in connexin 43 transduced myoblasts compared with transfer in non-transduced myoblasts. Rat cardiac myocytes were cultured in multielectrode array culture dishes together with connexin 43/EGFP transduced skeletal myoblasts, control non-transduced skeletal myoblasts or alone. Extracellular field action potential activation rates in the co-cultures of connexin 43 transduced skeletal myoblasts with cardiac myocytes were significantly higher than in the co-cultures of non-transduced skeletal myoblasts with cardiac myocytes and similar to the rates in pure cultures of cardiac myocytes. CONCLUSION: The observed elevated field action potential activation rate in the co-cultures of cardiac myocytes with connexin 43 transduced skeletal myoblasts indicates enhanced cell-to-cell electrical coupling due to overexpression of connexin 43 in skeletal myoblasts. This study suggests that retroviral connexin 43 transduction can be employed to augment engineering of the electrocompetent cardiac grafts from patients' own skeletal myoblasts.

Animals↗
PubMed2006

Alpha 1-acid glycoprotein reverses cocaine-induced sodium channel blockade in cardiac myocytes.

UNLABELLED: Alpha 1-acid glycoprotein (AAG) is an acute phase protein capable of binding basic drugs. This action explains its reversal of sodium channel blockade by drugs such as amitriptyline and quinidine. We report here the reversal of cocaine-induced sodium channel blockade by AAG. The sodium channel blocking property of cocaine is a major mechanism behind cocaine-induced sudden cardiac death, since sodium channels play a key role in the initiation and regulation of the heart beat. Voltage-gated sodium current (I(Na)) was recorded using whole-cell patch-clamp techniques. Guinea-pig cardiac ventricular myocytes were isolated and continuously perfused at room temperature with physiological solutions. At concentrations ranging from 5 to 320 microM cocaine showed a dose-dependent and reversible blockade of I(Na) with an IC50 of 45.9 microM. The addition of equimolar amounts of AAG to cocaine produced almost complete reversal of cocaine's effects, suggesting a single binding site for cocaine on the AAG molecule. With changes of peak I(Na) normalized against control as 1, cocaine at 20 and 40 microM reduced I(Na) to 0.62+/-0.042 (n = 6) and 0.57+/-0.052 (n = 9), respectively, and the addition of an equimolar concentration of AAG reversed I(Na) to 0.86+/-0.022 and 0.91+/-0.060, respectively. IN CONCLUSION: AAG reverses cocaine-induced sodium channel blockade in a dose-dependent manner, indicating a therapeutic potential to reverse acute cocaine cardiac toxicity.

Animals↗
PubMed2006

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Animals↗
PubMed2006

Human atrial conduction and arrhythmogenesis correlates with conformational exposure of specific epitopes on the connexin40 carboxyl tail.

BACKGROUND: Gap junction expression is considered to influence myocardial conduction and arrhythmogenesis, but studies in patients with atrial fibrillation (AF) have reported inconsistent results. We used human atrial conduction and arrhythmogenicity to provide clinical parameters with which to correlate quantification of connexin40 (Cx40) by different techniques to address the hypothesis that antibody-epitope binding properties may influence quantification methods. METHODS AND RESULTS: Atrial conduction properties were studied in patients undergoing coronary artery bypass grafting (N = 27) using multi-electrode array mapping. Patients were defined as having a vulnerable atrial substrate if pacing-induced AF lasted for more than 30 s. Using antibodies targeted at two different epitopes of the cytoplasmic carboxyl tail, Cx40 signal was quantified by immunoconfocal microscopy in biopsies taken from the mapped atria. Only patients with a vulnerable substrate subsequently developed post-operative AF (P < 0.02). Immunoconfocal Cx40 signal measured by one antibody, designated S15C(R85), was lower in patients with sustained induced AF (0.013 +/- 0.009 microm(2)/microm(2) vs. 0.024 +/- 0.010 microm(2)/microm(2), P = 0.005) and was negatively correlated with atrial conduction velocity during sinus rhythm (P < 0.05). However, these relationships did not exist when the Cx40 signal was measured using a different antibody (Y21Y(R968)). Further studies suggested that quantification technique was reproducible against the same epitope (P < 0.001) but not against different epitopes indicating variable exposure of Cx40 epitopes. CONCLUSIONS: Quantification of Cx40 by immunoconfocal microscopy appears to be epitope dependent and evidence of epitope masking raises the possibility of more than one conformational form of the Cx40 carboxyl tail, suggesting functionally important conformations of the protein.

Aged↗
PubMed2005

Long-term results after ablation of infarct-related ventricular tachycardia.

OBJECTIVES: The purpose of this study was to assess the long-term effects of ablation of infarct-related ventricular tachycardia (VT) and the subsequent requirement for implantable cardioverter-defibrillator (ICD) therapy. BACKGROUND: The long-term consequences after initially successful catheter ablation of infarct-related VT remain unclear. METHODS: Forty patients who presented with infarct-related VT were studied using noncontact mapping to guide ablation. RESULTS: One hundred forty VTs were mapped using the noncontact mapping system, including 36 (25.7%) clinical VTs. An endocardial exit site was determined in 100% of VT circuits, diastolic endocardial activity in 77 VTs (55%), and complete circuits in 24 VTs (17.1%). Eighty-one VTs (57.9%) were targeted for ablation, of which 67 (82.7% of targeted) were successfully ablated, including 27 clinical VTs (75% of clinical). Documented recurrence of an ablated VT occurred in 7.5% of patients over 36.3 +/- 21.0 months of follow-up. Episodes of new or recurrent, nontargeted VT or ventricular fibrillation (VF) occurred in 37.5% and VT recurrence without documentation of cycle length in 5%. In patients with ICDs, mean shock frequency was reduced from 6.8 +/- 7.3 per month in the year prior to ablation to 0.05 +/- 0.12 per month after ablation, over 24.7 +/- 18.9 months of follow-up (P < .0001). CONCLUSIONS: In patients with infarct-related VT, noncontact mapping-guided VT ablation is associated with a high procedural success rate, and VT recurrence necessitating ICD therapy delivery is significantly reduced. However, only 42.5% of patients remain free from VT/VF 3 years after ablation. Catheter ablation for infarct-related VT is indicated as an adjunctive therapy in patients with symptomatic VT but cannot substitute for ICDs and antiarrhythmic drugs.

Aged↗
PubMed2004

Mechanism of pacing-induced ventricular fibrillation in the infarcted human heart.

BACKGROUND: The mechanisms by which ventricular fibrillation (VF) is initiated in the infarcted human heart have not been defined. METHODS AND RESULTS: Left ventricular noncontact mapping of 8 episodes of pacing-induced VF in 6 patients (age 64.8+/-7.9 years, with previous myocardial infraction and left ventricular ejection fraction of 36+/-4%) undergoing ventricular tachycardia (VT) ablation revealed a consistent mechanism of VF induction. Whether during VT or sinus rhythm, the first of a train of paced extrastimuli to capture the LV produced an arc or arcs of functional block at regions bordering scar. With subsequent extrastimuli, the arcs elongated to circumscribe an enlarging area of increasingly late activation, with reentry through part of this functional (unidirectional) block leading to wavefront fragmentation and VF. These regions had longer fibrillation intervals (263+/-63 ms) than remote LV regions (209+/-23.4 ms; P<0.0001), implying longer refractory periods, and in 6 of the 8 VF episodes, these regions correlated with VT exit sites. In each of the 2 patients with 2 episodes of VF, both episodes formed arcs of functional block in the same location, despite pacing from different sites. CONCLUSIONS: Pacing-induced VF in the infarcted human heart is initiated by the development of functional lines of block dictated by the properties of a particular region of myocardium characterized by longer refractory periods, at or near VT circuit exit sites. Identification of these characteristic properties may help stratify risk of arrhythmic death and explain the potential for VT ablation to modify risk of VF in the infarcted heart.

Aged↗
PubMed2004

Novel use of postpacing interval mapping to guide radiofrequency ablation of focal atrial tachycardia with long intra-atrial conduction time.

If the intra-atrial conduction time of a focal tachycardia is prolonged and exceeds the tachycardia cycle length, isochronal electroanatomical maps may be confusing by not showing the classical centrifugal pattern of focal activation. In addressing the hypothesis that by mapping post pacing intervals (PPI), the shortest PPI (ideally identical to tachycardia cycle length) would clearly display the site of origin of a focal tachycardia; this technique was used successfully to identify the origin and ablate the atrial tachycardia of a patient with previously corrected Tetralogy of Fallot.

Adult↗
PubMed2004

Clinical usefulness of cryomapping for ablation of tachycardias involving perinodal tissue.

OBJECTIVES: Radiofrequency (RF) ablation near the AV node carries a significant risk of AV block. We report our initial experience of using cryomapping function to aid the safe cryoablation close to the compact atrioventricular (AV) node. METHODS: Five consecutive patients with para-Hisian accessory pathways (AP) ( n = 2), or focal atrial tachycardia (AT) originating near the AV node ( n = 3) underwent cryoablation using a 7F 4 mm-tipped catheter. At each prospective ablation site, cryo-mapping (-30 degrees C) which causes transient electrical dysfunction was performed, and in the absence of AH interval prolongation, a full cryoablation (<or=-70 degrees C) was applied to the same site. RESULTS: The AT foci, left in 2 patients and right in 1, and the APs were located 1.9 +/- 3.0 mm and 4.5 +/- 8.1 mm from the catheter recording the His deflection in two orthogonal radiographic projections. A His signal (0.18 +/- 0.07 mV) was recorded at the site of successful cryoablation in both patients with AP and 1 with right AT. There was no change in AV nodal function during/after ablation. At each successful cryoablation site, interruption of target pathway/focus function was observed during cryo-mapping after 19.8 +/- 12.4 s. Full cryoablation at sites where cryo-mapping had not caused an effect did not then produce any further electrophysiologic effect. All pathways and foci were ablated successfully without complications, using 3.2 +/- 3.9 cryothermic applications alone in 4 patients, and after a supplementary RF ablation in 1. All patients remained free of arrhythmia at 15 +/- 8 months follow-up. CONCLUSION: Cryomapping may help identify sites for safe and effective ablation of pathways and foci located near the AV node.

Adult↗
PubMed2004

Percutaneous pulmonary vein cryoablation to treat atrial fibrillation.

BACKGROUND: Cryothermic tissue injury, unlike hyperthermic tissue injury, preserves tissue architecture and causes less thrombus formation, and thus may prevent venous stenosis and stroke in ablating pulmonary veins (PVs) to treat patients with atrial fibrillation (AF). We investigate the feasibility, efficacy, safety and clinical outcome of using percutaneous cryoablation to treat such patients. METHODS: Thirty-one patients who had drug refractory paroxysmal (20) or persistent (11) AF underwent 37 PV ablative procedures using a 4 mm- or 6 mm-tipped 7F cryoablation catheter (CryoCath Technologies Inc., Quebec, Canada). Segmental isolation at the veno-atrial junction was guided by a distal circumferential mapping catheter. RESULTS: A total of 47 PV were ablated, of which 35/47 (74%) were electrically isolated and the remaining 12/47 had attenuation of PV electrograms, altered activation sequence, and marked slowing of left atrial-PV conduction. There was no change in PV diameter, either immediately following cryoablation (21 +/- 5 versus 22 +/- 6, p = 0.69), or at 18 +/- 9 months follow-up (22 +/- 5 versus 22 +/- 5 mm, p = 0.23). There was no clinical thromboembolic event. The duration of cryoablation for each treated PV and procedural duration was 65 +/- 39 and 290 +/- 101 min, respectively. Following cryoablation, 5/30 (6%) were free from AF and 12/30 (43%) showed improvement from previously ineffective antiarrhythmic drug therapy. 13/30 (43%) patients were unchanged by cryoablation. CONCLUSIONS: Cryothermic ablation shows great promise in reducing the risks of PV stenosis and thrombo-embolism associated with PV isolative procedures. However, cryoablation of these veins with linear catheters is time consuming, and the clinical outcomes are disappointing. Alternative catheter designs are required to overcome these difficulties.

Analysis of Variance↗
PubMed2004

Localization of the isthmus in reentrant circuits by analysis of electrograms derived from clinical noncontact mapping during sinus rhythm and ventricular tachycardia.

INTRODUCTION: New methods for electrogram analysis accurately estimated reentrant circuit isthmus location and shape in a canine model. It was hypothesized that these methods also would locate reentrant circuits causing clinical ventricular tachycardia (VT). METHODS AND RESULTS: Intracardiac electrogram recordings, obtained with a noncontact mapping system, were analyzed retrospectively from 14 patients with reentrant VT who had undergone successful radiofrequency ablation for prevention of VT initiation. Unipolar electrograms from 256 uniformly distributed endocardial sites were reconstructed by mathematical transformation. Twenty-seven tachycardias were mapped; 15 (in 11 patients) had a complete endocardial reentrant circuit with a figure-of-eight conduction pattern. During sinus rhythm, the location and axis of the slowest and most uniform conduction in the region of latest endocardial activation (the primary axis), the limits of which were defined as boundaries with >15 ms difference in electrogram duration between contiguous recordings, identified the location and shape of the reentrant circuit isthmus with a mean sensitivity compared with activation mapping of 79.3% and a mean specificity of 97.6%. The midpoint of a theoretical "estimated best ablation line" drawn perpendicular to the primary axis of activation, spanning the estimated isthmus location was within 1.3 +/- 0.2 cm (mean distance +/- SD) of the actual ablation site that terminated tachycardia. Analysis of VT electrograms, based on time shifts in the far-field component of the local electrogram when cycle length changed (piecewise linear adaptive template matching [PLATM] method) in 5 of the cases, accurately estimated the time interval between activation at the recording site and the circuit isthmus slow conduction zone where the effective ablation lesion had been placed, which is proportional to the distance between the two locations (mean difference compared with activation mapping: +/-37.3 ms). CONCLUSION: In selected patients with VT who have a complete endocardial circuit, isthmus location and shape can be discerned by analysis of sinus rhythm or tachycardia electrograms, and an effective ablation site can be predicted without the need to construct activation maps of reentrant circuits.

Algorithms↗
PubMed2004

Relationship between connexins and atrial activation during human atrial fibrillation.

INTRODUCTION: Gap junctional connexin proteins (connexin40 [Cx40], connexin43 [Cx43]) are a determinant of myocardial conduction and are implicated in the development of atrial fibrillation (AF). We hypothesized that atrial activation pattern during AF is related to connexin expression and that this relationship is altered by AF-induced remodeling in the fibrillating atria of chronic AF. METHODS AND RESULTS: Isochronal activation mapping was performed during cardiac surgery on the right atria of patients in chronic AF (n = 13) using an epicardial electrode array. The atrial activation pattern was categorized using a complexity score based on the number of propagating wavefronts of activation and by grouping atria into those capable of uniform planar activation (simple) and those that were not (complex). The activation pattern was correlated with the levels of Cx43 and Cx40 signal measured by immunoconfocal quantification of biopsies from the mapped region. We studied the impact of electrical remodeling by comparing these findings with the unremodeled atria of patients in sinus rhythm during pacing-induced sustained AF (n = 17). In chronic AF, atria with complex activation had lower Cx40 signal than atria showing simple activation (0.013 +/- 0.006 microm(2)/microm(2) vs 0.027 +/- 0.009 microm(2)/microm(2), P < 0.02), with the relative connexin signal (Cx40/Cx40+Cx43) correlating with complexity score (P = 0.01, r =-0.74). This relationship did not occur in the unremodeled atria, and increased heterogeneity of distribution of Cx40 labeling in chronic AF was the only evidence of connexin remodeling that we detected in the overall group. CONCLUSION: The pattern of atrial activation is related to immunoconfocal connexin signal only in the fully remodeled atria of chronic AF. This suggests that intercellular coupling and pattern of atrial activation are interrelated, but only in conjunction with the remodeling of atrial electrophysiology that occurs in chronic AF.

Adult↗