Antegrade slow pathway mapping of typical atrioventricular nodal reentrant tachycardia based on direct slow pathway capture.

BACKGROUND: Radiofrequency (RF) ablation of typical atrioventricular nodal reentrant tachycardia (tAVNRT) is performed without revealing out the location of antegrade slow pathway (ASp). In this study, we studied a new electrophysiological method of identifying the site of ASp. METHODS: This study included 19 patients. Repeated series of very high-output single extrastimulations (VhoSESts) were delivered at the anatomical slow pathway region during tAVNRT. Tachycardia cycle length (TCL), coupling interval (CI), and return cycle (RC) were measured and the prematurity of VhoSESts [ΔPM (= TCL - CI)] and the prolongation of RCs [ΔPL (= RC - TCL)] were calculated. Pacing sites were classified into two categories: (i) ASp capture sites [DSPC(+) sites], where two different RCs were shown, and ASp non-capture sites [DSPC(-) sites], where only one RC was shown. RF ablation was performed at DSPC(+) sites and/or sites with catheter-induced mechanical trauma (CIMT) to ASp. RESULTS: DSPC(+) sites were shown in 13 patients (68%). RF ablation was successful in all patients without any degree of atrioventricular block nor recurrence. Total number of RF applications was 1.8 ± 1.1. Minimal distance between successful ablation sites and DSPC(+)/CIMT sites and His bundle (HB) electrogram recording sites was 1.9 ± 0.8 mm and 19.8 ± 6.1 mm, respectively. ΔPL of more than 92.5 ms, ΔPL/TCL of more than 0.286, and ΔPL/ΔPM of more than 1.565 could identify ASp with sensitivity of 100%, 91.1%, and 88.9% and specificity of 92.9%, 97.0%, and 97.6%, respectively. CONCLUSIONS: Sites with ASp capture and CIMT were close to successful ablation sites and could be useful indicators of tAVNRT ablation.

Cardiac autonomic function measured by heart rate variability and turbulence in pre-hypertensive subjects.

Non-dipping blood pressure pattern was shown to be associated with increased cardiovascular events. In addition, cardiac autonomic dysfunction was found to be associated with non-dipper phenomenon. In this study, we aimed to evaluate the cardiac autonomic functions in dipper and non-dipper pre-hypertensive subjects. A total of 65 pre-hypertensive subjects were enrolled in this study. They were divided into two groups as non-dippers (40 subjects, 52% female) and dippers (25 subjects, 52.5% female). Cardiac autonomic functions of the two groups were compared with the aid of heart rate variability, heart rate turbulence (HRT), atrial premature contractions (APCs), ventricular premature contractions (VPCs), and mean heart rate (MHR). There was no significant difference between non-dippers and dippers in basal characteristics. The two parameters of HRT, turbulence onset and turbulence slope, were found to be significantly abnormal in non-dippers than in dippers (P < .011 and P < .002, respectively). Heart rate variability parameters, including SDNN, SDANN, RMSSD, and pNN50, were found to be similar in dipper and non-dipper pre-hypertensive subjects (P < .998, P < .453, P < .205, and P < .788, respectively). APCs, VPCs, and MHR were compared, and there were statistical differences between the groups (APCs 5.80 ± 4.55, 9.14 ± 7.33, P < .024; VPCs 8.48 ± 8.83, 13.23 ± 9.68, P < .044; and MHR 70.16 ± 11.08, 76.26 ± 11.31, P < .035; respectively). This study demonstrated a possible cardiac autonomic dysfunction in pre-hypertensive subjects with non-dipper pattern. This may be a basis for future studies related to pre-hypertension and non-dipping BP pattern.

The effect of metabolic syndrome on heart rate turbulence in non-diabetic patients.

BACKGROUND: Metabolic syndrome (MetS), which includes a cluster of risk factors, is being increasingly recognized as a new risk factor for cardiovascular disease. Heart rate turbulence (HRT) is a Holter-based non-invasive method for detecting cardiac autonomic imbalance and is an independent, powerful predictor of cardiac arrhythmias and sudden cardiac death in different patient groups. This study evaluated the effect of MetS on HRT in non-diabetic patients. METHODS: This study included 80 non-diabetic MetS subjects and 50 healthy subjects. All 130 subjects underwent a 24-h ambulatory Holter electrocardiogram recording. Two indices of HRT were analyzed: turbulence onset (TO) and turbulence slope (TS). HRT values were classified into 3 categories for risk stratification: 1) Category 0, TO and TS were normal; 2) Category 1, either TO or TS was abnormal; 3) Category 2, both TO and TS were abnormal. RESULTS: When we compared MetS rates in the HRT risk stratification groups, there were significant differences for all groups as compared with the controls (Category 0 = MetS 28.8%, n = 15, Control 71.2%, n = 37, p 〈 0.001; Category 1 = MetS 80.8%, n = 42, Control 19.2%, n = 10, p 〈 0.001; Category 2 = MetS 88.5%, n = 23, Control 11.5%, n = 3, p 〈 0.001). In addition, TO and TS abnormalities were correlated with the number of MetS components (r = 0.608, p 〈 0.001; r = -0.388, p 〈 0.001, respectively). CONCLUSIONS: To our knowledge, this is the first study to establish a relationship between HRT and MetS. These findings suggest that MetS adversely affects HRT scores. In addition, the number of MetS components is related to impaired HRT scores.

Novel method to evaluate the conduction velocity and conducting area during isthmus-dependent atrial flutter.

OBJECTIVE: The difference of the conduction velocity (CV) around the tricuspid valve annulus between the counter-clockwise (CCW) atrial flutter and the clockwise (CW) atrial flutter has not been well clarified. This study was undertaken to evaluate the CV and the conducting area (CA) per millisecond around the tricuspid valve annulus using the electroanatomical mapping. METHODS: The electroanatomical mapping was performed during the tachycardia for 30 consecutive patients (mean age: 61±16 years) with isthmus-dependent atrial flutter (CCW, 25; CW, 5). We measured the CV and the CA of five divided areas of the right atrium, that is, upper septum (US), lower septum (LS), isthmus (I), upper lateral wall (UL) and lower lateral wall (LL) using the novel measurement method in the isochronal map. Statistical differences of these data between the two groups were assessed by the Student's t-test and one-way analysis of variance methods. RESULTS: In total, the CV of the LS was significantly slower than other areas (m/sec: US, 0.57±0.18; LS, 0.43±0.18; UL, 0.60±0.26; LL, 0.53±0.20; I, 0.50±0.17; p<0.05) and the CA of the US and UL were significantly larger than other areas (mm2/sec: US, 34.5±16.2; LS, 16.2±9.5; UL, 40.0±14.1; LL, 27.0±17.0; I, 16.8±8.5; p<0.0001). There was no significant difference between the CCW and the CW atrial flutters in terms of the CV and the CA of equally divided five areas. CONCLUSION: In both of the CCW and the CW atrial flutters, the CV of the LS was significantly slower than other areas and the CA of the lower atrium was significantly smaller than the upper atrium.

Altered action potential dynamics in electrically remodeled canine atria: evidence for altered intracellular Ca2+ handling.

BACKGROUND: Electrical instability following sustained rapid excitation has been attributed to altered ion channels. Alterations of Ca(2+) handling could also contribute to abnormal dynamics of action potential, favoring the initiation and perpetuation of arrhythmia. METHODS AND RESULTS: Transmembrane action potentials and twitch force (TF) were recorded from normal (n=6) and remodeled (6-week atrial pacing at 400 beats/min, n=6) canine atria. When the cycle length (CL) was suddenly prolonged in normal atria, both TF and action potential duration (APD) increased on the first beat, and decreased subsequently. Opposite changes were observed with sudden CL shortening. These dynamics in both APD and TF were abolished by ryanodine, but augmented by cyclopiazonic acid, an inhibitor of the sarcoplasmic reticulum (SR) Ca(2+) pump. In remodeled atria (RA), dynamic changes in APD were also concordant with dynamic changes in TF. The transient increases in APD and TF were enhanced, and the transient decreases were reduced compared to normal atria. The maximal slopes of APD and TF restitution curves were flatter and the magnitude of alternans was reduced in RA. The protein expression of SR Ca(2+) ATPase and SR Ca(2+)-release channel in RA was significantly reduced. CONCLUSION: Altered Ca(2+) handling may underlie abnormal APD dynamics in RA.

Temporal patterns of progression and regression of electrical and mechanical remodeling of the atrium.

OBJECTIVES: We evaluated serial changes of electrical and mechanical parameters of atrial remodeling in dogs subjected to rapid atrial pacing. BACKGROUND: Prolonged rapid atrial excitation causes electrical and mechanical remodeling, which contributes to persistence of atrial fibrillation and clot formation. However, the temporal relationship between these two types of atrial remodeling remains unknown. METHODS: In 8 dogs, rapid pacing at 400 ppm was continued for 14 days. The electrophysiologic and transesophageal echocardiographic studies were performed on the day before and after 2, 7, and 14 days of rapid pacing, then 1 and 7 days after the cessation of pacing. These were compared with sham-operated dogs (instrumented but not paced, n=6). RESULTS: With rapid pacing, there was an immediate shortening of the effective refractory period (ERP) and decreases in the transmitral atrial wave velocity (MAV) and the left atrial appendage emptying velocity (LAAV). In contrast, conduction velocity (CV) decreased and the left atrial appendage area (LAAA) increased progressively over 14 days. During the recovery, ERP, MAV, and LAAV returned to the baseline in 1 day, whereas CV and LAAA did in 7 days. ERP was highly positively correlated with LAAV (r=0.78, p<0.001) and MAV (r=0.73, p<0.001), while CV was negatively correlated only with LAAA (r=-0.58, p<0.001). CONCLUSIONS: Pacing-induced electrical and mechanical remodeling of the atrium exhibits divergent patterns of progression and regression such that changes of ERP and contractile function take place more rapidly than those of CV and atrial size.

A comparison between calcium channel blocking drugs with different potencies for T- and L-type channels in preventing atrial electrical remodeling.

Calcium overload plays a key role in the development of atrial electrical remodeling. The effect of an L-type Ca channel blocker in preventing this remodeling has been reported to be short lasting, partly due to down-regulation of this channel and persisting Ca entry through the T-type Ca channel. To prove if efonidipine, a dual L- and T-type Ca channel blocker exerts a greater effect than an L-type Ca channel blocker verapamil, 21 dogs underwent rapid atrial pacing at 400 bpm for 14 days, pretreatment with efonidipine in 7 (E), verapamil in 7 (V), and none in 7 (C). We measured the atrial effective refractory period (ERP) serially during 14 days of rapid pacing. In response to rapid pacing, ERP decreased progressively in C. In contrast, in E and V, ERP remained greater than ERP in C (P < 0.01) on days 2 through 7. However, on the 14th day, ERP in V decreased to the level seen in C, whereas ERP in E remained significantly longer than ERPs in C or V (P < 0.01). The blockade L-type Ca channel alone is not sufficient, but the addition of a T-type Ca channel blockade shows a more sustained effect to prevent atrial electrical remodeling.

Oral verapamil attenuates the progression of pacing-induced electrical and mechanical remodeling of the atrium.

BACKGROUND: Calcium overload plays a major role in the development of electrical and mechanical remodeling during atrial fibrillation, but the potential of verapamil, a Ca blocker, for preventing atrial electrical remodeling remains controversial. METHODS AND RESULTS: Pacing and recording electrodes were sutured to the right atrium in 16 dogs. After a 5-day recovery period, rapid atrial pacing at 400 ppm was initiated in 8 dogs (control group). In the remaining 8 dogs, oral administration of verapamil (8 mg/kg per day) was started 1 week before the initiation of rapid pacing (verapamil group). On the day before and at 2, 7, 14 days after rapid pacing, electrophysiological (EP) and transesophageal echocardiographic (TEE) studies were performed under autonomic blockade. In response to rapid pacing, EP and TEE parameters changed progressively in the control group (p<0.05 vs day 0), whereas in the verapamil group, no significant changes in the various parameters were observed for the first 7 days. However, verapamil failed to prevent progression of both types of remodeling after 14 days of pacing. CONCLUSION: Verapamil can attenuate the progression of electrical and mechanical remodeling of the atrium for at least 7 days.

Preserved effects of potassium channel blockers in the pacing-induced remodeled canine atrium: a comparison between E4031 and azimilide.

This study was designed to evaluate the electrophysiologic effects of E4031 (a pure IKr blocker) and azimilide (AZ: a combined Ikr + IKs blocker) at various stages of atrial electrical remodeling. Twelve dogs underwent continuous rapid atrial pacing (400/min) for 14 days. The electrophysiologic study was performed on the day before as well as after 2, 7, and 14 days of rapid atrial pacing both before and after the administration of either E4031 (n = 6) or AZ (n = 6). In response to rapid atrial pacing, the atrial effective refractory period (ERP), conduction velocity, and wavelength decreased significantly at pacing cycle lengths (PCLs) of 200 and 400 ms (P < 0.05). E4031 prolonged ERP in a reverse use-dependent manner throughout the study period. AZ also prolonged ERP during the 14 days of rapid pacing. ERP prolongation at a PCL of 200 ms was significantly greater with AZ than with E4031 (P < 0.05). The effects of blocking IKr by E4031 and IKr + IKs by AZ were well preserved at various stages of atrial electrical remodeling. However, the effect of prolonging ERP at a shorter PCL was more prominent by AZ than by E4031. Thus, IKs blockade may add a favorable anti-fibrillatory effect to IKr blockade even in the remodeled atrium.

Density and function of inward currents in right atrial cells from chronically fibrillating canine atria.

OBJECTIVE: To determine whether I(Na) and I(CaL) are altered in function/density in right atrial (RA) cells from dogs with chronic atrial fibrillation (cAF dogs, episodes lasting at least 6 days) and whether the changes that occur differ from those in dogs with nonsustained or brief episodes of fibrillation (nAF dogs). METHODS: Using whole cell voltage clamp, sodium and calcium current density and function were determined in disaggregated RA cells from nAF, cAF and control atria (Con). Ca(2+) currents were studied with either Ca(2+) or Ba(2+) as charge carrier, as well as with either EGTA or BAPTA as the internal solution Ca(2+) chelator. RESULTS: After rapid atrial pacing, dogs can either fibrillate for short periods of time (nAF) or longer, more sustained periods (cAF). Both the Na(+) and Ca(2+) current decrease in cells of the nAF atria. Na(+) current density remains reduced in cAF cells with some slowing of recovery kinetics. Ca(2+) current density does not further decrease with persistent atrial fibrillation (cAF cells) remaining significantly different from Con cells. However, the difference in density of Ca(2+) currents between nAF and Con cells is negligible when Ba(2+) is charge carrier and when Ca(i) is quickly and effectively chelated with BAPTA. On the contrary, cAF I(BaL) densities remain significantly reduced compared to Con and nAF values when Ba(2+)/BAPTA conditions are used. CONCLUSIONS: Na(+) current density/function does not recover to Con values in cAF. Further these enhanced Ca(2+)-dependent inactivation processes contribute significantly to the reduction of I(CaL) density observed in nAF cells while reduction of Ca(2+) currents in cAF atria is probably by another mechanism

Daily oral verapamil before but not after rapid atrial excitation prevents electrical remodeling.

BACKGROUND: Intravenous verapamil has been reported to prevent electrical remodeling induced by rapid atrial excitation of several minutes to several hours. However, the clinical efficacy of verapamil when taken orally and daily remains controversial. PURPOSE: We attempted to demonstrate our hypothesis that if verapamil prevents calcium (Ca) overload, its efficacy would be greater when taken before, rather than after, the onset of rapid atrial excitation. METHODS: In 24 dogs, pacing and recording electrodes were sutured onto the right atrium. After a 5-day recovery period, rapid atrial pacing at 400 ppm was started, followed 2 days later by oral verapamil (8 mg/kg per day) in eight dogs (After group; A). In another eight dogs, oral verapamil administration was begun 1 week before the initiation of rapid pacing (Before group; B). In the remaining eight dogs, only rapid atrial pacing was started, without oral verapamil (Control group; C). We measured the effective refractory period (ERP) and conduction velocity (CV), and calculated wavelength (WL) at cycle lengths 200 and 300 ms on the day before (P0), and after 2 (P2), 7 (P7), 14(P14) days of rapid pacing. RESULTS: In response to rapid atrial pacing, ERP, CV, WL decreased and progressively and comparably in A and C (P<0.05 vs. P0). In contrast, in B, these parameters did not change significantly and remained greater than those in A and C (P<0.05). Moreover, the adaptation of ERP to rate was preserved only in B. The duration of atrial fibrillation (AF) was shorter in B than in A and C (P<0.05). The inducibility of AF tended to be lower, and the fibrillation cycle length was longer in B than in A and C. CONCLUSIONS: Oral verapamil started before but not after rapid atrial excitation prevents electrical remodeling. Verapamil may exert beneficial effects when it is taken during sinus rhythm, but not after more than 2 days of atrial tachyarrhythmia.

Anisotropic conduction properties in canine atria analyzed by high-resolution optical mapping: preferential direction of conduction block changes from longitudinal to transverse with increasing age.

BACKGROUND: Anisotropic conduction properties may provide a substrate for reentrant arrhythmias. We investigated the age-dependent changes of structural and functional anisotropy in isolated right atria from infant (1 to 2 months), young (6 to 12 months), and old (6 to 10 years) dogs. METHODS AND RESULTS: The histology of the mapped atrial tissues (a small subepicardial area, 2.8x4.2 mm) was characterized by an age-dependent increase of myofiber width and fat cell infiltration between myofibers. Cx43 was distributed homogeneously over the entire cell surface in infant dogs, whereas it progressively polarized to the cell termini with increasing age. The activation sequences were analyzed by high-resolution optical mapping using a voltage-sensitive dye. Activation fronts from the pacing site proceeded more rapidly along fiber orientation (longitudinal) than across it (transverse). Infant dogs showed "elliptical" isochrones with a smooth transition between longitudinal and transverse propagation, whereas old dogs had a "square" pattern with a sharp transition. Conduction block occurred predominantly during longitudinal propagation in infant dogs but during transverse propagation in old dogs. The shape of the wave front and the degree of lateral uncoupling seemed to decide the preferential direction of block. A zigzag activation causing an extremely slow transverse conduction was observed only in old dogs. CONCLUSIONS: Along with the age-dependent structural anisotropy, the preferential direction of block changed from longitudinal to transverse in association with a change in the wave front configuration. A zigzag propagation based on lateral uncoupling would predispose the elderly to multiple reentry and a higher incidence of atrial fibrillation.

Discordant temporal changes in electrophysiological properties during electrical remodeling and its recovery in the canine atrium.

Prolonged rapid atrial excitation gives rise to atrial electrical remodeling, which perpetuates atrial fibrillation (AF). However, there has been controversy regarding the nature of temporal changes in conduction characteristics during the development and recovery of electrical remodeling. This study was designed to clarify the nature of the development and recovery of electrical remodeling in relation to AF inducibility in dogs subjected to rapid atrial pacing. Eleven dogs underwent rapid atrial pacing (400/min) for 28 days. The electrophysiological study was performed on the day just prior to the commencement of pacing, on days 2, 7, 14, and 28 of rapid pacing, as well as 1 and 7 days after the cessation of pacing. In response to rapid atrial pacing, atrial effective refractory period (ERP), conduction velocity and wavelength decreased significantly (p < 0.05). ERP had shortened significantly and rapidly within 2 days of pacing, while conduction velocity decreased more gradually. During the recovery, ERP returned to almost baseline levels within a day, whereas conduction velocity returned to baseline by day 7. Sustained AF became inducible in 37% of the dogs from 7 days of pacing until 1 day after the cessation, when wavelength fell below 8.7 cm. In conclusion, rapid atrial excitation causes a progressive but discordant temporal pattern of a decrease in ERP and conduction velocity. The resultant shortening of the wavelength determines the inducibility and maintenance of AF. The electrophysiological changes produced by one month of rapid atrial pacing can be fully reversed within a week, although in a discordant temporal pattern.