Motoki Hara

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, 2.8×4.2 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.

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.

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.

Recovery of electrophysiological parameters after conversion of atrial fibrillation

We investigated the recovery of electrophysiological parameters from electrical remodeling after conversion of chronic lone atrial fibrillation in humans. Clinical studies have shown that the longer atrial fibrillation lasts, the more difficult it becomes to maintain the sinus rhythm after cardioversion. To explore the effects of the duration of atrial fibrillation on changes of electrophysiological parameters after conversion, we determined the atrial effective refractory period and P wave duration during right atrial pacing at 1 and 24 h after electrical cardioversion in 15 patients with chronic lone atrial fibrillation (median duration, 6 months). By 24 h after cardioversion, the effective refractory period at a pacing cycle length of 600 ms increased from 225+/-19 to 254+/-27 ms. However, the P wave duration did not decrease significantly 24 h after conversion. As the duration of atrial fibrillation became longer, the prolongation of effective refractory period was more delayed (P<0. 001, r=0.82), and the shortening of P wave duration was significantly smaller within 24 h after cardioversion (P<0. 001, r=0.67). After cardioversion of chronic lone atrial fibrillation, the recovery of shortened atrial refractoriness and prolonged intraatrial conduction time is dependent on the duration of preexisting atrial fibrillation.

Electropharmacologic effects of pilsicainide, a pure sodium channel blocker, on the remodeled atrium subjected to chronic rapid pacing.

Clinical experience suggests that sodium channel blockers are effective in converting atrial fibrillation of recent onset but not chronic atrial fibrillation. We investigated changes in the electrophysiologic effects of pilsicainide, a pure sodium channel blocker, on the canine atrium during chronic rapid pacing (400/min). Three pairs of bipolar electrodes were sutured to the right atrial appendage in six dogs. Five days later, rapid atrial pacing was started after baseline measurements of the effective refractory period (ERP), the intra-atrial conduction velocity, the atrial wavelength, and the inducibility of atrial fibrillation. These studies were repeated at 2, 7, and 14 days of pacing, both before and after pilsicainide administration. Before pacing, pilsicainide increased ERP more than it decreased conduction velocity, causing an increase of wavelength, particularly at faster rates. However, this use-dependent prolongation of ERP disappeared after 2 days of pacing. Thus, pilsicainide failed to prolong ERP during chronic pacing, allowing progressive shortening of wavelength in the remodeled atrium. The effect of sodium channel blockers on atrial refractoriness may decline as rapid atrial excitation persists, limiting the usefulness of these agents for the treatment of chronic atrial fibrillation.

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.

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.

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 Students 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.