Five-Year Impacts of Antithrombotic Therapy Based on 10-Year Clinical Outcomes of Cypher™ Stent Implantation.

INTRODUCTION: Few researchers have investigated the optimal long-term antithrombotic therapy regimen, especially after first-generation drug-eluting stent (DES) use. This study aimed to evaluate the impact of mid-term antithrombotic therapy on long-term outcomes in patients treated with the first sirolimus-eluting coronary stent (Cypher™). METHODS: Between 2004 and 2009, 1021 patients underwent Cypher™ implantation at our institute; among them, 567 patients had available data on antithrombotic therapy at year 5. We assessed patients' antithrombotic therapy at year 5 post Cypher™ implantation and examined their association with adverse events from year 5 to year 10 post Cypher™ implantation. RESULTS: Patients with dual-antiplatelet therapy (DAPT) at year 5 had significantly lower risk of stent thrombosis (ST) than those with single-antiplatelet therapy (SAPT) (hazard ratio [HR] 0.24, p = 0.034). The HR of major bleeding in DAPT, compared to SAPT, was high, but the difference was not significant (HR 1.72, p = 0.26). Risk of major bleeding was significantly higher in patients on oral anticoagulants (OAC) than in those in other groups (OAC/SAPT; HR 5.31, p = 0.0048, OAC/DAPT; HR 3.08, p = 0.022), without significant reduction in the risk of cardiovascular events. CONCLUSIONS: The incidence of ST after Cypher™ implantation in patients with DAPT at year 5 was significantly lower than that in SAPT. However, the risk of bleeding was higher with DAPT than with SAPT. Moreover, the risk of major bleeding was significantly higher in patients on anticoagulant therapy than in other patients. New options for the use of antithrombotic drugs after percutaneous coronary intervention warrant further studies on the optimal antithrombotic therapy for first-generation DES.

Fragmented QRS on far-field intracardiac electrograms as a predictor of arrhythmic events.

BACKGROUND: Studies suggest that fragmented QRS (fQRS) can predict arrhythmic events in various cardiac diseases. However, the association between fQRS recordings on intracardiac electrogram (EGM) and ventricular arrhythmic events remains unknown. METHODS: We enrolled 51 patients (age, 62 ± 12 years; 40 men) with an implantable cardioverter-defibrillator (ICD) and structural heart disease and evaluated surface electrocardiogram (ECG) and EGM measurement of fQRS and the association between fQRS and arrhythmic events. RESULTS: fQRS was detected on surface ECG and ICD-EGM in 12 (23.5%) and 15 (29.4%) patients, respectively. fQRS was detected more frequently on ICD-EGM in patients with fQRS on surface ECG than in patients without fQRS (7/12 [58.3%] vs 8/39 patients [20.5%], P = .01). Appropriate ICD therapies were documented in 16 patients. Among these patients, fQRS was detected more frequently on surface ECG and ICD-EGM in patients with appropriate ICD therapies (8/16, 50.0%; P = .001 and 11/16, 68.9%; P < .001). Nonsustained ventricular tachycardia was significantly more frequent in patients with appropriate ICD therapies (15/16, 93.8%; P = .04). Multiple logistic regression analysis showed that fQRS on ICD-EGM was a predictor of arrhythmic events (P = .03). Kaplan-Meier survival analysis revealed that ICD therapies were significantly more frequent among patients with fQRS on both surface ECG and ICD-EGM than among those without fQRS (66.7% vs 6.6%, P < .001). CONCLUSION: The presence of fQRS on ICD-EGM can be a predictor of arrhythmic events in ICD patients. Surface ECG and ICD-EGM measurement may help predict ventricular arrhythmic events.

Incidence of outflow tract ventricular tachycardia long after surgical aortic valve replacement.

BACKGROUND: The peri-outflow tract region could be the origin of ventricular tachycardia (VT) after aortic valve replacement (AVR). However, the clinical characteristics of outflow tract ventricular tachycardias (OTVTs) after AVR are yet to be clarified. This study investigated the incidence, risk factors, and clinical characteristics of patients with OTVTs after AVR. METHODS: We retrospectively analyzed the clinical course of 120 patients who had undergone surgical AVR (SAVR) between April 1980 and October 2018. The patients had no ischemic or diagnosed cardiomyopathies other than primary aortic valve diseases. RESULTS: Six patients (5.0%) developed OTVTs after SAVR. The average onset was at 10.8 ± 5.7 years after SAVR. All cases of VT arose from the inferior axis and included left and right bundle branch block configuration. Two patients who underwent cardiac magnetic resonance imaging (MRI) had late gadolinium enhancement (LGE) in the midlayer of the left ventricle basal anteroseptal wall. Patients with periaortic VTs had significantly larger left ventricular (LV) diameter at systole, lower LV ejection fraction, higher positive rates of signal-averaged electrocardiogram (SAECG), and nonsustained VTs on Holter monitoring. On ablation, local fragmented potentials with low voltage zones were observed in accordance with the LGE distribution. Multiple VTs originating from the periaortic region were provoked in the sessions. CONCLUSIONS: Acute OTVT was found in 5% of patients after SAVR. Arrhythmia risk stratification by SAECG, Holter ECG, and cardiac MRI should be considered for a long period in patients after SAVR.

Feasibility and safety of uninterrupted apixaban in patients undergoing radiofrequency ablation for atrial fibrillation.

BACKGROUND: An optimal periprocedural anticoagulation strategy is essential for minimizing bleeding and thromboembolic complications during atrial fibrillation (AF) ablation. Limited data are available on the uninterrupted use of apixaban in patients with AF undergoing catheter ablation. This study aimed to evaluate the safety and efficacy of uninterrupted apixaban in patients undergoing radiofrequency ablation for AF. In particular, we evaluated silent cerebral infarction (CI) during radiofrequency catheter ablation of AF. METHODS: This was a prospective and nonrandomized cohort study. A total of 259 consecutive patients who underwent AF ablation were evaluated; 157 patients received apixaban (Api group), and 102 patients received dose-adjusted (PT-INR 2.0-3.0) warfarin (Wf group). All oral anticoagulants were continued throughout the periprocedural period, including the morning of the procedure. Intravenous heparin was administered during the procedure and neutralized by protamine at the end of the procedure. Sixty-one patients underwent magnetic resonance imaging (MRI) after the procedure to evaluate for silent CI. RESULTS: Mean age was 66 ± 11 years; there were 91 men (73.7%) and 148 cases of paroxysmal AF (57.1%). No symptomatic CI was observed. Silent CI occurred in 6/61 patients (9.8%). No significant difference was observed between the Api group (4/30 patients, 13.3%) and the Wf group (2/31 patients, 6.5%). There was no significant difference regarding major bleeding events between the Api group (1/157 patients, 0.6%) and the Wf group (2/102 patients, 2.0%). CONCLUSIONS: The safety and efficacy of uninterrupted apixaban for patients undergoing AF ablation were equivalent to warfarin for preventing bleeding and thromboembolic complications.

Clinical experience of idarucizumab use in cases of cardiac tamponade under uninterrupted anticoagulation of dabigatran during catheter ablation of atrial fibrillation.

Anticoagulants are prescribed for prevention of thromboembolic events (TE) of atrial fibrillation (AF), however, their effects have a negative impact on disastrous bleeding outcomes. Idarucizumab was developed to reverse the anticoagulation effects of dabigatran. This study aimed to retrospectively investigate the clinical efficacy and safety of idarucizumab in the setting of progressive emergent bleeding events associated with catheter ablation (CA). Dabigatran is given uninterruptedly as an anticoagulant in patients undergoing CA of AF. The capacity of idarucizumab to reverse the anticoagulant effects of dabigatran in patients with cardiac tamponade associated with CA was examined by measuring the activated partial thromboplastin time (aPTT), active clotting time (ACT), and prothrombin international normalizing ratio (PT-INR). The primary endpoint was effective hemostasis. This analysis included 21 patients receiving idarucizumab, given for restoration of hemostasis. In all 21 patients, hemostasis was restored at a median of 205.6 ± 14.8 min. Normal intraoperative cessation of bleeding was reported in 16 patients, and completion of hemostasis was also ascertained in the remaining four within 5 h. No TEs occurred within 72 h after the idarucizumab administration. Despite a significant reduction in the aPTT and ACT, no significant change was observed in PT-INR after administering idarucizumab. In emergency situations, idarucizumab was able to reverse dabigatran within a relatively short period without any serious adverse events.

The proportion of asymptomatic recurrence after catheter ablation of atrial fibrillation in patients with a pacemaker for sick sinus syndrome.

BACKGROUND: Catheter ablation (CA) of paroxysmal atrial fibrillation (PAF) is an effective treatment. However, the frequency of asymptomatic AF recurrence after CA in patients with PAF and sick sinus syndrome (SSS) is not clear. The aim of this study was to elucidate the real AF recurrence after CA in patients with PAF and a pacemaker for SSS. METHODS AND RESULTS: Fifty-one consecutive patients (mean age 66.6 ± 7.0 years, male 34) with PAF and SSS and pacemakers underwent CA. All patients were followed at 1, 3, 6, 9, and 12 months after the CA using a 12-lead ECG, Holter-ECG, and 1-month event recorder as a conventional follow-up. In addition, the pacemakers were interrogated every 12 months. During a 5-year follow-up after the final CA procedure, AF recurrences were observed in 7 patients (13.7%) with a conventional follow-up, including 1 (2.0%) asymptomatic patient. Pacemaker-interrogation revealed another 10 patients (19.6%) with asymptomatic AF recurrences. Ultimately, the conventional follow-up plus pacemaker-interrogation provided a higher incidence of AF recurrences (P = 0.009). Multiple CA procedures contributed to a significant increase in the AF-free survival rate at 5 years: 58.6% after a single CA and 86.0% after multiple CA procedures with a conventional follow-up, but which decreased to 40.6% and 60.9% with a conventional follow-up plus a pacemaker interrogation, respectively. CONCLUSIONS: One-third of PAF patients with SSS and pacemakers recurred after multiple CA sessions. However, 65% of them were asymptomatic and difficult to be identified with conventional follow-up. Pacemaker interrogation significantly increased the detection rate of AF-recurrence.

Efficacy and safety of uninterrupted rivaroxaban taken preoperatively for radiofrequency catheter ablation of atrial fibrillation compared to uninterrupted warfarin.

PURPOSE: Data on uninterrupted rivaroxaban taken preoperatively for radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) is limited. The aim was to evaluate safety and efficacy of rivaroxaban taken in the morning for AF ablation, especially with regard to asymptomatic cerebral emboli (ACE) and anticoagulation parameters. METHODS: We prospectively evaluated 147 consecutive patients who underwent RFCA (mean age 66, 110 patients with paroxysmal AF), 76 of whom were on rivaroxaban, 71 on warfarin. The drugs were continued throughout the periprocedural period, including the morning of RFCA. Heparin infusion was maintained during RFCA to achieve an activated clotting time (ACT) of >300 s. RESULTS: There were no significant differences in basic patient characteristics and ablation procedure between the two groups. ACT during the procedure correlated significantly with prothrombin time and international normalized ratio in each group (correlation coefficient 0.799 in rivaroxaban, 0.705 in warfarin, p < 0.01). D-dimer level was more elevated after RFCA in the warfarin group than in the rivaroxaban group (warfarin 0.37 ± 0.28 to 0.67 ± 0.81, rivaroxaban 0.41 ± 0.33 to 0.51 ± 0.25, p = 0.02). One major bleeding event (1.3%), a cardiac tamponade, was observed in the warfarin group. No symptomatic thromboembolic complications were observed in either group. Two patients (3%) in each group had minor bleeding, specifically, groin hematoma. Postprocedural MRI indicated ACE in 5/46 (11%) patients in the rivaroxaban group and 4/39 (10%) in the warfarin group (p = 0.99). CONCLUSIONS: Uninterrupted rivaroxaban taken preoperatively for AF ablation is clinically effective and safe. Its ACE profile is similar to warfarin. ACT is sufficient for monitoring anticoagulation.

Impact of Alcohol Consumption on the Outcome of Catheter Ablation in Patients With Paroxysmal Atrial Fibrillation.

BACKGROUND: Although several studies have reported an association between atrial fibrillation (AF) and alcohol, the impact of alcohol consumption on the outcome after catheter ablation (CA) for AF has not been discussed. We aimed to elucidate the effect of alcohol consumption on the outcome of CA for paroxysmal AF. METHODS AND RESULTS: We examined 1361 consecutive patients with paroxysmal AF (mean age, 61±11 years, 334 women) who underwent CA, including 623 (45.8%) patients who consumed alcohol. The clinical characteristics and outcomes of CA were compared between patients who did and did not consume alcohol. No significant differences were seen in the left atrial size, duration of AF history, and incidence of nonpulmonary vein foci between 2 groups (P=NS). Although the AF recurrence-free rate after the initial CA was higher in patients who did not consume alcohol (261/623 [41.9%] versus 252/738 [34.1%]; mean follow-up, 44.4±30.7 months; P=0.003), the outcome after the final CA was similar between 2 groups (patients who consumed alcohol: 111/628 [17.7%] versus patients who did not consume alcohol: 138/738 [18.7%]; mean follow-up, 53.1±25.8 months; P=0.67). The frequency (hazard ratio 1.07 per 1 day/week increase, CI 1.00-1.15, P=0.04) of alcohol consumption was significantly associated with AF recurrence after CA. CONCLUSIONS: The frequency of alcohol consumption may be associated with AF recurrence after the initial CA for paroxysmal AF, but it may not affect the outcome after the final CA.

Plasmonic-heating-induced nanofabrication on glass substrates.

Fabricating nano-sized through-holes on a coverslip approximately 100 µm thick is challenging but rewarding when applied to ultrafine filters that separate proteins and DNA of various sizes and isolate viruses from cells. Toward this end, we developed an in situ etching-assisted laser processing technique exploiting gold nanoparticles. Plasmonic heating of a single gold nanoparticle through focused illumination of a continuous-wave laser beam enables structural modifications to be localized to the contact area on the glass surface. This results in the embedding of the particle forming nanocavities caused by chemical etching with aqueous tetrabutylammonium hydroxide. Depending on the shape of the nanoparticle, a highly flexible face geometry design such as a disk and triangle was achieved. The etching was monitored in situ through measurements of spectral red shifts in single-particle scattering, indicating an increasing medium refractive index consistent with embedding. The embedding process is unexpectedly fast, at 0.8 µm with 5 minutes of illumination. Besides nanoholes, we fabricated nanodomes around a single gold nanoparticle supported on a glass substrate through laser-heating-induced encapsulation. Overall, we were able to demonstrate true nano-laser processing free from diffraction-limited optics, with potential benefits of simple low-cost fabrication.

Serological survey of Encephalitozoon cuniculi infection in cats in Japan.

Antibodies to Encephalitozoon cuniculi (E. cuniculi) were examined by enzyme-linked immunosorbent assay using E. cuniculi PTP2 recombinant protein from serum samples that had been collected from a total of 295 cats in Japan. Of these samples, 6.1% (18/295) had antibodies against E. cuniculi, which included 6.3% (6/96) of the male cats and 6.0% (12/199) of the female cats. The incidence was slightly higher in feral cats (8.3%, 11/132) compared to domesticated cats (4.3%, 7/163). This suggests the possibility that the cats of our country have become a reservoir of E. cuniculi. This study is the first to demonstrate the prevalence of E. cuniculi infection in cats in Japan.

Identification of immunodiagnostic antigens for cerebrospinal filariasis in horses by western blot analysis.

In the present study, the serum and cerebrospinal fluid of horses diagnosed with Setaria digitata cerebrospinal filariasis were analyzed by western blot. The results revealed S. digitata protein bands measuring 65, 34, 22, and 18 kDa in molecular weight. In particular, the 18 kDa band is a possible candidate for clinical immunodiagnosis on the basis of western blot findings.

Seasonal, weekly, and circadian distribution of ventricular fibrillation in patients with J-wave syndrome from the J-PREVENT registry.

BACKGROUND: Ventricular fibrillation (VF) in Brugada syndrome (BrS) is known to occur more frequently during nighttime and from spring to early summer. In this study, we investigated whether early repolarization syndrome (ERS) has the same seasonal, weekly, and circadian distribution of VF events as BrS using data from the "J-wave associated with prior cardiac event" (J-PREVENT) registry. METHODS: The study included 90 consecutive patients with BrS and 31 patients with ERS during a mean follow-up of 49±37 months. Follow-up data from implantable cardioverter-defibrillators were evaluated in all cases. RESULTS: In patients with ERS, the circadian distribution of VF episodes differed among the four 6-h periods, with a significant peak from midnight to 6:00 am (p<0.01) similar to that observed in BrS patients. However, VF occurred more frequently on weekends in patients with ERS, whereas on weekdays in patients with BrS (p<0.01). The months of peak VF occurrence also differed between the groups, with the frequency of VF episodes at peak between December and March in ERS patients and between March and June in BrS patients. In ERS patients, VF events had an inverse correlation with air temperature (r=-0.726, p<0.01). CONCLUSIONS: ERS and BrS patients show similar nighttime increases in the occurrence of VF, but different seasonal and weekly distributions, suggesting a pathophysiological difference between the two syndromes.

Differences in catheter ablation of paroxysmal atrial fibrillation between males and females.

BACKGROUND: Catheter ablation (CA) has become a standard treatment for patients with atrial fibrillation (AF). However, gender-related differences associated with CA of paroxysmal AF (PAF) remain unclear. METHODS: We compared 1124 consecutive patients (mean age, 61 ± 10 years; male, n=864) with PAF scheduled for CA between the genders. RESULTS: Females were significantly older (p<0.0001), and had a lower body-mass-index (p=0.02), smaller left atrial dimension (LAD; p=0.04), larger LAD indexed by the body-surface-area (LADI; p<0.0001) and better left ventricular ejection fraction (p<0.0001) at baseline. Ischemic heart disease (p=0.007) was more frequent in males, whereas hypertrophic cardiomyopathy (p=0.007) and mitral stenosis (p=0.001) were more frequent in females. More additional procedures were performed to eliminate non-pulmonary vein foci in females than males (p<0.05), but those locations were similar between the genders. The incidence of procedure-related complications was similar between genders (p=0.73). Sinus rhythm was similarly maintained between females and males after the first CA (56.4% vs. 59.3% at 5 years, p=0.24), but was significantly lower in females after the last CA (76.5% vs. 81.3% at 5 years, p=0.007). More females did refuse multiple CA procedures (especially a second one) than males (37.8% in females vs. 27.4% in males, p=0.02). The age (HR, 0.98/y, p=0.01), duration of AF (HR, 1.04/y, p=0.0001), number of failed anti-arrhythmic-drugs (HR, 1.10, p=0.03) and LADI (HR, 1.89 per 10mm/m(2), p=0.001) were significantly associated with AF-recurrence in males, but not in females. CONCLUSIONS: Specific differences and similarities between the genders were observed in PAF patients undergoing CA.

The inhibitory effects of fluoroquinolones on L-carnitine transport in placental cell line BeWo.

L-Carnitine plays an important role in lipid metabolism by facilitating the transport of long-chain fatty acids across the mitochondrial inner membrane followed by fatty acid beta-oxidation. It is known that members of the OCTN family play an important role in L-carnitine transport in the placenta. Investigation of drug-drug or drug-nutrient interaction in the placenta is important for establishment of safety drug medication during pregnancy. The aim of this study was to determine the effects of fluoroquinolones, inhibitors of OCTN2, on L-carnitine transport in the placenta which is known to have a high expression level of OCTN2. We investigated the inhibitory effect of five fluoroquinolones, ciprofloxacin (CPFX), gatifloxacin (GFLX), ofloxacin (OFLX), levofloxacin (LVFX) and grepafloxacin (GPFX), on L-carnitine transport mediated by OCTN2 in placental cell line BeWo cells. We found that all of the fluoroquinolones inhibited L-carnitine transport, GPFX being the strongest inhibitor. We also found that the inhibitory effects of LVFX and GPFX depended on their existence ratio of zwitterionic forms as, we reported previously. Furthermore, we elucidated the LVFX transport mechanism in BeWo cells. LVFX was transported actively by transporters. However, we found that LVFX transport was Na+-independent and l-carnitine had no inhibitory effect on LVFX transport, suggesting that LVFX acts as inhibitor of OCTN2, not as a substrate for OCTN2.

Mechanism of the inhibitory effect of zwitterionic drugs (levofloxacin and grepafloxacin) on carnitine transporter (OCTN2) in Caco-2 cells.

L-Carnitine plays an important role in lipid metabolism by facilitating the transport of long-chain fatty acids across the mitochondrial inner membrane followed by fatty acid beta-oxidation. It is known that L-carnitine exists as a zwitterion and that member of the OCTN family play an important role in its transport. The aims of this study were to characterize L-carnitine transport in the intestine by using Caco-2 cells and to elucidate the effects of levofloxacin (LVFX) and grepafloxacin (GPFX), which are zwitterionic drugs, on L-carnitine uptake. Kinetic analysis showed that the half-saturation Na+ concentration, Hill coefficient and Km value of L-carnitine uptake in Caco-2 cells were 10.3 +/- 4.5 mM, 1.09 and 8.0 +/- 1.0 microM, respectively, suggesting that OCTN2 mainly transports L-carnitine. LVFX and GPFX have two pKa values and the existence ratio of their zwitterionic forms is higher under a neutral condition than under an acidic condition. Experiments on the inhibitory effect of LVFX and GPFX on L-carnitine uptake showed that LVFX and GPFX inhibited L-carnitine uptake more strongly at pH 7.4 than at pH 5.5. It was concluded that the zwitterionic form of drugs plays an important role in inhibition of OCTN2 function.