Hiroe Niwano

Prognostic Significance of Frequent Premature Ventricular Contractions Originating from the Ventricular Outflow Tract in Patients with Normal Left Ventricular Function.

Background: Recently, it has been reported that frequent premature ventricular contractions (PVCs) may be associated with causing heart failure in patients with left ventricular (LV) dysfunction. However, the prognostic significance of frequent PVCs in asymptomatic patients with a normal LV function is unclear. Methods: Two hundred and thirty-nine consecutive patients presenting with frequent PVCs (>1000 beats/day) originating from the right or left ventricular outflow tract without any detectable heart disease were enrolled in the study. Structural heart disease was ruled out by echocardiography and cardiac magnetic resonance imaging, and Holter-ECG monitoring was repeated two or three times to evaluate the PVC prevalence at the initial evaluation. All patients were followed up for at least 4 years, and further observation was continued if possible. Results: During an observation period of 5.6 (1.7) years, no patients exhibited any serious cardiac events. Although there was no significant change in the mean LV ejection fraction (LVEF) and mean LV diastolic dimension (LVDd), there was a significant negative correlation between the PVC prevalence and ΔLVEF (p<0.001) and positive correlation between the PVC prevalence and ΔLVDd (p<0.001). When the development of LV dysfunction was defined as ΔLVEF>−6%, 13 patients exhibited LV dysfunction. For the prediction of the development of LV dysfunction, PVC prevalence and LVEF at the initial evaluation were independent predicting factors (p<0.01). Conclusion: Although the prognosis in patients with frequent PVCs was considered relatively benign, attention should be paid to the progression of the LV dysfunction during a long-term observation, especially in patients with a high PVC prevalence.

Angiotensin II-mediated up-regulation of connective tissue growth factor promotes atrial tissue fibrosis in the canine atrial fibrillation model

Aims Remodelling of the extracellular matrix (ECM) plays an important role in the production of arrhythmogenic substrate for atrial fibrillation (AF), and is considered to be promoted by the connective tissue growth factor (CTGF). Our objective was to assess the relationship between CTGF and ECM synthesis, and the effect of olmesartan on these processes. Methods and results Fifteen canine AF models were produced by rapid atrial stimulation. They were divided into three groups: pacing control (n = 5): 6-week pacing, pacing + olmesartan (n = 5): pacing with olmesartan (2 mg/kg/day), and non-pacing group (n = 5). In the pacing control group, messenger ribonucleic acid expressions of CTGF and collagen types 1 and 3 were up-regulated in comparison with the non-pacing group (P < 0.05) while transforming growth factor-β (TGF-β) did not exhibit a significant difference. In the pacing + olmesartan group, these up-regulations were suppressed (P < 0.05). In fluorescent immunostaining, the expression of CTGF was localized in the cytoplasm. The protein level of collagen type 3 was increased in the pacing control and it was suppressed in the pacing + olmesartan group. Conclusions CTGF and associated genes were up-regulated in the atria with the appearance of fibrosis. Because this up-regulation was independent of TGF-β and suppressed by olmesartan, CTGF up-regulation was considered to be mediated by angiotensin II.

β2-Adrenergic Agonists Suppress Rat Autoimmune Myocarditis Potential Role of β2-Adrenergic Stimulants as New Therapeutic Agents for Myocarditis

Background— The therapeutic potential of β2-adrenergic receptor (AR) agonists in the treatment of autoimmune diseases has been reported. However, the role of these drugs in the myocardial structure–induced autoimmune process, which is thought to play a crucial role in the progression of myocarditis to subsequent complications, has not been elucidated. Methods and Results— Experimental autoimmune myocarditis (EAM) was induced in rats by immunization with cardiac myosin. On daily administration from day 0 after immunization, the β2-selective AR agonists formoterol or salbutamol ameliorated EAM on day 21 and increased myocardial interleukin-10/interferon-γ mRNA levels. Propranolol, a nonselective β-AR antagonist, aggravated EAM on day 21 and decreased mRNA levels, whereas metoprolol, a β1-selective AR antagonist, showed no effect. These results were reflected in vivo by the proliferation of cardiac myosin–primed lymph node cells from drug-treated rats. In vitro addition of β2-selective AR agonists inhibited the activation of cardiac myosin fragment–specific myocarditogenic T lymphocytes, and this effect was reversed by ICI118,551, a β2-selective AR antagonist. Furthermore, treatment with 2 different β2-selective AR agonists starting on day 14 also ameliorated EAM on day 21. Conclusions— β2-AR stimulation suppressed the development of EAM by inhibiting cardiac myosin–specific T-lymphocyte activation in lymphoid organs and by shifting the imbalance in Th1/Th2 cytokine toward Th2 cytokine. Furthermore, it also ameliorated established myocardial inflammation. β2-AR–stimulating agents may represent important immunomodulators of the cardiac myosin–induced autoimmune process and have potential as a new therapy for myocarditis.

Polytherapy with sodium channel-blocking antiepileptic drugs is associated with arrhythmogenic ST-T abnormality in patients with epilepsy

PURPOSE Recent reports have documented the appearance of Brugada-type ST elevation in cases of overdose of antiepileptic drugs (AEDs). However, little is known about changes on electrocardiographs (ECGs) during AED use at therapeutic doses. AEDs may cause Brugada-type ST elevation or J-wave-like intraventricular conduction delays through an ion channel-blocking effect. In the present study, we sought to elucidate ECG abnormalities in patients on AED therapy. METHODS The study population consisted of 120 consecutive patients with epilepsy who continued to take AEDs and had ECGs recorded during these therapies. Their clinical background and ECGs were retrospectively analyzed. Brugada-type ST elevation was classified according to the consensus report on Brugada syndrome. A J-wave-like ECG abnormality was defined as the appearance of notching or slurring of the QRS complex (>0.1mV) in the inferior/lateral leads. RESULTS Of the 120 patients, 15 (12.5%) exhibited Brugada-type ST elevation and 35 (29.2%) showed a J-wave-like ECG abnormality. Polytherapy with sodium channel-blocking AEDs (e.g., carbamazepine, phenytoin, lamotrigine) was more frequently observed in patients with Brugada-type ST elevation (p=0.048). However, the serum concentrations of these medicines did not differ between patients with and without ECG abnormalities (carbamazepine: 7.9±4.1 vs. 7.2±5.9μg/dL; phenytoin: 12.7±4.1 vs. 15.5±9.5μg/dL, NS). CONCLUSION ST-T abnormalities were frequently seen in patients using AEDs. The presence of Brugada-type ST elevation was associated with polytherapy with sodium channel-blocking AEDs.

Evaluation of the impact of atrial fibrillation on rehospitalization events in heart failure patients in recent years

BACKGROUND Although we have previously reported that the presence of paroxysmal atrial fibrillation (AF) is an independent risk factor for rehospitalization in patients with congestive heart failure (CHF) in a population from 1996 to 2002, the impact of AF configuration as a risk factor in a more recent population remains to be clarified. METHODS AND RESULTS 319 patients with CHF admitted to our institute in 2006-2007 were retrospectively evaluated. The patients were divided into 3 groups in accordance with their basic cardiac rhythm, i.e. sinus rhythm (n=210), chronic AF (n=68), and paroxysmal AF (n=41). During the follow-up period of 19 ± 17 months, there was no significant difference in mortality or rehospitalization events among the 3 groups (p=0.542). In the multivariate analysis, no administration of β-blockers was the only independent risk factor for rehospitalization due to CHF exacerbation. CONCLUSIONS The clinical impact of AF configuration as a risk factor of rehospitalization due to CHF exacerbation was considered to be decreased in recent years.

Rivaroxaban Inhibits Angiotensin II-Induced Activation in Cultured Mouse Cardiac Fibroblasts Through the Modulation of NF-κB Pathway

Cell migration, proliferation, and differentiation of cardiac fibroblasts (CFs) play a central role in cardiac fibrosis. Factor Xa (FXa)-dependent protease-activated receptor (PAR)-1 and PAR-2 have been reported as important targets in proinflammatory and fibroproliferative diseases. From this viewpoint, we aimed to investigate whether treatment of rivaroxaban, an approved oral direct FXa inhibitor, attenuates functional changes in angiotensin (Ang) II-induced mouse CFs.Confluent cultured mouse CFs were pretreated with or without rivaroxaban. Ang II-induced cell migration was decreased by 73% in rivaroxaban induced cells. Rivaroxaban inhibited Ang II-induced cell proliferation by 27% at 0.01 μg/ mL, 69% at 0.1 μg/mL, 71% at 1 μg/mL, and 69% at 5 μg/mL. In mouse cytokine array measuring 40 cytokines, the productions of interleukin-16, TIMP-1, and tumor necrosis factor-α (TNF-α) were significantly reduced with 0.1 μg/mL of rivaroxaban pretreatment (all P < 0.05). TIMP-1 levels in the culture supernatant measured by ELISA were also decreased by rivaroxaban pretreatment in Ang II-induced CFs (35% decrease at 0.01 μg/mL, 47% at 0.1 μg/mL, 47% at 1 μg/mL, and 57% at 5 μg/mL). In the dual reporter assay analysis, rivaroxaban inhibited various inflammatory signal pathways, including the nuclear factor-kappa B (NF-κB), active protein-1 (AP-1), and mitogen-activated protein kinase (MAPK) pathways (decreases of 82%, 78%, and 75%, respectively).These data suggest that rivaroxaban inhibits Ang II-induced functional activation in cultured mouse CFs via inhibiting NF-κB and MAPK/AP-1 signaling pathways, which may be a possible target of heart failure, through the antifibrotic and anti-inflammatory efficacy of rivaroxaban in Ang II-stimulated cardiac fibroblasts.

Combined effects of up- and downstream therapies on atrial fibrillation in a canine rapid stimulation model

BACKGROUND Recent reports suggest angiotensin receptor blockers (ARBs) and some antiarrhythmic agents affect atrial remodeling in atrial fibrillation (AF). We evaluated the effect of combination therapy with olmesartan (Olm) and bepridil (Bep) in a canine model of AF. METHODS AND RESULTS An atrial stimulation device was implanted in 10 dogs undergoing 6-week pacing at 400 bpm. They were divided into Olm (2 mg/kg/day) (n=5) and Olm+Bep (Olm, 2 mg/kg/day; Bep, 10 mg/kg/day) groups (n=5). Atrial effective refractory period (AERP), conduction velocity (CV), and AF inducibility were evaluated weekly, and hemodynamics, atrial histology, and mRNA expression and protein expression of ion-channel and gap junction-related molecules at 6 weeks. Data were compared between groups and with non-pacing control and pacing-control groups from our previous report. The pacing-control group exhibited shortened AERP, decreased CV, increased AF inducibility and tissue fibrosis, and down-regulated L-type Ca(2+) channel (LCC), SCN5A, Kv4.3 and connexin43 (Cx43). By comparison, the Olm group exhibited suppression of the decrease in CV and of the increase in AF inducibility, but no change in AERP shortening. The Olm+Bep group exhibited suppression of AERP shortening as well as the greatest decrease in AF inducibility. Histologically, tissue fibrosis was suppressed in Olm and Olm+Bep groups. Down-regulation of Cx43 was partly suppressed in the Olm group while that of LCC, SCN5A, and Cx43 was suppressed in the Olm+Bep group. CONCLUSION Olm and Bep in combination suppressed AF inducibility more strongly than Olm alone, and may be more useful in the suppression of AF.

The J-wave as a Predictor of Life-Threatening Arrhythmia in ICD Patients

The J-wave has been reported to be associated with life-threatening ventricular arrhythmia. However, the clinical implication of the J-wave is still unclear in patients with an implantable cardioverter defibrillator (ICD).The study population consisted of 170 ICD patients (age, 56 ± 16 years, 79.4% male) treated at Kitasato University Hospital between 2003 and 2014. Ventricular fibrillation (VF) and ventricular tachycardia (VT) events were documented via ICD interrogation, and the patients were divided into 3 groups: 1) VF event group, 2) VT event group, and 3) No-event group. To predict VT or VF events, univariate and multivariate analysis of clinical data including ECG findings were performed. A J-wave was defined as the presence of notching or slurring of the QRS complex (≥ 0.1 mV) in inferior/lateral leads. Among the 170 patients examined, 23 experienced VF and 38 experienced VT during 54 ± 39 months follow-up. In the multivariate Cox proportional hazards model, the J-wave was identified as an independent predictor for a VF event (HR: 3.886, 95% CI: 1.313-10.568, P = 0.012). In contrast, BNP (HR: 1.002, 95% CI: 1.000-1.003, P = 0.043) and left ventricular diastolic diameter (HR: 1.039, 95% CI: 1.002-1.081, P = 0.049) were independent predictors for a VT event.The results suggest J-waves in the stable phase in an ECG may be a useful predictor for a VF event in ICD patients.

Efficacy and Limitations of Tachycardia Detection Interval Guided Reprogramming for Reduction of Inappropriate Shock in Implantable Cardioverter-Defibrillator Patients

The avoidance of inappropriate shock therapy is an important clinical issue in implantable cardioverter-defibrillator (ICD) patients. We retrospectively analyzed therapeutic events in ICD patients, and the effect of tachycardia detection interval (TDI) and tachycardia cycle length (TCL) guided reprograming on the reduction of inappropriate ICD therapy. The clinical determinants of after reprogramming were also evaluated.A total of 254 consecutive ICD patients were included in the study, and the incidence of antitachycardia therapy was evaluated during the follow-up period of 27.3 ± 18.7 months. When inappropriate antitachycardia therapy appeared, TDI was reprogrammed not to exceed the detected TCL and the patients continued to be followed-up. Various clinical parameters were compared between patients with and without inappropriate ICD therapy. During the initial follow-up period of 18.6 ± 15.6 months, ICD therapy occurred in 127/254 patients (50%) including inappropriate antitachycardia pacing (ATP) (12.9%) and shock (44.35%). Determinants of initial inappropriate therapy were dilated cardiomyopathy (DCM), history of therapeutic hypothermia, and QRS duration. Of the 61 patients with inappropriate therapy, 24 received TCL guided reprogramming. During the additional observation period of 17.0 ± 16.8 months, inappropriate therapy recurred in 5/24 patients (2 ATP, 3 shocks). The determinant of these inappropriate therapy events after reprogramming was the presence of supraventricular tachycardia.By applying simple TCL and TDI guided reprogramming, inappropriate therapy was reduced by 79%. The determinant of inappropriate therapy after reprogramming was the presence of supraventricular tachycardia.

Discrimination of Paroxysmal and Persistent Atrial Fibrillation in Patients With New-Onset Atrial Fibrillation

Discrimination between paroxysmal and persistent atrial fibrillation (PAF and persistent AF) is important for determining the therapeutic strategy in patients with new-onset AF. We evaluated various clinical factors and P wave morphology to discriminate PAF and persistent AF patients in patients with new-onset AF.The study population consisted of 79 patients with new-onset AF (70.3 ± 10.8 years, female:male 33:46) who were retrospectively selected from 8,632 AF patients in the Kitasato University Hospital ECG storing system. PAF (n = 38) and persistent AF (n = 41) patients were diagnosed by whether the initial PAF episode continued for 1 week. The P wave morphologies were analyzed using the most recent 12 lead-ECG recording of sinus rhythm. P wave dispersion was defined as the difference between the maximum and minimum durations of all leads. Along with these data, various clinical factors were evaluated and compared between PAF and persistent AF patients.Multivariate analysis identified P wave dispersion (56.6 ± 14.8 versus 66.5 ± 12.8 msec, P = 0.002) and left atrial dimension (LAD: 40.2 ± 7.0 versus 47.7 ± 8.2 mm, P < 0.001) as independent factors for discrimination between PAF and persistent AF patients. Combining these two parameters achieved a specificity of 88.9%, a positive predictive value of 81.8%, a sensitivity of 95.3%, and a negative predictive value of 88.9%.In patients with new-onset AF, P wave dispersion and LAD were independent factors for discrimination between PAF and persistent AF.