Primary Care-Based Investigation of the Effect of Sitagliptin on Blood Pressure in Hypertensive Patients With Type 2 Diabetes.

BACKGROUND: The influence of long-term sitagliptin therapy on office blood pressure (BP) and home BP has been unclear. METHODS: In a retrospective cohort study of 454 patients with type 2 diabetes, the following variables were analyzed before and at 3, 6, 9, and 12 months after initiation of sitagliptin therapy: office systolic blood pressure (SBP), office diastolic blood pressure (DBP), office pulse rate, morning home SBP, morning home DBP, morning home pulse rate, evening home SBP, evening home DBP, evening home pulse rate, hemoglobin A1c (HbA1c), plasma glucose, lipid profile, and renal function parameters. RESULTS: The office SBP showed a significant decrease after 6 and 12 months of sitagliptin therapy (P < 0.01 and P < 0.01, respectively), while office DBP was decreased significantly at all time points of evaluation (3, 6, 9, and 12 months: P < 0.05, P < 0.001, P < 0.001, and P < 0.05, respectively). Analysis of covariance revealed a significant decrease in office SBP after 6 and 12 months, as well as significant reduction of office DBP after 6 and 9 months. Morning home SBP and DBP were significantly reduced after 6 months, as was evening home DBP after 6 and 12 months, but there was no significant decrease in evening home SBP. HbA1c and plasma glucose levels were significantly reduced at all time points of evaluation. Examination of the lipid profile revealed that total cholesterol, low-density lipoprotein cholesterol, and triglycerides were also decreased at all time points of evaluation, while high-density lipoprotein cholesterol was significantly reduced after 3, 9, and 12 months. Significant reduction of the estimated glomerular filtration rate was observed after 6, 9, and 12 months, and the urinary albumin/creatinine ratio was significantly lower at 9 and 12 months. Serum creatinine was increased significantly at all time points of evaluation. CONCLUSIONS: BP was slightly but significantly reduced from 6 months after initiation of sitagliptin therapy, indicating that this antidiabetic drug has pleiotropic effects, including an antihypertensive effect.

Inhomogenic effect of bepridil on atrial electrical remodeling in a canine rapid atrial stimulation model.

BACKGROUND: The antiarrhythmic or reverse remodeling effects of bepridil, a multi-ion channel blocker, have been recently reported, but inhomogeneity of the electrical remodeling and effects of bepridil have been observed in previous reports. In this study, the effect of long-term administration of bepridil on atrial electrical remodeling was evaluated in a comparison of the right and left atrium (RA and LA) in a canine rapid atrial stimulation model. METHODS AND RESULTS: In 10 beagle dogs, rapid atrial pacing (400 beats/min) was delivered for 6 weeks and the atrial effective refractory period (AERP), conduction velocity (CV) and inducibility of atrial fibrillation (AF) were evaluated every week. In 5 of the pacing dogs, bepridil (10 mg . kg(-1) . day(-1)) was administered orally, starting 2 weeks after the initiation of the rapid pacing. At the end of the protocol, the hemodynamic parameters and extent of tissue fibrosis were evaluated and the mRNA of SCN5A, Kv4.3, the L-type Ca2+ channel (LCC) and connexin (Cx) 40, 43, and 45 in both atria were examined by quantitative real-time reverse transcriptase-polymerase chain reaction. In the pacing control group, AERP shortening, decreased CV, increased AF inducibility and downregulation of the expression of SCN5A and LCC were observed. In the bepridil group, the AERP exhibited a relatively quick recovery after bepridil was started in the first week and continued to recover gradually until the end of the protocol, but that recovery was smaller in the LA than in the RA. The CV was not affected by bepridil administration. AF inducibility was well suppressed in the RA in the bepridil group, but the induction of short-duration AF could not be suppressed in the LA. The mRNA downregulation of the LCC and SCN5A was negated by bepridil administration in the RA; but not in the LA; however, the data showed similar tendencies. There were no significant differences in the hemodynamic parameters or tissue fibrosis and the mRNA expression of Kv4.3, Cx40, 43, and 45 between the pacing control and bepridil groups. CONCLUSION: Bepridil exhibited an anti-electrical remodeling effect in this study as previously reported, but the effect was inhomogeneous between the RA and LA, with the LA appearing to be more resistant to the effect of bepridil.

Arrhythmogenic difference between the left and right atria during rapid atrial activation in a canine model of atrial fibrillation.

BACKGROUND: Continuous rapid atrial stimulation causes atrial remodeling, but little is known about the difference in the arrhythmogenicity of the left (LA) and right atria (RA). METHODS AND RESULTS: In 14 beagle dogs, continuous rapid pacing (400 beats/min) was delivered from the right (n=7) or left (n=7) atrial appendage (RAA or LAA) for 2 weeks. The atrial effective refractory period (ERP), ERP dispersion, and inducibility of atrial fibrillation (AF) were evaluated along the time course from 4 atrial sites: (1) RAA, (2) area close to the inferior vena cava (IVC), (3) Bachmann's bundle (BB) and (4) LA. The ERP exhibited progressive shortening at all sites, but the degree of shortening differed among them. In the RA stimulation group, ERP shortening was more prominent in the RAA and LA than in the IVC or BB. In contrast, in the LA stimulation group, ERP shortening was more prominent in the LA than in the other sites. As a result, ERP dispersion was larger in the LA stimulation group than in the RA stimulation group and the AF inducibility was higher in the LA stimulation group than in the RA stimulation group, especially at the LA site (p<0.05). CONCLUSION: LAA stimulation was more arrhythmogenic than RAA stimulation in this model. This result may partly explain the importance of premature contractions occurring from the pulmonary veins in clinical cases of AF.

Primary cardiac osteosarcoma in a young man with severe congestive heart failure.

A primary cardiac malignant tumor is very rare; its prevalence is only 0.002-0.28%. Among most malignant tumors, angiosarcoma, leiomyosarcoma, and mesothelioma occupy the majority. A cardiac osteosarcoma is extremely rare: to our knowledge, only 36 cases have been reported worldwide. We present a 22-year-old case featuring severe congestive heart failure. Hemodynamically the tumor led to significant obstruction of the mitral valve. The patient underwent an emergency resection operation, but multiple metastases occurred. Though the characteristics still remain unclear because of the low prevalence, it is very important that these tumors be distinguished from benign tumors because of early resection operation.

Verapamil suppresses the inhomogeneity of electrical remodeling in a canine long-term rapid atrial stimulation model.

Verapamil is known to suppress shortening of the atrial effective refractory period (AERP) during relatively short-term atrial pacing, although the effect of a long-term stimulation model is unclear. The effect of verapamil on electrical remodeling was evaluated in a canine rapid atrial stimulation model. The right atrial appendage (RAA) was continuously paced (400 beats/min) for 2 weeks. Four pairs of electrodes were sutured at four atrial sites; the RAA, right atrium close to the inferior vena cava, Bachmann's bundle, and LA. AERP, AERP dispersion (AERPd), conduction time, and inducibility of AF were evaluated during the pacing phase and the recovery phase. The same protocol was performed under the administration of verapamil. In five control dogs, the AERP shortening was inhomogeneous and the shortening of the AERP was most prominent in the LA. AERPd increased during the rapid pacing phase by 5 +/- 2 ms, but recovered quickly in the recovery phase. The max AERPd was 46 +/- 4 ms in the control group and was larger than that in the verapamil group (31 +/- 3 ms, P = 0.001). At the LA site, the shortening of the AERP was decreased by verapamil administration (-19 +/- 3 vs -5 +/- 2 ms, P = 0.04). However, the AF inducibility was not significantly different between the two groups. The effect of verapamil on electrical remodeling was inhomogeneous, depending on the anatomic portion. As a result, AERPd widening during the rapid pacing phase was suppressed by verapamil, while the AF inducibility was unchanged.

Bepridil prevents paroxysmal atrial fibrillation by a class III antiarrhythmic drug effect.

BACKGROUND: [corrected] Bepridil, a multiple ion-channel blocker, has been reported to prevent paroxysmal atrial fibrillation (PAF). The f-f interval of PAF during treatment with bepridil versus class Ic antiarrhythmic drugs was compared. METHODS: Fifty-two patients with PAF were randomized to bepridil, 200 mg/day (n = 14) versus flecainide, 100 to 200 mg/day (n = 15) or pilsicainide, 75 to 150 mg/day (n = 23). The drug was considered effective when symptomatic episodes of PAF were decreased to < 50% during a follow-up of 2 to 6 months. The f-f interval was measured in 12-lead ECGs of initial PAF episodes. RESULTS: Bepridil and Ic were effective in 10 of 14 (71.4%) and 24 of 38 patients (63.2%), respectively (ns). In the Ic group, the f-f interval was longer in successfully (114 +/- 48 ms) than in unsuccessfully (68 +/- 25 ms) treated patients (P = 0.002). In the bepridil group, the f-f interval was shorter in successfully (84 +/- 27 ms) than unsuccessfully (155 +/- 68 ms) treated patients (P = 0.015). When comparing unsuccessfully treated patients, the f-f interval in the bepridil group was significantly longer than in the Ic group (P = 0.007). CONCLUSIONS: Bepridil was as effective as Ic drugs in the prevention of PAF. Because it was more effective in smaller (functional) than larger (anatomical) reentrant circuits, the effect of bepridil was considered to be mainly attributable to a class III antiarrhythmic action.

Effect of pilsicainide on atrial electrophysiologic properties in the canine rapid atrial stimulation model.

The heterogeneous process of atrial electrical remodeling (AER) in the canine rapid atrial stimulation model has been previously reported although it has been reported that a sodium channel blocker might suppress the shortening of the atrial effective refractory period (AERP), its effect on long-term electrical remodeling is unknown. In the present study, the effect of pilsicainide on AER was evaluated. The right atrial appendage (RAA) was paced at 400 beats/min for 2 weeks. In the RAA, Bachmann's bundle (BB), the right atrium near the inferior vena cava (IVC) and in the left atrium (LA), AERP, AERP dispersion (AERPd) and the inducibility of atrial fibrillation (AF) were evaluated at several time points of the pacing phase and the recovery phase (1 week). The same protocol was performed during the administration of pilsicainide (4.5 mg/kg per day) and the parameters were compared with the controls. In the control dogs, the AERP was significantly shortened by rapid pacing at all atrial sites studied and the AERP shortening (DeltaAERP) was larger at the RAA and LA sites (p<0.03). However, pilsicainide decreased these DeltaAERPs at all 4 atrial sites. AERPd was increased during the pacing phase whereas it was decreased during the recovery phase in the control dogs. In contrast, this pacing-induced AERPd was attenuated by the administration of pilsicainide. The AF inducibility was highest at the LA site in both groups, and the inducibility was lower in the pilsicainide group than the control group at all atrial sites. During the rapid pacing phase, the ventricular heart rate was significantly lower in the pilsicainide group than the control because of intra-atrial conduction block. In a canine rapid right atrial stimulation model, pilsicainide suppressed the shortening of the AERP at all atrial sites, possibly through the improvement of the hemodynamics as well as the action of the Na - Ca exchanger.

Monitoring the progression of the atrial electrical remodeling in patients with paroxysmal atrial fibrillation.

It is important to clarify how electrical remodeling develops in clinical cases of paroxysmal atrial fibrillation (PAF), because it has been suggested that this electrophysiological phenomenon promotes an increase in the frequency of PAF. In the present study, the f-f interval during PAF was analyzed from the ambulatory ECG recordings of 21 patients with PAF (total PAF duration >2/24 h with normal atrial size) to monitor the atrial electrophysiological changes. The patients were clinically followed-up for 6 months without any antiarrhythmic drugs. Before and after the follow-up period 24-h Holter monitoring was carried out and the duration of both the PAF and the f-f intervals during the PAF episode were evaluated. In selected cases, the atrial effective refractory period (ERP) was evaluated in an electrophysiologic study before and after the follow-up period. The total PAF duration was prolonged from 187+/-50 to 223+/-79 min (p=0.034) and the f-f interval was shortened from 0.14+/-0.03 to 0.12+/-0.02 ms (p=0.003). There was an inverse relationship between the changes in total PAF duration and f-f interval (p=0.027). The ERP was shortened from 214+/-15 to 194+/-5 ms (n=5, p=0.025) and there was a direct correlation between the changes in ERP and f-f interval (p=0.048). In clinical cases, the prolongation of the PAF was related to the shortening of the f-f interval during the PAF episodes and to the shortening of the atrial ERP. Electrical remodeling plays a role in promoting the development of the atrial fibrillation in patients with PAF.

Evaluation of the effect of bepridil on paroxysmal atrial fibrillation: relationship between efficacy and the f-f interval in surface ECG recordings.

Bepridil, a multi-ion channel blocker, is effective for some types of cardiac arrhythmias, and so its effect on the paroxysmal atrial fibrillation (PAF) was evaluated in the present study, comparing it with class Ic antiarrhythmic drugs. The relationship between efficacy and the f-f interval in the surface ECG recording was also analyzed. Sixty-one symptomatic PAF patients were randomized to a bepridil group (200 mg/day, n=23) or class Ic drug group (flecainide 100-200 mg/day or pilsicainide 75-150 mg/day, n=38). The drug was considered effective for PAF prevention when symptomatic episodes of PAF were decreased to less than 50% during the follow-up period of 2-6 months. The f-f interval in the surface 12-lead ECG trace was evaluated during a PAF episode. Both bepridil and the class Ic drugs were effectively prevented PAF (15/23 (65.2%) vs 24/38 (63.1%) patients, NS). In the class Ic drug group, the f-f interval was longer in the effective cases (114+/-48 ms) than in the non-effective cases (68+/-26 ms, p=0.0002). In contrast, in the bepridil group the f-f interval was shorter in the effective cases (85+/-26 ms) than in the non-effective ones (152+/-45 ms, p=0.0005). When comparing the non-effective cases in the 2 groups, the bepridil group showed a significantly longer f-f interval than the class Ic drug group (p=0.0003). As a result of drug administration, the class Ic drugs prolonged the f-f interval from 78+/-33 ms to 128+/-46 ms (p=0.0004) whereas bepridil showed no change (109+/-39 ms vs 135+/-47 ms). For clinical PAF prevention, the effect of bepridil matched that of class Ic antiarrhythmic drugs. Because bepridil was effective in PAF patients with relatively shorter f-f intervals without prolonging the f-f interval, bepridil is considered to work mainly as a class III antiarrhythmic drug.

Measurement of body surface energy leakage of defibrillation shock by an implantable cardioverter defibrillator.

Leakage of electrical current from the body surface during a defibrillation shock delivery by an ICD device was evaluated in 27 patients with life-threatening ventricular tachyarrhythmias. All patients underwent the implantation of the Medtronic Jewel Plus ICD system, and the defibrillation shocks were delivered between the active can implanted in the left subclavicular region and the endocardial lead placed in the right ventricle. At the time of measurement of the effect of electrical energy delivery for defibrillation, the shocks were delivered in a biphasic form at the energy level of 20 or 30 J. During each delivery of the defibrillation shock, the electrical current to the body surface was measured through large skin electrodes (6.2 cm2) that were pasted at the following positions: (1) parallel position: the electrodes were placed at the left shoulder and the right low-chest, and the direction of the electrode vector was parallel to the direction of the defibrillation energy flow, and (2) cross position: the electrodes were placed at the right shoulder and the left low-chest, and the vector of the electrodes was roughly perpendicular to the direction of the energy flow. The energy leakages were measured in 80 defibrillation shocks. The peak leakage current during the shock delivery at energy of 30 J was 48 +/- 26 mA at the parallel position and 19 +/- 15 mA at the cross position (P = 0.0002). The energy leakage at a 30-J shock was 7.4 +/- 7.2 mJ at the parallel position and 1.4 +/- 2.3 mJ at the cross position (P = 0.0002). The actual maximum energy leakage was 105 mA, 29 mJ, and 106 V that appeared at the parallel position. The body surface leakage of the defibrillation energy of the ICD device was evaluated. The power of the energy leakage strongly depended on the angle between the alignment of the recording electrodes and the direction of the energy flow. The highest current leakage to the body surface reached a considerable level, but the energy leakage was small because of the short duration of the defibrillation shock.

Electrical remodeling of the ventricular myocardium in myocarditis: studies of rat experimental autoimmune myocarditis.

The purpose of this study was to evaluate the electrical remodeling of the ventricular myocardium in the experimental autoimmune myocarditis (EAM) model in Lewis rats. EAM was induced by immunization with cardiac myosin. During the active myocarditis phase, the effective refractory period (ERP), the duration of the monophasic action potential (MAPD) was extracted from the left ventricular free wall, and the mRNA levels of Kv1.4, 4.2, 4.3 and L type Ca2+ channel were determined by RNase protection assays. The inducibility of ventricular arrhythmia was higher in EAM rats than in the control rat, and the direct relationship between the coupling intervals of the premature stimulus and the ventricular arrhythmia in EAM rats. The ERP was prolonged in EAM rats compared with the control group. The MAPDs determined as 20% and 90% repolarization time, were both longer in EAM rats than in the controls. The level of expression of Kv4.2 mRNA was reduced in EAM rats in comparison with the controls, whereas those of Kv1.4, 4.3 and the L type Ca2+ channel were unchanged. Ventricular vulnerability was higher in EAM rats than in the control rats, and some of the ventricular arrhythmias observed in the EAM group seemed to be based on triggered activity. The level of expression of Kv4.2 mRNA was significantly reduced, and this change was compatible with prolongation of the action potential duration.