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Introduction. The aim of this study was to investigate neutrophil elastase (NE) in amniotic fluid as a potential marker for predicting pregnancy continuation. Material and methods. We enrolled 34 pregnant women with bulging fetal membrane during the second trimester who underwent emergent cerclage after confirming the absence of intrauterine infection (amniotic fluid glucose >= 15 mg/dL). Amniotic fluid NE levels were compared between women who completed and did not complete 30, 34, and 36 weeks of gestation, and the optimal cut-off value for predicting pregnancy continuation was estimated. Moreover, the differences in the duration of continued pregnancy were compared between women with NE levels above and below the optimal cut-off value. Results. The optimal cut-off value for NE in amniotic fluid that predicted pregnancy continuation beyond 30, 34, and 36 weeks of gestation was 180 ng/mL; this cut-off value had a sensitivity, specificity, positive predictive value, and negative predictive value of 84.0, 77.8, 91.3, and 63.7% beyond 30 weeks of gestation; 87.5, 80.0, 91.5, and 72.3% beyond 34 weeks of gestation; and 85.0, 71.4, 80.9, and 76.9% beyond 36 weeks of gestation, respectively. The duration of continued pregnancy from emergent cerclage to delivery was significantly longer in women with amniotic fluid NE = 180 ng/mL (44.8 +/- 14.3 days). Conclusion. The NE levels in amniotic fluid may serve as a useful marker for predicting the duration of continued pregnancy after cervical cerclage.

Objective Cases of prolapsed myoma in which pregnancy was carried to full term or near term after vaginal myomectomy are very rare. Previously, only two such cases have been reported. In addition, both those patients had a pedunculated leiomyoma, which could be treated by twisting or clamping. Here, we report a case of a patient who was able to carry her pregnancy to term despite vaginal myomectomy for semipedunculated myoma at 13 weeks of pregnancy. Study Design This study is a case presentation. Results The myoma nucleus was removed by making an incision on the surface of the mass. Systemic and transvaginal antibiotics were prescribed after the surgery. Uterine contractions, short cervix, or cervical funneling was not observed in the remaining duration of pregnancy. Conclusion While performing myomectomy during pregnancy, removal of the myoma nucleus is safer than twisting. In addition, postoperative administration of local or systemic antibiotic agents does not adversely affect pregnancy.

Patients with recently diagnosed atrial fibrillation (AF) tend to exhibit a longer fibrillation cycle length (FCL) than those having a longer clinical history. However, the electrophysiological properties of new-onset AF may vary because of the clinical background of patients. In this study, we evaluated clinical factors to identify the determinants of FCL in new-onset AF. Electrocardiograms (ECGs) recorded from 2008 through 2011 were analyzed using our digital ECG-profiling system. In the 1,578 AF episodes recorded, 466 new-onset AF episodes were identified using clinical referral history and previous ECGs. After evaluating FCL in these new-onset AF episodes, using a customized fibrillation wave analyzer with fast Fourier transform analysis, we divided the patients into a longer-FCL group and a shorter-FCL group using the median FCL (158 ms). Propensity score matching yielded 135 matched pairs of patients with comparable mean ages between the two groups. Four factors (brain natriuretic peptide levels, and use of angiotensin receptor blockers, calcium channel blockers or statins) exhibited a significant difference between the two groups. Multivariate analysis revealed that statin use was the only significant independent predictor of longer FCL (Odds ratio, 3.86; 95% CI, 1.659.63; P = 0.003). Among various clinical parameters, statin use was related to longer FCL at the time of new-onset AF in patients with AF.

Problem: Yamada, a town of Iwate Prefecture in north-eastern Japan, was struck by the tsunami from the Great East Japan Earthquake. In Yamada, it was challenging to manage nutritional and diet support for food aid because these services were unavoidably drawn out for several months in evacuation shelters.Context: In Japan, food aid in disasters is often provided, divided and distributed erratically due to poor efforts made with regards to dietary support from the perspective of nutrition. The need for nationally registered dieticians to coordinate nutritional and dietary support in evacuation shelters was considered in this disaster.Action: A dietary support team was formed of nationally registered dieticians to study the dietary conditions of evacuees in shelters in Yamada and to develop a system to ensure the nutritional and balanced dietary needs of the evacuees.Outcome: In this disaster response, model menus were prepared and a menu–food matching system was put in place to order and distribute foods required for balanced meals. Every effort was made to avoid excesses and deficiencies in nutrition; the meals consisted of a staple, main dish, side dish and soup. Along with that, food sanitation and stock management were improved.Discussion: The menu–food matching system put together by the nationally registered dieticians was useful for nutritional and dietary support in this particular disaster. It is recommended that similar nutritional and dietary support coordinated by nationally registered dieticians be considered for disaster management plans where appropriate.

Although bucolome has been used empirically to enhance and stabilize warfarin action in some institutes, the clinical risks and benefits of this combination are unclear. In the present study, warfarin monotherapy (WM) and bucolome combination (BC) therapy were compared in anticoagulation therapy.One hundred and ninety-five patients indicated for anticoagulation therapy were randomly assigned to WM (n = 98) or BC (bucolome 300 mg/day, n = 97). The dosage of warfarin was optimized in each patient to maintain the international normalized ratio (INR) level in the appropriate zone, ie, 1.6-2.6 for lower risk and 2.0-3.0 for higher risk patients. The clinical characteristics, clinical events, and time in therapeutic range (TTR) were evaluated and compared between the two groups. TTR was calculated using Rosendaal's linear interpolation method.The optimal dosage of warfarin was 3.3 ± 1.0 mg/day in WM and 1.4 ± 0.5 mg/day in BC (P0.001). During the observation period of 18 ± 6 months, no serious complication was observed and INR was measured 11 ± 3 times in each case. TTR was 0.61 ± 0.13 in WM and 0.62 ± 0.14 in BC (NS), but TTR in the WM subgroup with warfarin3 mg (0.58 ± 0.13) was lower than in the WM subgroup with warfarin ≤ 3 mg (0.64 ± 0.13, P = 0.026) and BC (P = 0.042).BC reduced the optimal dosage of warfarin without increasing clinical events. There was no significant difference in TTR between WM and BC, but BC may have benefits in selected cases, such as warfarin resistance.

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.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.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 DeltaLVEF (p0.001) and positive correlation between the PVC prevalence and DeltaLVDd (p0.001). When the development of LV dysfunction was defined as DeltaLVEF-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 (p0.01).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.

Background: Antiarrhythmic agents may affect electrical remodeling but little is known regarding clinical cases. We evaluated fibrillation cycle length (FCL) of atrial fibrillation (AF) by spectral analysis of fibrillation waves (FW) in surface ECG for patients on antiarrhythmic agents. Methods and Results: 18 patients (14 males; 58 ± 2 year-old) with paroxysmal AF (pAF) lasting over 30 minutes recorded by Holter ECG were enrolled. FW was purified by subtraction of QRS-T, and calculated by fast Fourier transformation analysis. FCL was defined as reciprocal of mean peak frequency. Temporal variability was expressed as FCL coefficient of variation (FCL-CV). FCL and FCL-CV were calculated at 0, 1, 5, 10, and 30 minutes after the onset of AF. We evaluated three groups: control group (6 patients with no medication), class I group (6 patients with pilsicainide or flecainide), and bepridil group (6 patients with bepridil). FCL showed quick-shortening at first minute in control group (p < 0.001), and relatively slow-shortening in class I group. In bepridil group, FCL was not significantly shortened within 30 minutes. FCL-CV did not change, but was significantly larger in bepridil group. Conclusions: FCL of pAF showed significant shortening in control group, but FCL shortening was suppressed and FCL-CV was larger in bepridil group. This result may indicate the specific effect of bepridil for electrical changes in early phase of pAF.

It is unknown whether 12-lead ECG can predict new-onset AF. In the present study, we identified patients with new onset AF from our digitally stored ECG database, and the P wave morphologies were analyzed in their preceding sinus rhythm recordings as the precursor state for AF. The P wave was analyzed in the most recent ECG recording of sinus rhythm preceding new onset AF within 12 months. The duration and amplitude of P waves were analyzed in 12 leads and compared between the 2 groups with the other clinical parameters. The study population consisted of 68 patients with new-onset AF and 68 age and sex-matched controls. Multivariate analysis revealed that the P wave amplitude in leads II and V1 (0.157 ± 0.056 versus 0.115 ± 0.057 mV, P = 0.032, and 0.146 ± 0.089 versus 0.095 ± 0.036 mV, P = 0.002) and P wave dispersion (56.9 ± 14.8 versus 33.5 ± 12.9 ms, P = 0.001) were significant independent factors for the prediction of new-onset AF. By using these factors, new-onset AF could be predicted with a sensitivity of 69.1% and specificity of 88.2%. P wave analysis is useful for predicting new onset AF.

We examined the stereoselective membrane permeation of new fluorinated quinolone derivatives (NQs) across LLC-PK1 cell monolayers, using levofloxacin (LVFX) and its R-(+) isomer. LVFX permeation was 1.6-fold greater in the basal-to-apical direction than that in the apical-to-basal direction, suggesting that LVFX permeated LLC-PK1 cell monolayers in a secretory-oriented manner. In contrast to LVFX, the permeation of the R-(+) isomer was almost identical in both directions. LVFX permeation in the basal-to-apical direction was significantly reduced in the presence of guanidine, enoxacin, and L-arginine, whereas tetraethylammonium, D-arginine, D- and L-lysine had no effect on the basal-to-apical permeation of LVFX. Basal-to-apical permeation of the R-(+) isomer was not affected by these compounds. Cellular accumulation of LVFX was inversely increased when guanidine suppressed the appearance of LVFX in the apical medium in a concentration-dependent manner. These results imply that the inhibitory effect of guanidine on the basal-to-apical permeation of LVFX involves the permeation process across the apical membrane. Guanidine trans-stimulated the efflux of LVFX from LLC-PK1 cells but did not affect cimetidine efflux. These results suggest that some NQs, like LVFX and its R-(+) isomer, are stereoselectively secreted across LLC-PK1 cell monolayers and that an organic cation transport system, which favors guanidine as a typical substrate, may be involved in the secretory-oriented permeation of some NQs.

Background Ezetimibe (Zetia®) is a potent inhibitor of cholesterol absorption that has been approved for the treatment of hypercholesterolemia. Statin, an inhibitor of cholesterol synthesis, is the first-choice drug to reduce low-density lipoprotein-cholesterol (LDL-C) for patients with hypercholesterolemia, due to its strong effect to lower the circulating LDL-C levels. Because a high dose of statins cause concern about rhabdomyolysis, it is sometimes difficult to achieve the guideline-recommended levels of LDL-C in high-risk patients with hypercholesterolemia treated with statin monotherapy. Ezetimibe has been reported to reduce LDL-C safely with both monotherapy and combination therapy with statins. Results To investigate the effect of ezetimibe as "add-on" therapy to statin on hypercholesterolemia, we examined biomarkers and vascular endothelial function in 14 patients with hypercholesterolemia before and after the 22-week ezetimibe add-on therapy. Ezetimibe add-on therapy reduced LDL-C by 24% compared with baseline (p < 0.005), with 13 patients (93%) reaching their LDL cholesterol goals. Of the Ezetimibe add-on therapy significantly improved not only LDL-C, high-density lipoprotein-cholesterol (HDL-C), and apolipoprotein (apo)B levels, but also reduced levels of triglyceride (TG), the ratio of LDL/HDL-C, the ratio of apoB/apoA-I, and a biomarker for oxidative stress (d-ROMs). Furthermore, ezetimibe add-on therapy improved vascular endothelial function in high-risk patients with hypercholesterolemia. Conclusion In conclusion, ezetimibe as add-on therapy to statin might be a therapeutic good option for high-risk patients with atherosclerosis.

Spectral analysis of the fibrillation waves was performed in patients with persistent atrial fibrillation (PAF) to clarify the usefulness of this method of predicting the efficacy of antiarrhythmic agents.The 59 patients with PAF were randomly assigned to pilsicainide (150 mg/day) or bepridil (200 mg/day) therapy for 4 weeks under optimal anticoagulation therapy. When the first therapy did not interrupt PAF, the drugs were changed in a cross-over manner. The fibrillation cycle length (FCL) was calculated using spectral analysis of the fibrillation waves on the body-surface ECG every 2 weeks. Pilsicainide and bepridil were effective in 19 and 20 patients, respectively. The FCL at the basic state was longest in the pilsicainide-effective group, moderate in the bepridil-effective group and shortest in the failure group (P0.05). The change in FCL with drug administration (DeltaFCL) was larger in the effective than in the ineffective cases (P0.01). Successful interruption of the atrial fibrillation (AF) with pilsicainide could be expected for patients with a FCL148 ms (sensitivity =0.917, specificity =0.612, P=0.007) and DeltaFCL41 ms (sensitivity =0.875, specificity =0.833, P=0.001).The FCL reflects the electrophysiological properties of the AF substrate and is considered useful for predicting the efficacy of antiarrhythmic agents.

Aims The electrical remodelling is considered to play a role in promoting arrhythmogenic substrate of atrial fibrillation (AF), and intracellular calcium overload may play a key role, especially in its early phase. The effect of oral verapamil on repetitive paroxysmal AF (PAF) was evaluated in clinical cases. Methods and results Thirty-five patients with repetitive PAF (total PAF duration .2/24 h) were divided into two groups with and without verapamil administration (240 mg/day) and they were followed-up for 12 months. Before and after the follow-up period, 24 h Holter ECG was recorded. In each Holter recording, total PAF duration and the longest PAF duration was evaluated and spectral analysis was performed for fibrillation waves in PAF episodes to evaluate the fibrillatory frequency. Total PAF duration was prolonged by 45+ 79 min in the control group (n ¼ 18) whereas shortened by 25+ 55 min in the verapamil group (n ¼ 17, P ¼ 0.005). The fibrillatory frequency was increased from 5.66+ 1.05 to 6.73+ 1.02 Hz in the control group and was unchanged in the verapamil group. There was inverse relationship between Dtotal PAF duration and Dfibrillatory frequency (P ¼ 0.0002). Conclusion Verapamil prevented the increase in fibrillatory frequency in PAF patients in relatively longterm observation. Verapamil might be effective for prevention of the electrophysiological change and increase in PAF episodes at least in specific type of PAF cases.

This study was undertaken to examine the secretory transport of arbekacin, an aminoglycoside antibiotic, in the rat small intestine and to compare it with those in Caco-2 and LLC-PK1 cells. In vitro permeation of arbekacin was examined using an Ussing chamber technique. Serosal-to-mucosal (secretory)/mucosal-to-serosal (absorptive) permeation ratios of 0.5 mM arbekacin were 2.8 in the jejunum and 7.0 in the ileum, respectively, indicating that arbekacin permeation was highly secretory-oriented. In the ileum, the ratios became smaller with increase in arbekacin concentration applied. When d -glucose was replaced with 3-o-methyl- d -glucose in the experimental medium, the directionality of the arbekacin permeation disappeared almost completely. Absorptive permeation of arbekacin was not significantly influenced by verapamil, cyclosporin A, or probenecid. On the other hand, when gentamicin sulfate was added to the serosal medium, secretory transport of arbekacin was significantly inhibited. The results of this study strongly suggest that a specialized efflux system other than P-glycoprotein and multidrug resistance proteins was involved in the secretory transport of arbekacin in the rat intestine. There was no directionality in arbekacin permeation across Caco-2 cell monolayers, suggesting the absence or very slight expression of the secretory system for arbekacin in this cell line.

To investigate the correlation between in vitro permeation of 11 beta-lactam antibiotics across rat jejunum and their oral bioavailability in humans.The absorptive and secretory permeation across rat jejunum was evaluated and apparent permeability coefficients (P(app)) were determined.A steep, sigmoid-type curve was obtained for the relationship between P(app) in the absorptive permeation and human oral bioavailability. When the ratios of P(app) in the absorptive direction to P(app) in the secretory direction were plotted against human oral bioavailability, a much improved correlation was obtained (r = 0.98, P0.001). The addition of glycylglycine to both mucosal and serosal media modified the permeation of ceftibuten and cephalexin from the absorptive to the secretory direction.For 11 beta-lactam antibiotics rat intestinal permeation correlated well with human oral bioavailability, especially when corrected for secretory transport.

Late stent thrombosis occurred in the lesion of a sirolimus-eluting stent implanted 6 months previously for an in-stent restenosis lesion in the distal right coronary artery. Seventeen days before admission due to acute myocardial infarction this time, aspirin was discontinued for colon polypectomy. Ticlopidine had been discontinued 3 months before the discontinuation of aspirin. In drug-eluting stent era, the interventional strategy and antiplatelet therapy require long term attention.

A 71-year-old man visited our hospital complaining of increasing fatigue and exertional dyspnea. He had had severe epigastric pain for the past 5 months. On admission, chest radiogram showed marked cardiac dilatation and echocardiogram massive pericardial effusion with a small subepicardial aneurysm at the posterior wall of the left ventricle. An urgent pericardiocentesis removed 1300 ml of bloody effusion. The red blood cell count of the pericardial effusion was similar to that of the peripheral blood, and there were no abnormal findings on cytologic and bacteriological examinations. Coronary angiography showed a blunt occlusion of the mid-portion of the circumflex artery. Left ventricular angiogram revealed aneurysmal deformity of the left ventricular posterior wall. These findings suggested that an oozing type of left ventricular rupture via a subepicardial aneurysm had occurred after the onset of myocardial infarction (MI), resulting in massive accumulation of pericardial effusion. The patient is presently doing well without any clinical symptoms 18 months after pericardiocentesis. This is the first case report in which a subepicardial aneurysm with massive pericardial effusion was detected in the chronic stage of MI and successfully managed without surgical repair.

The renal handling of doxorubicin (DXR) was investigated using a kidney epithelial cell line, LLC-PK1. The uptake of DXR by LLC-PK1 cells cultured on plastic dishes was shown to be temperature and concentration dependent. The initial uptake of DXR was slightly saturable. The Km and Vmax of the saturable component were calculated to be 20.2 microM, and 0.355 nmol/mg protein/10 min, respectively. The release of DXR from LLC-PK1 cells was very slow at 37 degrees C and almost negligible at 4 degrees C, indicating that most of the DXR in the cells irreversibly binds to cellular constituents and that only a slight amount of unbound DXR participates in the efflux out of the cells. DXR uptake at 37 degrees C was significantly decreased in the presence of 2,4-dinitrophenol. However, organic cations and aminoglycoside antibiotics, such as tetraethylammonium, N1-methylnicotinamide, guanidine, gentamicin and neomycin, did not inhibit DXR uptake, suggesting that a process distinct from the organic cation transport system and absorptive endocytosis might be involved in the uptake of DXR by LLC-PK1 cells.

Systolic anterior motion (SAM) of the anterior mitral leaflet with mitral-septal contact was generally thought to be a major contributor to dynamic left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy. We report an interesting case of SAM of the posterior mitral leaflet in a patient without left ventricular hypertrophy, which led to dynamic left ventricular obstruction.

Background: Short-term success does not always correlate well with long-term outcome in cases of catheter ablation (CA) for atrial fibrillation (AF). The aim of this study is to examine about the predictor which can differentiate between short- and long-term recurrence of AF after CA of AF. Methods and Results: Total of 52 patients (48; ±9 years, male; 33) were involved. The patients were divided into two groups; Group A: AF recurred earlier than 3 months after CA for AF (35 cases), Group B: AF recurred later than 1 year after CA for AF (17 cases). With multivariate analysis, following parameters were analyzed between Group A and B; diameter of left atrium (LAD) (38.7; ±5.6 vs 40.3; ±9.3 mm, NS), left ventricular ejection fraction (LVEF) (66.0; ±11.9 vs 59.8; ±9.2%, NS), the maximum diameter of pulmonary veins (MDPV) (23.1; ±3.4 vs 25.0; ±2.9 mm, NS), score of CHADS2 (SCHADS) (1.35; ±0.14 vs 1.31; ±0.21, NS), cardiothoracic ration on chest X-ray (CTR) (49.3; ±3.9 vs 51.2; ±4.3, NS) and total number of radiofrequency energy application (RFAP) (62.4; ±11.8 vs 83.9; ±13.8, P

Introduction: The benefit of additional ablation of complex fractionated electrograms (CFE) has been reported in treating patients with persistent atrial fibrillation (per-AF). However, the ideal target patients group for this strategy remains unclear. We report a series of cases with per-AF in which addition of CFE ablation to PVI resulted in successful outcome in freedom from AF. Method and Results: Three patients with symptomatic per-AF (2 with lone AF and 1 with tachycardia-induced cardiomyopathy, AF duration 4–16 months, age 56±6 yrs, 3 male, LA diameter of 43, 46 and 49 mm) under went a single ablation with PVI plus CFE ablation using NavX. The amounts of CFE region were variable (12–34 cm2). However, the distribution was similar among patients (in both the LA roof toward the appendage and LA septum anterior to the right superior PV). All CFE regions were located along area with voltage of 0.5–1.0 mV. Although termination of AF was not achieved, the mean cycle length in the LA significantly prolonged by CFE ablation. Following a single procedure, all three patients remained in sinus rhythm at >4-months follow-up. Conclusion: The details of the clinical and electrophysiological characteristics underlying these three cases will be discussed.

An oxygen-deficient perovskite of composition SrFeO3−x selectively absorbs NO gas above approximately 100°C, and the analysis of the infrared spectrum of the system 14NO - 15NO - SrFeO3−x has revealed that the absorbed species in SrFeO3−x is possibly the nitrosyl ion (NO−) bound to the iron ion accomodating some oxygen vacancies.

A high-temperature form of a brownmillerite-like compound Sr2Fe2O5, which has a perovskite structure with the oxygen vacancies randomly distributed, showed a remarkable NO decomposition at 700–900°C, whereas another brownmillerite-like ferrate (III) of composition Ca2Fe2O5 did not exhibit any significant catalytic activity for NO decomposition over the temperature range from room temperature to 900°C. This difference in their catalytic activities has been explained on the basis of their crystallographic properties, i.e., ordering or disordering of the oxygen deficiencies.

The risk of cardiovascular complication in a diabetes patient is similar to that in a nondiabetic patient with a history of myocardial infarction. Although intensive control of glycemia achieved by conventional antidiabetic agents decreases microvascular complications such as retinopathy and nephropathy, no marked effect has been reported on macrovascular complications or all-cause mortality. Evidence from VADT, ACCORD, and ADVANCE would suggest that glycemic control has little effect on macrovascular outcomes. Moreover, in the case of ACCORD, intensive glycemic control may be associated with an increased risk of mortality. There is sufficient evidence that suggests that postprandial hyperglycemia may be an independent risk factor for cardiovascular disease in diabetes patients. However, there are no prospective clinical trials supporting the recommendation that lowering postprandial blood glucose leads to lower risk of cardiovascular outcomes. Mitiglinide is a short-acting insulinotropic agent used in type 2 diabetes treatment. It has a rapid stimulatory effect on insulin secretion and reduces postprandial plasma glucose level in patients with type 2 diabetes. Because of its short action time, it is unlikely to exert adverse effects related to hypoglycemia early in the morning and between meals. Mitiglinide reduces excess oxidative stress and inflammation, plays a cardioprotective role, and improves postprandial metabolic disorders. Moreover, mitiglinide add-on therapy with pioglitazone favorably affects the vascular endothelial function in type 2 diabetes patients. These data suggest that mitiglinide plays a potentially beneficial role in the improvement of postprandial hyperglycemia in type 2 diabetes patients and can be used to prevent cardiovascular diseases. Although the results of long-term, randomized, placebo-controlled trials for determining the cardiovascular effects of mitiglinide on clinical outcomes are awaited, this review is aimed at summarizing substantial insights into this topic.