Temporal Relationship between Impairment of Cerebellar Motor Learning and Deterioration of Ataxia in Patients with Cerebellar Degeneration.

Ataxia and impaired motor learning are both fundamental features in diseases affecting the cerebellum. However, it remains unclarified whether motor learning is impaired only when ataxia clearly manifests, nor it is known whether the progression of ataxia, the speed of which often varies among patients with the same disease, can be monitored by examining motor learning. We evaluated motor learning and ataxia at intervals of several months in 40 patients with degenerative conditions [i.e., multiple system atrophy (MSA), Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3), SCA6, and SCA31]. Motor learning was quantified as the adaptability index (AI) in the prism adaptation task and ataxia was scored using the Scale for the Assessment and Rating of Ataxia (SARA). We found that AI decreased most markedly in both MSA-C and MSA-P, moderately in MJD, and mildly in SCA6 and SCA31. Overall, the AI decrease occurred more rapidly than the SARA score increase. Interestingly, AIs remained normal in purely parkinsonian MSA-P patients (n = 4), but they dropped into the ataxia range when these patients started to show ataxia. The decrease in AI during follow-up (dAI/dt) was significant in patients with SARA scores < 10.5 compared with patients with SARA scores ≥ 10.5, indicating that AI is particularly useful for diagnosing the earlier phase of cerebellar degeneration. We conclude that AI is a useful marker for progressions of cerebellar diseases, and that evaluating the motor learning of patients can be particularly valuable for detecting cerebellar impairment, which is often masked by parkinsonisms and other signs.

Asymptomatic cerebral findings on 3-Tesla MRI in patients with severe carotid artery stenoses.

BACKGROUND AND PURPOSE: Small vessel diseases (SVDs) are often asymptomatic. However, SVDs significantly influence the prognosis in patients with large vessel diseases (LVDs). We investigated asymptomatic cerebral findings on 3-Tesla MRI in patients with severe carotid artery (CA) stenoses, compared to peoples without a past history of neurological disorders, including strokes. METHODS: We retrospectively analyzed the prevalences of various asymptomatic cerebral findings which were intracerebral hemorrhages (ICHs), cortical superficial siderosis, ventricular dilatation (Evans' index) and SVDs including cerebral microbleeds (CMBs), lacunar infarctions (LIs), deep white matter hyperintensities (WMHs), periventricular hyperintensities (PVHs). The prevalence of each finding was compared using multivariate logistic regression models with adjustment for stroke risk factors. RESULTS: We evaluated the findings in 54 patients with severe CA stenosis treated by stenting (CA stenosis group) and 200 adults with health screening tests of the brain and no past history of neurological disorders (control group). Multivariate analyses adjusted for age ≥ 65 years old, female gender, hypertension, hyperlipidemia, diabetes mellitus, alcohol consumption, and smoking index revealed that the prevalences of severe PVHs, severe deep WMHs, asymptomatic deep ICHs, and asymptomatic LIs were significantly higher in the CA stenosis group than the control group. However, there were no significant differences in the prevalences of CMBs, or the remaining asymptomatic findings described above. CONCLUSIONS: With pathological differences between SVD and LVD, asymptomatic SVDs except CMBs and deep ICHs often co-exists severe CA stenosis as a presentative LVD.

Discordance between subjective and objective evaluations of cognitive function in old Japanese patients with heart failure.

OBJECTIVES: Although cognitive impairment is common among patients with chronic heart failure (HF), the accuracy with which caregivers can recognize it is unknown. This study aimed to examine the degree to which subjective and objective evaluations coincide. METHODS: Cognitive function was evaluated subjectively and objectively in 184 hospitalized patients aged 65 or older (82 ± 7.2 years old and 49% male) with HF, who were divided into three groups: (i) normal; (ii) mild cognitive impairment; and (iii) severe cognitive impairment. RESULTS: The intrapatient agreement of the results of subjective and objective evaluations was tested, and weighted κ coefficients showed poor agreement (0.54, 95% confidence interval: 0.42-0.66, P < 0.001). CONCLUSION: Subjective and objective cognitive function evaluations in older patients with HF are poorly concordant.

Tandem internal models execute motor learning in the cerebellum.

In performing skillful movement, humans use predictions from internal models formed by repetition learning. However, the computational organization of internal models in the brain remains unknown. Here, we demonstrate that a computational architecture employing a tandem configuration of forward and inverse internal models enables efficient motor learning in the cerebellum. The model predicted learning adaptations observed in hand-reaching experiments in humans wearing a prism lens and explained the kinetic components of these behavioral adaptations. The tandem system also predicted a form of subliminal motor learning that was experimentally validated after training intentional misses of hand targets. Patients with cerebellar degeneration disease showed behavioral impairments consistent with tandemly arranged internal models. These findings validate computational tandemization of internal models in motor control and its potential uses in more complex forms of learning and cognition.

CSF cytokine profile in MOG-IgG+ neurological disease is similar to AQP4-IgG+ NMOSD but distinct from MS: a cross-sectional study and potential therapeutic implications.

OBJECTIVE: To evaluate cerebrospinal fluid (CSF) cytokine profiles in myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG+) disease in adult and paediatric patients. METHODS: In this cross-sectional study, we measured 27 cytokines in the CSF of MOG-IgG+ disease in acute phase before treatment (n=29). The data were directly compared with those in aquaporin-4 antibody-positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD) (n=20), multiple sclerosis (MS) (n=20) and non-inflammatory controls (n=14). RESULTS: In MOG-IgG+ disease, there was no female preponderance and the ages were younger (mean 18 years, range 3-68; 15 were below 18 years) relative to AQP4-IgG+ NMOSD (41, 15-77) and MS (34, 17-48). CSF cell counts were higher and oligoclonal IgG bands were mostly negative in MOG-IgG+ disease and AQP4-IgG+ NMOSD compared with MS. MOG-IgG+ disease had significantly elevated levels of interleukin (IL)-6, IL-8, granulocyte-colony stimulating factor and granulocyte macrophage-colony stimulating factor, interferon-γ, IL-10, IL-1 receptor antagonist, monocyte chemotactic protein-1 and macrophage inflammatory protein-1α as compared with MS. No cytokine in MOG-IgG+ disease was significantly different from AQP4-IgG+ NMOSD. Moreover many elevated cytokines were correlated with each other in MOG-IgG+ disease and AQP4-IgG+ NMOSD but not in MS. No difference in the data was seen between adult and paediatric MOG-IgG+ cases. CONCLUSIONS: The CSF cytokine profile in the acute phase of MOG-IgG+ disease is characterised by coordinated upregulation of T helper 17 (Th17) and other cytokines including some Th1-related and regulatory T cells-related ones in adults and children, which is similar to AQP4-IgG+ NMOSD but clearly different from MS. The results suggest that as with AQP4-IgG+ NMOSD, some disease-modifying drugs for MS may be ineffective in MOG-IgG+ disease while they may provide potential therapeutic targets.

Arterial inflammation measured by 18F-FDG-PET-CT to predict coronary events in older subjects.

BACKGROUND AND AIMS: Although 18F-fluorodeoxyglucose (FDG) uptake has emerged as a sensitive and reliable marker of atherosclerotic inflammation, its additive predictive value for future coronary disease in older subjects is unknown. The aim of this study was to test the prognostic value of aortic inflammation detected via FDG-positron emission tomography (PET)-computed tomography (CT) in older subjects. METHODS: We retrospectively utilized the records of 309 subjects aged over 65 years, without a history of coronary artery disease, who underwent 18F-FDG-PET-CT mostly due to the clinical suspicion of cancer, but eventually turned out to be cancer-free. Target-to-background ratio (TBR) was calculated at the ascending aorta. The endpoint was occurrence of coronary heart disease (CHD) events. RESULTS: During a median follow-up of 3.9 years, 28 subjects experienced CHD events and 12 patients died due to non-CHD causes. The highest TBR tertile was associated with a high CHD event rate, accounting for death due to non-CHD causes as a competing risk (Gray test, p = 0.005). In a Fine and Gray competing risk proportional hazard regression model, TBR was associated with significantly high CHD events independently of FRS, with a hazard ratio (HR) of 1.19 per 0.1 TBR increase (p < 0.001). Likewise, a significant increase in the area under the curve (from 0.57 to 0.73, p = 0.028) and a significant improvement in net reclassification (0.42, p = 0.038) were observed when TBR was added to the model with FRS alone. CONCLUSIONS: In older subjects with no history of malignant disease or overt coronary artery disease, arterial inflammation evaluated by FDG uptake provides information on future occurrence of coronary artery events.

Cardiovascular Outcomes in Patients With Previous Myocardial Infarction and Mild Diabetes Mellitus Following Treatment With Pioglitazone: Reports of a Randomised Trial From The Japan Working Group for the Assessment Whether Pioglitazone Protects DM Patients Against Re-Infarction (PPAR Study).

BACKGROUND: Secondary prevention in patients with myocardial infarction (MI) is critically important to prevent ischaemic heart failure and reduce social burden. Pioglitazone improves vascular dysfunction and prevents coronary atherosclerosis, mainly via anti-inflammatory and antiatherogenic effects by enhancing adiponectin production in addition to antihyperglycemic effects, thus suggesting that pioglitazone attenuates cardiovascular events in patients with mild (HbA1c levels < 6·5%) diabetes mellitus (DM). Therefore, we evaluated the effects of pioglitazone on cardiovascular events in patients with both previous MI and mild DM. METHODS: In this multicentre, prospective, randomised, open, blinded-endpoint trial, we randomly assigned 630 patients with mild DM with a history of MI to undergo either DM therapy with (pioglitazone group) or without (control group) pioglitazone. DM was diagnosed using the 75-g oral glucose tolerance test, and mild DM was defined if HbA1c level was < 6·5%. The primary endpoint was the composite of cardiovascular death and hospitalisation caused by acute MI, unstable angina, coronary revascularisation (including percutaneous coronary intervention and cardiac bypass surgery), and stroke. FINDINGS: HbA1C levels were 5·9 and 5·8% (p = 0·71) at baseline and 6·0 and 5·8% (p < 0·01) at 2 years for the control and pioglitazone groups, respectively.The primary endpoint was observed in 14·2% and 14·1% patients in the control and pioglitazone groups during two years (95% confidential interval (CI):0.662-1·526, p = 0·98), respectively; the incidence of MI and cerebral infarction was 0·3% and 2·2% (95%CI: 0·786-32·415, p = 0·09) and 1·0% and 0·3% (95%CI: 0·051-3·662, p = 0·44), respectively. Post-hoc analyses of the 7-year observation period showed that these trends were comparable (21·9% and 19·2% in the control and pioglitazone groups, 95%CI: 0.618-1·237, p = 0·45). INTERPRETATION: Pioglitazone could not reduce the occurrence of cardiovascular events in patients with mild DM and previous MI.

[Development of Deep Venous Thrombosis Shortly after Neurological Surgery].

Little is known about the incidence and characteristics of deep venous thrombosis(DVT)developing shortly after neurological surgery. Lower extremity venous ultrasound scanning was performed before and after surgery, and retrospective data of 157 surgical cases, including endovascular surgery(42.0%), craniotomy(28.7%), burr hole(24.2%), and shunt(3.2%), were evaluated. DVT that had not been pre-operatively observed was discovered in five cases of surgery(five patients, 3.2%)on the day following the surgery, and it was asymptomatic in all cases. One patient was diagnosed with pulmonary thromboembolism as a complication. No difference in characteristic factors was observed between the presence and absence of DVT development. In addition, DVT was detected on preoperative examinations in 10 cases of surgery(10 patients, 6.4%). On the basis of these results, ambulation on the first postoperative day is considered mostly safe. On the other hand, taking into account the increase in the number of patients with DVT and the possibility that a thrombus present in calf veins propagates toward the proximal side, pre-and post-operative screening tests should be performed more often.

Sequence configuration of spinocerebellar ataxia type 8 repeat expansions in a Japanese cohort of 797 ataxia subjects.

Spinocerebellar ataxia type 8 (SCA8), an autosomal dominant neurodegenerative disorder showing slowly progressive cerebellar ataxia, is caused by a tri-nucleotide CTG repeat expansion (CTGexp) in the SCA8 gene. As the CTGexp is not fully penetrant, the significance of screening CTGexp in ataxia subjects remains obscure. We tested SCA8 CTGexp in a cohort of 797 ataxia subjects, and if present, its sequence configuration was analyzed. CTGexp was found in 16 alleles from 14 individuals, 2 of which was homozygous for CTGexp. Nucleotide sequencing disclosed 3 types of CTGexp sequence configurations: uninterrupted CTGexp, tri-nucleotide CTA interruption and CCG interruption. The 2 individuals with homozygous expansions were both sporadic cases with clinical features compatible with SCA8, supporting gene dosage effect. Seven out of 14 CTGexp-positive subjects were also carriers of other SCA expansions [Machado-Joseph disease (n=1), SCA6 (n=3) and SCA31 (n=3)], whereas 7 others were not complicated with such major SCAs. Ages of onset in subjects with pure CTGexp tended to be earlier than those with interrupted CTGexp among the 7 subjects not complicated by major SCAs, suggesting that pure CTGexp have stronger pathogenic effect than interrupted CTGexps. The present study underscores importance of disclosing sequence configuration when testing SCA8.

Does Treatment of Impaired Glucose Tolerance Improve Cardiovascular Outcomes in Patients with Previous Myocardial Infarction?

PURPOSE: We evaluated the effects of an alpha-glucosidase inhibitor, voglibose, on cardiovascular events in patients with a previous myocardial infarction (MI) and impaired glucose tolerance (IGT). METHODS: This prospective, randomized, open, blinded-endpoint study was conducted in 112 hospitals and clinics in Japan in 3000 subjects with both previous MI and IGT receiving voglibose (0.6 mg/day, n = 424) or no drugs (n = 435) for 2 years. The Data and Safety Monitoring Board (DSMB) recommended discontinuation of the study in June 2012 after an interim analysis when the outcomes of 859 subjects were obtained. The primary endpoint was cardiovascular events including cardiovascular death, nonfatal MI, nonfatal unstable angina, nonfatal stroke, and percutaneous coronary intervention/coronary artery bypass graft. Secondary endpoints included individual components of the primary endpoint in addition to all-cause mortality and hospitalization due to heart failure. RESULTS: The age, ratio of males, and HbA1C were 65 vs. 65 years, 86 vs. 87%, and 5.6 vs. 5.5% in the groups with and without voglibose, respectively. Voglibose improved IGT; however, Kaplan-Meier analysis showed no significant between-group difference with respect to cardiovascular events [12.5% with voglibose vs. 10.1% without voglibose for the primary endpoint (95% confidence interval, 0.82-1.86)]; there were no significant differences in secondary endpoints. CONCLUSION: Although voglibose effectively treated IGT, no additional benefits for cardiovascular events in patients with previous MI and IGT were observed. Voglibose may not be a contributing therapy to the secondary prevention in patients with MI and IGT. TRIAL REGISTRATION: Clinicaltrials.gov number: NCT00212017.

Cerebral aneurysm neck diameter is an independent predictor of progressive occlusion after stent-assisted coiling.

BACKGROUND: Some intracranial aneurysms treated by stent-assisted coiling (SAC) with incomplete occlusion undergo progressive occlusion (PO) during follow-up period. We analyzed the predictors for the occurrence of PO. METHODS: Among 74 cerebral aneurysms treated by SAC using the Enterprise or Neuroform stents from 2010 to 2015, we included 43 aneurysms with occlusion grade of neck remnant (NR, n = 36) or residual aneurysm (RA, n = 7) at the post-procedure. We defined PO as improvement in occlusion grade from RA to NR, or from NR or RA to complete occlusion on angiographic follow-up imaging at 6 months after the procedure. We analyzed the independent predictors for PO using a multivariate logistic regression model and receiver operating characteristic (ROC) curve analysis. RESULTS: Forty-three aneurysms were analyzed, with mean volume embolization ratio of 30.3 ± 6.7%. Twenty aneurysms (47%) achieved PO. Univariate analysis found that the median neck diameter of the aneurysms was smaller in aneurysms with PO than others. Multivariate logistic regression analysis also found that the odds ratio of neck diameter of the aneurysm for PO was 0.44 (95% CI, 0.19-0.82, p < 0.01). Moreover, ROC curve analysis for PO found that the optimal cut-off value of the neck diameter was 5.5 mm, with a sensitivity of 95%, specificity of 57% (p < 0.01). CONCLUSIONS: Incompletely occluded aneurysms with a neck diameter of 5.5 mm or less might be more likely to develop PO within 6 months after SAC by using Enterprise or Neuroform stents.

Kaplan-Meier survival analysis and Cox regression analyses regarding right ventricular septal pacing: Data from Japanese pacemaker cohort.

The presented data were obtained from 982 consecutive patients receiving their first pacemaker implantation with right ventricular (RV) lead placement between January 2008 and December 2013 at two centers in Japan. Patients were divided into RV apical and septal pacing groups. Data of Kaplan-Meier survival analysis and Cox regression analysis are presented. Refer to the research article "Implications of right ventricular septal pacing for medium-term prognosis: propensity-matched analysis" (Mizukami et al., in press) [1] for further interpretation and discussion.

Implications of right ventricular septal pacing for medium-term prognosis: Propensity-matched analysis.

BACKGROUND: The effect of right ventricular (RV) septal pacing as opposed to RV apical pacing on prognosis in patients undergoing pacemaker implantation remains controversial. This study was performed to examine the clinical efficacy of RV septal pacing in a large cohort with medium-term follow-up and propensity-matched analysis. METHODS: A total of 982 consecutive patients with first pacemaker implantation between 2008 and 2013 at two centers in Japan (51.4% male, age 76.1±10.6years, 64.3% septal pacing, 94% preserved ejection fraction [EF]) were enrolled. Propensity matching successfully matched 446 patients into RV septal and apical pacing groups. The primary endpoint, a combination of all-cause death and hospitalization due to heart failure, was compared between the two groups. RESULTS: In the propensity-matched cohort, the primary endpoint was observed in 61 patients (13.7%) over a median follow-up period of 2.1years (interquartile range, 1.1-3.5years). The effects of septal pacing on prognosis were not statistically significant (hazard ratio [HR]=1.10, 95% confidence interval [CI]=0.60-2.04, P=0.752). No significant benefit of septal pacing was observed on all-cause death (HR=1.86, 95%CI=0.74-4.66, P=0.187) and heart failure hospitalization (HR=0.93, 95%CI=0.44-1.98, P=0.847) when assessed separately. CONCLUSION: Septal pacing did not show medium-term advantages in prognosis in this large-scale retrospective cohort study with propensity matching of patients with predominantly preserved EF.

A multicenter observational study of the effectiveness of antiarrhythmic agents in ventricular arrhythmias: A propensity-score adjusted analysis.

BACKGROUND: Ventricular tachyarrhythmias (VTs) are life-threatening events that result in hemodynamic compromise. Recurrence is common and may worsen a patient׳s clinical course despite appropriate treatment. This study aimed to examine the effectiveness of antiarrhythmic drugs for suppression of VTs. METHODS: In this cohort study, eligible patients were those who were admitted to one of the nine cardiovascular care centers and treated with continuous infusion of an antiarrhythmic drug for at least 1 h to prevent recurrence of VTs after return of spontaneous circulation. To adjust for differences in baseline characteristics among treatment groups, propensity scores for administered agents were generated and used as covariates in regression analyses. RESULTS: Seventy-two patients were enrolled and 67 patients were included in the final analysis. Amiodarone (n=21, 31.3%), nifekalant (n=24, 35.8%), and lidocaine (n=22, 32.8%) were administered as first-line therapy for suppression of VTs. In the adjusted analyses, the odds ratio (OR) of switching to a different drug was significantly higher in the lidocaine group (OR 37.6, 95% CI 5.1-279, p<0.001) than in the amiodarone group, but not in the nifekalant group (OR 4.1, 95% CI 0.72-23.2, p=0.11). There was no significant difference in mortality rate in the lidocaine group (OR 1.67, 95% CI 0.40-6.95, p=0.48) or the nifekalant group (OR 1.11, 95% CI 0.15-4.85, p=0.89) compared with the amiodarone group. CONCLUSION: Amiodarone and nifekalant are similarly effective in preventing VT recurrence, but their impact on survival rate is minimal. These data indicate that both nifekalant and amiodarone can be used for treatment of refractory VT.

Histological examination of the right atrial appendage after failed catheter ablation for focal atrial tachycardia complicated by cardiogenic shock in a post-partum patient.

A 26-year-old woman in her first pregnancy presented with persistent atrial tachycardia (AT). AT was resistant to medications, cardioversions, and the first attempt of catheter ablation. Two months after delivery she developed severe systolic dysfunction and circulatory collapse. Emergent catheter ablation was performed with the support of percutaneous cardiopulmonary bypass and intraaortic balloon pump. The AT originated in the apex of the right atrial appendage (RAA). Repeated attempts at ablation were unsuccessful, prompting surgical RAA resection, which terminated the tachycardia and improved the cardiac function. Histological examination of resected RAA provided insights into mechanism of resistance to catheter ablation.

Double balloon protection during carotid artery stenting for vulnerable carotid stenosis reduces the incidence of new brain lesions.

BACKGROUND: The use of distal filter protection alone is associated with a high risk of ischemic complications when vulnerable carotid stenosis is treated by carotid artery stenting (CAS). Double balloon protection, a combination of distal balloon protection and proximal balloon occlusion, can be utilized. We assessed the outcome and complications of the double balloon protection method for vulnerable carotid stenosis. METHODS: Among 130 patients who underwent CAS from 2009 to 2014, we enrolled the following patients: those whose target lesion was vulnerable as evaluated by MRI, i.e., a signal ratio of plaque to posterior cervical muscle on T1-weighted images before CAS of ≥1.5, and those who underwent diffusion-weighted imaging (DWI) studies within 48 h after the procedure. Ninety patients were enrolled. We investigated DWI findings of the double balloon protection group compared with those of the simple distal balloon protection and distal filter protection groups. RESULTS: Sixty-four patients (71 %) underwent double balloon protection, 15 patients (17 %) simple distal balloon protection, and 11 patients (12 %) distal filter protection. Symptomatic embolic complications and new lesions on DWI after CAS were significantly less common in patients undergoing double balloon protection compared to distal balloon protection or distal filter protection (0 % vs. 20 %, 9 %, P < 0.01, and 30 % vs. 67 %, 82 %, P < 0.01, respectively). Logistic regression analysis also identified the odds ratio of double balloon protection for new lesions on DWI after CAS of 0.23 (95 % confidence interval: 0.07-0.70, P < 0.01) compared to simple distal protections. CONCLUSIONS: In the patients who underwent CAS for vulnerable carotid stenosis, double balloon protection was an independent significant factor associated with a reduction in the risk of new lesions on DWI after the procedure compared to conventional distal protections.

Recovery from hyponatremia in acute phase is associated with better in-hospital mortality rate in acute heart failure syndrome.

BACKGROUND: Although hyponatremia on admission is a predictor of poor prognosis in acute heart failure (AHF) patients, little is known about the association between changes in sodium level in acute phase and in-hospital mortality. This study was performed to clarify the impact of sodium level improvement in the early phase on prognosis in AHF patients. METHODS: A total of 882 consecutive hospitalized AHF patients were retrospectively enrolled in this study. Sodium levels were evaluated on days 1 and 3 of admission, and patients were classified into three groups: patients with hyponatremia on admission and day 3 (hypo-hypo group); patients with hyponatremia on admission and normonatremia on day 3 (hypo-normo group); and patients with normonatremia on admission (normo group). RESULTS: Hyponatremia (sodium ≤135 mEq/L) was observed in 14.3% of cases. In multivariate linear regression analysis, age (standardized beta=0.084), male gender (standardized beta=-0.072), history of ischemic heart disease (standardized beta=-0.069), baseline sodium level (standardized beta=-0.435), and tolvaptan use (standardized beta=0.093) were independent determinants of changes in sodium level from day 1 to day 3. In-hospital mortality rates were significantly higher in the hypo-hypo group (23.7%) and hypo-normo group (9.7%) than the normo group (6.9%) (p<0.001). After adjustment for covariates, both hypo-normo (OR: 0.28, 95% CI: 0.08-0.93, p=0.038) and normo (OR: 0.42, 95% CI: 0.20-0.88, p=0.022) groups showed significantly lower in-hospital mortality rates than the hypo-hypo group. CONCLUSION: Early recovery from hyponatremia in AHF patients is associated with lower in-hospital mortality rate.

Moderate vasomotor response to acetylcholine provocation test as an indicator of long-term prognosis.

The acetylcholine (ACh) provocation test (ACh-test) is used for the diagnosis of vasospastic angina (VSA). However, subjects often show a moderate spasm (MS) response for which diagnosis of VSA is not definitive, and the clinical significance of this response is unknown. We assessed moderate coronary vasomotor response to the ACh test as an indicator of long-term prognosis. A total of 298 consecutive patients who underwent the ACh test for suspected VSA were retrospectively investigated. Coronary spasm severity after intracoronary administration of isosorbide dinitrate was evaluated by measuring epicardial coronary artery diameter reduction after ACh injection. Patients were divided into three groups according to the diameter reduction during the ACh test: severe spasm (SS) showing ≥75 % diameter reduction, MS showing ≥50 % diameter reduction, and others (N). In Kaplan-Meier analysis, the major adverse cardiac event (MACE) rates with a median follow-up of 4.6 years were significantly worse in SS (11.1 %) and MS (8.5 %) than N (1.9 %), (SS vs N; P = 0.009, MS vs N; P = 0.029). Significant difference in MACE rates was not observed between SS and MS (P = 0.534). Cox regression analysis revealed that MS remained an independent predictor of MACE after adjustment for other confounders (HR: 7.18, 95 % CI 1.42-36.4, P = 0.017). Patients with MS by ACh test had a cardiac event rate comparable with that of patients with SS and significantly worse than that of patients with normal vasomotor responses.

Renal function on admission modifies prognostic impact of diuretics in acute heart failure: a propensity score matched and interaction analysis.

Although intravenous diuretics have been mainstay drugs in patients with acute heart failure (AHF), they have been suggested to have some deleterious effects on prognosis. We postulated that renal function may modify their deleterious effects in AHF patients. The study population consisted of 1094 AHF patients from three hospitals. Renal dysfunction (RD) was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 on admission, and the cohort was divided into a high-dose furosemide (≥100 mg/48 h) and low-dose furosemide group according to the amount of intravenous furosemide used within 48 h from admission. In the whole cohort, in-hospital mortality rate was higher in the high-dose furosemide group than the low-dose furosemide group (12.5 vs. 6.6 %, respectively, P = 0.001). However, this difference in the in-hospital mortality rates was significant only in the RD subgroup (15.6 vs. 7.0 %, respectively, P < 0.001), and not in the non-RD subgroup (2.5 vs. 5.9 %, respectively, P = 0.384). Propensity score-matched analysis was performed to evaluate the impact of high-dose furosemide on prognosis. After propensity score matching, high-dose furosemide was not associated with in-hospital mortality (OR 1.25, 95 % CI 0.73-2.16, P = 0.408). However, there was a qualitative difference in OR for in-hospital mortality between AHF with RD (OR 1.77, 95 % CI 0.96-3.28, P = 0.068) and without RD (OR 0.23, 95 % CI 0.05-1.10, P = 0.064), and there was a significant interaction between eGFR and prognostic impact of high-dose furosemide (P for OR interaction = 0.013). An inverse relationship was observed between eGFR and OR for in-hospital death in the group treated with high-dose furosemide (decreasing OR with better eGFR). The deleterious effect of diuretics was significantly modified with renal function in AHF. This association may be one reason for poorer prognosis of AHF patients complicated with renal impairment.

A laboratory data-based evaluation of the efficacy and safety of generic pravastatin sodium for long-term use.

BACKGROUND: Increasing the use of generic drugs may reduce the growing healthcare spending. Nevertheless, in Japan, the generic drug market share remains low compared to that of European countries and the United States, mainly because of the general distrust of generic drugs. To address this problem, we retrospectively evaluated the efficacy and safety of the long-term use of generic pravastatin sodium in a study from January 2008 to December 2011. METHODS: Patients receiving generic pravastatin sodium for ≥15 months were defined as long-term users and were included in the study, totaling 595 out of 1337 patients. Efficacy assessment was based on the total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) plasma levels. Safety assessment was based on the aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine phosphokinase (CPK), gamma-glutamyl transferase (γ-GTP), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total-bilirubin (T-Bil), blood urea nitrogen (BUN), serum creatinine (Scr), and hemoglobin A1c (HbA1c) plasma levels. The patients' reasons for discontinuing generic pravastatin sodium were obtained from the electronic medical records. RESULTS & DISCUSSION: No significant difference in the laboratory data was observed between short-term and long-term users, except for significantly lower ALT levels in the long-term users than in the short-term users. No liver dysfunction was observed. Although 37 patients discontinued the study possibly owing to drug-related adverse events, we considered these events unrelated to generic pravastatin sodium. CONCLUSIONS: This study shows that the long-term use of generic pravastatin sodium is effective and safe, and may help dispel the concerns about generic drugs.