Real-world use of intravascular ultrasound in Japan: a report from contemporary multicenter PCI registry.

Clinical trial data suggest that intravascular ultrasound (IVUS) may improve clinical outcomes after PCI. The aim of this study was to investigate the safety of IVUS in its broader use for percutaneous coronary intervention (PCI). A total of 11,570 consecutive patients undergoing PCI between 2008 and 2014 in Japan were analyzed. Associations between IVUS use, PCI-related complications were assessed with logistic regression and propensity score matching analyses. Subgroup analysis was performed in elective PCI patients. IVUS was used in 84.8% of patients (N = 9814; IVUS group); its use was almost universal in elective PCIs (90.8 vs. 81.7% in urgent/emergent PCIs, P < 0.001). The non-IVUS group were older (68.7 ± 11.4 vs. 67.9 ± 10.8 years, P = 0.004), with more comorbid conditions. The non-IVUS group had smaller stent lumens (2.97 ± 0.42 mm vs. 3.09 ± 0.45 mm, P < 0.001) and a higher proportion of plain old balloon angioplasty. After matching, a lower rate of flow-impairing coronary dissections was observed in the IVUS group, although this was limited only to elective PCIs, not among urgent/emergent PCIs (non-IVUS vs. IVUS; 2.7% vs. 1.0%, P = 0.018, 0.7% vs. 1.2%, P = 0.32, respectively). With a multivariate logistic regression analysis, IVUS use remained an independent predictor to reduce risk of flow impairing severe coronary dissection among elective PCIs (odds ratio 0.38, 95% confidence interval 0.22-0.66: P = 0.001). In this Japanese PCI registry, IVUS was used extensively during the study period, particularly in elective cases. Using IVUS was associated with a lower event rate of flow-impairing coronary dissections that was limited to elective PCIs, not among urgent/emergent PCIs, without increasing PCI-related complications.

Outcomes of Percutaneous Coronary Intervention Performed With or Without Preprocedural Dual Antiplatelet Therapy.

BACKGROUND: Preprocedural dual antiplatelet therapy (DAPT) in percutaneous coronary interventions (PCI) has been shown to improve outcomes; however, the efficacy of the procedure and its complications in Japanese patients remain largely unexplored, so we examined the risks and benefits of DAPT before PCI and its association with in-hospital outcomes. METHODS AND RESULTS: We analyzed data from patients who had undergone PCI at 12 centers within the metropolitan Tokyo area between September 2008 and September 2013.Our study group comprised 6,528 patients, of whom 2,079 (31.8%) were not administered preprocedural DAPT. Non-use of preprocedural DAPT was associated with death, postprocedural shock, or heart failure (odds ratio [OR]: 1.47, 95% confidence interval [CI]: 1.10-1.96, P=0.009), and postprocedural myocardial infarction (OR: 1.41, 95% CI: 1.18-1.69, P<0.001) after adjusting propensity scores for known predictors of in-hospital complications. Non-use of DAPT was not associated with procedure-related bleeding complications (OR: 0.98, 95% CI: 0.71-1.59, P=0.764). CONCLUSIONS: Approximately one-third of the patients who underwent PCI did not receive preprocedural DAPT despite guideline recommendations. Our results indicate that patients undergoing PCI with DAPT have a lower risk of postprocedural cardiac events without any increased bleeding risk. Further studies are needed to implement the use of DAPT in real-world PCI.

Predictors and incidence of health status deterioration in patients with early atrial fibrillation.

BACKGROUND: Various treatment approaches for atrial fibrillation (AF) have demonstrated improved health status, yet the significance of these therapeutic interventions in individual patients remains unclear. OBJECTIVE: This study aimed to evaluate health status changes in patients with early AF, focusing on those who experience clinically significant deterioration after treatment initiation. METHODS: We analyzed data from a multicenter, prospective registry of newly diagnosed patients with AF. One-year changes in health status across different treatment strategies were assessed by the Atrial Fibrillation Effect on QualiTy-of-life Overall Summary (AFEQT-OS) score. Clinically relevant deterioration and improvement in health status were defined as ≥5-point decrease and increase in AFEQT-OS score, respectively; no change was -5 to 5 points. RESULTS: Overall, 1960 patients with AF were evaluated. Mean AFEQT-OS scores at baseline and 1-year follow-up were 76.7 ± 17.7 and 85.4 ± 14.8, respectively. Although most patients (53.9%) experienced clinically important improvement, a considerable proportion had no change (28.7%) or deterioration (17.4%) in their health status. Proportions of patients with no change or deterioration varied by treatment strategy: 59.9%, 53.9%, and 32.0% in rate control, antiarrhythmic drug, and catheter ablation groups, respectively. The multivariable model identified older age, female sex, heart failure, coronary artery disease, and higher baseline AFEQT-OS score as independent predictors of worsening health status, regardless of treatment strategy. CONCLUSION: Many patients with early AF experience worsening or no change in health status irrespective of treatment strategy. Standardizing patients' health status assessment, especially for patients with comorbidities, may aid in patients' selection and their outcomes.

Conventional medical therapy in heart failure patients eligible for the PARADIGM-HF, DAPA-HF, and SHIFT trials.

BACKGROUND: Recent trials on novel heart failure (HF) treatments (angiotensin receptor-neprilysin inhibitor, sodium-glucose cotransporter 2 inhibitor, and ivabradine) emphasize the use of conventional medical therapy (angiotensin-converting enzyme inhibitors, beta-blockers [BB], and mineral corticosteroid receptor antagonists). We aimed to evaluate the prescription rate of conventional medical therapy and its association with long-term outcomes in patients eligible for recent trials. METHODS: We examined 1295 consecutive patients with HF with reduced ejection fraction (HFrEF) from a multicenter registry (WET-HF registry). We assessed conventional medical therapy implementation among patients meeting the PARADIGM-HF/DAPA-HF and SHIFT enrollment criteria. We also examined the association between conventional medical therapy use and long-term outcomes within each enrollment criterion. RESULTS: Overall, 62.2% and 35.3% of HFrEF patients met the enrollment criteria of the PARADIGM-HF/DAPA-HF and SHIFT trials. Only 33.9% and 31.9% received full conventional medical therapy within each patient subset. Notably, 84.2% of patients who met the SHIFT enrollment criteria were on BB, and only 23.0% and 4.4% were on ≥50% or the full recommended dose, respectively. Implementation of full conventional medical therapy use was associated with lower 2-year mortality and HF readmission rates in the PARADIGM-HF/ DAPA-HF eligible group (HR 0.68, 95% CI 0.50-0.92). The use of BB at ≥50% of the recommended dose was associated with lower 2-year mortality and HF readmission rates in the SHIFT-eligible group (HR 0.50, 95% CI 0.30-0.84). CONCLUSIONS: Conventional medical therapy was underutilized among patients eligible for novel trials within a Japanese HF registry. Further efforts to optimize conventional medical therapy are needed.

Specific immunoadsorption therapy using a tryptophan column in patients with refractory heart failure due to dilated cardiomyopathy.

BACKGROUND: Certain cardiac-specific autoantibodies found in patients with dilated cardiomyopathy (DCM) play a role in mediating myocardial damage and fatal ventricular arrhythmias resulting in sudden cardiac death. Immunoadsorption therapy (IA) is one of the therapeutic tools to remove such autoantibodies. Clinical studies from Germany have shown that nonspecific IA using columns loaded by sheep antihuman IgG or protein A improved hemodynamic data and affected favorably cardiac function and survival in patients with heart failure (HF) due to DCM. The goal of this study is to determine if IA therapy using the high-profile tryptophan column, which has high affinity for IgG3 subclass, affects favorably cardiac function in patients with severe HF who are refractory to conventional therapy. METHODS AND RESULTS: IA therapy was conducted in 16 patients with DCM (age 53 ± 4, male 8, New York Heart Association functional class III/IV, mean ejection fraction 18 ± 2%). Study subjects had autoantibodies directed against either ß1-adrenergic or M2-muscarinic receptors. Plasma brain natriuretic peptide levels were significantly decreased after IA (P = 0.016). Plasma inflammatory cytokines including interleukin-6 and tumor necrosis factor-α did not change after each session of IA. Six-minute walk distance was significantly increased after IA (P = 0.01). Left ventricular ejection fraction increased by 3% 3 months after IA (P = 0.039). CONCLUSIONS: Our initial experience demonstrated safety and short-term efficacy of IA using a new IgG3-specific tryptophan column for patients with advanced HF due to DCM. Long-term follow-up is needed to confirm the effects on cardiac function and morbidity/mortality in such patients.

Burden of Mild (<13 g/dl) Anemia in Patients With Atrial Fibrillation (A Report from a Multicenter Registry With Patient-Reported Outcomes).

The prognostic impact of anemia, especially mild anemia, in atrial fibrillation (AF) remains unclear. We examined clinical burdens of mild anemia on the quality of life (QoL) and clinical outcomes of 1,677 AF patients. Patients were divided into a non-anemia (hemoglobin [Hb] ≥13 g/dl for men and Hb ≥12 g/dl for women) and a mild anemia group (10≤ Hb <13 g/dl for men and 10≤ Hb <12 g/dl for women). At baseline, 22.5% of patients (n = 378) had anemia; patients in the mild anemia group had higher CHA2DS2-VASc scores (3.7 vs 2.7; p <0.01) and brain natriuretic peptide levels (253.5 vs 159.6 pg/ml; p <0.01) and were more likely to develop chronic kidney disease (64.2 vs 42.9%; p <0.01) than those in the non-anemia group. During follow-up (mean 1.7 ± 0.4 years), patients with mild anemia had a higher risk of heart failure hospitalization and major bleeding events than those without (12.2 vs 3.8%; p <0.01 and 5.6 vs 2.5%; p <0.01, respectively). Mild anemia was an independent risk factor for heart failure hospitalization (adjusted hazard ratio: 1.67, 95% confidence interval 1.06 to 2.62, p = 0.03) but not for major bleeding (adjusted hazard ratio: 1.44, 95% confidence interval 0.80 to 2.62, p = 0.23). QoL improvement was less likely in the mild anemia group during follow-up, despite the lack of significant differences at baseline. In conclusion, the presence of even mild anemia was associated with increased risks of heart failure hospitalization and poor QoL improvement.

Cohort profile: patient characteristics and quality-of-life measurements for newly-referred patients with atrial fibrillation-Keio interhospital Cardiovascular Studies-atrial fibrillation (KiCS-AF).

PURPOSE: Besides the high rates of morbidity and mortality, atrial fibrillation (AF) is also associated with impairment of quality-of-life (QOL). However, reports covering non-selected AF population within Asian countries remain scarce. The objective of the Keio interhospital Cardiovascular Studies-atrial fibrillation (KiCS-AF) registry is to clarify the baseline and QOL profiles of the AF patients at the time of initial referral to identify areas for improvement and country-specific gaps. PARTICIPANTS: The KiCS-AF registry is a multicentre, prospective cohort study designed to specifically recruit AF patients newly referred to the 11 network hospitals within the Kanto area of Japan. The registry completed its enrolment in June 2018. All patients were requested to answer the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire both at baseline and 1 year, with planned clinical follow-up for 5 years. The registry also assessed individual treatment strategies including rate and rhythm control, stroke prophylaxis, and their impacts on patient-reported QOL. FINDINGS TO DATE: As of December 2016, 2464 AF patients were registered; their mean age was 67.1 years (SD, 11.7), majority (69.7%; n=1717) were men and 49.2% presented with paroxysmal AF. The mean CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age ≥75 years, diabetes, stroke including vascular disease, age 65-74 years, and sex category [female]) score was 2.3 (SD, 1.6) and oral anticoagulant therapy was used for 88.6% of patients with CHA2DS2-VASc scores ≥2. The median AFEQT-overall summary score was 79.1 (IQR, 66.6-89.1). Roughly 50% had significantly impaired QOL (ie, AFEQT <80) at baseline. Currently, 2307 eligible patients (93.6%) have completed the 1-year follow-up, of which 2072 patients (89.8%) answered the second AFEQT questionnaire. FUTURE PLANS: The KiCS-AF allowed for extensive investigation of AF-related QOL in a non-selected population with long-term follow-up using a rigorously validated QOL assessment tool. Almost half of patients had impaired QOL at baseline. Further investigations aimed at providing care and improving patient-reported QOL are required.

Evaluation of the ameliorative effects of immunosuppressants on crescentic glomerulonephritis in SCG/Kj mice.

The therapeutic efficacy of immunosuppressants for treating rapidly progressive glomerulonephritis (RPGN) with crescent formation remains controversial. SCG/Kj mice spontaneously develop RPGN-like symptoms, characteristic of crescentic glomerulonephritis and systemic small vessel vasculitis, associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). We evaluated the "ameliorative", not prophylactic, effects of immunosuppressive agents, deoxyspergualin (DSG), cyclophosphamide (CYC) and prednisolone (PDN), on RPGN in these mice. DSG at intraperitoneal doses of 3 and 6 mg/kg, CYC at an oral dose of 12 mg/kg, or PDN at an intraperitoneal dose of 120 mg/kg was administered once a day for 21 days to female mice "at the onset of hematuria". A set of control SCG/Kj mice received only saline injections. DSG and CYC significantly prolonged survival, improved the proteinuria, hematuria and hyperuremia, and decreased the serum level of myeloperoxidase-ANCA. Moreover, DSG significantly suppressed the formation of crescents in glomeruli. PDN failed to affect any of the parameters. DSG might be useful for inducing remission in crescentic glomerulonephritis involved in RPGN.

Differences of in-hospital outcomes within patients undergoing percutaneous coronary intervention at institutions with high versus low procedural volume: a report from the Japanese multicentre percutaneous coronary intervention registry.

Objective: We aimed to determine the relationship between the prevalence of in-hospital complications and annual institutional patient volume in a population of patients undergoing percutaneous coronary intervention (PCI). Methods: Clinical data of patients receiving PCI between January 2010 and June 2015 were collected from 14 academic institutions in the Tokyo area and subsequently used for analysis. We employed multivariate hierarchical logistic regression models to determine the effect of institutional volume on several in-hospital outcomes, including in-hospital mortality and procedure-related complications. Results: A total of 14 437 PCI cases were included and categorised as receiving intervention from either lower-volume (<200 procedures/year, n=6 hospitals) or higher-volume (≥200 procedures/year, n=8 hospitals) institutions. Clinical characteristics differed significantly between the two patient groups. Specifically, patients treated in higher-volume hospitals presented with increased comorbidities and complex coronary lesions. Unadjusted mortality and complication rate in lower-volume and higher-volume hospitals were 1.3% and 1.2% (p=0.0614) and 6.2% and 8.1% (p=0.001), respectively. However, multivariate hierarchical logistic regression models adjusting for differences in the patient characteristics demonstrated that institutional volume was not associated with adverse clinical outcomes. Conclusions: In conclusion, we observed no significant association between annual institutional volume and in-hospital outcomes within the contemporary PCI multicentre registry. Trial registration number: UMIN R000005598.

An in vivo mechanism for the reduced peripheral neurotoxicity of NK105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation.

In our previous rodent studies, the paclitaxel (PTX)-incorporating polymeric micellar nanoparticle formulation NK105 had showed significantly stronger antitumor effects and reduced peripheral neurotoxicity than PTX dissolved in Cremophor® EL and ethanol (PTX/CRE). Thus, to elucidate the mechanisms underlying reduced peripheral neurotoxicity due to NK105, we performed pharmacokinetic analyses of NK105 and PTX/CRE in rats. Among neural tissues, the highest PTX concentrations were found in the dorsal root ganglion (DRG). Moreover, exposure of DRG to PTX (Cmax_PTX and AUC0-inf._PTX) in the NK105 group was almost half that in the PTX/CRE group, whereas exposure of sciatic and sural nerves was greater in the NK105 group than in the PTX/CRE group. In histopathological analyses, damage to DRG and both peripheral nerves was less in the NK105 group than in the PTX/CRE group. The consistency of these pharmacokinetic and histopathological data suggests that high levels of PTX in the DRG play an important role in the induction of peripheral neurotoxicity, and reduced distribution of PTX to the DRG of NK105-treated rats limits the ensuing peripheral neurotoxicity. In further analyses of PTX distribution to the DRG, Evans blue (Eb) was injected with BODIPY®-labeled NK105 into rats, and Eb fluorescence was observed only in the DRG. Following injection, most Eb dye bound to albumin particles of ~8 nm and had penetrated the DRG. In contrast, BODIPY®-NK105 particles of ~90 nm were not found in the DRG, suggesting differential penetration based on particle size. Because PTX also circulates as PTX-albumin particles of ~8 nm following injection of PTX/CRE, reduced peripheral neurotoxicity of NK105 may reflect exclusion from the DRG due to particle size, leading to reduced PTX levels in rat DRG (275).

Antigen-specific effects of autoantibodies against sarcolemmal Na-K-ATPase pump in immunized cardiomyopathic rabbits.

OBJECTIVES: We examine antigen-specific actions of autoantibodies directed against sarcolemmal Na-K-ATPase. BACKGROUND: Autoantibodies against some receptors or pumps were detected in patients with dilated cardiomyopathy. Although immunoglobulin adsorption therapy improved cardiac function in such patients, direct pathogenic effects of autoantibodies remain to be proven. METHODS: Japanese white rabbits were immunized once a month with purified Na-K-ATPase (NKA rabbits, n=10) or a synthetic peptide corresponding to the second extracellular loop of beta1-adrenergic receptors (beta rabbits, n=10), respectively. Control rabbits (n=10) received vehicle in the same manner. RESULTS: At 6 months, cardiac hypertrophy along with increased left ventricular end-diastolic pressure was observed in both NKA and beta rabbits, and inhibitory G protein level increased in both NKA and beta rabbits. Histological findings showed similar myocyte hypertrophy and interstitial fibrosis in both rabbits. Enzymatic activities of Na-K-ATPase were lower in NKA rabbits than in other groups. Immunoblotting showed that alpha3-isoform of Na-K-ATPase was selectively reduced in myocardium from NKA rabbits. CONCLUSIONS: Our present findings suggested that isoform-specific alterations of myocardial Na-K-ATPase activity were induced by immunizing rabbits. This was not secondary change due to cardiac hypertrophy. Thus, autoantibodies against sarcolemmal Na-K-ATPase have antigen-specific effect on the heart in vivo.

Gender differences in in-hospital clinical outcomes after percutaneous coronary interventions: an insight from a Japanese multicenter registry.

BACKGROUND: Gender differences in clinical outcomes after percutaneous coronary intervention (PCI) among different age groups are controversial in the era of drug-eluting stents, especially among the Asian population who are at higher risk for bleeding complications. METHODS AND RESULTS: We analyzed data from 10,220 patients who underwent PCI procedures performed at 14 Japanese hospitals from September 2008 to April 2013. A total of 2,106 (20.6%) patients were women. Women were older (72.7±9.7 vs 66.6±10.8 years, p<0.001), and had a lower body mass index (23.4±4.0 vs 24.3±3.5, p<0.001), with a higher prevalence of hypertension (p<0.001), hyperlipidemia (p<0.001), insulin-dependent diabetes (p<0.001), renal failure (p<0.001), and heart failure (p<0.001) compared with men. Men tended to have more bifurcation lesions (p = 0.003) and chronic totally occluded lesions (p<0.001) than women. Crude overall complications (14.8% vs 9.5%, p<0.001) and the rate of bleeding complications (5.3% vs 2.8%, p<0.001) were significantly higher in women than in men. On multivariate analysis in the total cohort, female sex was an independent predictor of overall complications (OR, 1.47; 95% CI, 1.26-1.71; p<0.001) and bleeding complications (OR, 1.74; 95% CI, 1.36-2.24; p<0.001) after adjustment for confounding variables. A similar trend was observed across the middle-aged group (≥55 and <75 years) and old age group (≥75 years). CONCLUSIONS: Women are at higher risk than men for post-procedural complications after PCI, regardless of age.

Location of the culprit coronary lesion and its association with delay in door-to-balloon time (from a multicenter registry of primary percutaneous coronary intervention).

Current guidelines recommend shorter door-to-balloon times (DBTs) (<90 minutes) for patients with ST-elevation myocardial infarction (STEMI). Clinical factors, including patient or hospital characteristics, associated with prolonged DBT have been identified, but angiographic variables such as culprit lesion location have not been thoroughly investigated. We aimed to evaluate the effect of culprit artery location on DBT of patients with STEMI who underwent percutaneous coronary intervention (PCI). Data were analyzed from 1,725 patients with STEMI who underwent PCI from August 2008 to March 2014 at 16 Japanese hospitals. Patients were divided into 3 groups according to culprit artery location, right coronary artery (RCA), left anterior descending artery (LAD), and left circumflex artery (LC), and associations with DBT were assessed. The LC group had a trend toward a longer DBT among the 3 groups (97.1 [RCA] vs 98.1 [LAD] vs 105.1 [LC] minutes; p = 0.058). In-hospital mortality was also significantly higher in patients with a left coronary artery lesion (3.5% [RCA] vs 6.3% [LAD] vs 5.4% [LC]; p = 0.041). In-hospital mortality for patients with DBT >90 minutes was significantly higher compared with patients with DBT ≤90 minutes (6.5% vs 3.6%; p = 0.006). Multivariate logistic regression analysis revealed that the LC location was an independent predictor for DBT >90 minutes (odds ratio, 1.45; 95% confidence interval, 1.04 to 2.01; p = 0.028). In conclusion, LC location was an independent predictor of longer DBT. The difficulties in diagnosing LC-related STEMI need further evaluation.

Cardiopulmonary arrest induced by anaphylactoid reaction with contrast media.

Anaphylactoid reactions to iodinated contrast media can cause life-threatening events and even death. A 44-year-old woman presented with cardiopulmonary arrest (CPA) immediately following the administration of nonionic iodinated contrast media for an intravenous pyelography. Her cardiac rhythm during CPA was asystole. She was successfully resuscitated by the radiologists supported by paged emergency physicians using the prompt intravenous administration of 1 mg of epinephrine. Neither laryngeal edema nor bronchial spasm was observed during the course of treatment, and she was discharged on the 4th day without any complications. The patient did not have a history of allergy, but had experienced a myocardial infarction and aortitis. She had undergone 11 angiographies and had been taking a beta-adrenergic receptor antagonist. Planned emergency medical backup is advisable to ensure resuscitation in the event of an anaphylactoid reaction to the use of contrast media in-hospital settings.

Long-term survival of Japanese patients transported to an emergency department because of syncope.

STUDY OBJECTIVE: Cardiovascular disease mortality is affected by ethnic differences and is lower in Japan than in Western countries. Although patients with cardiac syncope have significantly higher mortality than patients with noncardiac syncope in Western countries, no such phenomenon has been described in Japan. The aim of this study is to clarify the long-term mortality of patients with syncope who are brought to an emergency department (ED) in Japan. METHODS: This retrospective observational study was conducted on patients treated in the ED of Keio University Hospital in Tokyo. Nine hundred twelve consecutive patients who presented with syncope were identified. The patients were classified into 2 groups according to the cause of syncope: cardiac syncope and noncardiac syncope. Follow-up information about mortality was obtained from mailed questionnaires and medical records. Mortality data were analyzed using the actuarial life-table method and a Cox proportional hazards model. RESULTS: Follow-up information was obtained for 715 patients. The median follow-up period was 38 months, during which 63 patients died. At 5 years, the 23.1% (95% confidence interval [CI] 12.7% to 33.4%) mortality of the patients with cardiac syncope was significantly higher than the 8.2% (95% CI 5.5% to 10.9%) mortality of the patients with noncardiac syncope (P<.0001). The incidence of cardiac death among the patients with cardiac syncope was 17.2% (95% CI 7.8% to 26.5%) compared with 0.9% (95% CI 0% to 1.8%) in the noncardiac syncope group (P<.0001). Cardiac syncope was an independent predictor of overall mortality and cardiac mortality (relative risk 2.81 [95% CI 1.53 to 5.16], 18.74 [95% CI 5.90 to 59.52]). CONCLUSION: Cardiac syncope is associated with higher mortality than noncardiac syncope in this Japanese patient population.

Neurally mediated syncope presenting with paroxysmal positional vertigo and tinnitus.

A 72-year-old man with positional vertigo and tinnitus was referred to us. He did not want to perform provoking test except once due to his fear. No positional nystagmus was provoked. He found that his attacks usually occurred when he lay on his right ear. From his clinical history, benign paroxysmal positional vertigo was suspected. Conventional pharmacotherapy as well as non-specific physical therapy did not have significant effect. His feeling of positional vertigo with pyrosis was actually presyncope. We suspected cardiovascular disorders, and referred him to a cardiologist. Portable cardiogram monitoring revealed paroxysmal bradycardia. He was diagnosed with neurally mediated syncope, and a pacemaker was implanted. His paroxysmal dizziness soon disappeared. It is important to study the clinical history of the patients in detail, as they are not always able to accurately explain their symptoms. We should carefully rule out cardiovascular disorders, especially when we see the patients with suspected BPPV without the characteristic positional nystagmus.

Comparative study of peripheral neurotoxicity after injection of two different paclitaxel formulations in rats.

Paclitaxel Inj. [NK] (test; paclitaxel, CAS 33069-62-4) is a generic version of the drug from the originator (reference). Both drugs contain the same active ingredient and showed identical pharmacokinetics in patients in the previous study; however, these two drugs may have different safety profiles because they contain different inactive ingredients. Thus, in this study, peripheral neurotoxicity, one of the dose-limiting toxicities of the reference, was compared between the test and the reference in rats electrophysiologically and histopathologically. In a nerve conduction study, the amplitude of the caudal sensory nerve action potential decreased significantly after either the test or the reference administration, compared with the amplitude after saline administration, but no significant differences were observed between the two drugs. Histopathologically, apparent degeneration of the myelinated fibers in the sciatic and the sural nerves was seen after either the test or the reference injection, compared with after saline injection, but no apparent differences were observed between the two formulations. These results suggest that no significant difference in peripheral neurotoxicity exists between the test and the reference in rats.

Comparison of the effects of carvedilol and metoprolol on exercise ventilatory efficiency in patients with congestive heart failure.

BACKGROUND: The slope of the relationship between ventilation and carbon dioxide production (VE/VCO2 slope), obtained during symptom-limited ramp exercise testing, reflects exercise ventilatory efficiency. Importantly, the VE/VCO2 slope is related to prognosis in patients with congestive heart failure (CHF). The aim of the present study was to determine the relationship between the institution of beta-blockers, carvedilol or metoprolol, and the VE/VCO2 slope during exercise in patients with CHF. METHODS AND RESULTS: Fifty-seven patients with New York Heart Association functional class II or III with a radionuclide left ventricular ejection fraction (LVEF) of less than 40% received carvedilol or metoprolol in a randomized fashion. The VE/VCO2 slope, LVEF and plasma brain natriuretic peptide (BNP) concentration were determined before and after 16 weeks of treatment. LVEF improved (p<0.01), but the VE/VCO2 slope and BNP did not. A significant improvement in the VE/VCO2 slope was observed in patients with LVEF <29% or BNP >63 pg/ml (respective baseline median values) (p<0.05, p<0.05). In patients with BNP >63 pg/ml, the improvement effect on the VE/VCO2 slope with carvedilol was significantly greater than that with metoprolol (p<0.05) and a significant improvement in the VE/VCO2 slope was observed only in those who took carvedilol (p<0.01). CONCLUSIONS: The VE/VCO2 slope was not improved after beta-blocker therapy in any of the patients. However, it did improve in patients with a lower LVEF or higher BNP level at baseline, and carvedilol was more effective than metoprolol in improving the VE/VCO2 slope in patients with higher BNP levels at baseline.

Carvedilol exerts more potent antiadrenergic effect than metoprolol in heart failure.

BACKGROUND: It is still uncertain whether or not there is a difference between metoprolol and carvedilol for the treatment of congestive heart failure. We attempted to determine the difference between the two beta-blockers in terms of their antiadrenergic effect during exercise in patients with heart failure and their efficacy based on the baseline plasma brain natriuretic peptide concentration. METHODS: Fifty-three patients with mild to moderate heart failure with a radionuclide left ventricular ejection fraction <40% received open label metoprolol or carvedilol in a randomized fashion. The increase in the heart rate normalized to the increase in the plasma norepinephrine concentration during exercise, was calculated as an index of adrenergic responsiveness during exercise. RESULTS: The increase in heart rate normalized by the increase in plasma norepinephrine concentration, decreased after the initiation of beta-blockers in the carvedilol group, but not in the metoprolol group. The change in cardiac function was more favorable for carvedilol than metoprolol in patients who exhibited a higher baseline brain natriuretic peptide concentration. CONCLUSIONS: Carvedilol exerts a more potent antiadrenergic effect than metoprolol during stress in patients with mild to moderate heart failure. Carvedilol appears to be more efficacious than metoprolol in patients who exhibit higher baseline brain natriuretic peptide concentrations. These differences should be kept in mind when selecting appropriate pharmacologic agents in the treatment of heart failure.