Shigeru Matsui

Cystatin C in Acute Heart Failure Without Advanced Renal Impairment

BACKGROUNDnThe prognostic value of cystatin C relative to glomerular filtration rate (GFR) estimated by the Modification of Diet in Renal Disease Study (MDRD) equation modified for Japan has not been investigated in acute heart failure patients with normal to moderately impaired renal function. More accurate detection of mild renal impairment might improve the risk stratification of heart failure patients, especially patients with normal to moderately impaired renal function.nnnMETHODSnCystatin C and creatinine levels were measured on admission in 328 consecutive patients hospitalized for worsening chronic heart failure with a GFR estimated by MDRD equation modified for Japan >or=30 mL/min/1.73 m(2).nnnRESULTSnDuring a median follow-up period of 915 days, there were 52 (16%) cardiac deaths. In stepwise Cox regression analyses including cystatin C and GFR estimated by MDRD equation modified for Japan (either as continuous variables or as variables categorized into quartiles), cystatin C (P <.0001), but not GFR estimated by MDRD equation modified for Japan, was independently associated with cardiac mortality. Adjusted relative risk according to the quartiles of these markers and Kaplan-Meier analyses revealed that the cystatin C was a better marker to separate low-risk from high-risk patients. Furthermore, receiver-operating characteristic curve analyses of these markers revealed that cystatin C showed a higher precision in predicting cardiac mortality.nnnCONCLUSIONnMeasurements of cystatin C might improve early risk stratification compared with GFR estimated by MDRD equation modified for Japan in acute heart failure patients with normal to moderately impaired renal function.

The effect of ezetimibe on lipid and glucose metabolism after a fat and glucose load

OBJECTIVESnThe clinical benefit of ezetimibe, an intestinal cholesterol transporter inhibitor, for treatment of postprandial hyperlipidemia was assessed in subjects who ingested a high-fat and high-glucose test meal to mimic westernized diet.nnnMETHODSnWe enrolled 20 male volunteers who had at least one of the following: waist circumference ≥ 85 cm, body mass index ≥ 25 kg/m(2), or triglycerides (TG) from 150 to 400mg/dL. After 4 weeks of treatment with ezetimibe (10mg/day), the subjects ingested a high-fat and high-glucose meal. Then changes in serum lipid and glucose levels were monitored after 0, 2, 4, and 6h, and the area under the curve (AUC) was calculated for the change in each parameter.nnnRESULTS AND CONCLUSIONnAt 4 and 6h postprandially, TG levels were decreased (p<0.01) after 4 weeks of ezetimibe treatment, and the AUC for TG was also decreased (p<0.01). Apolipoprotein B48 (apo-B48) levels at 4 and 6h postprandially were significantly decreased after ezetimibe treatment (p<0.01 and p<0.001, respectively), and the AUC for apo-B48 was also significantly decreased (p<0.01). Blood glucose and insulin levels at 2h postprandially were significantly decreased by ezetimibe (p<0.05). The AUCs for blood glucose and insulin were also significantly decreased (p<0.05 and p<0.01, respectively). Since ezetimibe improved postprandial lipid and glucose metabolism, this drug is likely to be beneficial for dyslipidemia in patients with postprandial metabolic abnormalities.

Tetrahydrobiopterin Biosynthesis Enhanced by Lipopolysaccharide Stimulation in Murine Neuroblastoma Cell Line N1E‐115

Abstract: We investigated for the first time the effect of lipopolysaccharide and the signal transduction pathway on the biosynthesis of tetrahydrobiopterin [(6R‐l‐erythro‐1′,2′‐dihydroxypropyl)‐2‐amino‐4‐hydroxy‐5,6,7,8‐tetrahydropteridine], the cofactor for the enzymatic hydroxylation of the aromatic amino acids, in the murine neuroblastoma cell line N1E‐115, which synthesizes tetrahydrobiopterin constitutively. Activation of N1E‐115 cells with 1 µg/ml lipopolysaccharide resulted in statistically significant increases in both intracellular tetrahydrobiopterin contents and the activity (Vmax) of GTP cyclohydrolase I, a rate‐limiting enzyme in tetrahydrobiopterin de novo biosynthesis. Following simultaneous addition of the inhibitors of protein tyrosine kinases and GTP‐binding proteins into serum‐free culture media with lipopolysaccharide, we analyzed the transduction pathway of lipopolysaccharide signal toward the tetrahydrobiopterin biosynthetic system in N1E‐115 cells. Our data indicate the following conclusions: (a) Protein tyrosine kinase systems are involved in mediating lipopolysaccharide signal to tetrahydrobiopterin production, and (b) there may be a cross‐talk between GTP‐binding protein and the protein tyrosine kinase system in mediating lipopolysaccharide signal. These observations suggest that a neuronal cell such as N1E‐115, which barely expresses CD14 on its cell surface, responds to lipopolysaccharide like macrophages and monocytes in the absence of soluble CD14.

Isolation of a full-length cDNA clone for human GTP cyclohydrolase I type 1 from pheochromocytoma

Although the existence of three different cDNA forms of human GTP cyclohydrolase I (GCH I) have been reported (Togari et al., 1992), the full-length sequence of any human GCH I cDNA involving poly (A) tail has not yet been documented. In the present study, we first isolated a full-length cDNA clone encoding human GCH I type 1 from human pheochromocytoma cDNA library. The length of the cDNA insert was 2,921 base pairs including poly (A) tail. RNA blot analysis showed a single niRNA species of 4.0kb in human pheochromocytoma tissue.

Multimarker Approach to Risk Stratification for Long-Term Mortality in Patients on Chronic Hemodialysis

BACKGROUNDnWe prospectively investigated the prognostic value of the combined use of cardiac troponin T (TnT), B-type natriuretic peptide (BNP), and high-sensitivity C-reactive protein (CRP) for long-term mortality in hemodialysis (HD) patients. METHODSu2004ANDu2004RESULTS: Baseline measurements of TnT, BNP, and CRP were performed in 516 patients on chronic HD. Patients were followed up for 10 years. Using the Cox multivariate model with these 3 biomarkers as variables categorized into tertiles for mortality, a simplified score was obtained by underscoring individual biomarkers based on the adjusted hazard ratio (HR). The multimarker score was defined as the sum of these points. TnT, BNP, and CRP levels were individually independent predictors for mortality (P<0.05). Among low-risk (multimarker score <4), intermediate-risk (multimarker score 4-7), and high-risk (multimarker score ≥7) groups, 10-year survival rates were 83.3%, 54.3%, and 27.2% (P<0.0001), respectively. After adjusting for other confounders, the multimarker score had strong predictive power for mortality (HR: 4.26; P<0.0001 for high-risk vs. low-risk group). Furthermore, adding the multimarker score to a baseline model with established risk factors improved the C-index (P<0.01), net reclassification improvement (P<0.0001), and integrated discrimination improvement (P<0.0001) greater than that of any single biomarker or baseline model alone.nnnCONCLUSIONSnThe multimarker approach (ie, simultaneous assessment of TnT, BNP, and CRP, which individually independently predict prognosis) may improve the prediction of long-term mortality in HD patients.

Combination of high-sensitivity troponin I and N-terminal pro-B-type natriuretic peptide predicts future hospital admission for heart failure in high-risk hypertensive patients with preserved left ventricular ejection fraction

Additional risk stratification may provide more aggressive and focalized preventive treatment to high-risk hypertensive patients according to the Japanese hypertension guidelines. We prospectively investigated the predictive value of high-sensitivity troponin I (hsTnI), both independently and in combination with N-terminal pro-B-type natriuretic peptide (NT-proBNP), for incident heart failure (HF) in high-risk hypertensive patients with preserved left ventricular ejection fraction (LVEF). Baseline hsTnI and NT-proBNP levels and echocardiography data were obtained for 493 Japanese hypertensive outpatients (mean age, 68.5 years) with LVEFu2009≥u200950%, no symptomatic HF, and at least one of the following comorbidities: stage 3–4 chronic kidney disease, diabetes mellitus, and stable coronary artery disease. During a mean follow-up period of 86.1 months, 44 HF admissions occurred, including 31 for HF with preserved ejection fraction (HFpEF) and 13 for HF with reduced ejection fraction (HFrEF; LVEF <50%). Both hsTnI (pu2009<u20090.01) and NT-proBNP (pu2009<u20090.005) levels were significant independent predictors of HF admission. Furthermore, when the patients were stratified into 4 groups according to increased hsTnI (≥highest tertile value of 10.6xa0pg/ml) and/or increased NT-proBNP (≥highest tertile value of 239.7xa0pg/ml), the adjusted relative risks for patients with increased levels of both biomarkers versus neither biomarker were 13.5 for HF admission (pu2009<u20090.0001), 9.45 for HFpEF (pu2009=u20090.0009), and 23.2 for HFrEF (pu2009=u20090.003). Finally, the combined use of hsTnI and NT-proBNP enhanced the C-index (pu2009<u20090.05), net reclassification improvement (pu2009=u20090.0001), and integrated discrimination improvement (pu2009<u20090.05) to a greater extent than that of any single biomarker. The combination of hsTnI and NT-proBNP, which are individually independently predictive of HF admission, could improve predictions of incident HF in high-risk hypertensive patients but could not predict future HF phenotypes.

Prognostic Value of Combination of Plasma D-Dimer Concentration and Estimated Glomerular Filtration Rate in Predicting Long-Term Mortality of Patients With Stable Coronary Artery Disease

BACKGROUNDnA modestly elevated circulating D-dimer level may be relevant to coronary artery disease (CAD), but its prognostic value, both independently and in combination with estimated glomerular filtration rate (eGFR), for long-term death has not been fully evaluated in stable CAD patients.Methodsu2004andu2004Results:Baseline plasma D-dimer levels and eGFR were measured in 1,341 outpatients (mean age: 65 years) with prior myocardial infarction (MI), coronary revascularization, and/or angiographic evidence of a significant stenosis (>50%) for at least one of the major coronary arteries. Among these patients, 43% had prior MI, 47% had prior coronary revascularization, 41% had multivessel CAD, 14% had paroxysmal or persistent atrial fibrillation, 32% had diabetes, and 32% had chronic kidney disease (eGFR <60 mL/min/1.73 m2). D-dimer levels weakly correlated with eGFR (r=-0.25; P<0.0001). During a mean follow-up period of 73 months, there were 124 deaths, including 61 cardiovascular deaths. Multivariate Cox regression analysis identified D-dimer levels (P=0.001) and eGFR (P=0.006) as independent predictors of all-cause death. Adding both D-dimer and eGFR to a baseline model with established risk factors improved the net reclassification (P<0.005) and integrated discrimination improvement (P<0.05) greater than that of any single biomarker or baseline model alone.nnnCONCLUSIONSnThe combinatorial value of assessing D-dimer levels and eGFR may provide useful insight regarding stable CAD patients long-term risk stratification.

Assessment of trough rivaroxaban concentrations on markers of coagulation activation in nonvalvular atrial fibrillation population

Whether trough-phase rivaroxaban concentrations provide sufficient anticoagulation needs more study. We evaluated levels of coagulation activation markers in the trough concentration phase in nonvalvular atrial fibrillation (NVAF) patients, and the correlation between these markers and rivaroxaban concentration. Fifty-five Japanese NVAF patients received 24-week rivaroxaban treatment of either 15 or 10xa0mg once-daily in the morning. Of these, 26 patients had no history of anticoagulant therapy (naive group) and 29 had switched from warfarin (warfarin group). D-dimer and prothrombin fragment 1xa0+xa02 (F1xa0+xa02) levels, and protein C activities were measured at 0 (baseline), 12 and 24xa0weeks of rivaroxaban treatment just before the patient’s regular dosing time (trough phase). For 49 patients, D-dimer, F1xa0+xa02, and rivaroxaban concentrations were also measured twice between 28 and 32xa0weeks of rivaroxaban treatment at non-trough times to achieve a range of drug concentrations for correlation analysis. For the naive group, D-dimer and F1xa0+xa02 levels were significantly reduced (pxa0<xa00.01) from baseline at 12 and 24xa0weeks. For the warfarin group, these values were unchanged for D-dimer but significantly increased (pxa0<xa00.01) for F1xa0+xa02. Protein C activity was unchanged in the naive group and was increased (pxa0<xa00.01) in the warfarin group. Prothrombin time (rxa0=xa00.92, pxa0<xa00.0001) and activated partial thromboplastin time (rxa0=xa00.54, pxa0<xa00.0001) correlated with rivaroxaban concentration, but not D-dimer and F1xa0+xa02 levels. In conclusion, rivaroxaban in the trough phase is comparable to warfarin in reducing D-dimer levels. Although trough level rivaroxaban suppresses F1xa0+xa02 less than warfarin, the higher activities of protein C with rivaroxaban treatment compared to warfarin treatment may counterbalance this. Lack of correlation between rivaroxaban concentration and D-dimer and F1xa0+xa02 levels suggests that trough concentrations of rivaroxaban reduce their concentrations as effectively as higher levels do.

Predicting acute kidney injury using urinary liver-type fatty-acid binding protein and serum N-terminal pro-B-type natriuretic peptide levels in patients treated at medical cardiac intensive care units

BackgroundThe early prediction of acute kidney injury (AKI) can facilitate timely intervention and prevent complications. We aimed to understand the predictive value of urinary liver-type fatty-acid binding protein (L-FABP) levels on admission to medical (non-surgical) cardiac intensive care units (CICUs) for AKI, both independently and in combination with serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels.MethodsWe prospectively investigated the predictive value of L-FABP and NT-proBNP for AKI in a large, heterogeneous cohort of patients treated in medical CICUs. Baseline urinary L-FABP and serum NT-proBNP were measured on admission. AKI was diagnosed according to the Kidney Disease: Improving Global Outcomes criteria. We studied 1273 patients (mean age, 68xa0years), among whom 46% had acute coronary syndromes, 38% had acute decompensated heart failure, 5% had arrhythmia, 3% had pulmonary hypertension, 2% had acute aortic syndrome, 2% had infective endocarditis, and 1% had Takotsubo cardiomyopathy.ResultsUrinary L-FABP levels correlated with serum NT-proBNP levels (ru2009=u20090.17, pu2009<u20090.0001). AKI occurred in 224 patients (17.6%), including 48 patients with stage 2 or 3 disease. Patients who developed AKI had higher one-week and 6-month mortality than those who did not develop AKI (pu2009=u20090.0002 and pu2009=u20090.003, respectively). In the multivariate logistic analysis, both L-FABP (pu2009<u20090.0001) and NT-proBNP (pu2009=u20090.006) were independently associated with the development of AKI. Adding L-FABP and NT-proBNP to a baseline model that included established risk factors further improved reclassification (pu2009<u20090.001) and discrimination (pu2009<u20090.01) beyond that of the baseline model or any single biomarker individually.ConclusionsUrinary L-FABP and serum NT-proBNP levels on admission are independent predictors of AKI, and when used in combination, improve early prediction of AKI in patients hospitalized at medical CICUs.