Relationship between left ventricular preload and N-terminal pro-brain natriuretic peptide in obese patients.

BACKGROUND: The reason for low plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with a high body mass index (BMI) is unknown. Although left ventricular end-diastolic pressure (LVEDP) is the gold standard of preload, the estimated trans left ventricular end-diastolic transmural pressure (eLVTMP) may be true preload especially in obese patients. MATERIALS AND METHODS: We measured hemodynamic parameters and the plasma NT-proBNP level in the aortic root (AO) and coronary sinus (CS) in 602 left-sided heart disease patients. We defined normal as BMI < 25 kg/m2 (n = 436), overweight as 25 ≤ BMI<30 kg/m2 (n = 117), and obese as BMI ≥ 30 kg/m2 (n = 49). RESULTS: There were no significant differences in left ventricular ejection fraction (LVEF) or LVEDP among the three groups, and log (CSAO) NT-proBNP was significantly lower in overweight or obese patients than in normal patients. From stepwise multivariate analyses, eLVTMP (eLVTMP = LVEDPright atrial pressure), LVEF, and BMI were independent predictors of log (CSAO) NT-proBNP, but LVEDP was not. The eLVTMP was significantly lower in obese patients than in overweight patients (7.5 ± 5.1 vs. 9.6 ± 5.3 mmHg, p < 0.05) or normal patients (7.5 ± 5.1 vs. 9.6 ± 4.7 mmHg, p < 0.01). CONCLUSION: Lower eLVTMP, as a marker of left ventricular preload, may contribute to the lower NT-proBNP secretion from the heart in obese patients.

Heart is the Target Organ of Endogenous Cardiac Natriuretic Peptides.

This study aimed to evaluate whether the heart is the target organ of endogenous atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in patients with heart failure (HF) with reduced ejection fraction (HFrEF).We measured the plasma levels of cyclic guanosine monophosphate (cGMP), which is a second messenger of ANP and BNP, in the aortic root (AO) and coronary sinus (CS) in 237 patients with HFrEF. Plasma levels of cGMP were significantly higher in the CS than those in the AO in 237 patients with HFrEF (10.0 ± 4.5 versus 10.5 ± 4.3 pmoL/mL, P < 0.0001) and were significantly higher in the CS than those in the AO (8.0 ± 3.6 versus 8.9 ± 3.8 pmoL/mL, P < 0.0001) in mild HF patients (New York Heart Association (NYHA) II, n = 114), but there was no difference in plasma cGMP between the AO and the CS (11.9 ± 4.4 versus 11.9 ± 4.3 pmoL/mL, NS) in severe HF patients (NYHA III-IV, n = 123). In mild HF patients, log (ANP + BNP) in the AO was an independent predictor of (CS-AO) cGMP among hemodynamics and nitrate therapy. There was a significant correlation between log [(CS-AO) ANP + (CS-AO) BNP] and (CS-AO) cGMP (r = 0.455, P < 0.0001) in mild HF patients.These findings indicate that cGMP is produced from the failing heart and that the heart is the target organ of endogenous ANP and BNP in patients with HFrEF. In severe HF patients, cGMP production may be attenuated because of the downregulation of biological receptors and/or increased cGMP degradation in the failing heart.

Renal Clearance of N-Terminal pro-Brain Natriuretic Peptide Is Markedly Decreased in Chronic Kidney Disease.

Background: The ratio of N-terminal pro-brain natriuretic peptide (NT-proBNP) secretion from the heart to peripheral NT-proBNP remains unknown in patients with chronic kidney disease (CKD). Methods and Results: We measured plasma NT-proBNP in the aortic root (AO; NT-proBNPAO) and in the coronary sinus (CS; NT-proBNPCS) in 544 patients. Patients were classified into 6 categories based on estimated glomerular filtration rate (eGFR): G1, n=44, eGFR ≥90 mL/min/1.73 m2; G2, n=221, 60≤eGFR<90 mL/min/1.73 m2; G3a, n=132, 45≤eGFR<60 mL/min/1.73 m2; G3b, n=77, 30≤eGFR<45 mL/min/1.73 m2; G4, n=34, 15≤eGFR<30 mL/min/1.73 m2; and G5, n=36, eGFR <15 mL/min/1.73 m2. In non-CKD patients, hemodynamics but not eGFR were independent predictors of log NT-proBNP. In CKD patients, eGFR and hemodynamics were independent predictors of log NT-proBNP. The ratio of NT-proBNP secretion from the heart to NT-proBNPAO significantly decreased with decreasing eGFR in 6 groups (P<0.0001): G1, 67±38%; G2, 50±24%; G3a, 40±21%; G3b, 30±16%; G4, 14.8±7.9%; and G5, 3.5±2.4%, respectively. Conclusions: eGFR contributes to the value of NT-proBNP for prediction of hemodynamic overload in CKD patients but not in non-CKD patients, and the ratio of NT-proBNP secretion from the heart to peripheral NT-proBNP is markedly decreased in CKD patients, especially those with eGFR <30 mL/min/1.73 m2.

Double-Blind, Randomized, Placebo-Controlled Trial Evaluating the Efficacy and Safety of Eplerenone in Japanese Patients With Chronic Heart Failure (J-EMPHASIS-HF).

BACKGROUND: The mineralocorticoid receptor antagonist eplerenone improved clinical outcomes among patients with heart failure with reduced ejection faction (HFrEF) in the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) study. However, similar efficacy and safety have not been established in Japanese patients. We evaluated the efficacy and safety of eplerenone in patients with HFrEF in a multicenter, randomized, double-blind placebo-controlled outcome study (ClinicalTrials.gov Identifier: NCT01115855). The aim of the study was to evaluate efficacy predefined as consistency of the primary endpoint with that of EMPHASIS-HF at a point estimate of <1 for the hazard ratio.Methods and Results:HFrEF patients with NYHA functional class II-IV and an EF ≤35% received eplerenone (n=111) or placebo (n=110) on top of standard therapy for at least 12 months. The primary endpoint was a composite of death from cardiovascular causes or hospitalization for HF. The primary endpoint occurred in 29.7% of patients in the eplerenone group vs. 32.7% in the placebo group [hazard ratio=0.85 (95% CI: 0.53-1.36)]. Hospitalization for any cause and changes in plasma BNP and LVEF were favorable with eplerenone. A total of 17 patients (15.3%) in the eplerenone group and 10 patients (9.1%) in the placebo group died. Adverse events, including hyperkalemia, were similar between the groups. CONCLUSIONS: Eplerenone was well-tolerated in Japanese patients with HFrEF and showed results consistent with those reported in the EMPHASIS-HF study.

MiR30-GALNT1/2 Axis-Mediated Glycosylation Contributes to the Increased Secretion of Inactive Human Prohormone for Brain Natriuretic Peptide (proBNP) From Failing Hearts.

BACKGROUND: Recent studies have shown that plasma levels of the biologically inactive prohormone for brain natriuretic peptide (proBNP) are increased in patients with heart failure. This can contribute to a reduction in the effectiveness of circulating BNP and exacerbate heart failure progression. The precise mechanisms governing the increase in proBNP remain unclear, however. METHODS AND RESULTS: We used our recently developed, highly sensitive human proBNP assay system to investigate the mechanisms underlying the increase in plasma proBNP levels. We divided 53 consecutive patients hospitalized with heart failure into 2 groups based on their aortic plasma levels of immunoreactive BNP. Patients with higher levels exhibited more severe heart failure, a higher proportion of proBNP among the immunoreactive BNP forms secreted from failing hearts, and a weaker effect of BNP as estimated from the ratio of plasma cyclic guanosine monophosphate levels to log-transformed plasma BNP levels. Glycosylation at threonines 48 and 71 of human proBNP contributed to the increased secretion of proBNP by attenuating its processing, and GalNAc-transferase (GALNT) 1 and 2 mediated the glycosylation-regulated increase in cardiac human proBNP secretion. Cardiac GALNT1 and 2 expression was suppressed by microRNA (miR)-30, which is abundantly expressed in the myocardium of healthy hearts, but is suppressed in failing hearts. CONCLUSIONS: We have elucidated a novel miR-30-GALNT1/2 axis whose dysregulation increases the proportion of inactive proBNP secreted by the heart and impairs the compensatory actions of BNP during the progression of heart failure.

Pro-B-type natriuretic peptide is cleaved intracellularly: impact of distance between O-glycosylation and cleavage sites.

We investigated the molecular mechanism underlying the processing of pro-B-type natriuretic peptide (proBNP). Rat neonatal atrial and ventricular myocytes were cultured separately. We examined the molecular forms of secreted and intracellular BNP in atrial and ventricular myocytes; levels of corin and furin mRNA in atrial and ventricular myocytes; the effect their knockdown on proBNP processing; plasma molecular forms of BNP from rats and humans with and without heart failure; and the impact of the distance between the glycosylation and cleavage sites in wild-type and mutant human proBNP, expressed in rat myocytes transfected with lentiviral vectors. BNP was the major molecular form secreted by atrial and ventricular myocytes. Transfection of furin siRNA reduced proBNP processing in both atrial and ventricular myocytes; however, transfection of corin siRNA did not reduce it. BNP was the major molecular form in rat plasma, whereas proBNP was the major form in human plasma. The relative fraction of human BNP in rat myocytes expressing human proBNP was about 60%, but increasing the distance between the glycosylation and cleavage sites through mutation, increased the processed fraction correspondingly. These results suggest that proBNP is processed into BNP intracellularly by furin. The level of proBNP processing is lower in humans than rats, most likely due to the smaller distance between the O-glycosylation and cleavage sites in humans.

Effects of tolvaptan on volume overload in Japanese patients with heart failure: results of a phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

PURPOSE: Tolvaptan may reduce the signs of volume overload in heart failure (HF) patients who experience volume overload despite using conventional diuretics. In this study, we evaluated the dose-response effects of tolvaptan on weight loss, urine volume and electrolyte excretion in furosemide-treated Japanese HF patients exhibiting volume overload. METHODS: In the study, 117 HF patients with volume overload on stable doses of furosemide (≥ 40 mg/day) were treated with tolvaptan (15, 30 or 45 mg) or placebo once-daily for 7 days. RESULTS: The decrease in body weight from baseline to the day after the final dose with 15, 30 or 45 mg tolvaptan (-1.62 ± 1.55, -1.35 ± 1.54 and -1.85 ± 1.10 kg, respectively), was significantly greater compared with that in the placebo group (-0.53 ± 0.96 kg) (p < 0.05). However, the decrease in body weight with tolvaptan was not significantly dose-dependent. Signs of volume overload improved at all doses of tolvaptan. Tolvaptan elicited a dose-dependent increase in urine volume and a decrease in urine osmolality, but did not affect urinary sodium or potassium excretion. Adverse reactions associated with diuresis were most frequently observed at the higher doses of tolvaptan. CONCLUSIONS: Once-daily tolvaptan (15, 30 or 45 mg) was effective and tolerable as an add-on treatment to furosemide therapy in Japanese HF patients with volume overload.

Prognostic value of serial measurements of highly sensitive cardiac troponin I in stable outpatients with nonischemic chronic heart failure.

BACKGROUND: Cardiac troponin I (cTnI) is a useful biomarker in patients with chronic heart failure (CHF), and a highly sensitive cTnI (hs-cTnI) commercial assay has become available. However, the prognostic role of serial measurements of hs-cTnI in stable outpatients with CHF remains unknown. METHODS: At entry to the study, we evaluated 95 stable outpatients with nonischemic CHF showing a serum hs-cTnI (Centaur TnI-Ultra [Siemens Medical Solution Diagnostics, New York, NY], lower limit of detection 0.006 ng/mL) value ≥0.006 ng/mL. To evaluate the role of repetitive measurements of hs-cTnI, we performed echocardiography and measured serum levels of cTnI and N-terminal proBNP at baseline and 6 months later and then prospectively followed up these patients for 4.25 years. RESULTS: During long-term follow-up, there were 27 cardiac deaths. On multivariate analyses, high plasma N-terminal pro-brain natriuretic peptide (≥711 pg/mL, P = .0008), high serum hs-cTnI at baseline (≥0.03 ng/mL, P = .0011), and an increase in hs-cTnI (Δhs-cTnI ≥0 ng/mL, P = .022) after 6 months were independent significant prognostic predictors. The hazard ratio for mortality of patients with high hs-cTnI (≥0.03 ng/mL) and an increase in hs-cTnI (Δhs-cTnI ≥0 ng/mL) was 3.59 (95% CI 1.3-9.9, P = .014) compared with that of those with high hs-cTnI (≥0.03 ng/mL) and a decrease in hs-cTnI (Δhs-cTnI <0 ng/mL). CONCLUSIONS: These findings indicated that not only the serum concentration of hs-cTnI at baseline but also an increase in hs-cTnI were independent and useful prognostic predictors in patients with nonischemic CHF.

Effect of atorvastatin vs. rosuvastatin on cardiac sympathetic nerve activity in non-diabetic patients with dilated cardiomyopathy.

BACKGROUND: Effects of statin therapy on cardiac sympathetic nerve activity in patients with chronic heart failure (CHF) have not previously been evaluated. METHODS AND RESULTS: To compare the effects of lipophilic atorvastatin and hydrophilic rosuvastatin on cardiac sympathetic nerve activity in CHF patients with dilated cardiomyopathy (DCM), 63 stable outpatients with DCM, who were already receiving standard therapy for CHF, were randomized to atorvastatin (n = 32) or rosuvastatin (n = 31). We evaluated cardiac sympathetic nerve activity by cardiac ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy, hemodynamic parameters and neurohumoral factors before and after 6 months of treatment. There were no differences in the baseline characteristics of the 2 groups. In the rosuvastatin group, there were no changes in MIBG parameters, left ventricular ejection fraction or plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) after 6 months of treatment. In contrast, the atorvastatin group showed a significant increase in the delayed heart/mediastinum count ratio (2.18 ± 0.4 vs. 2.36 ± 0.4, P < 0.0001), and the washout rate was significantly decreased (34.8 ± 5.7 vs. 32.6 ± 6.3%, P = 0.0001) after 6 months of treatment compared with the baseline values. The plasma NT-proBNP level was also significantly decreased (729 ± 858 vs. 558 ± 747 pg/ml, P = 0.0139). CONCLUSIONS: Lipophilic atorvastatin but not hydrophilic rosuvastatin improves cardiac sympathetic nerve activity in CHF patients with DCM.

Relationship between biological variation in B-type natriuretic peptide and plasma renin concentration in stable outpatients with dilated cardiomyopathy.

BACKGROUND: The aim of the present study was to interpret B-type natriuretic peptide (BNP) level in outpatients with stable chronic heart failure (CHF); it is important to clarify whether the change in BNP represents disease progression or a range of biological variation. METHODS AND RESULTS: To compare biological variation in BNP and biological variation in factors of the renin-angiotensin-aldosterone system (RAS) in stable CHF patients with dilated cardiomyopathy (DCM), the BNP plasma levels and RAS factors were measured in 115 stable outpatients with DCM. According to stepwise multivariate analysis, plasma BNP at baseline (P=0.005), presence of atrial fibrillation (P=0.015), and a high biological variation in plasma renin concentration (PRC; P=0.002) were significant independent dominant factors related to a high biological variation in BNP. Although there was no change in body weight or blood pressure during the 2-month study period, the % change in hematocrit was negatively correlated with % change in BNP (r=-0.327, P=0.0008), and positively correlated with % change in PRC (r=0.671, P=0.001). CONCLUSIONS: There was a significant relationship between biological variation in BNP and biological variation in PRC, suggesting that the physiological interaction between the natriuretic peptide system and RAS may contribute to the biological variation in plasma BNP in stable outpatients with DCM.

Prognostic role of high-sensitivity cardiac troponin T in patients with nonischemic dilated cardiomyopathy.

BACKGROUND: Cardiac troponin T (cTnT) is useful biomarker in patients with chronic heart failure (CHF). However, its clinical use is limited by the low sensitivity of the conventional commercial assay system. Recently, a highly sensitive cTnT (hs-cTnT) assay has become commercially available. METHODS AND RESULTS: To compare the prognostic value of conventional cTnT and hs-cTnT in patients with nonischemic dilated cardiomyopathy (DCM), hemodynamic parameters and the serum levels of conventional cTnT, hs-cTnT and brain natriuretic peptide (BNP) were measured in 85 consecutive CHF patients with nonischemic DCM and then these patients were followed for a mean of 4.1 years. During long-term follow up, there were 20 cardiac deaths. In 85 DCM patients, conventional cTnT was elevated (≥0.03ng/ml) in 4 patients (5%) and hs-cTnT was elevated (≥0.01ng/ml) in 46 patients (54%). In non-survivors (n=20), conventional cTnT was elevated (≥0.03ng/ml) in 2 patients (2%) and hs-cTnT was elevated (≥0.01ng/ml) in 17 patients (85%). In the stepwise multivariate analyses, a high plasma level of BNP (P=0.002), low left ventricular ejection fraction (<30%, P=0.012) and high hs-cTnT (≥0.01ng/ml, P=0.006) were independent significant prognostic predictors, but conventional cTnT (≥0.03ng/ml) was not. CONCLUSIONS: The findings of the present study indicated that a high serum concentration of hs-cTnT is a useful prognostic predictor that is independent of LVEF or BNP in CHF patients with non-ischemic DCM, suggesting that an increased hs-cTnT concentration sensitively reflects ongoing myocardial damage.

Biological variation of brain natriuretic peptide and cardiac events in stable outpatients with nonischemic chronic heart failure.

BACKGROUND: To evaluate the biological variation and prognostic value of brain natriuretic peptide (BNP) for stable outpatients with nonischemic chronic heart failure (NICHF). METHODS AND RESULTS: Biological variation in BNP was evaluated using an automated assay system in 140 outpatients with NICHF. The stable clinical condition during the 2-month study period was defined as unchanged NYHA and unchanged left ventricular ejection fraction; therefore, 7 patients were excluded during the 2 months. Thereafter, 133 patients were prospectively followed and the relationship between cardiac events and the plasma BNP concentrations (at baseline and after 2 months) were evaluated as well as the changes in BNP. The biological variation in BNP (2-month interval) was calculated as 22.3%. During a mean follow-up period of 42 months, 26 patients had cardiac events. According to stepwise multivariate analyses, plasma BNP after 2 months (P=0.0002) and % change in BNP (P=0.0067) were significant independent predictors of cardiac events. CONCLUSIONS: These findings indicated that a combination of the absolute value of BNP after 2 months and % increase in BNP (2-month interval) is useful for predicting cardiac events in stable outpatients with NICHF.

Effect of eplerenone versus spironolactone on cortisol and hemoglobin A1(c) levels in patients with chronic heart failure.

BACKGROUND: It has been reported that mineralocorticoid receptor antagonist improves the prognosis of chronic heart failure (CHF). Recently, hemoglobin A1(c) (HbA1(c)) levels have been reported to be an independent risk factor for mortality in CHF, suggesting the important role of insulin resistance in CHF. We compared the metabolic effect of a selective mineralocorticoid receptor blocker eplerenone with spironolactone in CHF patients. METHODS: One hundred seven stable outpatients with mild CHF, who were already receiving standard therapy for CHF, were randomized (1:2) to spironolactone (25 mg/d) or eplerenone (50 mg/d). Plasma levels of B-type natriuretic peptide, adiponectin, HbA1(c) and cortisol were measured before and after 4 months treatment with spironolactone or eplerenone. RESULTS: There were no differences in baseline characteristics including hemodynamic parameters and plasma levels of biomarkers between 2 groups. In both groups, plasma B-type natriuretic peptide levels were significantly decreased and plasma aldosterone levels were significantly increased after 4 months. In patients receiving spironolactone (n = 34), plasma adiponectin levels were significantly decreased (12.6 ± 1.4-11.2 ± 1.3 µg/mL, P < .0001) and HbA1(c) and cortisol levels were significantly increased (5.61 ± 0.1-5.8 ± 0.1%, P < .0001, 11.3 ± 0.8-14.7 ± 1.3 µg/dL, P = .003, respectively). In patients receiving spironolactone, there was a significant positive correlation between the change in cortisol and the change in HbA1(c) (r = 0.489, P = .003). In contrast, in patients receiving eplerenone (n = 73), plasma levels of adiponectin, HbA1(c) and cortisol did not change. CONCLUSION: These findings indicated that the metabolic effect of eplerenone differed from that of spironolactone and that eplerenone had a superior metabolic effect especially on HbA1(c) in CHF patients.

Clinical features of myocardial triglyceride in different types of cardiomyopathy assessed by proton magnetic resonance spectroscopy: comparison with myocardial creatine.

BACKGROUND: Myocardial lipid overstorage may produce cardiomyopathy, leading to dysfunction, but advanced heart failure may cause lipolysis via sympathetic nerve activation. In the failing heart, the creatine kinase system may also be impaired. The aims of this study were to assess myocardial triglyceride (TG) and creatine (CR) in different types of cardiomyopathy and to investigate whether they are related to the severity of cardiac dysfunction. METHODS AND RESULTS: In patients with hypertrophic cardiomyopathy (HCM, n = 8), dilated cardiomyopathy (DCM, n = 12) or ischemic cardiomyopathy (ICM, n = 10), and normal subjects (NML, n = 22), myocardial TG and CR were evaluated using proton magnetic resonance spectroscopy. To assess cardiac sympathetic nerve activity, myocardial MIBG (a radioactive guanethidine analog) uptake was measured in DCM. Myocardial TG was significantly lower in hypertrophic cardiomyopathy (HCM) (1.92 ± 0.99 µmol/g), but higher in ICM (7.59 ± 4.36 µmol/g) than in NML hearts (4.05 ± 1.94 µmol/g). There was no significant difference in TG between DCM (4.84 ± 6.45 µmol/g) and NML. Myocardial CR in HCM (20.4 ± 8.4 µmol/g), DCM (14.8 ± 4.8 µmol/g), and ICM (19.4 ± 6.3 µmol/g) was significantly lower than that in NML hearts (27.1 ± 4.3 µmol/g). Overall, myocardial CR correlated positively with the severity of heart failure estimated by ejection fraction or myocardial BMIPP (a radioactive fatty acid analog) uptake, but TG did not. In DCM, myocardial TG correlated with body mass index, but not with MIBG uptake. CONCLUSIONS: Myocardial TG may be related to the specific cause of disease rather than the severity of cardiac dysfunction. In contrast, myocardial CR reflects the severity of heart failure despite different pathoetiologic mechanisms of dysfunction. In DCM, myocardial TG may be affected by an overweight state rather than cardiac sympathetic nerve dysfunction. Thus, myocardial CR has a closer relationship to heart failure severity than does myocardial TG.

Detection and prevalence of chronic obstructive pulmonary disease in a cardiovascular clinic: evaluation using a hand held FEV1/FEV6 meter and questionnaire.

BACKGROUND AND OBJECTIVE: COPD is one of the leading causes of morbidity and mortality worldwide, and its prevalence continues to increase. Although spirometry is indispensable for the diagnosis of COPD, other simple and reliable tools are necessary for screening of COPD because spirometry is not widely available. This study investigated the usefulness of a combination of an electronic FEV1/FEV6 meter (PiKo-6) with a COPD questionnaire as a screening method in patients with cardiovascular diseases. METHODS: The PiKo-6 and the COPD questionnaire of the International Primary Care Airways Group were used to screen patients attending a cardiovascular outpatient clinic. Patients with FEV1/FEV6 < 70% were defined as having airflow limitation. Patients diagnosed with airflow limitation underwent spirometry. Using data from the PiKo-6 and the COPD questionnaire, patients were assigned to a COPD group or a non-COPD group. The relationship between PiKo-6 measurements and spirometry was also evaluated. RESULTS: Among 753 patients, 82 (10.9%) showed airflow limitation when assessed with the PiKo-6. Of these patients, 79 (10.5%) were assigned to the COPD group. FEV1, FEV6 and FEV1/FEV6, as measured with the PiKo-6, correlated significantly with FEV1, FVC and FEV1/FVC, respectively, as measured by spirometry (r = 0.865, 0.751 and 0.57). Among the cardiovascular comorbidities, heart failure and ischaemic heart disease showed slightly stronger associations with airflow limitation (13.8% and 12.5%, respectively). CONCLUSIONS: Combination of the PiKo-6 with a COPD questionnaire may be a useful and feasible method of identifying undiagnosed COPD patients attending a cardiovascular outpatient clinic.

Prognostic role of highly sensitive cardiac troponin I in patients with systolic heart failure.

BACKGROUND: Cardiac troponin T (cTnT) and cardiac troponin I (cTnI) are useful biomarkers in patients with chronic heart failure (CHF). However, the clinical use has limitations due to the low sensitivity of a conventional commercial assay system. Recently, a high sensitive-cTnI (hs-cTnI) commercial assay has become available. METHODS: To compare the prognostic value of cTnT and hs-cTnI, we measured hemodynamic parameters and serum levels of cTnT, hs-cTnI and N-terminal pro-brain natriuretic peptide (NT-proBNP)in 258 consecutive CHF patients and then followed these patients for a mean period of 2.6 years. In both assays of cTnT and hs-cTnI, the lowest concentration at which the coeffi cient of variation was < or =10% were 0.03 ng/mL, respectively. Therefore, in the present study, an elevated cTnT or cTnI test was defined as a level of > or =0.03 ng/mL. RESULTS: During long-term follow up, there were 20 cardiac deaths. In 258 CHF patients, serum cTnT were elevated (> or =0.03 ng/mL) in 32 patients (12%) and serum hs-cTnI was elevated (> or =0.03 ng/mL) in 112 patients (43%). On stepwise multivariate analyses, high plasma NT-proBNP (> or =627 pg/mL, P = .0063) and hs-cTnI (> or =0.03 ng/mL) (P = .016) were independent significant prognostic predictors but cTnT (> or =0.03 ng/mL) was not. The hazard ratio for mortality of patients with high plasma NT-proBNP (> or =627 pg/mL) and hs-cTnI (> or =0.03 ng/mL) was 5.74 (95% CI, 2.33-14.28, P < .0001) compared to that of those with low NT-proBNP (<627 pg/mL) or hs-cTnI (<0.03 ng/mL). CONCLUSIONS: These findings indicate that a high plasma concentration of hs-cTnI is an independent and useful prognostic predictor in patients with CHF.

Comparison of the long-term effects of candesartan and olmesartan on plasma angiotensin II and left ventricular mass index in patients with hypertension.

In general, treatment with most angiotensin receptor blockers (ARBs) increases plasma angiotensin II (Ang II) level because of a lack of negative feedback on renin activity. Olmesartan is a potential ARB inducing activation of angiotensin-converting enzyme 2 (ACE2) that hydrolyzes Ang II to Ang 1-7, and has shown a beneficial effect on ventricular remodeling. Indeed, a previous study reported that olmesartan treatment resulted in decreased plasma levels of Ang II and aldosterone. However, there has not yet been a study showing the relationship of chronic effects of olmesartan on Ang II and the left ventricular mass index (LVMI) in comparison with those of other ARB.A total of 50 stable outpatients with essential hypertension who had received candesartan for more than 1 year were randomized into two groups: control group (n=25): continuous candesartan treatment at a stable dose; and olmesartan group (n=25): candesartan (8 mg day(-1)) was changed to olmesartan given at a dose of 20 mg day(-1). There was no difference in the baseline characteristics between the two groups. In the control group, there were no significant changes in blood pressure, LVMI or biomarkers during 12 months of study. In the olmesartan group, blood pressure did not change and plasma levels of Ang II decreased during 12 months of study, whereas LVMI was significantly decreased after 12 months (135+/-36 vs. 123+/-29 g m(-2); P<0.01).These findings indicate that replacing candesartan with olmesartan decreased LVMI in association with a sustained decrease of plasma Ang II over a 12-month period without changing blood pressure or plasma aldosterone in patients with essential hypertension.

Serum cortisol as a useful predictor of cardiac events in patients with chronic heart failure: the impact of oxidative stress.

BACKGROUND: The pathophysiological role of cortisol, which binds to the mineralocorticoid receptor with an affinity equal to that of aldosterone (ALD), may be influenced by oxidative stress in patients with chronic heart failure. We evaluated cardiac event prediction using cortisol levels in chronic heart failure, in comparison with ALD, adrenocorticotropic hormone, and brain natriuretic peptide (BNP), and the impact of oxidative stress. METHODS AND RESULTS: We measured the plasma levels of biomarkers such as BNP, ALD, adrenocorticotropic hormone, serum cortisol, and oxidized low-density lipoprotein (oxLDL), a biomarker of oxidative stress, in 319 consecutive symptomatic patients with chronic heart failure, and we followed these patients for a mean period of 33 months. During the follow-up period, 29 patients had cardiac events (death or hospitalization). Plasma levels of BNP, ALD, adrenocorticotropic hormone, oxLDL, and serum cortisol (16.8+/-1.8 microg/dL versus 12.4+/-0.3 microg/dL, P=0.01) were significantly higher in patients with cardiac events than in those without cardiac events. On stepwise multivariate analyses, high levels of BNP (P=0.0003), renin (P=0.002), cortisol (P=0.02), and oxLDL (P=0.002) were independent predictors of cardiac events, but ALD and adrenocorticotropic hormone levels were not. In patients with serum cortisol > or =12.5 microg/dL, the hazard ratio of cardiac events in patients with oxLDL > or =12 U/mL was 3.5 compared with that in patients with oxLDL <12 U/mL (P=0.008). CONCLUSIONS: These findings indicate that serum cortisol levels were a complementary and incremental cardiac event risk predictor in combination with BNP in patients with chronic heart failure and that cardiac event prediction based on cortisol levels was influenced by oxidative stress.