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Aims: The study aims to evaluate the prognostic significance of impaired glucose tolerance (IGT) with reference to albuminuria in patients with chronic heart failure (CHF)., Methods and Results: We examined 535 CHF patients (mean 66 years, women 25%) in the control arm of our SUPPORT trial, in which we examined additive impact of olmesartan in hypertensive patients with symptomatic CHF treated with β-blockers and/or angiotensin-converting enzyme inhibitors. We examined the association between glycaemic abnormality (assessed by 75 g of oral glucose tolerance test) and albuminuria for a composite outcome of all-cause death, myocardial infarction, stroke, and HF hospitalization. IGT patients (N = 113, mean 67.2 years) were older and more frequently treated with β-blockers compared with those with normal glucose regulation (N = 142, mean 64.0 years) and those with diabetes mellitus (N = 280, mean 65.7 years). Multivariable Cox proportional hazard models revealed that, as compared with normal glucose regulation (NGR), IGT was associated with increased risk of the outcome when complicated by albuminuria [hazard ratio (HR) 2.25; 95% confidence interval (CI) 1.14-4.42; P = 0.019] but not when uncomplicated by albuminuria (HR 0.76; 95% CI 0.35-1.60, P = 0.47) (P for interaction = 0.041). This was also the case for diabetes mellitus and albuminuria (HR 2.06; 95% CI 1.17-3.61; P = 0.012). Among IGT patients without albuminuria, 21 (29%) developed albuminuria at 1-year visit, which was again associated with poor prognosis (HR 7.36; 95% CI 1.39-38.98, P = 0.019)., Conclusions: These results indicate that IGT is associated with poor prognosis when complicated by albuminuria in CHF patients, demonstrating the importance of combined early stages of glucose intolerance and renal dysfunction in the management of CHF., (© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: There is no robust evidence of pharmacological interventions to improve mortality in heart failure (HF) patients with preserved left ventricular ejection fraction (LVEF) (HFpEF). In this subanalysis study of the SUPPORT Trial, we addressed the influence of LVEF on the effects of olmesartan in HF., Methods and results: Among 1,147 patients enrolled in the SUPPORT Trial, we examined 429 patients with reduced LVEF (HFrEF, LVEF <50%) and 709 with HFpEF (LVEF ≥50%). During a median follow-up of 4.4 years, 21.9% and 12.5% patients died in the HFrEF and HFpEF groups, respectively. In HFrEF patients, the addition of olmesartan to the combination of angiotensin-converting enzyme inhibitor (ACEI) and β-blocker (BB) was associated with increased incidence of death (hazard ratio (HR) 2.26, P=0.002) and worsening renal function (HR 2.01, P=0.01), whereas its addition to ACEI or BB alone was not. In contrast, in HFpEF patients, the addition of olmesartan to BB alone was significantly associated with reduced mortality (HR 0.32, P=0.03), whereas with ACEIs alone or in combination with BB and ACEI was not. The linear mixed-effect model showed that in HFpEF, the urinary albumin/creatinine ratio was unaltered when BB were combined with olmesartan, but significantly increased when not combined with olmesartan (P=0.01)., Conclusions: LVEF substantially influences the effects of additive use of olmesartan, with beneficial effects noted when combined with BB in hypertensive HFpEF patients. (Circ J 2016; 80: 2155-2164).

We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96-1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19-2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and β-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11-1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01-2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24-2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and β-blockers was associated with increased adverse cardiac events. This study is registered at clinicaltrials.gov-NCT00417222., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Although the need for nursing care (NC) in heart failure (HF) patients is recognized, detailed information on the current status in Japan is lacking. METHODS AND RESULTS: In the CHART-2 Study, we obtained information on daily life, physical ability, nutrition and mental status for 4,174 patients (mean age, 67.1±10.8 years; 73.3% male) out of 10,219 patients. We examined the prevalence, baseline characteristics and clinical outcomes of stage B and C/D HF patients requiring NC. The prevalence of HF requiring NC was significantly higher in stage C/D (38.6%) than in stage B (30.4%; P<0.001). Among the reasons for requiring NC, physical dysfunction was most prevalent in both stage B (20.6%) and C/D (29.0%). Compared with the non-NC group, the NC group was characterized by higher age, higher prevalence of female gender and cerebrovascular disease, and increased plasma brain natriuretic peptide regardless of HF stage. During a median follow-up of 12.7 months after the survey, the NC group had a significantly higher mortality compared with the non-NC group (9.6% vs. 3.6%, P<0.001). On multivariate logistic analysis depressive mental status (hazard ratio [HR], 3.61; P<0.001) and dementia (HR, 2.70; P<0.001) were significantly associated with NC need., Conclusions: In HF patients, NC need is considerably high and is associated with increased mortality regardless of HF stage in Japan.

Background: Although angiotensin receptor blockers (ARBs) are now one of the first-line drug classes for the management of hypertension, recommendations for the management of chronic heart failure (CHF) are limited. The supplemental benefit of angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial investigates whether an additive treatment with an ARB, olmesartan, reduces the mortality and morbidity in hypertensive patients with stable chronic heart failure., Methods and Results: The SUPPORT trial is a prospective randomized open-label blinded endpoint study. Between October 2006 and March 2010, 1147 stable CHF patients treated with evidence-based medications were successfully randomized to either olmesartan or control group. In the olmesartan group, the ARB was initiated at the dose of 5.0-10mg, and was then increased up to 40mg/day, when possible. No ARBs were allowed in the control group. Primary outcome measure in the SUPPORT trial is the composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke and hospital admission due to worsening heart failure. The participants will be followed for at least 3 years until March 2013., Conclusions: The SUPPORT trial will elucidate the supplemental benefits of an ARB, olmesartan, in hypertensive patients with CHF., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Elevated blood urea nitrogen (BUN) observed in patients hospitalized for acute heart failure syndrome (AHFS) may represent increased neurohumoral activation. The purpose of this study was to examine the prognostic impact of BUN changes during hospitalization on the long-term prognosis of AHFS patients., Methods and Results: The Tohoku Acute Heart Failure Registry (n=497) is a multicenter retrospective cohort study enrolling AHFS patients who were admitted in 2007. The 337 survivors (mean age, 76 years; 52% male) were divided into 3 groups according to tertiles of BUN change during hospitalization: Decreased (D-BUN, ΔBUN (BUN level at discharge-BUN level at hospitalization)≤-1.63 mg/dl, n=112); Unchanged (U-BUN, ΔBUN-1.64 to 5.73 mg/dl, n=113); Increased (I-BUN, ΔBUN>5.73 mg/dl, n=112). The D-BUN group had higher prevalence of lowest glomerular filtration rate during hospitalization, whereas the I-BUN group had higher systolic blood pressure. During a median follow-up period of 2.3 years after discharge, the Kaplan-Meier curve showed that D-BUN and I-BUN had worse prognosis compared with U-BUN. Multivariable logistic model showed that all-cause death was more frequent in I-BUN (hazard ratio, 2.94; 95% confidence interval, 1.51-5.73; P<0.001). Subgroup analysis revealed that BUN increase during hospitalization was associated with all-cause death, regardless of renal function., Conclusions: AHFS patients with a BUN increase during hospitalization have worse long-term prognosis, independent of renal function.

Background: The appropriate target ranges of heart rate (HR) and systolic blood pressure (SBP) for the management of chronic heart failure (CHF) patients remain to be elucidated in a large-scale cohort study., Methods and Results: We examined 3,029 consecutive CHF patients with sinus rhythm (SR) (mean age, 67.9 years) registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 Study (CHART-2; NCT00418041). There were 357 deaths (11.8%) during the median follow-up of 3.1 years. We first performed the classification and regression tree analysis for mortality, identifying SBP <89 mmHg, HR >70 beats/min and SBP <115 mmHg as the primary, secondary and tertiary discriminators, respectively. According to these, we divided the patients into low- (n=1,131), middle- (n=1,624) and high-risk (n=274) groups with mortality risk <10%, 10-20% and >20%, respectively. The low-risk group was characterized by SBP >115 mmHg and HR <70 beats/min and the high-risk group by SBP <89 mmHg regardless of HR values or SBP 89-115 mmHg and HR >76 beats/min. Multivariate Cox regression analysis revealed that the hazard ratio of all-cause death for low-, middle- and high-risk groups was 1.00 (reference), 1.48 (95% confidence interval (CI): 1.10-1.99, P=0.009) and 2.44 (95% CI 1.66-3.58, P<0.001), respectively. Subgroup analysis revealed that age ≥70 years, diabetes, or reduced left ventricular function had higher hazard ratios in the high-risk group., Conclusions: The results demonstrate the usefulness of combined risk stratification of HR and SBP in CHF patients with SR.

Aims: Heart failure with preserved ejection fraction (HFpEF) is characterized by multiple co-morbidities, including chronic kidney disease that is one of the prognostic risks for these patients. This study was performed to evaluate the value of determination of albuminuria using a urine dipstick test (UDT), combined with estimated glomerular filtration rate (eGFR), for predicition of mortality in HFpEF., Methods and Results: We enrolled 2465 consecutive patients with overt HF with EF ≥50% in our Chronic Heart Failure Analysis and Registry in the Tohoku District 2 (CHART-2) study (NCT00418041). We defined trace or more UDT as positive. We divided the patients into the following four groups based on eGFR and UDT; group 1 (G1) (eGFR ≥60, negative UDT), G2 (eGFR ≥60, positive UDT), G3 (eGFR <60, negative UDT), and G4 (eGFR <60, positive UDT). In total, 29.5% of the HFpEF patients had a positive UDT. HFpEF patients with a positive UDT were characterized by higher brain natriuretic peptide levels and frequent histories of hypertension or diabetes. During a mean follow-up of 2.5 years, HFpEF patients with a positive UDT showed higher mortality in each stratum of eGFR levels. A multivariable adjusted Cox model showed that when compared with G1 (reference), the hazard ratio of all-cause death for G2, G3, and G4 was 2.44 (95% confidence interval 1.47-4.05, P=0.001), 1.43 (0.92-2.23, P=0.12), and 2.71 (1.72-4.27, P<0.001), respectively. Furthermore, the prognostic value of a positive UDT was robust for both cardiovascular and non-cardiovascular deaths., Conclusions: These results indicate that measurement of albuminuria in addition to eGFR is useful for appropriate risk stratification in HFpEF patients.

Chronic kidney disease (CKD) is common and the estimated prevalence is about 9-13% in the general adult population. CKD is defined by the presence of kidney damage or decreased glomerular filtration rate. Individuals with CKD have a far greater likelihood of cardiovascular death than progression to end-stage renal disease. Heart failure (HF) is a complex clinical syndrome that can result from any structural or functional cardiac disorder and the prevalence is reported to be 2-3% in the general population. The prognosis of HF patients is still poor despite recent advances in HF treatment. Both diseases are major and growing public health problems because aging of the population contributes to the increasing incidence of those diseases. More than 40% of HF patients have CKD and the close relationship between CKD and HF worsens their prognoses. All physicians must evaluate kidney function using estimated glomerular filtration rate calculated by the new Japanese equation in patients with HF. Accurate evaluation of pathophysiology between the two diseases and appropriate intervention are necessary to improve the prognosis of patients with the diseases., (Copyright © 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Hospitalization due to acute heart failure syndrome (AHFS) is an indicator of worsened prognosis for patients with cardiovascular disease (CVD). The Chronic Heart Failure Analysis and Registry in the Tohoku District 2 (CHART-2) Study was designed to elucidate characteristics and prognosis of patients at high risk for CVD progression due to AHFS., Methods and Results: The CHART-2 Study is a prospective observational multicenter cohort study. Patients with overt HF, structural cardiac disorder but without HF, or with coronary artery disease (CAD) have been consecutively enrolled from October 2006. As of March 2010, a total of 10,219 patients have been recruited, making the Study the largest multicenter prospective cohort of HF patients in Japan. The mean patient age was 68.2±12.3 years and male patients accounted for 69.8%. Overt HF was observed in 46.3% of patients; and 53.7% did not have HF but were at high risk for AHFS. As HF stage progressed, the prognostic risks (eg, chronic kidney disease, reduced ejection fraction, and increased B-type natriuretic peptide level) became more prominent. Compared with the previous CHART-1 study, the prevalence of ischemic etiology and risk factors (hypertension, diabetes) have increased, as in Western studies., Conclusions: This first report demonstrates the trend of westernization of ischemic etiology and clinical characteristics of HF patients in Japan, indicating the importance of appropriate management and prevention of CAD to prevent AHFS., (All rights are reserved to the Japanese Circulation Society.)

Background: Metabolic syndrome (MetS) is a pathological condition with a clustering of metabolic components and is a well-known risk and prognostic factor for ischemic heart disease (IHD). However, the prevalence and clinical significance of MetS remain to be fully elucidated in chronic heart failure (CHF), an important clinical syndrome caused by various cardiac abnormalities., Methods and Results: The present nationwide, large-scale clinical study enrolled 3,603 patients with stage C/D CHF from 6 institutes in Japan. First, the prevalence of MetS in CHF patients was demonstrated to be 45% in males and 19% in females, which is more than double compared with the general population in Japan. The CHF patients with MetS were characterized by younger age, higher prevalence of current smoking and drinking, IHD, and hypertensive heart disease, whereas the prevalence of HF with preserved ejection fraction and MetS was higher in elderly female patients. Next, the contribution of the metabolic components (waist circumference, hypertension, glucose intolerance/diabetes mellitus and dyslipidemia) was found to be comparable between the ischemic and the non-ischemic CHF patients., Conclusions: The prevalence of MetS in CHF patients is more than double compared with the general population in Japan and suggest that the metabolic components may have a substantial effect on the development of both ischemic and non-ischemic CHF.

Background: Prognostic impact of body mass index (BMI) in Japanese patients with chronic heart failure (HF) remains unclear., Methods and Results: We examined the relationship between BMI and the prognosis of Japanese HF patients in the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART) study. The study sample was 972 Japanese chronic HF patients (mean age, 68.2 ± 13.5; male 65.2%). We categorized them into 5 groups; BMI <18.5, 18.5 to 22.9, 23.0 to 24.9 (reference), 25.0 to 29.9, and ≥ 30.0. Using a Cox hazards model, the relationships between BMI and deaths or admission for worsening HF were studied in detail. Mean follow-up period was 3.4 ± 1.7 years. Multivariate analysis showed that, as compared with reference group (BMI 23.0 to 24.9), hazard ratios (HR) for all-cause death showed a U-shaped association with 1.70 (95% confidence interval; 1.04-2.76), 1.23 (0.85-1.78), 1.26 (0.84-1.90), and 2.75 (1.51-5.00) among those with BMI<18.5, 18.5 to 22.9, 25.0 to 29.9, and ≥ 30.0, respectively. There were significant and suggestive U-shaped associations between BMI and cardiac-cause death or admission for worsening HF., Conclusions: Both high and low BMIs were associated with increased outcomes, suggesting that extreme obesity is not beneficial in improving the prognosis of Japanese chronic HF patients., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: The prognosis of patients with chronic heart failure (CHF) is poor in both men and women. However, the characteristics of, and effective treatment strategy for, female CHF patients still remain unclear. This study was designed to evaluate the prognosis and characteristics of female patients in a CHF cohort termed the Chronic Heart Failure Analysis and Registry in the Tohoku District., Methods and Results: Of 1,278 patients registered in the cohort, the study population comprised 1,166 symptomatic CHF patients with sufficient data. As compared with male patients, female patients were more likely to be older, have preserved systolic function and non-ischemic etiology of CHF, and underuse standard CHF medications. Although a previous study showed that sex-difference was not a significant prognostic factor in CHF patients, the unadjusted survival analysis revealed an increased event rate in female patients in the present study. Multivariate analysis revealed that older age, diabetes, ventricular tachycardia and anemia were significant prognostic risks in both men and women with CHF., Conclusions: Female sex had a significant link with elderly CHF patients. Given the explosive increase in elderly patients in Westernized countries, further studies are needed to elucidate the evidence for treatment of female CHF patients.

Background: Renal insufficiency is common in patients with chronic heart failure (CHF), so to improve the prognosis of patients with cardiovascular risks clinical guidelines recommend estimating the glomerular filtration rate (GFR), which detects chronic kidney disease more accurately than does the serum creatinine level alone. However, the clinical usefulness of the estimated GFR (eGFR) in Japanese CHF patients is still unclear., Methods and Results: Of 1,278 patients registered in a Japanese CHF registry, termed the Chronic Heart Failure Analysis and Registry in the Tohoku District study, the study population included 920 symptomatic patients with sufficient data. Baseline eGFR (ml .min(-1) . 1.73 m(-2)) was calculated using the Cockcroft-Gault equation. Patients were divided into three groups based on eGFR: > or =60, 30-59, and <30 ml . min(-1) .1.73 m(-2). Kaplan-Meier analysis revealed that the incidence of the combined event of all-cause death and admission because of CHF was significantly higher in patients with reduced eGFR and such patients were older and more frequently had an ischemic etiology of CHF, a higher prevalence of diabetes, lower hemoglobin level, and higher B-type natriuretic peptide level. Multivariate Cox regression analysis showed that reduced eGFR was significantly associated with the combined endpoint., Conclusions: GFR should be evaluated in all Japanese patients with CHF to improve risk stratification and treatment.

The prognosis of patients with chronic heart failure (CHF) still remains poor, despite the recent advances in medical and surgical treatment. Furthermore, CHF is a major public health problem in most industrialized countries where the elderly population is rapidly increasing. Although the prevalence and mortality of CHF used to be relatively low in Japan, the disorder has been markedly increasing due to the rapid aging of the society and the Westernization of lifestyle that facilitates the development of coronary artery disease. The Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-1 study was one of the largest cohorts in Japan. The study has clarified the characteristics and prognosis of Japanese patients with CHF, demonstrating that their prognosis was similarly poor compared with those in Western countries. However, we still need evidence for the prevention and treatment of CHF based on the large cohort studies or randomized treatment trials in the Japanese population. Since the strategy for CHF management is now changing from treatment to prevention, a larger-size prospective cohort, called the CHART-2 study, has been initiated to evaluate the risk factors of CHF in Japan. This review summarizes the current status of CHF studies in Japan and discusses their future perspectives.

Background: Sudden death is common in chronic heart failure (CHF). Risk stratification is the first step for primary prevention., Aim: To evaluate the use of risk markers for estimating sudden death risk., Methods and Results: We prospectively examined 680 stable patients with CHF. Risk markers were evaluated using the Cox's proportional hazard model in a stepwise manner. Ejection fraction <30%, left ventricular end-diastolic diameter >60 mm, brain natriuretic peptide >200 pg/ml, non-sustained ventricular tachycardia, and diabetes were significantly associated with increased risk of sudden death. When the number of risk markers were included as co-variables, only "number of risk markers >or=3'' entered the model (hazard ratio 8.95, 95% confidence interval 4.57-17.52), while the effects of individual markers did not enter the model. The annual mortality from sudden death was 11% in patients with 3 or more risk markers and 1.4% in patients with 2 or less., Conclusions: Rather than particular risk markers, the number of accumulated risk markers was a more powerful predictor for sudden death in patients with CHF. The number of risk markers could be useful for risk stratification of sudden death.

Despite the recent remarkable advances in the medical treatment for severe end-stage heart failure, we still need a more powerful therapy to save patients presenting with cardiogenic shock or progressive cardiac deterioration. The implantation of ventricular assist system (VAS) is one of the available strategies in such patients and it has been used as a bridge to recovery or a bridge to transplantation. Because of the severe shortage of brain -dead donors, the role of VAS is now expanding into an alternative to transplantation, which is called a destination therapy. This review summarizes the current application and the future direction of VAS therapy for end -stage heart failure in Japan.

Background: We evaluated a combined assessment of brain natriuretic peptide (BNP) with left ventricular dimensions as a prognostic marker for sudden death in patients with chronic heart failure (CHF). Ventricular dimensions and BNP are separately recognized as prognostic markers for sudden death in patients with CHF., Methods and Results: CHF patients at Stage C and B were registered for a prospective study. From the database, we analyzed 417 patients with coronary arterial disease (CAD) or primary/secondary dilated cardiomyopathy (DCM). Main effects of BNP, left ventricular ejection fraction (EF), LV diastolic dimension (LVDD), and interaction of BNP with the EF and LVDD were tested with Cox's proportional hazard model. BNP in sudden death patients was significantly higher than that in event-free patients. Although multivariate analysis revealed that BNP by itself was not an independent risk factor for sudden death after adjustments, it was revealed that BNP entered the model via interaction with EF as a risk factor associating with sudden death. On the other hand, BNP was an independent risk factor associating with heart failure events (death and hospitalization), and BNP did not enter the model via an interaction with EF., Conclusion: BNP by itself was an independent risk factor for the heart failure events, but not for sudden death in CHF patients of the present study. However, BNP should be important in predicting sudden death when measured with EF.

Background: Myocardial infarction (MI) is one of the major etiologies of chronic heart failure (CHF) in Japan., Methods and Results: The prognoses of CHF patients after MI (n=283) were investigated by comparing them with those of CHF patients with nonischemic cardiomyopathy (NICM, n=310) from the CHF registry (CHART; n=1,154). The Kaplan-Meier (KM) analyses revealed that the 3-year all-cause mortality was significantly higher in the MI cohort compared with the NICM cohort (29.0% vs 12.4%, p<0.0005). Age/gender/treatment-adjusted KM analysis revealed significant differences only in the cohorts with preserved left ventricular ejection fraction (LVEF), defined as LVEF >45%, or in less symptomatic patients (New York Heart Association I or II). Multivariate Cox regression analysis showed that beta-blocker (BB) was associated with a significant reduction in mortality from cardiac causes, and either angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) was significantly related to the improvement of survival in the MI cohort (adjusted hazard ratio: 0.222 and 0.497, p<0.05), even though these medicines were used significantly less often in the MI cohort., Conclusions: Underlying MI has a significant impact on the survival of Japanese CHF patients, especially those with preserved LVEF or with fewer symptoms. The appropriate expansion of ACEI/ARB or BB therapy might be necessary to improve their survival.