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We aimed to compare the usefulness of plasma levels of B-type natriuretic peptide (BNP) for long-term risk stratification among patients with heart failure (HF) with preserved left ventricular ejection fraction (LVEF) (HFpEF), borderline HFpEF, and HF with reduced LVEF (HFrEF) in the same HF cohort. In the CHART-2 Study (N = 10,219), we categorized 4301 consecutive Stage C/D HF patients (mean age 68.7 years, female 32.4%) into 3 groups: HFpEF (LVEF ≥ 50%, N = 2893), borderline HFpEF (LVEF 40-50%, N = 666), and HFrEF (LVEF ≤ 40%, N = 742). During the median 6.3-year follow-up, all-cause deaths occurred in 887 HFpEF, 330 borderline HFpEF, and 330 HFrEF patients. Although median BNP levels increased from HFpEF, borderline HFpEF to HFrEF (85.3, 126 and 208 pg/ml, respectively, P < 0.001), the relationship between log 2 BNP levels and the mortality risk was comparable among the 3 groups. As compared with patients with BNP < 30 pg/ml, those with 30-99, 100-299 and ≥ 300 pg/ml had comparably increasing mortality risk among the 3 groups (hazard ratio 2.5, 4.7 and 7.8 in HFpEF, 2.1, 4.2 and 7.0 in borderline HFpEF, and 3.0, 4.7 and 9.5 in HFrEF, respectively, all P < 0.001). BNP levels have comparable prognostic impact among HFpEF, borderline HFpEF, and HFrEF patients.

Background: The new category of heart failure (HF), HF with mid-range left ventricular ejection fraction (LVEF) (HFmrEF), has recently been proposed. However, the clinical features of HFmrEF, with reference to HF with preserved LVEF (HFpEF) and HF with reduced LVEF (HFrEF) in the same HF cohort, remain to be fully examined., Methods and Results: In the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 Study, we examined 3480 consecutive HF patients with echocardiography data consisting of 2154 HFpEF (LVEF ≥50%), 596 HFmrEF (LVEF 40-49%) and 730 HFrEF (LVEF <40%). While clinical characteristics and prognostic factors of HFmrEF were intermediate between HFpEF and HFrEF, prognosis of HFmrEF resembled HFpEF and the prognostic impact of cardiovascular medications in HFmrEF resembled that of HFrEF. Analysis of LVEF transition among the three groups revealed that HFmrEF and HFrEF dynamically transitioned to other categories, especially within 1 year, whereas HFpEF did not; HFmrEF at registration transitioned to HFpEF and HFrEF by 44% and 16% at 1 year, and 45% and 21% at 3 years, respectively. Landmark analysis demonstrated that, regardless of HF stages at registration, HFmrEF patients at 1 year had mortality comparable to that of HFpEF patients, which was better than HFrEF patients, but HFmrEF patients at registration had increased mortality when transitioned to HFrEF at 1 year., Conclusions: These results indicate that clinical characteristics of HFmrEF are intermediate between HFpEF and HFrEF and that HFmrEF dynamically transitions to HFpEF or HFrEF, especially within 1 year, suggesting that HFmrEF represents a transitional status or an overlap zone between HFpEF and HFrEF, rather than an independent entity of HF., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Background: It remains to be elucidated whether addition of renin-angiotensin-aldosterone system (RAAS) inhibitors and/or β-blockers to loop diuretics has a beneficial prognostic impact on chronic heart failure (CHF) patients., Methods and results: From the Chronic Heart failure Analysis and Registry in the Tohoku district 2 (CHART-2) Study (n=10,219), we enrolled 4,134 consecutive patients with symptomatic stage C/D CHF (mean age, 69.3 years, 67.7% male). We constructed Cox models for composite of death, myocardial infarction, stroke and HF admission. On multivariate inverse probability of treatment weighted (IPTW) Cox modeling, loop diuretics use was associated with worse prognosis with hazard ratio (HR) 1.28 (P<0001). Furthermore, on IPTW multivariate Cox modeling for multiple treatments, both low-dose (<40 mg/day) and high-dose (≥40 mg/day) loop diuretics were associated with worse prognosis with HR 1.32 and 1.56, respectively (both P<0.001). Triple blockade with RAS inhibitor(s), mineral corticoid (aldosterone) receptor antagonist(s) (MRA), and β-blocker(s) was significantly associated with better prognosis in those on low-dose but not on high-dose loop diuretics., Conclusions: Chronic use of loop diuretics is significantly associated with worse prognosis in CHF patients in a dose-dependent manner, whereas the triple combination of RAAS inhibitor(s), MRA, and β-blocker(s) is associated with better prognosis when combined with low-dose loop diuretics. (Circ J 2016; 80: 1396-1403).

Background: The prognostic impact of new-onset atrial fibrillation (AF) is not fully elucidated., Methods and Results: We examined 4,818 consecutive stage C/D chronic heart failure (CHF) patients in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (n=10,219). At enrollment, 1,859 (38.6%) of them had AF. Compared with the 2,953 patients without AF, AF patients were characterized by higher age (71 vs. 68 years), lower estimated glomerular filtration rate (58.9 vs. 61.9 ml/min/1.73 m(2)), higher brain natriuretic peptide (152 vs. 74.5 pg/ml), similar left ventricular ejection fraction (56.8 vs. 56.5%), and a similar prescription rate of β-blockers (48.1 vs. 50.6%) and renin-angiotensin system (RAS) inhibitors (72.9 vs. 71.6%). Among the patients without AF at enrollment, 106 (3.6%) developed new AF during the median 3.2-year follow-up, which was associated with increased mortality (adjusted hazard ratio, 1.72; P=0.013). In contrast, neither paroxysmal nor chronic AF at enrollment was associated with increased mortality. The mortality rate was significantly high in the first year after the onset of new AF. On inverse probability of treatment weighting analysis using propensity score, RAS inhibitors and statins were associated with reduced incidence of new AF, and diuretics were associated with increase of new AF., Conclusions: Onset of new AF, but not a history of AF, is associated with increased mortality in CHF patients, especially in the first year.

Background: The effectiveness of statins remains to be examined in patients with heart failure (HF) with preserved ejection fraction (EF). METHODS AND RESULTS: Among 4,544 consecutive HF patients registered in the Chronic Heart Failure Registry and Analysis in the Tohoku district-2 (CHART-2) between 2006 and 2010, 3,124 had EF ≥50% (HFpEF; mean age 69 years; male 65%) and 1,420 had EF <50% (HF with reduced EF (HFrEF); mean age 67 years; male 75%). The median follow-up was 3.4 years. The 3-year mortality in HFpEF patients was lower in patients receiving statins [8.7% vs. 14.5%, adjusted hazard ratio (HR) 0.74; 95% confidence interval (CI), 0.58-0.94; P<0.001], which was confirmed in the propensity score-matched cohort (HR, 0.72; 95% CI, 0.49-0.99; P=0.044). The inverse probability of treatment weighted further confirmed that statin use was associated with reduced incidence of all-cause death (HR, 0.71; 95% CI, 0.62-0.82, P<0.001) and noncardiovascular death (HR, 0.53; 95% CI, 0.43-0.66, P<0.001), specifically reduction of sudden death (HR, 0.59; 95% CI, 0.36-0.98, P=0.041) and infection death (HR, 0.53; 95% CI, 0.35-0.77, P=0.001) in HFpEF. In the HFrEF cohort, statin use was not associated with mortality (HR, 0.87; 95% CI, 0.73-1.04, P=0.12), suggesting a lack of statin benefit in HFrEF patients., Conclusions: These results suggest that statin use is associated with improved mortality rates in HFpEF patients, mainly attributable to reductions in sudden death and noncardiovascular death.

Background: It is unclear whether the prognostic impact of diabetes mellitus (DM) in chronic heart failure (CHF) is influenced by ischemic heart disease (IHD) and/or nephropathy., Methods and Results: We enrolled 4,065 consecutive patients with stage C/D CHF (mean age, 69.0 years; 68.7% male) in the CHART-2 Study (n=10,219). We defined DM as current history of DM treatment or HbA1c ≥6.5% (National Glycohemoglobin Standardization Program [NGSP]), and nephropathy as urine albumin:creatinine ratio ≥30 mg/g or urine dipstick test ≥(±) at enrollment. Impacts of DM and nephropathy on the composite of death, myocardial infarction, stroke, and HF admission were examined. Among the 4,065 patients, 1,448 (35.6%) had DM, while IHD and nephropathy were also noted in 1,644 (40.4%) and in 1,549 (38.1%), respectively. During the median follow-up of 2.88 years, 1,025 (25.2%) reached the composite endpoint. On multivariate Cox regression, DM was significantly associated with the composite endpoint in all patients (HR, 1.17; P=0.02), and in those with IHD (HR, 1.38; P=0.004), but not in those without IHD (HR, 1.12; P=0.22; P for interaction=0.12). Furthermore, when the patients were stratified by nephropathy, DM was associated with worse prognosis only in the IHD patients with nephropathy., Conclusions: The prognostic impact of DM was more evident in patients with IHD than in those without IHD, particularly when complicated with nephropathy.

Background: We aimed to elucidate the prognostic impact of anemia with special reference to the clinical background of patients with chronic heart failure (CHF)., Methods and results: We examined 4,646 consecutive patients with Stage C/D CHF registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (n=10,219). Among them, 1,627 (35%) had anemia and were characterized by higher age (74 vs. 66 years), lower estimated glomerular filtration rate (52.8 vs. 66.1 ml/min/1.73 m(2)) and higher B-type natriuretic peptide levels (154.5 vs. 81.8 pg/ml) (all P<0.001) but comparable left ventricular ejection fraction (LVEF; 57.5 vs. 56.7%). Anemic patients were more frequently treated with diuretics (55.1 vs. 42.3%) but less often treated with β-blockers (45.4 vs. 51.1%) (both P<0.001). During a median follow-up of 3.8 years, 371 and 272 patients died with and without anemia, respectively (22.8 vs. 9.0%, adjusted hazard ratio 1.40; 95% confidence interval 1.15-1.71, P=0.001). Subgroup analysis revealed that the prognostic impact of anemia was comparable in terms of age, sex, renal function and double product, but differed by LVEF level and CHF etiology (both, P for interaction <0.001). In particular, a difference in the prognostic impact of LVEF level was noted in patients with ischemic heart disease., Conclusions: These results indicate that the prognostic impact of anemia is evident in CHF patients with preserved EF and it differs by CHF etiology.

Background: Temporal trends in clinical characteristics, management and prognosis of patients with symptomatic heart failure (HF) remain to be elucidated in Japan., Methods and results: From the Chronic Heart Failure Analysis and Registry in the Tohoku District-1 (CHART-1; 2000-2005, n=1,278) and CHART-2 (2006-present, n=10,219) Studies, we enrolled 1,006 and 3,676 consecutive symptomatic stage C/D HF patients, respectively. As compared with the patients in the CHART-1 Study, those in the CHART-2 Study had similar age and sex prevalence, and were characterized by lower brain natriuretic peptide, higher prevalence of preserved left ventricular ejection fraction (LVEF) and higher prevalence of hypertension, diabetes mellitus and ischemic heart disease (IHD), particularly IHD with LVEF ≥50%. From CHART-1 to CHART-2, use of renin-angiotensin system inhibitors, β-blockers and aldosterone antagonists was significantly increased, while that of loop diuretics and digitalis was decreased. Three-year incidences of all-cause death (24 vs. 15%; adjusted hazard ratio [adjHR], 0.73; P<0.001), cardiovascular death (17 vs. 7%; adjHR, 0.38; P<0.001) and hospitalization for HF (30 vs. 17%; adjHR, 0.51; P<0.001) were all significantly decreased from CHART-1 to CHART-2. In the CHART-2 Study, use of β-blockers was associated with improved prognosis in patients with LVEF <50%, while that of statins was associated with improved prognosis in those with LVEF ≥50%., Conclusions: Along with implementation of evidence-based medications, the prognosis of HF patients has been improved in Japan. (, Trial Registration: clinicaltrials.gov identifier: NCT00418041)

Background: Microalbuminuria, traditionally defined as urinary albumin/creatinine ratio (UACR) ≥30 mg/g, is a risk factor for mortality even in patients with preserved glomerular filtration rate (GFR). The prognostic impact of subclinical microalbuminuria, however, remains unknown in patients with chronic heart failure (CHF). METHODS AND RESULTS: In the Chronic Heart Failure Analysis and Registry in the Tohoku District 2 Study, we enrolled 2,039 consecutive symptomatic CHF patients (median age, 67.4 years; 68.9% male) after excluding those on hemodialysis. On classification and regression tree analysis, UACR=10.2 mg/g and 27.4 mg/g were identified as the first and second discriminating points to stratify the risk for composite of death, acute myocardial infarction, HF admission and stroke, therefore subclinical microalbuminuria was defined as UACR ≥10.2 and <27.4 mg/g. There were 506 composite endpoints (24.8%) during the median follow-up of 2.69 years. On Kaplan-Meier analysis and multivariate Cox modeling, subclinical microalbuminuria was significantly associated with increased composite endpoints with hazard ratios of 1.90 (P<0.001) and 2.29 (P<0.001) in patients with preserved (>60 ml·min(-1)·1.73 m(-2), n=1,129) or mildly reduced eGFR (30-59.9 ml·min(-1)·1.73 m(-2), n=789), respectively. In patients with severely reduced GFR (eGFR <30 ml·min(-1)·1.73 m(-2), n=121), >80% had microalbuminuria or macroalbuminuria, and only 9.1% were free from any composite endpoints., Conclusions: Subclinical microalbuminuria was associated with increased risk of cardiovascular events in CHF patients with mildly reduced or preserved renal function.

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 We and others have previously reported that the Great East Japan Earthquake (GEJE) caused a significant but transient increase in cardiovascular diseases and deaths in the disaster area. However, it remains to be examined whether the GEJE had a long-term prognostic influence in large-scale cohort studies. This point is important when analyzing the data before and after the GEJE in the cohort studies in the disaster area. Methods We examined 8676 patients registered in our Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study ( N = 10,219) between 2006 and 2010 and were alive after March 10, 2011. Results There were 48 GEJE-related deaths, causing a sharp and transient increase in all-cause death within a month after the GEJE. However, after excluding the GEJE-related deaths, the cubic polynomial spline smoothing showed no significant increase in all-cause death, heart failure admission, non-fetal acute myocardial infarction, or non-fetal stroke during the median 3-year follow-up after the GEJE. The extrapolation curves beyond the GEJE, which were obtained by the parametric survival models based on the survival data censored on the GEJE, were not significantly different from the Kaplan–Meier curves estimating the survival functions of deaths and cardiac events during the total follow-up period without considering the impacts of the GEJE. Furthermore, the multivariate Cox proportional hazard model applied to the matched cohort of the baseline data and the data after the GEJE showed no significant differences in the impacts of prognostic factors on all-cause mortality before and after the GEJE. Conclusions These results indicate that the GEJE had no significant long-term prognostic impact after the earthquake in cardiovascular patients in the disaster area. [ABSTRACT FROM AUTHOR]