Elevated Serum Non-HDL (High-Density Lipoprotein) Cholesterol and Triglyceride Levels as Residual Risks for Myocardial Infarction Recurrence Under Statin Treatment.

Objective- Secondary prevention for recurrent myocardial infarction (MI) is one of the most important therapeutic goals in patients with old MI (OMI). Although statins are widely used for this purpose, there remains considerable residual risk even after LDL (low-density lipoprotein cholesterol) is well controlled by statins. Approach and Results- We examined clinical impacts of nHDL (nonhigh-density lipoprotein cholesterol) and its major components triglyceride and LDL as residual risks for acute MI recurrence, using the database of our CHART (Chronic Heart Failure Analysis and Registry in the Tohoku District)-2 Study, the largest-scale cohort study of cardiovascular patients in Japan. We enrolled 1843 consecutive old MI patients treated with statins (mean age 67.3 years, male 19.2%) in the CHART-2 Study. The incidence of recurrent acute MI during the median 8.6-year follow-up was compared among the groups divided by the levels of nHDL (<100, 100-129, and ≥130 mg/dL), LDL (<70, 70-99, and ≥100 mg/dL), triglyceride (<84, 84-149, and ≥150 mg/dL), and combination of LDL and triglyceride. Kaplan-Meier curves and multiple Cox proportional hazards models showed that higher levels of nHDL, but not LDL or triglyceride alone, were associated with higher incidence of recurrent acute MI. Furthermore, higher triglyceride levels were associated with higher incidence of recurrent MI in patients with LDL <100 mg/dL but not in those with LDL ≥100 mg/dL. Conclusions- These results indicate that management of residual risks for acute MI recurrence should include nHDL management considering both LDL and triglyceride in old MI patients under statin treatment. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00418041.

Comparable prognostic impact of BNP levels among HFpEF, Borderline HFpEF and HFrEF: a report from the CHART-2 Study.

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 log2 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.

Prognostic Impact of Atrial Fibrillation and New Risk Score of Its Onset in Patients at High Risk of Heart Failure　- A Report From the CHART-2 Study.

BACKGROUND: The prognostic impact of atrial fibrillation (AF) among patients at high risk for heart failure (HF) remains unclear. In addition, there is no risk estimation model for AF development in these patients.Methods and Results:The present study included 5,382 consecutive patients at high risk of HF enrolled in the CHART-2 Study (n=10,219). At enrollment, 1,217 (22.6%) had AF, and were characterized, as compared with non-AF patients, by higher age, lower estimated glomerular filtration rate, higher B-type natriuretic peptide (BNP) level and lower left ventricular ejection fraction. A total of 116 non-AF patients (2.8%) newly developed AF (new AF) during the median 3.1-year follow-up. AF at enrollment was associated with worse prognosis for both all-cause death and HF hospitalization (adjusted hazard ratio (aHR) 1.31, P=0.027 and aHR 1.74, P=0.001, for all-cause death and HF hospitalization, respectively) and new AF was associated with HF hospitalization (aHR 4.54, P<0.001). We developed a risk score with higher age, smoking, pulse pressure, lower eGFR, higher BNP, aortic valvular regurgitation, LV hypertrophy, and left atrial and ventricular dilatation on echocardiography, which effectively stratified the risk of AF development with excellent accuracy (AUC 0.76). CONCLUSIONS: These results indicated that AF is associated with worse prognosis in patients at high risk of HF, and our new risk score may be useful to identify patients at high risk for AF onset.

Prognostic Impact of Loop Diuretics in Patients With Chronic Heart Failure　- Effects of Addition of Renin-Angiotensin-Aldosterone System Inhibitors and ß-Blockers.

BACKGROUND: It remains to be elucidated whether addition of renin-angiotensin-aldosterone system (RAAS) inhibitors and/or ß-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 ß-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 ß-blocker(s) is associated with better prognosis when combined with low-dose loop diuretics. (Circ J 2016; 80: 1396-1403).

Prognostic Impact of New-Onset Atrial Fibrillation in Patients With Chronic Heart Failure - A Report From the CHART-2 Study.

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 ß-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.

Temporal trends in clinical characteristics, management and prognosis of patients with symptomatic heart failure in Japan -- report from the CHART Studies.

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, ß-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 ß-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)

Clinical characteristics and prognostic factors in elderly patients with chronic heart failure -A report from the CHART-2 study.

BACKGROUND: Since most of the randomized clinical trials for heart failure (HF) were designed to exclude elderly patients, limited data are available on their clinical characteristics, prognosis, and prognostic factors. METHODS: We compared clinical characteristics, prognosis, and prognostic factors among Stage C/D HF patients in our CHART-2 Study (N = 4876, mean 69 years, women 32%, 6.3-year follow-up) by age (G1, ≤64 years, N = 1521; G2, 65-74 years, N = 1510; and G3, ≥75 years, N = 1845). RESULTS: From G1 to G3, the prevalence of women, left ventricular ejection fraction (LVEF) and plasma levels of B-type natriuretic peptide (BNP) increased (all P < 0.001). Similarly, 5-year mortality increased (9.9, 17.3 to 39.9%, P < 0.001) along with a decrease in proportion of cardiovascular death and an increase in non-cardiovascular death in both sexes. While all-cause and cardiovascular mortality was comparable between the sexes, women had significantly lower incidence of non-cardiovascular death than men in G2 and G3, which was attributable to the higher incidence of cancer death and pneumonia death in men than in women. Although NYHA functional class III-IV, chronic kidney disease, cancer, LVEF, and BNP had significant impacts on all-cause death in all groups, their impacts were less evident in G3 as compared with G1. CONCLUSIONS: The elderly HF patients, as compared with younger HF patients, were characterized by more severe clinical background, increased proportion of non-cardiovascular death and worse prognosis with different impacts of prognostic factors across the age groups.

Association between temporal changes in C-reactive protein levels and prognosis in patients with previous myocardial infarction - A report from the CHART-2 Study.

BACKGROUND: Several studies have reported that C-reactive protein (CRP), an inflammatory biomarker, predicts cardiovascular events independently of low-density lipoprotein cholesterol levels. However, no study examined whether temporal changes in CRP levels are associated with clinical events in patients with previous myocardial infarction (MI). METHODS AND RESULTS: We examined 2184 consecutive patients with previous MI and CRP data at baseline in the Chronic Heart Failure Registry and Analysis in the Tohoku district-2 (CHART-2) Study. During the median 6.4 years follow-up, 592 all-cause, 245 cardiovascular, and 273 non-cardiovascular deaths occurred. Patients with CRP ≥ 2.0 mg/L at baseline had significantly increased incidence of all-cause (hazard ratio (HR) 1.68, P < 0.001) and non-cardiovascular death (HR 1.86, P < 0.001), compared with those with CRP < 2.0 mg/L. Temporal changes in CRP levels were associated with prognosis; among patients with CRP ≥ 2.0 mg/L at baseline, those with CRP ≥ 2.0 mg/L at 1-year had significantly increased incidence of all-cause (HR 2.12, P < 0.001), cardiovascular (HR 2.31, P < 0.001), and non-cardiovascular death (HR 2.29, P < 0.001). Among patients with CRP < 2.0 mg/L at baseline, those with CRP ≥ 2.0 mg/L at 1-year had significantly increased incidence of all-cause (HR 1.76, P < 0.001) and cardiovascular death (HR 2.10, P = 0.001). These results remained significant after adjusted with the inverse probability of treatment weighted models using propensity sore. Furthermore, as compared with patients with CRP < 2.0 mg/L at both baseline and 1-year, those with CRP ≥ 2.0 mg/L at both baseline and 1-year had increased incidence of all-cause, cardiovascular, and non-cardiovascular death. CONCLUSIONS: These results provide the evidence that temporal increases in CRP levels are associated with increased clinical events in patients with previous MI.

Gender differences in prognostic relevance of self-care behaviors on mortality and hospitalization in patients with heart failure - A report from the CHART-2 Study.

BACKGROUND: Self-care behaviors (ScB) are associated with symptoms and outcomes in patients with heart failure (HF). However, little is known about gender differences in the prognostic relevance of ScB in HF patients. METHODS: We examined gender differences in ScB of HF patients regarding its prognostic associations with mortality and HF hospitalization with a reference to ScB dimensions. The European Heart Failure Self-Care Behavior Scale (EHFScBS) was used to evaluate ScB in 2233 patients with Stage C/D HF in the CHART-2 Study. RESULTS: Male patients (n=1583) were younger (71 vs. 73 yrs) and had lower ScB (median 33 vs. 31) (all p<0.001) than females (n=650). During the median follow-up of 2.57 years, patients with high ScB (score 12-32, n=1090), as compared with low ScB patients (score 33-60, n=1143), had significantly increased all-cause mortality in males [adjusted hazard ratio (aHR) 1.44, p=0.02] but not in females (aHR 0.80, p=0.40) (p for interaction 0.02), while ScB was not significantly associated with incidence of HF hospitalization in both genders. Among the 3 dimensions in EHFScBS, complying with regimen was associated with decreased mortality in females, but not in males (p for interaction 0.003), while asking for help was related with increased incidence of HF hospitalization in males (aHR 1.34, p=0.072) but not in females (aHR 0.98, p=0.931) (p for interaction 0.048). CONCLUSIONS: There were gender differences in the prognostic relevance of self-care with mortality and incidence of HF hospitalization, suggesting that self-care should be implemented considering gender differences to improve prognosis.

Prognostic impact of residual stenosis after percutaneous coronary intervention in patients with ischemic heart failure - A report from the CHART-2 study.

BACKGROUND: Complete revascularization with PCI is not always achieved in patients with ischemic HF. Therefore, this study aimed to elucidate the prognostic impact of residual coronary stenosis (RS) after percutaneous coronary intervention (PCI) in patients with ischemic heart failure (HF). METHODS: We analyzed a total of 1307 patients with symptomatic HF and a history of PCI registered in our Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study. RS that was defined as the presence of ≥70% luminal stenosis in major coronary arteries at the last coronary angiography. RESULTS: Among the study population, 851 patients (65.1%) had RS. During a median follow-up period of 3.2 years, patients with RS had higher all-cause mortality than those without it even after propensity score matching (21.9 vs. 11.6%, log-rank P = 0.027). Multivariable Cox hazard analysis also showed the negative impact of RS on all-cause death in ischemic HF patients [hazard ratio (HR):1.62, 95% confidence interval (CI): 1.07-2.46, P = 0.024]. Importantly, when divided all subjects into three subgroups by left ventricular ejection fraction (LVEF) [LVEF < 40% (HFrEF), LVEF 40-49% (HFmrEF), and LVEF ≥ 50% (HFpEF)], inverse probability of treatment weighted method provided a similar result that RS after PCI was an independent risk factor for death in the HFpEF [HR(95%CI); 1.94(1.22-3.09), P < 0.01] and HFmrEF [4.47(1.13-14.98), P < 0.01] groups, but not in the HFrEF group [1.20(0.59-2.43), P = 0.62]. CONCLUSIONS: These results indicate that RS after PCI could aggravate long-term prognosis of ischemic HF patients with moderate- to well-preserved EF, but not those with reduced EF.

Increased risk of cancer death in patients with chronic heart failure with a special reference to inflammation-A report from the CHART-2 Study.

BACKGROUND: Although several factors, including heart failure (HF) and inflammation, are known to increase the incidence of cancer, it remains unknown whether HF may increase cancer mortality, especially with a reference to inflammation. METHODS AND RESULTS: We examined 8843 consecutive cardiovascular patients without a prior history of cancer in our CHART-2 Study (mean 68 yrs., female 30.9%). As compared with patients without HF (Stage A/B, N = 4622), those with HF (Stage C/D, N = 4221) were characterized by higher prevalence of diabetes, previous myocardial infarction, atrial fibrillation, and stroke. During the median 6.5-year follow-up (52,675 person-years), 282 cancer deaths occurred. HF patients had significantly higher cancer mortality than those without HF in both the overall (3.7 vs, 2.8%, hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.12-1.79, P = 0.004) and the propensity score-matched cohorts (HR 1.46, 95%CI 1.10-1.93, P = 0.008), which was confirmed in the competing risk models. The multivariable Cox proportional hazard model in the matched cohort showed that HF was associated with increased cancer mortality in patients with C-reactive protein (CRP) ≥ 2.0 mg/L (HR 1.87, 95%CI 1.18-2.96, P = 0.008) at baseline, but not in those with CRP < 2.0 mg/L (HR 0.89, 95%CI 0.54-1.45, P = 0.64) (P for interaction = 0.03). Furthermore, temporal changes in CRP levels were associated with cancer death in the overall cohort; HF patients with CRP ≥ 2.0 mg/L at both baseline and 1-year had significantly increased cancer death, while those with CRP ≥ 2.0 mg/L at baseline and < 2.0 mg/L at 1-year not. CONCLUSIONS: These results provide the first evidence that HF is associated with increased cancer death, especially when associated with prolonged inflammation.

The 3A3B score: The simple risk score for heart failure with preserved ejection fraction - A report from the CHART-2 Study.

BACKGROUND: Few simple risk models, without echocardiography have been developed for patients with heart failure (HF) and preserved left ventricular ejection fraction (LVEF) (HFpEF). METHODS: To develop a risk score to predict all-cause death for HFpEF patients, we examined 1277 HF patients with LVEF ≥50% and BNP ≥100 pg/ml in the CHART-2 Study, a large-scale prospective cohort study for HF in Japan. We selected the optimal subset of covariates for the score with Cox proportional hazard models and random survival forests (RSF). RESULTS: During the median 5.7-year follow-up, 576 deaths occurred. Cox models and RSF analyses consistently indicated age ≥75 years, albumin <3.7 g/dl, anemia, BMI <22 kg/m2, BNP ≥300 pg/ml (or NT-proBNP ≥1400 pg/ml), and BUN ≥25 mg/dl, as the important 6 prognostic variables. Incorporating these 6 variables, we developed a scoring system (3A3B score, with 2 points given to age ≥75 years and 1 point to the others based on the hazard ratios. The discrimination ability of the risk score was excellent (c-index 0.708). Regarding model goodness-of-fit, the overall gradient in 5-year risk was well captured by the score. The predictive accuracy of the 3A3B score was confirmed in the external validation cohorts from the TOPCAT trial (N = 835, c-index 0.652) and the ASIAN-HF registry (N = 170, c-index 0.741). CONCLUSIONS: We developed a simple risk score to predict long-term prognosis of HFpEF patients. The 3A3B score, comprising 6 commonly available parameters in daily practice, has potential utility in the risk stratification and management of HFpEF patients.

Prognostic Impact of Statin Intensity in Heart Failure Patients With Ischemic Heart Disease: A Report From the CHART-2 (Chronic Heart Failure Registry and Analysis in the Tohoku District 2) Study.

BACKGROUND: The beneficial prognostic impact of statins has been established in patients with ischemic heart disease but not in those with heart failure (HF). In addition, it is still unclear whether patients benefit from statins regardless of low-density lipoprotein cholesterol levels. METHODS AND RESULTS: We examined 2444 consecutive stage C or D HF patients with ischemic heart disease registered in CHART-2 (Chronic Heart Failure Registry and Analysis in the Tohoku District 2), a multicenter, prospective, observational cohort study in Japan. Patients were divided into 3 groups according to the Japanese standard doses of statins and statin-intensity categories defined by the 2013 American College of Cardiology and American Heart Association guidelines: higher (moderate-high)-intensity (n=868), lower (low)-intensity (n=526), and no statin (n=1050). The median follow-up period was 6.4 years (13929 person-years). Analysis with the inverse probability of treatment weighted using a propensity score for multiple treatment revealed that both the higher-intesity group (hazard ratio [HR]: 0.68; P<0.001) and the lower-intensity group (HR: 0.82; P<0.001) had significantly lower incidence of the primary end point-a composite of all-cause death and HF admission-compared with the no statin group. The higher-intensity statin group had significantly lower incidence of the primary end point (HR: 0.82; P<0.001), all-cause death (HR: 0.83; P<0.001), and HF admission (HR: 0.78; P<0.001) than the lower-intensity statin group. Moreover, the use of statins, either higher- or lower-intensity, was associated with reduced incidence of the primary end point, regardless of low-density lipoprotein cholesterol levels. CONCLUSIONS: These results suggest that statin use, particularly the use of higher-intensity statins, has a beneficial prognostic impact in HF patients with ischemic heart disease, regardless of low-density lipoprotein cholesterol levels. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00418041.

[Evaluation of efficacy and safety of manidipine hydrochloride among essential hypertensive patients: Substitution from branded product (Calslot) to Generic Product (Manidip)].

Calcium channel blockers are most commonly used in hypertensive patients in Japan. However, information on the efficacy and safety of generic calcium channel blockers is insufficient. The objective of the present study was to retrospectively evaluate the efficacy and safety of manidipine hydrochloride in 21 essential hypertensive patients (mean age; 70.6+/-10.6 years, male/female; 14/7) in Sendai Postal Services Agency Hospital who were switched (substituted) from a brand product (Calslot) to a generic product (Manidip). For this retrospective study, we used data from patient medical records and drug prescription information. Data from patients who were taking both types of manidipine hydrochloride, whose regimen were not changed for > 6 months before and after switching, and who provided informed consent were included in the analysis. Control values of blood pressure were not significantly different between before and after substitution (systolic/diastolic; from 137.9+/-9.1/78.7+/-5.4 mmHg to 137.3+/-9.1/77.8+/-6.3 mmHg, p=0.73/p=0.36). The level of patient compliance for the antihypertensive drugs was also not different between before and after substitution (from 94.0+/-8.8% to 93.1+/-9.6%, p=0.72). There were 8 cases of adverse effects before substitution and 4 after substitution. No patient stopped taking the generic drug due to an adverse effect. In conclusion, significant differences in the efficacy, safety, and patient compliance were not observed between the brand product and generic product among patients who were switched from the brand product to the generic product.

Sex differences in post-traumatic stress disorder in cardiovascular patients after the Great East Japan Earthquake: a report from the CHART-2 Study.

Aims: The temporal changes and sex differences in post-traumatic stress disorder (PTSD) after natural disasters remain unclear. Therefore, we examined the prevalence, prognostic impacts, and determinant factors of PTSD after the Great East Japan Earthquake (GEJE) of 11 March 2011 in cardiovascular (CV) patients registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-2 Study (n = 10 219), with a special reference to sex. Methods and results: By self-completion questionnaires of the Japanese-language version of the Impact of Event Scale-Revised (IES-R-J), the prevalence of PTSD, defined as IES-R-J score ≥25, was 14.8, 15.7, 7.4, and 7.5% in 2011, 2012, 2013, and 2014, respectively. The PTSD rate was higher in women than in men in all years (all P < 0.01). During a median 3.5-year follow-up period, the patients with PTSD in 2011 more frequently experienced a composite of all-cause death and hospitalization for acute myocardial infarction, stroke, and heart failure than those without PTSD [adjusted hazard ratio (aHR) 1.27, P < 0.01]. Importantly, the prognostic impacts of PTSD on all-cause death (aHR 2.10 vs. 0.87, P for interaction = 0.03) and CV death (aHR 3.43 vs. 0.90, P for interaction = 0.02) were significant in women but not in men. While insomnia medication was a prominent determinant factor of PTSD in both sexes during 2011-14, economic poverty was significantly associated with PTSD only in men. Conclusion: After the GEJE, marked sex differences existed in the prevalence, prognostic impacts, and determinant factors of PTSD, suggesting the importance of sex-sepcific mental stress care in disaster medicine.

Long-term prognostic impact of the Great East Japan Earthquake in patients with cardiovascular disease - Report from the CHART-2 Study.

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.

Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.

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.

Characteristics of resistant hypertension determined by self-measured blood pressure at home and office blood pressure measurements: the J-HOME study.

OBJECTIVES: To diagnose resistant hypertension using self-measured blood pressure (BP) at home and office BP, and to evaluate the characteristics of resistant hypertensive patients. METHODS: The subjects were 528 hypertensive patients taking at least three or more different antihypertensive drugs. Subjects were classified into four groups (controlled hypertension, isolated office resistant hypertension, isolated home resistant hypertension and sustained resistant hypertension) on the basis of the cut-off values of home BP (135/85 mmHg) and office BP (140/90 mmHg). The relationship between each resistant hypertension group and various factors was analysed using univariate and multivariate analyses. RESULTS: Of the 528 patients, 17.8% were classified with controlled hypertension, 16.1% with isolated office resistant hypertension, 23.5% with isolated home resistant hypertension and 42.6% with sustained resistant hypertension. The presence of hypercholesterolemia was found to have a significant and independent association with isolated office resistant hypertension. Higher office systolic blood pressure (SBP), a past history of ischaemic heart disease, and a lower prescription rate of potassium-sparing diuretics were found to have a significant and independent association with isolated home resistant hypertension. Patients with sustained resistant hypertension had a significantly lower prescription rate of potassium-sparing diuretics than those with controlled hypertension. CONCLUSIONS: The present study demonstrated that resistant hypertension is mediated at least partly by the white-coat effect. Home BP measurements and other relevant factors associated with resistant hypertension, such as relatively higher office SBP, type of drugs prescribed, and cardiovascular complications, should be taken into account for the diagnosis and treatment of resistant hypertension.

Current usage of diuretics among hypertensive patients in Japan: the Japan Home versus Office Blood Pressure Measurement Evaluation (J-HOME) study.

In the Japan Home versus Office Blood Pressure Measurement Evaluation (J-HOME) study, we examined the current situation with respect to the prescription of diuretics, including the prevalence of diuretic treatment and the dosages used for patients with essential hypertension in primary care settings. Of the 3,400 hypertensive patients included in the study, 315 (9.3%) patients (mean age: 66.9+/-10.4 years; males: 43.5%) were prescribed diuretics. Compared with patients who were not using diuretics, those who were using diuretics were more obese and had more complications. The most commonly prescribed diuretic among the 331 prescriptions in the 315 diuretic users was trichlormethiazide (44%), followed by indapamide (15%) and spironolactone (14%). Among patients being treated with diuretics, monotherapy was used in only 5% of patients; in the majority of patients combination therapy including diuretics (95%) was used. Relatively low dosages of diuretics were generally used. There was a difference between the actual dosages prescribed and those recommended by the Japanese Society of Hypertension (JSH) guidelines or the product information approved in Japan. Compared with previous estimates of the prevalence of diuretic use in hypertensives in Japan (4.0-5.4%), the rate in the J-HOME study (9.3%) was higher. This may be attributable at least in part to the results of the many published, large-scale intervention trials confirming the clinical significance of diuretics. Although a relatively high dosage is recommended in the diuretic product information and in the JSH guidelines, dosages of diuretics should be reconsidered in Japan.

The current status of home and office blood pressure control among hypertensive patients with diabetes mellitus: the Japan Home Versus Office Blood Pressure Measurement Evaluation (J-HOME) study.

Although self-measured blood pressure (BP) at home (HBP) has become popular in clinical practice, little information is available regarding the proportion of diabetic patients with properly controlled HBP. We evaluated the status of HBP control in diabetic hypertensives. HBP control status was cross-sectionally evaluated among 3400 essential hypertensives taking antihypertensive treatment. Of these, 466 (14%) had diabetes. Physicians evaluated the subjects' HBP control as "poor", "fairly good", or "excellent" using a self-administered questionnaire. When the HBP threshold in diabetic patients was set tentatively at 130/80 mmHg or 135/85 mmHg, HBP was properly controlled in 18% or 30% of diabetic patients, respectively. The same trend was observed in office BP. The average number of drugs prescribed for diabetic patients was 2.0 drugs. In the majority of diabetic patients with uncontrolled BP, the BP control status in two-thirds of those was evaluated as "excellent" or "fairly good" by their physicians. In Japan, HBP and office BP were not adequately controlled in most diabetic hypertensives. The main reason for this would appear to be a lack of intensive treatment and a lack of recognition by physicians that their patients' BP was insufficiently controlled.