Combined Fat Mass and Fat-free Mass Indices and Lung Function Among Japanese Population: The Tohoku Medical Megabank Community-based Cohort Study.

BACKGROUND: Although fat mass index (FMI) and fat-free mass index (FFMI) affect lung function, FMI and FFMI are not independent of each other, since FMI and FFMI were calculated as fat mass and fat-free mass divided by height squared, respectively. We aimed to examine the association of combined FMI and FFMI with lung function. METHODS: In this cross-sectional study, lung function was evaluated using forced expiratory volume at 1 s (FEV1) and forced vital capacity (FVC) measured using spirometry. Both FMI and FFMI were classified into sex-specific quartiles (16 groups). Analysis of covariance was used to assess the associations of combined FMI and FFMI with lung function. The trend test was conducted by stratifying the FMI and FFMI, scoring the categories from 1-4 (lowest-highest), and entering the number as a continuous term in the regression model. RESULTS: This study included 3,736 men and 8,821 women aged ≥20 years living in Miyagi Prefecture, Japan. The mean FEV1 was 3.0 (standard deviation [SD], 0.7) L for men and 2.3 (SD, 0.5) L for women. The mean FVC was 3.8 (SD, 0.7) L for men and 2.8 (SD, 0.5) L for women. FMI was inversely associated with lung function among all FFMI subgroups in both sexes. Conversely, FFMI was positively associated with lung function in all FMI subgroups in both sexes. CONCLUSION: Higher FMI was associated with lower lung function independent of FFMI; higher FFMI was associated with higher lung function independent of FMI. Reducing FMI and maintaining FFMI might be important for respiratory health.

End-of-Life Discussions and Their Timing for Patients With Cardiovascular Diseases　- From the Perspective of Bereaved Family Members.

BACKGROUND: Enhanced discussions regarding end-of-life (EOL) are crucial to provide appropriate care for seriously ill patients. However, the current status of EOL discussions, especially their timing and influencing factors, among patients with cardiovascular diseases (CVD) remains unknown.Methods and Results: We conducted a cross-sectional questionnaire survey of bereaved family members of CVD patients who died at 10 tertiary care institutes in Japan. In all, 286 bereaved family members (38.2% male; median age 66.0 [interquartile range 58.0-73.0] years) of CVD patients were enrolled; of these, 200 (69.9%) reported that their families had had EOL discussions with physicians. The major topic discussed was resuscitation (79.0%), and 21.5% discussed the place of EOL care. Most discussions were held during hospitalization of the patient (88.2%). More than half (57.1%) the discussions were initiated less than 1 month before the patient died, and 22.6% of family members felt that this timing of EOL discussions was late. Bereaved family members' perception of late EOL discussions was associated with the family members aggressive attitude towards life-prolonging treatment, less preparedness for bereavement, and less satisfaction with EOL care. CONCLUSIONS: Approximately 70% of bereaved family members of CVD patients had EOL discussions, which were often held shortly before the patient died. Further research is required to establish an ideal approach to EOL discussions at an appropriate time, which may improve the quality of EOL care.

Sex Differences in Long-Term Outcomes in Patients With Chronic Coronary Syndrome After Percutaneous Coronary Intervention　- Insights From a Japanese Real-World Database Using a Storage System.

BACKGROUND: Several studies have reported some sex differences in patients with coronary artery diseases. However, the results regarding long-term outcomes in patients with chronic coronary syndrome (CCS) are inconsistent. Therefore, the present study investigated sex differences in long-term outcomes in patients with CCS after percutaneous coronary intervention (PCI).Methods and Results: This was a retrospective, multicenter cohort study. We enrolled patients with CCS who underwent PCI between April 2013 and March 2019 using the Clinical Deep Data Accumulation System (CLIDAS) database. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, or hospitalization for heart failure. In all, 5,555 patients with CCS after PCI were included in the analysis (4,354 (78.4%) men, 1,201 (21.6%) women). The median follow-up duration was 917 days (interquartile range 312-1,508 days). The incidence of MACE was not significantly different between the 2 groups (hazard ratio [HR] 1.20; 95% confidential interval [CI] 0.97-1.47; log-rank P=0.087). After performing multivariable Cox regression analyses on 4 different models, there were still no differences in the incidence of MACE between women and men. CONCLUSIONS: There were no significant sex differences in MACE in patients with CCS who underwent PCI and underwent multidisciplinary treatments.

Relationships Among Heart Rate, ß-Blocker Dosage, and Prognosis in Patients With Coronary Artery Disease in a Real-World Database Using a Multimodal Data Acquisition System.

BACKGROUND: The optimal heart rate (HR) and optimal dose of ß-blockers (BBs) in patients with coronary artery disease (CAD) have been unclear. We sought to clarify the relationships among HR, BB dose, and prognosis in patients with CAD using a multimodal data acquisition system.Methods and Results: We evaluated the data for 8,744 CAD patients who underwent cardiac catheterization from 6 university hospitals and the National Cerebral and Cardiovascular Center and who were registered using the Clinical Deep Data Accumulation System. Patients were divided into quartile groups based on their HR at discharge: Q1 (HR <60 beats/min), Q2 (HR 60-66 beats/min), Q3 (HR 67-74 beats/min), and Q4 (HR ≥75 beats/min). Among patients with acute coronary syndrome (ACS) and patients with chronic coronary syndrome (CCS), those in Q4 (HR ≥75 beats/min) had a significantly greater incidence of major adverse cardiac and cerebral events (MACCE) compared with those in Q1 (ACS patients: hazard ratio 1.65, P=0.001; CCS patients: hazard ratio 1.45, P=0.019). Regarding the use of BBs (n=4,964), low-dose administration was significantly associated with MACCE in the ACS group (hazard ratio 1.41, P=0.012), but not in patients with CCS after adjustment for covariates. CONCLUSIONS: HR ≥75 beats/min was associated with worse outcomes in patients with CCS or ACS.

Endoscopic radial incision and cutting for benign stenosis of the lower gastrointestinal tract: An investigation of novel endoscopic treatment in multicenter trial.

BACKGROUND AND AIM: The standard therapies for benign gastrointestinal stenosis are endoscopic balloon dilation or surgery; each have their advantages and disadvantages. In contrast, radial incision and cutting (RIC) is a novel approach for such stenosis. This study aimed to investigate the feasibility, safety, and effectiveness of RIC. METHODS: We enrolled 20 patients with benign stenosis of the lower gastrointestinal tract developed by various causes and conducted RIC. We evaluated the re-intervention free rate 52 weeks after RIC, technical success rate, adverse events, procedure time, and improvement of symptoms using a visual analog scale. RESULTS: We performed 20 sessions of first RIC for 20 lesions and seven sessions of additional RIC due to re-stenosis. The cumulative re-intervention-free survival rate 52 weeks after the first RIC was 55.8%. The technical success rate of the first RIC was 100% (20/20) while that of the additional RIC was 85.7% (6/7). One case developed perforation during the additional RIC and urgent surgery was performed. The additional RIC tended to show worse results in adverse events and procedure time compared with the first RIC. The patients' symptoms including abdominal bloating and dyschezia were significantly improved. CONCLUSIONS: Although RIC demonstrated a higher technical success rate for lower gastrointestinal stricture and subsequent improvement of patient symptoms, several issues including preventing delayed bleeding, perforation, and the long-term prognosis should be solved and clarified in further investigations.

Worsening Right Ventricular Function during Cardiac Surgery Is a Strong Predictor of Postoperative Acute Kidney Injury: A Prospective Observational Study.

This prospective, observational study was conducted in a university hospital to verify that intraoperative worsening of right ventricular function causes cardiac surgery-associated acute kidney injury. Adult patients undergoing cardiac surgery under mid-sternal incision with cardiopulmonary bypass were included. Echocardiographic right and left ventricular function parameters were measured before and after bypass and compared using the Wilcoxon signed-rank test. Perioperative serum creatinine values at baseline and within the first 48 hours postoperatively were measured for the diagnosis of acute kidney injury. Spearman rank-order correlation (ρ) and receiver operating characteristic analysis were used to reveal relationships. Thirty-four patients were evaluated. Right ventricular ejection fraction (56.2 ± 7.0 vs. 51.6 ± 7.2%; P = 0.0002), right ventricular fractional area change (49.1 ± 6.4 vs. 46.6 ± 5.3%; P = 0.0201; mean ± standard deviation), and left ventricular ejection fraction (57.4 ± 6.1 vs. 51.7 ± 6.2%; P < 0.0001) were significantly decreased. Central venous pressure was significantly increased (7.2 ± 3.5 vs. 9.7 ± 3.7; P = 0.0001). Serum creatinine values increased from 0.82 [0.70-1.08] to 0.99 [0.82-1.54] mg/dL (P < 0.0001; median [interquartile range]). Changes in right ventricular ejection fraction, fractional area change, and right ventricular strain during cardiovascular surgery were significantly correlated with changes in serum creatinine values. Fractional area change exhibited the strongest correlation (ρ = -0.61, P < 0.0001). Change in fractional area change showed an area under the curve of 0.902 and a cutoff value of -2.1, which predicted acute kidney injury with 92% sensitivity, 73% specificity, and 79% accuracy. The functions of both ventricles were decreased after cardiopulmonary bypass. Worsening right ventricular function was independently correlated with postoperative renal dysfunction, and fractional area change was the strongest predictor of cardiac surgery-associated acute kidney injury.

Usefulness of Right Ventricular Free Wall Strain Obtained with Two-Dimensional Speckle-Tracking Echocardiography in Patients with Repaired Tetralogy of Fallot and Pulmonary Regurgitation.

Right ventricular (RV) dysfunction caused by chronic pulmonary regurgitation (PR) is a major determinant of clinical outcome in adults with repaired tetralogy of Fallot (rTOF). However, the accurate assessment of RV function by conventional echocardiography remains challenging. This study tested the feasibility and usefulness of RV free-wall (RVFW) strain obtained by two-dimensional (2D) speckle-tracking echocardiography (STE) in evaluation of RV function in adults with rTOF by comparing cardiac magnetic resonance (CMR) imaging. We enrolled 22 consecutive patients (male/female, 8/14; mean age, 25.0 years) with rTOF who underwent transthoracic echocardiography at Tohoku University Hospital from July 2016 to June 2019. We measured RVFW strain by STE and compared them with 22 hemodynamically normal subjects (NOR) (male/female, 9/13; mean age, 32.0 years). The correlation between RV strain and CMR-derived RV ejection fraction (RVEF) or PR fraction (PRF) were also evaluated. All rTOF patients had more than moderate PR but were near asymptomatic. RVFW longitudinal strain (RVFW-LS) was significantly decreased in the rTOF group compared with that in the NOR group (-19.6 vs. -24.7, P < 0.01). In the rTOF group, RVFW-LS correlated with PRF (r = 0.44, P < 0.05), whereas RVFW circumferential strain at the mid-ventricular level correlated with RVEF (r = 0.57, P < 0.01). Intra-observer variability of RVFW strain was acceptable. These results indicate that RV systolic function and PR severity in rTOF could be assessed by RVFW strain measured by 2D STE. This method is feasible and can be used as a complement to CMR imaging.

Marked Impairment of Endothelium-Dependent Digital Vasodilatations in Patients With Microvascular Angina: Evidence for Systemic Small Artery Disease.

OBJECTIVE: It remains to be elucidated whether and how endothelial functions are impaired in peripheral circulation of patients with coronary functional disorders, such as vasospastic angina (VSA) and microvascular angina (MVA). We simultaneously examined endothelial functions of peripheral conduit and resistance arteries in patients with coronary functional disorders, with a special reference to NO and endothelium-dependent hyperpolarization factors. Approach and Results: Based on the results of invasive coronary acetylcholine testing and coronary physiological measurements, we divided 43 patients into 3 groups; VSA, MVA, and VSA+MVA. Endothelium-dependent vasodilatations of the brachial artery and fingertip arterioles to intra-arterial infusion of bradykinin were simultaneously evaluated by ultrasonography and peripheral arterial tonometry, respectively. To assess NO and endothelium-dependent hyperpolarization factors, measurements were repeated after oral aspirin and intra-arterial infusion of NG-monomethyl-L-arginine. Additionally, endothelium-independent vasodilatations to sublingual nitroglycerin and plasma levels of biomarkers for endothelial functions were measured. Surprisingly, digital vasodilatations to bradykinin were almost absent in patients with MVA alone and those with VSA+MVA compared with those with VSA alone. Mechanistically, both NO- and endothelium-dependent hyperpolarization-mediated digital vasodilatations were markedly impaired in patients with MVA alone. In contrast, endothelium-independent vasodilatations to nitroglycerin were comparable among the 3 groups. Plasma levels of soluble VCAM (vascular cell adhesion molecule)-1 were significantly higher in patients with MVA alone compared with those with VSA alone. CONCLUSIONS: These results provide the first evidence that both NO- and endothelium-dependent hyperpolarization-mediated digital vasodilatations are markedly impaired in MVA patients, suggesting that MVA is a cardiac manifestation of the systemic small artery disease.

Study Profile of the Tohoku Medical Megabank Community-Based Cohort Study.

BACKGROUND: We established a community-based cohort study to assess the long-term impact of the Great East Japan Earthquake on disaster victims and gene-environment interactions on the incidence of major diseases, such as cancer and cardiovascular diseases. METHODS: We asked participants to join our cohort in the health check-up settings and assessment center based settings. Inclusion criteria were aged 20 years or over and living in Miyagi or Iwate Prefecture. We obtained information on lifestyle, effect of disaster, blood, and urine information (Type 1 survey), and some detailed measurements (Type 2 survey), such as carotid echography and calcaneal ultrasound bone mineral density. All participants agreed to measure genome information and to distribute their information widely. RESULTS: As a result, 87,865 gave their informed consent to join our study. Participation rate at health check-up site was about 70%. The participants in the Type 1 survey were more likely to have psychological distress than those in the Type 2 survey, and women were more likely to have psychological distress than men. Additionally, coastal residents were more likely to have higher degrees of psychological distress than inland residents, regardless of sex. CONCLUSION: This cohort comprised a large sample size and it contains information on the natural disaster, genome information, and metabolome information. This cohort also had several detailed measurements. Using this cohort enabled us to clarify the long-term effect of the disaster and also to establish personalized prevention based on genome, metabolome, and other omics information.

Sex- and age-related differences in the predictive capability of circulating biomarkers: from the MONICA 10 cohort.

OBJECTIVES: The purpose of this study was to assess whether high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and soluble urokinase plasminogen activator receptor (suPAR) differed in their ability to predict cardiovascular outcomes beyond traditional risk factors in younger and older men and women without known cardiovascular disease. Design. Prospective population-based cohort study of 1951 individuals from the MONItoring of trends and determinants in Cardiovascular disease (MONICA) study, examined 1993-1994. Participants were stratified into four groups based on sex and age. Subjects aged 41 or 51 years were classified as younger; those aged 61 or 71 years were classified as older. The principal endpoint was death from cardiovascular causes. Predictive capabilities of biomarkers were tested using Cox proportional-hazards regression, Harrell's concordance-index, net reclassification improvement, and classification and regression tree (CART) analysis. Results. Median follow-up was 18.5 years, during which 19/597 younger men, 100/380 older men, 12/607 younger women, and 46/367 older women had died from a cardiovascular cause. NT-proBNP was independently associated with death from cardiovascular causes among all participants (p ≤ .02) except younger women (p = .70), whereas hs-CRP was associated with this endpoint in men (p ≤ .007), and suPAR in older men only (p < .001). None of the biomarkers improved discrimination ability beyond traditional risk factors (p ≥ .07). However, NT-proBNP enhanced reclassification in men and older women. CART-analysis showed that NT-proBNP was generally of greater value among men, and suPAR among women. Conclusions. Hs-CRP, NT-proBNP, and suPAR displayed different associations with cardiovascular death among apparently healthy younger and older men and women.

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.

Factors limiting habitual exercise in patients with chronic heart failure: a multicenter prospective cohort study.

Physical activity (PA) in the daily life is strongly related to prognosis in patients with or at high risk of heart failure (HF). However, factors limiting habitual exercise and their prognostic impacts remain unknown in HF patients. We sent questionnaires asking factors limiting habitual exercise in the daily life to 8370 patients with Stage A/B/C/D HF in our nationwide registry and received valid responses from 4935 patients (mean age 71.8 years, 71.0% male). Among the 5 components consisting of "busyness", "weak will", "dislike, "socioeconomic reasons" and "diseases" in the questionnaires, "busyness" (34.5%) and "diseases" (34.7%) were the most frequently reported factors limiting habitual exercise, while "socioeconomic reasons" were the least (15.3%). Multiple Cox proportional hazard models indicated that "busyness"and "diseases" were associated with better (hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.39-0.72, P < 0.001) and worse prognosis (HR 1.57, 95% CI 1.21-1.98, P < 0.001), respectively, while other components were not. Furthermore, it was noted that, while prognostic relevance of "busyness" limiting exercise did not differ by age or sex, negative impact of "diseases" was particularly evident in patients with age < 75 years (P for interaction < 0.01). Factors limiting habitual exercise were associated with "busyness" and "diseases", but not with "weak will", "dislike, or "socioeconomic reasons". While "busyness" was associated with better prognosis regardless of age and sex, "diseases" was associated with worse prognosis in younger populations. Thus, physicians may pay more attentions to the reasons that limit exercise in the daily lives of HF patients rather than the low amount of exercise itself.

Nationwide Survey of Hospitalization Due to Pediatric Food-Induced Anaphylaxis in the United States.

OBJECTIVE: Anaphylaxis is a common, serious, systemic allergic reaction. In the United States, the change of annual hospitalization rates by anaphylaxis-trigger foods and risk factors associated with severity remain unclear. METHODS: Hospital discharge records of food-induced anaphylactic reactions of individuals younger than 20 years were obtained from Kids' Inpatient Database in 2006, 2009, and 2012 and were weighted to estimate the number of hospitalizations in the United States. We identified annual hospitalization rates by patients' characteristics and anaphylaxis-trigger foods and investigated factors associated with severity and use of mechanical ventilation with multivariable logistic regression. RESULTS: A total of 3427 hospitalizations were obtained, and annual hospitalization rates showed a significantly increasing trend from 1.2 per 100,000 children in 2006 to 1.5 per 100,000 children in 2012 (P < 0.001). The leading causes of hospitalizations due to food-induced anaphylaxis were peanuts (0.35-0.48 per 100,000 children), tree nuts and seeds (0.20-0.32 per 100,000 children), and milk products (0.09-0.13 per 100,000 children), with significantly increasing trends during 2006-2012. Milk products were significantly associated with severity (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.3-2.9). Ages between 13 and 20 years (OR, 2.7; 95% CI, 1.4-5.1) and comorbidity of asthma (OR, 2.1; 95% CI, 1.3-3.4) were significantly associated with the use of mechanical ventilation. CONCLUSIONS: The annual hospitalization rates in the entire United States showed an increasing trend during 2006-2012. The rates of peanuts, tree nuts and seeds, and milk products demonstrated upward trends. Milk products, ages between 13 and 20 years, and comorbidities of asthma were related to severity and morbidity.

Second generation drug-eluting stents versus bare-metal stents for percutaneous coronary intervention of the proximal left anterior descending artery: An analysis of the BASKET-PROVE I and II trials.

OBJECTIVES: To compare mid-term outcomes between patients undergoing proximal left anterior descending artery (LAD) percutaneous coronary intervention (PCI) with second generation drug-eluting stent (DES) or bare-metal stent (BMS). BACKGROUND: PCI with BMS and first-generation DES have shown to be safe options for the treatment of proximal LAD stenosis, however associated with considerable reintervention rates. Overall, second-generation DES has proven to be superior to BMS and first-generation DES, nevertheless, its effect for proximal LAD PCI has not previously been reported. METHODS: We analyzed 2-year outcomes of 1,100 patients from the BASKET-PROVE I and II trials, referred for proximal LAD PCI with second generation DES (n = 680) or BMS (n = 420). RESULTS: The cumulative 2-year incidence of major adverse cardiac events (MACE, composite of cardiac death, myocardial infarction (MI) and target vessel revascularization (TVR)) was lower in second generation DES than in BMS treated patients (7.3% vs. 12.3%; HR 0.57, 95% CI 0.39/0.85), mainly driven by a reduced rate of TVR (3.7% vs. 10.0%; HR 0.35, CI 0.21/0.58). No difference was found in cardiac death (1.9% vs. 1.9%; HR 1.01, CI 0.42/2.44) and MI (4.4% vs. 4.7%; HR 0.93, CI 0.53/1.64). The benefit of DES use seemed to be more prominent in female patients with a reduction in MACE (P for interaction = 0.025). CONCLUSIONS: In patients with proximal LAD stenosis, treatment with second-generation DES was associated with reduced 2-year rates of adverse cardiac events and TVR compared to BMS, with reintervention rates similar to those earlier reported from bypass surgery.

Sex differences in hemodynamic responses and long-term survival to optimal medical therapy in patients with pulmonary arterial hypertension.

It is widely known that the incidence of pulmonary arterial hypertension (PAH) is higher in female, whereas prognosis is poorer in male patients. However, sex differences in hemodynamic response to and long-term prognosis with PAH-targeted treatment in the modern era remain to be fully elucidated. We examined the long-term prognosis of 129 consecutive PAH patients (34 males and 95 females) diagnosed in our hospital from April 1999 to October 2014, and assessed hemodynamic changes in response to PAH-targeted therapy. Female patients had better 5-year survival compared with male patients (74.0 vs. 53.4%, P = 0.003); however, higher age quartiles in females were associated with poor outcome. Follow-up examination after medical treatment showed significant decreases in mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and pulmonary arterial capacitance (PAC) in both sexes (both P < 0.05), whereas only females had a significant improvement in right ventricular end-diastolic pressure (RVEDP), right atrial pressure (RAP), cardiac index, and mixed venous oxygen saturation (SvO2) (all P < 0.05). Baseline age significantly correlated with the hemodynamic changes only in female patients; particularly, there were significant sex interactions in RVEDP and RAP (both P < 0.10). The multivariable analysis showed that SvO2 at baseline and mPAP and SvO2 at follow-up were significant prognostic factors in males, whereas the changes in mPAP, PVR, and PAC and use of endothelin-receptor antagonist in females. These results indicate that female PAH patients have better long-term prognosis than males, for which better improvements of right ventricular functions and hemodynamics may be involved.

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.

The first multicenter, randomized, controlled trial of home telemonitoring for Japanese patients with heart failure: home telemonitoring study for patients with heart failure (HOMES-HF).

Home telemonitoring is becoming more important to home medical care for patients with heart failure. Since there are no data on home telemonitoring for Japanese patients with heart failure, we investigated its effect on cardiovascular outcomes. The HOMES-HF study was the first multicenter, open-label, randomized, controlled trial (RCT) to elucidate the effectiveness of home telemonitoring of physiological data, such as body weight, blood pressure, and pulse rate, for Japanese patients with heart failure (UMIN Clinical Trials Registry 000006839). The primary end-point was a composite of all-cause death or rehospitalization due to worsening heart failure. We analyzed 181 recently hospitalized patients with heart failure who were randomly assigned to a telemonitoring group (n = 90) or a usual care group (n = 91). The mean follow-up period was 15 (range 0-31) months. There was no statistically significant difference in the primary end-point between groups [hazard ratio (HR), 0.95; 95% confidence interval (CI), 0.548-1.648; p = 0.572]. Home telemonitoring for Japanese patients with heart failure was feasible; however, beneficial effects in addition to those of usual care were not demonstrated. Further investigation of more patients with severe heart failure, participation of home medical care providers, and use of a more integrated home telemonitoring system emphasizing communication as well as monitoring of symptoms and physiological data are required.

Combination Therapy of Renin Angiotensin System Inhibitors and ß-Blockers in Patients with Heart Failure.

Renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system play crucial roles in heart failure with reduced ejection fraction (HFrEF). Clinical trials provide strong evidence of prognostic benefits for combination therapy with angiotensin-converting enzyme inhibitor (ACEI) and ß-blocker in the treatment of HFrEF. Angiotensin receptor blocker (ARB) is not superior to ACEI in improving mortality and an alternative for patients who are intolerant to ACEI. Prognostic evidence for triple therapy which combined angiotensin receptor blocker (ARB) and ACEI in addition to ß-blocker therapy, is still controversial in HFrEF. Moreover, a recent clinical trial showed that triple therapy did not provide additional benefit compared with ACEI or ARB therapy alone in mildly symptomatic HFrEF. Of note, the triple therapy can even cause harm and renal dysfunction in HF with a history of hypertension. Direct renin inhibitor (DRI) has the theoretical benefit of upstream RAAS inhibition at the point of pathway activation. However, the results from clinical trials do not support upstream renin inhibition by DRI in addition to standard therapy with ACEI in patients with HFrEF. Angiotensin receptor-neprilysin inhibitor (ARNI) which combines a neprilysin inhibitor and ARB valsartan have a unique mode of action targeting both RAAS and the natriuretic peptide systems. In contrast to the evidence in HFrEF, clinical value of combination therapy with RAAS inhibitors and ß-blocker is not well established in HF with preserved EF (HFpEF). The heterogeneity of diagnostic criteria and baseline characteristics of HFpEF need further evidence for the combination therapy. However, a recent clinical trial of LCZ696 showed promising results in reducing NT-proBNP in patients with HFpEF.

Transition of Left Ventricular Ejection Fraction in Heart Failure.

Along with a worldwide epidemiological transition and dramatic increase in the elderly population, both the incidence and prevalence of heart failure (HF) are increasing worldwide. This epidemic of HF is characterized by an increase of HF with preserved left ventricular ejection fraction (LVEF) (HFpEF) and a decrease of HF with reduced LVEF (HFrEF). Of note, transition between HFpEF and HFrEF has been recently highlighted, since it significantly relates with prognosis. Our recent studies indicated that temporary changes in LVEF are common and associated with prognosis in patients with HF. In this chapter, we summarize recent findings on temporal changes in LVEF and their prognostic impact in HF patients, acknowledging that further studies are needed to fully elucidate the pathophysiology of LVEF recovery and deterioration to improve clinical outcomes of HF patients, and also to develop therapies targeting novel pathways of myocardial recovery.

Comprehensive evaluation of the effectiveness and safety of balloon pulmonary angioplasty for inoperable chronic thrombo-embolic pulmonary hypertension: long-term effects and procedure-related complications.

AIMS: Although balloon pulmonary angioplasty (BPA) improves haemodynamics and short-term prognosis in patients with inoperable chronic thrombo-embolic pulmonary hypertension (CTEPH), the long-term effects of BPA, and procedure-related complications remain to be fully elucidated. METHODS AND RESULTS: From July 2009 to October 2016, we performed a total of 424 BPA sessions in 84 consecutive patients with inoperable CTEPH. We used 3D reconstructed computed tomography to determine target lesions of pulmonary arteries and optical computed tomography to select balloon size, if needed. In 77 patients (92%) who completed the BPA treatment [65 ± 14 (SD) years-old, male/female 14/63], haemodynamics and exercise capacity were examined at 6 months after last BPA and in the chronic phase [>12 months after first BPA, 31 (20, 41) months]. The BPA treatment significantly improved mean pulmonary arterial pressure (38 ± 10 to 25 ± 6 mmHg), pulmonary vascular resistance (7.3 ± 3.2 to 3.8 ± 1.0 Wood units), and 6-minute walk distance (380 ± 138 to 486 ± 112 m) (all P < 0.01), and the improvements persisted throughout the follow-up period (43 ± 27 months) (N = 53). In the 424 sessions, haemoptysis was noted in 60 sessions (14%), and non-invasive positive pressure ventilation (NPPV) was used to treat haemoptysis and/or hypoxemia in 33 sessions (8%). Furthermore, 5-year survival was 98.4% (only one patient died of colon cancer) with no peri-procedural death. CONCLUSION: These results indicate that BPA improves haemodynamics and exercise capacity in inoperable CTEPH patients with acceptable complication rate and that the beneficial haemodynamic effects of BPA persist for years with resultant good long-term prognosis.