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Abstract: A 64-year-old woman with recurrent mitral valve stenosis was hospitalized 30 years after open commissurotomy. Severe right cerebral embolism occurred at age 58, with left hemiparesis. She was debilitated with cardiac cachexia. Based on symptomatic valvular disease findings, surgery was considered, but deemed too high risk due to the combined insufficiencies. She refused this surgical operation and requested conservative therapy. Optimized medication and cardiac rehabilitation improved her general condition allowing transfer to another hospital. We explained the short life expectancy both to her and to her family. They decided to transfer to a hospice at a chronic care hospital and she was given best supportive care. Eventually, her urine output decreased and respiration deteriorated. She and her family refused resuscitation in the event of cardiopulmonary arrest, requesting only suffering reduction. Thus, continuous intravenous infusion of morphine was started. The optimized doses for pain alleviation were determined in consultation with palliative care specialists and maximized her consciousness level for the last four days. “Heart-failure hospice” is potentially a place to die for end-of-life patients, attended by their families and healthcare providers. They need prognostic information and options for end-stage. Our experience confirms results about palliative care from previous studies conducted overseas demonstrating the effectiveness of opioids relieving end-stage symptoms. [Copyright &y& Elsevier]

Abstract: Background: Suppressed plasma B-type natriuretic peptide (BNP) levels have been reported in obese individuals with heart failure (HF). However, the precise mechanism and significance of this relationship in the clinical setting of HF are unknown. Recently, we reported a close association between BNP levels and left ventricular end-diastolic wall stress (EDWS) as the underlying mechanism of BNP secretion; therefore, we investigated the relationship between BMI and plasma BNP levels in HF while adjusting for EDWS. Methods and Results: In 245 consecutive patients who presented with HF, we measured plasma BNP levels and performed echocardiography and cardiac catheterization. Meridional EDWS was calculated from echocardiographic and hemodynamic parameters. The body mass index (BMI) for the total population was 22.9 ± 0.2 kg/m2; 21% were lean (BMI <20) and 27% overweight and obese (BMI ≥ 25). The correlation between plasma BNP and EDWS [r = 0.771 (P <.001)] was more robust than any other echocardiographic or hemodynamic parameter as well as any patient''s characteristics. By a univariate analysis, BMI was inversely correlated with both BNP levels and EDWS (P <.001 in both). However, a multivariable regression analysis that took into account EDWS demonstrated a significant inverse association between BMI and BNP (P <.001). Conclusion: The present study demonstrates that BMI determines the BNP level in a manner that is independent of the hemodynamic load in patients with HF. Overweight and obesity should be considered to be associated with the interindividual variability of plasma BNP levels in the diagnosis and management of HF patients. [Copyright &y& Elsevier]

Abstract: Cardiac apelin has recently been suggested to contribute to the pathophysiology of heart failure (HF) in humans. In animal experiments, its infusion acutely improved systolic as well as diastolic LV function. Although its deficit could critically determine the cardiac dysfunction, its regulatory mechanism is unknown. Accordingly, we investigated the role and regulation of the cardiac apelin system in the diseased heart using Dahl salt-sensitive rats, which show a distinctive transition from compensatory LV hypertrophy (LVH) to HF. In the compensatory LVH stage, apelin and its receptor APJ mRNA showed no change compared with control animals, while these were markedly down-regulated in the HF stage (72% and 57% decrease, respectively). The rats were chronically treated with telmisartan (angiotensin type 1 receptor blocker [ARB], 5 mg/kg/day, n =9), ONO-4817 (matrix metalloproteinase [MMP] inhibitor, 200 mg/kg/day, n =9), bisoprolol (β blocker, 3 mg/kg/day, n =6) or vehicle (0.5%CMC, n =9) from the LVH stage. Although the functional improvements were similar among the three treated groups 6 weeks after treatment, restoration of cardiac apelin and APJ expression was observed only in the ARB group. Furthermore, in angiotensin II-infused rats, cardiac apelin mRNA was decreased after 24 h of treatment and its restoration was achieved by treatment with ARB. These results indicate that the cardiac apelin system is markedly down-regulated in experimental HF and may be regulated by the angiotensin II–angiotensin type 1 receptor system directly. Inhibition of the renin–angiotensin system may have beneficial effects, at least in part, through restoration of the cardiac apelin system in the treatment of HF. [Copyright &y& Elsevier]

Adaptive servo-ventilation (ASV) therapy using an innovative ventilator-originally developed to treat sleep-disordered breathing (SDB)-is a novel modality of noninvasive positive pressure ventilation and is gaining acceptance among Japanese cardiologists in expectation of its applicability to treat patients with chronic heart failure (CHF) based on its acute beneficial hemodynamic effects. We conducted a multicenter, retrospective, real-world observational study in 115 Japanese patients with CHF, who had undergone home ASV therapy for the first time from January through December 2009, to examine their profile and the effects on their symptoms and hemodynamics. Medical records were used to investigate New York Heart Association (NYHA) class, echocardiographic parameters including left ventricular ejection fraction (LVEF), cardiothoracic ratio (CTR), brain natriuretic peptide (BNP), and other variables. Most of the patients were categorized to NYHA classes II (44.4 %) and III (40.7 %). SDB severity was not determined in 44 patients, and SDB was not detected or was mild in 27 patients. In at least 71 patients (61.7 %), therefore, ASV therapy was not applied for the treatment of SDB. CHF was more severe, i.e., greater NYHA class, lower LVEF, and higher CTR, in 87 ASV-continued patients (75.7 %) than in 28 ASV-discontinued patients (24.3 %). However, SDB severity was not related to continuity of ASV. The combined proportion of NYHA classes III and IV ( P = 0.012) and LVEF ( P = 0.009) improved significantly after ASV therapy. CTR and BNP did not improve significantly after ASV therapy but showed significant beneficial changes in their time-course analysis ( P < 0.05, respectively). Improvements in LVEF and NYHA class after ASV therapy were not influenced by SDB severity at onset. The present study suggests that ASV therapy would improve the symptoms and hemodynamics of CHF patients, regardless of SDB severity. A randomized clinical study to verify these effects is warranted. [ABSTRACT FROM AUTHOR]

Background Adaptive servo-ventilation (ASV) therapy, which is a form of noninvasive positive pressure ventilation therapy and uses an innovative ventilator that has simple operability and provides good patient adherence, potentially has therapeutic benefits—suppression of the deterioration and progression of chronic heart failure (CHF) and a reduction in the number of repeated hospitalizations. Therefore, ASV therapy draws attention as a novel, noninvasive nonpharmacotherapy for patients with CHF owing to its hemodynamics-improving effect, and it is currently being accepted in real-world clinical settings in Japan. However, clinical evidence sufficient for treatment recommendation is lacking because a multicenter, randomized, controlled study of ASV therapy has never been conducted. Methods/Design The present study is a confirmatory, prospective, multicenter, collaborative, open-label, blinded-endpoint, parallel-group, randomized, controlled study. At 40 medical institutions in Japan, 200 Japanese outpatients with mild to severe CHF (age: = 20 years; New York Heart Association classification: greater than or equal to class II) will be randomly assigned to either of the following two study groups: the ASV group, in which 100 outpatients undergo guideline-directed medical therapy and ASV therapy for 24 weeks; and the control group, in which 100 outpatients undergo only guideline-directed medical therapy for 24 weeks. The objective of the present study is to confirm whether the ASV group is superior to the control group concerning the improvement of left ventricular contractility and remodeling, both assessed by two-dimensional echocardiography. Furthermore, the present study will also secondarily examine the effects of ASV therapy on the prognosis and quality of life of patients with CHF. Discussion ASV therapy using the device has the potential to provide therapeutic benefits based on its simple operability and good patient adherence and possesses the potential to improve left ventricular contractility and remodeling. Therefore, the present study is expected to afford more solid scientific evidence regarding ASV therapy as a novel, noninvasive, nonpharmacological, in-home, long-term ventilation therapy for patients with mild to severe CHF. Trial registration UMIN identifier: UMIN000006549, registered on 17 October, 2011 (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type =summary&recptno = R000007761&language = J). [ABSTRACT FROM AUTHOR]

The effects of outpatient cardiac rehabilitation (OCR) implementation and home nursing-care services (HNS) use are not well defined in patients with heart failure (HF) with mid-range or preserved left-ventricular ejection fraction (EF) (HFmrEF or HFpEF). Through a post-hoc analysis of the HF registry in Hiroshima Prefecture of Japan (REAL-HF), we investigated the current conditions and significance of OCR and HNS in HFmrEF or HFpEF patients. The REAL-HF enrolled adult patients hospitalized with HF in eight regional core hospitals. Patients discharged home were followed for conditions of OCR and HNS and the primary endpoints (all-cause death or unscheduled readmission) for 1 year. The patients were classified into HF with reduced EF (< 40%) (HFrEF) or HFmrEF (40% ≤ EF < 50%) or HFpEF (EF ≥ 50%) group. We followed 195 HFrEF and 381 HFmrEF or HFpEF patients. OCR was generally underutilized, especially in HFmrEF or HFpEF patients (rate of completion [5-month program], 3.2%), whereas HFmrEF or HFpEF patients were more likely to use HNS after discharge home than HFrEF patients (44.1% vs. 27.2%, P < 0.0001). Patients with the use of HNS generally had lower scores of Mini-Mental State Examination and EuroQol 5 dimensions than those without. Multivariate analysis adjusted for medical and social factors showed that the completion of OCR was a strong negative predictor of the primary endpoints both in HFrEF (hazard ratio [HR] 0.10; 95% confidence interval [CI] 0.01–0.75; P = 0.025) and HFmrEF or HFpEF (HR 0.11; 95% CI 0.01–0.78; P = 0.028) patients, whereas the use of HNS was a positive predictor only in HFmrEF or HFpEF patients (HR 1.41; 95% CI 1.00–1.97; P = 0.047). In conclusion, continuous OCR, despite its inadequate implementation, was associated with favorable overall outcomes, while the necessity for HNS related to impaired cognitive function and quality of life was associated with poorer overall outcomes in HFmrEF or HFpEF patients discharged home. Further study is warranted to fully consider the factors related to OCR implementation and HNS use. [ABSTRACT FROM AUTHOR]

The development of a comprehensive assessment tool based on the International Classification of Functioning, Disability, and Health (ICF) for elderly patients with heart failure is urgently required. In this study, we classified the ICF categories relevant to heart failure in the elderly through a Delphi survey (3-step questionnaire survey) of 108 Registered Instructors of Cardiac Rehabilitation in the Hiroshima Prefecture. Questionnaires were conducted using postal mail or a web-based platform. The survey was conducted three times, and the survey results were provided as feedback to the participants in the second and third rounds. More than 80% of the respondents selected categories according to the ICF core set methodology. Data were collected from December 2018 to March 2019, with 67, 54, and 46 participants in the first, second, and third rounds, respectively. A total of 58 ICF items were adopted based on the results: 27 body function items, 4 body structure items, 20 activity and participation items, and 7 environmental factor items. This study is characterised by the inclusion of a large number of ICF items for mental function. This result seems to be influenced by the increasing interest in cognitive dysfunction in elderly patients with heart failure. The ICF categories selected for this study allow for a comprehensive assessment of clients for occupational therapy. The findings of this study are expected to provide a basis for an outcome measure to determine the effectiveness of occupational therapy for these patients. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) tachycardia causes heart failure and requires more attention. The genetic background of individual heart rate (HR) variations during AF are unclear. We hypothesized that HR-associated single nucleotide polymorphisms (SNPs) reported in Genome-Wide Association Studies (GWAS) are also associated with HR during AF. We enrolled patients with persistent AF (311 for screening and 146 for replication) who underwent AF ablation and were genotyped for the 21 h-associated SNPs reported in GWAS. The patients underwent 24-h Holter monitoring before AF ablation and electrophysiological study after AF ablation during sinus rhythm. Only the GJA1 SNP rs1015451 (T>C) was significantly associated with total HR (TT 110,643 ± 17,542 beats/day, TC 116,350 ± 19,060 beats/day, CC 122,163 ± 25,684 beats/day, P = 8.5 × 10−4). We also confirmed this significant association in the replication set. The intra-atrial conduction was faster in AF patients with the GJA1 minor allele than in those without it. Multivariate analysis revealed the presence of a GJA1 SNP rs1015451 additive model, female gender, lower left ventricular ejection fraction, and higher 1:1 atrioventricular nodal conduction were independently associated with higher HR during AF. The GJA1 SNP might be a new genetic marker for AF tachycardia. [ABSTRACT FROM AUTHOR]

Among heart failure patients diagnosed as having exertional oscillatory ventilation (OV), some present with OV at rest that persists during exercise, and others develop OV only after the onset of exercise during cardiopulmonary exercise (CPX) testing. We tested whether or not there was any difference in the prognostic significance between the two abnormal breathing patterns. Patients with New York Heart Association class III-heart failure were categorized into the following 3 groups according to their ventilation pattern during the CPX: patients with an OV pattern at rest that persisted for ≥60% of the exercise test at an amplitude of ≥15% of the average resting value (group 1), patients with the same abnormal ventilatory pattern as group 1 that was observed only during exercise (group 2), and patients without any OV (group 3). The patients were followed-up for at least 2 years to assess the composite outcome of cardiac death or hospitalization for worsening heart failure. The occurrence of the composite outcome differed significantly across the groups with its highest occurrence in group 1 (21/29 [72.4%], 15/38 [39.5%] and 48/167 [28.7%]; log-rank P < 0.001). In multivariate hazard analyses, an N-terminal pro-brain natriuretic peptide of >900 pg/mL (hazard ratio [HR] = 1.72, P = 0.04), and group 1 (HR 2.03, P = 0.02) were independently associated with the composite outcome. Checking for the resting OV prior to incremental exercise during CPX testing may be helpful in risk-stratification among subjects with advanced heart failure. • OV seen only during exercise never increased adverse cardiac events. • OV observed both during rest and exercise increased adverse cardiac events. • OV seen both during rest and exercise independently predicted cardiac events. [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure (HF) are reportedly at high risk for ‘all-cause’ re-hospitalization. A biomarker for HF, N-terminal pro-brain natriuretic peptide (NT-proBNP), enables to simply detect patients with possible HF (pHF). We examined the hospitalization and medical cost of Japanese patients detected by an elevated serum NT-proBNP, and also evaluated the effects of institutional team approaches for HF on their all-cause hospitalizations. Methods: We retrospectively extracted all adult patients with serum NT-proBNP ≥400 pg/ml measured between January and March 2012 in Hiroshima University Hospital as pHF-positive patients. We studied their all-cause hospitalization records during the past 3-year period. We also extracted all pHF-negative patients with NT-proBNP <400 pg/ml and studied as well. In the pHF-positive patients followed for 3 years after starting interprofessional team approaches to prevent the onset and exacerbation of HF in the hospital, we compared the hospitalization and medical cost between the 3-year periods before and after the start of the team approaches. Results: We enrolled 432 pHF-positive and 485 pHF-negative patients with one or more hospitalization records. Compared to the pHF-negative patients, the pHF-positive patients had longer total hospitalization days (median [interquartile range], 30 [13–58] versus. 18 [8–39], p <0.0001) and higher total medical cost for hospitalizations (2.42 [1.07–5.08] versus. 1.80 [0.79–3.65] million yen, p <0.0001). A subset of 303 pHF-positive patients was followed for 3 years after starting the team approaches, and we found that both total hospitalization days (30 [13–57] to 8 [0–31]) and medical cost for hospitalizations (2.59 [1.37–5.05] to 0.76 [0–2.38] million yen) showed marked reduction in them. Conclusions: Patients with an elevated serum NT-proBNP have longer hospitalizations and higher costs for all-cause hospitalizations than those without. Institutional team approaches for HF may reduce them. [ABSTRACT FROM AUTHOR]

Background Endothelial dysfunction and abnormal vascular structure may be involved in the pathogenesis of chronic heart failure (HF). The purpose of this study was to evaluate simultaneously vascular function and vascular structure in patients with heart failure with preserved ejection fraction (HFpEF). Methods We measured flow-mediated vasodilatation (FMD) and nitroglycerine-induced vasodilation as indices of vascular function and intima-media thickness (IMT) as an index of vascular structure of the brachial artery in 41 patients with HFpEF (23 men and 18 women; mean age, 66 ± 12 yr) and 165 patients without HF (95 men and 70 women; mean age, 54 ± 16 yr). Results FMD was significantly smaller in patients with HFpEF than in patients without HF (2.9 ± 2.1% versus 4.6 ± 2.7%, P = 0.0002). Nitroglycerine-induced vasodilation was significantly smaller in patients with HFpEF than in patients without HF (9.3 ± 4.1% versus 12.9 ± 4.9%, P < 0.0001). Brachial artery IMT was significantly larger in patients with HFpEF than in patients without HF (0.35 ± 0.06 mm versus 0.31 ± 0.07 mm, P = 0.0002). After adjustment for age, sex, hypertension, dyslipidemia, and diabetes mellitus, the associations remained significant between HFpEF and FMD (odds ratio, 0.79; 95% confidence interval, 0.66–0.92; P = 0.0032), nitroglycerine-induced vasodilation (odds ratio, 0.88; 95% confidence interval, 0.80–0.96; P = 0.0039), and brachial artery IMT (odds ratio, 1.08; 95% confidence interval, 1.01–1.17; P = 0.033). Conclusions These findings suggest that both endothelial dysfunction and abnormal vascular structure may contribute to the pathogenesis and maintenance of HFpEF. Endothelial function and vascular structure may be potential therapeutic targets for HFpEF. [ABSTRACT FROM AUTHOR]

Background Nearly half of patients with heart failure have normal left ventricular ejection fraction ( LVEF), but their prognosis is no better than those with reduced LVEF. Although peak oxygen consumption ( VO2) is an independent predictor of mortality in heart failure, it is unclear how cardiac function during exercise contributes to peak VO2. Therefore, we explored the useful parameters measured by exercise stress echocardiography to predict peak VO2 in patients with heart failure with preserved LVEF ( HFp EF). Methods and Results We assessed 80 patients being investigated for effort intolerance or dyspnea and finally analyzed 50 patients who satisfied the HFp EF criteria. Mean peak VO2 was 16.4±2.8 mL/kg/min. Twenty-three patients (46.0%) achieved a peak VO2 <16.0 mL/kg/min (Weber class C or D). There was a significant relationship between mitral systolic velocity (S′) and cardiac output ( CO) at rest ( R=.55, P<.0001) and peak exercise ( R=.64, P<.0001). The absolute increase in S′ from rest to peak exercise also correlated with the absolute increase in CO ( R=.32, P=.02). Multivariate logistic regression analysis showed that S′ at peak exercise independently predicted peak VO2. Receiver-operator characteristic curve analysis identified that an S′ at peak exercise of ≤8.13 cm/s predicted a peak VO2 <16.0 mL/kg/min (sensitivity 95.7%, specificity 44.4%, area under curve 0.70, 95% confidence interval 0.55-0.84, P=.004). Conclusions Mitral systolic velocity at peak exercise accurately reflects peak VO2 and may facilitate stratification of risk in patients with HFp EF. [ABSTRACT FROM AUTHOR]

Objectives: We explored the stimulus for B-type natriuretic peptide (BNP) secretion in the clinical setting of heart failure (HF). Background: Increasingly, plasma BNP levels are being incorporated into the clinical assessment and management of systolic heart failure (SHF) as well as diastolic heart failure (DHF). However, heterogeneity in BNP levels among individuals with HF can cause some confusion in interpreting results. Methods: In 160 consecutive patients presenting with HF, we measured plasma BNP levels and performed echocardiography and cardiac catheterization. Systolic and diastolic meridional wall stress was calculated from echocardiographic and hemodynamic data. Results: Although plasma BNP had a significant correlation (r2 = 0.296 [p < 0.001]) with left ventricular end-diastolic pressure (EDP) as previously reported, the correlation between plasma BNP and end-diastolic wall stress (EDWS) (r2 = 0.887 [p < 0.001]) was more robust. In a subanalysis of 62 patients with DHF, a similar result was obtained (r2 = 0.143 for EDP and r2 = 0.704 for EDWS). In a comparison between SHF and DHF, the BNP level was significantly higher in SHF (p < 0.001). Although EDP did not show any difference, EDWS was significantly higher in SHF than in DHF (p < 0.001). Conclusions: The present study shows that plasma BNP levels reflect left ventricular EDWS more than any other parameter previously reported, not only in patients with SHF, but also in patients with DHF. The relationship of left ventricular EDWS to plasma BNP may provide a better fundamental understanding of the interindividual heterogeneity in BNP levels and their clinical utility in the diagnosis and management of HF. [Copyright &y& Elsevier]

Background: It is known that arginine vasopressin (AVP) level is secreted in patients with heart failure. Recent studies have shown that plasma AVP level is proportional to the severity of heart failure. However, there is little information on the relationship between plasma AVP level and cardiac events after initiation of heart failure treatment. The purpose of this study was to evaluate the relationship between plasma AVP level one week after hospitalization and cardiac event. Methods: In 91 patients with congestive heart failure, plasma AVP levels were measured at hospitalization and one week after hospitalization. We evaluated length of hospital stay and cardiac events (cardiac death and re-hospitalization of heart failure). Results: The average of length of hospital stay was 19 days, we divided the length of hospital stay into two groups within 19 days (short term hospitalization group; SH group) or more (long term hospitalization group; LH group). In 38 cases, cardiac events were observed during the follow up period. Plasma AVP level one week after hospitalization was significantly lower in the SH group than in the LH group (3.01±1.54 vs. 6.91±6.44 pg/ml, P<0.001, respectively), whereas there was no significant difference in Plasma AVP levels at hospitalization between the SH group and LH group. Plasma AVP level one week after hospitalization was significantly higher in the cardiac events group than in the event free group (7.61±6.43 vs. 3.04±2.28 pg/ml, P<0.001, respectively), whereas there was no significant difference in plasma AVP level at hospitalization between the cardiac event group and event free group. Conclusions: Plasma AVP level one week after hospitalization was significantly higher in LH group and cardiac events group. These findings suggest that plasma AVP level one week after hospitalization may be a predictor of the prognosis of patients with congestive heart failure. [ABSTRACT FROM AUTHOR]

Introduction: The usefulness of vascular function tests for management of patients with a history of coronary artery disease (CAD) is not fully known. Methods: We measured flow-mediated vasodilation (FMD) and brachial-ankle pulse wave velocity (baPWV) in 462 patients with CAD for assessment of the predictive value of vascular function tests for future cardiovascular events in a prospective multicenter observational study. The primary outcome was coronary events, and the secondary outcome was a composite of coronary events, stroke, heart failure, and sudden death. Results: During a median follow-up period of 49.2 months, the primary outcome occurred in 56 patients and the secondary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver-operator curve analyses for the primary and secondary outcomes, was significantly associated with lower risk of the primary (hazard ratio, 0.27; 95% confidence interval [CI], 0.06-0.74; P=0.008) and secondary (hazard ratio, 0.32; 95% CI, 0.09-0.79; P=0.01) outcomes. baPWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the primary (hazard ratio, 1.86; 95% CI, 1.01-3.44; P=0.04) and secondary (hazard ratio, 2.19; 95% CI, 1.23-3.90; P=0.008) outcomes. Among four groups stratified according to the combination of cutoff values of FMD and baPWV, stepwise increases in the calculated risk ratio for the primary and secondary outcomes were observed. Conclusions: In patients with CAD, both FMD and baPWV were independent predictors of cardiovascular events. The combination of FMD and baPWV provided further cardiovascular risk stratification. [ABSTRACT FROM AUTHOR]