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Background: Whether comprehensive risk assessment predicts post-referral outcome in patients with pulmonary arterial hypertension (PAH) referred for lung transplantation (LT) in Japan is unknown., Methods and Results: We retrospectively analyzed 52 PAH patients referred for LT. Risk status at referral was assessed using 3- and 4-strata models from the 2022 European Society of Cardiology and European Respiratory Society guidelines. The 3-strata model intermediate-risk group was further divided into 2 groups based on the median proportion of low-risk variables (modified risk assessment [MRA]). The primary outcome was post-referral mortality. During follow-up, 9 patients died and 13 patients underwent LT. There was no survival difference among 3-strata model groups. The 4-strata model classified 33, 16, and 3 patients as low intermediate, high intermediate, and high risk, respectively. The 4-strata model identified high-risk patients with a 1-year survival rate of 33%, but did not discriminate survival between the intermediate-risk groups. The MRA classified 15, 28, 8, and 1 patients as low, low intermediate, high intermediate, and high risk, respectively. High intermediate- or high-risk patients had worse survival (P<0.001), with 1- and 3-year survival rates of 64% and 34%, respectively. MRA high intermediate- or high-risk classification was associated with mortality (hazard ratio 12.780; 95% confidence interval 2.583-63.221; P=0.002)., Conclusions: Patients classified as high intermediate or high risk by the MRA after treatment should be referred for LT.

Background: With aging population, the prevalence and incidence of heart failure (HF) have been increasing worldwide. However, the characteristics and outcomes of patients with HF in an era of aging are not well established in Japan., Methods and results: The Japanese Registry Of Acute Decompensated Heart Failure (JROADHF), a retrospective, multicenter, nationwide registry, was designed to study the clinical characteristics and outcomes of patients hospitalized with HF throughout Japan in 2013. One hundred and twenty-eight hospitals were selected by cluster random sampling and 13,238 hospitalized patients with HF were identified by medical record review. Demographics, medical history, severity, treatment, and in-hospital and long-term outcome data were collected from the Diagnostic Procedure Combination and medical charts. Data were analyzed using univariate and multivariate logistic regression or Cox regression analysis. The mean age of registered patients was 78.0±12.5 years and 52.8% were male. Elderly patients (age >75 years) accounted for 68.9%, and HF with preserved ejection fraction (HFpEF) accounted for 45.1%. Median length of hospital stay was 18 days and in-hospital mortality was 7.7%. The median follow-up period was 4.3 years, and the incidence rates for cardiovascular death and rehospitalization for HF were 7.1 and 21.1 per 100 person-years, respectively., Conclusions: A contemporary nationwide registry demonstrated that hospitalized HF patients were very elderly, HFpEF was common, and their prognosis was still poor in Japan.

Background: The trend of the initial treatment strategy for pulmonary arterial hypertension (PAH) has changed from monotherapies to upfront combination therapies. This study analyzed treatments and outcomes in Japanese patients with PAH, using data from the Japan PH Registry (JAPHR), which is the first organized multicenter registry for PAH in Japan.Methods and Results:We studied 189 consecutive patients (108 treatment-naïve and 81 background therapy patients) with PAH in 8 pulmonary hypertension (PH) centers enrolled from April 2008 to March 2013. We performed retrospective survival analyses and analyzed the association between upfront combination and hemodynamic improvement, adjusting for baseline NYHA classification status. Among the 189 patients, 1-, 2-, and 3-year survival rates were 97.0% (95% CI: 92.1-98.4), 92.6% (95% CI: 87.0-95.9), and 88.2% (95% CI: 81.3-92.7), respectively. In the treatment-naïve cohort, 33% of the patients received upfront combination therapy. In this cohort, 1-, 2-, and 3-year survival rates were 97.6% (95% CI: 90.6-99.4), 97.6% (95% CI: 90.6-99.4), and 95.7% (95% CI: 86.9-98.6), respectively. Patients on upfront combination therapy were 5.27-fold more likely to show hemodynamic improvement at the first follow-up compared with monotherapy (95% CI: 2.68-10.36)., Conclusions: According to JAPHR data, initial upfront combination therapy is associated with improvement in hemodynamic status.

Background: Selexipag is an orally available prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. In this open-label Phase II trial, the efficacy and safety of selexipag in Japanese patients with pulmonary arterial hypertension (PAH) is examined.Methods and Results:Selexipag was administered at 200 μg twice daily and titrated up to 1,600 μg by increments of 200 μg in 37 subjects to reach the individual maximum tolerated dose. At 16 weeks, in 33 patients comprising the per-protocol set, the pulmonary vascular resistance (PVR; primary endpoint) decreased from 683.2±237.3 to 560.3±238.7 dyn·s/cm 5 (P<0.0001). For the secondary endpoint, the 6-min walk distance (6MWD) increased from 445.0±102.2 to 459.1±112.8 m (P=0.0324); World Health Organization functional class improved in 4 patients (12.1%), and was maintained in 29 patients (87.9%). A decrease in PVR was also shown in patients treated with selexipag, on top of a phosphodiesterase inhibitor and endothelin receptor antagonist. Most of the commonly reported adverse events were consistent with those reported for other PGI 2 formulations. Thirty-four patients attained the individual maximum tolerated dose (maintenance dose)., Conclusions: The efficacy and tolerability of selexipag in Japanese PAH patients was confirmed by improvement in pulmonary hemodynamics, exercise capacity, symptoms. Selexipag is an efficacious treatment option for Japanese PAH patients. (Trial registration: JAPIC Clinical Trials Information [JapicCTI-111532].).

Background: Macitentan is a novel, dual endothelin receptor antagonist with sustained receptor binding, used for the long-term treatment of pulmonary arterial hypertension (PAH). In the present study, we assessed the efficacy and safety of macitentan in Japanese patients with PAH., Methods and results: Macitentan was administered at a once-daily dose of 10 mg in 30 patients. The primary endpoint was change in pulmonary vascular resistance (PVR) from baseline to week 24. Change to week 24 in the other hemodynamic parameters, 6-min walk distance (6MWD), World Health Organization (WHO) functional class, and plasmaN-terminal pro-brain natriuretic peptide (NT-pro-BNP), as well as time to clinical deterioration up to week 52 were also assessed as secondary endpoints. In the 28 patients on per-protocol analysis, PVR decreased from 667±293 to 417±214 dyn·sec·cm(-5)(P<0.0001). 6MWD increased from 427±128 to 494±116 m (P<0.0001). WHO functional class improved in 13 patients (46.4%) and was maintained in 15 patients (53.6%), and NT-pro-BNP was reduced by 18% (P<0.0001). The favorable treatment effect on PVR was apparent regardless of concomitant therapy for PAH., Conclusions: Macitentan was efficacious and well tolerated and improved the hemodynamic parameters, exercise capacity, symptoms, and clinical biomarkers in Japanese PAH patients. Macitentan can be a valuable therapeutic option for Japanese patients with PAH. (, Trial Registration: JAPIC Clinical Trials Information [JapicCTI-121986].) (Circ J 2016; 80: 1478-1483).

Background: Although destination therapy (DT) is now expected to be a promising strategy for those who are not suitable for heart transplantation in Japan, there has not been any investigation into ineligibility for bridging to implantable left ventricular assist device (I-LVAD) as DT among patients with extracorporeal LVAD., Methods and results: We retrospectively studied 85 patients who had received an extracorporeal LVAD. To assess ineligibility for a bridge to I-LVAD for DT, we defined DT ineligibility (DTI) as BiVAD requirement, death within 6 months, and persistent end-organ dysfunction (medium or high J-VAD risk score) at 6 months after extracorporeal LVAD implantation. DTI was recorded for 32 patients. Uni/multivariate analysis showed that smaller left ventricular diastolic dimension (<64 mm; [odds ratio (OR) 4.522]), continuous hemodiafiltration (OR 4.862), past history of cardiac surgery (OR 6.522), and low serum albumin level (<3.1 g/dl; OR 10.064) were significant predictors of DTI. By scoring 2, 2, 3, 4 points, respectively, considering each OR, we constructed a novel scoring system for DTI (DTI score), which stratified patients into 3 risk strata: low (0-3 points), medium (4-6 points), and high (7-11 points), from the view point of DTI risk (low 8%, medium 46%, high 93%, respectively)., Conclusions: DTI score is a promising tool for predicting ineligibility for I-LVAD as DT before extracorporeal VAD implantation.

Background: Although cardiopulmonary exercise (CPX) testing is an established tool for predicting survival in patients with heart failure (HF), its prognostic impact on explantation of left ventricular assist device (LVAD) was unknown. METHODS AND RESULTS: We enrolled 33 patients who had undergone implantation of extracorporeal pulsatile flow LVAD and symptom-limited CPX testing at 3 months after operation, and who were followed between 2005 and 2014. Patients who received conversion to continuous flow LVAD were excluded. On Cox regression analysis, E1 (maximum load ≥51W; HR, 27.55), E2 (minute ventilation/carbon dioxide output [V̇E/V̇CO2] slope ≤34; HR, 16.86), and E3 (peak oxygen consumption [PV̇O2] ≥12.8 ml·kg(-1)·min(-1); HR, 18.35) significantly predicted explantation expectancy during 2 years after LVAD implantation (P<0.05 for all). Explantation score, the sum of positive E1-3, significantly stratified 2-year cumulative explantation rate into low (0 points), intermediate (1-2 points), and high (3 points) expectancy groups (0%, 29%, and 86%, respectively, P<0.001). When the scoring system was used for 45 patients with continuous flow LVAD, the 2 patients who had explantation were assigned to the high expectancy group., Conclusions: Explantation score, calculated simply from 3 postoperative symptom-limited CPX testing parameters, is a novel tool to predict explantation expectancy of LVAD and to select good candidates for the weaning test.

Background: Improving quality of life (QOL) has become an important goal in left ventricular assist device (LVAD) therapy. We aimed (1) to assess the effect of an implantable LVAD on patients' QOL, (2) to compare LVAD patients' QOL to that of patients in different stages of heart failure (HF), and (3) to identify factors associated with patients' QOL., Methods and results: The QOL of 33 Japanese implantable LVAD patients was assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and Short-form 8 (SF-8), before and at 3 and 6 months afterwards. After LVAD implantation, QOL significantly improved [MLHFQ, SF-8 physical component score (PCS), SF-8 mental component score (MCS), all P<0.05]. Implanted LVAD patients had a better QOL than extracorporeal LVAD patients (n=33, 32.1±21.9 vs. n=17, 47.6±18.2), and Stage D HF patients (n=32, 51.1±17.3), but the score was comparable to that of patients who had undergone a heart transplant (n=13). In multiple regression analyses, postoperative lower albumin concentration and right ventricular failure were independently associated with poorer PCS. Female sex and postoperative anxiety were 2 of the independent factors for poorer MCS (all P<0.05)., Conclusions: Having an implantable LVAD improves patients' QOL, which is better than that of patients with an extracorporeal LVAD. Both clinical and psychological factors are influence QOL after LVAD implantation.

Background: Although intra-aortic balloon pump (IABP) is sometimes used before cardiac surgery to achieve better outcome in high-risk patients, the clinical impact of prophylactic IABP support before left ventricular assist device (LVAD) implantation in patients with worsening hemodynamics was unknown., Methods and results: We enrolled 22 patients with worsening hemodynamics who had received IABP support before LVAD (IABP group), and also enrolled 22 patients receiving neither IABP nor extracorporeal membrane oxygenation before LVAD, who were selected on propensity score matching (non-IABP group). Although both groups had similar preoperative background, the IABP group had shorter postoperative intensive care unit (ICU) stay, and more improved hemodynamics (P<0.05 for all). Serum total bilirubin and creatinine decreased significantly in the IABP group compared with the non-IABP group during 1 month after LVAD implantation (P<0.05 for both). Medical expenses during perioperative ICU stay were significantly lower in the IABP group compared with the non-IABP group, even including the cost of preoperative IABP support (P<0.05)., Conclusions: Prophylactic IABP support in heart failure patients with worsening hemodynamics improves post-LVAD clinical course and reduces perioperative medical expenses.

Background: Among variables obtained from cardiopulmonary exercise testing (CPXT), peak oxygen consumption (PV̇O2) and the minute ventilation vs. carbon dioxide output (V̇E vs. V̇CO2) slope were established as predictors of death of patients with heart failure (HF) at the cutoff points of 14 ml·min(-1)·kg(-1)and 34, respectively. However, a recent update of guideline-directed medical treatment (GDMT) might alter the implication of these variables., Methods and Results: We enrolled 77 HF patients receiving GDMT who had undergone symptom-limited CPXT between 2006 and 2014. Among them, 29 patients were re-hospitalized for HF and there were 13 cardiac deaths during the 4-year study period. Cox regression analyses demonstrated that the V̇E vs. V̇CO2slope, peak heart rate, peak systolic blood pressure, and PV̇O2were significant predictors of both re-admission and cardiac death at each cutoff point calculated by receiver-operating characteristic analyses. A new scoring system was constructed using the following criteria: 1 point was assigned to a variable meeting the cutoff point for re-admission; 2 points were assigned to that for cardiac death. The total scores calculated as the summation of each point (range, 0-8 points) had significantly highest area under the curves compared with each CPXT variable (P<0.05), and significantly stratified both event-free rate into 3 groups (P<0.05)., Conclusions: A novel scoring system using 4 CPXT variables simultaneously predicted re-admission and cardiac death even in patients with HF receiving GDMT.

Background: Predicting the occurrence of aortic insufficiency (AI) during left ventricular assist device (LVAD) support has remained unsolved., Methods and Results: We enrolled 52 patients who had received continuous flow LVAD (14 axial and 38 centrifugal pumps) and who been followed for ≥6 months between Jun 2006 and Dec 2013. Native aortic valve (AV) opening was observed in 18 patients (35%) with improved LV systolic function, and none of them had AI. On multivariate logistic regression analysis preoperative shorter heart failure duration was the only independent predictor of postoperative native AV opening (P=0.042; odds ratio [OR], 0.999). Of the remaining 34 patients (65%) with closed AV, 11 had AI with enlargement of the aortic root and narrow pulse pressure. Among those with closed AV, axial pump use (n=13) was the only significant predictor of the development of AI (P=0.042; OR, 4.950). Patients with AI had lower exercise capacity and a higher readmission rate than those without AI during 2-year LVAD support (55% vs. 8%; P<0.001)., Conclusions: Native AV opening during LVAD support is profoundly associated with reversal of LV systolic function, especially in patients with preoperative shorter heart failure duration. Among those in whom the native AV remains closed, low pulsatility of axial flow pump may facilitate aortic root remodeling and post-LVAD AI development that results in worse clinical outcome.

Background: A continuous flow (CF) left ventricular assist device (LVAD) has various advantages over a pulsatile flow (PF) LVAD, but the extent of preventing aortic insufficiency (AI) by each type of LVAD remains controversial., Methods and results: Of 86 patients with non-ischemic cardiomyopathy who underwent LVAD implantation between 2006 and 2015, 20 propensity score-matched patients with PF LVADs and 20 with CF LVADs were enrolled in this study. There were no significant differences in the baseline variables of both groups. During the 6-month LVAD treatment, the LV ejection fraction of the PF group was significantly higher than that of the CF group; the PF group also had a wider pulse pressure and less enlargement of the aortic root (P<0.05 for all). Patients in the PF group experienced more frequent opening of the native aortic valve and less AI than those in the CF group (P<0.05 for both). The PF LVAD was explanted in 5 patients (25%), and a CF LVAD was explanted in 1 patient (5%)., Conclusions: Compared with CF LVADs, PF LVADs seem to have an advantage in improving LV reverse remodeling and preventing AI. It may be best to incorporate pulsatility into current CF LVADs while retaining their existing benefits.

Background: Although survival rates have improved for patients receiving implantable continuous flow left ventricular assist devices (I-CF LVAD), postoperative exercise tolerance levels are not necessarily satisfactory., Methods and results: We enrolled 51 patients who had received an I-CF LVAD and underwent follow-up between 2006 and 2014; all patients underwent cardiopulmonary exercise testing 3 months following surgery: 26 (51%) patients achieved peak oxygen consumption (PV̇O2) ≥14 ml·kg(-1)·min(-1)and had significantly lower readmission rates for cardiovascular events than those with PV̇O2<14 ml·kg(-1)·min(-1)during 2 years of LVAD treatment (17 vs. 43%, P=0.033). Uni- and multivariate logistic regression analyses showed that the preoperative serum albumin (S-ALB) level was an independent predictor for PV̇O2≥14 ml·kg(-1)·min(-1)at 3 months (P=0.023, odds ratio 6.132). Patients with persistently normal S-ALB levels during the perioperative period had the lowest preoperative serum C-reactive protein level (S-CRP, 0.7±0.9 mg/dl), and the majority (77%) showed improved exercise tolerance. Conversely, patients with persistently low S-ALB levels during this period had the highest preoperative S-CRP level (2.8±1.2 mg/dl) and did not achieve the test endpoint., Conclusions: Both pre- and postoperative low S-ALB impedes recovery of exercise tolerance after I-CF LVAD surgery, and this may be attributable to inflammatory responses caused by heart failure.

Background:The timing of ventricular assist device (VAD) implantation is always a matter of debate, especially when a patient is referred from a non-VAD institute. We focused on objective noninvasive parameters at the time of admission to a VAD implant center and analyzed the factors predicting the necessity of early VAD.Methods and Results:We retrospectively analyzed advanced heart failure (HF) patients referred since January 2011, including patients less than 65 years old. They all had a history of hospitalization for HF management in non-VAD institutes within 1 month before referral. We excluded patients transferred with mechanical circulatory support. We enrolled 46 patients (40 males, 39.8±13.4 years old). Among them, 26 patients had a VAD implanted or died within 120 days. By multivariable logistic analysis using admission parameters, systolic blood pressure (BP) <93 mmHg [odds ratio (OR) 13.335], hemoglobin <12.7 g/dl (OR 12.175) and serum total cholesterol <144 mg/dl (OR 8.096) were significant predictors of early VAD requirement. We constructed a scoring system according to the ORs, and the area under the receiver-operating characteristic curve was 0.913.Conclusions:Low BP, low serum cholesterol and anemia on admission predict early VAD in advanced HF patients who have been treated in non-VAD institutes. Such patients should be promptly referred to a VAD implant center.

Background: Indication for mechanical circulatory support (MCS) has been a matter of debate in less sick status 2 patients., Methods and Results: Data were obtained from 183 consecutive patients assigned to stage D heart failure (HF) who were evaluated by the institutional review board of the University of Tokyo Hospital and then listed for heart transplantation as status 1 or 2 of the Japan Organ Transplant Network. Patients with status 2 (n=38) had a prognosis as poor as those dependent on inotropes (n=54) or MCS (n=91; P=0.615, log-rank test), and only 4 of them had eventual ventricular assist device (VAD) implantation (10.5%). Patients who eventually received VAD (n=92) had better 4-year survival than those without MCS among status 1 and 2 (P=0.030, log-rank test). On Cox regression analysis plasma B-type natriuretic peptide (BNP) >740pg/ml was the only significant predictor for 4-year survival among the status 2 group (P=0.014; hazard ratio, 8.267). Ten patients with status 2 died: 6 due to acute hemodynamic compromise and 4 due to ventricular fibrillation., Conclusions: Prognosis in status 2 patients was as poor as that of those dependent on inotrope infusion or VAD, mostly because of out-of-hospital sudden death without MCS. Status 2 patients with considerably high plasma BNP may be good candidates for continuous flow VAD therapy.

Background: Preserved function of the renal collecting duct may be essential for response to the vasopressin V2receptor antagonist, tolvaptan (TLV), but the predictors of response to TLV are unknown. METHODS AND RESULTS: Sixty consecutive patients with stage D decompensated heart failure (HF) who had received TLV on a de novo basis were retrospectively enrolled (TLV(+) group). Among them, 41 patients were responders defined according to urine volume (UV) increase after TLV initiation. In the UV-defined responders, plasma arginine vasopressin (P-AVP) had a close correlation with urine aquaporin-2 (U-AQP2; 5.42±3.54 ng/ml; r=0.843, P<0.001). In contrast, 19 were UV-defined non-responders, and they had extremely low U-AQP2 (0.76±0.59 ng/ml, P<0.001 vs. responders) regardless of P-AVP level. On receiver operating characteristic analysis, U-AQP2/P-AVP ≥0.5×10(3)clearly separated the UV-defined responders from the non-responders. We then identified AQP-defined responders as having U-AQP2/P-AVP ≥0.5×10(3). Sixty propensity score-matched HF patients without TLV treatment were examined, and exactly the same number of patients as that of the AQP-defined responders (n=41) was selected. These patients had a poorer survival without TLV than the TLV-treated responders during a 2-year observation period (73.8% vs. 94.8%, P=0.034)., Conclusions: U-AQP2/P-AVP is a novel predictor of response to TLV in patients with decompensated HF. AQP-defined responders may have a better prognosis on TLV treatment.

Background:  The continuous flow (CF) left ventricular assist device (LVAD) has replaced the pulsatile flow (PF) LVAD because of its advantages of better patient survival and higher quality of life. However, "late-onset right ventricular failure (RVF)" after CF LVAD implantation has emerged as an increasing concern, but little is known about the mechanism., Methods and Results:  We retrospectively analyzed the 3-month hemodynamic and echocardiographic data from 38 consecutive patients who had received CF LVADs, and from 22 patients who had received PF LVADs. Late-onset RVF was defined as persistent right ventricular stroke work index (RVSWI) <4.0g/m(2) at any rotation speed and after saline infusion test at 5 weeks after implantation of CF LVAD. Patients with late-onset RVF had significantly impaired exercise tolerance indicated by shorter 6-min walking distance and lower peak VO2, and worsened tricuspid regurgitation, together with enlargement of the RV under CF LVAD treatment (all P<0.05). Univariable analyses demonstrated that preoperative smaller LV diastolic diameter (LVDd) was the risk factor for late-onset RVF with a cutoff value of 64mm calculated by ROC analysis (area under curve, 0.925). In contrast, there was no correlation between preoperative LVDd and postoperative RVSWI in the PF LVAD group, though their preoperative background was worse than that of the CF group., Conclusions:  In the setting of preoperative small LVDd, CF LVAD may cause late-onset RVF by leftward shift of the interventricular septum.  (Circ J 2014; 78: 625-633).

Background: The timing of ventricular assist device (VAD) implantation is always a matter of debate, especially when a patient is referred from a non-VAD institute. We focused on objective noninvasive parameters at the time of admission to a VAD implant center and analyzed the factors predicting the necessity of early VAD. METHODS AND RESULTS: We retrospectively analyzed advanced heart failure (HF) patients referred since January 2011, including patients less than 65 years old. They all had a history of hospitalization for HF management in non-VAD institutes within 1 month before referral. We excluded patients transferred with mechanical circulatory support. We enrolled 46 patients (40 males, 39.8±13.4 years old). Among them, 26 patients had a VAD implanted or died within 120 days. By multivariable logistic analysis using admission parameters, systolic blood pressure (BP) <93 mmHg [odds ratio (OR) 13.335], hemoglobin <12.7 g/dl (OR 12.175) and serum total cholesterol <144 mg/dl (OR 8.096) were significant predictors of early VAD requirement. We constructed a scoring system according to the ORs, and the area under the receiver-operating characteristic curve was 0.913., Conclusions: Low BP, low serum cholesterol and anemia on admission predict early VAD in advanced HF patients who have been treated in non-VAD institutes. Such patients should be promptly referred to a VAD implant center.

Background: Depressed hemodynamics stimulates arginine vasopressin (AVP) release, but the relationship between plasma AVP levels (P-AVP) and cardiac parameters, especially in patients with stage D heart failure (HF) receiving guideline-directed medical therapy, has not examined. METHODS AND RESULTS: Data including P-AVP were obtained from 162 in-hospital patients with stage D HF and from 80 patients receiving ventricular assist device (VAD, n=46) or heart transplantation (HTx, n=34) at 3 months after surgery. In the HF group, considerably high P-AVP (5.9±6.1 pg/ml) negatively correlated with serum sodium concentration (S-Na, 135.3±5.8 mEq/L, r=-0.548 [P<0.01]) and cardiac index (CI, 2.2±0.5 L·min(-1)·m(-2), r=-0.458 [P<0.01]). After VAD/HTx treatment, improvement in the CI (2.7±0.5 L·min(-1)·m(-2)[P<0.01] vs. HF) was accompanied by normalization of serum sodium concentration (S-Na; 138.2±2.0 mEq/L [P<0.01] vs. HF) and suppressed release of AVP (1.7±3.4 pg/ml [P<0.01] vs. HF). P-AVP positively correlated with only S-Na (r=0.454 [P<0.01]), whereas no correlation was observed with CI after VAD/HTx treatment. P-AVP ≥5.3 pg/ml well predicted poor 2-year survival in HF group (60% [P<0.01] vs. 90%)., Conclusions: Low cardiac output stimulates AVP release via a non-osmotic process that results in hyponatremia and poor prognosis in patients with stage D HF. After sufficient recovery of cardiac output by cardiac replacement therapy, AVP release is suppressed and is mainly regulated by serum osmolality.

Background: Urine osmolality (U-OSM) is valuable to predict response to tolvaptan (TLV) in decompensated heart failure patients, but measurement of U-OSM is not always available on site., Methods and Results: Data were collected from 66 hospitalized patients with decompensated heart failure who had received TLV at 3.75-15 mg/day. U-OSM, which was estimated using the following formula: 1.07×{2×[(urine sodium (mEq/L)]+[urine urea nitrogen (mg/dl)]/2.8+[urine creatinine (mg/dl)]×2/3}+16, was well correlated with the actual measurement (r=0.938, P<0.001). Criteria consisting of C1 (estimated baseline U-OSM>358 mOsm/L) and C2 (%decrease in estimated U-OSM>24% at 4-6 h after the first TLV dose) significantly discriminated responders from non-responders (P<0.05)., Conclusions: Response to TLV can be predicted using U-OSM, which can be estimated using urine urea nitrogen, sodium, and creatinine concentration data.

Background: Non-invasive assessment of volume and function on the right ventricle (RV) for pulmonary hypertension (PH) is limited., Methods and Results: Patients with PH (n=23) underwent 3-dimensional (D) echocardiography (3DECHO), with cardiac magnetic resonance imaging to confirm its precision, and right heart catheterization. On linear regression analysis the RV end-systolic volume index (ESVI) was positively correlated with pulmonary vascular resistance (PVR) and mean pulmonary arterial pressure (mPAP; R=0.42 and 0.46, P=0.03 and 0.03, respectively). The RV end-diastolic volume index (EDVI) was positively correlated with mPAP (R=0.41, P<0.05). The left ventricular (LV) EDVI was inversely correlated with PVR (R=-0.48, P=0.02). The RV ejection fraction was inversely correlated with PVR and mean right atrial pressure (mRAP; R=-0.57, and -0.45, P=0.004, and 0.03, respectively). RVEDVI/LVEDVI and RVESVI/LVESVI (the diastolic and systolic remodeling indices, respectively) had a significantly positive linear relationship with PVR (R=0.67 and 0.55, P=0.0005 and 0.006, respectively), and the former had a significantly positive linear relationship with mRAP (R=0.42, P<0.05). During the recovery process in 1 specific case, the remodeling indices maintained a significant linear relationship with the hemodynamic parameters., Conclusions: Novel indices provided by 3DECHO may be utilized as alternative indicators of hemodynamic changes in PH patients.

Background: It is often difficult to predict reversibility of liver or renal function after left ventricular assist device (LVAD) implantation in patients with stage D heart failure., Methods and Results: Data were obtained for 69 patients who had received a LVAD (18 continuous-flow, 51 pulsatile). Persistent hepatic or renal dysfunction was defined as levels of total bilirubin (TB) or creatinine (Cre) >1.5mg/dl at 6 months after LVAD implantation. TB score or Cre score was calculated: 0.15 × age+1.1 × (preoperative TB) or 0.2 × age+3.6 × (preoperative Cre), in which coefficients were determined on the basis of odds ratios for persistent hepatic or renal dysfunction, respectively. Receiver-operating characteristics analyses showed good predictabilities for persistent end-organ dysfunction (area under curve: 0.794 for TB score and 0.839 for Cre score). High-risk strata of TB score (>11.0 points) or Cre score (>14.1 points) were associated with persistently higher levels of TB or Cre (TB, 1.32 ± 0.51; Cre, 1.23 ± 0.41 mg/dl; both P<0.001 vs. low-risk strata)., Conclusions: Reversibility of end-organ function with LVAD implantation can be well predicted by our new risk scoring system that consists of the preoperative TB or Cre level adjusted by the patient's age. The scoring system would be beneficial, especially in considering the indication of a bridge to candidacy.

Background: A newly-developed vasopressin type 2 receptor antagonist, tolvaptan (TLV), has a unique feature of diuresis, but the response to this drug can be unpredictable., Methods and Results: Data were collected from hospitalized patients with decompensated congestive heart failure who were administered TLV at 3.75-15 mg/day (n=61). A responder/non-responder to TLV was determined as having any increase/decrease in urine volume (UV) during the next 24h after TLV treatment on the first day. Logistic regression analyses for increases in UV were performed, and independent predictors of the responder were the following: C1, baseline urine osmolality (U-OSM) >352 mOsm/L; and C2, %decrease in U-OSM >26% at 4-6h after TLV administration. Criteria consisting of C1 and C2 had a good predictability for responders by receiver-operating characteristic analysis (area under the curve=0.960). Kidneys of the non-responders no longer had diluting ability (%decrease of U-OSM at 4-6h=2.7 ± 14.6%*), but also barely kept concentrating ability (baseline U-OSM=296.4 ± 68.7*mOsm/L) with markedly reduced estimated glomerular filtration ratio (35.5 ± 29.4 m l · min(-1) · 1.73 m(-2)*) (*P<0.05 vs. patients who had at least 1 positive condition [n=42])., Conclusions: More than 26% decrease in U-OSM from a baseline >352 mOsm/L for the first 4-6h predicts responders to TLV. Unresponsiveness to TLV is attributable to nephrogenic diabetes insipidus complicated by chronic renal disease.

Background: The aim of this study was to examine trends of clinical outcome and to clarify surrogate markers when titrating β-blocker in heart failure patients with reduced left ventricular ejection fraction (HFrEF, LVEF <50%)., Methods and Results: Consecutive HFrEF patients starting on β-blocker were divided into 2 groups according to time of dose fixation attainment: before 31 December 2005 (group 1, n=108) or after 1 January 2006 (group 2, n=119). There were no significant differences in patient characteristics between the 2 groups at baseline. Beta-blocker fixed dose was higher with lower resting heart rate in group 2 (6.2±5.7mg/day vs. 9.5±9.1mg/day in carvedilol equivalent dose, P=0.001; 74.2±11.1beats/min vs. 70.2±9.7beats/min, P=0.004). The rate of HF hospitalization and/or all-cause death after 36 months was lower in group 2 than in group 1 (22% vs. 38%, P=0.011; hazard ratio, 0.90; P=0.012). Cox regression analysis showed that β-blocker ≥10mg/day and achieved heart rate ≤71beats/min predicted a better outcome (both P<0.05)., Conclusions: Recent improvement of clinical outcome among HFrEF patients may be attributable to the up-titration policy accompanying lowered heart rate. Resting heart rate ≤71beats/min and β-blocker ≥10mg/day (ie, 50% of the target dose for Japanese patients) could be surrogate markers when titrating β-blocker.

Background: Patients with biventricular assist device (BiVAD) placement have a poor prognosis, but preoperative risk factors for the necessity of BiVAD have not been fully elucidated., Methods and Results: Data from 79 patients who received left ventricular assist device (LVAD) between November 2002 and December 2011 were retrospectively reviewed. Overall, 9 patients (11.4%) required BiVAD, and the survival rate of BiVAD patients was significantly lower than that of LVAD patients (P<0.001). Multivariate analysis for BiVAD requirement showed left ventricular diastolic diameter (LVDd) ≤62 mm (odds ratio [OR], 10.97; P=0.009) to be significantly associated with BiVAD requirement. Preoperative central venous pressure (CVP)/pulmonary capillary wedge pressure (PCWP) ratio ≥0.5 (OR, 13.09; P=0.028) was also significantly associated with BiVAD requirement. A new scoring system for predicting BiVAD requirement was created from the combination of CVP/PCWP ratio (≥0.5), body surface area (≤1.4 m(2)), preoperative continuous hemodiafiltration use, B-type natriuretic peptide (≥1,200 pg/ml) and LVDd (≤62 mm), and this had a significantly larger area under the curve (0.909; P=0.003) than right ventricular stroke work index on receiver operating characteristic analysis. A score >20 using the new scoring method indicated significantly high probability of BiVAD requirement (OR, 16.00; P=0.019)., Conclusions: The new scoring method, which includes CVP/PCWP ratio, is a novel risk stratification tool for BiVAD therapy.

Background: As we have previously reported, the preoperative profile defined by INTERMACS is a good predictor for the prognosis after left ventricular assist device (LVAD) implantation, but is largely dependent on the physician's decision. Several other risk stratification systems including objective parameters (eg, Leitz-Miller, Columbia, Seattle Heart Failure Model, APACHE II) have been proposed to estimate patient's mortality after LVAD implantation., Methods and Results: According to the preoperative data from 59 patients who received LVAD (10 implantable, 49 extracorporeal) since 2002 through 2010, we performed a logistic analysis and constructed a new scoring system (ie, the TODAI VAD score (TVAD score), assigning 8 points to serum albumin <3.2mg/dl (odds ratio [OR] 8.475), 7 points to serum total bilirubin >4.8mg/dl (OR 7.300), 6 points to left ventricular end-diastolic diameter <55mm (OR 5.917), 5 points to central venous pressure >11mmHg (OR 5.128)). The receiver-operating characteristic analysis showed that the area under the curve of our new scoring system (0.864) was significantly larger than any of the abovementioned 5 scoring methods (all P<0.05). With the TVAD score, low (0-8 points), intermediate (9-17 points), and high (18-26 points) risk strata had significantly different 1-year survival rates of 95%, 54%, and 14%, respectively (all P<0.001)., Conclusions: The TVAD score can predict the prognosis after LVAD implantation much better than the previously known methods.

Background: Postoperative development of aortic insufficiency (AI) after implantation of left ventricular assist devices (LVADs) has recently been recognized, but the devices in the previous reports have been limited to the HeartMate I or II. The purposes of this study were to determine whether AI develops with other types of LVADs and to elucidate the factors associated with the development of AI., Methods and Results: Thirty-seven patients receiving LVADs without evident abnormalities in native aortic valves were enrolled (pulsatile flow LVAD [TOYOBO]: 76%, continuous flow LVAD [EVAHEART, DuraHeart, Jarvik2000, HeartMate II]: 24%). Frequency of aortic valve opening and grade of AI were evaluated by the most recent echocardiography during LVAD support. None of the patients had more than trace AI preoperatively. During LVAD support AI >- grade 2 developed in 9 patients (24%) across all 5 types of devices. More severe grade of AI correlated with higher plasma B-type natriuretic peptide concentration (r = 0.53, P < 0.01) and with less frequent of the aortic valve (r = 0.45, P < 0.01). Multivariate analysis revealed that lower preoperative left ventricular ejection fraction and a continuous flow device type were independent risk factors for higher incidence of AI., Conclusions: AI, which is hemodynamically significant, develops after implantation of various types of LVADs. Physicians need to be more alert to the development of AI particularly with continuous flow devices.

Background: Little is known about health-related quality of life (QOL) in Japanese patients with heart failure. The purpose of this study was to identify factors related to QOL using a disease-specific QOL instrument, and to clarify whether QOL independently predicts clinical outcomes among Japanese patients with heart failure., Methods and Results: A total of 114 outpatients with heart failure were enrolled (mean age 64.7 ± 15.8 years; 73.7% males). The Minnesota Living with Heart Failure Questionnaire (MLHFQ) to assess patient's QOL was used. At baseline, depressive symptoms and chronic kidney disease were significantly associated with worse QOL in multiple regression analysis. During a 2-year follow up, patients with a MLHFQ score ≥ 26, indicating worse QOL, had a higher incidence of the combined endpoint of cardiac death or hospitalization for heart failure, and a higher all-cause mortality than those with a score < 26 (25.3% vs. 7.5%, P = 0.011; 18.5% vs. 6.4%, P = 0.018; respectively). Multivariate Cox proportional hazard models demonstrated that a higher MLHFQ score was significantly associated with increased risks of cardiac events (hazard ratio, 1.02, 95% confidential interval, 1.001-1.05, P = 0.038) and of all-cause death (hazard ratio, 1.04, 95% confidential interval, 1.02-1.07, P = 0.001)., Conclusions: Depressive symptoms and chronic kidney disease are major determinants of impaired QOL, and the MLHFQ score is an independent predictor of both cardiac events and death among Japanese patients with heart failure.

Background: In Japan, the TOYOBO left ventricular assist device (LVAD) has been commercially available for heart failure patients as of 2010, but clinical risk stratification before implantation has not been widely performed., Methods and Results: In the present study data from 47 patients (age 38.6 ± 14.6 [SD] years, male 74.5%, non-ischemic 74.5%) implanted with a TOYOBO LVAD between November 2002 and February 2010 were analyzed. Kaplan-Meier survival analysis showed significantly higher mortality in the patients who had cardiogenic shock preoperatively (P = 0.031). Multivariate analysis revealed that the preoperative total bilirubin level (odds ratio [OR] 1.312, P < 0.001) and age (OR 1.076, P = 0.013) were independent risk factors for death. Perioperative necessity of a right ventricular assist device was also an independent risk factor for poor prognosis., Conclusions: LVAD implantation is preferable before the patient experiences hemodynamic collapse. The preoperative total bilirubin level can be used to predict prognosis after device implantation in end-stage heart failure patients.

Background: Left ventricular remodeling might be involved in the pathophysiology of right ventricular hypertrophy/failure due to pulmonary arterial hypertension (PAH), while the left ventricle is considered not under pressure/volume overload., Methods and Results: Rats with monocrotaline-induced PAH were used in the present study to examine whether upregulated neurohumoral factors may induce left ventricular (LV) remodeling and(/or) contribute to prognosis. Morphological analysis revealed a significant increase in the weight of the free walls of both ventricles and the interventricular septum, indicating biventricular hypertrophy, although systemic blood pressure was not elevated. RNase protection assay demonstrated the activation of a fetal gene program in the cardiac muscle of the left and right ventricular free walls. Similar activation of the fetal gene program was observed in the LV of rats continuously infused with angiotensin (AT) II, although this was not the case for rats infused with isoproterenol. Measured plasma levels of ATII, noradrenaline, and brain natriuretic peptide (BNP) were all significantly elevated in the PAH rats. Furthermore, the plasma BNP level positively correlated with the ratio of heart weight to body weight and the plasma level of ATII. Not right but LV hypertrophy was significantly reduced by treatment with an AT II type 1 receptor blocker, valsartan, whereas the effect of an adrenergic alpha1 and beta1,2 blocker, carvedilol, was borderline. Survival rate in the PAH rats was significantly improved when they were treated with valsartan or carvedilol., Conclusions: Upregulated neurohumoral factors seem to play an important role in LV remodeling without mechanical overload, and are associated with impairment of prognosis in rats with PAH.