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The closure of small/coincidental atrial septal defects (ASDs) in patients with pulmonary arterial hypertension (PAH) has been described in recent major guidelines as useless or even contraindicated. We confirm the effectiveness of "Treat and Repair" for ASD closure through one patient diagnosed with idiopathic PAH with small ASD, under careful observation with right heart catheterization and cardiac magnetic resonance imaging. The clinical decision concerning the closure of ASD with PAH should be made not only by referring to the guidelines but also by evaluating the benefits and risks specific to that case.

Aim Systemic sclerosis (SSc) is a chronic autoimmune disease resulting in vasculopathy and fibrosis of the skin and major internal organs. Especially, interstitial lung disease and pulmonary arterial hypertension are the leading causes of mortality. C-C motif ligand 20 (CCL20) is known as a homeostatic and inflammatory chemokine, which is associated with fibrosis and angiogenesis and constantly expressed in organs involved in SSc. Therefore, we investigated the potential contribution of CCL20 to the development of SSc. Method We conducted cross-sectional analyses of 67 SSc patients and 20 healthy controls recruited in a single center for 9 years. Serum CCL20 levels were measured by enzyme-linked immunosorbent assay. Statistical analyses were performed with the Mann-Whitney U test, the Kruskal-Wallis test followed by Dunn's multiple comparison test, Fisher's exact probability test and the Spearman's rank correlation coefficient. Results SSc patients had significantly higher serum CCL20 levels than healthy controls. In SSc patients, serum CCL20 levels correlated inversely with the percentage of predicated diffusion lung capacity for carbon monoxide and positively with mean pulmonary artery pressure (mPAP). In addition, SSc patients with increased serum CCL20 levels had anti-mitochondrial antibody M2 titer significantly elevated relative to those with normal levels, and SSc patients with asymptomatic primary biliary cholangitis (PBC) possessed higher serum CCL20 levels than those without. Importantly, serum CCL20 levels were associated positively with mPAP values and PBC presence by multivariate regression analysis. Conclusion Serum CCL20 levels may be involved in the development of pulmonary vascular involvement leading to pulmonary arterial hypertension and asymptomatic PBC in SSc patients.

Percutaneous coronary intervention (PCI) is sometimes considered as an alternative therapeutic strategy to surgical revascularization in patients with coronary artery disease (CAD) and reduced left ventricular ejection fraction (LVEF). However, the types or conditions of patients that receive the clinical benefit of left ventricular reverse remodelling (LVRR) remain unknown. The purpose of this study was to investigate the determinants of LVRR following PCI in CAD patients with reduced LVEF. From 4394 consecutive patients who underwent PCI, a total of 286 patients with reduced LV systolic function (LVEF

Pulmonary valve stenosis (PVS) accounts for approximately 10% of all congenital heart defects. Echocardiography and right heart catheterization are the gold standards for diagnosis of PVS and for assessing disease severity and responsiveness to treatment.Recently, cardiac magnetic resonance imaging (cMRI) has been established as an important tool to comprehensively evaluate cardiac structure and function; however, research into the usefulness of cMRI for PVS management is limited. Here, we describe a case of a 59-year-old female with isolated, severe PVS who was successfully treated with balloon pulmonary valvuloplasty (BPV) followed by sequential cMRI at 1 and 12 months. Exertional dyspnea and elevated plasma BNP concentration were observed 1 month after BPV; however, echocardiographic findings did not indicate recurrent stenosis or increased pulmonary valve regurgitation but an increase in mitral E/e'. cMRI demonstrated improved systolic forward flow and RV function with enlargement of LV volume, and the rapid increase in LV preload might be associated with the transient deterioration in symptoms and BNP level, which both gradually improved within 3 months after BPV. cMRI further depicted that a reduced RV mass index and increased RV cardiac output were achieved gradually during the follow-up period.In conclusion, cMRI in combination with echocardiography was sufficiently informative to follow-up this PVS patient both before and after BPV. cMRI is easily reproducible in adult patients; therefore, cMRI should be recommended for long-term follow-up in adult PVS patients.

Candida prosthetic endocarditis (CPE) is an uncommon and fatal complication in adults with congenital heart disease. The current guidelines for the management of fungal endocarditis recommend a combination of surgical and medical therapy. However, it still remains uncertain when surgical management in CPE patients should be performed. Therefore, the prognosis of CPE patients is very poor. Here we report a case of CPE in a 31-year-old woman who had undergone surgical repair for tetralogy of Fallot during childhood and pulmonary valve replacement at the age of 21 years. She underwent re-pulmonary valve replacement after being sufficiently sterilized with a 5-week course of antifungal medical therapy, leading to clinical improvement. In CPE patients, it is necessary to perform surgical therapy while suppressing the activity of fungi as much as possible.

Background Fractional exhaled nitric oxide levels are related to various clinical diseases. This study investigated the associations between the clinical characteristics and the level of fractional exhaled nitric oxide in patients with adult congenital heart disease. Methods and results Fractional exhaled nitric oxide values were measured in 30 adult patients with stable congenital heart disease who had undergone right heart catheterization and 17 healthy individuals (controls). There was no significant difference in fractional exhaled nitric oxide values between patients with congenital heart disease and healthy controls. Depending on whether their fractional exhaled nitric oxide values were above or below the median value, patients with congenital heart disease were divided into two groups (low vs. high fractional exhaled nitric oxide groups). The relationship between fractional exhaled nitric oxide values and clinical characteristics was investigated. There was a higher percentage of patients with cyanosis in the low fractional exhaled nitric oxide group (50%) than in the high fractional exhaled nitric oxide group (7.1%). There was no significant difference in right heart catheterization data between the low and high fractional exhaled nitric oxide groups. The fractional exhaled nitric oxide value was correlated to the number of neutrophils in patients with cyanosis (r = 0.84 (N = 8), p = 0.005). Conclusions In this cohort of patients with adult congenital heart disease, lower levels of fractional exhaled nitric oxide corresponded to the presence of cyanosis.

It is widely known that β-blockers exert beneficial effects on non-ischemic and ischemic systolic heart failure (sHF) in nonstructural hearts. However, whether β-blockers exert similar effects on sHF associated with congenital heart disease (CHD), particularly in an anatomical right ventricle, remains under debate.Here we report the case of an adult man with repaired tetralogy of Fallot suffering from biventricular heart failure. Treatment with carvedilol directly improved the systolic function of the right and left ventricles. This case report strongly suggests there is potential for carvedilol to exert a beneficial effect on heart failure in CHD. The appropriate titration of carvedilol and patient follow-up for long-term effects are important when treating adult patients with CHD with β-blockers.

Tachyarrhythmias such as atrial fibrillation (AF) or atrial flutter (AFL) sometimes invoke life-threatening collapse of hemodynamics in patients with severe heart failure. Recently, landiolol, an ultra-short acting β1-selective antagonist, has been reported to be safe and useful for the treatment of supraventricular tachyarrhythmias with reduced left ventricular function. Here we report a case of advanced heart failure with severe hypotension who was treated successfully by landiolol for rapid AF. The patient was a 20-year old male with dilated cardiomyopathy. He presented with low output syndrome in spite of optimal medical therapy and was referred to our department to consider ventricular assist device implantation and heart transplantation. Soon after admission, he developed rapid atrial fibrillation at 180 beats per minute (bpm) followed by severe hypotension and liver enzyme elevation. Low dose landiolol at 2 μg/kg/minute was started because digoxin was not effective. After landiolol administration, his heart rate decreased to 110 bpm, and finally returned to sinus rhythm without hemodynamic deterioration. Intra-aortic balloon pumping was inserted soon after sinus recovery and he was discharged successfully with an implantable left ventricular assist device.

Although sympathetic reinnervation is accompanied by the improvement of exercise tolerability during the first years after heart transplantation (HTx), little is known about parasympathetic reinnervation and its clinical impact. We enrolled 21 recipients (40 ± 16 years, 71% male) who had received successive cardiopulmonary exercise testing at 6 months, and 1 and 2 years after HTx. Exercise parameters such as peak oxygen consumption or achieved maximum load remained unchanged, whereas recovery parameters including heart rate (HR) recovery during 2 minutes and the delay of peak HR, which are influenced by parasympathetic activity, improved significantly during post-HTx 2 years (P < 0.05 for both). HR variability was analysed at post-HTx 6 months in 18 recipients, and high frequency power, representing parasympathetic activity, was significantly associated with the 2 recovery parameters (P < 0.05 for all). We also assessed quality of life using the Minnesota Living with Heart Failure (HF) Questionnaire at post-HTx 6 months and 2 years in the same 18 recipients, and those with improved recovery parameters enjoyed a better HF-specific quality of life (P < 0.05 for both). In conclusion, parasympathetic reinnervation emerges along with improved post-exercise recovery ability of HR and quality of life during post-HTx 2 years.

Serial endomyocardial biopsies (EMBs) are scheduled even several years after heart transplantation (HTx) to monitor for late rejection (LR). However, repeated EMBs are associated with an increased risk for fatal complications and decrease the quality of life of the recipient. We retrospectively analyzed clinical data from 42 adult recipients who had received HTx and were followed > 1 year at the University of Tokyo Hospital. Five recipients experienced LR at 1130 ± 157 days after HTx, and all 5 had experienced acute cellular rejection (ACR) with ISHLT grade ≥ 2R within the first year, which was treated with methylprednisolone pulse therapy (sensitivity, 1.000; specificity, 0.7027). Logistic regression analyses demonstrated that positive panel reactive antibody (PRA) was the only significant predictor for LR among all parameters at 1 year after HTx (P = 0.020, odds ratio 24.00). Among the 5 recipients with LR, LR occurred earlier in the two PRA positive recipients than in those with a negative PRA (981 ± 12 versus 1230 ± 110 days, P = 0.042). Among the perioperative parameters, gender mismatch [n = 13 (31%)] was the only significant predictor for ACR within the first year in logistic regression analyses (P = 0.042, odds ratio 4.200). In conclusion, the current schedule of serial EMBs should perhaps be reconsidered for recipients without any history of ACR within the first year due to their lower risk of LR.

BACKGROUND Therapeutic strategies for pulmonary arterial hypertension (PAH) associated with atrial septal defect (ASD) remain a matter of debate. METHODS AND RESULTS We identified 5 outpatients who had been diagnosed with ASD-PAH and undergone ASD closure in combination with targeted therapy with certified PAH drugs. We assessed changes in hemodynamic parameters and exercise capacity. The combination of ASD closure and targeted therapy significantly increased systemic blood flow (Qs) from the baseline (from 3.3 ± 0.6 L/minute to 4.2 ± 1.0 L/minute, P < 0.05) with a significant improvement in the World Health Organization Functional Class (WHO-FC; from 2.8 ± 0.4 to 1.6 ± 0.5, P < 0.05). The hemodynamic data before and after ASD closure without targeted therapy showed further elevation of pulmonary vascular resistance shortly after ASD closure (678 dyne · s/cm(5) to 926 dyne · s/cm(5)) in 1 case, as well as after a long time since ASD closure (491.0 ± 53.7 dyne · s/cm(5) to 1045.0 ± 217.8 dyne · s/cm(5)) in 2 cases. This worsening was reversed after the targeted therapy, accompanied by an increase in Qs and an improvement in WHO-FC in all cases. CONCLUSIONS Targeted therapy should be added to ASD closure in adult patients with ASD-PAH.

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 [VE/VCO2] slope ≤34; HR, 16.86), and E3 (peak oxygen consumption [PVO2] ≥12.8 ml·kg(-1)·min(-1); HR, 18.35) significantly predicted explantation expectancy during 2 years after LVAD implantation (P

Background Due to the recent progress of vasodilators for pulmonary arterial hypertension (PAH), the prognosis of PAH has been getting better for the past 10 years. Among them, idiopathic PAH (IPAH) well improved but PAH associated with connective tissue disease (CTD-PAH) especially scleroderma (SSc-PAH) have poorer prognosis than IPAH. Objectives This study intended to clarify the clinical features and prognosis of CTD-PAH in modern era when multiple PAH drugs are available, in addition, compare between SSc-PAH and PAH associated with other CTD-PAH (non SSc-PAH). Methods Fifty-seven consecutive CTD-PAH patients were enrolled to this study, who received hemodynamic examination with right heart catheterization between 2004 and 2016. Thirty of 57 patients were SSc-PAH patients and other 27 patients were non SSc-PAH patients (11 mixed connective tissue disease, 8 systemic lupus erythematosus, 5 primary sjogren syndrome, 1 polymyositis, 1 rheumatoid arthritis and 1 Still9s disease were included). We retrospectively analyzed the relationship between clinical parameters at baseline and the prognosis of CTD-PAH patients. Results Mean age at entry were 65.3±10.3 and 48.3±15.5 years old each other (SSc-PAH vs non SSc-PAH P Conclusions SSc-PAH patients had poor prognosis among CTD-PAH patients despite the progression of PAH drugs. As well as the report from REVEAL registry, not only PAH severity but also respiratory dysfunction may predict the prognosis of CTD-PAH patient. Scleroderma is multiorgan disease affected by complex pathology of vasoconstriction (ischemia), proliferation, inflammation, autoimmune disorder and fibrosis. Our data suggest that vasodilator alone is not enough to improve the prognosis of CTD-PAH patients. Comprehensive therapeutic strategy for scleroderma is needed. References Chung L.et al. Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the REVEAL registry. Chest 2014;146(6):1494–1504. Disclosure of Interest H. Maki: None declared, M. Hatano Grant/research support from: Ministry of Health, Labour and Welfare, Bayer Japan, Nippon Shinyaku Co,.Ltd, GlaxoSmithKline K.K., Speakers bureau: Actelion pharmaceuticals Japan Ltd, Bayer Japan, S. Minatsuki: None declared, T. Inaba: None declared, I. Komuro Grant/research support from: Actelion pharmaceuticals Japan Ltd, Y. Asano Grant/research support from: Ministry of Health, Labour and Welfare, S. Sato Grant/research support from: Ministry of Health, Labour and Welfare

Although the suppression of sympathetic activity is an essential mission for the current heart failure treatment strategy, little is known about the relationship between the rotation speed setting and autonomic nervous activity during continuous-flow left ventricular assist device (LVAD) treatment. We evaluated 23 adult patients with sinus rhythm (36 ± 13 years) who had received continuous-flow LVAD and been followed at our institute between March 2013 and August 2014. Heart rate variability measurement was executed along with hemodynamic study at 3 rotation speeds (low, middle, and high) at 5 weeks after LVAD implantation. Lower rotation speed was associated with higher ratio of low-frequency over high-frequency spectral level (LF/HF), representing enhanced sympathetic activation (p

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease characterized by elevated pulmonary vascular resistance, which results in right-heart failure. We present a case of interferon (IFN)-α-induced PAH developed after living donor liver transplantation. Although IFN is categorized as a "possible" risk factor for PAH in the current international classification, it is still under recognized. Moreover, the prognosis of IFN-induced PAH is poor in the limited number of published cases. In our case, we achieved good outcome by the withdrawal of IFN and administration of combination therapy using tadalafil, beraprost, and treprostinil. Since IFN is an important treatment option in current medical therapy, its contribution to the pathogenesis of PAH should be taken into consideration. In conclusion, our case suggests the importance of PAH screening in patients treated with IFN.

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.

Several studies have demonstrated that tolvaptan (TLV) can improve hyponatremia in advanced heart failure (HF) patients with rare chance of hypernatremia. However, changes in serum sodium concentrations (S-Na) in patients with or without hyponatremia during TLV treatment have not been analyzed.Ninety-seven in-hospital patients with decompensated HF who had received TLV at 3.75-15 mg/day for 1 week were enrolled. Among 68 "responders", who had achieved any increases in urine volume (UV) during the fi rst day, urinary sodium excretion during 24 hours (U-NaEx(24)) increased significantly during one week of TLV treatment along with higher baseline S-Na (P < 0.05 and r = 0.325). Considering a cut-off value (S-Na, 132 mEq/L; AUC, 0.711) for any increases in U-NaEx(24), we defined "hyponatremia" as S-Na < 132 mEq/L. In hyponatremic responders (n = 25), S-Na increased significantly, although 1 week was not sufficient for normalization (125.8 ± 5.0 versus 128.9 ± 4.3 mEq/L, P < 0.05), along with unchanged U-NaEx(24) (2767 ± 2703 versus 2972 ± 2950 mg/day, NS). In contrast, in normonatremic responders (n = 43), S-Na remained unchanged (136.6 ± 3.1 versus 137.4 ± 2.9 mEq/L, NS) along with increased U-NaEx(24) (2201 ± 1644 versus 4198 ± 3550 mg/day, P < 0.05). TLV increased S-Na only in hyponatremic responders by way of pure aquaresis, but increased U-NaEx(24) only in normonatremic responders, which explains the scarcity of hypernatremia. Epithelial Na-channels in the distal nephrons, whose repression by TLV increases urinary sodium excretion, may be attenuated by reduced ATP-supply in worse hemodynamics under hyponatremia.

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)

There has been no established medical therapy to ameliorate pulmonary hypertension (PH) owing to left heart disease (LHD-PH). It has recently been shown that the left ventricular assist device (LVAD) can improve LHD-PH and therefore has the potential to become a major bridge tool for heart transplantation (HTx). However, some patients still have persistent PH even after LVAD treatment. It is essential to demonstrate the reversibility of end-organ dysfunction, including PH, prior to implantable LVAD treatment, especially in Japan, because implantable LVAD treatment is indicated only as bridge to transplantation. Here we report a patient with LHD-PH whose PH was demonstrated to be reversible by the acute pulmonary vasoreactivity test (APVT) with nitrogen monoxide (NO) and the phosphodiesterase-5 inhibitor sildenafil. Both inhaled NO and sildenafil reduced pulmonary vascular resistance, but pulmonary capillary wedge pressure was increased by NO, which was conversely decreased under increased cardiac output by sildenafil. After the patient was listed as an HTx recipient, pulmonary vascular resistance recovered down to an acceptable range with LVAD treatment. Based on these findings, we suggest that the APVT with sildenafil may be a useful and safe tool to predict improvement of PH after LVAD treatment.

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.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-OSM26% 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)*) (*P0.05 vs. patients who had at least 1 positive condition [n=42]).More than 26% decrease in U-OSM from a baseline352 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.

We previously defined "responders" as patients with increases in urine volume (UV) on day 1 after the administration of tolvaptan (TLV), and demonstrated that responders to TLV could be predicted with considerable accuracy by urine osmolality (U-OSM) levels. Responders and non-responders to TLV should be associated with different clinical courses after a certain time following TLV administration. Therefore, the aim of the present study was to validate our definition of responders by clinical parameters 1 week after administration of TLV. Data (n = 85) were obtained from in hospital patients with decompensated heart failure (HF) who had received TLV at 3.75-15 mg daily, and clinical data at 1 week after the administration of TLV were compared with those of baseline. Sixty patients (70.6%) were "responders", in whom UV on day 1 increased after the administration of TLV compared with day 0. "Non-responders" were older, and had higher serum creatinine concentration and lower baseline U-OSM than "responders". Serum creatinine concentration increased significantly in "non-responders", but was unchanged in "responders". Body weight, plasma B-type natriuretic peptide concentration, and HF symptom score decreased significantly in "responders", but remained unchanged in "non-responders". Increases in UV after the first administration of TLV were closely correlated with improvement of congestive HF after 1 week of TLV treatment, which verified our definition of "responders" to TLV.

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) greater than1.5 mg/dl at 6 months after LVAD implantation. TB score or Cre score was calculated: 0.15 x age+ 1.1x (preoperative TB) or 0.2 x age + 3.6 x (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 (greater than11.0 points) or Cre score (greater than14.1 points) were associated with persistently higher levels of TB or Cre (TB, 1.32 +/- 0.51; Cre, 1.23 +/- 0.41 mg/dl; both Pless than0.001 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 patients age. The scoring system would be beneficial, especially in considering the indication of a bridge to candidacy.

No medical treatment has been established to ameliorate pulmonary hypertension (PH) due to left heart disease. Heart transplantation (HTx) is thus far the definitive therapy for stage D heart failure, but concomitant PH is one of the major risk factors for death after HTx. Recently, implantation of a left ventricular assist device (LVAD) has been reported to improve PH and has become a major bridge tool for HTx. We experienced a rare case with persistent PH even after the implantation of a continuous-flow LVAD. The administration of an endothelin receptor antagonist, bosentan, significantly decreased pulmonary vascular resistance. Combination therapy with LVAD implantation and anti-PH medication may be useful for patients with stage D heart failure complicated with severe PH.

Refractory ventricular tachyarrhythmias are life threatening, especially in patients with stage D heart failure, and left ventricular assist device therapy is virtually the sole option to resolve the fatal conditions in many cases. The Interagency Registry for Mechanically Assisted Circulatory Support defines modifier A as complicating recurrent ventricular tachyarrhythmias. However, the optimal timing to implant a left ventricular assist device remains to be determined in less sick patients with modifier A. We experienced three patients with stage D heart failure with revised modifier A, i.e., at least two appropriate operations of implantable cardiac defibrillators within 2 weeks. Two of them were rescued by extracorporeal left ventricular assist device implantation, but one died because of an electrical storm before left ventricular assist device support was available. We would like to emphasize that we should consider implantable left ventricular assist device therapy as soon as possible for those who are assigned modifier A to prevent sudden arrhythmic death.

SummaryCardiac allograft rejection can be accompanied by diastolic dysfunction, but the hemodynamic change is usually compensated and hard to be recognized noninvasively. Here we report on two transplanted patients who showed electrocardiogram (ECG) changes suggesting right ventricular overload. Hemodynamic measurement revealed increased right ventricular pressure and endomyocardial biopsy confirmed grade 3R rejection. After rejection was treated with steroid pulse, the ECG alterations were reversed and right ventricular pressure was normalized. In such cases, asymptomatic rejection may be diagnosed by ECG changes that are reversible along with the treatment of rejection, although those ECG changes are apparently non-specific.

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.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 albumin3.2mg/dl (odds ratio [OR] 8.475), 7 points to serum total bilirubin4.8mg/dl (OR 7.300), 6 points to left ventricular end-diastolic diameter55mm (OR 5.917), 5 points to central venous pressure11mmHg (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 P0.05). 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 P0.001).The TVAD score can predict the prognosis after LVAD implantation much better than the previously known methods.

Background The prevalence of pulmonary arterial hypertension (PAH) in primary Sjogren's syndrome (SS) had been reported to be rare. However, recent studies using echocardiography as a screening method showed conflicting results, and the true prevalence is still unclear. Since diagnosing primary SS is difficult because of its heterogeneous nature, a number of patients with primary-SS-associated PAH may be misdiagnosed with idiopathic PAH, losing their chance to undergo immunosuppressive therapy. Therefore, we sought to elucidate the prevalence of primary SS among patients who initially present with PAH. Methods From our prospective institutional PAH database, 40 consecutive patients without any obvious cause of PAH at the time of PAH diagnosis were identified. We retrospectively evaluated the prevalence of primary SS diagnosed during or after the initial assessment of PAH. Results During the initial assessment, one patient was diagnosed with primary-SS-associated PAH. Among the 25 patients who were initially diagnosed with idiopathic PAH, five were diagnosed with primary SS during their course of the disease. Of the five patients, three had key signs suggesting primary SS and were probably underdiagnosed at the time of initial evaluation. The remaining two patients, who were finally diagnosed with primary SS, did not have any specific signs suggesting primary SS at the time of initial evaluation but showed positive conversion of their autoantibodies during the course of PAH. Conclusion The prevalence of primary-SS-associated PAH may be relatively high among patients who undergo initial evaluation for PAH. Furthermore, primary-SS-associated PAH may be underdiagnosed with routine evaluation for the primary cause of PAH. Clinicians should pay specific attention and carefully evaluate the possibility of primary SS in patients with PAH.

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 (

Systemic sclerosis (SSc) is a chronic autoimmune inflammatory disease characterized by extensive tissue fibrosis and various vascular complications. A wealth of evidence suggests the substantial contribution of pro-inflammatory cytokines to the development of SSc, but the role of interleukin (IL)-18 signaling in this disease still remains elusive. To address this issue, we herein determined serum levels of IL-18-binding protein isoform a (IL-18BPa), a soluble decoy receptor for IL-18, by enzyme-linked immunosorbent assay in 57 SSc patients and 20 healthy controls and evaluated their clinical correlation. Serum IL-18BPa levels were higher in SSc patients than in healthy controls, while comparable between diffuse cutaneous SSc and limited cutaneous SSc patients. Although serum IL-18BPa levels were not associated with dermal and pulmonary fibrotic parameters in SSc patients, there was a significant positive correlation between serum IL-18BPa levels and right ventricular systolic pressure estimated by echocardiography. Furthermore, in 24 SSc patients who underwent right heart catheterization, serum IL-18BPa levels positively correlated with mean pulmonary arterial pressure. As for systemic inflammatory markers, significant positive correlations of circulating IL-18BPa levels with erythrocyte sedimentation rate and C-reactive protein were noted. These results suggest that the inhibition of IL-18 signaling by IL-18BPa may be involved in the development of pulmonary vascular involvement leading to pulmonary hypertension and modulate the systemic inflammation in SSc.

Pulmonary hypertension (PH) induced by pulmonary tumor thrombotic microangiopathy (PTTM) can be fatal because its rapid progression confounds diagnosis, and it is difficult to control with therapy. Here we describe a woman with symptomatic PTTM-PH accompanying gastric cancer that was suspected from perfusion scintigraphy. PTTM-PH was diagnosed by gastroesophageal endoscopy and lung biopsy after partial control of PH using the platelet-derived growth factor (PDGF) receptor (PDGFR) tyrosine kinase inhibitor, imatinib. Treatment with sildenafil and ambrisentan further decreased PH, and she underwent total gastrectomy followed by adjuvant TS-1 chemotherapy. PH did not recur before her death from metastasis. Postmortem histopathology showed recanalized pulmonary arteries where the embolized cancer masses disappeared. PDGF-A, -B, and PDGFR-α, β expression was detected in cancer cells and proliferating pulmonary vascular endothelial cells. Thus, PTTM-PH was successfully controlled using a combination of imatinib, drugs to treat pulmonary arterial hypertension, and cancer management.

BACKGROUND Among variables obtained from cardiopulmonary exercise testing (CPXT), peak oxygen consumption (PVO2) and the minute ventilation vs. carbon dioxide output (VE vs. VCO2) 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 VE vs. VCO2slope, peak heart rate, peak systolic blood pressure, and PVO2were 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

Chronic kidney disease (CKD) is often complicated with advanced heart failure because of not only renal congestion and decreased renal perfusion but also prolonged use of diuretics at higher doses, which sometimes results in hyponatremia. Preoperative CKD is known to be associated with poor prognosis after heart transplantation (HTx). We experienced a stage D heart failure patient with CKD and hyponatremia who was switched from trichlormethiazide to tolvaptan. His hyponatremia was normalized, and his renal function was improved after conversion to tolvaptan. In patients with stage D heart failure, it may be useful to administer tolvaptan with a concomitant reduction in the dose of diuretics in order to preserve renal function and avoid hyponatremia before HTx.

Hypervolemic hyponatremia is often complicated with advanced heart failure together with increased excretion of sodium by diuretics. Tolvaptan, an oral vasopressin-2-receptor antagonist, has been previously reported to improve congestion and correct hyponatremia through increased excretion of free water. However, there is little evidence concerning the administration of tolvaptan in patients with stage D heart failure. We experienced 2 patients with stage D heart failure who received 3.75 mg/day of tolvaptan to correct hyponatremia before ventricular assist device implantation. It may be useful, even for patients with stage D heart failure, to administer a low dose of tolvaptan to treat hyponatremia before ventricular assist device implantation to avoid a drastic alteration in serum sodium concentration perioperatively.

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 Pless than0.05]. 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 Pless than0.05). 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. Funding Agencies|Pfizer Health Research Foundation

Scheduled serial endomyocardial biopsies are executed by an internal jugular vein (IJV) or femoral vein (FV) approach to survey acute rejection after heart transplantation (HTx). However, a better approach site is needed. A total of 379 sessions consisting of 329 IJV approaches and 50 FV approaches in 48 HTx recipients executed at 75 ± 127 days (41182 days) after HTx between September 2007 and April 2014 at University of Tokyo Hospital were retrospectively analyzed. The IJV approach had shorter operation and radiation exposure times, and a lower dose of radiation exposure and lower usage of contrast agents than the FV approach (all P < 0.001). There were no fatal complications requiring surgical management or resulting in death during all sessions. The IJV approach had less complications than the FV approach (2.7% versus 10.0%, P = 0.011). Among the complications, atrial tachyarrhythmia occurred only with the IJV approach (0.9%), whereas transient ventricular tachyarrhythmia and bundle branch block were more frequently observed in the FV approach (8.0% versus 0.9%, P = 0.042). In conclusion, endomyocardial biopsy from the IJV approach was safer and less invasive than that of the FV approach if we only consider the incidence of atrial tachyarrhythmia.

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

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

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) less than4.0 g/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 (V) over dot O-2, and worsened tricuspid regurgitation, together with enlargement of the RV under CF LVAD treatment (all Pless than0.05). Univariable analyses demonstrated that preoperative smaller LV diastolic diameter (LVDd) was the risk factor for late-onset RVF with a cutoff value of 64 mm 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.

To date, there have been few reports demonstrating preoperative predictors for left ventricular reverse remodeling (LVRR) after LV assist device (LVAD) implantation, especially among patients with dilated cardiomyopathy (DCM). We retrospectively analyzed 60 patients with stage D heart failure due to DCM who had received LVAD treatment [pulsatile flow (PF) type, 26; continuous flow type, 34]. Data were evaluated at 6 months or just before explantation of the LVAD. We defined "LV reverse remodeling" (LVRR) by the achievement of an LV ejection fraction (LVEF) of ≥ 35 % after 6 months of LVAD support or explantation of LVAD within 6 months. LVRR occurred in 16 of our patients (26.7 %). Uni/multivariate logistic regression analyses for LVRR demonstrated that of the preoperative variables evaluated, PF LVAD usage and insufficient preoperative β-blocker treatment were independent predictors for LVRR. Patients who accomplished LVRR had a better clinical course, including lower levels of aortic valve insufficiency and lower levels of plasma B-type natriuretic peptide. Of the six patients (10.0 %) in whom LVADs were eventually explanted, all had an LVEF of ≥ 35 % before explantation or at 6 months. Based on these results, we conclude that DCM patients with insufficient preoperative β-blocker treatment have a chance to achieve LVRR under LVAD support as a bridge to recovery.

The long-term survival of heart transplantation (HTx) recipients has increased significantly in recent years, however, the nephrotoxic adverse effects of calcineurin inhibitors (CNIs) are still a major concern. Recently, an inhibitor of mammalian target of rapamycin, everolimus (EVL), has emerged as an alternative immunosuppressant drug that may allow CM dosage reduction and thereby spare renal function. Data were collected from 20 HTx recipients who had received EVL (target trough level 3-8 ng/mL) along with a dose reduction of CNIs and/or mycophenolate mophetil (MMF) and had been followed for 1 year. Estimated glomerular filtration rate increased significantly with a reduction in the CM dosage in a dose-dependent manner (P less than 0.001, r = -0.807). Neutrophil count increased significantly (P less than 0.05) with a reduction in the dosage of MMF (P = 0.009, r = -0.671). Cytomegalovirus antigenemia remained negative after EVL administration among all candidates without any antiviral agents (P = 0.001). There were no significant increases in the acute rejection rates among recipients with EVL compared to those without EVL (P = 0.132). An immunosuppressant strategy incorporating EVL could reduce the CM and MMF dosages, which resulted in improvements in renal dysfunction and neutropenia while maintaining low rejection rates among HTx recipients.

Tolvaptan (TLV), a vasopressin type 2 receptor antagonist, has been demonstrated to be effective in patients with decompensated heart failure (HF) refractory to incremental doses of diuretics, but the responsiveness has not always been predictable. We have recently proposed that urine osmolality (U-OSM) is a valuable parameter for the prediction of responses to TLV, because U-OSM reflects the activity of the collecting ducts, where TLV plays its unique role. Acute kidney injury (AKI) is often associated with severe tubular dysfunction, including the collecting ducts, and in such cases a response to TLV may not be expected. We here experienced a patient with HF and AKI in whom TLV was not effective during AKI. We also observed recovery of responsiveness to TLV along with remission of AKI as well as increased U-OSM later on. We believe that this is the first report on the reversibility of the TLV response in relation to U-OSM.

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 3.75–15mg/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 358mOsm/L) and C2 (%decrease in estimated U-OSM >24% at 4–6h after the first TLV dose) significantly discriminated responders from non-responders (P

A 60-year-old man with severe heart failure underwent an orthotopic heart transplant. Maintenance immunosuppression consisted of a calcineurin inhibitor, mycophenolate mofetil (MMF), and a glucocorticoid. Six months after the transplantation, coronary angiography (CAG) and intravascular ultrasound sonography (IVUS) showed rapidly progressive cardiac allograft vasculopathy (CAV) along with acute cellular rejection. Methylprednisone pulse therapy resulted in the resolution of acute rejection. MMF was exchanged for everolimus (EVL) and 6 months after EVL therapy, CAG and IVUS revealed the regression of CAV. EVL can improve established CAV as well as prevent the progression of CAV.

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

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

Cytomegalovirus (CMV) infection remains a major problem in recipients with heart transplantation (HTx), because it may play a significant role in the development of cardiac allograft vasculopathy, which is one of the major causes of death after HTx. Valganciclovir (VGC) is effective for the treatment of CM V infection, but is often associated with neutropenia, especially when used with mycophenolate mophetil (MMF). We experienced an HTx recipient with positive CMV antigenemia who suffered progressive neutropenia after administration of VGC. We switched MMF to everolimus (EVL) and assay for CM V antigenemia was constantly negative even after discontinuation of VGC. In all other 14 HTx recipients who received EVL for any reason, we found that assay for CMV antigenemia remained negative throughout the period of EVL administration. Considering the prophylactic effect on CMV, EVL can not only be an alternative to rescue from comorbidity, but might also be indicated earlier especially in CMV-seronegative HTx recipients.

Malignancy is not uncommon with immunosuppressive therapy, but pancreatic cancer is infrequently complicated in recipients of heart transplantation. Here we report a transplant case diagnosed with pancreatic cancer 4 years and 8 months after the heart transplantation. We changed the immunosuppressive regimen after the malignancy was detected, and administered everolimus along with chemotherapy using S-1, an oral fluoropyrimidine prodrug. The patient lived for 8 months after the diagnosis, and received metallic stenting for the biliary and duodenal obstruction. Also, to the best of our knowledge, this is the first report about chemotherapy and endoscopic intervention for pancreatic cancer in a heart transplantation patient.

For the time being, in Japan, two recently approved implantable ventricular assist devices (VADs) are indicated only when a patient has been listed for heart transplantation or approved to be eligible for heart transplantation by in-hospital committee. The reversibility of end-organ dysfunction must be expected before VAD implantation, but it is often hard to prove during worsening clinical status. We report two patients whose end-organ dysfunction had been eventually demonstrated to be reversible by invasive procedures such as transluminal liver biopsy or transient insertion of intra-aortic balloon pumping.

Postoperative right ventricular failure is usually apparent perioperatively or soon after left ventricular assist device insertion. Here, we report a case complicated by right ventricular failure that manifested 3 weeks after HeartMate II implantation. This case is also unique because the postoperative right ventricular failure was progressive over the years. We discuss how the smaller size of the left ventricle and untreated tricuspid regurgitation contributed to the development of right ventricular failure in this case.