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The errors in the following list appeared in the article titled "Characteristics of Pulmonary Arterial Hypertension in Patients with Systemic Sclerosis and Anticentriole Autoantibodies" by Hisataka Maki, Kana Kubota, Masaru Hatano, Shun Minatsuki, Eisuke Amiya, Ayumi Yoshizaki, Yoshihide Asano, Hiroyuki Morita, Shinichi Sato, Issei Komuro (Vol 61, No.2, 413-418, 2020).

Anticentriole autoantibodies-positive systemic sclerosis (SSc) has been reported to develop pulmonary arterial hypertension (PAH) at a high rate. In this report, we describe two patients with anticentriole antibodies-positive SSc-PAH who were treated with pulmonary vasodilators. Both cases were elderly women with poor physical conditions and clinical findings of SSc. Case 1 was resistant to combination therapy with pulmonary vasodilators; in Case 2, hemodynamic improvement was obtained by upfront combination therapy at an early stage. Because anticentriole antibodies-positive SSc-PAH rapidly deteriorates, careful hemodynamic observation and timely aggressive use of pulmonary vasodilators should be considered.

This study aimed to clarify the usefulness of the Ikari-curve left (IL) guiding catheter for balloon pulmonary angioplasty (BPA).The current BPA strategy for chronic thromboembolic pulmonary hypertension is dilation of as many branches as possible to normalize hemodynamics and oxygenation. The shape of the guiding catheter is a major factor in achieving this. However, conventional guiding catheters are difficult to introduce into particular branches. The IL guiding catheter may be suitable; however, its utility remains unclear.We retrospectively analyzed 202 consecutive BPA sessions of 40 patients from November 2016 to October 2019 and divided these sessions into two groups: the IL group where the IL guiding catheter was used and the non-IL group where other catheters were utilized. The occurrence of lung injury was determined by the presence of bloody sputum. We compared the rates of successful introduction into target vessels and assessed for the occurrence of lung injury.The average age of enrolled patients was 60.3 ± 14.4 years, with females comprising 65%. There were 99 sessions in the IL group. The median treated branches per session differed between the 2 groups (IL group: 15 versus non-IL group: 10, P < 0.05). The occurrence of lung injury was lower in the IL group (4.0% versus 11.7%, P = 0.07). The IL group had more successful vessel insertions than the non-IL group (78.8% versus 42.7%, P < 0.01).The IL guiding catheter may be introduced into branches that cannot be accessed by conventional guiding catheters.

Therapeutic strategies for pulmonary arterial hypertension (PAH) have made remarkable progress over the last two decades. Currently, 3 types of drugs can be used to treat PAH; prostacyclins, phosphodiesterase 5 inhibitors, and endothelin receptor antagonists (ERA). In Japan, the first generation ERA bosentan was reimbursed in 2005, following which the 2nd generation ERAs ambrisentan and macitentan were reimbursed in 2009 and 2015, respectively. The efficacy of each ERA on hemodynamics in PAH patients remains to be elucidated. The aims of this study were to evaluate the hemodynamic effects of ERAs and compare these effects among each generation of ERAs.We retrospectively examined the clinical parameters of 42 PAH patients who were prescribed an ERA (15 bosentan, 12 ambrisentan, and 15 macitentan) and who underwent a hemodynamic examination before and after ERA introduction at our institution from January 2007 to July 2019.In a total of 42 patients, mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were significantly decreased and cardiac index was significantly increased after ERA introduction (P < 0.001) and the World Health Organization-Functional class (WHO-Fc) was significantly improved after ERA introduction (P = 0.005). Next, in a comparison between 1st and 2nd generation ERAs, 2nd generation ERAs were found to have brought about greater improvements in hemodynamic parameters (mPAP and PVR. P < 0.01), heart rate, brain natriuretic peptide, arterial oxygen saturation, and mixed venous oxygen saturation than the 1st generation ERA bosentan.We conclude that all ERAs could successfully improve the hemodynamics of PAH patients and that the newer generation ERAs, ambrisentan and macitentan, seemed to be preferable to bosentan.

Current therapeutic methods for chronic thromboembolic pulmonary hypertension (CTEPH) can improve hemodynamic status and are expected to improve prognoses. However, some patients experience dyspnea during effort and continue supplemental oxygenation despite their hemodynamic status being fully improved. Considering the pathogenesis of CTEPH, the dead space and intrapulmonary shunt are assumed to be responsible for hypoxia in CTEPH, but their contributions are unclear. It is also unclear whether they are improved after treatment. The aim of this study was to investigate the implications of the dead space ratio (DSR) and the intrapulmonary shunt ratio (ISR) for hypoxia in CTEPH and treatment for CTEPH.We retrospectively measured the DSR and ISR of 23 consecutive patients with CTEPH. For 11 of these 23 (10 were treated by balloon pulmonary angioplasty, one with riociguat), we also measured these parameters before and after CTEPH treatments. Overall, the DSR and ISR were abnormally elevated (DSR: 0.63 ± 0.06; ISR: 0.20 ± 0.05). After treatment, mean pulmonary artery pressure was improved (from 40.3 ± 8.1 to 25.5 ± 2.7 mmHg). Although atrial oxygen saturation (SaO 2 ), DSR and ISR were improved (SaO 2 : from 90.2 ± 3.2 to 93.7 ± 1.8%; DSR: from 0.64 ± 0.06 to 0.58 ± 0.05; ISR: from 0.20 ± 0.04 to 0.18 ± 0.02), these improvements were slight compared with that of mean pulmonary artery pressure.The DSR and ISR were abnormally elevated in patients with CTEPH and their improvement by treatment was limited. Only DSR can be a useful marker for normalization of hypoxia in CTEPH.

Pulmonary hypertension (PH) is defined as a mean pulmonary artery pressure (PAP) ≥ 25 mmHg at rest as assessed by right heart catheterization (RHC), and Doppler-derived systolic PAP (sPAP ECHO ) or tricuspid regurgitation pressure gradient (TRPG) is widely used to screen for PH. However, the cutoff value of sPAP ECHO or TRPG for detecting a mean PAP ≥ 25 mmHg that was determined invasively has not been well defined.We studied 189 patients who underwent RHC. Echocardiography was performed within 24 hours of invasive evaluation, and sPAP ECHO was defined as the TRPG with right atrial pressure estimated on the basis of the current guideline.From the receiver operating characteristic (ROC) curve analysis, the optimal sPAP ECHO, and TRPG cutoffs for detecting PH were 41 mmHg (sensitivity, 92%; specificity, 91%; area under the curve = 0.95) and 36 mmHg (sensitivity, 90%; specificity, 93%; area under the curve = 0.95), respectively. The area under the TRPG ROC curve was similar to the area under the sPAP ECHO ROC curve.Given that Doppler echocardiography is required to accurately detect PH rather than to accurately estimate systolic PAP, our results provide useful information with regard to screening patients for PH and recommending further investigations on PH.

Chronic thromboembolic pulmonary hypertension (CTEPH) develops as a consequence of unresolved pulmonary embolism or clots in the pulmonary arteries. The obstruction not only reduces the area of the pulmonary vascular bed, but also elicits high pressure and high shear stress in the spared unobstructed arteries. Subsequent overflow of the small pulmonary arteries induces vascular remodeling, termed as overflow vasculopathy (OV). While the development of OV significantly contributes to the occurrence of pulmonary hypertension, its precise molecular mechanisms are yet to be determined.We established a novel murine pulmonary artery OV (PAOV) model, in which we resected left lung and induced redistribution of the cardiac output to the remaining pulmonary artery of the right lung. At 21 days after operation, mice showed an increase in the vascular media area, indicating the development of pulmonary arterial remodeling. In addition, right ventricular hypertrophy was detected in the PAOV model. Intriguingly, marked accumulation of F4/80-positive monocytes/macrophages was visualized in high-flow arteries, implying the role of an inflammatory process in the pathogenesis of overflow-induced vascular remodeling.

Riociguat, a soluble guanylate cyclase stimulator, induces pulmonary artery dilatation through blood flow and is effective in treating chronic thromboembolic pulmonary hypertension (CTEPH). There are two types of vasculopathies in CTEPH based upon its location, in other words, proximal or distal to the thrombus-medicated obstruction. Distal vasculopathy is characterized by intrapulmonary shunts due to diminished blood flow. While other therapeutic interventions for CTEPH including pulmonary endarterectomy and balloon pulmonary angioplasty achieve reperfusion to the distal vasculopathy vessels, the effects of riociguat on distal vasculopathy vessels remain undetermined. Herein, we describe a case of a 66-year-old woman who exhibited deterioration of mean pulmonary artery pressure and exercise tolerance after a 4-month treatment with riociguat. She received balloon pulmonary angioplasty prior to riociguat administration. Her lung perfusion scintigraphy and pulmonary angiography findings did not change over the course of treatment. Notably, after the discontinuation of riociguat, her clinical values returned to their levels prior to riociguat administration. Her intrapulmonary shunt ratio followed a similar course as her hemodynamic status. We demonstrate that riociguat can deteriorate hemodynamic status, which may mediate the dilatation of intrapulmonary shunts. We should perform close monitoring of symptoms and hemodynamic status after riociguat administration, especially in patients in whom the reperfused DVs occurred due to invasive treatment.

Lung bleeding (LB) and hemoptysis is a common but life-threating complication of balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension. LBs related to BPA mostly occur acutely during BPA session. Therefore, it can usually be managed with occlusion balloon or other catheter-based approaches. While LB also develops subacutely after BPA session, the pharmacological option to subacute LB is currently limited. Here, we present a case of subacute LB which can be managed with intravenous administration of nitroglycerin. Nitrate mediated venous dilation can be an effective therapeutic option in managing LB and hemoptysis after BPA session.

A pouching defect, which is a type of angiographic classification in chronic thromboembolic pulmonary hypertension (CTEPH), is equivalent to a chronic total occlusion (CTO). Thus far, treating CTO involves high risk of the lung bleeding and is difficult because the structure and treating strategy have not been clarified, yet treating it has great potential to improve hemodynamic status and ventilation perfusion mismatch. Here, we describe a case of successfully treated the CTO. In this case, we treated it safely by two balloon pulmonary angiography (BPA) sessions. In first session, the surface of the CTO was partially broken by the catheter. However, the distal vessels of it were not observed. Pulmonary angiogram was performed 4 months later, the distal vessels of CTO were observed. This lesion was no longer the CTO, we performed BPA safely and pulmonary arterial pressure was improved dramatically. Furthermore, pulmonary angiogram revealed the surface of the CTO has a cap which is comprised of cross-aggregation of organized thrombi. Partial breakage of the cap is a key to recanalization of the CTO, even if the distal vessels were not seen in same BPA session.

Cardiac involvement in systemic sarcoidosis sometimes provokes life-threatening ventricular tachyarrhythmia. Steroid administration is one of the fundamental anti-arrhythmia therapies. For an indication of steroid therapy, a definitive diagnosis of sarcoidosis is required. 1) However, cases that are clearly suspected of cardiac sarcoidosis based on their clinical courses sometimes do not meet the current diagnostic criteria and result in the loss of an appropriate opportunity to perform steroid therapy.Here we report a case that was diagnosed as sarcoidosis by incidental biopsy of an inguinal lymph node during cardiac resuscitation for cardiac tamponade. 2) While the inguinal lymph node was not swollen on computed tomography, a specimen obtained from an incidental biopsy during the exposure of a femoral vessel for the establishment of extracorporeal cardio-pulmonary resuscitation showed a non-caseating granuloma.This findings suggest a non-swelling lymph node biopsy might be an alternative strategy for the diagnosis for sarcoidosis if other standard strategies do not result in a diagnosis of sarcoidosis.

Although we recently demonstrated that opening of a native aortic valve (AV) after left ventricular assist device (LVAD) implantation is a sufficient condition to prevent development of aortic insufficiency (AI), its preoperative predictors remain unknown. Data were obtained from 58 patients who had been treated with continuous flow LVAD for ≥ 6 months at our institute between 2006 and 2014. Opening of native AV was accomplished in 21 patients (36%) at postoperative 6 months. Uni/Multivariate logistic regression analyses demonstrated that a preoperative lower cumulative dose of β-blocker was the only independent predictor for postoperative opening of native AV (P = 0.020, OR 0.905) at the cutoff level of 4.5g (equivalent dose of carvedilol), calculated by an ROC analysis. Prevalence of native AV opening was increased gradually along with improvement of LV ejection fraction only in patients with preoperative insufficient β-blocker treatment during postoperative 6 months (P < 0.05 for both). Patients with opening of native AV had higher exercise capacity and a lower re-admission rate than those with closed native AV during 2-year LVAD support (5% versus 44%, P < 0.05). Opening of native AV during LVAD support is profoundly associated with LV reverse remodeling especially in patients with insufficient preoperative β-blocker exposure probably due to their better responsiveness to combination therapy with β-blocker and LVAD. Patients who accomplished native AV opening can enjoy better exercise performance and avoid re-admission due to cardiovascular events.

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.

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 endothelin receptor antagonists (ERAs) including bosentan and ambrisentan are essential tools for the treatment of pulmonary arterial hypertension (PAH), each agent has a specific adverse effect with non-negligible frequency, ie, liver dysfunction for bosentan and peripheral edema for ambrisentan. These adverse effects often hinder the titration of the doses of ERAs up to the therapeutic levels. Portopulmonary hypertension, which is complicated with liver cirrhosis and successive portal hypertension, is one of the PAHs refractory to general anti-PAH agents because of the underlying progressed liver dysfunction and poor systemic condition. We here present a patient with portopulmonary hypertension, which was treated safely by combination therapy that included low-dose bosentan and ambrisentan, minimizing the adverse effects of each ERA. Combination therapy including different types of ERAs at each optimal dose may become a breakthrough to overcome portopulmonary hypertension in the future.

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.

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.

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.

Although survival after heart transplantation (HTx) has improved in recent years, cardiac allograft vasculopathy (CAV) is still the leading cause of remote morbidity and mortality in HTx recipients, partly because of difficulty with its diagnosis. In general, routine surveillance for CAV is advocated with coronary angiography accompanied by intravascular ultrasound (IVUS) if necessary. However, these modalities have limitations with respect to low spatial resolution, and sufficient qualitative/quantitative assessment of coronary intima has not been accomplished. Recently, optical coherence tomography (OCT) has emerged as a novel intracoronary imaging technique using an optical analogue of ultrasound with a spatial resolution of 10-20 µm, which is 10 times greater than IVUS. We here experienced a 49-year-old male who received a HTx 3 years ago, and OCT was executed during low molecular weight dextran injection. OCT demonstrated distinct double intimal layers probably consisting of a donor-transmitted atherosclerotic layer and an inner intimal proliferation due to CAV, which was indistinguishable by IVUS and virtual histological analyses. We believe that OCT imaging is not only a new loadstar during treatment of CAV but also a new generation modality for screening for early CAV in HTx recipients.

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.

Although cross-sectional late-phase reinnervation in heart transplantation (HTx) recipients has been demonstrated by several earlier studies, early-phase successive analyses especially for parasympathetic reinnervation remain unknown. Successive heart rate variability (HRV) data calculated by the MemCalc power spectral density method were obtained from 16 non-rejection recipients 1-24 weeks after HTx. High frequency (HF) level representing parasympathetic magnitude increased significantly at 6 months after HTx (from 0.9 ± 0.7 to 4.1 ± 2.8 ms(2*)). Only intraoperative shorter cardiopulmonary bypass time (181 ± 59 minutes) correlated with a higher level of HF at post-HTx 6 months among all baseline variables (r = -0.530(*)). Higher level of HF was associated with recovery of tachycardia at post-HTx 6 months (r = -0.514(*)). In conclusion, parasympathetic reinnervation emerges along with recovery of tachycardia < 6 months after HTx, which is accelerated by shorter intraoperative cardiopulmonary bypass time ((*)P < 0.05 for all).

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.

Self-care is a cornerstone for the successful management of heart failure (HF). The purpose of this study was to examine the impacts of HF self-care on prognosis in Japanese patients with HF. A total of 283 HF outpatients (age 64 ± 14, 70% male, 52% HFrEF) were enrolled. We asked patients to answer about their adhevence to 5 self-care behaviors (medication, eating a low-sodium diet, regular exercise, daily weight check, and treatment seeking behavior). On the basis of the results, we classified patients into a good self-care group and a poor self-care group. The primary outcome was HF hospitalization and/or cardiac death. In total, 65% of patients were classified into the poor self-care group. During a median follow-up of 2 years, cardiac events occurred more frequently in the poor self-care group (22% versus 9.6%, P = 0.013). Poor self-care was an independent risk factor for cardiac events in Cox regression analysis adjusted for clinical parameters (hazard ratio = 2.86, P = 0.005). Poor self-care was also associated with an increased number of HF hospitalizations as well as an extended length of hospital stay for HF. Poor knowledge about HF was an independent determinant for poor self-care in multivariate logistic regression analysis (odds ratio = 0.92, P = 0.019). Insufficient self-care is an independent risk factor for cardiac events in Japanese patients with HF.

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.

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 CNI 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 CNI dosage in a dose-dependent manner (P < 0.001, r = -0.807). Neutrophil count increased significantly (P < 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 CNI and MMF dosages, which resulted in improvements in renal dysfunction and neutropenia while maintaining low rejection rates among HTx recipients.

Heart transplantation (HTx) is an established therapy for stage D heart failure due to recent advances in immunosuppressive regimens. However, antibody-mediated rejection remains an unsolved problem because of its refractoriness to standard immunosuppressive therapy with high mortality and graft loss. We experienced a 16-year old patient with hemodynamic compromise caused by both cellular and antibody-mediated rejection 12 years after HTx. The rejection was refractory to repeated steroid pulse treatment, intravenous immunoglobulin administration, and intensifying immunosuppression including addition of everolimus. Eventually, she was successfully treated with repeated plasma exchange accompanied by a single administration of the anti-CD20 monoclonal antibody rituximab.

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.

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.

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.

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.

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 CMV 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 CMV 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.

A 49-year-old woman suffering from rapidly progressing right-sided heart failure assessed as World Health Organization functional class (WHO-FC) IV is described. After treatment with oxygen and diuretics, she was in WHO-FC III on admission to our hospital, as confirmed by her poor exercise tolerance in cardiopulmonary exercise testing. Upon detailed examination, she was diagnosed as having idiopathic pulmonary arterial hypertension (IPAH). Right heart catheterization (RHC) revealed severe pulmonary hypertension (mPAP = 65 mmHg) with a markedly decreased cardiac index (CI = 1.0 L/minute/m(2)), and an acute vasoreactivity test with nitric oxide inhalation did not show any response. Due to her severe condition, we decided to attempt oral combination therapy consisting of bosentan, tadalafil, and beraprost, prescribed in the same order and titrated up to their maximum respective doses, instead of intravenous (IV) epoprostenol therapy. Her clinical symptoms improved day by day, and the hemodynamic parameters recovered to nearly normal ranges about 6 months after initiation of the combination therapy. Initial/programmed oral combination therapy for severe IPAH patients is not yet fully established, and there is less evidence concerning its efficacy than IV epoprostenol therapy. However, it has tremendous advantages for PAH patients when they respond well. It is very important to further identify what types of PAH patients will respond to this oral combination therapy and should be treated with it as the first-line therapy.