A case of interferon-α-induced pulmonary arterial hypertension after living donor liver transplantation.

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.

Quality of Life and Influential Factors in Patients Implanted With a Left Ventricular Assist Device.

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

Reverse Remodeling Achieved by Combination Therapy With High-Dose Beta Blocker and Cardiac Resynchronization.

Although both beta-blocker treatment and cardiac resynchronization therapy (CRT) have been established as the standard therapeutic strategy to achieve left ventricular reverse remodeling (LVRR) and improve prognosis in heart failure (HF) patients with systolic LV dysfunction, some patients do not respond to such treatments. We here report a HF patient with left bundle branch block due to nonischemic cardiomyopathy who did not respond to 20 mg/day of carvedilol in terms of LVRR. Subsequent CRT only achieved insufficient LVRR, and we further titrated carvedilol up to 40 mg/day. Marked LVRR was accomplished at a fixed 70 bpm heart rate under CRT, and therefore it was considered as heart rate-independent. Up-titration of beta-blocker after CRT may be necessary to induce optimal LVRR in some populations.

Secure Combination Therapy With Low-Dose Bosentan and Ambrisentan to Treat Portopulmonary Hypertension Minimizing Each Adverse Effect.

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.

Targeted therapy is required for management of pulmonary arterial hypertension after defect closure in adult patients with atrial septal defect and associated pulmonary arterial hypertension.

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.

Platelet-derived growth factor receptor-tyrosine kinase inhibitor, imatinib, is effective for treating pulmonary hypertension induced by pulmonary tumor thrombotic microangiopathy.

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, ß 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.

Low blood pressure, low serum cholesterol and anemia predict early necessity of ventricular assist device implantation in patients with advanced heart failure at the time of referral from non-ventricular assist device institutes.

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

Low Blood Pressure, Low Serum Cholesterol and Anemia Predict Early Necessity of Ventricular Assist Device Implantation in Patients With Advanced Heart Failure at the Time of Referral From Non-Ventricular Assist Device Institutes.

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

Urine sodium excretion after tolvaptan administration is dependent upon baseline serum sodium levels: a possible explanation for the improvement of hyponatremia with scarce chance of hypernatremia by a vasopressin receptor antagonist.

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.

Cardiac allograft vasculopathy can be distinguished from donor-transmitted coronary atherosclerosis by optical coherence tomography imaging in a heart transplantation recipient: double layered intimal thickness.

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.

Late-onset right ventricular failure in patients with preoperative small left ventricle after implantation of continuous flow left ventricular assist device.

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

Preoperative beta-blocker treatment is a key for deciding left ventricular assist device implantation strategy as a bridge to recovery.

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 ß-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 ß-blocker treatment have a chance to achieve LVRR under LVAD support as a bridge to recovery.

Immunoglobulin G4-related multiple systemic aneurysms and splenic aneurysm rupture during steroid therapy.

Immunoglobulin G4 (IgG4)-related disorders in various organs have recently been described, but multiple systemic aneurysms have not yet been reported. Here, we present a 68-year-old Japanese man with multiple systemic aneurysms and tumor-forming pericoronary arteritis who was undergoing low-dose corticosteroid therapy. Elevated serum IgG4 (2390 mg/dL) and IgG4-positive plasmacyte infiltration in the salivary glands led to a diagnosis of IgG4-related disease. High-dose corticosteroid therapy was initiated, whereupon the inflammatory lesions shrank. However, the large, well-developed common hepatic aneurysm and splenic aneurysm did not change. Our patient died of splenic aneurysm rupture in the sixth month of treatment. The autopsy revealed IgG4-positive plasmacyte infiltration in the coronary wall and a thinned splenic aneurysm wall. This case suggests that early high-dose corticosteroid therapy may be necessary for the treatment of IgG4-related cardiovascular disorders. A minor salivary gland biopsy might facilitate the early diagnosis of IgG4-related disease even if (18)F-fluorodeoxyglucose positron emission tomography provides no inflammatory findings.

Tolvaptan can improve clinical course in responders.

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.

Successful treatment of hemodynamic compromise caused by antibody-mediated and cellular rejection in a recipient 12 years after heart transplantation.

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.

Everolimus-incorporated immunosuppressant strategy improves renal dysfunction while maintaining low rejection rates after heart transplantation in Japanese patients.

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.

A case with recovery of response to tolvaptan associated with remission of acute kidney injury and increased urine osmolality.

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.

Acute pulmonary vasoreactivity test with sildenafil or nitric monoxide before left ventricular assist device implantation.

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.

Successful conversion from thiazide to tolvaptan in a patient with stage d heart failure and chronic kidney disease before heart transplantation.

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.