Evaluating haemodynamic changes: vericiguat in patients with heart failure with reduced ejection fraction.

AIMS: Vericiguat has been used to treat patients with heart failure with reduced ejection fraction (HFrEF) who demonstrated worsening heart failure despite treatment with other guideline-directed medical therapies. The haemodynamic effects of vericiguat remain unclear. METHODS AND RESULTS: This study enrolled 12 patients (median age, 63 [quartiles 53.5, 70] years; 16.7%(N=2) women) with symptomatic HFrEF (New York Heart Association functional class II-IV) who demonstrated worsening heart failure despite treatment with the four foundational guideline-recommended therapies between March and December 2022, with follow-ups completed in June 2023. A balloon-tipped pulmonary artery thermodilution catheter was placed in the right internal jugular vein to perform right heart catheterisation (RHC) on day 1. Haemodynamic data were acquired before and after vericiguat intake (2.5 mg) on days 2 and 3. The data on days 2 and 3 were averaged. RHC was repeated on day 105 (37, 168). Oral intake of vericiguat 2.5 mg decreased mean pulmonary artery pressure (19.3 [14.3, 26.8] mmHg) and pulmonary artery wedge pressure (PAWP) (11 [7.5, 15] mmHg) before the intake to mean pulmonary artery pressure (17.5 [12.5, 24] mmHg) and PAWP (9.3 [6.8, 14] mmHg) at 30 min after (both P < 0.05). Reduction in PAWP was also found from 14.5 [9.5, 19.5] mmHg on day 1 to 9.5 [6.5, 12.5] mmHg on day 105 (37, 168) (P < 0.05), when vericiguat was titrated to 2.5 mg 25% (N = 3), 5 mg 50% (N = 6), and 10 mg 25% (N = 3). CONCLUSIONS: The consistent reduction in PAWP underscores the well-tolerated nature of vericiguat and its potential to enhance cardiac performance in patients with HFrEF.

Clinical and Sociodemographic Factors Associated With Health-Related Quality of Life in Patients With Adult Congenital Heart Disease　- A Nationwide Cross-Sectional Multicenter Study.

BACKGROUND: Little is known about clinical or sociodemographic factors that influence health-related quality of life (HRQoL) in patients with adult congenital heart disease (ACHD).Methods and Results: We conducted a nationwide prospective cross-sectional multicenter study at 4 large ACHD centers in Japan. From November 2016 to June 2018, we enrolled 1,223 ACHD patients; 1,025 patients had an HRQoL score. Patients completed a questionnaire survey, including sociodemographic characteristics, and the 36-Item Short-Form Health Survey (SF-36). To determine factors associated with HRQoL, correlations between 2 SF-36 summary scores (i.e., physical component score [PCS] and mental component score [MCS]) and other clinical or sociodemographic variables were examined using linear regression analysis. In multivariable analysis, poorer PCS was significantly associated with 11 variables, including older age, higher New York Heart Association class, previous cerebral infarction, being unemployed, and limited participation in physical education classes and sports clubs. Poorer MCS was associated with congenital heart disease of great complexity, being part of a non-sports club, current smoking, and social drinking. Student status and a higher number of family members were positively correlated with MCS. CONCLUSIONS: This study demonstrates that HRQoL in ACHD patients is associated with various clinical and sociodemographic factors. Further studies are needed to clarify whether some of these factors could be targets for future intervention programs to improve HRQoL outcomes.

Inhaled nitric oxide testing in predicting prognosis in pulmonary hypertension due to left-sided heart diseases.

AIMS: The pathophysiology of pulmonary hypertension (PH) due to left-sided heart disease (Group 2 PH) is distinct from that of other groups of PH, yet there are still no approved therapies that selectively target pulmonary circulation. The increase in pulmonary capillary pressure due to left-sided heart disease is a trigger event for physical and biological alterations of the pulmonary circulation, including the nitric oxide (NO)-soluble guanylate cyclase-cyclic guanosine monophosphate axis. This study investigated inhaled NO vasoreactivity tests for patients with Group 2 PH and hypothesized that these changes may have a prognostic impact. METHODS AND RESULTS: This was a single-centre, retrospective study with a median follow-up of 365 days. From January 2011 to December 2015, we studied 69 patients with Group 2 PH [age, 61.5 ± 13.0 (standard deviation) years; male:female, 49:20; left ventricular ejection fraction, 50.1 ± 20.4%; mean pulmonary arterial pressure, ≥25 mmHg; and pulmonary arterial wedge pressure (PAWP), >15 mmHg]. No adverse events were observed after NO inhalation. Thirty-four patients with Group 2 PH showed increased PAWP (ΔPAWP: 3.26 ± 2.22 mmHg), while the remaining 35 patients did not (ΔPAWP: -2.11 ± 2.29 mmHg). Multivariate analysis revealed that increased PAWP was the only significant predictor of all-cause death or hospitalization for heart failure (HF) after 1 year (hazard ratio 4.35; 95% confidence interval, 1.27-14.83; P = 0.019). The acute response of PAWP to NO differed between HF with preserved and reduced ejection fractions. CONCLUSIONS: Patients with Group 2 PH were tolerant of the inhaled NO test. NO-induced PAWP is a novel prognostic indicator.

Usefulness of cardiac magnetic resonance for early detection of cancer therapeutics-related cardiac dysfunction in breast cancer patients.

BACKGROUND: Prognosis of breast cancer patients has been improved along with the progress in cancer therapies. However, cancer therapeutics-related cardiac dysfunction (CTRCD) has been an emerging issue. For early detection of CTRCD, we examined whether native T1 mapping and global longitudinal strain (GLS) using cardiac magnetic resonance (CMR) and biomarkers analysis are useful. METHODS: We prospectively enrolled 83 consecutive chemotherapy-naïve female patients with breast cancer (mean age, 56 ± 13 yrs.) between 2017 and 2020. CTRCD was defined based on echocardiography as left ventricular ejection fraction (LVEF) below 53% at any follow-up period with LVEF>10% points decrease from baseline after chemotherapy. To evaluate cardiac function, CMR (at baseline and 6 months), 12­lead ECG, echocardiography, and biomarkers (at baseline and every 3 months) were evaluated. RESULTS: A total of 164 CMRs were performed in 83 patients. LVEF and GLS were significantly decreased after chemotherapy (LVEF, from 71.2 ± 4.4 to 67.6 ± 5.8%; GLS, from -27.9 ± 3.9 to -24.7 ± 3.5%, respectively, both P < 0.01). Native T1 value also significantly elevated after chemotherapy (from 1283 ± 36 to 1308 ± 39 msec, P < 0.01). Among the 83 patients, 7 (8.4%) developed CTRCD. Of note, native T1 value before chemotherapy was significantly higher in patients with CTRCD than in those without it (1352 ± 29 vs. 1278 ± 30 msec, P < 0.01). The multivariable logistic regression analysis revealed that native T1 value was an independent predictive factor for the development of CTRCD [OR 2.33; 95%CI 1.15-4.75, P = 0.02]. CONCLUSIONS: These results indicate that CMR is useful to detect chemotherapy-related myocardial damage and predict for the development of CTRCD in breast cancer patients.

Status of adult outpatients with congenital heart disease in Japan: The Japanese Network of Cardiovascular Departments for Adult Congenital Heart Disease Registry.

BACKGROUND: The Japanese Network of Cardiovascular Departments for Adult Congenital Heart Disease (JNCVD-ACHD) was founded in 2011 for the lifelong care of adult patients with congenital heart disease (ACHD patients). This network maintains the first Japanese ACHD registry. METHODS AND RESULTS: From 2011 to 2019, the JNCVD-ACHD registered 54 institutions providing specialized care for ACHD patients in 32 of the 47 prefectures in Japan. The registry collected data on the disease profile for 24,048 patients from 50 institutions and the patient characteristics for 9743 patients from 24 institutions. The most common ACHDs were atrial septal defect (20.5 %), ventricular septal defect (20.5 %), tetralogy of Fallot (12.9 %), and univentricular heart (UVH)/single ventricle (SV; 6.6 %). ACHD patients without biventricular repair accounted for 37.0 % of the population. Also examined were the serious anatomical and/or pathophysiological disorders such as pulmonary arterial hypertension (3.0 %) including Eisenmenger syndrome (1.2 %), systemic right ventricle under biventricular circulation (sRV-2VC; 2.8 %), and Fontan physiology (6.0 %). The sRV-2VC cases comprised congenitally corrected transposition of the great arteries without anatomical repair (61.9 %) and transposition of the great arteries with atrial switching surgery (38.1 %). The primary etiology (86.4 %) for Fontan physiology was UVH/SV. In addition, developmental/chromosomal/genetic disorders were heterotaxy syndromes (asplenia, 0.9 %; polysplenia, 0.7 %), trisomy 21 (4.0 %), 22q11.2 deletion (0.9 %), Turner syndrome (0.2 %), and Marfan syndrome (1.1 %). CONCLUSIONS: Although the specific management of ACHD has systematically progressed in Japan, this approach is still evolving. For ideal ACHD care, the prospective goals for the JNCVD-ACHD are to create local networks and provide a resource for multicenter clinical trials to support evidence-based practice.

Systemic-pulmonary collateral supply associated with clinical severity of chronic thromboembolic pulmonary hypertension: a study using intra-aortic computed tomography angiography.

OBJECTIVES: To assess whether systemic-pulmonary collaterals are associated with clinical severity and extent of pulmonary perfusion defects in chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: This prospective study was approved by a local ethics committee. Twenty-four patients diagnosed with inoperable CTEPH were enrolled between July 2014 and February 2017. Systemic-pulmonary collaterals were detected using pulmonary vascular enhancement on intra-aortic computed tomography (CT) angiography. The pulmonary enhancement parameters were calculated, including (1) Hounsfield unit differences (HUdiff) between pulmonary trunks and pulmonary arteries (PAs) or veins (PVs), namely HUdiff-PA and HUdiff-PV, on the segmental base; (2) the mean HUdiff-PA, mean HUdiff-PV, numbers of significantly enhanced PAs and PVs, on the patient base. Pulmonary perfusion defects were recorded and scored using the lung perfused blood volume (PBV) based on intravenous dual-energy CT (DECT) angiography. Pearson's or Spearman's correlation coefficients were used to evaluate correlations between the following: (1) segment-based intra-aortic CT and intravenous DECT parameters (2) patient-based intra-aortic CT parameters and clinical severity parameters or lung PBV scores. Statistical significance was set at p < 0.05. RESULTS: Segmental HUdiff-PV was correlated with the segmental perfusion defect score (r = 0.45, p < 0.01). The mean HUdiff-PV was correlated with the mean pulmonary arterial pressure (PAP) (r = 0.52, p < 0.01), cardiac output (rho = - 0.41, p = 0.05), and lung PBV score (rho = 0.43, p = 0.04). And the number of significantly enhanced PVs was correlated with the mean PAP (r = 0.54, p < 0.01), pulmonary vascular resistance (r = 0.54, p < 0.01), and lung PBV score (rho = 0.50, p = 0.01). CONCLUSIONS: PV enhancement measured by intra-aortic CT angiography reflects clinical severity and pulmonary perfusion defects in CTEPH. KEY POINTS: • Intra-aortic CT angiography demonstrated heterogeneous enhancement within the pulmonary vasculature, showing collaterals from the systemic arteries to the pulmonary circulation in CTEPH. • The degree of systemic-pulmonary collateral development was significantly correlated with the clinical severity of CTEPH and may be used to evaluate disease progression. • The distribution of systemic-pulmonary collaterals is positively correlated with perfusion defects in the lung segments in CTEPH.

Usefulness of Right Ventricular Free Wall Strain Obtained with Two-Dimensional Speckle-Tracking Echocardiography in Patients with Repaired Tetralogy of Fallot and Pulmonary Regurgitation.

Right ventricular (RV) dysfunction caused by chronic pulmonary regurgitation (PR) is a major determinant of clinical outcome in adults with repaired tetralogy of Fallot (rTOF). However, the accurate assessment of RV function by conventional echocardiography remains challenging. This study tested the feasibility and usefulness of RV free-wall (RVFW) strain obtained by two-dimensional (2D) speckle-tracking echocardiography (STE) in evaluation of RV function in adults with rTOF by comparing cardiac magnetic resonance (CMR) imaging. We enrolled 22 consecutive patients (male/female, 8/14; mean age, 25.0 years) with rTOF who underwent transthoracic echocardiography at Tohoku University Hospital from July 2016 to June 2019. We measured RVFW strain by STE and compared them with 22 hemodynamically normal subjects (NOR) (male/female, 9/13; mean age, 32.0 years). The correlation between RV strain and CMR-derived RV ejection fraction (RVEF) or PR fraction (PRF) were also evaluated. All rTOF patients had more than moderate PR but were near asymptomatic. RVFW longitudinal strain (RVFW-LS) was significantly decreased in the rTOF group compared with that in the NOR group (-19.6 vs. -24.7, P < 0.01). In the rTOF group, RVFW-LS correlated with PRF (r = 0.44, P < 0.05), whereas RVFW circumferential strain at the mid-ventricular level correlated with RVEF (r = 0.57, P < 0.01). Intra-observer variability of RVFW strain was acceptable. These results indicate that RV systolic function and PR severity in rTOF could be assessed by RVFW strain measured by 2D STE. This method is feasible and can be used as a complement to CMR imaging.

Atrial Septal Defect Closure via Left Subclavian Vein Approach in a Patient With Absent Inferior Vena Cava.

Without the femoral venous approach, transcatheter closure of an atrial septal defect is challenging. We performed percutaneous closure via the left subclavian vein in a patient with absence of the inferior vena cava with azygos continuation. Considering that inferior vena cava anomalies are not extremely rare among those with congenital heart disease, the left subclavian vein approach can be an alternative to the femoral approach.

Association between RNF213 c.14576G>A Variant (rs112735431) and Peripheral Pulmonary Artery Stenosis in Moyamoya Disease.

BACKGROUND: Moyamoya disease (MMD) and peripheral pulmonary artery stenosis (PPAS) are relatively rare and demonstrate steno-occlusive vascular lesions in different organs. Genetic studies identified RNF213 polymorphism c.14576G>A (rs112735431) as a susceptibility variant for East Asian MMD. RNF213 polymorphism c.14576G>A is further associated with various vascular lesions of other organs. In this study, we aimed to clarify the incidence and clinical manifestations of PPAS in MMD patients and analyze the correlation between RNF213 genotype and PPAS. METHODS: This retrospective case-control study investigated the association between RNF213 polymorphism and PPAS in 306 MMD/quasi-MMD patients, reviewing the medical charts and imaging records of consecutive patients with MMD admitted from January 2015 to December 2020. RESULTS: PPAS was observed in 3 MMD/quasi-MMD patients (0.98%, 3/306). RNF213 polymorphism c.14576G>A was determined for all 306 MMD/quasi-MMD patients. The incidence of PPAS in RNF213-wildtype, RNF213-heterozygote, and RNF213-homozygote MMD/quasi-MMD patients was 0% (0/101), 0.5% (1/200), and 40% (2/5), respectively. The association between PPAS and homozygote polymorphism of RNF213 c.14576G>A was statistically significant in MMD/quasi-MMD patients (p = 0.0018). In all cases, pulmonary artery hypertension due to PPAS was evident during their childhood and young adolescent stages. Surgical indications for MMD were discouraged in 1 case due to her severe cardiopulmonary dysfunction. CONCLUSIONS: The homozygote variant of RNF213 polymorphism c.14576G>A can be a potential predisposing factor for PPAS in MMD/quasi-MMD patients. Despite the relatively rare entity, PPAS should be noted to determine surgical indications for MMD/quasi-MMD patients.

Detection of intracellular histological abnormalities using cardiac magnetic resonance T1 mapping in patients with Danon disease: a case series.

BACKGROUND: Danon disease is an X-linked dominant disorder with defects in the lysosome-associated membrane protein 2 (LAMP2) gene and is characterized histologically by intracellular autophagic vacuoles in skeletal and cardiac muscles. Cardiac magnetic resonance (CMR) T1 mapping potentially allows to differentiate intracellular and extracellular cardiac abnormalities with a combination of native T1 value and extracellular volume (ECV) fraction. CASE SUMMARY: We assessed CMR T1 mapping in two Danon disease patients (a 22-year-old man and his 48-year-old mother), who had a LAMP2 c.864G>A p. Val288Val mutation, and two blood relatives without Danon disease (his 47-year-old maternal aunt and 49-year-old father). The male patient underwent a left ventricular (LV) assist device implantation at 15 months after the image acquisition because he was inotrope dependent (INTERMACS profile 3) and had no noticeable psychological or musculoskeletal symptoms. His mother was in New York Heart Association Class II with mildly reduced LV ejection fraction (46%). The Danon group showed late gadolinium enhancement (LGE) in the anterior and posterolateral LV walls. In the interventricular wall, where evident LGE was not noted, the Danon group had high native T1 value, compared with the T1 value in the non-Danon group, and normal ECV fraction. Cardiac biopsy from the interventricular wall showed intracytoplasmic autophagic vacuoles, which are characteristics of Danon disease. DISCUSSION: This characteristic pattern of high native T1 and normal ECV fraction in the areas without LGE, which may reflect the existence of intracytoplasmic autophagic vacuoles, may support the differential diagnosis of Danon disease from other cardiomyopathies.

Identification of the Novel Variants in Patients With Chronic Thromboembolic Pulmonary Hypertension.

Background Although chronic thromboembolic pulmonary hypertension (CTEPH) and acute pulmonary embolism (APE) share some clinical manifestations, a limited proportion of patients with CTEPH have a history of APE. Moreover, in histopathologic studies, it has been revealed that pulmonary vasculature lesions similar to pulmonary arterial hypertension existed in patients with CTEPH. Thus, it remains unknown whether these 3 disorders also share genetic backgrounds. Methods and Results Whole exome screening was performed with DNA isolated from 51 unrelated patients with CTEPH of Japanese ancestry. The frequency of genetic variants associated with pulmonary arterial hypertension or APE in patients with CTEPH was compared with those in the integrative Japanese Genome Variation Database 3.5KJPN. Whole exome screening analysis showed 17 049 nonsynonymous variants in patients with CTEPH. Although we found 6 nonsynonymous variants that are associated with APE in patients with CTEPH, there was no nonsynonymous variant associated with pulmonary arterial hypertension. Patients with CTEPH with a history of APE had nonsynonymous variants of F5, which encodes factor V. In contrast, patients with CTEPH without a history of APE had a nonsynonymous variant of THBD, which encodes thrombomodulin. Moreover, thrombin-activatable fibrinolysis inhibitor, which is one of the pathogenic proteins in CTEPH, was significantly more activated in those who had the variants of THBD compared with those without it. Conclusions These results provide the first evidence that patients with CTEPH have some variants associated with APE, regardless of the presence or absence of a history of APE. Furthermore, the variants might be different between patients with CTEPH with and without a history of APE.

Beneficial effects of riociguat on hemodynamic responses to exercise in CTEPH patients after balloon pulmonary angioplasty - A randomized controlled study.

BACKGROUND: Although balloon pulmonary angioplasty (BPA) improves symptoms and pulmonary hemodynamics in patients with chronic thromboembolic pulmonary hypertension (CTEPH), the effects of riociguat on hemodynamics and exercise capacity in patients after BPA remain to be elucidated. METHODS AND RESULTS: This study was a single-center, prospective, randomized, open-label trial. From November 2015 to November 2018, we prospectively examined 21 patients with CTEPH (65 ± 9 years old, M/F 2/19) who showed hemodynamic improvement with mean pulmonary arterial pressure (mPAP) < 30 mmHg after BPA without any vasodilators. We performed hemodynamic evaluation and expired gas analysis both at rest and during exercise in supine position using cycle ergometer. After right heart catheterization during exercise, they were randomly assigned to 2 groups with minimized method, using age, sex, and resting mPAP; riociguat (N = 10) and control (N = 11) groups. After 6 months, exercise capacity evaluated by 6-min walk distance and cardiopulmonary exercise testing, and resting hemodynamic parameters were comparable in both groups. However, cardiac output (CO) (6.0 ± 1.7-7.4 ± 1.6, P < 0.01) and pulmonary vascular resistance (4.8 ± 1.8-3.2 ± 0.7 Wood units, P = 0.02) at peak workload were significantly improved in the riociguat group as compared with the control group. The slope of linearized mPAP-CO relationship was significantly decreased in the riociguat group [14.5 (7.8, 14.7) to 6.41 (5.1, 11.4), P < 0.01] but not in the control group. CONCLUSIONS: These results indicate that riociguat exerts beneficial effects on hemodynamic response to exercise in CTEPH patients even after hemodynamic improvement by BPA.

Non-invasive screening using ventilatory gas analysis to distinguish between chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension.

BACKGROUND AND OBJECTIVE: Clinical presentations associated with chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) at rest are highly similar. Differentiating between CTEPH and PAH using non-invasive techniques remains challenging. Thus, we examined whether analysis of ventilatory gas in response to postural changes can be useful as a non-invasive screening method for pulmonary hypertension (PH), and help differentiate CTEPH from PAH. METHODS: We prospectively enrolled 90 patients with suspected PH and performed right heart catheterization, ventilation/perfusion scan and ventilatory gas analysis. Various pulmonary function parameters were examined in the supine and sitting postures, and postural changes were calculated (Δ(supine - sitting)). RESULTS: In total, 25 patients with newly diagnosed PAH, 40 patients with newly diagnosed CTEPH and 25 non-PH patients were included. ΔEnd-tidal CO2 pressure (PET CO2 ) was significantly lower in patients with CTEPH and PAH than in non-PH patients (both P < 0.001). ΔPET CO2 < 0 mm Hg could effectively differentiate PH from non-PH (area under the curve (AUC) = 0.969, sensitivity = 89%, specificity = 100%). Postural change from sitting to supine significantly increased the ratio of ventilation to CO2 production (VE/VCO2 ) in the CTEPH group (P < 0.001). By contrast, VE/VCO2 significantly decreased in the PAH group (P = 0.001). Notably, CTEPH presented with higher ΔVE/VCO2 than PAH, although no differences were observed in haemodynamic and echocardiographic parameters between the two groups (P < 0.001). Furthermore, ΔVE/VCO2 > 0.8 could effectively differentiate CTEPH from PAH (AUC = 0.849, sensitivity = 78%, specificity = 88%). CONCLUSION: Postural changes in ventilatory gas analysis are useful as a non-invasive bedside evaluation to screen for the presence of PH and distinguish between CTEPH and PAH.

Cyclophilin A as a biomarker for the therapeutic effect of balloon angioplasty in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Although cardiac troponin and natriuretic peptide have been shown to decrease after balloon pulmonary angioplasty (BPA) with improved right ventricular afterload in chronic thromboembolic pulmonary hypertension (CTEPH), biomarkers to evaluate the effects of BPA independently of heart failure status remain to be developed. METHODS: In 39 consecutive CTEPH patients including 31 who underwent BPA, we measured plasma levels of cyclophilin A (CyPA), which we demonstrated is secreted from pulmonary vascular smooth muscle cells in response to mechanical stretch and hypoxia. RESULTS: CyPA levels were elevated in CTEPH patients (12.7, IQR: 7.6-16.0) compared with 8 thromboembolic controls with a history of venous thromboembolism (4.9, IQR: 2.4-11.2) or 18 healthy controls (4.1, IQR: 2.4-6.8) (both p< 0.05) and were linearly correlated with mean pulmonary arterial pressure (r=0.50, p = 0.0003) and pulmonary vascular resistance (r=0.32, p= 0.026). BPA reduced CyPA levels and tended to lower brain-type natriuretic peptide (BNP) levels (p< 0.01 and p = 0.07). When comparing the changes in CyPA before and after BPA in the two subgroups with higher (≥35pg/mL) and normal (<35pg/mL) BNP at baseline, CyPA decreased both in patients with higher BNP and those with normal BNP (both p< 0.05). In contrast, BNP decreased only in patients with higher BNP (p< 0.05). Also, CyPA decreased both in patients with lower (<25 kg/m2) and higher (≥25kg/m2) body mass index (BMI) at baseline (both p<0.05), whereas BPA tended to reduce BNP in patients with lower BMI (p = 0.12) but not in those with higher BMI (p = 0.55). CONCLUSIONS: CyPA could be a useful biomarker to evaluate the effects of BPA even in patients with normal BNP or high BMI.

Prognostic value of the model for end-stage liver disease excluding INR score (MELD-XI) in patients with adult congenital heart disease.

Patients with adult congenital heart disease (ACHD) are at increased risk of developing late cardiovascular complication. However, little is known about the predictive factors for long-term outcome. The Model for End-Stage Liver Disease eXcluding INR (MELD-XI) score was originally developed to assess cirrhotic patients and has the prognostic value for heart failure (HF) patients. In the present study, we examined whether the score also has the prognostic value in this population. We retrospectively examined 637 ACHD patients (mean age 31.0 years) who visited our Tohoku University hospital from 1995 to 2015. MELD-XI score was calculated as follows; 11.76 x ln(serum creatinine) + 5.11 x ln(serum total bilirubin) + 9.44. We compared the long-term outcomes between the high (≥10.4) and the low (<10.4) score groups. The cutoff value of MELD-XI score was determined based on the survival classification and regression tree (CART) analysis. The major adverse cardiac event (MACE) was defined as a composite of cardiac death, HF hospitalization, and lethal ventricular arrhythmias. During a mean follow-up period of 8.6 years (interquartile range 4.4-11.4 years), MACE was noted in 51 patients, including HF hospitalization in 37, cardiac death in 8, and lethal ventricular arrhythmias in 6. In Kaplan-Meier analysis, the high score group had significantly worse MACE-free survival compared with the low score group (log-rank, P<0.001). Multivariable Cox regression analysis showed that the MELD-XI score remained a significant predictor of MACE (hazard ratio 1.36, confidence interval 1.17-1.58, P<0.001) even after adjusting for patient characteristics, such as sex, functional status, estimated glomerular filtration rate, and cardiac function. Furthermore, CART analysis revealed that the MELD-XI score was the most important variable for predicting MACE. These results demonstrate that the MELD-XI score can effectively predict MACE in ACHD patients, indicating that ACHD patients with high MELD-XI score need to be closely followed.

Identification of Adipsin as a Novel Prognostic Biomarker in Patients With Coronary Artery Disease.

Background Circulating proteins are exposed to vascular endothelial layer and influence their functions. Among them, adipsin is a member of the trypsin family of peptidases and is mainly secreted from adipocytes, monocytes, and macrophages, catalyzing the rate-limiting step of the alternative complement pathway. However, its pathophysiological role in cardiovascular disease remains to be elucidated. Here, we examined whether serum adipsin levels have a prognostic impact in patients with coronary artery disease. Methods and Results In 370 consecutive patients undergoing diagnostic coronary angiography, we performed a cytokine array analysis for screening serum levels of 50 cytokines/chemokines and growth factors. Among them, classification and regression analysis identified adipsin as the best biomarker for prediction of their long-term prognosis (median 71 months; interquartile range, 55-81 months). Kaplan-Meier curve showed that higher adipsin levels (≥400 ng/mL) were significantly associated with all-cause death (hazard ratio [HR], 4.2; 95% CI, 1.7-10.6 [P<0.001]) and rehospitalization (HR, 2.4; 95% CI, 1.7-3.5 [P<0.001]). Interestingly, higher high-sensitivity C-reactive protein levels (≥1 mg/L) were significantly correlated with all-cause death (HR, 3.2; 95% CI, 1.7-5.9 [P<0.001]) and rehospitalization (HR, 1.5, 95% CI, 1.1-1.9 [P<0.01]). Importantly, the combination of adipsin (≥400 ng/mL) and high-sensitivity C-reactive protein (≥1 mg/L) was more significantly associated with all-cause death (HR, 21.0; 95% CI, 2.9-154.1 [P<0.001]). Finally, the receiver operating characteristic curve demonstrated that serum adipsin levels predict the death caused by acute myocardial infarction in patients with coronary artery disease (C-statistic, 0.847). Conclusions These results indicate that adipsin is a novel biomarker that predicts all-cause death and rehospitalization in patients with coronary artery disease, demonstrating the novel aspects of the alternative complementary system in the pathogenesis of coronary artery disease.

Usefulness of ventilatory gas analysis for the non-invasive evaluation of the severity of chronic thromboembolic pulmonary hypertension.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by organic thrombotic obstructions in the pulmonary arteries with reduced pulmonary vascular reserve. This study aimed to examine whether postural changes in ventilatory gas analysis parameters are useful for assessing pulmonary hemodynamics in patients with CTEPH. METHODS: A total of 44 patients with newly diagnosed CTEPH (CTEPH group), 33 patients with improved CTEPH (mean pulmonary arterial pressure [mPAP] <25 mm Hg), and 25 controls were enrolled. Patients with improved CTEPH referred to patients without residual PH who were previously diagnosed with CTEPH and already received optimal therapies. Various pulmonary function parameters were examined in supine and sitting positions, and postural changes were calculated (Δ[supine - sitting]). In 32 patients with CTEPH, we examined hemodynamic and ventilatory gas analysis parameters before the first balloon pulmonary angioplasty (BPA) and during follow-up. RESULTS: Patients with CTEPH had significantly lower supine end-tidal carbon dioxide pressure (PETCO2) and ΔPETCO2 than controls (both P < 0.001), and these parameters were significantly correlated with mPAP (R2 = 0.507, P < 0.0001 and R2 = 0.470, P < 0.001, respectively). Supine PETCO2 and ΔPETCO2 were significantly lower in patients with improved CTEPH than in controls (both P < 0.001). Hemodynamic and echocardiographic parameters were comparable in both groups. Furthermore, significant correlation between the change in mPAP and change in supine PETCO2 by BPA was noted (R2 = 0.478, P < 0.001). CONCLUSION: These results indicate that postural changes in ventilatory gas analysis parameters are useful and non-invasive method for the evaluation of mPAP, which is one of the hemodynamic parameters of CTEPH severity.

Successful Management of Acute Congestive Heart Failure by Emergent Caesarean Section Followed by Adrenalectomy in a Pregnant Woman with Cushing's Syndrome-induced Cardiomyopathy.

Congestive heart failure (CHF) is rare during pregnancy. We herein report a 35-year-old woman who developed CHF with severe left ventricular dysfunction at 35 weeks' gestation. She underwent emergency Caesarean section followed by intensive-care treatment for CHF. The diagnosis of Cushing's syndrome (CS) caused by adrenal adenoma was confirmed by endocrinological examinations and histology after adrenalectomy. She was discharged on heart failure medications and glucocorticoid replacement therapy. Both the symptoms and cardiac function had recovered after 12 months of follow-up. This case highlights the importance of considering CS-induced cardiomyopathy as a cause of CHF in pregnant women.

Beneficial Effects of Imatinib in a Patient with Suspected Pulmonary Veno-Occlusive Disease.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension (PH). The prognosis of PVOD patients remains poor, since no effective medical therapy is yet available. Imatinib is a tyrosine kinase inhibitor specific for platelet-derived growth factor receptor and is expected as a treatment option for pulmonary arterial hypertension (PAH). Recently, it has been reported that imatinib improved functional capacity of a patient with PVOD. We here report a patient with suspected PVOD who has been successfully treated with imatinib and is alive for 6 years after diagnosis. A 57-year-old woman was admitted to a hospital for severe dyspnea. Echocardiography suggested the presence of PH, because tricuspid regurgitation pressure gradient was elevated. The patient was then transferred to our hospital by an ambulance ahead of schedule due to fever and worsening dyspnea. Because the patient had no left heart disease, we diagnosed that she had PAH associated with severe right heart failure. We immediately started treatment with nitric oxide (NO) for her severe hypoxia; however, it caused pulmonary edema. We suspected PVOD from CT characteristics and pulmonary edema after PAH-targeted vasodilator therapy, and then started oral imatinib treatment. In response to imatinib, her pulmonary edema gradually improved. Since then, the patient has been alive for 6 years with imatinib and pulmonary vasodilators. At present, lung transplantation is the only effective therapy for PVOD with limited availability. We therefore propose that imatinib may be a treatment option for PVOD and a bridge to lung transplantation.