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Vascular Ehlers–Danlos syndrome (vEDS) is a hereditary connective tissue disorder (HCTD) characterized by arterial dissection/aneurysm/rupture, sigmoid colon rupture, or uterine rupture. Diagnosis is confirmed by detecting heterozygous variants in COL3A1. This is the largest Asian case series and the first to apply an amplification‐based next‐generation sequencing through custom panels of causative genes for HCTDs, including a specific method of evaluating copy number variations. Among 429 patients with suspected HCTDs analyzed, 101 were suspected to have vEDS, and 33 of them (32.4%) were found to have COL3A1 variants. Two patients with a clinical diagnosis of Loeys–Dietz syndrome and/or familial thoracic aortic aneurysm and dissection were also found to have COL3A1 variants. Twenty cases (57.1%) had missense variants leading to glycine (Gly) substitutions in the triple helical domain, one (2.9%) had a missense variant leading to non‐Gly substitution in this domain, eight (22.9%) had splice site alterations, three (8.6%) had nonsense variants, two (5.7%) had in‐frame deletions, and one (2.9%) had a multi‐exon deletion, including two deceased patients analyzed with formalin‐fixed and paraffin‐embedded samples. This is a clinically useful system to detect a wide spectrum of variants from various types of samples. [ABSTRACT FROM AUTHOR]

Urinary fatty acid binding protein 1 (FABP1, also known as liver‐type FABP) has been implicated as a biomarker of acute kidney injury (AKI) in humans. However, the precise biological mechanisms underlying its elevation remain elusive. Here, we show that urinary FABP1 primarily reflects impaired protein reabsorption in proximal tubule epithelial cells (PTECs). Bilateral nephrectomy resulted in a marked increase in serum FABP1 levels, suggesting that the kidney is an essential organ for removing serum FABP1. Injected recombinant FABP1 was filtered through the glomeruli and robustly reabsorbed via the apical membrane of PTECs. Urinary FABP1 was significantly elevated in mice devoid of megalin, a giant endocytic receptor for protein reabsorption. Elevation of urinary FABP1 was also observed in patients with Dent disease, a rare genetic disease characterized by defective megalin function in PTECs. Urinary FABP1 levels were exponentially increased following acetaminophen overdose, with both nephrotoxicity and hepatotoxicity observed. FABP1‐deficient mice with liver‐specific overexpression of FABP1 showed a massive increase in urinary FABP1 levels upon acetaminophen injection, indicating that urinary FABP1 is liver‐derived. Lastly, we employed transgenic mice expressing diphtheria toxin receptor (DT‐R) either in a hepatocyte‐ or in a PTEC‐specific manner, or both. Upon administration of diphtheria toxin (DT), massive excretion of urinary FABP1 was induced in mice with both kidney and liver injury, while mice with either injury type showed marginal excretion. Collectively, our data demonstrated that intact PTECs have a considerable capacity to reabsorb liver‐derived FABP1 through a megalin‐mediated mechanism. Thus, urinary FABP1, which is synergistically enhanced by concurrent liver injury, is a biomarker for impaired protein reabsorption in AKI. These findings address the use of urinary FABP1 as a biomarker of histologically injured PTECs that secrete FABP1 into primary urine, and suggest the use of this biomarker to simultaneously monitor impaired tubular reabsorption and liver function. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Aims: Few biomarkers to evaluate pathophysiological changes in extra‐cardiac tissues have been identified in patients with heart failure (HF). Fatty acid‐binding protein 1 (FABP), also known as liver FABP, is predominantly expressed in the liver. Circulating FABP1 has been proposed to be a sensitive biomarker for liver injury. However, little is known about the potential role of FABP1 as a biomarker for HF. Methods and results: Measurements of serum FABP1 and echocardiography were performed in subjects with compensated HF (n = 162) and control subjects without HF (n = 20). Patients were prospectively followed‐up for a composite outcome of all‐cause mortality or HF hospitalization. Compared with control subjects, levels of FABP1 were elevated in HF patients [7.9 (6.4–11.7) vs. 17.6 (10.4–28.9) ng/mL, P < 0.0001]. There were significant correlations between FABP1 levels and estimated right ventricular systolic pressure and right atrial pressure. During a median follow‐up of 12.0 months, there were 55 primary composite endpoints in the HF cohort. The highest FABP1 tertile was associated with a three‐fold increased risk of the composite outcome compared with the lowest tertile [95% confidence interval (1.46–6.68), P = 0.003], but other conventional hepatobiliary markers did not predict the outcome. After adjusting for age, sex, atrial fibrillation, and N‐terminal pro‐B‐type natriuretic peptide levels, serum FABP1 remained independently associated with the outcome. Adding FABP1 to the model based on clinical factors and N‐terminal pro‐B‐type natriuretic peptide significantly improved the prognostic value (global χ2 20.8 vs. 15.5, P = 0.01). Conclusion: Serum FABP1 levels are elevated in compensated HF patients, and the magnitude of elevation is independently associated with pulmonary hypertension, right atrial hypertension, and worse clinical outcomes. FABP1 may serve as a new potential biomarker for the assessment of hitherto unrecognized derangement of cardio‐hepatic interaction in HF. [ABSTRACT FROM AUTHOR]

Aims: Systemic metabolic impairment is the key pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). Fatty acid‐binding protein 4 (FABP4) is highly expressed in adipocytes and secreted in response to lipolytic signals. We hypothesized that circulating FABP4 levels would be elevated in patients with HFpEF, would correlate with cardiac structural and functional abnormalities, and could predict clinical outcomes. Methods and results: Serum FABP4 measurements and echocardiography were performed in patients with HFpEF (n = 92) and those with coronary artery disease free of HF (n = 20). Patients were prospectively followed‐up for a composite endpoint of all‐cause mortality or HF hospitalization. Compared with patients with coronary artery disease, those with HFpEF had higher FABP4 levels [12.5 (9.1–21.0) vs. 43.5 (24.6–77.4) ng/mL, P < 0.0001]. FABP4 levels were associated with cardiac remodelling (left ventricular mass index: r = 0.29, P = 0.002; left atrial volume index: r = 0.40, P < 0.0001), left ventricular systolic and diastolic dysfunction (global longitudinal strain: r = −0.24, P = 0.01; E/e′ ratio: r = 0.29, P = 0.002; and N‐terminal pro‐B‐type natriuretic peptide: r = 0.62, P < 0.0001), and right ventricular dysfunction (tricuspid annular plane systolic excursion: r = −0.43, P < 0.0001). During a median follow‐up of 9.1 months, there were 28 primary endpoints in the HFpEF cohort. Event‐free survival was significantly decreased in patients with FABP4 levels ≥43.5 ng/mL than in those with FABP4 levels <43.5 ng/mL (P = 0.003). Conclusions: Serum FABP4 levels were increased in HFpEF and were associated with cardiac remodelling and dysfunction, and poor outcomes. Thus, FABP4 could be a potential biomarker in the complex pathophysiology of HFpEF. [ABSTRACT FROM AUTHOR]

Abstract: Background: Connective tissue growth factor (CTGF) has been recently reported as a mediator of myocardial fibrosis; however, the significance of plasma CTGF concentration has not been evaluated in patients with heart failure. The aim of this study was to investigate the clinical utility of plasma CTGF concentration for the diagnosis of heart failure. Methods and results: We evaluated fifty-two patients with chronic heart failure. The plasma concentration of CTGF and other markers of fibrosis were assessed and compared with clinical and echocardiographic data. Plasma CTGF was significantly elevated in symptomatic patients in proportion to their NYHA classes and was significantly correlated with plasma brain natriuretic peptide (BNP) concentration (r =0.395, P <0.01). Plasma CTGF was also correlated with plasma transforming growth factor beta (TGF-β) (r =0.512, P <0.01), matrix metalloproteinase (MMP)-2 (r =0.391, P <0.05) and tissue inhibitor of MMP (TIMP)-2 (r =0.354, P <0.05) concentrations. Interestingly, plasma CTGF was correlated with E/E'' value evaluated by tissue Doppler echocardiography (r =0.593, P =0.012), but not with systolic function and left ventricular mass. Conclusion: Our study suggests that plasma CTGF concentration is a novel diagnostic marker for cardiac dysfunction and may provide additional specific information about myocardial fibrosis in chronic heart failure patients. [Copyright &y& Elsevier]

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening complication post-acute pulmonary embolism (PE). The assessment of CTEPH incidence and risk factors post-acute PE in the era of direct oral anticoagulants remains insufficient., Methods and Results: The COMMAND VTE Registry-2 (contemporary management and outcomes in patients with venous thromboembolism registry-2) is a multicenter registry that recruited consecutive patients with acute symptomatic venous thromboembolism from 31 centers across Japan. The primary outcome was to demonstrate the detection rate of CTEPH after acute PE in routine clinical practice. Out of the 5197 patients with venous thromboembolism included in the COMMAND VTE Registry-2, 2787 were diagnosed with acute PE. Following a median follow-up duration of 747 days, 48 cases of CTEPH were detected, and the cumulative diagnosis of CTEPH in routine clinical practice was 2.3% at 3 years. Independent risk factors for the detection of CTEPH by multivariable Cox regression analysis included women (hazard ratio [HR] 2.09 [95% CI, 1.05-4.14]), longer interval from symptom onset to diagnosis of PE (each 1 day, HR 1.04 [95% CI, 1.01-1.07]), hypoxemia at diagnosis (HR 2.52 [95% CI, 1.26-5.04]), right heart load (HR 9.28 [95% CI, 3.19-27.00]), lower D-dimer value (each 1 μg/mL, HR 0.96 [95% CI, 0.92-0.99]), and unprovoked PE (HR 2.77 [95% CI, 1.22-6.30])., Conclusions: In the direct oral anticoagulant era, the cumulative diagnosis of CTEPH after acute PE was 2.3% at 3 years, and several independent risk factors for CTEPH were identified, which could be useful for screening a high-risk population after acute PE.

Background: The simplified Pulmonary Embolism Severity Index (sPESI) score could help identify low-risk patients with pulmonary embolism for home treatment. However, the application of the sPESI score and selection for home treatment have not been fully evaluated in the direct oral anticoagulants era., Methods and Results: The COMMAND VTE (Contemporary Management and Outcomes in Patients With Venous Thromboembolism) Registry-2 is a multicenter registry enrolling consecutive patients with acute symptomatic venous thromboembolism. The current study population consists of 2496 patients with hemodynamically stable pulmonary embolism (2100 patients [84%] treated with direct oral anticoagulants), who were divided into 2 groups: sPESI scores of 0 and ≥1. We investigated the 30-day mortality, home treatment prevalence, and factors predisposing to home treatment using the Kaplan-Meier method and logistic regression model. Patients with an sPESI score of 0 accounted for 612 (25%) patients, and only 17% among 532 patients with out-of-hospital pulmonary embolism were treated at home. The cumulative 30-day mortality was lower in patients with an sPESI score of 0 than the score of ≥1 (0% and 4.8%, log-rank P <0.001). There was no patient with 30-day mortality with an sPESI score of 0. Independent factors for home treatment among out-of-hospital pulmonary embolism patients with an sPESI score of 0 were no transient risk factors for venous thromboembolism, no cardiac biomarker elevation, and direct oral anticoagulants use in the acute phase., Conclusions: The 30-day mortality rate was notably low in an sPESI score of 0. Nevertheless, only a minority of patients with an sPESI score of 0 were treated at home between 2015 and 2020 after the introduction of direct oral anticoagulants for venous thromboembolismin Japan.

Background: There have been limited data on the changes in clinical outcomes after the introduction of direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) in real clinical practice. We evaluated the changes in management strategies and long-term outcomes from the warfarin era to the DOAC era., Methods and Results: We compared the 2 series of multicenter COMMAND VTE (Contemporary Management and Outcomes in Patients With Venous Thromboembolism) registries in Japan enrolling consecutive patients with acute symptomatic VTE: Registry 1: 3027 patients in the warfarin era (2010-2014) and Registry 2: 5197 patients in the DOAC era (2015-2020). The prevalence of DOAC use increased more in Registry 2 than in the Registry 1 (Registry 1: 2.6% versus Registry 2: 79%, P <0.001). The cumulative 5-year incidence of recurrent VTE was significantly lower in Registry 2 than in Registry 1 (10.5% versus 9.5%, P =0.02), and the risk reduction of recurrent VTE in Registry 2 remained significant even after adjusting the confounders (hazard ratio [HR], 0.78 [95% CI, 0.65-0.93]; P =0.005). The cumulative 5-year incidence of major bleeding was not significantly different between the 2 registries (12.1% versus 13.7%, P =0.26), and the risk of major bleeding between the 2 registries was not significantly different even after adjusting the confounders (HR, 1.04 [95% CI, 0.89-1.21]; P =0.63)., Conclusions: Along with the shift from warfarin to DOACs, there was a lower risk of recurrent VTE in the DOAC era than in the warfarin era, whereas there was no apparent change in the risk of major bleeding, which might still be an unmet need even in the DOAC era.