Alternatively activated (also known as M2) macrophages are involved in the repair of various types of organs. However, the contribution of M2 macrophages to cardiac repair after myocardial infarction (MI) remains to be fully characterized. Here, we identified CD206⁺F4/80⁺CD11b⁺ M2-like macrophages in the murine heart and demonstrated that this cell population predominantly increases in the infarct area and exhibits strengthened reparative abilities after MI. We evaluated mice lacking the kinase TRIB1 (Trib1^–/–), which exhibit a selective depletion of M2 macrophages after MI. Compared with control animals, Trib1^–/– mice had a catastrophic prognosis, with frequent cardiac rupture, as the result of markedly reduced collagen fibril formation in the infarct area due to impaired fibroblast activation. The decreased tissue repair observed in Trib1^–/– mice was entirely rescued by an external supply of M2-like macrophages. Furthermore, IL-1α and osteopontin were suggested to be mediators of M2-like macrophage–induced fibroblast activation. In addition, IL-4 administration achieved a targeted increase in the number of M2-like macrophages and enhanced the post-MI prognosis of WT mice, corresponding with amplified fibroblast activation and formation of more supportive fibrous tissues in the infarcts. Together, these data demonstrate that M2-like macrophages critically determine the repair of infarcted adult murine heart by regulating fibroblast activation and suggest that IL-4 is a potential biological drug for treating MI.

Background: A number of case reports show various outcomes of premature closure of the ductus arteriosus in utero, including persistent pulmonary hypertension of the newborn and fetal or neonatal death; however, no study clarifies the clinical observations that are related to their prognoses. We aimed to clarify the prognostic factors of intrauterine ductal closure by a systematic literature review.Data sources: We searched PubMed database (1975–2014) to identify case reports and studies on intrauterine closure of the ductus arteriosus, including maternal, fetal, and neonatal clinical information and their prognoses.Results: We analysed the data of 116 patients from 39 articles. Of these, 12 (10.3%) died after birth or in utero. Fetal or neonatal death was significantly correlated with fetal hydrops (odds ratio=39.6, 95% confidence interval=4.6–47.8) and complete closure of the ductus arteriosus (odds ratio=5.5, 95% confidence interval=1.2–15.1). Persistent pulmonary hypertension was observed in 33 cases (28.4%), and was also correlated with fetal hydrops (odds ratio=4.2, 95% confidence interval=1.3–4.6) and complete closure of the ductus arteriosus (odds ratio=5.5, 95% confidence interval=1.6–6.0). Interestingly, maternal drug administration was not correlated with the risk of death and persistent pulmonary hypertension.Conclusions: Fetal hydrops and complete ductal closure are significant risk factors for both death and persistent pulmonary hypertension. Cardiac or neurological prognoses could be favourable if the patients overcome right heart failure during the perinatal period.

Objectives: Tricuspid valve dysplasia (TVD) and Ebstein's anomaly (EA) diagnosed by fetal echocardiography vary greatly in terms of clinical severity and prognosis. The Celermajer index and Simpson–Andrews–Sharland (SAS) score have been reported previously for the prediction of prognosis in cases of TVD/EA; however, they do not take into account the hemodynamic impact of left ventricular (LV) function, which has recently been implicated as being important in the pathophysiology of TVD/EA. The aim of this study was to develop a novel scoring system that includes LV function for the prediction of perinatal death in fetuses diagnosed with TVD/EA.Methods: The clinical records of 36 fetuses diagnosed prenatally with TVD/EA between 2000 and 2015 in our hospital were reviewed. Univariate analysis was used to assess the association between perinatal death (defined as death between 22 weeks' gestation and 4 weeks after delivery) and gestational age at diagnosis, cardiothoracic area ratio (CTAR), degree of pulmonary artery flow, direction of ductal flow, right‐to‐left ventricular diameter ratio, tricuspid regurgitation (TR) maximum velocity, Celermajer index, SAS score and LV‐Tei index. A new prognostic score, the TRIPP score (TRIcuspid malformation Prognosis Prediction score), was developed using the parameters found to be associated significantly with perinatal death. The predictive value of this score was assessed in an additional nine fetuses diagnosed with TVD/EA.Results: Thirty‐six fetuses were diagnosed prenatally with TVD/EA, two of which were terminated, one was lost to follow‐up and two died before 22 weeks' gestation. Of the 31 included fetuses, 10 (32%) died in the perinatal period. Univariate analysis demonstrated that TR maximum velocity was significantly lower (2.22 ± 0.17 m/s vs 3.26 ± 0.12 m/s; P < 0.001) and SAS score was significantly higher (5.7 ± 0.6 points vs 2.8 ± 0.4 points; P = 0.0014) in cases of perinatal death than in surviving fetuses. The degree of pulmonary artery flow and the direction of ductal flow were also associated significantly with perinatal death (P < 0.01 for both). Notably, LV‐Tei index was significantly higher in cases of perinatal death than in surviving fetuses (0.81 ± 0.08 vs 0.50 ± 0.05; P < 0.001). In contrast, there was no significant difference in Celermajer index, CTAR or right‐to‐left ventricular diameter ratio. Finally, we established a novel combinatorial scoring system, the TRIPP score, including the four significant factors: TR maximum velocity, pulmonary artery flow, direction of ductal flow and LV‐Tei index. The TRIPP score was found to predict efficiently perinatal mortality in fetuses with TVD/EA.Conclusions: Our novel combinatorial score of echocardiographic parameters, the TRIPP score, including LV‐Tei index, is easy to measure and provides a good tool for the prediction of perinatal mortality in fetuses diagnosed prenatally with TVD/EA. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

BACKGROUND: Restrictive cardiomyopathy in children is rare and outcomes are very poor. However, little information is available concerning genotype-outcome correlations. METHODS: We analyzed the clinical characteristics and genetic testing, including whole exome sequencing, of 28 pediatric restrictive cardiomyopathy patients who were diagnosed from 1998 to 2021 at Osaka University Hospital in Japan. RESULTS: The median age at diagnosis (interquartile range) was 6 (2.25–8.5) years. Eighteen patients received heart transplantations and 5 patients were on the waiting list. One patient died while waiting for transplantation. Pathologic or likely-pathogenic variants were identified in 14 of the 28 (50%) patients, including heterozygous TNNI3 missense variants in 8 patients. TNNT2 , MYL2 , and FLNC missense variants were also identified. No significant differences in clinical manifestations and hemodynamic parameters between positive and negative pathogenic variants were detected. However, 2- and 5-year survival rates were significantly lower in patients with pathogenic variants (50% and 22%) compared with survival in patients without pathogenic variants (62% and 54%; P =0.0496, log-rank test). No significant differences were detected in the ratio of patients diagnosed at nationwide school heart disease screening program between positive and negative pathogenic variants. Patients diagnosed by school screening showed better transplant-free survival compared with patients diagnosed by heart failure symptoms ( P =0.0027 in log-rank test). CONCLUSIONS: In this study, 50% of pediatric restrictive cardiomyopathy patients had pathogenic or likely-pathogenic gene variants, and TNNI3 missense variants were the most frequent. Patients with pathogenic variants showed significantly lower transplant-free survival compared with patients without pathogenic variants.

Riociguat, a soluble guanylate cyclase stimulator, is approved for treatment of adults with pulmonary arterial hypertension (PAH). The safety, tolerability, and pharmacokinetics (PK) of oral riociguat in a pediatric population with PAH was assessed in PATENT–CHILD (NCT02562235), a multicenter, single‐arm, 24‐week, open‐label, Phase 3 study. Patients aged 6–17 years in World Health Organization functional class (WHO‐FC) I–III treated with stable endothelin receptor antagonists and/or prostacyclin analogs received riociguat equivalent to 0.5–2.5 mg three times daily in adults, as either oral pediatric suspension or tablets, based on bodyweight. Primary outcomes were safety, tolerability, and PK of riociguat. Twenty‐four patients (mean age 12.8 years), 18 of whom were in WHO‐FC II, were enrolled. Adverse events (AEs), mostly mild or moderate, were reported in 20 patients (83%). Four patients (17%) experienced a serious AE; all resolved by study end and two (8%) were considered study‐drug related. Hypotension was reported in three patients and hemoptysis in one (all mild/moderate intensity). Riociguat plasma concentrations in pediatric patients were consistent with those published in adult patients. From baseline to Week 24, mean ± standard deviation increase in 6‐minute walking distance was 23 ± 69 m (n = 19), and mean decrease in NT‐proBNP was –66 ± 585 pg/ml (n = 14). There was no change in WHO‐FC. Two patients experienced clinical worsening events of hospitalization for right heart failure. PK results confirmed a suitable riociguat dosing strategy for pediatric patients with PAH. The data suggest an acceptable safety profile with potential efficacy signals.

Down syndrome (DS) is the most prevalent chromosomal disorder associated with a higher incidence of pulmonary arterial hypertension (PAH). The dysfunction of vascular endothelial cells (ECs) is known to cause pulmonary arterial remodeling in PAH, although the physiological characteristics of ECs harboring trisomy 21 (T21) are still unknown. In this study, we analyzed the human vascular ECs by utilizing the isogenic pairs of T21-induced pluripotent stem cells (iPSCs) and corrected disomy 21 (cDi21)-iPSCs. In T21-iPSC-derived ECs, apoptosis and mitochondrial reactive oxygen species (mROS) were significantly increased, and angiogenesis and oxygen consumption rate (OCR) were significantly impaired as compared with cDi21-iPSC-derived ECs. The RNA-sequencing identified that EGR1 on chromosome 5 was significantly upregulated in T21-ECs. Both EGR1 suppression by siRNA and pharmacological inhibitor could recover the apoptosis, mROS, angiogenesis, and OCR in T21-ECs. Alternately, the study also revealed that DYRK1A was responsible to increase EGR1 expression via PPARG suppression, and that chemical inhibition of DYRK1A could restore the apoptosis, mROS, angiogenesis, and OCR in T21-ECs. Finally, we demonstrated that EGR1 was significantly upregulated in the pulmonary arterial ECs from lung specimens of a patient with DS and PAH. In conclusion, DYRK1A/PPARG/EGR1 pathway could play a central role for the pulmonary EC functions and thus be associated with the pathogenesis of PAH in DS.