Fibroblast Primary Cilia are Required for Cardiac Fibrosis

Background: The primary cilium is a singular cellular structure that extends from the surface of many cell types and plays crucial roles in vertebrate development, including that of the heart. Whereas ciliated cells have been described in developing heart, a role for primary cilia in adult heart has not been reported. This, coupled with the fact that mutations in genes coding for multiple ciliary proteins underlie polycystic kidney disease, a disorder with numerous cardiovascular manifestations, prompted us to identify cells in adult heart harboring a primary cilium and to determine whether primary cilia play a role in disease-related remodeling. Methods: Histological analysis of cardiac tissues from C57BL/6 mouse embryos, neonatal mice, and adult mice was performed to evaluate for primary cilia. Three injury models (apical resection, ischemia/reperfusion, and myocardial infarction) were used to identify the location and cell type of ciliated cells with the use of antibodies specific for cilia (acetylated tubulin, γ-tubulin, polycystin [PC] 1, PC2, and KIF3A), fibroblasts (vimentin, α-smooth muscle actin, and fibroblast-specific protein-1), and cardiomyocytes (α-actinin and troponin I). A similar approach was used to assess for primary cilia in infarcted human myocardial tissue. We studied mice silenced exclusively in myofibroblasts for PC1 and evaluated the role of PC1 in fibrogenesis in adult rat fibroblasts and myofibroblasts. Results: We identified primary cilia in mouse, rat, and human heart, specifically and exclusively in cardiac fibroblasts. Ciliated fibroblasts are enriched in areas of myocardial injury. Transforming growth factor β-1 signaling and SMAD3 activation were impaired in fibroblasts depleted of the primary cilium. Extracellular matrix protein levels and contractile function were also impaired. In vivo, depletion of PC1 in activated fibroblasts after myocardial infarction impaired the remodeling response. Conclusions: Fibroblasts in the neonatal and adult heart harbor a primary cilium. This organelle and its requisite signaling protein, PC1, are required for critical elements of fibrogenesis, including transforming growth factor β-1-SMAD3 activation, production of extracellular matrix proteins, and cell contractility. Together, these findings point to a pivotal role of this organelle, and PC1, in disease-related pathological cardiac remodeling and suggest that some of the cardiovascular manifestations of autosomal dominant polycystic kidney disease derive directly from myocardium-autonomous abnormalities

Transverse aortic constriction induces gut barrier alterations, microbiota remodeling and systemic inflammation

Accumulating evidence suggests that modifications of gut function and microbiota composition might play a pivotal role in the pathophysiology of several cardiovascular diseases, including heart failure (HF). In this study we systematically analysed gut microbiota composition, intestinal barrier integrity, intestinal and serum cytokines and serum endotoxin levels in C57BL/6 mice undergoing pressure overload by transverse aortic constriction (TAC) for 1 and 4 weeks. Compared to sham-operated animals, TAC induced prompt and strong weakening of intestinal barrier integrity, long-lasting decrease of colon anti-inflammatory cytokine levels, significant increases of serum levels of bacterial lipopolysaccharide and proinflammatory cytokines. TAC also exerted effects on microbiota composition, inducing significant differences in bacterial genera inside Actinobacteria, Firmicutes, Proteobacteria and TM7 phyla as shown by 16S rDNA sequencing of fecal samples from TAC or sham mice. These results suggest that gut modifications represent an important element to be considered in the development and progression of cardiac dysfunction in response to TAC and support this animal model as a valuable tool to establish the role and mechanisms of gut-heart crosstalk in HF. Evidence arising in this field might identify new treatment options targeting gut integrity and microbiota components to face adverse cardiac events

Risk Factors Associated with Adverse Fetal Outcomes in Pregnancies Affected by Coronavirus Disease 2019 (COVID-19): A Secondary Analysis of the WAPM study on COVID-19

To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Mean gestational age at diagnosis was 30.6\ub19.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; p<0.001), birthweight (OR: 1.17, 95% CI 1.09-1.12.7 per 100 g decrease; p=0.012) and maternal ventilatory support, including either need for oxygen or CPAP (OR: 4.12, 95% CI 2.3-7.9; p=0.001) were independently associated with composite adverse fetal outcome. Early gestational age at infection, maternal ventilatory supports and low birthweight are the main determinants of adverse perinatal outcomes in fetuses with maternal COVID-19 infection. Conversely, the risk of vertical transmission seems negligible

Electrical imaging and self-potential survayes to study the geological setting of the Quaternary, slope depositsin the Agri high valley (Southern Italy)

We present the results of a geophysical survey carried out to outline the structural modelling of Quaternary slopedeposits in the northern part of the Agri high valley (Basilicata, Southern Italy). Quaternary folding and brittle deformations of the subaerial slope deposits have been studied combining electrical imaging and self-potential surveys with geological structural analysis. This integrated approach indicates that the area underwent both transpressional and transtensional tectonics during Pleistocene times as testified by the existence of a push up structure in the basement buried by deformed Quaternary breccias. On this basis, the valley appears to be a more complex structure than a simple extensional graben, as traditionally assumed in the literature

Electrical imaging and self-potential survayes to study the geological setting of the Quaternary, slope depositsin the Agri high valley (Southern Italy)

We present the results of a geophysical survey carried out to outline the structural modelling of Quaternary slopedeposits in the northern part of the Agri high valley (Basilicata, Southern Italy). Quaternary folding and brittle deformations of the subaerial slope deposits have been studied combining electrical imaging and self-potential surveys with geological structural analysis. This integrated approach indicates that the area underwent both transpressional and transtensional tectonics during Pleistocene times as testified by the existence of a push up structure in the basement buried by deformed Quaternary breccias. On this basis, the valley appears to be a more complex structure than a simple extensional graben, as traditionally assumed in the literature

Caratteri morfoevolutivi e valutazione dei distacchi potenziali di un versante in roccia nei pressi di San Chirico Raparo (Basilicata): applicazione integrata di metodi geologici e geofisici

. Un approccio multidisciplinare basato su indagini geomorfologiche, geostrutturali e geofisiche ha permesso di valutare l’evoluzione morfodinamica e le tipologie prevalenti di instabilità di un versante in roccia ubicato nell'Appennino lucano, nei pressi dell’abitato di San Chirico Raparo. L’area di studio è rappresentata da un plateau di travertino posto a circa 810 metri s.l.m. che poggia su conglomerati quaternari appartenenti alla successione plio-pleistocenica del bacino di Sant’Arcangelo Auctt. e su un'alternanza arenaceo-pelitica oligo-miocenica ascrivibile alla Formazione di Albidona. Il litosoma di travertino è inciso trasversalmente da corsi d’acqua di basso ordine gerarchico che - in un intervallo temporale di circa 80.000-90.000 anni - hanno prodotto una parete verticale di 30 metri circa non in equilibrio con il sistema morfoclimatico attuale. Il versante in roccia evolve attualmente con meccanismi di rock fall, causando frequenti danni alle infrastrutture circostanti. Episodi di crolli sono stati registrati anche in coincidenza dell’evento sismico del Settembre 1998 con epicentro nella contigua area della Catena del Pollino. Rilievi geologici e strutturali hanno permesso di ricostruire la geometria e lo stato di fratturazione del corpo roccioso. I dati giaciturali sono stati elaborati con il metodo della sovrapposizione che ha rivelato i meccanismi di instabilità dominanti lungo la parete rocciosa e le famiglie di discontinuità cinematicamente attivabili. Gli aspetti relativi alla distribuzione ed all’andamento delle fratture in profondità e la geometria della superficie di appoggio dei travertini sono stati investigati tramite tomografie geoelettriche ad alta risoluzione, grazie alle quali è stato possibile riconoscere anche la spaziatura dei principali sistemi e dunque – unitamente alle misure sul campo - le volumetrie potenzialmente instabili. L'integrazione dei dati acquisiti con le diverse metodologie ha fornito un quadro sufficientemente chiaro sui caratteri morfoevolutivi del fronte roccioso nell'attuale contesto climatico ed in coincidenza di triggering sismico