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Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder of vascular malformations characterized by mucocutaneous telangiectases and arteriovenous malformations (AVMs) in internal organs. HHT is caused by inheritance of a loss of function mutation in one of three genes. Although individuals with HHT are haploinsufficient for one of these genes throughout their entire body, rather than exhibiting a systemic vascular phenotype, vascular malformations occur as focal lesions in discrete anatomic locations. The inconsistency between genotype and phenotype has provoked debate over whether haploinsufficiency or a different mechanism gives rise to the vascular malformations. We previously showed that HHT-associated skin telangiectases develop by a two-hit mutation mechanism in an HHT gene. However, somatic mutations were identified in only half of the telangiectases, raising the question whether a second-hit somatic mutation is a necessary (required) event in HHT pathogenesis. Here, we show that another mechanism for the second hit is loss of heterozygosity across the chromosome bearing the germline mutation. Secondly, we investigate the two-hit mutation mechanism for internal organ AVMs, the source of much of the morbidity of HHT. Here, we identified somatic molecular genetic events in eight liver telangiectases, including point mutations and a loss of heterozygosity event. We also identified somatic mutations in one pulmonary AVM and two brain AVMs, confirming that mucocutaneous and internal organ vascular malformations undergo the same molecular mechanisms. Together, these data argue that bi-allelic loss of function in an HHT gene is a required event in the pathogenesis of HHT-associated vascular malformations., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Tricuspid annular plane systolic excursion (TAPSE) is usually measured with M-mode using sector line, however, this may not align with the anatomical shortening of the right ventricular (RV). In this study, we compared the different methods to measure TAPSE using three different reference lines (sector line, anatomical line, and apico-annular line). We included 148 patients diagnosed with pulmonary arterial hypertension (PAH) who underwent TTE and right heart catheterization within 2 weeks of each other. TAPSE was measured by M-mode (sector, anatomical), 2D (sector, anatomical), or as tricuspid apico-annular displacement (TAAD). Agreement between measures was assessed using coefficient of variation (COV), Spearman's correlation, and Bland-Altman analysis. Receiver-operating characteristics and Kaplan-Meier analysis were used to explore associations with the combined outcome of death or lung transplantation at 5 years. There was a good concordance between anatomical and sector M-mode with a COV of 15.5 ± 1.6% and a bias of -0.6 ± 3.2 mm. In contrast, anatomical M-mode TAPSE and TAAD differed significantly with the mean difference of 3.3 ± 3.8 mm (COV 30.5 ± 6.1%; p  < 0.0001). Among the different 2D methods, anatomical 2D agreed well with anatomical M-mode TAPSE (COV of 11.8 ± 2.0%; r  = 0.89; p  < 0.0001). Among the five methods, TADD had the strongest association with the combined endpoint of death or transplantation at 5 years (C-statistic 0.64, 95% confidence interval [CI] 0.57-0.71). We concluded that different measures of TAPSE are not interchangeable., Competing Interests: Dr. Haddad reports research grants from Actelion Pharmaceuticals, a Janssen Company of Johnson & Johnson, focused on computational approaches for the diagnosis and monitoring of pulmonary hypertension. The other authors report no conflicts relevant to this study., (© 2024 The Author(s). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background: Pathogenic concepts of right ventricular (RV) failure in pulmonary arterial hypertension focus on a critical loss of microvasculature. However, the methods underpinning prior studies did not take into account the 3-dimensional (3D) aspects of cardiac tissue, making accurate quantification difficult. We applied deep-tissue imaging to the pressure-overloaded RV to uncover the 3D properties of the microvascular network and determine whether deficient microvascular adaptation contributes to RV failure., Methods: Heart sections measuring 250-µm-thick were obtained from mice after pulmonary artery banding (PAB) or debanding PAB surgery and properties of the RV microvascular network were assessed using 3D imaging and quantification. Human heart tissues harvested at the time of transplantation from pulmonary arterial hypertension cases were compared with tissues from control cases with normal RV function., Results: Longitudinal 3D assessment of PAB mouse hearts uncovered complex microvascular remodeling characterized by tortuous, shorter, thicker, highly branched vessels, and overall preserved microvascular density. This remodeling process was reversible in debanding PAB mice in which the RV function recovers over time. The remodeled microvasculature tightly wrapped around the hypertrophied cardiomyocytes to maintain a stable contact surface to cardiomyocytes as an adaptation to RV pressure overload, even in end-stage RV failure. However, microvasculature-cardiomyocyte contact was impaired in areas with interstitial fibrosis where cardiomyocytes displayed signs of hypoxia. Similar to PAB animals, microvascular density in the RV was preserved in patients with end-stage pulmonary arterial hypertension, and microvascular architectural changes appeared to vary by etiology, with patients with pulmonary veno-occlusive disease displaying a lack of microvascular complexity with uniformly short segments., Conclusions: 3D deep tissue imaging of the failing RV in PAB mice, pulmonary hypertension rats, and patients with pulmonary arterial hypertension reveals complex microvascular changes to preserve the microvascular density and maintain a stable microvascular-cardiomyocyte contact. Our studies provide a novel framework to understand microvascular adaptation in the pressure-overloaded RV that focuses on cell-cell interaction and goes beyond the concept of capillary rarefaction., Competing Interests: Disclosures None.

Cardiorenal syndrome (CRS) due to right ventricular (RV) failure is a disease entity emerging as a key indicator of morbidity and mortality. The multifactorial aspects of CRS and the left-right ventricular interdependence complicate the link between RV failure and renal function. RV failure has a direct pathophysiological link to renal dysfunction by leading to systemic venous congestion in certain circumstances and low cardiac output in other situations, both leading to impaired renal perfusion. Indeed, renal dysfunction is known to be an independent predictor of mortality in patients with pulmonary arterial hypertension (PAH) and RV failure. Thus, it is important to further understand the interaction between the RV and renal function. RV adaptation is critical to long-term survival in patients with PAH. The RV is also known for its remarkable capacity to recover once the aggravating factor is addressed or mitigated. However, less is known about the renal potential for recovery following the resolution of chronic RV failure. In this review, we provide an overview of the intricate relationship between RV dysfunction and the subsequent development of CRS, with a particular emphasis on PAH. Additionally, we summarize potential RV-targeted therapies and their potential beneficial impact on renal function., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The right ventricle (RV) is at risk in patients with complex congenital heart disease involving right-sided obstructive lesions. We have shown that capillary rarefaction occurs early in the pressure-loaded RV. Here we test the hypothesis that microRNA (miR)-34a, which is induced in RV hypertrophy and RV failure (RVF), blocks the hypoxia-inducible factor-1α-vascular endothelial growth factor (VEGF) axis, leading to the attenuated angiogenic response and increased susceptibility to RV failure., Methods and Results: Mice underwent pulmonary artery banding to induce RV hypertrophy and RVF. Capillary rarefaction occurred immediately. Although hypoxia-inducible factor-1α expression increased (0.12±0.01 versus 0.22±0.03, P =0.05), VEGF expression decreased (0.61±0.03 versus 0.22±0.05, P =0.01). miR-34a expression was most upregulated in fibroblasts (4-fold), but also in cardiomyocytes and endothelial cells (2-fold). Overexpression of miR-34a in endothelial cells increased cell senescence (10±3% versus 22±2%, P <0.05) by suppressing sirtulin 1 expression, and decreased tube formation by 50% via suppression of hypoxia-inducible factor-1α, VEGF A, VEGF B, and VEGF receptor 2. miR-34a was induced by stretch, transforming growth factor-β1, adrenergic stimulation, and hypoxia in cardiac fibroblasts and cardiomyocytes. In mice with RVF, locked nucleic acid-antimiR-34a improved RV shortening fraction and survival half-time and restored capillarity and VEGF expression. In children with congenital heart disease-related RVF, RV capillarity was decreased and miR-34a increased 5-fold., Conclusions: In summary, miR-34a from fibroblasts, cardiomyocytes, and endothelial cells mediates capillary rarefaction by suppressing the hypoxia-inducible factor-1α-VEGF axis in RV hypertrophy/RVF, raising the potential for anti-miR-34a therapeutics in patients with at-risk RVs.

The laboratory rat emerges as a useful tool for studying the interaction between the host and its microbiome. To advance principles relevant to the human microbiome, we systematically investigated and defined the multitissue microbial biogeography of healthy Fischer 344 rats across their lifespan. Microbial community profiling data were extracted and integrated with host transcriptomic data from the Sequencing Quality Control consortium. Unsupervised machine learning, correlation, taxonomic diversity and abundance analyses were performed to determine and characterize the rat microbial biogeography and identify four intertissue microbial heterogeneity patterns (P1-P4). We found that the 11 body habitats harbored a greater diversity of microbes than previously suspected. Lactic acid bacteria (LAB) abundance progressively declined in lungs from breastfed newborn to adolescence/adult, and was below detectable levels in elderly rats. Bioinformatics analyses indicate that the abundance of LAB may be modulated by the lung-immune axis. The presence and levels of LAB in lungs were further evaluated by PCR in two validation datasets. The lung, testes, thymus, kidney, adrenal and muscle niches were found to have age-dependent alterations in microbial abundance. The 357 microbial signatures were positively correlated with host genes in cell proliferation (P1), DNA damage repair (P2) and DNA transcription (P3). Our study established a link between the metabolic properties of LAB with lung microbiota maturation and development. Breastfeeding and environmental exposure influence microbiome composition and host health and longevity. The inferred rat microbial biogeography and pattern-specific microbial signatures could be useful for microbiome therapeutic approaches to human health and life quality enhancement., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

This study analyzed microarray data of right ventricular (RV) tissue from rats exposed to pulmonary embolism to understand the initial dynamic transcriptional response to mechanical stress and compare it with experimental pulmonary hypertension (PH) models. The dataset included samples harvested from 55 rats at 11 different time points or RV locations. We performed principal component analysis (PCA) to explore clusters based on spatiotemporal gene expression. Relevant pathways were identified from fast gene set enrichment analysis using PCA coefficients. The RV transcriptomic signature was measured over several time points, ranging from hours to weeks after an acute increase in mechanical stress, and was found to be highly dependent on the severity of the initial insult. Pathways enriched in the RV outflow tracts of rats at 6 weeks after severe PE share many commonalities with experimental PH models, but the transcriptomic signature at the RV apex resembles control tissue. The severity of the initial pressure overload determines the trajectory of the transcriptomic response independent of the final afterload, but this depends on the location where the tissue is biopsied. Chronic RV pressure overload due to PH appears to progress toward similar transcriptomic endpoints.

Background: Pulmonary hypertension (PH) can occur as a complication of schistosomiasis. In humans, schistosomiasis-PH persists despite antihelminthic therapy and parasite eradication. We hypothesized that persistent disease arises as a consequence of exposure repetition., Methods: Following intraperitoneal sensitization, mice were experimentally exposed to Schistosoma eggs by intravenous injection, either once or three times repeatedly. The phenotype was characterized by right heart catheterization and tissue analysis., Results: Following intraperitoneal sensitization, a single intravenous Schistosoma egg exposure resulted in a PH phenotype that peaked at 7-14 days, followed by spontaneous resolution. Three sequential exposures resulted in a persistent PH phenotype. Inflammatory cytokines were not significantly different between mice exposed to one or three egg doses, but there was an increase in perivascular fibrosis in those who received three egg doses. Significant perivascular fibrosis was also observed in autopsy specimens from patients who died of this condition., Conclusions: Repeatedly exposing mice to schistosomiasis causes a persistent PH phenotype, accompanied by perivascular fibrosis. Perivascular fibrosis may contribute to the persistent schistosomiasis-PH observed in humans with this disease., (© 2023 The Author(s).)

Ventricular interdependence plays an important role in pulmonary arterial hypertension (PAH). It can decrease left ventricular (LV) longitudinal strain (LVLS) and lead to a leftward displacement ("transverse shortening") of the interventricular septum (sTS). For this study, we hypothesized the ratio of LVLS/sTS would be a sensitive marker of systolic ventricular interactions in PAH. In a cross-sectional cohort of patients with PAH ( n  = 57) and matched controls ( n  = 57), we quantified LVLS and septal TS in the amplitude and time domain. We then characterized LV phenotypes using upset plots, ventricular interactions using network analysis, and longitudinal analysis in a representative cohort of 45 patients. We also measured LV metrics in mice subjected to pulmonary arterial banding (PAB) using a 7 T magnetic resonance imaging at baseline, Week 1, and Week 7 post-PAB ( N  = 9). Patients with PAH had significantly reduced absolute LVLS (15.4 ± 3.4 vs. 20.1 ± 2.3%, p  < 0.0001), higher sTS (53.0 ± 12.2 vs. 28.0 ± 6.2%, p  < 0.0001) and lower LVLS/sTS (0.30 ± 0.09 vs. 0.75 ± 0.16, p  < 0.0001) compared to controls. Reduced LVLS/sTS was observed in 89.5% of patients, while diastolic dysfunction, impaired LVLS (<16%), and LV atrophy were observed in 73.7%, 52.6%, and 15.8%, respectively. In the longitudinal cohort, changes in LVLS/sTS were closely associated with changes in N-terminal pro B-type natriuretic peptide ( r  = 0.73, p  < 0.0001) as well as survival. Mice subjected to PAB showed significant RV systolic dysfunction and decreased LVLS/sTS compared to sham animals. We conclude that in PAH, LVLV/sTS is a simple ratio that can reflect ventricular systolic interactions., Competing Interests: Francois Haddad reports research grants from Actelion Pharmaceuticals, a Janssen Company of Johnson & Johnson focused on computational approaches for the diagnosis and monitoring of pulmonary hypertension. The other authors declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Microorganisms colonize the human body. The lungs and respiratory tract, previously believed to be sterile, harbor diverse microbial communities and the genomes of bacteria (bacteriome), viruses (virome), and fungi (mycobiome). Recent advances in amplicon and shotgun metagenomic sequencing technologies and data-analyzing methods have greatly aided the identification and characterization of microbial populations from airways. The respiratory microbiome has been shown to play roles in human health and disease and is an area of rapidly emerging interest in pulmonary medicine. In this review, we provide updated information in the field by focusing on four lung conditions, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, and idiopathic pulmonary fibrosis. We evaluate gut, oral, and upper airway microbiomes and how they contribute to lower airway flora. The discussion is followed by a systematic review of the lower airway microbiome in health and disease. We conclude with promising research avenues and implications for evolving therapeutics.

Circular RNAs (circRNAs) are endogenous, covalently circularised, non-protein-coding RNAs generated from back-splicing. Most circRNAs are very stable, highly conserved, and expressed in a tissue-, cell- and developmental stage-specific manner. circRNAs play a significant role in various biological processes, such as regulation of gene expression and protein translation via sponging of microRNAs and binding with RNA-binding proteins. circRNAs have become a topic of great interest in research due to their close link with the development of various diseases. Their high stability, conservation and abundance in body fluids make them promising biomarkers for many diseases. A growing body of evidence suggests that aberrant expression of circRNAs and their targets plays a crucial role in pulmonary vascular remodelling and pulmonary arterial hypertension (group 1) as well as other forms (groups 3 and 4) of pulmonary hypertension (PH). Here we discuss the roles and molecular mechanisms of circRNAs in the pathogenesis of pulmonary vascular remodelling and PH. We also highlight the therapeutic and biomarker potential of circRNAs in PH., Competing Interests: Conflict of interest: The authors have no conflicts of interest to declare., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Introduction: Chronic lung disease, that is, bronchopulmonary dysplasia (BPD) is the most common complication in preterm infants and develops as a consequence of the misguided formation of the gas-exchange area undergoing prenatal and postnatal injury. Subsequent vascular disease and its progression into pulmonary arterial hypertension critically determines long-term outcome in the BPD infant but lacks identification of early, disease-defining changes., Methods: We link impaired bone morphogenetic protein (BMP) signalling to the earliest onset of vascular pathology in the human preterm lung and delineate the specific effects of the most prevalent prenatal and postnatal clinical risk factors for lung injury mimicking clinically relevant conditions in a multilayered animal model using wild-type and transgenic neonatal mice., Results: We demonstrate (1) the significant reduction in BMP receptor 2 (BMPR2) expression at the onset of vascular pathology in the lung of preterm infants, later mirrored by reduced plasma BMP protein levels in infants with developing BPD, (2) the rapid impairment (and persistent change) of BMPR2 signalling on postnatal exposure to hyperoxia and mechanical ventilation, aggravated by prenatal cigarette smoke in a preclinical mouse model and (3) a link to defective alveolar septation and matrix remodelling through platelet derived growth factor-receptor alpha deficiency. In a treatment approach, we partially reversed vascular pathology by BMPR2-targeted treatment with FK506 in vitro and in vivo., Conclusion: We identified impaired BMP signalling as a hallmark of early vascular disease in the injured neonatal lung while outlining its promising potential as a future biomarker or therapeutic target in this growing, high-risk patient population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Myocardial fibrosis is a remodeling process of the extracellular matrix (ECM) following cardiac stress. "Replacement fibrosis" is a term used to describe wound healing in the acute phase of an injury, such as myocardial infarction. In striking contrast, ECM remodeling following chronic pressure overload insidiously develops over time as "reactive fibrosis" leading to diffuse interstitial and perivascular collagen deposition that continuously perturbs the function of the left (L) or the right ventricle (RV). Examples for pressure-overload conditions resulting in reactive fibrosis in the LV are systemic hypertension or aortic stenosis, whereas pulmonary arterial hypertension (PAH) or congenital heart disease with right sided obstructive lesions such as pulmonary stenosis result in RV reactive fibrosis. In-depth phenotyping of cardiac fibrosis has made it increasingly clear that both forms, replacement and reactive fibrosis co-exist in various etiologies of heart failure. While the role of fibrosis in the pathogenesis of RV heart failure needs further assessment, reactive fibrosis in the LV is a pathological hallmark of adverse cardiac remodeling that is correlated with or potentially might even drive both development and progression of heart failure (HF). Further, LV reactive fibrosis predicts adverse outcome in various myocardial diseases and contributes to arrhythmias. The ability to effectively block pathological ECM remodeling of the LV is therefore an important medical need. At a cellular level, the cardiac fibroblast takes center stage in reactive fibrotic remodeling of the heart. Activation and proliferation of endogenous fibroblast populations are the major source of synthesis, secretion, and deposition of collagens in response to a variety of stimuli. Enzymes residing in the ECM are responsible for collagen maturation and cross-linking. Highly cross-linked type I collagen stiffens the ventricles and predominates over more elastic type III collagen in pressure-overloaded conditions. Research has attempted to identify pro-fibrotic drivers causing fibrotic remodeling. Single key factors such as Transforming Growth Factor β (TGFβ) have been described and subsequently targeted to test their usefulness in inhibiting fibrosis in cultured fibroblasts of the ventricles, and in animal models of cardiac fibrosis. More recently, modulation of phenotypic behaviors like inhibition of proliferating fibroblasts has emerged as a strategy to reduce pathogenic cardiac fibroblast numbers in the heart. Some studies targeting LV reactive fibrosis as outlined above have successfully led to improvements of cardiac structure and function in relevant animal models. For the RV, fibrosis research is needed to better understand the evolution and roles of fibrosis in RV failure. RV fibrosis is seen as an integral part of RV remodeling and presents at varying degrees in patients with PAH and animal models replicating the disease of RV afterload. The extent to which ECM remodeling impacts RV function and thus patient survival is less clear. In this review, we describe differences as well as common characteristics and key players in ECM remodeling of the LV vs. the RV in response to pressure overload. We review pre-clinical studies assessing the effect of anti-fibrotic drug candidates on LV and RV function and their premise for clinical testing. Finally, we discuss the mode of action, safety and efficacy of anti-fibrotic drugs currently tested for the treatment of left HF in clinical trials, which might guide development of new approaches to target right heart failure. We touch upon important considerations and knowledge gaps to be addressed for future clinical testing of anti-fibrotic cardiac therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schimmel, Ichimura, Reddy, Haddad and Spiekerkoetter.)