A perfectly imperfect engine: Utilizing the digital twin paradigm in pulmonary hypertension.

Pulmonary hypertension (PH) is a severe medical condition with a number of treatment options, the majority of which are introduced without consideration of the underlying mechanisms driving it within an individual and thus a lack of tailored approach to treatment. The one exception is a patient presenting with apparent pulmonary arterial hypertension and shown to have vaso-responsive disease, whose clinical course and prognosis is significantly improved by high dose calcium channel blockers. PH is however characterized by a relative abundance of available data from patient cohorts, ranging from molecular data characterizing gene and protein expression in different tissues to physiological data at the organ level and clinical information. Integrating available data with mechanistic information at the different scales into computational models suggests an approach to a more personalized treatment of the disease using model-based optimization of interventions for individual patients. That is, constructing digital twins of the disease, customized to a patient, promises to be a key technology for personalized medicine, with the aim of optimizing use of existing treatments and developing novel interventions, such as new drugs. This article presents a perspective on this approach in the context of a review of existing computational models for different aspects of the disease, and it lays out a roadmap for a path to realizing it.

Bicoastal Spontaneous Coronary Artery Dissection: A Therapeutic Dilemma.

Due to the potential for severe maternal morbidity and even mortality, pregnancy-associated spontaneous coronary artery dissection (P-SCAD) often presents as a clinical conundrum. While current recommendations encourage coronary interventions when medically indicated even during pregnancy, the hesitation still understandably exists. Meanwhile, given the rarity of the condition, the guidelines for management are still based on expert consensus. We present a case of P-SCAD in a 38-year-old woman with initial presentation at 28 weeks' gestation and recurrence at 9 days postpartum. A unique complication of this case is its transcontinental nature: the initial event occurred while the patient was on vacation across the country from her home. Questions arose not only with regard to her immediate management and care but also when she would be able to travel and how her complex care would be continued cross-country. This case raised important questions regarding the antepartum management of acute coronary syndrome (ACS). It also highlights the importance of multidisciplinary care, especially with a cardio-obstetrics team, in the management of P-SCAD and emphasizes the role for universal screening for cardiac diseases in pregnancy.

Non-Interferon-Dependent Role of STING Signaling in Pulmonary Hypertension.

BACKGROUND: Patients with constitutive activation of DNA-sensing pathway through stimulator of IFN (interferon) genes (STING), such as those with STING-associated vasculopathy with onset in infancy, develop pulmonary hypertension (PH). However, the role of STING signaling in general PH patients is heretofore undescribed. Here, we seek to investigate the role of STING in PH development. METHODS: STING expression in patient lung samples was examined. PH was induced in global STING-deficient mice and global type I IFN receptor 1-deficient mice using bleomycin or chronic hypoxia exposure. PH development was evaluated by right ventricular systolic pressure and Fulton index, with additional histological and flow cytometric analysis. VEGF (vascular endothelial growth factor) expression on murine immune cells was quantified and evaluated with multiplex and flow cytometry. Human myeloid-derived cells were differentiated from peripheral blood mononuclear cells and treated with either STING agonist or STING antagonist for evaluation of VEGF secretion. RESULTS: Global STING deficiency protects mice from PH development, and STING-associated PH seems independent of type I IFN signaling. Furthermore, a role for STING-VEGF signaling pathway in PH development was demonstrated, with altered VEGF secretion in murine pulmonary infiltrated myeloid cells in a STING-dependent manner. In addition, pharmacological manipulation of STING in human myeloid-derived cells supports in vivo findings. Finally, a potential role of STING-VEGF-mediated apoptosis in disease development and progression was illustrated, providing a roadmap toward potential therapeutic applications. CONCLUSIONS: Overall, these data provide concrete evidence of STING involvement in PH, establishing biological plausibility for STING-related therapies in PH treatment.

The common TMEM173 HAQ, AQ alleles rescue CD4 T cellpenia, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice.

The significance of STING (encoded by the TMEM173 gene), in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human STING alleles R71H-G230A-R293Q (HAQ) and G230A-R293Q (AQ) are carried by ~60% of East Asians and ~40% of Africans, respectively. Here, we examine the modulatory effects of HAQ, AQ alleles on STING-associated vasculopathy with onset in infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused by gain-of-function human STING mutations. CD4 T cellpenia is evident in SAVI patients and mouse models. Using STING knock-in mice expressing common human STING alleles HAQ, AQ, and Q293, we found that HAQ, AQ, and Q293 splenocytes resist STING-mediated cell death ex vivo, establishing a critical role of STING residue 293 in cell death. The HAQ/SAVI(N153S) and AQ/SAVI(N153S) mice did not have CD4 T cellpenia. The HAQ/SAVI(N153S), AQ/SAVI(N153S) mice have more (~10-fold, ~20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while they have comparable TBK1, IRF3, and NFκB activation as the WT/SAVI, the AQ/SAVI mice have no tissue inflammation, regular body weight, and normal lifespan. We propose that STING activation promotes tissue inflammation by depleting T-regs cells in vivo. Billions of modern humans have the dominant HAQ, AQ alleles. STING research and STING-targeting immunotherapy should consider TMEM173 heterogeneity in humans.

Defining the age-dependent and tissue-specific circadian transcriptome in male mice.

Cellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience. Emerging evidence has demonstrated age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profile the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in three age groups. We find age-dependent and tissue-specific clock output changes. Aging reduces the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. REGs are enriched for the hallmarks of aging, adding another dimension to our understanding of aging. Analyzing differential gene expression within a tissue at four different times of day identifies distinct clusters of differentially expressed genes (DEGs). Increased variability of gene expression across the day is a common feature of aged tissues. This analysis extends the landscape for understanding aging and highlights the impact of aging on circadian clock function and temporal changes in gene expression.

The Third Man: DNA sensing as espionage in pulmonary vascular health and disease.

For as long as nucleic acids have been utilized to vertically and horizontally transfer genetic material, living organisms have had to develop methods of recognizing cytosolic DNA as either pathogenic (microbial invasion) or physiologic (mitosis and cellular proliferation). Derangement in key signaling molecules involved in these pathways of DNA sensing result in a family of diseases labeled interferonopathies. An interferonopathy, characterized by constitutive expression of type I interferons, ultimately manifests as severe autoimmune disease at a young age. Afflicted patients present with a constellation of immune-mediated conditions, including primary lung manifestations such as pulmonary fibrosis and pulmonary hypertension. The latter condition is especially interesting in light of the known role that DNA damage plays in a variety of types of inherited and induced pulmonary hypertension, with free DNA detection elevated in the circulation of affected individuals. While little is known regarding the role of cytosolic DNA sensing in development of pulmonary vascular disease, exciting new research in the related fields of immunology and oncology potentially sheds light on future areas of fruitful exploration. As such, the goal of this review is to summarize the state of the field of nucleic acid sensing, extrapolating common shared pathways that parallel our knowledge of pulmonary hypertension, in a molecular and cell-specific manner. Principles of DNA sensing related to known pulmonary injury inducing stimuli are also evaluated, in addition to potential therapeutic targets. Finally, future directions in pulmonary hypertension research and treatments will be briefly discussed.

Reproducibility and sources of variability in radiographic texture analysis of densitometric calcaneal images.

Radiographic texture analysis (RTA) is a computerized analysis of the spatial pattern of radiographic images used as a way of evaluating bone structure. We have shown that RTA performed on high-resolution heel images obtained using a portable densitometer differentiates subjects with and without osteoporotic fractures. In the present study, short-term precision of RTA was examined on densitometric heel images obtained from 33 subjects scanned 8 times each, with 3 observers placing a region of interest (ROI) 3 times on each image. The long-term precision was examined on images obtained from 10 subjects 3 times on each of 3 days separated by 1 week, with 2 observers placing an ROI on each image. The RTA features examined included the root mean square (RMS) variation, a measure of the contrast between the light and dark areas of the image, the first moment of the power spectrum, a measure of the spatial frequency of the trabecular pattern, and Minkowski fractal (MINK), a measure of roughness/smoothness of the trabecular pattern. The precision of the RTA features expressed as coefficient of variation ranged between the lowest of 0.5-0.7% for MINK and the highest of 14-16% for RMS. The short- and long-term precision was similar, and was not significantly influenced by repositioning and rescanning, or by ROI placement by the same or different observers. Significant sources of variability of RTA were the between-subject differences and differences between regions of the heel, but not differences due to repositioning, rescanning in the same position, or ROI placement by the same or different observers. We conclude that technical aspects of image acquisition and processing are adequate to allow further development of RTA of the densitometric images for clinical application as a method for noninvasive assessment of bone structure.

Risk factors for prevalent vertebral fractures in black and white female densitometry patients.

This cross-sectional study compared risk factors for prevalent vertebral fractures (diagnosed using densitometric spine image Vertebral Fracture Assessment [VFA]) in 176 black and 345 white women recruited during their clinical bone mineral density (BMD) testing at the University of Chicago Hospitals. We used logistic regression to assess the association of prevalent vertebral fractures and risk factors (age, height loss, history of nonvertebral fractures, BMD, and use of corticosteroids). The prevalence of vertebral fractures was 21% for both races. All risk factors of interest were significantly associated with vertebral fractures in white women. Among black women, only age and corticosteroid use were found to be significant predictors of presence of vertebral fracture(s). In women without history of corticosteroid use, the probability of having vertebral fracture(s) given age was lower (p=0.02) in black subjects. In 77 patients with a history of corticosteroid use, the probability of having vertebral fracture(s) was higher in black than in white women after adjustment for age (p=0.045), BMD (p=0.045), or cumulative corticosteroid dose (p=0.08). Fewer black women were prescribed pharmacologic therapy for osteoporosis, regardless of their BMD level and corticosteroid use. We conclude that use of corticosteroids may be associated with relatively greater vertebral fracture risk in blacks than in whites.