A molecular single-cell lung atlas of lethal COVID-19.

Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection1,2, but the host response at the lung tissue level is poorly understood. Here we performed single-nucleus RNA sequencing of about 116,000 nuclei from the lungs of nineteen individuals who died of COVID-19 and underwent rapid autopsy and seven control individuals. Integrated analyses identified substantial alterations in cellular composition, transcriptional cell states, and cell-to-cell interactions, thereby providing insight into the biology of lethal COVID-19. The lungs from individuals with COVID-19 were highly inflamed, with dense infiltration of aberrantly activated monocyte-derived macrophages and alveolar macrophages, but had impaired T cell responses. Monocyte/macrophage-derived interleukin-1ß and epithelial cell-derived interleukin-6 were unique features of SARS-CoV-2 infection compared to other viral and bacterial causes of pneumonia. Alveolar type 2 cells adopted an inflammation-associated transient progenitor cell state and failed to undergo full transition into alveolar type 1 cells, resulting in impaired lung regeneration. Furthermore, we identified expansion of recently described CTHRC1+ pathological fibroblasts3 contributing to rapidly ensuing pulmonary fibrosis in COVID-19. Inference of protein activity and ligand-receptor interactions identified putative drug targets to disrupt deleterious circuits. This atlas enables the dissection of lethal COVID-19, may inform our understanding of long-term complications of COVID-19 survivors, and provides an important resource for therapeutic development.

Cell-Specific Mechanisms in the Heart of COVID-19 Patients.

From the onset of the pandemic, evidence of cardiac involvement in acute COVID-19 abounded. Cardiac presentations ranged from arrhythmias to ischemia, myopericarditis/myocarditis, ventricular dysfunction to acute heart failure, and even cardiogenic shock. Elevated serum cardiac troponin levels were prevalent among hospitalized patients with COVID-19; the higher the magnitude of troponin elevation, the greater the COVID-19 illness severity and in-hospital death risk. Whether these consequences were due to direct SARS-CoV-2 infection of cardiac cells or secondary to inflammatory responses steered early cardiac autopsy studies. SARS-CoV-2 was reportedly detected in endothelial cells, cardiac myocytes, and within the extracellular space. However, findings were inconsistent and different methodologies had their limitations. Initial autopsy reports suggested that SARS-CoV-2 myocarditis was common, setting off studies to find and phenotype inflammatory infiltrates in the heart. Nonetheless, subsequent studies rarely detected myocarditis. Microthrombi, cardiomyocyte necrosis, and inflammatory infiltrates without cardiomyocyte damage were much more common. In vitro and ex vivo experimental platforms have assessed the cellular tropism of SARS-CoV-2 and elucidated mechanisms of viral entry into and replication within cardiac cells. Data point to pericytes as the primary target of SARS-CoV-2 in the heart. Infection of pericytes can account for the observed pericyte and endothelial cell death, innate immune response, and immunothrombosis commonly observed in COVID-19 hearts. These processes are bidirectional and synergistic, rendering a definitive order of events elusive. Single-cell/nucleus analyses of COVID-19 myocardial tissue and isolated cardiac cells have provided granular data about the cellular composition and cell type-specific transcriptomic signatures of COVID-19 and microthrombi-positive COVID-19 hearts. Still, much remains unknown and more in vivo studies are needed. This review seeks to provide an overview of the current understanding of COVID-19 cardiac pathophysiology. Cell type-specific mechanisms and the studies that provided such insights will be highlighted. Given the unprecedented pace of COVID-19 research, more mechanistic details are sure to emerge since the writing of this review. Importantly, our current knowledge offers significant clues about the cardiac pathophysiology of long COVID-19, the increased postrecovery risk of cardiac events, and thus, the future landscape of cardiovascular disease.

Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of multiple sulfatase deficiency.

Multiple sulfatase deficiency (MSD) is a severe, lysosomal storage disorder caused by pathogenic variants in the gene SUMF1, encoding the sulfatase modifying factor formylglycine-generating enzyme. Patients with MSD exhibit functional deficiencies in all cellular sulfatases. The inability of sulfatases to break down their substrates leads to progressive and multi-systemic complications in patients, similar to those seen in single-sulfatase disorders such as metachromatic leukodystrophy and mucopolysaccharidoses IIIA. Here, we aimed to determine if hematopoietic stem cell transplantation with ex vivo SUMF1 lentiviral gene therapy could improve outcomes in a clinically relevant mouse model of MSD. We first tested our approach in MSD patient-derived cells and found that our SUMF1 lentiviral vector improved protein expression, sulfatase activities, and glycosaminoglycan accumulation. In vivo, we found that our gene therapy approach rescued biochemical deficits, including sulfatase activity and glycosaminoglycan accumulation, in affected organs of MSD mice treated post-symptom onset. In addition, treated mice demonstrated improved neuroinflammation and neurocognitive function. Together, these findings suggest that SUMF1 HSCT-GT can improve both biochemical and functional disease markers in the MSD mouse.

Volumetric Analysis: Effect on Diagnosis and Management of Indeterminate Solid Pulmonary Nodules in Routine Clinical Practice.

OBJECTIVE: To evaluate the effect of volumetric analysis on the diagnosis and management of indeterminate solid pulmonary nodules in routine clinical practice. METHODS: This was a retrospective study with 107 computed tomography (CT) cases of solid pulmonary nodules (range, 6-15 mm), 57 pathology-proven malignancies (lung cancer, n = 34; metastasis, n = 23), and 50 benign nodules. Nodules were evaluated on a total of 309 CT scans (average number of CTs/nodule, 2.9 [range, 2-7]). CT scans were from multiple institutions with variable technique. Nine radiologists (attendings, n = 3; fellows, n = 3; residents, n = 3) were asked their level of suspicion for malignancy (low/moderate or high) and management recommendation (no follow-up, CT follow-up, or care escalation) for baseline and follow-up studies first without and then with volumetric analysis data. Effect of volumetry on diagnosis and management was assessed by generalized linear and logistic regression models. RESULTS: Volumetric analysis improved sensitivity (P = 0.009) and allowed earlier recognition (P < 0.05) of malignant nodules. Attending radiologists showed higher sensitivity in recognition of malignant nodules (P = 0.03) and recommendation of care escalation (P < 0.001) compared with trainees. Volumetric analysis altered management of high suspicion nodules only in the fellow group (P = 0.008). κ Statistics for suspicion for malignancy and recommended management were fair to substantial (0.38-0.66) and fair to moderate (0.33-0.50). Volumetric analysis improved interobserver variability for identification of nodule malignancy from 0.52 to 0.66 (P = 0.004) only on the second follow-up study. CONCLUSIONS: Volumetric analysis of indeterminate solid pulmonary nodules in routine clinical practice can result in improved sensitivity and earlier identification of malignant nodules. The effect of volumetric analysis on management recommendations is variable and influenced by reader experience.

COVID-19 and Cardiovascular Disease: From Bench to Bedside.

A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.

The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability.

Mitochondrial calcium (mCa2+) has a central role in both metabolic regulation and cell death signalling, however its role in homeostatic function and disease is controversial. Slc8b1 encodes the mitochondrial Na+/Ca2+ exchanger (NCLX), which is proposed to be the primary mechanism for mCa2+ extrusion in excitable cells. Here we show that tamoxifen-induced deletion of Slc8b1 in adult mouse hearts causes sudden death, with less than 13% of affected mice surviving after 14 days. Lethality correlated with severe myocardial dysfunction and fulminant heart failure. Mechanistically, cardiac pathology was attributed to mCa2+ overload driving increased generation of superoxide and necrotic cell death, which was rescued by genetic inhibition of mitochondrial permeability transition pore activation. Corroborating these findings, overexpression of NCLX in the mouse heart by conditional transgenesis had the beneficial effect of augmenting mCa2+ clearance, preventing permeability transition and protecting against ischaemia-induced cardiomyocyte necrosis and heart failure. These results demonstrate the essential nature of mCa2+ efflux in cellular function and suggest that augmenting mCa2+ efflux may be a viable therapeutic strategy in disease.

How Does COVID-19 Affect the Heart?

PURPOSE OF REVIEW: Cardiac consequences occur in both acute COVID-19 and post-acute sequelae of COVID-19 (PASC). Here, we highlight the current understanding about COVID-19 cardiac effects, based upon clinical, imaging, autopsy, and molecular studies. RECENT FINDINGS: COVID-19 cardiac effects are heterogeneous. Multiple, concurrent cardiac histopathologic findings have been detected on autopsies of COVID-19 non-survivors. Microthrombi and cardiomyocyte necrosis are commonly detected. Macrophages often infiltrate the heart at high density but without fulfilling histologic criteria for myocarditis. The high prevalences of microthrombi and inflammatory infiltrates in fatal COVID-19 raise the concern that recovered COVID-19 patients may have similar but subclinical cardiac pathology. Molecular studies suggest that SARS-CoV-2 infection of cardiac pericytes, dysregulated immunothrombosis, and pro-inflammatory and anti-fibrinolytic responses underlie COVID-19 cardiac pathology. The extent and nature by which mild COVID-19 affects the heart is unknown. Imaging and epidemiologic studies of recovered COVID-19 patients suggest that even mild illness confers increased risks of cardiac inflammation, cardiovascular disorders, and cardiovascular death. The mechanistic details of COVID-19 cardiac pathophysiology remain under active investigation. The ongoing evolution of SARS-CoV-2 variants and vast numbers of recovered COVID-19 patients portend a burgeoning global cardiovascular disease burden. Our ability to prevent and treat cardiovascular disease in the future will likely depend on comprehensive understanding of COVID-19 cardiac pathophysiologic phenotypes.

Artificial Intelligence (AI) for Lung Nodules, From the AJR Special Series on AI Applications.

Interest in artificial intelligence (AI) applications for lung nodules continues to grow among radiologists, particularly with the expanding eligibility criteria and clinical utilization of lung cancer screening CT. AI has been heavily investigated for detecting and characterizing lung nodules and for guiding prognostic assessment. AI tools have also been used for image postprocessing (e.g., rib suppression on radiography or vessel suppression on CT) and for noninterpretive aspects of reporting and workflow, including management of nodule follow-up. Despite growing interest in and rapid development of AI tools and FDA approval of AI tools for pulmonary nodule evaluation, integration into clinical practice has been limited. Challenges to clinical adoption have included concerns about generalizability, regulatory issues, technical hurdles in implementation, and human skepticism. Further validation of AI tools for clinical use and demonstration of benefit in terms of patient-oriented outcomes also are needed. This article provides an overview of potential applications of AI tools in the imaging evaluation of lung nodules and discusses the challenges faced by practices interested in clinical implementation of such tools.

The RSNA International COVID-19 Open Radiology Database (RICORD).

The coronavirus disease 2019 (COVID-19) pandemic is a global health care emergency. Although reverse-transcription polymerase chain reaction testing is the reference standard method to identify patients with COVID-19 infection, chest radiography and CT play a vital role in the detection and management of these patients. Prediction models for COVID-19 imaging are rapidly being developed to support medical decision making. However, inadequate availability of a diverse annotated data set has limited the performance and generalizability of existing models. To address this unmet need, the RSNA and Society of Thoracic Radiology collaborated to develop the RSNA International COVID-19 Open Radiology Database (RICORD). This database is the first multi-institutional, multinational, expert-annotated COVID-19 imaging data set. It is made freely available to the machine learning community as a research and educational resource for COVID-19 chest imaging. Pixel-level volumetric segmentation with clinical annotations was performed by thoracic radiology subspecialists for all COVID-19-positive thoracic CT scans. The labeling schema was coordinated with other international consensus panels and COVID-19 data annotation efforts, the European Society of Medical Imaging Informatics, the American College of Radiology, and the American Association of Physicists in Medicine. Study-level COVID-19 classification labels for chest radiographs were annotated by three radiologists, with majority vote adjudication by board-certified radiologists. RICORD consists of 240 thoracic CT scans and 1000 chest radiographs contributed from four international sites. It is anticipated that RICORD will ideally lead to prediction models that can demonstrate sustained performance across populations and health care systems.

United network for organ sharing outcomes after heart transplantation for al compared to ATTR cardiac amyloidosis.

Light-chain (AL) cardiac amyloidosis (CA) has a worse prognosis than transthyretin (ATTR) CA. In this single-center study, we compared post-heart transplant (OHT, orthotopic heart transplantation) survival for AL and ATTR amyloidosis, hypothesizing that these differences would persist post-OHT. Thirty-nine patients with CA (AL, n = 18; ATTR, n = 21) and 1023 non-amyloidosis subjects undergoing OHT were included. Cox proportional hazards modeling was used to evaluate the impact of amyloid subtype and era (early era: from 2001 to 2007; late era: from 2008 to 2018) on survival post-OHT. Survival for non-amyloid patients was greater than ATTR (P = .034) and AL (P < .001) patients in the early era. One, 3-, and 5-year survival rates were higher for ATTR patients than AL patients in the early era (100% vs 75%, 67% vs 50%, and 67% vs 33%, respectively, for ATTR and AL patients). Survival in the non-amyloid cohort was 87% at 1 year, 81% at 3 years, and 76% at 5 years post-OHT. In the late era, AL and ATTR patients had unadjusted 1-year, 3-year, and 5-year survival rates of 100%, which was comparable to non-amyloid patients (90% vs 84% vs 81%). Overall, these findings demonstrate that in the current era, differences in post-OHT survival for AL compared to ATTR are diminishing; OHT outcomes for selected patients with CA do not differ from non-amyloidosis patients.

Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies.

Background Peripartum cardiomyopathy shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in more than 40 genes, including TTN, which encodes the sarcomere protein titin. Methods In 172 women with peripartum cardiomyopathy, we sequenced 43 genes with variants that have been associated with dilated cardiomyopathy. We compared the prevalence of different variant types (nonsense, frameshift, and splicing) in these women with the prevalence of such variants in persons with dilated cardiomyopathy and with population controls. Results We identified 26 distinct, rare truncating variants in eight genes among women with peripartum cardiomyopathy. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than that in a reference population of 60,706 persons (4.7%, P=1.3×10(-7)) but was similar to that in a cohort of patients with dilated cardiomyopathy (55 of 332 patients [17%], P=0.81). Two thirds of identified truncating variants were in TTN, as seen in 10% of the patients and in 1.4% of the reference population (P=2.7×10(-10)); almost all TTN variants were located in the titin A-band. Seven of the TTN truncating variants were previously reported in patients with idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of 83 women with peripartum cardiomyopathy, the presence of TTN truncating variants was significantly correlated with a lower ejection fraction at 1-year follow-up (P=0.005). Conclusions The distribution of truncating variants in a large series of women with peripartum cardiomyopathy was remarkably similar to that found in patients with idiopathic dilated cardiomyopathy. TTN truncating variants were the most prevalent genetic predisposition in each disorder.

Feasibility and Safety of Intrathoracic Biopsy and Repeat Biopsy for Evaluation of Programmed Cell Death Ligand-1 Expression for Immunotherapy in Non-Small Cell Lung Cancer.

Purpose To determine feasibility and safety of biopsy and repeat biopsy for assessment of programmed cell death ligand-1 (PD-L1) status. Materials and Methods This retrospective analysis reviewed 101 patients who underwent transthoracic core needle biopsy for the KEYNOTE-001 (MK-3475) clinical trial of pembrolizumab, an antiprogrammed cell death-1 therapy for non-small cell lung cancer, from May 2012 to September 2014. Sixty-one male patients (mean age, 66.1 years; range 36-83 years) and 40 female patients (mean age, 66.8 years; age range, 36-90 years) were included. Data collected included population characteristics, treatment history, target location, size, and depth from pleura. Adequacy of the tissue sample for diagnostic testing and rates of biopsy-related complications were assessed. Statistical analysis was performed by using univariate and multivariate generalized linear models to determine significant risk factors for biopsy complications. Results A total of 110 intrathoracic biopsies were performed, and 101 (91.8%) were performed as repeat biopsies subsequent to a previous percutaneous or bronchoscopic biopsy or previous surgical biopsy or resection. More than 84.5% (93 of 110) of biopsies were performed in patients who had undergone previous local or systemic therapy. Specimens were adequate for evaluation of PD-L1 expression in 96.4% of biopsies. Procedure-related complications occurred in 28 biopsies (25.4%); pneumothorax was most common (22.7%). Overall mean number of core needle biopsy samples obtained was 7.9 samples. Conclusion Image-guided transthoracic core needle biopsy is an effective method for obtaining tissue for PD-L1 expression analysis. © RSNA, 2017.

Lung Adenocarcinoma: Correlation of Quantitative CT Findings with Pathologic Findings.

Purpose To identify the ability of computer-derived three-dimensional (3D) computed tomographic (CT) segmentation techniques to help differentiate lung adenocarcinoma subtypes. Materials and Methods This study had institutional research board approval and was HIPAA compliant. Pathologically classified resected lung adenocarcinomas (n = 41) with thin-section CT data were identified. Two readers independently placed over-inclusive volumes around nodules from which automated computer measurements were generated: mass (total mass) and volume (total volume) of the nodule and of any solid portion, in addition to the solid percentage of the nodule volume (percentage solid volume) or mass (percentage solid mass). Interobserver agreement and differences in measurements among pathologic entities were evaluated by using t tests. A multinomial logistic regression model was used to differentiate the probability of three diagnoses: invasive non-lepidic-predominant adenocarcinoma (INV), lepidic-predominant adenocarcinoma (LPA), and adenocarcinoma in situ (AIS)/minimally invasive adenocarcinoma (MIA). Results Mean percentage solid volume of INV was 35.4% (95% confidence interval [CI]: 26.2%, 44.5%)-higher than the 14.5% (95% CI: 10.3%, 18.7%) for LPA (P = .002). Mean percentage solid volume of AIS/MIA was 8.2% (95% CI: 2.7%, 13.7%) and had a trend toward being lower than that for LPA (P = .051). Accuracy of the model based on total volume and percentage solid volume was 73.2%; accuracy of the model based on total mass and percentage solid mass was 75.6%. Conclusion Computer-assisted 3D measurement of nodules at CT had good reproducibility and helped differentiate among subtypes of lung adenocarcinoma. (©) RSNA, 2016.

Cardiac fibroblast glycogen synthase kinase-3ß regulates ventricular remodeling and dysfunction in ischemic heart.

BACKGROUND: Myocardial infarction-induced remodeling includes chamber dilatation, contractile dysfunction, and fibrosis. Of these, fibrosis is the least understood. After myocardial infarction, activated cardiac fibroblasts deposit extracellular matrix. Current therapies to prevent fibrosis are inadequate, and new molecular targets are needed. METHODS AND RESULTS: Herein we report that glycogen synthase kinase-3ß (GSK-3ß) is phosphorylated (inhibited) in fibrotic tissues from ischemic human and mouse heart. Using 2 fibroblast-specific GSK-3ß knockout mouse models, we show that deletion of GSK-3ß in cardiac fibroblasts leads to fibrogenesis, left ventricular dysfunction, and excessive scarring in the ischemic heart. Deletion of GSK-3ß induces a profibrotic myofibroblast phenotype in isolated cardiac fibroblasts, in post-myocardial infarction hearts, and in mouse embryonic fibroblasts deleted for GSK-3ß. Mechanistically, GSK-3ß inhibits profibrotic transforming growth factor-ß1/SMAD-3 signaling via interactions with SMAD-3. Moreover, deletion of GSK-3ß resulted in the significant increase of SMAD-3 transcriptional activity. This pathway is central to the pathology because a small-molecule inhibitor of SMAD-3 largely prevented fibrosis and limited left ventricular remodeling. CONCLUSIONS: These studies support targeting GSK-3ß in myocardial fibrotic disorders and establish critical roles of cardiac fibroblasts in remodeling and ventricular dysfunction.

Chronic ß1-adrenergic blockade enhances myocardial ß3-adrenergic coupling with nitric oxide-cGMP signaling in a canine model of chronic volume overload: new insight into mechanisms of cardiac benefit with selective ß1-blocker therapy.

The ß1-adrenergic antagonist metoprolol improves cardiac function in animals and patients with chronic heart failure, isolated mitral regurgitation (MR), and ischemic heart disease, though the molecular mechanisms remain incompletely understood. Metoprolol has been reported to upregulate cardiac expression of ß3-adrenergic receptors (ß3AR) in animal models. Myocardial ß3AR signaling via neuronal nitric oxide synthase (nNOS) activation has recently emerged as a cardioprotective pathway. We tested whether chronic ß1-adrenergic blockade with metoprolol enhances myocardial ß3AR coupling with nitric oxide-stimulated cyclic guanosine monophosphate (ß3AR/NO-cGMP) signaling in the MR-induced, volume-overloaded heart. We compared the expression, distribution, and inducible activation of ß3AR/NO-cGMP signaling proteins within myocardial membrane microdomains in dogs (canines) with surgically induced MR, those also treated with metoprolol succinate (MR+ßB), and unoperated controls. ß3AR mRNA transcripts, normalized to housekeeping gene RPLP1, increased 4.4 × 10(3)- and 3.2 × 10(2)-fold in MR and MR+ßB hearts, respectively, compared to Control. Cardiac ß3AR expression was increased 1.4- and nearly twofold in MR and MR+ßB, respectively, compared to Control. ß3AR was detected within caveolae-enriched lipid rafts (Cav3(+)LR) and heavy density, non-lipid raft membrane (NLR) across all groups. However, in vitro selective ß3AR stimulation with BRL37344 (BRL) triggered cGMP production within only NLR of MR+ßB. BRL induced Ser (1412) phosphorylation of nNOS within NLR of MR+ßB, but not Control or MR, consistent with detection of NLR-specific ß3AR/NO-cGMP coupling. Treatment with metoprolol prevented MR-associated oxidation of NO biosensor soluble guanylyl cyclase (sGC) within NLR. Metoprolol therapy also prevented MR-induced relocalization of sGCß1 subunit away from caveolae, suggesting preserved NO-sGC-cGMP signaling, albeit without coupling to ß3AR, within MR+ßB caveolae. Chronic ß1-blockade is associated with myocardial ß3AR/NO-cGMP coupling in a microdomain-specific fashion. Our canine study suggests that microdomain-targeted enhancement of myocardial ß3AR/NO-cGMP signaling may explain, in part, ß1-adrenergic antagonist-mediated preservation of cardiac function in the volume-overloaded heart.

Pressure-overload-induced subcellular relocalization/oxidation of soluble guanylyl cyclase in the heart modulates enzyme stimulation.

RATIONALE: Soluble guanylyl cyclase (sGC) generates cyclic guanosine monophophate (cGMP) upon activation by nitric oxide (NO). Cardiac NO-sGC-cGMP signaling blunts cardiac stress responses, including pressure-overload-induced hypertrophy. The latter itself depresses signaling through this pathway by reducing NO generation and enhancing cGMP hydrolysis. OBJECTIVE: We tested the hypothesis that the sGC response to NO also declines with pressure-overload stress and assessed the role of heme-oxidation and altered intracellular compartmentation of sGC as potential mechanisms. METHODS AND RESULTS: C57BL/6 mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and dysfunction. NO-stimulated sGC activity was markedly depressed, whereas NO- and heme-independent sGC activation by BAY 60-2770 was preserved. Total sGCα(1) and ß(1) expression were unchanged by TAC; however, sGCß(1) subunits shifted out of caveolin-enriched microdomains. NO-stimulated sGC activity was 2- to 3-fold greater in Cav3-containing lipid raft versus nonlipid raft domains in control and 6-fold greater after TAC. In contrast, BAY 60-2770 responses were >10 fold higher in non-Cav3 domains with and without TAC, declining about 60% after TAC within each compartment. Mice genetically lacking Cav3 had reduced NO- and BAY-stimulated sGC activity in microdomains containing Cav3 for controls but no change within non-Cav3-enriched domains. CONCLUSIONS: Pressure overload depresses NO/heme-dependent sGC activation in the heart, consistent with enhanced oxidation. The data reveal a novel additional mechanism for reduced NO-coupled sGC activity related to dynamic shifts in membrane microdomain localization, with Cav3-microdomains protecting sGC from heme-oxidation and facilitating NO responsiveness. Translocation of sGC out of this domain favors sGC oxidation and contributes to depressed NO-stimulated sGC activity.

Accuracy of self-reported weight and height in women from Bogotá, Colombia.

AIM: To identify correlates of bias in self-reported anthropometry among reproductive-aged Colombian women and to correct overweight/obesity and obesity prevalence based on self-reported data using two calibration techniques. SUBJECTS AND METHODS: Self-reported and objectively measured anthropometry were obtained from 597 women aged 21-55 years from Bogotá, Colombia. This study identified correlates of reporting bias (self-reported minus measured anthropometry) by examining its distribution across categories of sociodemographic characteristics, objectively measured anthropometry and body shape perception using linear regression. Next, weight status misclassification was assessed using self-reported anthropometry. Finally, multivariable linear regression and ROC curves were used to calibrate weight status misclassification from self-reported data; these techniques were applied in half of the study population and validated in the remaining half. RESULTS: Women under-estimated weight by 2.0 ± 5.0 kg and over-estimated height by 0.6 ± 4.0 cm. Correlates of bias included objectively measured anthropometry and marital status. Self-reported BMI yielded spuriously low prevalences of overweight/obesity and obesity. The ROC approach effectively corrected overweight/obesity prevalence, while the regression method provided a more accurate estimate of obesity prevalence. CONCLUSIONS: Bias in self-reported anthropometry varied with respect to objectively measured anthropometry and sociodemographic characteristics. BMI from self-reported anthropometry under-estimates overweight/obesity and obesity prevalence; calibration methods can effectively correct reporting bias.

Artificial Intelligence in Radiology: Opportunities and Challenges.

Artificial intelligence's (AI) emergence in radiology elicits both excitement and uncertainty. AI holds promise for improving radiology with regards to clinical practice, education, and research opportunities. Yet, AI systems are trained on select datasets that can contain bias and inaccuracies. Radiologists must understand these limitations and engage with AI developers at every step of the process - from algorithm initiation and design to development and implementation - to maximize benefit and minimize harm that can be enabled by this technology.

Extracellular Matrix Instability and Chronic Inflammation Underlie Maladaptive Right Ventricular Pressure Overload Remodeling and Failure in Male Mice.

Background: Right ventricular dysfunction (RVD) portends increased death risk for heart failure (HF) and pulmonary arterial hypertension (PAH) patients, regardless of left ventricular function or etiology. In both, RVD arises from the chronic RV pressure overload, and represents advanced cardiopulmonary disease. RV remodeling responses and survival rates of HF and PAH patients, however, differ by sex. Men develop more severe RVD and die at younger ages than do women. Mechanistic details of this sexual dimorphism in RV remodeling are incompletely understood. We sought to elucidate the cardiac pathophysiology underlying the sex-specific RV remodeling phenotypes, RV failure (RVF) versus compensated RVD. Methods: We subjected male (M-) and female (F-) adult mice to moderate pulmonary artery banding (PAB) for 9wks. Mice underwent serial echocardiography, cardiac MRI, RV pressure-volume loop recordings, histologic and molecular analyses. Results: M-PAB developed severe RVD with RVF, increased RV collagen deposition and degradation, extracellular matrix (ECM) instability, and activation and recruitment of macrophages. Despite the same severity and chronicity of RV pressure overload, F-PAB had more stable ECM, lacked chronic inflammation, and developed mild RVD without RVF. Conclusions: ECM destabilization and chronic activation of recruited macrophages are associated with maladaptive RV remodeling and RVF in male PAB mice. Adaptive RV remodeling of female PAB mice lacked these histopathologic changes. Our findings suggest that these two pathophysiologic processes likely contribute to the sexual dimorphism of RV pressure overload remodeling. Further mechanistic studies are needed to assess their pathogenic roles and potential as targets for RVD therapy and RVF prevention. CLINICAL PERSPECTIVE: What is new?: In a mouse model of pure PH, males but not females showed an association between ECM instability, chronic inflammation with activation of recruited macrophages, and severe RV dysfunction and failure.What are the clinical implications?: In male HF and PH patients, enhancing ECM stability and countering the recruitment and activation of macrophages may help preserve RV function such that RVF can be prevented or delayed. Further preclinical mechanistic studies are needed to assess the therapeutic potential of such approaches. RESEARCH PERSPECTIVE: What new question does this study raise? What question should be addressed next?: What mechanisms regulate RV ECM stability and macrophage recruitment and activation in response to chronic RV pressure overload? Are these regulatory mechanisms dependent upon or independent of sex hormone signaling?