Heme induced loss of renovascular endothelial protein C receptor promotes chronic kidney disease in sickle mice.

Chronic kidney disease (CKD) is a major contributor to morbidity and mortality in sickle cell disease (SCD). Anemia, induced by chronic persistent hemolysis, is associated with progressive deterioration of renal health resulting in CKD. Moreover, patients with SCD experience acute kidney injury (AKI), a risk factor for CKD, often during vasoocclusive crisis associated with acute intravascular hemolysis. However, the mechanisms of the hemolysis-driven pathogenesis of the AKI-to-CKD transition in SCD remain elusive. Here, we investigated the role of increased renovascular rarefaction and the resulting substantial loss of vascular endothelial protein C receptor (EPCR) on the progressive deterioration of renal function in transgenic SCD mice. Multiple hemolytic events raised circulating levels of soluble EPCR (sEPCR) indicating loss of EPCR from the cell surface. Using bone marrow transplantation and super-resolution ultrasound imaging, we demonstrated that SCD mice overexpressing EPCR were protective against heme-induced CKD development. In a cohort of SCD patients, plasma sEPCR was significantly higher in individuals with CKD than in those without CKD. This study concludes that multiple hemolytic events may trigger CKD in SCD through the gradual loss of renovascular EPCR. Thus, restoration of EPCR may be a therapeutic target, and plasma sEPCR can be developed as a prognostic marker for sickle CKD.

SOD2 V16A amplifies vascular dysfunction in sickle cell patients by curtailing mitochondria complex IV activity.

Superoxide dismutase 2 (SOD2) catalyzes the dismutation of superoxide to hydrogen peroxide in mitochondria, limiting mitochondrial damage. The SOD2 amino acid valine-to-alanine substitution at position 16 (V16A) in the mitochondrial leader sequence is a common genetic variant among patients with sickle cell disease (SCD). However, little is known about the cardiovascular consequences of SOD2V16A in SCD patients or its impact on endothelial cell function. Here, we show SOD2V16A associates with increased tricuspid regurgitant velocity (TRV), systolic blood pressure, right ventricle area at systole, and declined 6-minute walk distance in 410 SCD patients. Plasma lactate dehydrogenase, a marker of oxidative stress and hemolysis, significantly associated with higher TRV. To define the impact of SOD2V16A in the endothelium, we introduced the SOD2V16A variant into endothelial cells. SOD2V16A increases hydrogen peroxide and mitochondrial reactive oxygen species (ROS) production compared with controls. Unexpectedly, the increased ROS was not due to SOD2V16A mislocalization but was associated with mitochondrial complex IV and a concomitant decrease in basal respiration and complex IV activity. In sum, SOD2V16A is a novel clinical biomarker of cardiovascular dysfunction in SCD patients through its ability to decrease mitochondrial complex IV activity and amplify ROS production in the endothelium.

Serum cytokine profiles of adults with idiopathic inflammatory myopathies.

OBJECTIVES: There is a paucity of available biomarkers of disease activity in idiopathic inflammatory myopathies (IIM), and serum cytokines/chemokines hold potential as candidate biomarkers. We aimed to determine serum cytokine profiles of IIM patients with active disease as compared to patients in remission and healthy controls. METHODS: The IIM patients with active disease (included patients enrolled in repository corticotropin injection trial), in remission, and healthy controls were enrolled in this cross-sectional observational study. Serum concentrations of 51 cytokines/chemokines were obtained by utilising a bead-based multiplex cytokine assay (Luminex®). The myositis core set measures were obtained for all the patients. Cytokines with the best predictive ability to differentiate these clinical groups were assessed with three methods: 1) Least Absolute Shrinkage and Selection Operator modelling, 2) stepwise approach, and 3) logistic regression model. RESULTS: Twenty-one IIM patients with active disease, 11 IIM patients in remission and 10 healthy controls were enrolled. Myositis patients had elevated levels of chemokines that attract eosinophils (eotaxin) and dendritic cells, NK cells, cytotoxic T-cells and monocytes/macrophages (CXCL-9, IP-10), cytokines that drive T-helper 1 responses (TNF-a, lymphotoxin-a), matrix degrading enzymes (MMP-3 and -9), and IGFBP-2 compared to healthy controls. Myositis patients with active disease had higher levels of lymphotoxin-a, CXCL-9, MIP-1a, MIP-1b and MMP-3 than patients in remission. CONCLUSIONS: This study demonstrated differences in cytokine profiles of IIM patients (active and inactive disease) compared to healthy controls and identified some cytokines that could potentially be used as biomarkers. Larger longitudinal studies are needed to validate our findings.

Serum metabolomic signatures of fatty acid oxidation defects differentiate host-response subphenotypes of acute respiratory distress syndrome.

BACKGROUND: Fatty acid oxidation (FAO) defects have been implicated in experimental models of acute lung injury and associated with poor outcomes in critical illness. In this study, we examined acylcarnitine profiles and 3-methylhistidine as markers of FAO defects and skeletal muscle catabolism, respectively, in patients with acute respiratory failure. We determined whether these metabolites were associated with host-response ARDS subphenotypes, inflammatory biomarkers, and clinical outcomes in acute respiratory failure. METHODS: In a nested case-control cohort study, we performed targeted analysis of serum metabolites of patients intubated for airway protection (airway controls), Class 1 (hypoinflammatory), and Class 2 (hyperinflammatory) ARDS patients (N = 50 per group) during early initiation of mechanical ventilation. Relative amounts were quantified by liquid chromatography high resolution mass spectrometry using isotope-labeled standards and analyzed with plasma biomarkers and clinical data. RESULTS: Of the acylcarnitines analyzed, octanoylcarnitine levels were twofold increased in Class 2 ARDS relative to Class 1 ARDS or airway controls (P = 0.0004 and < 0.0001, respectively) and was positively associated with Class 2 by quantile g-computation analysis (P = 0.004). In addition, acetylcarnitine and 3-methylhistidine were increased in Class 2 relative to Class 1 and positively correlated with inflammatory biomarkers. In all patients within the study with acute respiratory failure, increased 3-methylhistidine was observed in non-survivors at 30 days (P = 0.0018), while octanoylcarnitine was increased in patients requiring vasopressor support but not in non-survivors (P = 0.0001 and P = 0.28, respectively). CONCLUSIONS: This study demonstrates that increased levels of acetylcarnitine, octanoylcarnitine, and 3-methylhistidine distinguish Class 2 from Class 1 ARDS patients and airway controls. Octanoylcarnitine and 3-methylhistidine were associated with poor outcomes in patients with acute respiratory failure across the cohort independent of etiology or host-response subphenotype. These findings suggest a role for serum metabolites as biomarkers in ARDS and poor outcomes in critically ill patients early in the clinical course.

Long Range Endocrine Delivery of Circulating miR-210 to Endothelium Promotes Pulmonary Hypertension.

RATIONALE: Unproven theories abound regarding the long-range uptake and endocrine activity of extracellular blood-borne microRNAs into tissue. In pulmonary hypertension (PH), microRNA-210 (miR-210) in pulmonary endothelial cells promotes disease, but its activity as an extracellular molecule is incompletely defined. OBJECTIVE: We investigated whether chronic and endogenous endocrine delivery of extracellular miR-210 to pulmonary vascular endothelial cells promotes PH. METHODS AND RESULTS: Using miR-210 replete (wild-type [WT]) and knockout mice, we tracked blood-borne miR-210 using bone marrow transplantation and parabiosis (conjoining of circulatory systems). With bone marrow transplantation, circulating miR-210 was derived predominantly from bone marrow. Via parabiosis during chronic hypoxia to induce miR-210 production and PH, miR-210 was undetectable in knockout-knockout mice pairs. However, in plasma and lung endothelium, but not smooth muscle or adventitia, miR-210 was observed in knockout mice of WT-knockout pairs. This was accompanied by downregulation of miR-210 targets ISCU (iron-sulfur assembly proteins)1/2 and COX10 (cytochrome c oxidase assembly protein-10), indicating endothelial import of functional miR-210. Via hemodynamic and histological indices, knockout-knockout pairs were protected from PH, whereas knockout mice in WT-knockout pairs developed PH. In particular, pulmonary vascular engraftment of miR-210-positive interstitial lung macrophages was observed in knockout mice of WT-knockout pairs. To address whether engrafted miR-210-positive myeloid or lymphoid cells contribute to paracrine miR-210 delivery, we studied miR-210 knockout mice parabiosed with miR-210 WT; Cx3cr1 knockout mice (deficient in myeloid recruitment) or miR-210 WT; Rag1 knockout mice (deficient in lymphocytes). In both pairs, miR-210 knockout mice still displayed miR-210 delivery and PH, thus demonstrating a pathogenic endocrine delivery of extracellular miR-210. CONCLUSIONS: Endogenous blood-borne transport of miR-210 into pulmonary vascular endothelial cells promotes PH, offering fundamental insight into the systemic physiology of microRNA activity. These results also describe a platform for RNA-mediated crosstalk in PH, providing an impetus for developing blood-based miR-210 technologies for diagnosis and therapy in this disease.

Reversal of Right Ventricular Hypertrophy and Dysfunction by Prostacyclin in a Rat Model of Severe Pulmonary Arterial Hypertension.

Prostacyclin analogs are among the most effective and widely used therapies for pulmonary arterial hypertension (PAH). However, it is unknown whether they also confer protection through right ventricle (RV) myocardio-specific mechanisms. Moreover, the use of prostacyclin analogs in severe models of PAH has not been adequately tested. To further identify underlying responses to prostacyclin, a prostacyclin analogue, treprostinil, was used in a preclinical rat Sugen-chronic hypoxia (SuCH) model of severe PAH that closely resembles the human disease. Male Sprague-Dawley rats were implanted with osmotic pumps containing vehicle or treprostinil, injected concurrently with a bolus of Sugen (SU5416) and exposed to 3-week hypoxia followed by 3-week normoxia. RV function was assessed using pressure-volume loops and hypertrophy by weight assessed. To identify altered mechanisms within the RV, tissue samples were used to perform a custom RNA array analysis, histological staining, and protein and transcript level confirmatory analyses. Treprostinil significantly reduced SuCH-associated RV hypertrophy and decreased the rise in RV systolic pressure, mean pulmonary arterial (mPAP), and right atrial (RAP) pressure. Prostacyclin treatment was associated with improvements in RV stroke work, maximum rate of ventricular pressure change (max dP/dt) and the contractile index, and almost a complete reversal of SuCH-associated increase in RV end-systolic elastance, suggesting the involvement of load-independent improvements in intrinsic RV systolic contractility by prostacyclin treatment. An analysis of the RV tissues showed no changes in cardiac mitochondrial respiration and ATP generation. However, custom RNA array analysis revealed amelioration of SuCH-associated increases in newly identified TBX20 as well as the fibrotic markers collagen1α1 and collagen 3α1 upon treprostinil treatment. Taken together, our data support decreased afterload and load-independent improvements in RV function following prostacyclin administration in severe PAH, and these changes appear to associate with improvements in RV fibrotic responses.

Long-term tolerability of phosphodiesterase-5 inhibitors in pulmonary hypertension of sickle cell disease.

OBJECTIVES: Sickle cell disease-related pulmonary hypertension (SCD-PH) is a complex disorder with multifactorial contributory mechanisms. Previous trials have evaluated the efficacy of pulmonary arterial hypertension (PAH) therapies in SCD-PH with mixed results. We hypothesized that a subset of patients with right heart catheterization (RHC) confirmed disease may benefit from PAH therapy. METHODS: We performed a retrospective chart review of patients with SCD-PH diagnosed by RHC who were treated with phosphodiesterase 5 inhibitor (PDE5-I) therapy for ≥4 months between 2008 and 2019 at two institutions. RESULTS: Thirty-six patients were included in the analysis. The median age (IQR) upon PDE5-I initiation was 47.5 years (35-51.5 years); 58% were female and twenty-nine (81%) had HbSS disease. Of these, 53% of patients had a history of acute chest syndrome, 42% had a history of venous thromboembolism, and 38% had imaging consistent with chronic thromboembolic PH. Patients were treated for a median duration of 25 months (IQR 13-60 months). Use of PDE5-I was associated with a significant improvement in symptoms as assessed by NYHA Class (P = .002). CONCLUSIONS: In SCD patients with PH defined by RHC, PDE5-I therapy was tolerated long-term and may improve physical activity.

Effect of Blood Product Transfusion on Perioperative Outcomes After Heart Transplantation.

OBJECTIVE(S): The objective of this study was to identify transfusion-related in-hospital outcomes in orthotopic heart transplantation (OHT) recipients. DESIGN: Retrospective chart review. SETTING: Tertiary care hospital. PARTICIPANTS: Adult OHT recipients undergoing transplantation between January 2010 and December 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary composite outcome was occurrence of any of the following events during admission for OHT: (1) graft dysfunction requiring mechanical circulatory support (MCS); (2) respiratory failure requiring tracheostomy; (3) renal failure requiring hemodialysis; (4) 30-day mortality; (5) complication requiring readmission to intensive care unit; (6) sepsis; and (7) stroke. The authors evaluated these outcomes in relation to all blood component transfusions received intraoperatively and in the first 24 hours postoperatively. The study included 197 patients and the primary composite outcome was present in 72 (36.6%). After adjusting for propensity score, red blood cell (RBC) transfusion was associated with composite outcomes (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.05-1.31, p = 0.004), postoperative MCS use (OR 1.36, 95% CI 1.18-1.58, p < 0.001), acute renal failure requiring hemodialysis (OR 1.21, 5% CI 1.06-1.38, p = 0.004), and 30-day mortality (OR 1.29, 95% CI 1.05-1.59, p = 0.02). Fresh frozen plasma was associated with composite outcome (OR 1.07, 95% CI [1.003-1.15], p = 0.042) and renal failure (OR 1.08, 95% CI 1.08 [1.002-1.17], p = 0.04). CONCLUSIONS: Intra- and postoperative transfusions (first 24 hours) of RBC and FFP were associated with adverse postoperative composite outcomes in patients undergoing OHT.

Yes-Associated Protein (Yap) Is Up-Regulated in Heart Failure and Promotes Cardiac Fibroblast Proliferation.

Left ventricular (LV) heart failure (HF) is a significant and increasing cause of death worldwide. HF is characterized by myocardial remodeling and excessive fibrosis. Transcriptional co-activator Yes-associated protein (Yap), the downstream effector of HIPPO signaling pathway, is an essential factor in cardiomyocyte survival; however, its status in human LV HF is not entirely elucidated. Here, we report that Yap is elevated in LV tissue of patients with HF, and is associated with down-regulation of its upstream inhibitor HIPPO component large tumor suppressor 1 (LATS1) activation as well as upregulation of the fibrosis marker connective tissue growth factor (CTGF). Applying the established profibrotic combined stress of TGFß and hypoxia to human ventricular cardiac fibroblasts in vitro increased Yap protein levels, down-regulated LATS1 activation, increased cell proliferation and collagen I production, and decreased ribosomal protein S6 and S6 kinase phosphorylation, a hallmark of mTOR activation, without any significant effect on mTOR and raptor protein expression or phosphorylation of mTOR or 4E-binding protein 1 (4EBP1), a downstream effector of mTOR pathway. As previously reported in various cell types, TGFß/hypoxia also enhanced cardiac fibroblast Akt and ERK1/2 phosphorylation, which was similar to our observation in LV tissues from HF patients. Further, depletion of Yap reduced TGFß/hypoxia-induced cardiac fibroblast proliferation and Akt phosphorylation at Ser 473 and Thr308, without any significant effect on TGFß/hypoxia-induced ERK1/2 activation or reduction in S6 and S6 kinase activities. Taken together, these data demonstrate that Yap is a mediator that promotes human cardiac fibroblast proliferation and suggest its possible contribution to remodeling of the LV, opening the door to further studies to decipher the cell-specific roles of Yap signaling in human HF.

Commercial 4-dimensional echocardiography for murine heart volumetric evaluation after myocardial infarction.

BACKGROUND: Traditional preclinical echocardiography (ECHO) modalities, including 1-dimensional motion-mode (M-Mode) and 2-dimensional long axis (2D-US), rely on geometric and temporal assumptions about the heart for volumetric measurements. Surgical animal models, such as the mouse coronary artery ligation (CAL) model of myocardial infarction, result in morphologic changes that do not fit these geometric assumptions. New ECHO technology, including 4-dimensional ultrasound (4D-US), improves on these traditional models. This paper aims to compare commercially available 4D-US to M-mode and 2D-US in a mouse model of CAL. METHODS: 37 mice underwent CAL surgery, of which 32 survived to a 4 week post-operative time point. ECHO was completed at baseline, 1 week, and 4 weeks after CAL. M-mode, 2D-US, and 4D-US were taken at each time point and evaluated by two separate echocardiographers. At 4 weeks, a subset (n = 12) of mice underwent cardiac magnetic resonance (CMR) imaging to serve as a reference standard. End systolic volume (ESV), end diastolic volume (EDV), and ejection fraction (EF) were compared among imaging modalities. Hearts were also collected for histologic evaluation of scar size (n = 16) and compared to ECHO-derived wall motion severity index (WMSI) and global longitudinal strain as well as gadolinium-enhanced CMR to compare scar assessment modalities. RESULTS: 4D-US provides close agreement of ESV (Bias: -2.55%, LOA: - 61.55 to 66.66) and EF (US Bias: 11.23%, LOA - 43.10 to 102.8) 4 weeks after CAL when compared to CMR, outperforming 2D-US and M-mode estimations. 4D-US has lower inter-user variability as measured by intraclass correlation (ICC) in the evaluation of EDV (0.91) and ESV (0.93) when compared to other modalities. 4D-US also allows for rapid assessment of WMSI, which correlates strongly with infarct size by histology (r = 0.77). CONCLUSION: 4D-US outperforms M-Mode and 2D-US for volumetric analysis 4 weeks after CAL and has higher inter-user reliability. 4D-US allows for rapid calculation of WMSI, which correlates well with histologic scar size.

Global Epidemiology of Nonalcoholic Fatty Liver Disease and Perspectives on US Minority Populations.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome predicted to be the next global epidemic affecting millions of people worldwide. The natural course of this disease including its subtype, non-alcoholic steatohepatitis (NASH), is not clearly defined especially in the African-American segment of the US population. AIMS: To conduct a review of the global epidemiology of NAFLD with emphasis on US minority populations. METHODS: A thorough search of evidence-based literature was conducted using the Pubmed database and commercial web sources such as Medscape and Google Scholar. RESULTS: NAFLD and its subtype NASH are becoming the principal cause of chronic liver disease across the world. In the US, Hispanics are the most disproportionately affected ethnic group with hepatic steatosis, and elevated aminotransferase levels, whereas African-Americans are the least affected. Genetic disparities involved in lipid metabolism seem to be the leading explanation for the lowest incidence and prevalence of both NAFLD and NASH in African-Americans. CONCLUSIONS: The unprecedented rise in the prevalence of NAFLD globally requires an initiation of population cohort studies with long-term follow-up to determine the incidence and natural history of NAFLD and its underrepresentation in African-Americans. Future studies should also focus on the delineation of the interplay between genetic and environmental factors that trigger the development of NAFLD and NASH.

Subphenotypes of self-reported symptoms and outcomes in long COVID: a prospective cohort study with latent class analysis.

OBJECTIVE: To characterise subphenotypes of self-reported symptoms and outcomes (SRSOs) in postacute sequelae of COVID-19 (PASC). DESIGN: Prospective, observational cohort study of subjects with PASC. SETTING: Academic tertiary centre from five clinical referral sources. PARTICIPANTS: Adults with COVID-19 ≥20 days before enrolment and presence of any new self-reported symptoms following COVID-19. EXPOSURES: We collected data on clinical variables and SRSOs via structured telephone interviews and performed standardised assessments with validated clinical numerical scales to capture psychological symptoms, neurocognitive functioning and cardiopulmonary function. We collected saliva and stool samples for quantification of SARS-CoV-2 RNA via quantitative PCR. OUTCOMES MEASURES: Description of PASC SRSOs burden and duration, derivation of distinct PASC subphenotypes via latent class analysis (LCA) and relationship with viral load. RESULTS: We analysed baseline data for 214 individuals with a study visit at a median of 197.5 days after COVID-19 diagnosis. Participants reported ever having a median of 9/16 symptoms (IQR 6-11) after acute COVID-19, with muscle-aches, dyspnoea and headache being the most common. Fatigue, cognitive impairment and dyspnoea were experienced for a longer time. Participants had a lower burden of active symptoms (median 3 (1-6)) than those ever experienced (p<0.001). Unsupervised LCA of symptoms revealed three clinically active PASC subphenotypes: a high burden constitutional symptoms (21.9%), a persistent loss/change of smell and taste (20.6%) and a minimal residual symptoms subphenotype (57.5%). Subphenotype assignments were strongly associated with self-assessments of global health, recovery and PASC impact on employment (p<0.001) as well as referral source for enrolment. Viral persistence (5.6% saliva and 1% stool samples positive) did not explain SRSOs or subphenotypes. CONCLUSIONS: We identified three distinct PASC subphenotypes. We highlight that although most symptoms progressively resolve, specific PASC subpopulations are impacted by either high burden of constitutional symptoms or persistent olfactory/gustatory dysfunction, requiring prospective identification and targeted preventive or therapeutic interventions.

Pulmonary comorbidities in psoriasis are associated with a high risk of respiratory failure.

OBJECTIVES: To identify respiratory comorbidities associated with a high risk of developing respiratory failure in subjects with psoriasis. METHODS: This was a cross-sectional analysis of data from subjects enrolled in the UK Biobank cohort. All diagnoses were self-reported. The risk of each respiratory comorbidity was compared by logistic regression models adjusting for age, sex, weight, diabetes mellitus, and smoking history; the risk of comorbid respiratory failure for each pulmonary comorbidity was also compared. RESULTS: Of the 472,782 Caucasian subjects in the database, 3,285 self-reported a diagnosis of psoriasis. More men and smokers reported psoriasis and were older, had higher weight and body mass index, and lower pulmonary function than non-psoriatic subjects. Those with psoriasis were at significantly higher risk for multiple pulmonary comorbidities compared to those without psoriasis. Furthermore, those with psoriasis had a higher risk for respiratory failure accompanied by asthma and airflow limitation than non-psoriatic subjects. CONCLUSIONS: Subjects with psoriasis and pulmonary comorbidities, such as asthma and airflow limitation, are at increased risk for respiratory failure. Common immunopathological links implicating a 'skin-lung axis' may underlie psoriasis and pulmonary comorbidities.

Distinct profiles of host responses between plasma and lower respiratory tract during acute respiratory failure.

Current plasma-based subphenotyping approaches in acute respiratory failure represent host responses at a systemic level but do not capture important differences in lower respiratory tract biology https://bit.ly/40kTdDG.

Iron bioavailability regulates Pseudomonas aeruginosa interspecies interactions through type VI secretion expression.

The cystic fibrosis (CF) respiratory tract harbors pathogenic bacteria that cause life-threatening chronic infections. Of these, Pseudomonas aeruginosa becomes increasingly dominant with age and is associated with worsening lung function and declining microbial diversity. We aimed to understand why P. aeruginosa dominates over other pathogens to cause worsening disease. Here, we show that P. aeruginosa responds to dynamic changes in iron concentration, often associated with viral infection and pulmonary exacerbations, to become more competitive via expression of the TseT toxic effector. However, this behavior can be therapeutically targeted using the iron chelator deferiprone to block TseT expression and competition. Overall, we find that iron concentration and TseT expression significantly correlate with microbial diversity in the respiratory tract of people with CF. These findings improve our understanding of how P. aeruginosa becomes increasingly dominant with age in people with CF and provide a therapeutically targetable pathway to help prevent this shift.

Omics and Extreme Phenotyping Reveal Longitudinal Association Between Left Atrial Size and Pulmonary Vascular Resistance in Group 2 Pulmonary Hypertension.

BACKGROUND: Left heart disease is the most common cause of pulmonary hypertension (PH) and is frequently accompanied by increases in pulmonary vascular resistance. However, the distinction between phenotypes of PH due to left heart disease with a normal or elevated pulmonary vascular resistance-isolated postcapillary PH (IpcPH) and combined pre- and postcapillary PH (CpcPH), respectively-has been incompletely defined using unbiased methods. METHODS AND RESULTS: Patients with extremes of IpcPH versus CpcPH were identified from a single-center record of those who underwent right heart catheterization. Individuals with left ventricular ejection fraction <40% or with potential causes of PH beyond left heart disease were excluded. Medication usage in IpcPH and CpcPH was compared across Anatomical Therapeutic Chemical classes and identified vitamin K antagonists as the only medication with pharmacome-wide significance, being more commonly used in CpcPH and for an indication of atrial fibrillation in ≈90% of instances. Accordingly, atrial fibrillation prevalence was significantly higher in CpcPH in a phenome-wide analysis. Review of echocardiographic data most proximal to right heart catheterization revealed that left atrial diameter indexed to body surface area-known to be associated with atrial fibrillation-was increased in CpcPH regardless of the presence of atrial fibrillation. An independent cohort with serial right heart catheterizations and PH-left heart disease showed a significant positive correlation between change in left atrial diameter indexed to body surface area and change in pulmonary vascular resistance. CONCLUSIONS: Guided by pharmacomic and phenomic screens in a rigorously phenotyped cohort, we identify a longitudinal association between left atrial diameter indexed to body surface area and pulmonary vascular resistance with implications for the future development of diagnostic, prognostic, and therapeutic tools.

Metabolic correlates to critical speed in murine models of sickle cell disease.

Introduction: Exercise intolerance is a common clinical manifestation in patients with sickle cell disease (SCD), though the mechanisms are incompletely understood. Methods: Here we leverage a murine mouse model of sickle cell disease, the Berkeley mouse, to characterize response to exercise via determination of critical speed (CS), a functional measurement of mouse running speed upon exerting to exhaustion. Results: Upon observing a wide distribution in critical speed phenotypes, we systematically determined metabolic aberrations in plasma and organs-including heart, kidney, liver, lung, and spleen-from mice ranked based on critical speed performances (top vs. bottom 25%). Results indicated clear signatures of systemic and organ-specific alterations in carboxylic acids, sphingosine 1-phosphate and acylcarnitine metabolism. Metabolites in these pathways showed significant correlations with critical speed across all matrices. Findings from murine models were thus further validated in 433 sickle cell disease patients (SS genotype). Metabolomics analyses of plasma from 281 subjects in this cohort (with HbA < 10% to decrease confounding effects of recent transfusion events) were used to identify metabolic correlates to sub-maximal exercise test performances, as measure by 6 min walking test in this clinical cohort. Results confirmed strong correlation between test performances and dysregulated levels of circulating carboxylic acids (especially succinate) and sphingosine 1-phosphate. Discussion: We identified novel circulating metabolic markers of exercise intolerance in mouse models of sickle cell disease and sickle cell patients.

Genetic regulation of fetal hemoglobin across global populations.

Human genetic variation has enabled the identification of several key regulators of fetal-to-adult hemoglobin switching, including BCL11A, resulting in therapeutic advances. However, despite the progress made, limited further insights have been obtained to provide a fuller accounting of how genetic variation contributes to the global mechanisms of fetal hemoglobin (HbF) gene regulation. Here, we have conducted a multi-ancestry genome-wide association study of 28,279 individuals from several cohorts spanning 5 continents to define the architecture of human genetic variation impacting HbF. We have identified a total of 178 conditionally independent genome-wide significant or suggestive variants across 14 genomic windows. Importantly, these new data enable us to better define the mechanisms by which HbF switching occurs in vivo. We conduct targeted perturbations to define BACH2 as a new genetically-nominated regulator of hemoglobin switching. We define putative causal variants and underlying mechanisms at the well-studied BCL11A and HBS1L-MYB loci, illuminating the complex variant-driven regulation present at these loci. We additionally show how rare large-effect deletions in the HBB locus can interact with polygenic variation to influence HbF levels. Our study paves the way for the next generation of therapies to more effectively induce HbF in sickle cell disease and ß-thalassemia.

Characteristics and survival of patients diagnosed with cardiac sarcoidosis: A case series.

Background: Sarcoidosis is a multiorgan system granulomatous disease of unknown etiology. It is hypothesized that a combination of environmental, occupational, and/or infectious factors provoke an immunological response in genetically susceptible individuals, resulting in a diversity of manifestations throughout the body. In the United States, cardiac sarcoidosis (CS) is diagnosed in 5% of patients with systemic sarcoidosis, however, autopsy results suggest that cardiac involvement may be present in > 50% of patients. CS is debilitating and significantly decreases quality of life and survival. Currently, there are no gold-standard clinical diagnostic or monitoring criteria for CS. Methods: We identified patients with a diagnosis of sarcoidosis who were seen at the Simmons Center from 2007 to 2020 who had a positive finding of CS documented with cardiovascular magnetic resonance (CMR) and/or endomyocardial biopsy as found in the electronic health record. Medical records were independently reviewed for interpretation and diagnostic features of CS including late gadolinium enhancement (LGE) patterns, increased signal on T2-weighted imaging, and non-caseating granulomas, respectively. Extracardiac organ involvement, cardiac manifestations, comorbid conditions, treatment history, and vital status were also abstracted. Results: We identified 44 unique patients with evidence of CS out of 246 CMR reports and 9 endomyocardial biopsy pathology reports. The first eligible case was diagnosed in 2007. The majority of patients (73%) had pulmonary manifestations, followed by hepatic manifestations (23%), cutaneous involvement (23%), and urolithiasis (20%). Heart failure was the most common cardiac manifestation affecting 59% of patients. Of these, 39% had a documented left ventricular ejection fraction of < 50% on CMR. Fifty eight percent of patients had a conduction disease and 44% of patients had documented ventricular arrhythmias. Pharmacotherapy was usually initiated for extracardiac manifestations and 93% of patients had been prescribed prednisone. ICD implantation occurred in 43% of patients. Patients were followed up for a median of 5.4 (IQR: 2.4-8.5) years. The 10-year survival was 70%. In addition to age, cutaneous involvement was associated with an increased risk of death (age-adjusted OR 8.47, 95% CI = 1.11-64.73). Conclusion: CMR is an important tool in the non-invasive diagnosis of CS. The presence of LGE on CMR in a pattern consistent with CS has been shown to be a predictor of mortality and likely contributed to a high proportion of patients undergoing ICD implantation to decrease risk of sudden cardiac death. Clinical implications: Additional studies are necessary to develop robust criteria for the diagnosis of CS with CMR, assess the benefit of serial imaging for disease monitoring, and evaluate the effect of immunosuppression on disease progression.

Trends in the Incidence of Hepatocellular Carcinoma in Washington DC: A Single Institutional Cohort Study (1959-2013).

The African American (AA) community in Washington DC is at an elevated risk for hepatocellular carcinoma (HCC) that has a dismal prognosis. The recent rapid increase in the incidence and diagnosis of HCC and liver metastases (LM) in DC prompted us to evaluate the past six decades of this incidence and some of its underlying causes using a single institutional cohort in a hospital located in the center of the city. Electronic medical and pathology records of 454 liver cancer patients from 1959 to 2013 at Howard University Hospital (HUH) were reviewed. Demographic, clinical and pathology characteristics were examined, and statistical analysis was performed using Wilcoxon rank-sum test. Incidence of HCC rose substantially between 1959 and 2013, increasing eight-fold from 1.05 to 8.0 per 100,000 AAs. The rate of increase in the last decade was highest at 550%. Cases were disproportionately male (67.2%), and median age at diagnosis was 57 years. Towards the last decade, the most common etiology for HCC was nonalcoholic fatty liver disease (NAFLD) followed by NAFLD/HCV combination. Liver cancer was clustered in the eastern region of DC in wards 4, 5, 7, and 8. Cases of liver metastases clinically diagnosed and confirmed by biopsies increased 96.4% from 1959 to 1968 to 2009-2013. This study confirms that HCC incidence has been increasing (initially driven by HCV, and NAFLD in the latter decades) more rapidly in DC than previously believed, highlighting the impact of case definitions especially regarding NAFLD in the context of changing diagnostic approaches including the revised ICD10. The rising burden, disproportionate population distribution, and low survival rate among AAs emphasize the importance of prevention and early detection as a public health imperative.