Citations

Abstract Rationale Idiopathic Pulmonary Fibrosis (IPF) is characterized by chronic progressive pulmonary fibrosis and high mortality. Genetic markers, summarized into a polygenic risk score (PRS), associate with IPF in well-phenotyped research cohorts. Objectives To evaluate the performance of the PRS using real-world data from routinely captured electronic healthcare records. Methods We conducted an observational study evaluating the association of a PRS for IPF with electronic healthcare record diagnosis of IPF as well as lung transplant-free survival in four independent cohorts; the Mass General Brigham Biobank (MGBB), Mayo Clinic Biobank (MCBB), Mayo Clinic Tapestry Cohort (Tapestry), and U.K. Biobank (UKBB). We used multivariable logistic regression and multivariable Cox proportional hazards models adjusting for age, gender, and principal components of ancestry. The cohorts then underwent fixed and random effects meta-analysis. Measurements and Main Results Of 37,709; 44,195; 43,202; and 447,422 participants from MGBB, MCBB, Tapestry and UKBB respectively, 1,015 (2.7%) 2,879 (6.5%), 1,310 (3.0%), and 2,742 (0.6%) participants had an IPF diagnosis. Meta-analysis demonstrated a high-risk PRS associated with IPF diagnosis, OR 2.88 (95%CI 2.41-3.44) compared to all other individuals. A high-risk PRS also associated with the composite endpoint of mortality or lung transplant among those with an IPF diagnosis, HR 1.23(95%CI 1.11-1.35) compared to all other individuals. Conclusions A PRS can identify those at risk for an IPF diagnosis and mortality in biobank-scale data, which may have implications for clinical decisions. Further work is necessary to evaluate the utility of adding genetics in clinical settings.

Cholangiocytes are specialized epithelial cells that line the intrahepatic and extrahepatic biliary tree and play a critical role in bile modification, liver homeostasis, and response to injury. Cholangiocytes exhibit notable heterogeneity and plasticity, and their dysfunction is central to a spectrum of diseases targeting the bile ducts, collectively called cholangiopathies. These disorders include genetic, infectious, immune-mediated, and malignant diseases, with primary sclerosing cholangitis (PSC) representing one of the most complex and enigmatic of these disorders. PSC is a progressive, fibro-inflammatory disease of the bile ducts that is closely linked to inflammatory bowel disease, carries a heightened risk of cancer, and lacks any approved therapies. This review explores the biology of cholangiocytes, including their development, functional plasticity, and roles in secretion, absorption, and cellular signaling. We provide a detailed examination of cholangiopathies, particularly PSC, a complex cholangiopathy characterized by a paradoxical state of cholangiocyte senescence and hyperproliferation. We describe how immune cell dysfunction, the gut microbiome, genetic predispositions, and environmental factors converge to mediate PSC pathogenesis. We revisit the foundational technologies that empowered early discoveries and shaped the field as we know it today. We also explore how newer techniques such as organoid cultures, single-cell transcriptomics, epigenomics, and spatialomics have transformed our modern understanding of biliary pathophysiology. Finally, we provide an overview of existing rodent models of cholangiopathies and discuss their relevance to human disease. PSC remains therapeutically unaddressed, and thus ongoing multidisciplinary efforts are essential to developing targeted interventions. This review serves as a comprehensive resource for researchers and clinicians navigating the rapidly evolving landscape of cholangiocyte-centered liver disease research.

ABSTRACT Background and Aims Cellular senescence is a hallmark of several liver diseases, including primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Senescent cholangiocytes exhibit a senescence‐associated secretory phenotype (SASP), characterized by profibroinflammatory mediator release. Current cost‐effective biomarkers predicting disease progression, particularly for PSC, are limited and often lack mechanistic relevance. We sought to define a plasma biomarker signature for PSC and PBC. Methods Plasma from early‐ and late‐stage PSC and PBC, alcoholic liver disease (ALD), inflammatory bowel disease (IBD) patients, and healthy controls was analyzed. Seventy‐one analytes were quantified using Luminex Multiplex Immunoassay or enzyme‐linked immunosorbent assay (ELISA). Principal component analysis (PCA) identified key patterns. Findings from the PSC cohort were then applied to additional cohorts. Results Second principal component (PC2) (17 analytes, 17.1% variability) best separated PSC from controls. ANOVA showed significant differences in PC2 between early PSC vs. controls ( p = 0.0001), late PSC vs. controls ( p < 0.0001), and early vs. late PSC ( p < 0.0001). PC2 analytes also distinguished early PBC vs. controls ( p < 0.0332), late PBC ( p < 0.0001), and ALD ( p < 0.0001), and early vs. late PBC ( p < 0.0001), but not IBD vs. controls ( p = 0.119). Logistic regression using PC2 demonstrated strong discrimination of early‐ and late‐stage PSC (AUC = 0.86) and control vs. early‐stage PSC (AUC = 0.83). Conclusion This is the first study to define a plasma SASP biomarker signature associated with cholestatic liver disease. These analytes track disease stage and represent both mechanistic indicators and potential clinical trial endpoints.

Abstract Background Non-bacterial thrombotic endocarditis (NBTE) is a non-infectious condition characterized by thrombotic and/or inflammatory depositions involving the cardiac valves. It is a challenging diagnosis of exclusion. Purpose This study aimed to better characterize patients with pathologically proven NBTE and assess its clinical, echocardiographic characteristics and prognostic implications. Methods We retrospectively identified patients with pathology-proven NBTE at a single center. Patients with positive preoperative blood cultures, a history of active or treated infective endocarditis, or identification of valvular organisms by special stains were excluded from the study. Patients with pathology reports of valve perforation or chordal rupture were also excluded because of the high likelihood of an infectious etiology for these lesions. Results A total of 53 patients with NBTE (median age 57 years; 61% females) were identified. In this cohort, 22% had a history of malignancy, 30% had connective tissue disease, 32% had coronary artery disease, and 11% prior history of NBTE. Neurological events accounted for 18 (34%) of the presenting symptoms (TIA n=17, CVA n=9), while new valvular dysfunction in 7 (13%) and fever in 8 (15%) of patients. Five patients (9%) had NBTE involving more than one valve. NBTE involved the mitral valve in 64%, aortic valve in 38% prosthetic/mechanical valve in 11%, and tricuspid valve in 5%. NBTE was identified at the time of autopsy in 34% of patients. NBTE recurred in 3 patients during follow-up. Excluding patients diagnosed at the time of autopsy, 9% of patients died within 1 year of NBTE diagnosis. Conclusion NBTE was diagnosed pathologically in the presence of hyper-inflammatory states due to critical illness or immunological diseases. It was predominantly on the left side of the heart and was associated with embolic phenomena, either clinically or on imaging. Patients diagnosed with antemortem with NBTE have a high mortality in the first year (9%).

Background Myocardial bridging (MB) is accompanied by the dynamic extravascular compression of epicardial coronary arteries, leading to intracoronary hemodynamic disturbance with abnormal coronary flow profiles. We aimed to evaluate the prognostic implications of resistive reserve ratio (RRR), a composite measure of flow and pressure parameters that represents the vasodilatory capacity of the coronary arteries, in patients with angina with nonobstructive coronary artery disease (ANOCA) and MB, in comparison with coronary flow reserve (CFR). Methods and Results In this retrospective cohort study, we included patients with ANOCA who underwent coronary reactivity testing, where MB was identified by transient constriction in coronary artery segments between systole and diastole. Abnormal CFR and RRR were defined as <2.5 and <2.62, respectively. Major adverse cardiac events, including cardiovascular death, stroke, myocardial infarction, heart failure, and late revascularization, served as outcomes. Among 1251 patients with ANOCA, 191 (15.3%) had MB. The prevalence of abnormal CFR or RRR was not significantly different between patients with and without MB ( P =0.144 and P =0.398, respectively). Over a median follow‐up time of 6.9 years, abnormal RRR predicted major adverse cardiac events in patients with MB (hazard ratio [HR], 4.38 [95% CI, 1.71–11.21]; P =0.002) and without MB (HR, 1.91 [95% CI, 1.38–2.64]; P <0.001). Abnormal CFR predicted major adverse cardiac events in patients without MB (HR, 2.15 [95% CI, 1.54–3.00]; P <0.001), whereas it was not predictive of major adverse cardiac events in patients with MB (HR, 2.29 [95% CI, 0.93–5.65]; P =0.073). Conclusions In patients with ANOCA and MB, impaired RRR was superior to impaired CFR in distinguishing patients at a higher risk of future adverse events, suggesting that RRR may serve as a risk stratification tool in patients with MB and ANOCA.

Introduction: The endothelium controls coronary blood flow (CBF) by regulating microvascular tone, which is an important index of microcirculatory health. The difference in vasomotor response of the microvasculature between males and females is not well described. Hypothesis: Males and females react differently to different doses of intracoronary (IC) acetylcholine (Ach) injections. Methods: Patients with angina and non-obstructive coronary artery disease (<50% stenosis) that underwent coronary reactivity study were enrolled. A doppler wire was positioned and incremental IC Ach doses were injected (10 -6 , 10 -5 , and 10 -4 mol/L). CBF (mL/min) was then calculated from CAD and doppler-derived flow velocity. Comparisons between the 2 sexes were performed. Results: A total of 1927 patients (mean age 51±13 years, 67% females) were included. Males were significantly younger (49±13 vs 53±12, P<0.0001) than females and had a higher smoking exposure rate (56% vs 41%, P<0.0001). Baseline (B) CBF was significantly lower in males (27.7 [19.2; 40.8] vs 30.2 [20.6; 43.4], P=0.04). The gap between females and males widened the first 2 doses, but then diminished after the highest dose (41.2 [24.5; 67.8] vs 44.5 [25.9; 72.0], P=0.09) (Fig 1A) . On multivariable analyses, female sex was an independent predictor of higher CBF at all doses (Estimate±StdError) (B= 1.14±0.53; 10 -6 : 1.59±0.61; 10 -5 : 2.54±0.82; 10 -4 : 2.70±1.2; P<0.05 for all). When calculating the %ΔCBF, females had a significantly larger augmentation of flow after the first 2 doses of IC Ach (10 -6 : 3 [-14; 24] vs. -2 [-16; 19], P=0.02; 10 -5 : 21 [-7;68] vs. 12 [-10; 50], P=0.003). However, with the highest Ach dose, there was an equalization of overall augmentation (10 -4 : 49 [-1; 109] vs. 46 [-5; 106], P=0.46) (Fig 1B). Conclusions: Females had higher CBF regardless of given Ach concentration. Females have a higher sensitivity to Ach at smaller doses, while males exhibit a greater vasodilatory reaction at higher doses.

Introduction: Coronary microvascular dysfunction (CMD) is associated with increased morbidity and mortality. Anemia is an important predictor of outcomes in several cardiovascular diseases, such as heart failure and coronary artery disease (CAD), however its significance in patients with non-obstructive CAD is not fully elucidated. Hypothesis: We hypothesized that anemia would be associated with CMD and future adverse outcomes. Methods: We enrolled 1334 patients with signs and/or symptoms of ischemia and with non-obstructive CAD (<50% angiographic stenosis) who underwent invasive CMD evaluation and had follow-up data. CMD was defined as coronary flow reserve (CFR) (hyperemic flow/baseline flow as measured by the doppler wire) of ≤2 in response to intracoronary adenosine injection. Anemia was defined as a Hgb < 13.0 g/L in males and <12.0 g/L in females. MACE was defined as any incidence of myocardial infarction, cardiac revascularization (PCI, CABG) and all-cause mortality. Results: Overall mean age was 51.3±12.4 years, 66% were female. Patients with anemia were more likely to be female and have diabetes mellitus. Anemics were more likely to be diagnosed with CMD (Odds Ratio 2.01, 95% Confidence Interval [1.14-3.54]; P = 0.02). This relationship remained significant even after adjusting for cardiovascular risk factors like age, sex, hypertension, diabetes mellitus and dyslipidemia (OR 1.84, 95% CI [1.03-3.29], P = 0.04). Furthermore, patients with anemia were more likely to experience MACE (OR 1.86, 95% CI [1.30-2.66], P = 0.001), independent of possible confounders (OR 1.84, 95% CI [1.27-2.69], P = 0.002). Conclusions: Anemia is an independent predictor of CMD and future adverse cardiovascular events in patients with NOCAD. Moreover, it was associated with an increased risk of future adverse events. Further studies are needed to elucidate whether treatment of anemia in this population translates into outcomes.

Introduction: Changes in coronary artery diameter (CAD) and coronary blood flow (CBF) in reaction to acetylcholine are important surrogates of endothelial health, and abnormalities in these parameters might represent early atherosclerosis. Menopause is associated with an increased risk of coronary artery disease, yet the role of menopause on the endothelium is not well described. Hypothesis: The vasodilatory response of the endothelium to acetylcholine (Ach) decreases after menopause. Methods: A total of 1271 (42% pre-menopausal) females with angina and non-obstructive coronary artery disease (<50% angiographic stenosis) that underwent coronary reactivity study were enrolled. A doppler wire was positioned and incremental Ach doses were injected (10 -6 , 10 -5 , and 10 -4 mol/L). CBF was then calculated from CAD and doppler-derived flow velocity. Comparisons between the pre-and post-menopause groups were performed. Results: Mean age of the pre-menopausal group was 44±10 years, while that of the post-menopausal 59±9 years. Pre-menopausal females had higher baseline CAD as compared to post-menopausal females (2.22 [1.90; 2.65] vs. 2.20 [1.85; 2.55] mm, P=0.03). However, this difference was nullified with subsequent doses of Ach (Figure 1A&B ). Pre-menopausal females had a higher baseline CBF than post-menopausal females (32.1 [21.7; 44.9] vs. 29.2 [19.8; 42.0] mL/min; P=0.01). This difference progressively increased with successive doses of Ach (10 -4 :49.5 [30.3; 77.0] vs. 41.7 [24.4; 69.0] mL/min; P=0.0002), revealing a greater microvascular vasodilatory response in pre-menopausal females (Cumulative %ΔCBF after highest dose= 60 [2.6; 122] vs 45 [-4; 98], P=0.002) ( Figure 1C&D ). Conclusions: Premenopausal females have greater sensitivity of the microvascular endothelium to Ach compared to post-menopausal, suggesting a possible role for estrogen in mediating the effect of stress on the microvasculature through the endothelium.