Disease States Research Articles

Disease states are increasingly recognized as being shaped by spatially organized inflammatory niches, in which immune and non-immune cells coordinate diverse biological processes, including tissue development, homeostasis and pathology. The activation and composition of specific inflammatory responses, as well as the signalling pathways involved, are highly context- and location-dependent. Recent technological advances-particularly the integration of single-cell sequencing with spatial profiling-have greatly enhanced our ability to dissect these processes at a molecular level. Such approaches have revealed disease-specific mechanisms, including IL-36-driven feed-forward amplification in the upper layers of psoriatic epidermis, the complex inflammatory architecture of hidradenitis suppurativa and T-cell-basal keratinocyte interactions in lichen planus. Continued investigation of inflammatory niches across diseases will deepen our understanding of their pathogenic mechanisms, enable the identification of patient-specific cellular networks and pave the way for more personalized therapeutic strategies.

Medication, particularly antibiotics, significantly alters gut microbiome composition, often reducing microbial diversity and affecting host health. Given that the gut microbiome may influence cancer progression, we integrated clinical, shotgun metagenomic, and medication data to assess microbiome composition across diseased and healthy cohorts, as well as the impact of medication on microbiome variation. The study cohorts included patients with chronic lymphocytic leukemia (CLL, n = 85), acute myeloid leukemia (AML, n = 61), myeloid dysplastic syndrome (MDS), and other severe hematological malignancies (n = 104); patients scheduled for elective cardiac surgery (n = 89); and kidney donors (n = 9), all collected as part of a consecutive microbiome sampling effort at Copenhagen University Hospital, Denmark; and healthy individuals (N = 59). First, our analyses revealed similarities in both diversity and composition between microbiomes of patients with CLL and patients prior to elective cardiac surgery, whereas patients with AML and MDS exhibited the least diverse and most distinct microbiomes. Second, when we quantified sources of microbiome variation, the combination of medication, disease, age, and sex accounted for 4% of variation between all cohorts and 10.4% of variation between CLL and pre-cardiac surgery patients only; the two cohorts selected for comparison due to their similar microbiomes. Notably, this left 90%-95% of the variation unexplained, emphasizing the need for better identification of the parts of the microbiome variation impacting health and disease. Third, using a machine learning approach, we validated and further refined the CLL-associated microbiome pattern from our previous studies. Overall, our data provide a foundation for further investigation into disease-specific microbial signatures and the potential interactions between medication, underlying disease, and the microbiome, with the ultimate goal to improve our understanding and clinical management of CLL.IMPORTANCEThis study reveals how disease and medication influence the gut microbiome in patients with chronic lymphocytic leukemia (CLL) when compared to other more severe hematological malignancies, a cohort of patients scheduled for elective cardiac surgery representing a severely diseased nonhematological cohort, and a cohort of healthy individuals. We found that patients with CLL and those scheduled for cardiac surgery had the most similar microbiome diversity and composition. Similarities across very different disease contexts suggest that disease status alone has limited impact. Consistently, across all cohorts, medication, disease, age, and sex together explained only less of microbiome variation, leaving 90%-95% unexplained. This underscores the important need for better identification of factors shaping the microbiome. In addition, we validated a previously published, machine learning-based CLL-associated microbiome signature, demonstrating the robustness of our previous findings differentiating the microbiome signature for CLL as compared to healthy individuals. The findings expand knowledge on how disease states and medical treatments shape gut microbiome composition and diversity, potentially leading to new ways of managing CLL and improving patient outcomes through microbiome signatures.

In complex diseases, it is challenging to assess a patient's disease state, trajectory, treatment exposures, and risk of multiple outcomes simultaneously, efficiently, and at the point of care. We developed an interactive patient-level data visualization and analysis tool (VAT) that automates illustration of the trajectory of a patient with scleroderma across multiple organs and illustrates this relative to a reference population, including patient subgroups who share risk factors with the index patient, to improve estimation of disease state. We conducted VAT usability testing with patients and clinicians. We then embedded results from internally cross-validated, Bayesian multivariate mixed models that calculate an individual's risk of critical events, using baseline risk factors, patient-level information in past trajectories in multiple dimensions, and known outcomes from the entire population and relevant subgroups. The web-based application aggregates complex, longitudinal data to illustrate patient-, subgroup-, and population-level health trajectories across multiple organ systems. Patients (n = 7) exposed to the VAT reported increased knowledge about their disease and confidence in medical decision-making. Rheumatologists (n = 4) were able to access 8.6 times more data in 81.5% of the time using two-thirds fewer clicks using the VAT compared with an electronic medical record system. Statistical modeling was successfully embedded in the VAT, enabling real-time estimation of a patient's risks of multiple complications. Systematic analysis and visualization of individual- and population-level data in a complex disease has potential to improve medical decision-making and warrants further study. Individualized risk estimation disseminated at the point of care may enable targeted screening and early intervention in high-risk patients.

Purpose: There are reported barriers to implementation of esophageal screening during the videofluoroscopic swallow study (VFSS) completed by the speech-language pathologist (SLP). Often, patients referred to the SLP for a VFSS have an esophageal component that may explain their complaint. In this article, authors explore roadblocks to esophageal screening and potential roadmaps to improve patient care through standardization of esophageal screening procedures. Conclusions: A strong body of literature supports physiologic, anatomic, and disease state relationships of the oropharynx and esophagus. Despite this, the assessment of the oropharynx and esophagus is dichotomized. There remain billing limitations for same-day esophagram and VFSS, and the well-documented esophageal screen provides a view of bolus flow in an upright, typical eating position with consideration of oropharyngeal function to provide a comprehensive view of the continuous process of swallowing from mouth to stomach. The continued practice of evaluating the oropharynx without consideration of the esophagus poses a threat to patient safety and may delay care. A collaborative, multidisciplinary effort among healthcare professionals to create streamlined practice parameters, update position statements, and enhance education parameters will allow for cohesive practices among professionals. Assessment of the swallow mechanism is incomplete without consideration of the entire continuum.

Evidence-based and/or consensus guidance regarding exercise and return-to-play for the adolescent and young adult (AYA) athlete with cardio-oncology concerns is lacking. Many of the recommendations utilized for the diagnosis, surveillance, and management of cancer therapeutic-related cardiotoxicity in children have been extrapolated from adult literature and myocarditis guidelines, the latter of which are primarily concerned with potential for arrhythmias secondary to inflammation and myocardial scarring. In addition, the athlete's heart itself brings about several diagnostic challenges including physiologic changes due to endurance or isometric training. Exercise-induced cardiac remodeling, with enlarged cavity size, lower resting ejection fraction and increased left ventricular wall thickness, depending on the type of exercise, can mimic disease states including both underlying pathologies and the response to cancer therapeutics. A high school cancer survivor had borderline ejection fraction and abnormal strain indices. He was able to return to competitive sports without complication after clinical evaluation and through a shared decision-making process. The difficulty in differentiating physiologic from potentially pathologic echocardiographic changes can result in unnecessary disqualification, depriving athletes from social, psychological, and possibly financial benefits. Stress echocardiography indices, such as contractile reserve and mitral E/e' ratio, may inform assessment of systolic and diastolic function, respectively, and may be helpful in risk stratifying and understanding potential performance limitations in AYA athletes with cardio-oncology concerns for exercise and return-to-play. Most recent consensus statements regarding sports participation in the athlete with heart disease focus on a shared decision-making process amongst all stakeholders involved to formulate an informed, safe, and cohesive prescription to enable the athlete to safely re-engage in sports after recovering from a cardiac illness or surgery. Multidisciplinary recommendations emphasize the importance of exercise before, during, and after chemotherapy in an individualized approach to reduce risk factors in oncology patients and improve cardiovascular outcomes. Further research is needed to delineate protocols for the adolescent and young adult cardio-oncology athlete regarding exercise prescriptions and their return-to-play following oncology treatment.

Fluorescent in-situ hybridisation (FISH) facilitates visualisation of intracellular bacteria in tissues. There is little research looking at the role of intracellular bacteria in inflammatory disease within feline medicine.To determine whether bacteria are present in feline cardiac, hepatic and renal tissues where inflammation has been identified and compare the location of any bacteria with areas of inflammation within those tissues.Study group (SG) cases were selected from Ross University School of Veterinary Medicine's pathology archive, 2012-2022. 23 cases fulfilled inclusion requirements. Three sequential sections were assessed by FISH (using eubacterial and non-eubacterial probes) and hematoxylin-eosin staining. Control group (CG) cases were selected from the same archive (n=6) where death was trauma-related; no other disease states were noted; the same three tissues were available for testing. Known bacteria-positive sections were included with each batch of slides processed to confirm successful hybridization.52.12%, CI 30.6-73.2 SG cases demonstrated bacteria within some or all tissues tested. 78.3%, CI 56.3-92.5 demonstrated the presence of inflammatory cells (IC) in one or more tissues. Of the IC-positive SG cases, 61.1%, CI 35.7-82.7 demonstrated bacteria by FISH; the presence of bacteria in either the liver or kidney, was frequently associated with the presence of IC 77.7%, CI 40.0-97.2 cases and 80%, CI 28.4-99.5 cases respectively. In these, IC distribution did not match bacterial distribution. Of CG cases, 83.3%, CI 35.9-99.6 were negative for IC. Notably, in the IC-negative CG cases, two were positive for bacteria by FISH 40%, CI 5.3-85.3. Pearson-Chi2-test demonstrated a Chi2 of 0.71; P=0.40.Despite this pilot study being limited by a small sample size, bacteria were successfully detected within FFPE samples of feline heart, liver and kidney. We demonstrated that bacteria may not co-locate with all instances of inflammation, suggesting the need for greater vigilance for the presence of fastidious bacteria and/or low-grade infection.

Background Limited-stage small-cell lung cancer (LS-SCLC) has suboptimal long-term survival despite standard chemoradiotherapy. Durvalumab, an anti-PD-L1 antibody, demonstrated survival benefits in the ADRIATIC Phase III trial, but its cost-effectiveness in China remains uncertain. This study evaluates the economic value of durvalumab as consolidation therapy for LS-SCLC post-chemoradiotherapy. Methods A Markov model was constructed using data from the ADRIATIC trial (NCT03703297), simulating three health states: progression-free survival (PFS), progressive disease (PD), and death state, transition probabilities were derived from trial outcomes. A 10-year horizon, 5.0% discount rate, and willingness-to-pay (WTP) thresholds (1-3×per capita gross domestic product (GDP): $12,569.82-$37,709.46/QALY) were applied. All costs were converted to unified currency using the average exchange rate of 1 USD = 7.11 CNY, based on exchange rates from 1 January 2024, to 31 October 2024. Results The study results demonstrated that while durvalumab provided clinical benefits by extending quality-adjusted life years (QALYs) by 0.44 compared to placebo (2.24 vs. 1.80), its high cost resulted in poor cost-effectiveness within China’s healthcare system. The incremental cost reached $108,609.45, yielding an ICER of $245,591.59 per QALY, exceeding China’s standard willingness-to-pay thresholds. Sensitivity analyses revealed drug pricing as the most influential factor, where a 30% price reduction could improve the ICER by 30.3%. The negative incremental net monetary benefit (-$107,394.34) further confirmed the economic challenges. These findings suggest that despite its clinical advantages, durvalumab’s current pricing makes it economically unviable for routine use in China’s LS-SCLC treatment without substantial cost reductions or alternative reimbursement strategies. Conclusion Durvalumab improves survival in LS-SCLC but lacks cost-effectiveness under current pricing in China. Drug costs and health utilities are critical determinants. Policy measures, such as price negotiation, risk-sharing agreements, or subgroup targeting, may enhance affordability. Balancing clinical benefits with economic burden is essential for optimizing durvalumab’s role in LS-SCLC management.

Changes in the mechanical properties, i.e., mechanotypes, of tissues are powerful indicators of disease states and drug-induced injuries. Although differential mechanotyping has emerged as a valuable tool for non-invasive disease diagnostics, it remains particularly underutilized for drug safety and efficacy screening in preclinical studies. This is largely due to the lack of scalable mechanotyping methods compatible with modern 3D organoid models. Here, the Centrifugal Mechanical Testing (CeMeT) platform is presented, which enables rapid, robust, and label-free mechanotyping of 3D organoids. Utilizing centrifugal mechanical principles and high-speed imaging, this platform achieves high accuracy and precision and can assess a wide range of tissue stiffness. It is demonstrated that the CeMeT platform distinguishes mechanical properties, i.e., stiffness and elastic recovery, among various hydrogel bead formulations and hiPSC-derived cardiac organoids, successfully detecting pathological changes in mechanotype with high sensitivity. Through experiments on organoids treated with drugs like pergolide and Cytochalasin-D, it is established that changes in organoid mechanotypes can serve as reliable indicators of drug-induced tissue injuries in vitro. These findings position the CeMeT platform as a potentially transformative tool for early-stage drug safety assessment through mechanotyping,with immediate applications extending to fundamental disease pathology research and drug efficacy testing using organoid models.

Introduction: Chronic pain worsens symptom burden, physical function, and quality of life in heart failure (HF). Social determinants of health (SDOH) can shape the trajectory of HF and other disease states. Healthcare-related SDOH may also be related to the severity of pain among people with HF, but these relationships are unexplored. The aims among adults with HF and chronic pain were to: 1) describe healthcare-related SDOH; 2) compare healthcare utilization by pain severity; and 3) examine the relationship between healthcare-related SDOH and pain severity. Methods: In this cross-sectional study, descriptive statistics and multiple linear regression were used to analyze data from 3,988 participants with HF and chronic pain enrolled in the All of Us Research Program. Pain severity was assessed using a 0-10 scale. Healthcare-related SDOH variables were insurance coverage, self-reported access barriers, and healthcare affordability. Healthcare utilization variables were the number of general provider visits, prescribing advanced practice clinician visits, and specialist visits in the past 12 months. Results: The sample was mean age 70.04 years, 58% female, and 69.8% White race. Over 98% of participants had health insurance. The most common self-reported access barrier, unaffordable service, and medication cost-saving behavior was “no transportation” (14.7%), “dental care” (19.7%), and “asking for lower cost prescriptions” (24.2%), respectively (see Figure 1). Most participants saw a provider 2-3 times over 12 months, but those with higher pain severity saw a general provider more frequently than other pain groups (see Figure 2). Participants with a higher number of self-reported access barriers (β = 0.221 ± 0.044, p < .001), and a higher number of unaffordable services (β = 0.165 ± 0.034, p < .001), experienced higher pain severity. In contrast, participants who adopted a higher number of medication cost-saving behaviors experienced significantly lower pain severity (β = -0.108 ± 0.040, p = .007). Participants who were younger, female sex, non-White race, had more comorbidities, a positive depression diagnosis, and lower reported fatigue, experienced significantly higher pain severity (see Table 1). Conclusions: Despite the high percentage of insured participants, there were notable access and affordability barriers, which were associated with pain severity. These barriers should be confirmed with targeted studies that directly examine pain-related services.

Introduction: Endothelial cell (EC) heterogeneity across vascular beds and disease states is increasingly recognized. However, tissue-specific EC heterogeneity in individuals with type 2 diabetes mellitus (T2DM) is poorly characterized. Hypothesis: We hypothesized that ECs from different tissue beds exhibit distinct transcriptional responses to T2DM. Specifically, we investigated whether subcutaneous adipose tissue ECs (ATECs) and skeletal muscle ECs (SkMECs) from individuals with T2DM show differential activation of endoplasmic reticulum (ER) stress. Materials and Methods: We prospectively recruited patients undergoing cardiac implantable electronic device implantation at Leeds Teaching Hospitals and obtained paired biopsies of pectoralis major and adipose tissue. ECs were isolated using CD31 coated beads and purity confirmed using flow cytometry. Bulk RNA sequencing (RNAseq) of cultured EC isolates was performed. Differentially expressed genes (DEGs) were identified between people with T2DM versus no T2DM (ND) using DESeq2. Gene ontology (GO) enrichment analysis was used to identify differential pathways between tissue beds. The presence of ER stress markers was validated by immunoblotting and correlated with clinical data. Results: We recruited 16 participants (mean age 72 years, 56% male, mean BMI 28). Among individuals with T2DM, mean HbA1c was 57 mmol/mol. RNAseq revealed 63 DEG in SkMEC and 1085 in ATEC in people with T2DM vs ND, with key stress-response genes (e.g. ATF6B, EIF2AK2, ERP29) differentially expressed (Panel A). GO analysis identified response to ER stress as an enriched biological process in ATEC but not SkMECs in people with T2DM. Immunoblotting confirmed increased protein expression of ER stress markers IRE1α and CHOP in ATECs but not in SkMECs (Panel C). Serum HbA1c showed a strong positive correlation with IRE1α (r = 0.78, p = 0.02) and CHOP (r = 0.75, p = 0.02) in ATECs, but not in SkMECs (Panel D). Regression analysis further identified HbA1c as an independent predictor of ER stress in ATECs, after adjustment for age, sex, and BMI (Panel E). Conclusion: Our study reveals a striking tissue-specific heterogeneity in EC response to T2DM, with selective activation of ER stress via the IRE1α pathway in ATECs. These findings suggest that ATECs are uniquely susceptible to hyperglycemia-induced stress and highlight the unfolded protein response as a potential therapeutic target in adipose-specific microvascular dysfunction in T2DM.

Introduction: Arterio-venous (AV) gradients across tissue beds provide insights into the metabolic activity by measuring the net uptake or release of lipids and metabolites. In the heart, these gradients can reflect real-time changes in myocardial substrate utilization in disease states like atrial fibrillation (AF). Aims: We aimed to explore the lipidomic and metabolic alterations due to acute rhythm changes in AF patients. Methods: Blood samples were collected from the left atrium (LA), coronary sinus (CS), and the vein of Marshall (VOM) during AF ablation procedures, representing the arterial and venous sides of the whole myocardial and atrial tissue, respectively. Samples were collected in the presenting rhythm (SR or AF), after which patients were either cardioverted or underwent AF induction before any ablation delivery. Sampling was repeated 5 minutes after the onset of the new rhythm (Panel A). Blood samples were analyzed for lipid species and metabolites using the Sciex Lipidyzer system and LC-MS metabolite analysis, respectively. Results: We analyzed 16 arterio-venous blood samples (8 in AF, 8 in SR) to measure 1,561 lipid species across 18 lipid classes and 29 metabolites, including those specific to the heart and atria. Oxygen saturation in the VOM was lower in AF (median 53%, IQR 40–58%) compared to SR (58%, IQR 46–68%; P=0.021), indicating greater oxygen extraction in AF by the atria (Panel B). However, there was no significant difference in oxygen saturation in the CS samples: AF (median 56%, IQR 44–63%) and SR (median 57%, 42– 62%; P=0.1). Differences in AV gradients between AF and SR were assessed in both whole-heart and atrial-specific samples. In whole-heart samples, there was a general balance between lipid import and export. However, atrial-specific samples showed a clear shift toward net lipid import in AF (Panel C). For metabolites, we found a mismatch between atrial and ventricular metabolism in AF. Specifically, glucose, valine, and isoleucine showed net export from the whole heart, but net import at the atrial level (Panel D). Conclusion: Atrial-specific metabolic alterations, characterized by increased lipid and amino acid uptake, altered glucose utilization, and increased oxygen extraction were observed with AF compared to SR. These findings point to an acute metabolic shift, with increased energetic demand in atrial tissue, and potential atrial–ventricular metabolic desynchrony during AF.

Hexokinase domain containing protein 1 (HKDC1) is a recently discovered fifth human hexokinase isozyme that is significantly upregulated in several disease states, including lung and liver cancers. Cellular studies suggest that HKDC1 is a low activity hexokinase; however, its functional characteristics have remained enigmatic. Here, we describe the kinetic and regulatory features of recombinant human HKDC1, demonstrating it to be a robust hexokinase (kcat/Km,glucose = 1.5 × 104 M-1 s-1) with a unique glucose Km value (0.49 ± 0.07 mM) that differs markedly from all other human hexokinase isozymes. The isolated C-terminal domain of HKDC1 displays kinetic characteristics nearly identical to the full-length enzyme, whereas the N-terminal domain is inactive. Unlike all other 100 kDa vertebrate hexokinases characterized to date, HKDC1 is insensitive to product inhibition by physiological concentrations of glucose 6-phosphate, with apparent inhibition constants above 1 mM. The hexokinase activity of HKDC1 is also insensitive to Dinaciclib, a pan cyclin-dependent kinase inhibitor that reportedly disrupts the ability of nuclear localized HKDC1 to phosphorylate retinoblastoma-binding protein 5. Conversely, the hexokinase activity of HKDC1 is potently inhibited by a synthetic glucosamine derivative previously developed for hexokinase 1 and 2, with an IC50 value of 103 ± 6 nM. An HKDC1 variant associated with retinitis pigmentosa, T58M, displays a modest, but statistically significant 2-fold decrease in catalytic efficiency (kcat/Km,glucose) compared to the wild-type enzyme. Together, our results provide a detailed functional characterization of recombinant HKDC1 and set the stage for investigating the link between HKDC1 catalysis and human disease.

Introduction: While genetic variants linked to dilated cardiomyopathy (DCM) are increasingly well characterized, the molecular mechanisms driving pathogenesis remain poorly understood. Traditional bulk and in vitro methods lack the resolution to capture the cellular heterogeneity and complexity of DCM. Here, we use single-nucleus multiome chromatin accessibility and RNA sequencing to resolve cell-type-specific gene regulatory changes in genetic DCM. Methods: We performed 10X Genomics Multiome (simultaneous RNA and chromatin accessibility) profiling on nuclei isolated from left ventricular tissue of 13 DCM patients with diverse genetic etiologies ( LMNA , PLN , RBM20 , TNNT2 , TTN ) and 5 non-failing hearts. Integrated analysis identified 12 distinct cardiac cell types based on joint transcriptomic and epigenomic signatures. Intercellular communication networks were inferred using CellChat. We leveraged paired RNA and chromatin accessibility data to elucidate potential enhancer-gene interactions driving disease-associated cell state changes. Results: We observed disease-specific alterations in cellular composition and signaling networks across DCM genetic etiologies. Integrated chromatin accessibility and gene expression data revealed changes in the gene regulatory networks of cardiomyocytes, fibroblasts, and endothelial cells. Notably, the transcription factor PRRX1 emerged as a key differentially regulated gene in LMNA -related DCM. Functional assays in iPSC-derived cardiomyocytes demonstrated that PRRX1 knockdown significantly improved calcium handling and reduced arrythmia incidence. Conclusions: This single nucleus multiomic atlas of genetic DCM provides insights into cell-type-specific gene regulation and cell communication programs associated with disease states. Our findings highlight PRRX1 as a potential therapeutic target in LMNA -related DCM and underscore the value of multiomic profiling for uncovering the regulatory basis of cardiomyopathies.

Background: Vulnerable plaques are the immediate cause of acute coronary syndromes such as acute myocardial infarction (AMI). However, current preventive strategies including lipid-lowering and imaging-based approaches focus on overall cardiovascular risk and lack precision in identifying high-risk plaques before clinical events. One major limitation is the insufficient understanding of cell-type heterogeneity and dynamic changes across the full course of atherosclerosis. Methods and Results: We established a cross-species, multi-stage framework integrating human single-cell data from advanced stable and unstable plaques with multi-timepoint mouse models. This allowed reconstruction of a continuous trajectory of atherosclerosis and led to identification of a monocyte-derived population, Plaque Instability Monocytes (PIMs), enriched in unstable lesions and characterized by inflammatory and matrix-remodeling programs. To validate their relevance, we profiled additional lesions across multiple arteries and disease states, including in-stent restenosis. PIM signatures were consistently recovered, and spatial transcriptomics revealed preferential localization to fibrous caps, confirmed by confocal imaging. Circulating PIM-like cells were also elevated in patients with unstable plaques. From the PIM transcriptome, we derived a 362-gene blood signature, and used interpretable deep learning to identify a stable 20-gene panel distinguishing unstable from stable cases (AUC = 0.907). A composite risk score built using L1-logistic regression was validated in an independent cohort (n = 338, AUC = 0.92). Cytokine genes within the panel showed elevated plasma levels in AMI patients (n = 26), and UK Biobank proteomics (n = 3,798) confirmed upregulation of key panel proteins in myocardial infarction. Conclusions: By bridging single-cell discoveries with peripheral biomarker modeling and clinical validation, this study identifies a conserved monocyte subset associated with plaque vulnerability and provides a practical tool for early detection and risk stratification in coronary artery disease.

Background: Mitral valve prolapse (MVP) is frequently associated with mitral regurgitation (MR), which increases left ventricular (LV) preload and can lead to LV hypertrophy. In other disease states, elevated LV preload, has been associated with reduced coronary flow reserve due to increased resting coronary flow, resulting in impaired myocardial perfusion. However, myocardial perfusion at rest and under stress has not previously been characterized in patients with MVP and significant MR. Aim: To evaluate myocardial perfusion in patients with moderate or severe MR due to MVP compared with controls without MVP and MR, using cardiac magnetic resonance (CMR) imaging with adenosine stress perfusion mapping. Methods: Patients with MVP and moderate or severe MR referred for mitral valve surgery were prospectively enrolled in the MitraVT study (NCT06255457) and were compared to age- and sex-matched controls without MVP and primary MR. All participants underwent CMR at 1.5T (MAGNETOM Sola, Siemens Healthineers), including cine imaging and adenosine stress perfusion mapping. Exclusion criteria included coronary artery disease, rheumatic mitral disease, mitral stenosis, endocarditis, or primary cardiomyopathy. Myocardial perfusion was quantified for each of the 16 segments defined by the American Heart Association, both at rest and under stress. Global perfusion values were calculated as the mean across all segments. Clinical data were obtained from medical records. Results: In total, 20 patients and 20 controls were included (age 53.9±15.2 vs. 52.2±13.2 years, 55% vs. 55% female) with no differences in the prevalence of diabetes, hypertension, hyperlipidemia, or smoking status. Compared to controls, patients with primary MR had higher indexed end-diastolic LV volume, stroke volume index, and ejection fraction. Global myocardial perfusion was significantly reduced among patients with MVP and MR, both at rest (0.82±0.20 vs.1.04±0.32 ml/min/g, p=0.01) and at stress (2.46±0.45 vs. 3.44±0.71 ml/min/g, p<0.001) (Figure 1). These differences remained significant when comparing the mean perfusion values across basal, midventricular, and apical levels. Conclusion: Patients with MVP and moderate or severe MR exhibited significantly reduced myocardial perfusion both at rest and at stress, indicative of coronary microvascular dysfunction. Future studies are needed to assess whether mitral valve surgery restores myocardial perfusion and improves symptom burden in this population.

Introduction: Exercise testing has been proven to improve phenotypic resolution and risk stratification in patients with heart failure with preserved ejection fraction (HFpEF). We hypothesized that exercise pulmonary artery pulse pressure (PA PP) has the potential to differentiate HFpEF disease states and predict outcomes. Methods: In a single-center cohort of patients referred for invasive cardiopulmonary exercise testing, we identified patients with hemodynamically confirmed HFpEF (resting pulmonary capillary wedge pressure (PCWP) ≥ 15 mmHg or PCWP/cardiac output (CO) slope > 2 mmHg/L/min, and left ventricular ejection fraction > 50%). Patients with respiratory exchange ratio < 1 indicating submaximal exercise and < 2 years of follow-up were excluded. We measured PA PP at 3 time points: rest, end of unloaded exercise, and peak exercise. Patients were categorized as having a low versus high PA PP at each time point based on the median value of our cohort, as no cutoff values for PA PP have been defined in the literature thus far. We identified four distinct phenotypes based on PA PP at each time point: Low-Low-Low (Trajectory 1, n=71); Low-Low-High (Trajectory 2, n=29); Low-High-High (Trajectory 3, n=43); and High-High-High (Trajectory 4, n=85) ( Figure Panel A ). Survival was assessed by Kaplan-Meier analysis and Cox proportional hazards analysis adjusted for age, sex, body mass index, peak oxygen consumption, and ventilation/carbon dioxide production slope. Results: Baseline characteristics were similar across PA PP trajectories. Rest and exercise hemodynamics are shown in Panel B . We found that higher PA PP trajectory was associated with worse survival (log rank p=0.0025, Panel C ). Specifically, survival in patients who had a rise in PA PP at the end of unloaded exercise (Trajectory 3) was similar to patients with high PA PP throughout (Trajectory 4). In a multivariate Cox proportional hazards model, PA PP trajectory remained a significant predictor of survival (HR 1.58, 95% CI [1.12-2.25], p=0.009). Conclusion: We identified four clinically distinct phenotypes of HFpEF based on PA PP trajectory during exercise. In our single-center cohort, exercise PA PP trajectory predicted all-cause mortality in hemodynamically defined HFpEF and may be an early indicator of abnormal pulmonary vasculature. Future studies are needed to correlate PA PP with known measures of ventricular-vascular coupling.

Identifying biomarkers of periodontal diseases and early diagnosis of the disease serves to enhance treatmenteffectiveness for numerous patients suffering from periodontal diseases worldwide. Starting from gingivitis,which is inflammation of the gum tissues, it can progress to periodontitis, an irreversible condition thatleads to the destruction of periodontal tissues, including periodontal pockets and alveolar bones. It is knownthat during the development of periodontitis, at the gingivitis stage, patients experience gum inflammationwithout loss of soft and hard tissues. In the initial stages of periodontitis, gum inflammation is observedin patients, while in the subsequent stages of the disease, loss of soft and hard tissues is noted. Therefore,the sequential levels of change in markers across different stages of periodontitis development, along withcombinations of biomarkers, provide effective results for diagnosing the disease state

Background: Transthyretin cardiac amyloidosis (ATTR-CM) is a progressive, infiltrative cardiomyopathy increasingly recognized in older adults. Despite improved awareness, and diagnostic modalities, diagnosis is often delayed due to symptom overlap with more common conditions. Patients with preexisting comorbidities, such as autoimmune disease or ischemic heart disease, are at even higher risk of diagnostic overshadowing. Herein, we describe a diagnostic conundrum of ATTR-CM in a patient with coexisting systemic lupus erythematosus (SLE) and Ischemic cardiomyopathy. Case Description: A 70-year-old female with coronary artery disease post-CABG, SLE with prior lupus nephritis and kidney transplant, and recurrent DVTs presented with dyspnea and bilateral leg edema. Her labs revealed macrocytic anemia, elevated NT-proBNP (41,167 pg/mL), and HS troponin-I (peak 689 ng/L). EKG showed sinus bradycardia, right bundle branch block, and low-voltage QRS complexes (Figure 1). Echocardiography demonstrated preserved ejection fraction of 55%, mild concentric LVH, and biatrial enlargement (Figure 2). Coronary angiography showed a mid-RCA lesion treated with PCI, but her symptoms persisted. The discordance between a low-voltage EKG and increased wall thickness on echocardiography raised suspicion of infiltrative cardiomyopathy. Serum and urine immunofixation and light chain analysis ruled out AL amyloidosis. A technetium-99m PYP scan showed grade 3 uptake with a heart-to-contralateral ratio of 1.52 (Figure 3). Genetic testing ruled out TTR mutation, confirming wild-type ATTR-CM. She was treated with cautious diuresis using lasix and referred for outpatient disease-modifying treatment. Discussion: This case highlights the diagnostic complexity of ATTR-CM in patients with overlapping cardiac and systemic comorbidities. Initial symptoms were attributed to ischemic and autoimmune causes, delaying recognition of amyloidosis. Red flags, such as disproportionate biomarker elevation, low-voltage EKG with LVH, and persistent symptoms despite intervention, prompted re-evaluation. . A stepwise non-invasive workup led to a timely, biopsy-free diagnosis. Early identification is critical, as novel disease-modifying therapies can significantly alter prognosis. This case highlights the importance of heightened clinical suspicion and awareness of ATTR-CM in patients with coexisting chronic disease states and overlapping symptomatology.

Abstract Large-bore thrombectomy has emerged as a critical treatment option in the management of iliocaval thrombosis, a condition associated with high morbidity and mortality. These devices are designed for rapid removal of clot and symptom resolution while minimizing the need for thrombolytic therapy. Ongoing trials, prospective registries, and retrospective reviews are also investigating the role of early thrombectomy or thrombolysis on subsequent development of post-thrombotic syndrome. These interventions are particularly beneficial for patients with contraindications to systemic or catheter-directed thrombolysis, those at high risk for post-thrombotic syndrome, or those with chronic thrombus, which is less likely to respond to lytic therapy. These devices utilize mechanical, aspiration, and rotatory systems to break up and remove acute and chronic, densely adherent thrombus. Each has unique characteristics that make them preferred in different disease states and many cases require use of multiple devices in conjunction with one another. This review describes the importance of large-bore thrombectomy in the treatment of iliocaval thromboembolic disease and highlights modern devices and case-specific uses for each.

Recent advances in mass spectrometry-based proteomics have enabled increasingly precise characterization of protein modifications in clinical specimens. Among these, glycosylation is one of the most structurally complex and biologically informative post-translational modifications, reflecting cellular differentiation and disease states. Ohashi et al. (J. Biochem. 2024; 175: 561-572) performed a site-specific N-glycosylation analysis of LAMP1 in breast cancer tissue samples, demonstrating the feasibility of targeted glycoproteomics in patient-derived specimens and revealing tumor-associated glycoform heterogeneity. Their study exemplifies how focusing on a single glycoprotein target can provide detailed insight into disease-specific glycan remodeling within the tumor microenvironment. In this commentary, I discuss the significance of such targeted approaches in the broader context of clinical glycoproteomics and highlight their potential contribution to cancer biomarker discovery and precision medicine. Continued integration of glycoproteomic data with genomic and clinical information is expected to further advance our understanding of tumor biology and therapeutic response.