Citations

Background: Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis characterized by chronic inflammation and immune dysregulation. Single-cell RNA sequencing (scRNA-seq) studies of human atherosclerotic plaques have identified distinct transcriptional programs within plaque-associated immune cells. We sought to determine whether transcriptional features described within these plaque-resident cells can be identified in peripheral blood mononuclear cells (PBMCs). Methods: PBMCs from patients with PAD (n = 4) and healthy controls (HC) (n = 5) were profiled using scRNA-seq using the Parse Biosciences platform, yielding approximately 135,000 high-quality cells. Data analysis was conducted in R, using Seurat for quality control, dimensionality reduction and clustering. Cell-type annotation was performed using Azimuth reference-based mapping. Plaque-associated inflammatory and metabolic gene programs were curated from published human plaque single-cell atlases. Results: Gene expression differences between HC and PAD cells were visualized using UMAP plots. CD14+ mononuclear phagocytes (MNPs) exhibited the most prominent and consistent transcriptional differences between HC and PAD samples (Figure 1). Within CD14+ MNPs, genes involved in lipid handling and macrophage metabolic function demonstrated a higher median percentage of expressing cells in PAD compared with HC (Figure 2). Further analysis of AQP9 and CD36, genes implicated in macrophage metabolic activation and lipid uptake in atherosclerotic plaques, with z-score normalization and subject-level averaging revealed modest but consistent increases in relative expression in PAD across subjects. These findings support the relevance of these circulating transcriptional shifts to PAD pathophysiology. Conclusions: Circulating CD14+ MNPs in PAD have detectable transcriptional features consistent with potential engagement of plaque-associated myeloid activation programs. In PAD, increased expression of CD36, which encodes the immune cell scavenger receptor for oxidized LDL, and AQP9, associated with unstable plaques and the endothelial-to-mesenchymal transition, suggest altered immunometabolism states in circulating MNPs. Although effect sizes are modest, they are consistent across subjects and statistically robust. These findings highlight PBMC scRNA-seq as a minimally invasive approach to interrogate systemic immune programs relevant to PAD pathobiology.

Background: The timing of coronary artery bypass grafting (CABG) in patients with non-ST-elevation myocardial infarction (NSTEMI) may critically impact clinical outcomes, yet the ideal surgical window remains unclear. We aimed to evaluate the association between time-to-CABG and in-hospital outcomes among NSTEMI admissions undergoing CABG. Methods: This retrospective cohort study utilized the US National Inpatient Sample database from 2017 to 2021 to evaluate the association between time-to-CABG and key in-hospital outcomes, including mortality, cardiac arrest, cardiogenic shock, ischemic stroke, acute kidney injury, and blood transfusion rates, while assessing length of stay (LOS) and hospital charges exclusively among survivors. Adult admissions with principal diagnosis of NSTEMI who underwent CABG without prior interhospital transfer were grouped by the calendar day of CABG from admission (0, 1, 2, 3, 4, 5, 6, and ≥7). Multivariate regression models were used to assess the outcomes across these eight groups. Results: Of 142,200 included admissions, same-day CABG (hospital day 0) was associated with the highest rates of in-hospital mortality, cardiac arrest, cardiogenic shock, and ischemic stroke. The adjusted odds of mortality, cardiac arrest, and cardiogenic shock were lower among admissions undergoing CABG between days 2 and 5. Likewise, the adjusted odds of ischemic stroke were lowest when CABG occurred on days 2 to 4. The odds of AKI increased when CABG was delayed beyond day 6, whereas blood transfusion rates showed no statistically significant association with time-to-CABG. Among survivors, LOS and hospital charges progressively increased with delayed CABGs. Conclusions: Among NSTEMI admissions undergoing CABG, CABG performed on hospital days 2 to 4 was associated with lower adjusted odds of several adverse in-hospital outcomes compared with same-day CABG. Further prospective studies are needed to validate these results and guide clinical decision-making.

aims: We assessed the diagnostic accuracy of the SVEAT score in predicting 30-day major adverse cardiac events (MACE) in comparison with the well-established HEART and TIMI scores. background: Acute chest pain (ACP) is a common symptom in emergency departments. Various risk stratification tools have been developed to assess patients presenting with ACP. The Simple Vascular Event Assessment Tool (SVEAT) is the most recent scoring system introduced, based on five variables: Symptoms of chest pain, history of Vascular disease, ECG, Age, and Troponin-I. objective: We assessed the diagnostic accuracy of the SVEAT score in predicting 30-day major adverse cardiac events (MACE) in comparison with the well-established HEART and TIMI scores. method: Following PRISMA guidelines, a systematic literature search was conducted across five databases until June 22, 2024. Four studies comprising 1,520 patients were included in this meta-analysis. The predictive accuracy of the SVEAT, HEART, and TIMI scores for 30-day MACE was assessed by the area under the receiver operating characteristic curve (AUC). Heterogeneity was evaluated using the I² statistic, with values over 75% indicating significant heterogeneity. Indirect comparisons among the scores were performed using the Z-test. result: Pooled AUC for the SVEAT score was 0.92 (95% CI: 0.86-0.98), indicating superior predictive accuracy compared to the HEART (AUC: 0.86, 95% CI: 0.81-0.92) and TIMI (AUC: 0.82, 95% CI: 0.69-0.96) scores. However, significant heterogeneity (I² = 90.6%) was observed across studies, potentially due to variations in patient demographics, clinical settings, and outcome definitions. Despite the higher AUC, indirect Z-test comparisons revealed no statistically significant differences between the scoring systems. conclusion: SVEAT score demonstrates potential as an accurate tool for predicting 30-day MACE in patients with ACP. other: N/A

ABSTRACT Background Prolonged QT interval is common in end‐stage renal disease (ESRD) on dialysis, but its long‐term cardiovascular (CV) implications remain unclear. Methods Using TriNetX network (2010–2024), we identified adults with ESRD on dialysis and categorized them by QTc status. After 1:1 propensity score matching ( n = 3428/group), outcomes (hazard ratio [HR]) were assessed using Cox regression. Results Prolonged QTc (> 500 ms) was associated with higher risk of all‐cause mortality (HR 1.67; p < 0.001), MACEs (HR 1.40; p < 0.001), cardiac arrest (HR 1.75; p < 0.001), sustained ventricular arrhythmia (HR 1.66; p < 0.001), new‐onset atrial fibrillation (HR 1.12; p = 0.01), and acute myocardial infarction (HR 2.19; p < 0.001). Conclusions In ESRD patients on dialysis, prolonged QT interval was independently associated with adverse CV outcomes and mortality.

Abstract Aims We evaluated clinical outcomes with GLP-1 RA use post-TAVI in patients with T2D. GLP-1 receptor agonists (GLP1-RAs) lower cardiovascular risk in type 2 diabetes (T2D), but their impact in patients with valvular heart disease, including those undergoing transcatheter aortic-valve implantation (TAVI), remained unexplored. Methods and results We conducted a retrospective cohort study using the TriNetX network, including 25 184 adults (≥18 years) with T2D who underwent TAVI (2015–2023). Patients were stratified based on GLP1-RA initiation within 14 days post-TAVI. Baseline characteristics, comorbidities, medications, and laboratory data were balanced using 1:1 propensity score matching (PSM). Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for events from one-month post-TAVI until the most recent follow-up. PSM yielded 1101 patients per group, with a mean age of 73 years and 39% female. Mean follow-up duration was 2.2 ± 1.1 and 2.6 ± 1.8 years for GLP1-RA users and non-users, respectively. GLP1-RA use was also associated higher survival probability (HR: 0.708 [95% CI: 0.583–0.859]), and lower rates of all-cause hospitalization (HR: 0.790 [95% CI, 0.706–0.885]), major cardiovascular events (HR: 0.849 [95% CI: 0.749–0.963]), and acute heart failure exacerbation (HR: 0.785 [95% CI: 0.677–0.909]), acute kidney injury (HR: 0.843 [95% CI: 0.719–0.988]), and major kidney events (HR: 0.665 [95% CI: 0.510–0.866]). No differences were observed in acute myocardial infarction, cerebral infarction, or cardiac arrest. Conclusion In patients with T2D undergoing TAVI, GLP1-RA use is associated with significant survival benefits and improved cardiorenal outcomes. However, these findings are limited by the observational design, high comorbidity burden, lack of data on medication compliance, and specific cause of death. Prospective trials are warranted to confirm these benefits.

Introduction: In patients with type 2 diabetes (T2D) at high cardiovascular risk, glucagon-like peptide-1 receptor agonists (GLP1-RAs) have been shown to reduce major adverse cardiovascular events. However, patients with valvular heart disease, including those undergoing transcatheter aortic-valve implantation (TAVI), have been largely excluded from randomized trials. Hypothesis: We investigated whether GLP1-RA use is associated with improved one-year cardiovascular outcomes in patients with T2D undergoing TAVI. Methods: We conducted a retrospective cohort study using the TriNetX network. Adults (≥18 years) with T2D who underwent TAVI between 2015 and 2023 were included and stratified based on GLP1-RA initiation within 14 days post-TAVI. Baseline characteristics, comorbidities, medications, and laboratory data were balanced using 1:1 propensity score matching (PSM). The primary outcome was a composite of all-cause mortality or hospitalization at 1 year. Secondary outcomes included acute heart failure (HF) exacerbation, acute myocardial infarction (AMI), cardiac arrest, and ischemic stroke. Outcomes were assessed from 1 month to 1 year after TAVI. Survival probabilities were estimated using Kaplan-Meier analysis, and hazard ratios (HRs) were calculated with Cox proportional hazards models. Results: Among 20,454 patients with T2D undergoing TAVI from 2015-2023, 937 received GLP1-RAs. After PSM, 930 patients were included in each cohort, with a mean age of 73 years and 37% female. The mean follow-up duration was 342 days for GLP1-RA users and 325 days for non-users. GLP1-RA cohort exhibited a higher 1-year survival probability (93.8%) compared to non-users (89.5%) (HR 0.573 [95% CI, 0.410-0.801]; p=0.001). GLP1-RA use was also associated lower rates of all-cause hospitalization (HR 0.762 [95% CI, 0.652-0.891]; p=0.001), acute HF exacerbation (HR 0.687 [95% CI, 0.566-0.834]; p<0.001), and cardiac arrest (HR 0.452 [95% CI, 0.213-0.960]; p=0.034). No differences were observed in AMI (HR 1.033 [95% CI, 0.750-1.423]; p=0.844), or ischemic stroke (HR 0.875 [95% CI, 0.659-1.162]; p=0.356). Conclusions: In patients with T2D undergoing TAVI, GLP1-RA use is associated with significant survival benefits and improved cardiovascular outcomes, including reductions in acute HF exacerbation, all-cause hospitalization, and cardiac arrest. These findings highlight the need for prospective clinical trials to confirm these results.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, contributing to significant morbidity and mortality worldwide. The relationship between physical exercise and AF is complex, with studies showing both beneficial and potentially adverse effects. Moreover, evidence suggests a U-shaped association between exercise intensity and AF risk. Moderate exercise has been shown to reduce AF burden by improving cardiovascular risk factors, enhancing autonomic regulation, and mitigating atrial fibrosis. In contrast, excessively high-intensity endurance exercise may increase AF risk, particularly in young athletes, due to atrial stretching, dilation, fibrosis, autonomic imbalances, and heightened inflammation. The current guidelines emphasize exercise as a core lifestyle intervention for AF management, recommending moderate-intensity aerobic activity for optimal outcomes. This review examines the current evidence on the effects of exercise on AF, identifies knowledge gaps, and proposes potential future research directions.

Introduction: Amyloidosis complicated by heart failure (HF) poses significant mortality. We sought to identify trends in comorbid amyloidosis and HF mortality in the recent 22- year period. Methods: Mortality due to amyloid and HF as contributors of death were queried from death certificates using the CDC database from 1999 to 2020. Mortality rates and their 95% confidence intervals were adjusted for age (AAMR) through the Direct method and compared by demographic subpopulations. The Monte-Carlo permutation test was used to estimate the annual percentage change (APC). Log-linear regression models were utilized to assess temporal variation in mortality. Results: Age-adjusted mortality rates (AAMR) increased from 0.09 [0.08-0.10] in 1999 to 0.27 [0.25-0.29] in 2020. Mortality increased from 1999 to 2013 (APC +1.4, p=0.048) with an accelerating inflection point in 2013 to 2020 (APC +13.3, p<0.001). AAMR was higher among male populations (AAMR 0.20 [0.20-0.21]) compared to female populations (AAMR 0.07 [0.07- 0.07]). A significant inflection point in uprising mortality rates was observed for both male and female populations in 2013 (p<0.001). Mortality was highest among Black populations (AAMR 0.33), followed by White (AAMR 0.10), Asian/Pacific Islander (AAMR 0.06), and American Indian/Alaska Native populations (AAMR 0.04). Among Black populations, mortality remained consistent from 1999 to 2012 (APC +1.1, p=0.184), followed by an increase from 2012 to 2020 (APC +14.0, p<0.001). Among White populations, mortality remained stagnant from 1999 to 2013 (APC +0.7, p=0.302), followed by an increase starting in 2013 to 2020 (APC +13.5, p<0.001). Discussion: Our findings of a marked rise in HF-related mortality in patients with amyloidosis since 2013 highlighted the profound impact of enhanced diagnostic awareness, novel imaging techniques, and emerging therapeutics. Our analysis also showed mortality disparities between sexes, and geographic locations, races, and ethnicity that warrant targeted public health interventions. Conclusions: Amyloid and HF mortality increased in the recent 22-year period, primarily starting in 2013, emphasizing the urgent need for targeted intervention to address these disparities.

Introduction: Atherosclerotic arterial disease is the leading cause of death throughout the world. One of the most advanced forms of atherosclerosis, peripheral arterial disease (PAD), affects over 8.5 million people in the United States and over 230 million globally. This disease begins from an inflammatory lesion, known as the fatty streak, formed by mononuclear phagocytes (MNPs), a broad cell type classification that includes monocytes, dendritic cells, and macrophages. Development of more efficacious treatments for PAD requires that we better understand the cellular and molecular processes by which MNPs form these inflammatory lesions. Methods: To compare gene expression of MNPs, we performed scRNAseq on PBMCs from an initial cohort of 4 patients with PAD, mild claudicants to minor tissue loss (Rutherford 1-5), and 5 healthy individuals, defined as those without any chronic diseases and a hsCRP <2.0 mg/L. We conducted single cell RNA library generation using Parse Bio and sequenced to a depth of 70k reads per cell and downstream bioinformatic and differentially gene expression analysis via R and Seurat. Results: Gene expression differences in healthy versus PAD cells were visualized on a UMAP plot. Aligning our cells to the human PBMC Cell Atlas, we found that the cell type with the greatest transcriptional change (healthy vs. PAD) was CD14 + MNPs. Next, we screened for differentially expressed genes within this CD14 + MNP cluster between healthy and PAD subjects and identified 854 upregulated and 730 downregulated genes (log 2 fold change ≥ 0.25 and p < 0.05, Welch’s t-test). Two of the most significantly upregulated genes in PAD CD14 + MNPs are FAM20A and TMTC1. FAM20A encodes a psuedokinase important in calcium homeostasis as well as bone mineralization and that is upregulated in advanced atherosclerotic plaques. TMTC1 encodes for an endoplasmic reticulum protein also involved in calcium homeostasis, vascular homeostasis, and endothelial cadherin egress. Finally, one gene we found downregulated in PAD is CD83, a molecule implicated in resolution of inflammation, that when downregulated promotes an inflammatory state. Conclusion: Based on these findings we hypothesize that in PAD there exists a distinct transcriptional program along the CD14 + MNP cell type lineage that is pro-inflammatory and that may play a role in disease progression and response to intervention.

Abstract RATIONALE: Alveolar Type 2 (AT2) cells play a critical role in maintaining alveolar function and facilitating repair processes in the lung. Despite recent advancement on transcriptomic mapping of cell identities and AT fate selection, the mechanisms governing AT2 fate plasticity remain elusive. Notably, in AT2-derived pulmonary diseases such as COPD and IPF, disruptions in AT2 differentiation are observed, suggesting alterations may exist in the regulation of fate plasticity. Therefore, a refined model describing the regulation of AT2 fate plasticity is needed, along with an assessment of the model's conservation across murine and human AT2s. METHODS: We performed scRNA-sequencing, ATAC-seq, and bioinformatic analysis on samples across murine lung development and validating findings by immunostaining of embryonic lungs. We conducted organotypic cultures as well as genetically engineered mouse model experiments to assess changes in AT2 fate plasticity in. Further, we established a Mayo Clinic patient lung cell biorepository from patient tissue derived AT2s. In parallel, we performed long read scRNA-sequencing for isoform discovery, organotypic culture and immunostaining in human AT2 organoids, to characterize the presence of similar regulatory mechanisms. RESULTS: Throughout the late embryonic and early perinatal period, we found a window of fate plasticity exists in AT2s whereby they retain the capacity to give rise to AT1s, and that its being closed over time by the bZIP transcription factor C/EBPα, as its genetic deletion in AT2s results in regaining fate plasticity. By ATAC-seq and ChIP-seq, we found C/EBPα binds closely to the Dlk1 locus, a Notch signaling regulator implicated in AT2-to-AT1 conversion that is upregulated following Cebpa deletion. Following adult lung injury, we found C/EBPα downregulation is required for re-accessing AT2 fate plasticity and is likely mediated by the dominant negative C/EBP family member CHOP. Finally, we observe Cebpa loss also activates a “defender” AT2 state enriched in interferon stimulated antipathogenic gene expression that is distinct from its reparative state and propose AT2s can toggle between these states following infection to robustly protect and repair alveoli.Further, we validated the presence of C/EBPα and absence of Dlk1 in human AT2s isolated from healthy adult patients, which persists following in vitro expansion. We conclude that AT2 cells window of fate plasticity is dictated by a molecular circuit involving C/EBPα suppressing and Dlk1. Future works aim to remove C/EBPα in human AT2s to reopen their fate plasticity for cell therapy.