tbuckley/cabot-search huggingface dataset:
Abstract 4142264: De-escalation of Dual Antiplatelet Therapy by Changing Ticagrelor to Clopidogrel Versus Ticagrelor Monotherapy in Patients With Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention
Authors: Yi-Heng Li, I-Chang Hsieh, Hui-Wen Lin, Sheng-Hsiang Lin
Journal: Circulation (2024)

Background: Two de-escalation options of dual antiplatelet therapy (DAPT) have been proposed to mitigate bleeding risk in patients (pts) with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI), including maintaining DAPT but reducing its intensity by changing potent P2Y12 inhibitor (P2Y12i) to clopidogrel or discontinuation of DAPT by using P2Y12i monotherapy. Our study aims to evaluate the use of de-escalation therapies after discharge in AMI pts undergoing PCI and compare the clinical outcomes of the two de-escalation options. Methods and Results: In the Taiwan National Health Insurance Research Database, we included adult pts (≥ 18 yrs) who received PCI for AMI and survived to discharge with DAPT. Pts who need oral anticoagulant were excluded. From 2011 to 2021, 58989 pts (mean age 61.9±13.2 yrs, male 81.4%) were included. After 2016, &gt;70% pts were treated with aspirin plus ticagrelor (A+T) at discharge. In A+T users (n=28698), de-escalation for any reason occurred in 52.2% during follow-up. Among de-escalation therapy, aspirin plus clopidogrel (A+C, 55.8%) and ticagrelor monotherapy (T mono, 15.5%) were most commonly used in the first 6 mo. The mean duration from discharge to de-escalation to T mono vs. A+C was 52.5±69.3 vs. 68.4±70.7 days (p&lt;0.01). Multivariable logistic regression analysis showed that multi-vessel PCI and bleeding risk at baseline were more likely to receive T mono than A+C. We used inverse probability of treatment weighting (IPTW) to balance all differences and compared the outcomes after de-escalating to T mono vs. A+C (reference) with Cox proportional hazards analysis. Among pts with multi-vessel PCI, the composite ischemic outcome (cardiovascular death, recurrent MI and ischemic stroke) (HR 0.73, 95% CI 0.50-1.05) and the composite major bleeding outcome (major gastrointestinal bleeding and intracerebral hemorrhage) (HR 0.97, 95% CI 0.46-2.06) were similar between the groups. Among pts with bleeding risk (at least 1 ARC-HBR risk factor), the composite ischemic outcome was similar (HR 1.05, 95% CI 0.76-1.44) and the composite major bleeding outcome was also similar (HR 1.78, 95% CI 0.91-3.50). Conclusions: In pts with AMI undergoing PCI initially received A+T, de-escalation was common after discharge. The clinical outcomes were similar after de-escalating to T mono vs. A+C in pts with multi-vessel PCI or bleeding risk. Further randomized trial is needed to confirm our finding.
Abstract 4142260: Single-cell analysis on peripheral blood mononuclear cells reveals immunodeficiency in pediatric patients with conotruncal defects
Authors: Qiyu He, Peng Wang, Huayan Shen, Shoujun Li
Journal: Circulation (2024)

Background: Congenital heart diseases (CHD) are the most common birth defects. Previous studies have revealed the susceptibility of CHD patients to immunodeficiency; however, the heterogeneity of immune cells landscape underlying CHD patients remains poorly understood. Research question: Are peripheral blood mononuclear cells dysregulated in pediatric CHD patients? Aims: We aimed to investigate the landscape of peripheral blood mononuclear cells in CHD patients with conotruncal defects by comparison against healthy controls. Methods: Peripheral blood samples were collected in 5 patients with conotruncal defects and 3 healthy children. We conducted single-cell transcriptome analysis on peripheral blood mononuclear cells from these samples. Results: The scheme of whole study was shown in Figure 1A. A total of 44,530 cells were identified after quality-control, clustered into 8 groups, and annotated with canonical PBMC markers (Figure 1B). Compared with healthy controls, patients were characterized with a prominent decrease in natural killer T (NKT) cells and an increased proportion of monocytes were observed (Figure 1C). Zooming into NK-like cells confirmed a significant contribution of NKT cells in difference between groups, whilst other types were similar in both groups (Figure 2A). The differentially expressed gene in NKT were enriched in pathway involving T helper cells differentiation, signal transduction and regulation (Figure 2B). Furthermore, NKT in patients showed a significantly lower proliferation score in contrast with a higher apoptosis score (Figure 2C&amp;D). Although monocytes in patients were more in quantity, the composition of CD14 + and CD16 + subtypes were comparable between groups (Figure 3A). Concordantly, apoptosis score of monocytes were similar. However, the T cell proliferation score was lower in case group (Figure 3B&amp;C). In addition, CD14 + and CD16 + monocytes both showed distinct transcriptome between groups and the differentially expressed genes were prevalently enriched in inflammation-related pathways (Figure 3D&amp;E). Conclusion: Single-cell analysis revealed a dysregulated PBMC landscape in pediatric patients with conotruncal defects, exhibiting a prominent decrease in NKT population and an increased proportion of monocytes. Transcriptome analysis further indicated a less mature immune phenotype in NKT and monocytes differentiation. Future study is warranted to further investigate the roles of these cells on immunoregulation in these patients.
Abstract 4142679: Involvement of PCSK9 in progression of coronary atherosclerosis through molecular mechanisms beyond LDL-cholesterol regulation in patients with chronic coronary disease.
Authors: Rosetta Ragusa, Silvia Rocchiccioli, Serena Del Turco, Antonio Morlando, Giuseppina Basta, Danilo Neglia, Chiara Caselli
Journal: Circulation (2024)

Background: PCSK9, a key regulator of serum LDL-cholesterol levels, is associated with presence and severity of atherosclerosis, but data on the association between PCSK9 and coronary disease progression are lacking . Hypothesis: Beyond the well-known role on the LDL-C regulation, PCSK9 has been hypothesized to interfere with inflammation and endothelial function affecting atherogenesis. Aims: The purpose of the present study is to evaluate whether PCSK9 is associated with coronary plaque progression in patients with chronic coronary disease (CCD) and to assess its molecular involvement on fundamental processes conditioning the atherosclerotic process. Approach: PCSK9 plasma levels were measured in 202 CCD patients (68±7 years of age; 58% males) undergoing coronary computed tomography angiography at baseline and after a follow up period of 6.5±1.1 years to assess progression of Total, Fibrous, Fibro-fatty, Necrotic Core, and Dense Calcium plaque volumes (PV). Molecular pathways linked with PCSK9 were further studied by RNA-sequencing of whole blood and in vitro studies using Human Umbilical Vein Endothelial Cells (HUVEC). Results: PCSK9 plasma levels were positively related with LDL-C and HDL-C as well as ICAM1, IL6 and MMP9 (Fig A). At multivariate analysis, plasma PCSK9 was associated with annual increase of Necrotic Core PV (Coefficient 3.499, SE 1.507, P=0.022), independently from cardiovascular risk factors, LDL-C, and statin use (Fig B). At RNA-seq analysis, plasma PCSK9 was linked to the expression of genes involved in the regulation of innate-immuno response and cytokine mediated signal pathways (Fig C). A significant increase in ICAM-1, VCAM-1, MCP1 and IL6 expression was observed after treatment of HUVEC with increasing concentration of PCSK9 (Fig D). Conclusion: In CCD patients, PCSK9 is independently associated with progression of necrotic core PV, possibly reflecting the activity on inflammatory/endothelial pathways conditioning adverse plaque phenotypes. Understanding these mechanisms might shed further light on the therapeutic benefits of PCSK9 inhibitors beyond LDL-C regulation.
Abstract 4142656: The Lack of Sphingosine Kinase 1 in Smooth Muscle Cells Protects Mice Against Angiotensin II-Induced Hypertension
Authors: Ewelina Jozefczuk, Piotr Szczepaniak, Tomasz Mikolajczyk, Ryszard Nosalski, Karol Urbanski, Emilia Wojciechowska, Grzegorz Filip, Monika Stefanska, Przemyslaw Blyszczuk, Tomasz Guzik, Mateusz Siedlinski
Journal: Circulation (2024)

Introduction: The function of the cardiovascular system is regulated by sphingosine-1-phosphate (S1P) signaling. Vascular sphingosine kinase 1 (Sphk1), an S1P-producing enzyme, is upregulated in hypertension (HTN), and mice lacking Sphk1 globally exhibit alleviated AngII-induced HTN. Identifying cellular mechanisms providing this protection remains challenging due to the pleiotropic action of S1P. Aim: To identify the contributions of Sphk1 within endothelial cells (ECs) or vascular smooth muscle cells (SMCs) to the blood pressure-lowering effect of global Sphk1 deletion in mice. Methods: Mice lacking Sphk1 either in SMCs or ECs were generated using the Cre-loxP system. Male mice were infused with AngII (490 ng/min/kg for 14 days), using osmotic minipumps, to induce HTN. Systolic blood pressure (SBP) was monitored, and vascular structure and function were examined ex vivo using wire/pressure myography and histological analysis. To identify key mechanistic pathways, RNA Sequencing was performed in mouse aortas and mesenteric arteries, followed by Gene set enrichment analysis. The expression patterns of the identified genes were confirmed by RT-qPCR and Western Blotting in mouse arteries and human internal mammary arteries (IMAs). Results: The lack of Sphk1 in SMC conferred significant protection against HTN (mean SBP±SD 132±14.6 mmHg vs. 168±14.3 mmHg as compared to WT flox/flox control, p&lt;0.05, Fig. 1), while EC KO- Sphk1 developed HTN to the same extent as WT flox/flox controls (mean SBP±SD: 166±22.8 mmHg vs. 171±27.7 mmHg respectively). Lower SBP in SMC KO- Sphk1 in HTN was associated with a significantly reduced myogenic tone of mesenteric arteries and lower expression of Rock1/2. In spite of impaired HTN development, mesenteric arteries of AngII-infused SMC KO- Sphk1 mice were significantly stiffer and showed impaired vasorelaxations compared to the control arteries of AngII-infused WT mice, which was associated with excessive fibronectin 1 deposition. Likewise, an inverse correlation between FN1 and SPHK1 protein expression was observed in human IMAs. Conclusion: Our findings indicate a prevailing role of SMC-derived Sphk1 in the regulation of myogenic tone as an important molecular regulator of AngII-induced HTN.
Abstract 4142374: The Impacts of Achieved Blood Pressure During the First 12 hours on Clinical Outcomes in Patients with Out-of-hospital Cardiac Arrest
Authors: Chen-Hsi Chang, Shih-Neng Lin, Chin-Chou Huang
Journal: Circulation (2024)

Background: Out-of-hospital cardiac arrest (OHCA) typically results in low survival rates and undesirable neurological outcome. There is a significant correlation between mean arterial pressure (MAP) levels after the return of spontaneous circulation (ROSC) and the outcomes of OHCA patients, yet the optimal blood pressure target remains unclear. This study explores how achieved blood pressure within the initial 12 hours after ROSC impacts the clinical outcomes of OHCA patients. Methods: We conducted a retrospective analysis of patients who experienced OHCA and achieved ROSC. Patients were divided into three tertiles based on the distribution of patient numbers, with each tertile defined as follows: MAP &lt; 80 mmHg, 80 mmHg ≤ MAP &lt; 95 mmHg, and MAP ≥ 95 mmHg. MAP levels were measured within the first 12 hours. Mortality and cerebral performance category (CPC) were utilized in the study to assess the clinical outcomes at 30 days post-OHCA event. Results: A total of 231 non-traumatic OHCA patients who survived for 12 hours after ROSC were enrolled. Among the three tertiles (n = 77 in each), significant difference in mortality and CPC score were found between tertile 1 and the remaining two tertiles, but no notable difference were observed between tertile 2 and 3. Higher MAP level, specifically target MAP ≥ 80 mmHg (hazard ratio [HR]: 0.960, 95% confidence interval [CI]: 0.949-0.971, P &lt; 0.001) was associated with lower 30-day mortality. Additionally, a higher MAP level with target MAP ≥ 80 mmHg within the first 12 hours was correlated with better neurological outcomes (odd ratio [OR]: 0.370, 95% CI: 0.147-0.935, P = 0.035). Conclusions: MAP levels within the initial 12 hours after ROSC is a practical predictor of 30-day mortality and neurological outcomes among OHCA patients. Maintaining MAP levels above 80mmHg exhibits strong correlation with short-term outcomes improvement in the early post-arrest period.
Abstract 4142532: Vasovagal Syncope Due to Tonsillar Malignancy
Authors: Purnima Gurung, Yicheng Tang, Cy Kim, Michael Paikal
Journal: Circulation (2024)

Introduction: Vasovagal syncope occurs when an overwhelming parasympathetic tone is triggered by causes including emotion, pain, or baroreceptor stimulation. We present a rare case of vasovagal syncope mediated by locally invasive tonsillar squamous cell carcinoma (SCC). Case: A 66 year old man with untreated L tonsillar SCC presented with recurrent syncope, hypotension, sinus bradycardia and sinus arrest up to 6 seconds as observed on telemetry (figure 1, bottom). Symptoms were atropine responsive and reliably reproduced with head turning to the L or palpation. CT neck (figure 1A-B) showed extension of the tumor into the L carotid body and adjacent vagal sheath. Echocardiogram revealed no structural heart disease. Pacemaker implantation was deferred due to suspected reversible vasovagal mechanism. He received a course of steroids, targeted cancer therapy with weekly Cetuximab infusion and daily radiation to the neck mass. After treatment initiation, the patient remained hospitalized for 3 days with no recurrent syncope or bradycardia observed. He continued outpatient treatments with resolution of his neck mass (figure 1C-D) and had no syncopal episodes over the next year. Discussion: We highlight this case as an example of locally invasive tumor causing mechanical disruption of the carotid body and neural reflex stimulation via the vagal sheath. When associated with vasovagal syncope, this phenomenon has been previously named carotid body syndrome. Although vasovagal mechanism remains the most common cause of syncope, diagnosis and treatment can prove challenging, particularly due to variable demonstration of vasodepressor and cardioinhibitory reflexes amongst individual patients. Treatment of vasovagal syncope focuses on trigger avoidance and treatment for predisposing conditions. Pacemaker implantation remains controversial and may be offered to patients with predominantly cardioinhibitory reflex and high-risk recurrent syncope, with a possible role for implantable cardiac monitoring. In this case, the management strategy was guided by association of symptoms with head turning, and treatment of the culprit neoplastic process yielded resolution of vasovagal syncope with avoidance of device implantation.
Abstract 4142554: Prevalently carried HLA allele associates with inflammation and poor prognosis in HF patients via co-stimulatory and MHC-II enhanceosome regulation
Authors: Wesley Abplanalp, Maximilian Merten, Sebastian Cremer, Tina Rasper, Emina Mustafic, Mariano Ruz Jurado, David John, Valentina Puntmann, Eike Nagel, Jaya Krishnan, Tomasz Guzik, Mateusz Siedlinski, Andreas Zeiher, Stefanie Dimmeler
Journal: Circulation (2024)

Background: Cardiovascular diseases, including chronic heart failure with reduced ejection fraction (HFrEF), pose a substantial global health burden, emphasizing the need for better understanding of their genetic and immune-related mechanisms. While the immune system, particularly human leukocyte antigens (HLAs), has garnered attention in cardiovascular research, their specific role in HFrEF remains unclear. This study aims to explore the association between HLA alleles and cardiovascular risk in HFrEF, focusing on disease progression, prognosis, and underlying mechanisms. Methods and Results: Ninety-six chronic HFrEF patients underwent four-digit HLA typing analysis in a case-control study. Analysis of HLA alleles revealed the HLA-DR2 family (mostly HLA-DRB5*0101) carried by 14 patients (15.1%). HLA-DR2 showed the highest significant association with mortality. Additional cohort analysis confirmed elevated cardiac injury markers, including Troponin T, in HLA-DR2 carriers, independent of renal function. Multivariate analysis revealed a higher incidence of myocardial infarction in DRB5 carriers, while non-carriers had higher associations with stroke, CKD, and hyperuricemia. Analysis of 3000 plasma proteins from 30,000 UK participants also showed increased inflammatory (TIMD4,CD80) and CV risk associated (IGFBP7) markers were strongly elevated in HLA-DR2 subjects. Mechanistic insights were obtained through CITE-seq analysis of immune cells from HLA-DR2 carriers and non-carriers, revealing enhanced antigen presentation and pro-inflammatory gene expression in carriers. Functional experiments confirmed that silencing HLA-DRB5 in macrophages reduced antigen presentation and T cell activation. HLA-DR2 carriers also exhibited greater T cell activation and polarization, with HLA-DR2 (specifically HLA-DRB5*0101 allele) silencing in dendritic cells diminishing T cell invasion potential into cardiac organoids. Conclusions: This study associates HLA-DR2 alleles, specifically HLA-DRB5*0101, with prognosis in chronic heart failure and myocardial injury, indicating an increased risk for cardiovascular pathology in carriers. These findings underscore the potential of HLA typing for enhancing risk stratification and informing targeted therapies in HFrEF. Further research is warranted to explore targeted treatments for HLA-DRB5 carriers, offering potential avenues for precision medicine in managing heart failure.
Abstract 4142555: Late Gadolinium Enhancement in Childhood Hypertrophic Cardiomyopathy：A Long-term Prognosis Study
Authors: Xingrui Chen, Shujuan Yang, Xuan Ma, Yun Tang, Shihua Zhao
Journal: Circulation (2024)

Background: Myocardial fibrosis could be detected by cardiac MRI (CMR) with late gadolinium enhancement (LGE) which provides important prognostic information of risk stratification for adult hypertrophic cardiomyopathy (HCM). However, in childhood HCM, it remains uncertain the prevalence, pattern of LGE, and whether it is associated with adverse outcomes. Aims: This study aims to explore the characteristics of LGE in childhood HCM and to evaluate the prognostic value of LGE for adverse outcomes. Methods: In this retrospective study, a total of 231 consecutive childhood patients with primary HCM who were ≤18 years of age at diagnosis and underwent contrast-enhanced CMR from January 2011 to December 2019 were enrolled. The extent of LGE was quantified by measuring areas with the increased signal intensity of ≥6 standard deviations above the mean of normal myocardium. The primary outcome included a composite of sudden cardiac death (SCD) or equivalent events (resuscitated sudden cardiac arrest or aborted SCD), heart failure-related events (heart transplantation, death from heart failure, rehospitalization for heart failure). Results: Patients were 15±3 years of age at baseline and 65% were male. During a median follow-up of 61.7 months (IQR:39.2-84.5), 26(11.3%) patients with HCM reached the primary end points, 13 of whom experienced SCD events. LGE was present in 195(84.4%) childhood HCM patients with a median LGE extent 4.77%(IQR:2.01-9.18) and higher in the mid regions. After univariable analysis, multivariable Cox analysis adjusting clinical and cardiac functional factors, LGE extent was an independent predictor for the primary endpoints (HR, 1.11; P&lt;0.01) and SCD event (HR, 1.09; P&lt;0.01). Time-dependent receiver operating characteristic (ROC) analysis showed that LGE extent performed a superior efficacy of the five-year risk prediction of primary endpoints (AUC=0.80) and SCD event (AUC=0.82). Kaplan-Meier analysis showed a significantly increased risk of primary endpoints (log-rank P&lt;0.01) and SCD event (log-rank P&lt;0.01) in high LGE group (LGE extent&gt;mean). LGE extent could improve the predictive model, such as HCM Risk-Kids model (C statistic 0.65 vs 0.79, P=0.011) and PRIMaCY SCD risk prediction model (C statistic 0.61 vs 0.80, P=0.014). Conclusion: LGE assessed by CMR is a common characteristic and an independent predictor of adverse outcomes among childhood HCM, providing incremental value to improve risk stratification in current clinical risk models.
Abstract 4142540: Using Three-Dimensional Strain Deformation Imaging To Quantify Replacement Fibrosis In Hypertrophic Cardiomyopathy
Authors: kunjing pang, Rong Wang, lei song
Journal: Circulation (2024)

Background: Three-dimensional speckle tracking deformation STE (3D-STE) can overcome some limitations of 2D imaging. This study aims to verify the feasibility of using 3D-STE to quantify replacement fibrosis against enhanced cardiac magnetic resonance imaging (CMR-LGE). Method: 3D-STE and the extent of LGE (%LGE) were prospectively measured in a large cohort of HCM patients, with an interval ≦ of 72 hours. Results: 511 HCM patients (age 49.0 ± 14.3 years; 66.5% male) were enrolled. Three-dimensional global longitudinal strain (GLS-3D) moderately correlated with GLS-2D (r=0.622, p=0.000). GLS-3D showed the strongest correlation with %LGE (r = 0.699, p &lt; 0.001). A quadratic model (R2=0.448, p=0.000) for the relationship between GLS-3D and %LGE performed better than a linear model. GLS-3D (OR = 0.632, p &lt; 0.001) was independently associated with extensive LGE (%LGE≧15%). GLS-3D exhibited the highest area under the curve (AUC 0.894, p &lt; 0.001) for detecting extensive LGE With a cutoff of -15.25%, sensitivity 87.3%, specificity 78.3%. Conclusion: GLS-3D is the most strongly correlated with %LGE among all strain parameters, demonstrating potential as a surrogate marker for LGE in HCM.