Dataset Information

A Platelet Reactivity ExpreSsion Score derived from patients with peripheral artery disease predicts cardiovascular risk.

ABSTRACT: Platelets are key mediators of atherothrombosis, yet, limited tools exist to identify individuals with a hyperreactive platelet phenotype. In this study, we investigate the association of platelet hyperreactivity and cardiovascular events, and introduce a tool, the Platelet Reactivity ExpreSsion Score (PRESS), which integrates platelet aggregation responses and RNA sequencing. Among patients with peripheral artery disease (PAD), those with a hyperreactive platelet response (>60% aggregation) to 0.4 µM epinephrine had a higher incidence of the 30 day primary cardiovascular endpoint (37.2% vs. 15.3% in those without hyperreactivity, adjusted HR 2.76, 95% CI 1.5-5.1, p = 0.002). PRESS performs well in identifying a hyperreactive phenotype in patients with PAD (AUC [cross-validation] 0.81, 95% CI 0.68 -0.94, n = 84) and in an independent cohort of healthy participants (AUC [validation] 0.77, 95% CI 0.75 -0.79, n = 35). Following multivariable adjustment, PAD individuals with a PRESS score above the median are at higher risk for a future cardiovascular event (adjusted HR 1.90, CI 1.07-3.36; p = 0.027, n = 129, NCT02106429). This study derives and validates the ability of PRESS to discriminate platelet hyperreactivity and identify those at increased cardiovascular risk. Future studies in a larger independent cohort are warranted for further validation. The development of a platelet reactivity expression score opens the possibility for a personalized approach to antithrombotic therapy for cardiovascular risk reduction.

SUBMITTER: Berger JS

PROVIDER: S-EPMC11336089 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A Platelet Reactivity ExpreSsion Score derived from patients with peripheral artery disease predicts cardiovascular risk.

Berger Jeffrey S JS Cornwell Macintosh G MG Xia Yuhe Y Muller Matthew A MA Smilowitz Nathaniel R NR Newman Jonathan D JD Schlamp Florencia F Rockman Caron B CB Ruggles Kelly V KV Voora Deepak D Hochman Judith S JS Barrett Tessa J TJ

Nature communications 20240820 1

Platelets are key mediators of atherothrombosis, yet, limited tools exist to identify individuals with a hyperreactive platelet phenotype. In this study, we investigate the association of platelet hyperreactivity and cardiovascular events, and introduce a tool, the Platelet Reactivity ExpreSsion Score (PRESS), which integrates platelet aggregation responses and RNA sequencing. Among patients with peripheral artery disease (PAD), those with a hyperreactive platelet response (>60% aggregation) to ...[more]

PMID: 39164233

Similar Datasets

Project description:BackgroundPrecision estimation of cardiovascular risk remains the cornerstone of atherosclerotic cardiovascular disease (ASCVD) prevention. While coronary artery calcium (CAC) scoring is the best available non-invasive quantitative modality to evaluate risk of ASCVD, it excludes risk related to prior myocardial infarction, cardiomyopathy, and arrhythmia which are implicated in ASCVD. The high-dimensional and inter-correlated nature of ECG data makes it a good candidate for analysis using machine learning techniques and may provide additional prognostic information not captured by CAC. In this study, we aimed to develop a quantitative ECG risk score (eRiS) to predict major adverse cardiovascular events (MACE) alone, or when added to CAC. Further, we aimed to construct and validate a novel nomogram incorporating ECG, CAC and clinical factors for ASCVD.MethodsWe analyzed 5,864 patients with at least 1 cardiovascular risk factor who underwent CAC scoring and a standard ECG as part of the CLARIFY study (ClinicalTrials.gov Identifier: NCT04075162). Events were defined as myocardial infarction, coronary revascularization, stroke or death. A total of 649 ECG features, consisting of measurements such as amplitude and interval measurements from all deflections in the ECG waveform (53 per lead and 13 overall) were automatically extracted using a clinical software (GE Muse™ Cardiology Information System, GE Healthcare). The data was split into 4 training (Str) and internal validation (Sv) sets [Str (1): Sv (1): 50:50; Str (2): Sv (2): 60:40; Str (3): Sv (3): 70:30; Str (4): Sv (4): 80:20], and the results were compared across all the subsets. We used the ECG features derived from Str to develop eRiS. A least absolute shrinkage and selection operator-Cox (LASSO-Cox) regularization model was used for data dimension reduction, feature selection, and eRiS construction. A Cox-proportional hazards model was used to assess the benefit of using an eRiS alone (Mecg), CAC alone (Mcac) and a combination of eRiS and CAC (Mecg+cac) for MACE prediction. A nomogram (Mnom) was further constructed by integrating eRiS with CAC and demographics (age and sex). The primary endpoint of the study was the assessment of the performance of Mecg, Mcac, Mecg+cac and Mnom in predicting CV disease-free survival in ASCVD.FindingsOver a median follow-up of 14 months, 494 patients had MACE. The feature selection strategy preserved only about 18% of the features that were consistent across the various strata (Str). The Mecg model, comprising of eRiS alone was found to be significantly associated with MACE and had good discrimination of MACE (C-Index: 0.7, p = <2e-16). eRiS could predict time-to MACE (C-Index: 0.6, p = <2e-16 across all Sv). The Mecg+cac model was associated with MACE (C-index: 0.71). Model comparison showed that Mecg+cac was superior to Mecg (p = 1.8e-10) or Mcac (p < 2.2e-16) alone. The Mnom, comprising of eRiS, CAC, age and sex was associated with MACE (C-index 0.71). eRiS had the most significant contribution, followed by CAC score and other clinical variables. Further, Mnom was able to identify unique patient risk-groups based on eRiS, CAC and clinical variables.ConclusionThe use of ECG features in conjunction with CAC may allow for improved prognostication and identification of populations at risk. Future directions will involve prospective validation of the risk score and the nomogram across diverse populations with a heterogeneity of treatment effects.

Project description:Background and aimsPeripheral artery disease (PAD) is a systemic manifestation of atherosclerosis that is associated with a high risk of major adverse cardiovascular events (MACE). LDL aggregation contributes to atherosclerotic plaque progression and may contribute to plaque instability. We aimed to determine if LDL aggregation is associated with MACE in patients with PAD undergoing lower extremity revascularization (LER).MethodsTwo hundred thirty-nine patients with PAD undergoing LER had blood collected at baseline and were followed prospectively for MACE (myocardial infarction, stroke, cardiovascular death) for one year. Nineteen age, sex and LDL-C-matched control subjects without cardiovascular disease also had blood drawn. Subject LDL was exposed to sphingomyelinase and LDL aggregate size measured via dynamic light scattering.ResultsMean age was 72.3 ± 10.9 years, 32.6% were female, and LDL-cholesterol was 68 ± 25 mg/dL. LDL aggregation was inversely associated with triglycerides, but not associated with demographics, LDL-cholesterol or other risk factors. Maximal LDL aggregation occurred significantly earlier in subjects with PAD than in control subjects. 15.9% of subjects experienced MACE over one year. The 1st tertile (shortest time to maximal aggregation) exhibited significantly higher MACE (25% vs. 12.5% in tertile 2 and 10.1% in tertile 3, p = 0.012). After multivariable adjustment for demographics and CVD risk factors, the hazard ratio for MACE in the 1st tertile was 4.57 (95% CI 1.60-13.01; p = 0.004) compared to tertile 3. Inclusion of LDL aggregation in the Framingham Heart Study risk calculator for recurrent coronary heart disease events improved the c-index from 0.57 to 0.63 (p = 0.01).ConclusionsWe show that in the setting of very well controlled LDL-cholesterol, patients with PAD with the most rapid LDL aggregation had a significantly elevated MACE risk following LER even after multivariable adjustment. This measure further improved the classification specificity of an established risk prediction tool. Our findings support broader investigation of this assay for risk stratification in patients with atherosclerotic CVD.

Project description:BACKGROUND:Peripheral artery disease (PAD), a diffuse manifestation of atherothrombosis, is a major cardiovascular threat. Although platelets are primary mediators of atherothrombosis, their role in the pathogenesis of PAD remains unclear. OBJECTIVES:The authors sought to investigate the role of platelets in a cohort of symptomatic PAD. METHODS:The authors profiled platelet activity, mRNA, and effector roles in patients with symptomatic PAD and in healthy controls. Patients with PAD and carotid artery stenosis were recruited into ongoing studies (NCT02106429 and NCT01897103) investigating platelet activity, platelet RNA, and cardiovascular disease. RESULTS:Platelet RNA sequence profiling mapped a robust up-regulation of myeloid-related protein (MRP)-14 mRNA, a potent calcium binding protein heterodimer, in PAD. Circulating activated platelets were enriched with MRP-14 protein, which augmented the expression of the adhesion mediator, P-selectin, thereby promoting monocyte-platelet aggregates. Electron microscopy confirmed the firm interaction of platelets with monocytes in vitro and colocalization of macrophages with MRP-14 confirmed their cross talk in atherosclerotic manifestations of PAD in vivo. Platelet-derived MRP-14 was channeled to monocytes, thereby fueling their expression of key PAD lesional hallmarks and increasing their directed locomotion, which were both suppressed in the presence of antibody-mediated blockade. Circulating MRP-14 was heightened in the setting of PAD, significantly correlated with PAD severity, and was associated with incident limb events. CONCLUSIONS:The authors identified a heightened platelet activity profile and unraveled a novel immunomodulatory effector role of platelet-derived MRP-14 in reprograming monocyte activation in symptomatic PAD. (Platelet Activity in Vascular Surgery and Cardiovascular Events [PACE]; NCT02106429; and Platelet Activity in Vascular Surgery for Thrombosis and Bleeding [PIVOTAL]; NCT01897103).

Dataset Information

A Platelet Reactivity ExpreSsion Score derived from patients with peripheral artery disease predicts cardiovascular risk.

Publications

A Platelet Reactivity ExpreSsion Score derived from patients with peripheral artery disease predicts cardiovascular risk.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets