Background Natriuretic peptides are routinely quantified to diagnose heart failure (HF). Their concentrations are also elevated in atrial fibrillation (AF). To clarify their value in predicting future cardiovascular events, we measured natriuretic peptides in unselected patients with cardiovascular conditions and related their concentrations to AF and HF status and outcomes. Methods and Results Consecutive patients with cardiovascular conditions presenting to a large teaching hospital underwent clinical assessment, 7‐day ECG monitoring, and echocardiography to diagnose AF and HF. NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) was centrally quantified. Based on a literature review, four NT‐proBNP groups were defined (<300, 300–999, 1000–1999, and ≥2000 pg/mL). Clinical characteristics and NT‐proBNP concentrations were related to HF hospitalization or cardiovascular death. Follow‐up data were available in 1616 of 1621 patients (99.7%) and analysis performed at 2.5 years (median age, 70 [interquartile range, 60–78] years; 40% women). HF hospitalization or cardiovascular death increased from 36 of 488 (3.2/100 person‐years) in patients with neither AF nor HF, to 55 of 354 (7.1/100 person‐years) in patients with AF only, 92 of 369 (12.1/100 person‐years) in patients with HF only, and 128 of 405 (17.7/100 person‐years) in patients with AF plus HF ( P <0.001). Higher NT‐proBNP concentrations predicted the outcome in patients with AF only (C‐statistic, 0.82; 95% CI, 0.77–0.86; P <0.001) and in other phenotype groups (C‐statistic in AF plus HF, 0.66; [95% CI, 0.61–0.70]; P <0.001). Conclusions Elevated NT‐proBNP concentrations predict future HF events in patients with AF irrespective of the presence of HF, encouraging routine quantification of NT‐proBNP in the assessment of patients with AF.
Background Large-scale screening for atrial fibrillation (AF) requires reliable methods to identify at-risk populations. Using an experimental semi-quantitative biomarker assay, B-type natriuretic peptide (BNP) and fibroblast growth factor 23 (FGF23) were recently identified as the most suitable biomarkers for detecting AF in combination with simple morphometric parameters (age, sex, and body mass index [BMI]). In this study, we validated the AF model using standardised, high-throughput, high-sensitivity biomarker assays. Methods and findings For this study, 1,625 consecutive patients with either (1) diagnosed AF or (2) sinus rhythm with CHA2DS2-VASc score of 2 or more were recruited from a large teaching hospital in Birmingham, West Midlands, UK, between September 2014 and February 2018. Seven-day ambulatory ECG monitoring excluded silent AF. Patients with tachyarrhythmias apart from AF and incomplete cases were excluded. AF was diagnosed according to current clinical guidelines and confirmed by ECG. We developed a high-throughput, high-sensitivity assay for FGF23, quantified plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and FGF23, and compared results to the previously used multibiomarker research assay. Data were fitted to the previously derived model, adjusting for differences in measurement platforms and known confounders (heart failure and chronic kidney disease). In 1,084 patients (46% with AF; median [Q1, Q3] age 70 [60, 78] years, median [Q1, Q3] BMI 28.8 [25.1, 32.8] kg/m2, 59% males), patients with AF had higher concentrations of NT-proBNP (median [Q1, Q3] per 100 pg/ml: with AF 12.00 [4.19, 30.15], without AF 4.25 [1.17, 15.70]; p < 0.001) and FGF23 (median [Q1, Q3] per 100 pg/ml: with AF 1.93 [1.30, 4.16], without AF 1.55 [1.04, 2.62]; p < 0.001). Univariate associations remained after adjusting for heart failure and estimated glomerular filtration rate, known confounders of NT-proBNP and FGF23. The fitted model yielded a C-statistic of 0.688 (95% CI 0.656, 0.719), almost identical to that of the derived model (C-statistic 0.691; 95% CI 0.638, 0.744). The key limitation is that this validation was performed in a cohort that is very similar demographically to the one used in model development, calling for further external validation. Conclusions Age, sex, and BMI combined with elevated NT-proBNP and elevated FGF23, quantified on a high-throughput platform, reliably identify patients with AF. Trial registration Registry IRAS ID 97753 Health Research Authority (HRA), United Kingdom
ObjectiveThe pharmacological management of atrial fibrillation (AF) comprises anticoagulation, for stroke prophylaxis, and rate or rhythm control drugs to alleviate symptoms and prevent heart failure. The aim of this study was to investigate trends in the proportion of patients with AF prescribed pharmacological therapies in the UK between 2008 and 2018.MethodsEleven sequential cross-sectional analyses were performed yearly from 2008 to 2018. Data were derived from an anonymised UK primary care database. Outcomes were the proportion of patients with AF prescribed anticoagulants, rhythm and rate control drugs in the whole cohort, those at high risk of stroke and those with coexisting heart failure.ResultsBetween 2008 and 2018, the proportion of patients prescribed anticoagulants increased from 45.3% (95% CI 45.0% to 45.7%) to 71.1% (95% CI 70.7% to 71.5%) driven by increased prescription of non-vitamin K antagonist anticoagulants. The proportion of patients prescribed rate control drugs remained constant between 2008 and 2018 (69.3% (95% CI 68.9% to 69.6%) to 71.6% (95% CI 71.2% to 71.9%)). The proportion of patients prescribed rhythm control therapy by general practitioners (GPs) decreased from 9.5% (95% CI 9.3% to 9.7%) to 5.4% (95% CI 5.2% to 5.6%).ConclusionsThere has been an increase in the proportion of patients with AF appropriately prescribed anticoagulants following National Institute for Health and Care Excellence and European Society of Cardiology guidelines, which correlates with improvements in mortality and stroke outcomes. Beta-blockers appear increasingly favoured over digoxin for rate control. There has been a steady decline in GP prescribing rates for rhythm control drugs, possibly related to concerns over efficacy and safety and increased availability of AF ablation.
Introduction Aspirin and a potent platelet P2Y12 inhibitor, such as prasugrel or ticagrelor, are not always sufficient to prevent thrombus formation in patients with ST-elevation MI (STEMI), leading to “slow flow” or “no reflow” effects after stenting. GPIIb/IIIa inhibitors, such as eptifibatide, may help in this setting, but are not used routinely due to their bleeding risk. GPVI has critical roles in thrombosis and a minimal role in haemostasis. Here we tested whether depletion of GPVI has effects on thrombus formation after MI in an animal model and investigated the effects of a novel platelet GPVI inhibitor, glenzocimab (a Fab fragment of a monoclonal antibody), on platelet activation and thrombus formation when combined with aspirin and ticagrelor. Methods We used intravital microscopy in a murine model of ST-elevation myocardial infarction and ischaemia-reperfusion injury to investigate microvascular thrombosis. We investigated the antithrombotic effects of adding glenzocimab (previously known as ACT017) to blood from healthy donors and 20 patients with ACS treated with aspirin and ticagrelor. We compared the effect of glenzocimab with the GPIIb/IIIa inhibitor eptifibatide ex-vivo. We stimulated platelets with collagen and atherosclerotic plaque material that was sourced from patients undergoing carotid endarterectomy. We investigated effects on platelet aggregation, spreading, signalling, adhesion, thrombin generation, thrombus formation and clot stability ex vivo. Results Genetic depletion of GPVI in an animal model of myocardial infarction reduced microvascular thrombosis. Ex vivo, aspirin and ticagrelor partially inhibited atherosclerotic plaque-induced platelet aggregation (assessed by multiple electrode aggregometry) by 48% compared to control (34±3 vs. 65±4 U; P<0.001; Figure 1). Atherosclerotic plaque-induced platelet aggregation, adhesion, secretion and activation were critically dependent on platelet GPVI activation and were potently inhibited by glenzocimab. Glenzocimab alone reduced atherosclerotic plaque-induced platelet aggregation by 75% compared to control (16±4 vs. 65±4 U; P<0.001; Figure 1) and by over 95% when combined with aspirin and ticagrelor (3±1 vs 65±4 U; P<0.001; Figure 1). Furthermore, glenzocimab provided multiple synergistic antithrombotic effects when added to the blood of aspirin and ticagrelor-treated patients with ACS ex vivo. Glenzocimab and the GPIIb/IIIa inhibitor, eptifibatide, had many similar antithrombotic effects but glenzocimab had less effect on mechanisms of general haemostasis compared to eptifibatide, as assessed by ROTEM (Figure 2). Conclusions The addition of glenzocimab to aspirin and ticagrelor provides synergistic inhibition of multiple critical mechanisms of atherothrombosis. Glenzocimab and the GPIIb/IIIa inhibitor, eptifibatide, share many similar antithrombotic effects, although glenzocimab has less impact on mechanisms involved in haemostasis compared to eptifibatide. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Academy of Medical Sciences UK Clinical Lecturer Starter GrantRoyal Embassy of Saudi Arabia
Background/Introduction Cardiovascular (CV) diseases including atrial fibrillation and arteriosclerosis are associated with impaired cognitive function. Cognitive dysfunction can impact the process of shared clinical decision making, reduce adherence to polypharmacy, and decrease quality of life. The prevalence of cognitive dysfunction in contemporary patients with CV diseases and its implication on future CV events is not well known. Purpose We 1) quantified cognitive function in patients presenting to hospital with CV diseases, 2) identified clinical variables and blood biomarkers associated with cognitive dysfunction, and 3) quantified the hazard of abnormal cognitive function for predicting MACCE (major adverse CV and cerebrovascular events). Methods and results Of 1625 consecutive patients presenting acutely to a large teaching hospital with CV diseases, 614 patients (median age [Q1, Q3] 68 [58, 76] years; 66% male) who completed the Montreal Cognitive Assessment (MoCA) were analysed. The median [Q1, Q3] MoCA score was 25 points [21, 27]. 360 patients (59%) had an abnormal score (<26). At baseline, patients with abnormal scores were more likely to be female (odds ratio, OR [95% confidence intervals], 1.874 [1.287, 2.728]), have BMI<30 (OR 0.584 [0.410, 0.831]), heart failure (OR 1.492 [1.043, 2.135]), diabetes (OR 2.212 [1.529, 3.199]), chronic kidney disease (CKD-EPI<60 ml/min, OR 1.553 [1.021, 2.361]), and have more CV co-morbidities (OR per additional co-morbidity 1.415 [1.246, 1.605]). Amongst 12 CV biomarkers tested, elevated Bone Morphogenetic Protein 10 (OR 1.325 [1.022, 1.719]) and Growth Differentiation Factor 15 (OR 1.419 [1.054, 1.912]) increased odds of abnormal scores. Cox proportional hazards model adjusted for competing risk of non-CV death assessed the relationship between abnormal cognitive function and MACCE (stroke, TIA, myocardial infarction, hospitalisation for heart failure, CV death). Follow-up time ranged from 2.7 to 6.1 years. Patients were censored at 2.5 years for this analysis. 130 out of 614 patients experienced a MACCE (21%) and 71 had a non-CV death (12%). Patients with abnormal MoCA scores were at higher risk for MACCE (subhazard ratio, sHR [95% CI] 1.827 [1.253, 2.664]). The hazard remained significant after adjustment for age, sex, obesity, atrial fibrillation, stroke, heart failure, hypertension, coronary artery disease, diabetes, peripheral artery disease and renal dysfunction (sHR 1.367 [1.056, 2.326]; Figure). All-cause mortality was 1.785 times higher for those with abnormal MoCA scores [1.061, 3.002]. Conclusion In this study, 3 out of 5 patients with CV diseases had abnormal MoCA scores at baseline. Abnormal cognitive scores significantly predicted patients who went on to experience a MACCE within 2.5 years of follow-up. These observations call for further research and action to provide additional diagnostics, support and early intervention to address cognitive dysfunction in CV patients. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): EU H2020 CATCH ME Cumulative incidence function
Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): CATCH ME European Commission H2020 grant (no. 633196) Background Several novel blood biomarkers were recently found to reflect underlying pathophysiology implicated in atrial fibrillation (AF). These biomarkers could be used for stratifying patients at risk of developing AF or AF-related adverse events. Purpose We combined 9 clinical risk factors and 12 biomarkers to model composite outcomes of 1) incident AF, hospitalisation for arrhythmias, and cardiovascular death in sinus rhythm patients at risk of AF, and 2) recurrent AF, hospitalisation for arrhythmias, and cardiovascular death in patients with AF. Methods 1455 patients presenting acutely to hospital with either diagnosed AF (n = 648) or sinus rhythm and ≥2 CHA2DS2-VASc risk factors (n = 807, silent AF ruled out by 7-day ECG monitoring) were followed up for two years. Outcomes were collected from linked hospital episode statistics (HES) and Office of National Statistics (ONS) data from NHS Digital. We univariately evaluated 12 cardiovascular biomarkers quantified from EDTA plasma collected at baseline (ANG2, BMP10, CA125, CRP, ESM1, FABP3, FGF23, GDF15, IGFBP7, IL6, NTproBNP, Troponin T). Two predictive models combining clinical characteristics and biomarkers were developed for each patient group, using Cox regression with backward elimination and considering non-cardiovascular death as a competing risk. Results In sinus rhythm patients (n = 117/807 with outcome), elevated BMP10, ANG2, CA125, IGFBP7, NTproBNP univariately predicted the composite outcome (adjusted for age, sex, body mass index (BMI), eGFR, heart failure, stroke/TIA, hypertension, diabetes, coronary artery disease – see Figure part A). In the combined model, age, prior stroke/TIA, coronary artery disease, ANG2, IGFBP7 and NTproBNP predicted the outcome (C-statistic [95% confidence interval (CI)] 0.733 [0.683, 0.784]). In patients with AF (n = 193/648 with outcome), elevated BMP10, ANG2, CA125, troponin T, GDF15, IGFBP7, NTproBNP univariately predicted the composite outcome (adjusted for same variables as above – see Figure part B). In the combined model, high BMI, low eGFR, hypertension, IGFBP7, NTproBNP and troponin T were predictive of the composite outcome (C-statistic [95% CI]: 0.643 [0.596, 0.689]). Conclusion Combinations of clinical risk factors and biomarkers were predictive of two-year AF-related adverse events in sinus rhythm patients at risk of AF and in patients with AF. These markers could be used to identify patients for more intensive follow-up or therapy. IGFBP7 and NTproBNP were present in both models, implicating pathways involved with cardiac overload, inflammation, and oxidative stress. These findings call for external validation of these markers and prospective evaluation in at-risk populations. Abstract Figure. Biomarkers predicting 2-year AF outcomes
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