The Effect of Protease-Activated Receptor-1 (PAR-1) Inhibition on Endothelial-Related Biomarkers in Patients with Coronary Artery Disease

Background: Vorapaxar has been shown to reduce cardiovascular mortality in postmyocardial infarction (MI) patients. Pharmacodynamic biomarker research related to protease-activated receptor-1 (PAR-1) inhibition with vorapaxar in humans has short follow-up (FU) duration and is mainly focused on platelets rather than endothelial cells. Aim: This article assesses systemic changes in endothelial-related biomarkers during vorapaxar treatment compared with placebo at 30 days’ FU and beyond, in patients with coronary heart disease. Methods: Local substudy patients in Norway were included consecutively from two randomized controlled trials; post-MI subjects from TRA2P-TIMI 50 and non-ST-segment elevation MI (NSTEMI) patients from TRACER. Aliquots of citrated blood were stored at–80°C. Angiopoietin-2, angiopoietin-like 4, vascular endothelial growth factor, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, von Willebrand factor, thrombomodulin, and plasminogen activator inhibitor-1 and -2 were measured at 1-month FU and at study completion (median 2.3 years for pooled patients). Results: A total of 265 consecutive patients (age median 62.0, males 83%) were included. Biomarkers were available at both FUs in 221 subjects. In the total population, angiopoietin-2 increased in patients on vorapaxar as compared with placebo at 1-month FU (p ¼ 0.034). Angiopoietin-like 4 increased (p ¼ 0.028) and plasminogen activator inhibitor-2 decreased (p ¼ 0.025) in favor of vorapaxar at final FU. In postMI subjects, a short-term increase in E-selectin favoring vorapaxar was observed, p ¼ 0.029. Also, a short-term increase in von Willebrand factor (p ¼ 0.032) favoring vorapaxar was noted in NSTEMI patients. Conclusion: Significant endothelial biomarker changes during PAR-1 inhibition were observed in post-MI and NSTEMI patients.publishedVersio

The Effect of Protease-Activated Receptor-1 (PAR-1) Inhibition on Endothelial-Related Biomarkers in Patients with Coronary Artery Disease

Abstract Background: Vorapaxar has been shown to reduce cardiovascular mortality in postmyocardial infarction (MI) patients. Pharmacodynamic biomarker research related to protease-activated receptor-1 (PAR-1) inhibition with vorapaxar in humans has short follow-up (FU) duration and is mainly focused on platelets rather than endothelial cells. Aim: This article assesses systemic changes in endothelial-related biomarkers during vorapaxar treatment compared with placebo at 30 days’ FU and beyond, in patients with coronary heart disease. Methods: Local substudy patients in Norway were included consecutively from two randomized controlled trials; post-MI subjects from TRA2P-TIMI 50 and non-ST-segment elevation MI (NSTEMI) patients from TRACER. Aliquots of citrated blood were stored at–80°C. Angiopoietin-2, angiopoietin-like 4, vascular endothelial growth factor, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, von Willebrand factor, thrombomodulin, and plasminogen activator inhibitor-1 and -2 were measured at 1-month FU and at study completion (median 2.3 years for pooled patients). Results: A total of 265 consecutive patients (age median 62.0, males 83%) were included. Biomarkers were available at both FUs in 221 subjects. In the total population, angiopoietin-2 increased in patients on vorapaxar as compared with placebo at 1-month FU (p ¼ 0.034). Angiopoietin-like 4 increased (p ¼ 0.028) and plasminogen activator inhibitor-2 decreased (p ¼ 0.025) in favor of vorapaxar at final FU. In postMI subjects, a short-term increase in E-selectin favoring vorapaxar was observed, p ¼ 0.029. Also, a short-term increase in von Willebrand factor (p ¼ 0.032) favoring vorapaxar was noted in NSTEMI patients. Conclusion: Significant endothelial biomarker changes during PAR-1 inhibition were observed in post-MI and NSTEMI patients

Predictors of long-term symptom burden and quality of life in patients hospitalised with chest pain: a prospective observational study

Objective: To describe the magnitude and predictors of symptom burden (SB) and quality of life (QoL) 3 months after hospital admission for acute chest pain. Design: Prospective observational study. Setting: Single centre, outpatient follow-up. Participants: 1506 patients. Outcomes: Scores reported for general health (RAND-12), angina-related health (Seattle Angina Questionnaire 7 (SAQ-7)) and dyspnoea (Rose Dyspnea Scale) 3 months after hospital admission for chest pain. Methods: A total of 1506 patients received questionnaires assessing general health (RAND-12), angina-related health (SAQ-7) and dyspnoea (Rose Dyspnea Scale) 3 months after discharge. Univariable and multivariable regression models identified predictors of SB and QoL scores. A mediator analysis identified factors mediating the effect of an unstable angina pectoris (UAP) diagnosis. Results: 774 (52%) responded. Discharge diagnoses were non-ST elevation myocardial infarction (NSTEMI) (14.2%), UAP (17.1%), non-coronary cardiac disease (6.6%), non-cardiac disease (6.3%) and non-cardiac chest pain (NCCP) (55.6%). NSTEMI had the most favourable, and UAP patients the least favourable SAQ-7 scores (median SAQ7-summary; 88 vs 75, p±10%) of an UAP diagnosis for all SAQ-7 and RAND-12 outcomes. Conclusions: Patients with NSTEMI reported the most favourable outcome 3 months after hospitalisation for chest pain. Patients with other diseases, in particular UAP patients, reported lower scores. Revascularised NSTEMI and UAP patients reported higher QoL scores compared with patients receiving conservative treatment. Revascularisation mediated all outcomes in UAP patients.publishedVersio

Arterial Stiffness: A Prognostic Marker in Coronary Heart Disease. Available Methods and Clinical Application

Multiple biomarkers may predict short and long-term prognosis in patients with coronary heart disease, but their impact is limited when used in addition to established risk factors such blood pressure, cholesterol levels, diabetes mellitus, smoking as well as age and sex. Arteries are an integral part of the cardiovascular (CV) system. Arterial stiffness has been shown to be a predictor of cardiovascular events and mortality independent of traditional risk factors. It has also been shown that increased arterial stiffness may predict cardiovascular events in asymptomatic individuals without overt cardiovascular disease. Measuring arterial stiffness may, therefore, identify patients at risk at an early stage. Antihypertensive treatment has been shown to reduce arterial stiffness beyond its antihypertensive effect. Arterial stiffness could, therefore, be a surrogate marker of treatment that relates to prognosis. Arterial stiffness has mostly been used in research protocols, and its use as a prognostic indicator in clinical practice is still uncommon. Several methods exist that can determine parameters related to arterial stiffness, both local and in specific artery beds such as the aorta. In this brief review we present methods to evaluate arterial stiffness, their clinical utility, limitations and the advantages of a novel method, the Cardio-Ankle Vascular Index. Easier and more reproducible methods to evaluate arterial stiffness may increase the use of parameter as a risk factor for coronary heart disease in common clinical practice

Association between symptoms and risk of non-ST segment elevation myocardial infarction according to age and sex in patients admitted to the emergency department with suspected acute coronary syndrome: a single-centre retrospective cohort study

Objectives Evaluate the association between symptoms and risk of non-ST segment elevation myocardial infarction (NSTEMI) in patients admitted to an emergency department with suspected acute coronary syndrome based on sex and age. Design Post hoc analysis of a prospective observational study conducted between September 2015 and May 2019. Setting University hospital in Norway. Participants 1506 participants >18 years of age (39.6% women and 31.0% 70 years of age or older). Findings The OR for NSTEMI was 9.4 if pain radiated to both arms, 3.0 if exertional chest pain was present during the last week and 2.9 if pain occurred during activity. Men had significantly lower OR compared with women if pain was dependent of position, respiration or palpation (OR 0.17 vs 0.53, p value for interaction 0.047). Patients <70 years had higher predictive value than older patients if they reported exertional chest pain the last week (OR 4.08 vs 1.81, 95%, p value for interaction 0.025) and lower if pain radiated to the left arm (OR 0.73 vs 1.67, p value for interaction 0.045). Conclusions Chest pain with radiation to both arms, exertional chest pain during the last week and pain during activity had the strongest predictive value for NSTEMI. The differences in symptom presentation and risk of NSTEMI between sex and age groups were small. Trial registration number WESTCOR study ClinicalTrials.gov (NCT02620202)