Atherothrombotic Cardiovascular Disease Research Articles

The Molecular Bases of Anti-Oxidative and Anti-Inflammatory Properties of Paraoxonase 1

The anti-oxidative and anti-inflammatory properties of high-density lipoprotein (HDL) are thought to be mediated by paraoxonase 1 (PON1), a calcium-dependent hydrolytic enzyme carried on a subfraction of HDL that also carries other anti-oxidative and anti-inflammatory proteins. In humans and mice, low PON1 activity is associated with elevated oxidized lipids and homocysteine (Hcy)-thiolactone, as well as proteins that are modified by these metabolites, which can cause oxidative stress and inflammation. PON1-dependent metabolic changes can lead to atherothrombotic cardiovascular disease, Alzheimer’s disease, and cancer. The molecular bases underlying these associations are not fully understood. Biochemical, proteomic, and metabolic studies have significantly expanded our understanding of the mechanisms by which low PON1 leads to disease and high PON1 is protective. The studies discussed in this review highlight the changes in gene expression affecting proteostasis as a cause of the pro-oxidative and pro-inflammatory phenotypes associated with attenuated PON1 activity. Accumulating evidence supports the conclusion that PON1 regulates the expression of anti-oxidative and anti-inflammatory proteins, and that the disruption of these processes leads to disease.

Somatic Variants Acquired Later in Life Associated with Thoracic Aortic Aneurysms: JAK2 V617F.

The JAK2 V617F somatic variant is a well-known driver of myeloproliferative neoplasms (MPN) associated with an increased risk for athero-thrombotic cardiovascular disease. Recent studies have demonstrated its role in the development of thoracic aortic aneurysm (TAA). However, limited clinical information and level of JAK2 V617F burden have been provided for a comprehensive evaluation of potential confounders. A retrospective genotype-first study was conducted to identify carriers of the JAK2 V617F variant from an internal exome sequencing database in Yale DNA Diagnostics Lab. Additionally, the overall incidence of somatic variants in the JAK2 gene across various tissue types in the healthy population was carried out based on reanalysis of SomaMutDB and data from the UK Biobank (UKBB) cohort to compare our dataset to the population prevalence of the variant. In our database of 12,439 exomes, 594 (4.8%) were found to have a thoracic aortic aneurysm (TAA), and 12 (0.049%) were found to have a JAK2 V617F variant. Among the 12 JAK2 V617F variant carriers, five had a TAA (42%), among whom four had an ascending TAA and one had a descending TAA, with a variant allele fraction ranging from 11.2% to 20%. Among these five patients, 60% were female, and average age at diagnosis was 70 (49-79). The mean ascending aneurysm size was 5.05 cm (range 4.6-5.5 cm), and four patients had undergone surgical aortic replacement or repair. UKBB data revealed a positive correlation between the JAK2 V617F somatic variant and aortic valve disease (effect size 0.0086, p = 0.85) and TAA (effect size = 0.004, p = 0.92), although not statistically significant. An unexpectedly high prevalence of TAA in our dataset (5/594, 0.84%) is greater than the prevalence reported before for the general population, supporting its association with TAA. JAK2 V617F may contribute a meaningful proportion of otherwise unexplained aneurysm patients. Additionally, it may imply a potential JAK2-specific disease mechanism in the developmental of TAA, which suggests a possible target of therapy that warrants further investigation.

Abstract 2097: Jak2 V617f Clonal Hematopoiesis Promotes Arterial Thrombosis Via Platelet Activation And Cross-talk

JAK2 V617F ( JAK2 VF ) clonal hematopoiesis (CH) is associated with a marked increase in atherothrombotic cardiovascular disease (CVD). The role of JAK2 VF CH in arterial thrombosis has not been assessed. Using mice simulating JAK2 VF CH, we showed accelerated carotid artery thrombosis, with increased platelet counts and activation and increased leukocytes and red blood cells. There was increased platelet activation in both Jak2 VF and wild type (WT) platelets in Jak2 VF CH suggesting cross-talk between mutant and WT platelets. To assess platelet-specific effects, we used Gp1ba-Cre (VFGp1ba) to selectively express Jak2 VF in platelets. VFGp1ba increased platelet counts to a similar level as in 20% Jak2 VF CH mice but had no effect on leukocyte counts. Like Jak2 VF CH, VFGp1ba increased platelet activation and accelerated arterial thrombosis. Mechanistically, Jak2 VF platelets showed 2.8-fold up-regulation of COX-1, increased activation of cytosolic phospholipase A2, an enzyme important for arachidonic acid generation, and increased thromboxane A2 production. Conditioned media from activated Jak2 VF platelets induced WT platelet activation that was reversed by a thromboxane receptor antagonist. Low dose aspirin ameliorated carotid thrombosis in VFGp1ba and Jak2 VF CH but not in WT control mice. This study shows increased arterial thrombosis in Jak2 VF CH related to Jak2 VF platelet activation and cross-talk with WT platelets via thromboxane, suggesting a potential beneficial role of aspirin treatment in JAK2 VF CH.

Jak2V617F clonal hematopoiesis promotes arterial thrombosis via platelet activation and cross talk

AbstractJAK2V617F (JAK2VF) clonal hematopoiesis (CH) has been associated with atherothrombotic cardiovascular disease (CVD). We assessed the impact of Jak2VF CH on arterial thrombosis and explored the underlying mechanisms. A meta-analysis of 3 large cohort studies confirmed the association of JAK2VF with CVD and with platelet counts and adjusted mean platelet volume (MPV). In mice, 20% or 1.5% Jak2VF CH accelerated arterial thrombosis and increased platelet activation. Megakaryocytes in Jak2VF CH showed elevated proplatelet formation and release, increasing prothrombogenic reticulated platelet counts. Gp1ba-Cre–mediated expression of Jak2VF in platelets (VFGp1ba) increased platelet counts to a similar level as in 20% Jak2VF CH mice while having no effect on leukocyte counts. Like Jak2VF CH mice, VFGp1ba mice showed enhanced platelet activation and accelerated arterial thrombosis. In Jak2VF CH, both Jak2VF and wild-type (WT) platelets showed increased activation, suggesting cross talk between mutant and WT platelets. Jak2VF platelets showed twofold to threefold upregulation of COX-1 and COX-2, particularly in young platelets, with elevated cPLA2 activation and thromboxane A2 production. Compared with controls, conditioned media from activated Jak2VF platelets induced greater activation of WT platelets that was reversed by a thromboxane receptor antagonist. Low-dose aspirin ameliorated carotid artery thrombosis in VFGp1ba and Jak2VF CH mice but not in WT control mice. This study shows accelerated arterial thrombosis and platelet activation in Jak2VF CH with a major role of increased reticulated Jak2VF platelets, which mediate thromboxane cross talk with WT platelets and suggests a potential beneficial effect of aspirin in JAK2VF CH.

Abstract 10469: Time Averaged Lipoprotein(a) Reduction With Sln360, a Novel Sirna Targeting Lp(a,) in Healthy Adults With Elevated Lp(a)

Introduction: Lipoprotein(a) [Lp(a)] is an important risk factor for atherothrombotic cardiovascular disease for which there are no approved drugs. SLN360 is a short interfering RNA (siRNA) designed to reduce hepatic production of apolipoprotein(a). Primary safety, tolerability and Lp(a) lowering effects have previously been reported in a phase 1 single ascending dose study. Methods: Adults with Lp(a) plasma concentrations ≥ 150 nmol/L at entry and no clinically overt cardiovascular disease were randomized to receive a subcutaneous dose of SLN360 or placebo. The primary efficacy evaluation was percent reduction in Lp(a). Time-averaged reductions were determined to further inform dosing frequency and better evaluate potential clinical benefits. Results: Thirty-two adults received study drug in 4 cohorts. Large, dose-dependent reductions in Lp(a) were observed. For the top 2 doses (300 mg and 600 mg), median (IQR) maximal reductions of 96% (89%, 98%) and 98% (97%, 98%), with reductions of 71% and 81% persisting to day 150, respectively. The time-averaged effect from administration to 150 days, including the time to reach the Lp(a) nadir, was 82% and 87% for the 300 mg and 600 mg groups, respectively. To reflect the anticipated effects of repeat dosing, additional analyses excluded the time to achieve Lp(a) nadir (the first 30 days). This analysis showed 85% and 92% time-averaged median reductions in the 300 mg and 600 mg doses, respectively. Conclusions: In adults with elevated Lp(a), single doses of SLN360 substantially reduced Lp(a) with observed median maximal percent lowering of >95% for doses of 300mg and above, with effects persisting for 150 days. Median time-averaged reductions during 150 days of follow up exceeded 80% in 300 mg and 600 mg treatment groups. Infrequent SLN360 dosing has the potential to substantially reduce Lp(a) to clinically meaningful levels.

JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm

JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development and complications remains unknown. In a cohort of patients with myeloproliferative neoplasm, JAK2V617F mutation was identified as an independent risk factor for dilation of both the ascending and descending thoracic aorta. Using single-cell RNA-seq, complementary genetically-modified mouse models, as well as pharmacological approaches, we found that JAK2V617F mutation was associated with a pathogenic pro-inflammatory phenotype of perivascular tissue-resident macrophages, which promoted deleterious aortic wall remodeling at early stages, and dissecting aneurysm through the recruitment of circulating monocytes at later stages. Finally, genetic manipulation of tissue-resident macrophages, or treatment with a Jak2 inhibitor, ruxolitinib, mitigated aortic wall inflammation and reduced aortic dilation and rupture. Overall, JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm.

Analysis on Cause-Specific Atherothrombotic Cardiovascular Disease Mortality in Mexico: 2011-2015

IntroductionIn Mexico, cardiovascular disease (CVD) represents the most important cause of mortality and disability. We aimed to analyze the mortality rate due to specific causes of atherothrombotic CVD from 2011 to 2015.Material and methodsWe analyzed 3,105,975 death certificates issued from January 2011 through December 2015. The 10th version of the International Classification of Diseases (ICD) codes was used to select CVD death records for ischemic heart disease, heart failure, cerebrovascular disease, and peripheral artery disease. Regional analyses from the different federal states were also performed.ResultsWe analyzed 594,370 (19.1%) death certificates. Age-standardized CVD mortality showed a more stable pattern, from 96.7 per 100,000 people in 2011, to 111.7 per 100,000 in 2015. Cause-specific mortality rates increased more during the period for ischemic heart disease (63.8 vs. 74.8 per 100,000 people, in 2011 vs. 2015, respectively), as compared to heart failure (6.9 vs. 8.1 per 100,000 people), cerebrovascular disease (28.4 vs. 30.2 per 100,000 people), or peripheral artery disease (0.52 vs. 0.55 per 100,000 people). Overall, the survival age was significantly shorter in men (mean age at death 72.04±16.23 years) than in women (77.73±14.77). Ischemic heart disease and cerebrovascular disease showed the shortest survivals. The number of deaths increased steadily among the older population, with the steepest increase for overall ischemic heart disease over time.ConclusionsAtherothrombotic CVD mortality in Mexico increased during the study period due to ischemic heart disease. Compared to their counterparts, survival age was shorter in men and in patients with ischemic heart disease and stroke.

Current lipid-lowering approach and LDL target achievement in very high-risk patients: in-hospital results of a high-volume primary percutaneous coronary intervention tertiary center

Abstract Funding Acknowledgements Type of funding sources: None. Background Low-density lipoprotein-cholesterol (LDL-C) is a well-accepted causal risk factor for atherothrombotic cardiovascular disease. Several randomized controlled trials and meta-analyses have shown that lipid-lowering therapies reduce cardiovascular events and have a positive effect in reducing vulnerable plaques. In particular, the recommended target for LDL-C has become more and more stringent, moving to 1.4 mmol/l (55 mg/dl) for very high-risk patients. According to the 2019 ESC/EAS Guidelines, the current paradigm for lipid management favors a stepwise approach consisting of early initiation of high-intensity statin, followed by subsequent addition of ezetimibe, and ultimately a consideration of PCSK9 inhibitor treatment if LDL-C levels remain elevated. Methods We recruited 307 patients admitted for acute coronary syndrome (ACS) during the COVID-19 pandemic from March 2020 to December 2020. Baseline LDL-C concentration and prescribed hypolipemiant treatment at hospital admission and discharge were registered. Therefore, we included all consecutive patients identified as very-high cardiovascular risk, according to 2019 ESC guidelines. We stratified our population through variables independently associated with non-attainment of LDL-cholesterol such as hypertension, diabetes, peripheral arterial disease, clinical manifestations of ACS, number of main vessels treated, and complexity of the atherosclerotic disease. Results 274 patients were included. Mean age was 69,9 years (SD 11,4), 20,8 % were women, 23,7 % had diabetes, 16,4 % had PAD and 32,1 % suffered from valvular disease, mainly with mitral regurgitation or aortic stenosis no more than mild or moderate. Of 25.1% with a previous history of acute myocardial infarction, the 33,3% of whom didn’t have statin therapy pre-ACS index (p =0,001). At admission, medium cholesterol levels of patients that underwent previous coronary revascularization (25,5% of the total population) were 84,21 ± 31,2 mg/dL, not in range according to both 2016 and 2019 ESC guidelines. At discharge, 77,37 % of all the patients included received only statin therapy VS 22,63% with statin plus ezetimibe. In the subpopulation of patients with recurring ACS events with LDL pre-admission > 100 mg/dL,despite high dose statin, only 25% of this population were discharged adding ezetimibe (VS 75% who kept on the treatment of high dose statin without up-titration). Conclusions Management of dyslipidemia is frequently suboptimal and the gap between guidelines and clinical practice for lipid management across Europe has been exacerbated by the 2019 guidelines. A greater utilization of non-statin lipid-lowering therapies is likely needed to reach the LDL-C optimal target. A correct stratification of the risk class would help to identify, in a personalized perspective of treatment, patients at very high risk that would take advantage of more aggressive therapy to reach the lowest target of LDL-C ("the lower is better").

Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With Elevated Plasma Lipoprotein(a) Levels

ImportanceLipoprotein(a) (Lp[a]) is an important risk factor for atherothrombotic cardiovascular disease and aortic stenosis, for which there are no treatments approved by regulatory authorities.ObjectivesTo assess adverse events and tolerability of a short interfering RNA (siRNA) designed to reduce hepatic production of apolipoprotein(a) and to assess associated changes in plasma concentrations of Lp(a) at different doses.Design, Setting, and ParticipantsA single ascending dose study of SLN360, an siRNA targeting apolipoprotein(a) synthesis conducted at 5 clinical research unit sites located in the US, United Kingdom, and Australia. The study enrolled adults with Lp(a) plasma concentrations of 150 nmol/L or greater at screening and no known clinically overt cardiovascular disease. Participants were enrolled between November 18, 2020, and July 21, 2021, with last follow-up on December 29, 2021.InterventionsParticipants were randomized to receive placebo (n = 8) or single doses of SLN360 at 30 mg (n = 6), 100 mg (n = 6), 300 mg (n = 6), or 600 mg (n = 6), administered subcutaneously.Main Outcomes and MeasuresThe primary outcome was evaluation of safety and tolerability. Secondary outcomes included change in plasma concentrations of Lp(a) to a maximum follow-up of 150 days.ResultsAmong 32 participants who were randomized and received the study intervention (mean age, 50 [SD, 13.5] years; 17 women [53%]), 32 (100%) completed the trial. One participant experienced 2 serious adverse event episodes: admission to the hospital for headache following SARS-CoV-2 vaccination and later for complications of cholecystitis, both of which were judged to be unrelated to study drug. Median baseline Lp(a) concentrations were as follows: placebo, 238 (IQR, 203-308) nmol/L; 30-mg SLN360, 171 (IQR, 142-219) nmol/L; 100-mg SLN360, 217 (IQR, 202-274) nmol/L; 300-mg SLN360, 285 (IQR, 195-338) nmol/L; and 600-mg SLN360, 231 (IQR, 179-276) nmol/L. Maximal median changes in Lp(a) were −20 (IQR, −61 to 3) nmol/L, −89 (IQR, −119 to −61) nmol/L, −185 (IQR, −226 to −163) nmol/L, −268 (IQR, −292 to −189) nmol/L, and −227 (IQR, −270 to −174) nmol/L, with maximal median percentage changes of −10% (IQR, −16% to 1%), −46% (IQR, −64% to −40%), −86% (IQR, −92% to −82%), −96% (IQR, −98% to −89%), and −98% (IQR, −98% to −97%), for the placebo group and the 30-mg, 100-mg, 300-mg, and 600-mg SLN360 groups, respectively. The duration of Lp(a) lowering was dose dependent, persisting for at least 150 days after administration.Conclusions and RelevanceIn this phase 1 study of 32 participants with elevated Lp(a) levels and no known cardiovascular disease, the siRNA SLN360 was well tolerated, and a dose-dependent lowering of plasma Lp(a) concentrations was observed. The findings support further study to determine the safety and efficacy of this siRNA.Trial RegistrationClinicalTrials.gov Identifier: NCT04606602; EudraCT Identifier: 2020-002471-35

Cardiovascular Diseases and Periodontitis.

Periodontitis is a chronic inflammatory disease of the tooth-supporting connective tissue and alveolar bone that is initiated by a bacterial biofilm in periodontal pockets. It affects about half of adults in the Western world, and is associated with a range of systemic comorbidities, e.g., cardiovascular disease (CVD), diabetes and rheumatoid arthritis, and these diseases share overlapping systemic and target tissue inflammatory mechanisms. Indeed, mounting evidence has indicated that their association is causal and built on the presence of systemic low-grade inflammation (LGI). Prior research linking periodontitis to CVD has mainly been derived from experimental studies, observational data, and small interventional trials with surrogate markers of CVD, e.g., endothelial dysfunction. However, recent data from randomised studies have demonstrated that intensive treatment of periodontitis can reduce blood pressure in patients with hypertension in conjunction with reduction of systemic inflammatory markers. Furthermore, targeted anti-inflammatory therapy has been shown to reduce recurrent events in patients with established CVD and LGI. Along this line, the concept of residual inflammatory risk has emerged as an independent new risk factor for atherothrombotic CVD. The present review summarizes translational evidence indicating that periodontitis is a risk factor for CVD dependent on LGI, and we conclude that treatment of periodontitis is likely to contribute importantly to reduction of residual inflammatory risk.

Using Health-Related Quality of Life to Identify the Incident Cardiovascular Disease Risk

Previous studies have revealed that poor health-related quality of life (HRQoL) is associated with a higher risk of hospital readmission and mortality in patients with cardiovascular disease (CVD). The association between HRQoL and incident CVD is still limited for general older people. This study explored the associations between baseline HRQoL and incident and fatal CVD in community-dwelling Australian and the United States older people enrolled in ASPREE clinical trial. A cohort of 19,106 individuals aged 65 to 98 years, who were initially free of CVD, dementia, or disability, were followed between March 2010 and June 2017. The SF-12 questionnaire was used to assess HRQoL, and the physical (PCS) and mental component scores (MCS) of SF-12 were derived using norm-based methods. Incident major adverse CVD events included fatal CVD (death due to atherothrombotic CVD), hospitalizations for heart failure, myocardial infarction or stroke. Analyses were performed using Cox proportional-hazard regression. Over a median 4.7 follow-up years, there were 922 incident CVD events, 203 fatal CVD events, 171 hospitalizations for heart failure, 355 fatal or nonfatal myocardial infarction and 403 fatal or nonfatal strokes. A 10-unit higher PCS, but not MCS, was associated with a lower risk of incident CVD (HR=0.86, 95%CI 0.79-0.92), hospitalization for heart failure (HR=0.72, 95%CI 0.60-0.85), and myocardial infarction (HR=0.85, 95%CI 0.75-0.96). Neither PCS nor MCS was associated with fatal CVD events or stroke. Physical HRQoL can be used in combination with clinical data to identify the incident CVD risk among community-dwelling older people.

Dual pathway inhibition in atherothrombosis prevention: yes, now we can!

Despite ongoing developments, prevention and treatment of atherothrombotic cardiovascular disease remains a common challenge. Antithrombotic options for cardiocerebrovascular disease prevention involves a choice between dual antiplatelet therapy (DAPT) and dual pathway inhibition (DPI), which includes an antiplatelet agent and a reduced dose anticoagulant agent. In selected patients at high risk of event and low risk of bleeding, especially those undergoing recent and complex coronary revascularization using drug-eluting stents (DES) ("revascularization-driven effect"), DAPT is superior to single antiplatelet therapy with aspirin. DPI involves a wider potential range of treatment and is superior to single antiplatelet therapy with aspirin, particularly in patients with atherothrombotic involvement in different vascular beds both previously revascularized and not ("no revascularization-driven effect"). After nearly thirty years of randomized trials and observational registries, we have sufficient data to customize antithrombotic therapy in patients at high cardiovascular risk. Therefore, "atherothrombosis stakeholders" must identify the right patient for the right therapy to ensure high levels of efficacy and safety with the best of current therapeutic opportunities.

EICOSAPENTAENOIC ACID REDUCES EXPRESSION OF PLATELET ACTIVATION AND AGGREGATION PROTEINS IN PULMONARY AND VASCULAR ENDOTHELIUM DURING INFLAMMATION

BACKGROUND Atherothrombotic cardiovascular (CV) disease leads to platelet aggregation and thrombus formation. Icosapent ethyl is an ethyl ester of eicosapentaenoic acid (EPA), and was shown to reduce ischemic events in high-risk patients (REDUCE-IT). IPE is approved by Health Canada to reduce CV risk among patients with elevated TG levels as an add-on to maximally tolerated statin therapy. In this study, the effects of EPA on expression of proteins associated with platelet activation and aggregation were measured in cytokine (IL-6) treated pulmonary and vascular endothelial cells (ECs). METHODS AND RESULTS Human pulmonary ECs (PECs) and umbilical vein ECs (HUVECs) were treated with vehicle or EPA (40/10 µM in PECs/HUVECs) and IL-6 (12 ng/mL) for 24 h. Proteomic analysis was performed using liquid chromatography/mass spectroscopy that detected modulation of >1,000 proteins. Proteins which showed significantly (p < 0.05) greater than 1-fold change between treatment groups were further assessed. EPA significantly downregulated a total of 36 proteins involved in platelet activation, signaling, aggregation, in EC following cytokine exposure. Platelet endothelial cell adhesion molecule (PECAM) was downregulated in both HUVECs and PECs (1.2-fold) by EPA. In PECs, EPA significantly modulated 26 additional proteins related to platelet activation, including amyloid-beta precursor protein (1.1-fold decrease) and thrombin receptor (PAR-1,1.3-fold decrease). In HUVECs, the expression of nine other proteins were modulated related to platelet activation, including superoxide dismutase (1.6-fold increase). CONCLUSION EPA significantly reduced expression of multiple EC proteins required for platelet activation and aggregation, including PECAM in both pulmonary and vascular tissues. These findings indicate potential novel anti-platelet mechanisms for EPA that may account for reduced ischemic events in REDUCE-IT. Atherothrombotic cardiovascular (CV) disease leads to platelet aggregation and thrombus formation. Icosapent ethyl is an ethyl ester of eicosapentaenoic acid (EPA), and was shown to reduce ischemic events in high-risk patients (REDUCE-IT). IPE is approved by Health Canada to reduce CV risk among patients with elevated TG levels as an add-on to maximally tolerated statin therapy. In this study, the effects of EPA on expression of proteins associated with platelet activation and aggregation were measured in cytokine (IL-6) treated pulmonary and vascular endothelial cells (ECs). Human pulmonary ECs (PECs) and umbilical vein ECs (HUVECs) were treated with vehicle or EPA (40/10 µM in PECs/HUVECs) and IL-6 (12 ng/mL) for 24 h. Proteomic analysis was performed using liquid chromatography/mass spectroscopy that detected modulation of >1,000 proteins. Proteins which showed significantly (p < 0.05) greater than 1-fold change between treatment groups were further assessed. EPA significantly downregulated a total of 36 proteins involved in platelet activation, signaling, aggregation, in EC following cytokine exposure. Platelet endothelial cell adhesion molecule (PECAM) was downregulated in both HUVECs and PECs (1.2-fold) by EPA. In PECs, EPA significantly modulated 26 additional proteins related to platelet activation, including amyloid-beta precursor protein (1.1-fold decrease) and thrombin receptor (PAR-1,1.3-fold decrease). In HUVECs, the expression of nine other proteins were modulated related to platelet activation, including superoxide dismutase (1.6-fold increase). EPA significantly reduced expression of multiple EC proteins required for platelet activation and aggregation, including PECAM in both pulmonary and vascular tissues. These findings indicate potential novel anti-platelet mechanisms for EPA that may account for reduced ischemic events in REDUCE-IT.

Health-related quality of life and incident cardiovascular disease events in community-dwelling older people: A prospective cohort study

BackgroundLower health-related quality of life (HRQoL) has been shown to predict a higher risk of hospital readmission and mortality in patients with cardiovascular disease (CVD). Few studies have explored the associations between HRQoL and incident CVD. We explored the associations between baseline HRQoL and incident and fatal CVD in community-dwelling older people in Australia and the United States. MethodsLongitudinal study using ASPirin in Reducing Events in the Elderly (ASPREE) trial data. This includes 19,106 individuals aged 65–98 years, initially free of CVD, dementia, or disability, and followed between March 2010 and June 2017. The physical (PCS) and mental component scores (MCS) of HRQoL were assessed using the SF-12 questionnaire. Incident major adverse CVD events included fatal CVD (death due to atherothrombotic CVD), hospitalizations for heart failure, myocardial infarction or stroke. Analyses were performed using Cox proportional-hazard regression. ResultsOver a median 4.7 follow-up years, there were 922 incident CVD events, 203 fatal CVD events, 171 hospitalizations for heart failure, 355 fatal or nonfatal myocardial infarction and 403 fatal or nonfatal strokes. After adjustment for sociodemographic, health-related behaviours and clinical measures, a 10-unit higher PCS, but not MCS, was associated with a 14% lower risk of incident CVD, 28% lower risk of hospitalization for heart failure and 15% lower risk of myocardial infarction. Neither PCS nor MCS was associated with fatal CVD events or stroke. ConclusionPhysical HRQoL can be used in combination with clinical data to identify the incident CVD risk among older individuals.

A narrative review of low-dose rivaroxaban in patients with atherothrombotic cardiovascular disease: vascular protection beyond anticoagulation.

Major cardiovascular (CV) events often complicate the natural history of apparently stable atherothrombotic cardiovascular disease (CVD) despite appropriate guideline-based preventive treatment. This finding has been termed residual risk and it has been the focus of recent investigation. New and revisited targets to tackle this so-called residual risk have been proposed, including antithrombotic treatment intensification, further lowering targets of low-density lipoprotein (LDL) cholesterol, novel oral antidiabetic agents with a CV benefit, and drugs to reduce systemic inflammation. In this narrative review, we discuss the evidence, mechanisms and gaps in knowledge concerning the vascular protection derived from low-dose (2.5 mg twice daily) rivaroxaban. On this topic, the main trials (ATLAS ACS 2-TIMI 51, COMPASS and VOYAGER PAD), will be summarized in a comprehensive manner. Indeed, these have shown that a drug developed to prevent thrombus formation (selective Factor Xa inhibition) reduced events that were traditionally platelet-related in concept. Moreover, we propose a simple evidence-based clinically oriented algorithm to thoroughly identify patients at increased risk and who may benefit from this strategy in different clinical scenarios. Low-dose rivaroxaban portrays a novel promising era in atherothrombotic CVD prevention, providing a mechanistic protection beyond traditional strategies in patients overwhelmed by recurrent dismal events.

Circulating neurotrophins and hemostatic risk factors of atherothrombotic cardiovascular disease at baseline and during sympathetic challenge: the SABPA study

Sympathetic activation may trigger acute coronary syndromes. We examined the relation between circulating neurotrophic factors and hemostatic risk factors of atherothrombotic cardiovascular disease at baseline and in response to acute mental stress to establish a brain–heart link. In 409 black and white South Africans, brain-derived neurotrophic factor (BDNF) and fibrinolytic measures were assessed at baseline. Glial cell-derived neurotrophic factor (GDNF), S100 calcium-binding protein (S100B), von Willebrand factor (VWF), fibrinogen and D-dimer were assessed at baseline and 10 min after the Stroop test. Neurotrophins were regressed on hemostatic measures adjusting for demographics, comorbidities, cardiometabolic factors and health behaviors. Higher baseline BDNF was associated with greater stress-induced increase in fibrinogen (p = 0.003) and lower D-dimer increase (p = 0.016). Higher baseline S100B was significantly associated with higher baseline VWF (p = 0.031) and lower fibrinogen increase (p = 0.048). Lower baseline GDNF was associated with higher baseline VWF (p = 0.035) but lower VWF increase (p = 0.001). Greater GDNF (p = 0.006) and S100B (p = 0.042) increases were associated with lower VWF increase. All associations showed small-to-moderate effect sizes. Neurotrophins and fibrinolytic factors showed no significant associations. The findings support the existence of a peripheral neurothrophin-hemostasis interaction of small-to-moderate clinical relevance. The implications for atherothrombotic cardiovascular disease need further exploration.

Aspirin use in chronic kidney disease: Is cardiovascular risk reduction worth the risk?

Chronic kidney disease patients are at increased risk of atherothrombotic cardiovascular disease but are also at high risk of bleeding complications. Aspirin is an overall safe and efficacious therapy for the secondary prevention of CVD in certain populations. However, its use as primary prevention has not been proven to be of benefit and is counterbalanced by high risk of adverse events in patients with kidney disease. In this review, we present relevant differences in pathophysiology of CVD in patients with impaired kidney function and discuss the balance between benefit and harm and review controversial aspects of aspirin therapy for both primary and secondary prevention of cardiovascular disease in patients with CKD.

P3 Influencia de hábitos: el consumo de fibra, el omega 3 y la actividad física en el desarrollo de síndrome metabólico

Introducción: múltiples factores contribuyen al desarrollo de síndrome metabólico (SM) aumentando el riesgo de enfermedad cardiovascular aterotrombótica.Objetivos: estudiar el impacto y la asociación del consumo de fibra, omega 3 y la práctica de actividad física (AF) con la prevalencia de SM. Analizar la asociación entre: el consumo de fibra con valores antropométricos, el consumo de fibra con consumo de omega 3 y triglicéridos.Materiales y métodos: estudio transversal. Se realizó cuestionario dirigido e individualizado que incluyó frecuencia de consumo semicuantitativo y recordatorio de 24 horas, antropometría y laboratorio por conveniencia a 179 adultos del Hospital Sirio Libanés y de un centro de asistencia privada en áreas de nutrición de septiembre de 2019 a marzo 2020. Se consideró diagnóstico de SM según ultima definición de IDF. Se excluyeron aquellos con patología intestinal malabsortiva, patología psiquiátrica, tratamiento oncológico o sin consentimiento informado.

Genetic Variation in PEAR1, Cardiovascular Outcomes and Effects of Aspirin in a Healthy Elderly Population.

The platelet endothelial aggregation receptor-1 (PEAR1) rs12041331 variant has been identified as a genetic determinant of platelet aggregation in response to antiplatelet therapies, including aspirin. However, association with atherothrombotic cardiovascular events is less clear, with limited evidence from large trials. Here, we tested association of rs12041331 with cardiovascular events and aspirin use in a randomized trial population of healthy older individuals. We undertook post hoc analysis of 13,547 participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial, median age 74years. Participants had no previous diagnosis of atherothrombotic cardiovascular disease at enrollment, and were randomized to either 100mg daily low-dose aspirin or placebo for median 4.7years follow-up. We used Cox proportional hazard regression to model the relationship between rs12041331 and the ASPREE primary cardiovascular disease (CVD) end point, and composites of major adverse cardiovascular events (MACE) and ischemic stroke (STROKE); and bleeding events; major hemorrhage (MHEM) and intracranial bleeding (ICB). We performed whole-population analysis using additive and dominant inheritance models, then stratified by treatment group. Interaction effects between genotypes and treatment group were examined. We observed no statistically significant association (P<0.05) in the population, or by treatment group, between rs12041331 and cardiovascular or bleeding events in either model. We also found no significant interaction effects between rs12041331-A and treatment group, for CVD (P=0.65), MACE (P=0.32), STROKE (P=0.56), MHEM (P=0.59), or ICB (P=0.56). The genetic variant PEAR1 rs12041331 is not associated with cardiovascular events in response to low-dose aspirin in a healthy elderly population.

Effects of Caloric Intake and Aerobic Activity in Individuals with Prehypertension and Hypertension on Levels of Inflammatory, Adhesion and Prothrombotic Biomarkers-Secondary Analysis of a Randomized Controlled Trial.

Background: Cardiopulmonary fitness and low calorie diets have been shown to reduce inflammation but few studies have been conducted in individuals with elevated blood pressure (BP) in a randomized intervention setting. Thereby, adhesion biomarkers, e.g., soluble intercellular adhesion molecule (sICAM)-3, have not been examined so far. Methods: Sixty-eight sedentary prehypertensive and mildly hypertensive individuals (mean age ± SEM: 45 ± 1 years; mean BP: 141/84 ± 1/1 mmHg) were randomized to one of three 12-week intervention groups: cardio training and caloric reduction, cardio training alone, or wait-list control group. Plasma levels of inflammatory, adhesion and prothrombotic biomarkers were assessed. In a second step, intervention groups were combined to one sample and multivariate regression analyses were applied in order to account for exercise and diet behavior changes. Results: There were no significant differences among the intervention groups. In the combined sample, greater caloric reduction was associated with a larger increase of sICAM-3 (p = 0.026) and decrease of C-reactive protein (p = 0.018) as a result of the interventions. More cardio training was associated with increases of sICAM-3 (p = 0.046) as well as interleukin-6 (p = 0.004) and a decrease of tumor necrosis factor-α (p = 0.017) levels. Higher BP predicted higher plasminogen activator inhibitor (PAI)-1 (p = 0.001), and greater fitness predicted lower PAI-1 levels (p = 0.006) after the intervention. Conclusions: In prehypertensive and hypertensive patients, plasma levels of the adhesion molecule sICAM-3 and inflammatory biomarkers have different response patterns to cardio training with and without caloric reduction. Such anti-inflammatory and anti-thrombotic effects may have implications for the prevention of atherothrombotic cardiovascular disease among individuals at increased risk.