Polyfluoro- and perfluoro-alkyl substances (PFAS) are organic chemicals extensively used worldwide for industry and consumer products. Due to their chemical stability, PFAS represent a major cause of ...environmental pollution. PFAS accumulate in animal and human blood and tissues exerting their toxicity. We performed a review of the epidemiological studies exploring the relationship between exposure to PFAS and thromboembolic cardiovascular disease. An increase in cardiovascular disease or death related to PFAS exposure has been reported from cross-sectional and longitudinal observational studies with evidence concerning the relation with early vascular lesions and atherosclerosis. Several studies indicate an alteration in lipid and glucose metabolism disorders and increased blood pressure as a possible link with cardiovascular thromboembolic events. We also examined the recent evidence indicating that legacy and new PFAS can be incorporated in platelet cell membranes giving a solid rationale to the observed increase risk of cardiovascular events in the populations exposed to PFAS by directly promoting thrombus formation. Exposure to PFAS has been related to altered plasma membrane fluidity and associated with altered calcium signal and increased platelet response to agonists, both
and
in subjects exposed to PFAS. All the functional responses are increased in platelets by incorporation of PFAS: adhesion, aggregation, microvesicles release and experimental thrombus formation. These findings offer mechanistic support the hypothesis that platelet-centred mechanisms may be implicated in the increase in cardiovascular events observed in populations chronically exposed to PFAS.
Pulmonary thrombosis is observed in severe acute respiratory syndrome coronavirus 2 pneumonia. Aim was to investigate whether subpopulations of platelets were programmed to procoagulant and ...inflammatory activities in coronavirus disease 2019 (COVID-19) patients with pneumonia, without comorbidities predisposing to thromboembolism. Approach and Results: Overall, 37 patients and 28 healthy subjects were studied. Platelet-leukocyte aggregates, platelet-derived microvesicles, the expression of P-selectin, and active fibrinogen receptor on platelets were quantified by flow cytometry. The profile of 45 cytokines, chemokines, and growth factors released by platelets was defined by immunoassay. The contribution of platelets to coagulation factor activity was selectively measured. Numerous platelet-monocyte (mean±SE, 67.9±4.9%, n=17 versus 19.4±3.0%, n=22;
<0.0001) and platelet-granulocyte conjugates (34.2±4.04% versus 8.6±0.7%;
<0.0001) were detected in patients. Resting patient platelets had similar levels of P-selectin (10.9±2.6%, n=12) to collagen-activated control platelets (8.7±1.5%), which was not further increased by collagen activation on patient platelets (12.4±2.5%,
=nonsignificant). The agonist-stimulated expression of the active fibrinogen receptor was reduced by 60% in patients (
<0.0001 versus controls). Cytokines (IL interleukin-1α, IL-1β, IL-1RA, IL-4, IL-10, IL-13, IL, 17, IL-27, IFN interferon-α, and IFN-γ), chemokines (MCP-1/CCL2 monocyte chemoattractant protein 1), and growth factors (VEGF vascular endothelial growth factor-A/D) were released in significantly larger amounts upon stimulation of COVID-19 platelets. Platelets contributed to increased fibrinogen, VWF (von Willebrand factor), and factor XII in COVID-19 patients. Patients (28.5±0.7 s, n=32), unlike controls (31.6±0.5 s, n=28;
<0.001), showed accelerated factor XII-dependent coagulation.
Platelets in COVID-19 pneumonia are primed to spread proinflammatory and procoagulant activities in systemic circulation.
Platelet-derived large extracellular vesicles (often referred to as microparticles in the field of cardiovascular disease) have been identified as effector in the atherothrombotic process, therefore ...representing a target of pharmacological intervention of potential interest. Despite that, limited evidence is so far available concerning the effects of antiplatelet agents on the release of platelet-derived extracellular vesicles. In the present narrative review, the mechanisms leading to vesiculation in platelets and the pathophysiological processes implicated will be discussed. This will be followed by a summary of the present evidence concerning the effects of antiplatelet agents under experimental conditions and in clinical settings.
The global rate of intensive care unit (ICU) admission during the COVID-19 pandemic varies within countries and is among the main challenges for health care systems worldwide. Conflicting results ...have been reported about the response to coronavirus infection and COVID-19 outcomes in men and women. Understanding predictors of intensive care unit admission might be of help for future planning and management of the disease.
We designed a cross-sectional observational multicenter nationwide survey in Italy to understand gender-related clinical predictors of ICU admission in patients with COVID-19. We analyzed information from 2378 charts of Italian patients certified for COVID-19 admitted in 26 hospitals. Three hundred ninety-five patients (16.6%) required ICU admission due to COVID19 infection, more frequently men (74%), with a higher prevalence of comorbidities (1,78±0,06 vs 1,54±0,03 p<0.05). In multivariable regression model main predictors of admission to ICU are male gender (OR 1,74 95% CI 1,36-2,22 p<0.0001) and presence of obesity (OR 2,88 95% CI 2,03-4,07 p<0.0001), chronic kidney disease (OR: 1,588; 95%, 1,036-2,434 p<0,05) and hypertension (OR: 1,314; 95% 1,039-1,662; p<0,05). In gender specific analysis, obesity, chronic kidney disease and hypertension are associated with higher rate of admission to ICU among men, whereas in women, obesity (OR: 2,564; 95% CI 1,336-4.920 p<0.0001) and heart failure (OR: 1,775 95% CI: 1,030-3,057) are associated with higher rate of ICU admission.
Our study demonstrates that gender is the primary determinant of the disease's severity among COVID-19. Obesity is the condition more often observed among those admitted to ICU within both genders.
Clinicaltrials.gov: NCT04331574.
•Exposure to legacy PFAS associates with endocrine disruption and health concerns.•Legacy PFOA was demonstrated to increase basal platelet pro-aggregation profile.•Supposed with a lower accumulation ...profile, novel C6O4 is expected to be with safer.•C6O4 equally accumulates on platelets membrane likely altering their properties.•C6O4 increases in vitro platelets aggregation profile and micro-particles production.
Health concerns associated with the exposure to legacy perfluoro-alkyl substances (PFAS) led to the development of new-generation PFAS, such as C6O4. Here we investigated the possible effects of C6O4 on the platelet’s activation profile, by incubating human platelets from healthy donors with C6O4 at different concentrations and evaluating the effects on activation, production and phenotype of platelets micro-particles (MPV) and aggregation under-flow. Based on the eventual platelet pro-aggregation profile detected, the preventive effect of acetylsalicylic acid (ASA) was also explored.
Adhesion-induced platelet aggregation of platelet rich plasma (PRP) under flow was evaluated on collagen-coated microchip at a shear stress of 10 Dyne. The turbidimetric method was used to investigate platelet aggregation. Finally, the in vitro generation of pro-coagulant MPV in PRP was evaluated by flow cytometry, as characterized by CD41 and annexin V positive events, under resting conditions and after stimulation with agonists at low shear stress.
The generation of platelet aggregates under flow was significantly increased by the pretreatment of PRP with 100–200 ng/mL C6O4, compared to both the control condition and the experiment performed in presence of ASA. Arachidonic acid (AA), ADP and collagen induced an higher maximal aggregation, at turbidimetric evaluation, when PRP was pretreated with 100–500 ng/mL C6O4. In addition, PRP stimulated with AA also showed a steeper slope of the aggregation curve. The aggregation induced by the tested agonists was almost abolished by ASA. Finally, pretreatment with C6O4 increased the number of MPV in resting conditions and in presence of ADP and TRAP. ASA tended to reduce MPV generation.
Exposure to C6O4 associates with an increased platelet response to agonists, translating into a possible increased risk of cardiovascular events. Pending a further clarification on the toxicokinetics of this compound, our results claim the possible prophylactic use of ASA.
Non alcoholic steatohepatitis (NASH) is the inflammatory reaction of the liver to excessive accumulation of lipids in the hepatocytes. NASH can progress to cirrhosis and hepatocellular carcinoma ...(HCC). Fatty liver is the hepatic manifestation of metabolic syndrome. A subclinical inflammatory state is present in patients with metabolic alterations like insulin resistance, type-2 diabetes, obesity, hyperlipidemia, and hypertension. Platelets participate in immune cells recruitment and cytokines-induced liver damage. It is hypothesized that lipid toxicity cause accumulation of platelets in the liver, platelet adhesion and activation, which primes the immunoinflammatory reaction and activation of stellate cells. Recent data suggest that antiplatelet drugs may interrupt this cascade and prevent/improve NASH. They may also improve some metabolic alterations. The pathophysiology of inflammatory liver disease and the implication of platelets are discussed in details.
Recent Genome-Wide Association Studies (GWAS) have pinpointed different single nucleotide polymorphisms consistently associated with blood pressure (BP) and hypertension prevalence. However, little ...data exist regarding single nucleotide polymorphisms predicting BP variation over time and hypertension incidence. The aim of this study was to confirm the association of a genetic risk score (GRS), based on 29 independent single nucleotide polymorphisms, with cross-sectional BP and hypertension prevalence and to challenge its prediction of BP change over time and hypertension incidence in >17 000 middle-aged Swedes participating in a prospective study, the Malmö Preventive Project, investigated at baseline and over a 23-year average period of follow-up. The GRS was associated with higher systolic and diastolic BP values both at baseline (β ± SEM, 0.968 ± 0.102 mm Hg and 0.585 ± 0.064 mm Hg; P<1E-19 for both) and at reinvestigation (β ± SEM, 1.333 ± 0.161 mm Hg and 0.724 ± 0.086 mm Hg; P<1E-15 for both) and with increased hypertension prevalence (odds ratio 95% CI, 1.192 1.140-1.245 and 1.144 1.107-1.183; P<1E-15 for both). The GRS was positively associated with change (Δ) in BP (β ± SEM, 0.033 ± 0.008 mm Hg/y and 0.023 ± 0.004 mm Hg/y; P<1E-04 for both) and hypertension incidence (odds ratio 95% CI, 1.110 1.065-1.156; P=6.7 E-07), independently from traditional risk factors. The relative weight of the GRS was lower in magnitude than obesity or prehypertension, but comparable with diabetes mellitus or a positive family history of hypertension. A C-statistics analysis does not show any improvement in the prediction of incident hypertension on top of traditional risk factors. Our data from a large cohort study show that a GRS is independently associated with BP increase and incidence of hypertension.
Endothelial dysfunction, evaluated by flow-mediated dilatation (FMD), predicts adverse cardiovascular events in patients with intermittent claudication (IC). IC is an example of repeated ...ischemia/reperfusion injury that may contribute to the progression of vascular disease by worsening endothelial function, a trigger for acute cardiovascular events. The predictive value of effort-induced endothelial dysfunction for cardiovascular events in patients with IC has not been studied previously. The objective of this study was to assess whether exercise-induced endothelial dysfunction is predictive of adverse cardiovascular outcome in IC. In 44 patients with IC, we measured brachial artery FMD by B-mode ultrasonography at rest and 10 minutes after a maximal treadmill exercise. Treadmill exercise halved the FMD (from 3.5 ± 0.6% to 1.45 ± 0.46%, p < 0.05). After a follow-up period of 85 (72–98) months, a total of 20 major cardiovascular events occurred. In a multivariate analysis, a post-exercise reduction of brachial FMD > 1.3% was predictive for cardiovascular events. Maximal exercise-induced endothelial dysfunction is predictive of cardiovascular events in patients with IC.
Platelet microparticles (PMPs) contribute to thrombogenesis but the effects of antiplatelet drugs on PMPs generation is undefined. The present study investigated the cellular events regulating PMPs ...shedding, testing
platelet agonists and inhibitors. Platelet-rich plasma from healthy subjects was stimulated with arachidonic acid (AA), U46619, collagen type-I (10 and 1.5 μg/mL), epinephrine, ADP or TRAP-6 and pre-incubated with acetylsalicylic acid (ASA, 100 and 10 μmol/L), SQ-29,548, apyrase, PSB-0739, or eptifibatide. PMPs were detected by flow-cytometry using CD61 and annexin-V as fluorescent markers. Platelet agonists induced annexin V-positive PMPs shedding. The strongest response was to high concentration collagen. ADP-triggered PMPs shedding was dose-independent. ASA reduced PMPs induced by AA- (645, 347-2946 vs. 3061, 446-4901 PMPs/μL; median ad range,
= 9,
< 0.001), collagen 10 μg/mL (5317, 2027-15935 vs. 10252, 4187-46316 PMPs/μL;
= 13,
< 0.001), collagen 1.5 μg/mL (1078, 528-2820 vs. 1465, 582-5948 PMPs/μL;
= 21,
< 0.001) and TRAP-6 (2008, 1621-2495 vs. 2840, 2404-3031 PMPs/μL;
= 3,
< 0.01) but did not affect the response to epinephrine or ADP. The ADP scavenger apyrase reduced PMPs induced by U46619 (1256, 395-2908 vs. 3045, 1119-5494 PMPs/μL,
= 6,
< 0.05), collagen 1.5 μg/mL (1006, 780-1309 vs. 2422, 1839-3494 PMPs/μL,
= 3,
< 0.01) and TRAP-6 (904, 761-1224 vs. 2840, 2404-3031 PMPs/μL,
= 3,
< 0.01). The TP receptor antagonist SQ-29,548 and the P2Y
receptor antagonist PSB-0739 markedly inhibited PMPs induced by low doses of collagen. Except for high-dose collagen, eptifibatide abolished agonist-induced PMPs release. Both TXA
generation and ADP secretion are required as amplifiers of PMP shedding. The crucial role of the fibrinogen receptor and the collagen receptor in PMPs generation, independently of platelet aggregation, was identified.
•Sacubitril/Valsartan is an angiotensin receptor-neprilysin inhibitor (ARNi) approved for heart treatment of heart failure.•Sacubitril/valsartan reduces cardiovascular mortality/morbidity in heart ...failure with reduced ejection fraction.•Our study was performed in elderly hypertensives with heart failure with reduced ejection fraction and comorbidities.•Sacubitril/valsartan was safe and effective in reducing mortality and re-hospitalization for heart failure.
Sacubitril/valsartan, the first agent to be approved in a new class of drugs called angiotensin receptor neprilysin inhibitors (ARNIs), has been shown to reduce cardiovascular mortality and morbidity compared to enalapril in outpatient subjects with chronic heart failure (HF) and reduced left ventricular ejection fraction (HFrEF). However, there is little real-world evidence about the efficacy of ARNIs in elderly hypertensive patients with HFrEF and comorbidities.
In this prospective open-label study, 108 subjects, 54 of them (mean age 78.6 ± 8.2 years, 75.0 % male), with HFrEF (29.8 ± 4.3 %) and New York Heart Association (NYHA) class II-III symptoms were assigned to receive ARNIs twice daily, according to the recommended dosage of 24/26, 49/51, 97/103 mg. Patients were gender- and age-matched with a control arm of patients with HFrEF receiving the optimal standard therapy for HF. The clinic blood pressure (BP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), estimated glomerular filtration rate (eGFR), blood glucose and glycated hemoglobin (HbA1c), uric acid (UA), left ventricular ejection fraction (LVEF) and NYHA class were evaluated at a mean follow-up of 12 months. During the follow-up, the clinical outcomes, including mortality and re-hospitalization for HF, were collected.
NYHA class significantly improved in the ARNI arm compared to the control (24.9 vs. 6.4 %, shifting from class III to II, and 55.4 vs. 25.2 %, from class II to I, p < 0.05 for all). A significant improvement in LVEF and eGFR levels was found in the ARNI arm compared to controls (42.4 vs. 34.2 %, 73.8 vs. 61.2 mL/min, respectively; p < 0.001 for all). NT-proBNP, clinic systolic and diastolic BP, blood glucose, HbA1c and UA values were reduced in both treatment arms, but they were lower in the ARNI arm compared controls (3107 vs. 4552 pg/mL, 112.2 vs. 120.4 and 68.8 vs. 75.6 mmHg, 108.4 vs. 112.6 mg/dL, 5.4 vs. 5.9 % and 5.9 vs. 6.4 mg/dL, respectively, p < 0.05). Mortality and re-hospitalization for HF was lower in the ARNI arm than controls (20.1 vs. 33.6 % and 27.7 vs. 46.3 % respectively; p < 0.05 for all). Gender differences were not found in either arm. No patients refused to continue the study, and no side effects to the ARNI treatment were observed.
In elderly patients with HFrEF and comorbidities, ARNI treatment seems effective and safe. The improvement in LVEF and cardiac remodeling, BP, eGFR, serum glucose, UA and HbA1c could be the mechanisms by which ARNIs play their beneficial role on clinical outcomes. However, these results need to be confirmed in studies involving a greater number of subjects, and with a longer follow-up.
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