scholarly journals Platelet Toll-like Receptors in Healthy and Acute Myocardial Infarction Subjects

2021 ◽  
Author(s):  
◽  
Kathryn Hally
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Platelet Activation ◽  
Healthy Subjects ◽  
High Dose ◽  
Toll Like Receptors ◽  
Chemokine Production ◽  
Tlr Agonists ◽  
Anti Platelet Therapy ◽  
Increased Risk

<p>Platelet activation is pathological in acute myocardial infarction (AMI). Despite treatment with dual anti-platelet therapy (DAPT), platelet activation can continue to occur post-AMI and has been linked to an increased risk of recurrent cardiovascular events. Toll-like receptors (TLRs) are important innate immune receptors, and platelets are known to express a subset of TLRs. The functional significance of these platelet-TLR pathways in AMI has not been fully examined but may contribute to persistent post-AMI platelet activation. Platelet-TLR expression, TLR-mediated platelet activation and the platelet effect on leukocyte responses to TLR stimulation were examined in this thesis.   Platelet-TLR expression and TLR-mediated platelet activation was examined for a subset of these receptors (TLR1, 2, 4, 6 and 9) in healthy subjects and in AMI subjects on DAPT. We observed an increase in platelet expression of TLR1, 4 and 9 in AMI platelets compared to healthy subjects. Further investigation into platelet-TLR9 expression showed an increase in expression upon platelet activation in healthy, but not AMI, subjects. We observed direct, dose-dependent platelet activation in response to Pam3CSK4 (TLR2/1 agonist) and ODN2009 (TLR9 agonist) in healthy subjects and in AMI on DAPT. For both cohorts, platelets were also directly activated by a high dose of LPS (TLR4 agonist) but were not directly activated by FSL-1 (TLR6 agonist). These results demonstrate that some (TLR1, 2, 4 and 9), but not other (TLR6), platelet-TLR pathways can cause platelet activation in AMI despite treatment with potent anti-platelet therapy.   For the results described above, we were unable to assess TLR-mediated platelet activation in the absence of anti-platelet therapy in AMI subjects as these drugs are administered before or immediately upon presentation to hospital. It was therefore not possible to exclude the possibility that DAPT was providing a degree of inhibition of platelet activation in AMI patients. To address this, we determined the extent to which aspirin monotherapy or DAPT could inhibit platelet activation in response to TLR2/1, TLR4 and TLR9 stimulation in a cross-over study in healthy subjects. We demonstrated that DAPT only modestly inhibited, and aspirin monotherapy did not inhibit, platelet activation in response to all TLR agonists tested and platelets still became potently activated despite treatment with anti-platelet agents. These platelet-TLRs represent intact on-treatment platelet activation pathways.   Lastly, we determined the extent to which platelets modulate leukocyte responses to TLR2/1, TLR2/6 and TLR4 stimulation. Platelets were able to reduce neutrophil responses to TLR stimulation, and modulated PBMC cytokine and chemokine production in a complex manner following stimulation with LPS and FSL-1. The presence of platelets did not change cytokine/chemokine production in response to Pam3CSK4, demonstrating a TLR agonist-specific manner of platelet modulation. We further investigated the effect of platelets on neutrophil responses to TLR stimulation. With platelets, neutrophil activation was attenuated, and phagocytic activity was increased in unstimulated cultures and in response to various doses of Pam3CSK4 and FSL-1. Neutrophil elastase secretion was attenuated in unstimulated cultures and in response to low-dose stimulation with all three TLR agonists. We show that platelets can both augment and attenuate various markers of neutrophil function.  Together, this work indicates that platelets express functional TLR pathways that can differentially regulate a number of thrombotic and inflammatory responses in healthy subjects and in subjects with AMI.</p>

scholarly journals Platelet Toll-like Receptors in Healthy and Acute Myocardial Infarction Subjects

2021 ◽  
Author(s):  
◽  
Kathryn Hally
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Platelet Activation ◽  
Healthy Subjects ◽  
High Dose ◽  
Toll Like Receptors ◽  
Chemokine Production ◽  
Tlr Agonists ◽  
Anti Platelet Therapy ◽  
Increased Risk

<p>Platelet activation is pathological in acute myocardial infarction (AMI). Despite treatment with dual anti-platelet therapy (DAPT), platelet activation can continue to occur post-AMI and has been linked to an increased risk of recurrent cardiovascular events. Toll-like receptors (TLRs) are important innate immune receptors, and platelets are known to express a subset of TLRs. The functional significance of these platelet-TLR pathways in AMI has not been fully examined but may contribute to persistent post-AMI platelet activation. Platelet-TLR expression, TLR-mediated platelet activation and the platelet effect on leukocyte responses to TLR stimulation were examined in this thesis.   Platelet-TLR expression and TLR-mediated platelet activation was examined for a subset of these receptors (TLR1, 2, 4, 6 and 9) in healthy subjects and in AMI subjects on DAPT. We observed an increase in platelet expression of TLR1, 4 and 9 in AMI platelets compared to healthy subjects. Further investigation into platelet-TLR9 expression showed an increase in expression upon platelet activation in healthy, but not AMI, subjects. We observed direct, dose-dependent platelet activation in response to Pam3CSK4 (TLR2/1 agonist) and ODN2009 (TLR9 agonist) in healthy subjects and in AMI on DAPT. For both cohorts, platelets were also directly activated by a high dose of LPS (TLR4 agonist) but were not directly activated by FSL-1 (TLR6 agonist). These results demonstrate that some (TLR1, 2, 4 and 9), but not other (TLR6), platelet-TLR pathways can cause platelet activation in AMI despite treatment with potent anti-platelet therapy.   For the results described above, we were unable to assess TLR-mediated platelet activation in the absence of anti-platelet therapy in AMI subjects as these drugs are administered before or immediately upon presentation to hospital. It was therefore not possible to exclude the possibility that DAPT was providing a degree of inhibition of platelet activation in AMI patients. To address this, we determined the extent to which aspirin monotherapy or DAPT could inhibit platelet activation in response to TLR2/1, TLR4 and TLR9 stimulation in a cross-over study in healthy subjects. We demonstrated that DAPT only modestly inhibited, and aspirin monotherapy did not inhibit, platelet activation in response to all TLR agonists tested and platelets still became potently activated despite treatment with anti-platelet agents. These platelet-TLRs represent intact on-treatment platelet activation pathways.   Lastly, we determined the extent to which platelets modulate leukocyte responses to TLR2/1, TLR2/6 and TLR4 stimulation. Platelets were able to reduce neutrophil responses to TLR stimulation, and modulated PBMC cytokine and chemokine production in a complex manner following stimulation with LPS and FSL-1. The presence of platelets did not change cytokine/chemokine production in response to Pam3CSK4, demonstrating a TLR agonist-specific manner of platelet modulation. We further investigated the effect of platelets on neutrophil responses to TLR stimulation. With platelets, neutrophil activation was attenuated, and phagocytic activity was increased in unstimulated cultures and in response to various doses of Pam3CSK4 and FSL-1. Neutrophil elastase secretion was attenuated in unstimulated cultures and in response to low-dose stimulation with all three TLR agonists. We show that platelets can both augment and attenuate various markers of neutrophil function.  Together, this work indicates that platelets express functional TLR pathways that can differentially regulate a number of thrombotic and inflammatory responses in healthy subjects and in subjects with AMI.</p>

scholarly journals Case report of an acute myocardial infarction after high-dose recreational nitrous oxide use: a consequence of hyperhomocysteinaemia?

2021 ◽  
Vol 5 (2) ◽  
Author(s):  
Thomas Oomens ◽  
Robert K Riezebos ◽  
Giovanni Amoroso ◽  
Remko S Kuipers
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Nitrous Oxide ◽  
Vitamin B12 ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
High Dose ◽  
Ventricular Ejection Fraction ◽  
Increased Risk ◽  
Very High

Abstract Background Nitrous oxide (N2O, laughing gas) is increasingly used as a recreational drug and is presumed relatively safe and innocent. It is often being used in combination with other substances, such as cannabis. Case summary A young adult attended the emergency room because of chest pain after recreational use of very high-dose nitrous oxide in combination with cannabis. Electrocardiography demonstrated ST-elevation in the anterior leads. Coronary angiography showed thrombus in the proximal and thrombotic occlusion of the distal left anterior descending coronary artery for which primary percutaneous coronary intervention was attempted. Thrombus aspiration was unsuccessful and the patient was further treated with a glycoprotein IIb/IIIa in addition to dual platelet therapy. Blood results showed low vitamin B12 and folic acid status with concomitant hyperhomocysteinaemia, a known cause of hypercoagulation. Transthoracic echocardiogram showed a moderately reduced left ventricular ejection fraction (LVEF). Three months later, an improvement in LVEF and no recurrent angina or symptoms of heart failure were noticed. Discussion We report a case of acute myocardial infarction secondary to very high-dose nitrous oxide abuse in combination with cannabis and possible hypoxia. We propose that severe hyperhomocysteinaemia secondary to nitrous oxide-induced vitamin B12 deficiency together with the vasoconstrictive effects of cannabis might pose a seriously increased risk for intracoronary, among others, thrombus formation. In conclusion, we contest the safety and innocence of recreational nitrous oxide (ab)use, notably in the context of other factors increasing the risk of coagulation.

Relationship Between Fibrinopeptide A and Fibrinogen/Fibrin Fragment E in Thromboembolism, DIC and Various Non-Thromboembolic Diseases

1987 ◽  
Vol 58 (02) ◽  
pp. 758-763 ◽  
Author(s):  
G Mombelli ◽  
R Monotti ◽  
A Haeberli ◽  
P W Straub
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Liver Cirrhosis ◽  
Healthy Subjects ◽  
Vascular Diseases ◽  
Fibrinopeptide A ◽  
Normal Range ◽  
Collagen Vascular Diseases ◽  
Intravascular Coagulation ◽  
Fibrin Formation

SummaryIncreased fibrinopeptide A (FPA) levels have been reported in various non-thrombotic disorders, including cancer, acute myocardial infarction, liver cirrhosis and collagen vascular diseases. To investigate the significance of these findings, the present study combined the radioimmunoassay of FPA with that of fibrinogen/fibrin degradation fragment E (FgE) in the aforementioned disorders and compared the results with those observed in healthy subjects as well as in patients with thromboembolism and overt disseminated intravascular coagulation (DIC). Mean FPA and FgE in malignancy were 6.3 and 305 ng/ml, in myocardial infarction 5.6 and 98 ng/ml, in liver cirrhosis 2.7 and 132 ng/ml and in collagen vascular diseases 5.6 and 142 ng/ml. All these values were significantly higher than in healthy controls (mean FPA 1.6 ng/ml, mean FgE 49 ng/ml) but significantly lower than in thromboembolism (mean FPA 10.7 ng/ml, mean FgE 639 ng/ ml) and DIC (mean FPA 22.0 ng/ml, mean FgE 1041 ng/ml). The overall correlation between FPA and FgE was highly significant. Elowever, different disorders showed peculiar patterns in FPA, FgE and fibrinogen levels. In malignancy, a definite increase of FPA, FgE and plasma fibrinogen levels was observed. This finding probably indicates a compensated state of (intra- or extravascular) fibrin formation and lysis. Acute myocardial infarction was characterized by a high FPA to FgE ratio, which is interpreted to reflect acute thrombin generation and fibrin formation. FPA in cirrhosis was only marginally elevated with most single values within the normal range, indicating that intravascular coagulation was infrequent and unimportant in quantitative terms.

scholarly journals MiR-126-3p and MiR-223-3p as Biomarkers for Prediction of Thrombotic Risk in Patients with Acute Myocardial Infarction and Primary Angioplasty

2021 ◽  
Vol 11 (6) ◽  
pp. 508
Author(s):  
Milan Hromadka ◽  
Zuzana Motovska ◽  
Ota Hlinomaz ◽  
Petr Kala ◽  
Frantisek Tousek ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Predictive Accuracy ◽  
Cardiovascular Death ◽  
Primary Angioplasty ◽  
Bleeding Complications ◽  
Clinical Predictors ◽  
Thrombotic Risk ◽  
Increased Risk ◽  
One Year

Aim. This study was designed to evaluate the relationship between microRNAs (miRNAs), miR-126-3p and miR-223-3p, as new biomarkers of platelet activation, and predicting recurrent thrombotic events after acute myocardial infarction (AMI). Methods and Results. The analysis included 598 patients randomized in the PRAGUE-18 study (ticagrelor vs. prasugrel in AMI). The measurements of miRNAs were performed by using a novel miRNA immunoassay method. The association of miRNAs with the occurrence of the ischemic endpoint (EP) (cardiovascular death, nonfatal MI, or stroke) and bleeding were analyzed. The miR-223-3p level was significantly related to an increased risk of occurrence of the ischemic EP within 30 days (odds ratio (OR) = 15.74, 95% confidence interval (CI): 2.07–119.93, p = 0.008) and one year (OR = 3.18, 95% CI: 1.40–7.19, p = 0.006), respectively. The miR-126-3p to miR-223-3p ratio was related to a decreased risk of occurrence of EP within 30 days (OR = 0.14, 95% CI: 0.03–0.61, p = 0.009) and one year (OR = 0.37, 95% CI: 0.17–0.82, p = 0.014), respectively. MiRNAs were identified as independent predictors of EP even after adjustment for confounding clinical predictors. Adding miR-223-3p and miR-126-3p to miR-223-3p ratios as predictors into the model calculating the ischemic risk significantly increased the predictive accuracy for combined ischemic EP within one year more than using only clinical ischemic risk parameters. No associations between miRNAs and bleeding complications were identified. Conclusion. The miR-223-3p and the miR-126-3p are promising independent predictors of thrombotic events and can be used for ischemic risk stratification after AMI.

scholarly journals Individuals with familial hypercholesterolemia have increased risk of re-hospitalization after acute myocardial infarction compared with controls

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K Svendsen ◽  
H.W Krogh ◽  
J Igland ◽  
G.S Tell ◽  
L.J Mundal ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Familial Hypercholesterolemia ◽  
Cox Regression ◽  
Public Institution ◽  
University Hospital ◽  
Funding Source ◽  
Hazard Ratios ◽  
Increased Risk ◽  
University Of Oslo

Abstract Background and aim We have previously reported that individuals with familial hypercholesterolemia (FH) have a two-fold increased risk of acute myocardial infarction (AMI) compared with the general population. The consequences of having an AMI on re-hospitalization and mortality are however less known. The aim of the present study was to compare the risk of re-hospitalization with AMI and CHD and risk of mortality after incident (first) AMI-hospitalization between persons with and without FH (controls). Methods The original study population comprised 5691 persons diagnosed with FH during 1992–2014 and 119511 age and sex matched controls randomly selected from the general Norwegian population. We identified 221 individuals with FH and 1947 controls with an incident AMI registered in the Norwegian Patient Registry (NPR) or the Cardiovascular Disease in Norway Project during 2001–2017. Persons with incident AMI were followed until December 31st 2017 for re-hospitalization with AMI or coronary heart disease (CHD) registered in the NPR, and for mortality through linkage to the Norwegian Cause of Death Registry. Risk of re-hospitalization was compared with sub-hazard ratios (SHR) from competing risk regression with death as competing event, and mortality was compared using hazard ratios (HR) from Cox regression. All models were adjusted for age. Results Risk of re-hospitalization was 2-fold increased both for AMI [SHR=2.53 (95% CI: 1.88–3.41)] and CHD [SHR=1.82 (95% CI: 1.44–2.28)]. However, persons with FH did not have increased 28-day mortality following an incident AMI (HR=1.05 (95% CI: 0.62–1.78), but the longer-term (&gt;28 days) mortality after first AMI was increased in FH [HR=1.45 (95% CI: 1.07–1.95]. Conclusion This study yields the important finding that persons with FH have increased risk of re-hospitalization of both AMI and CHD after incident AMI. These findings call for more intensive follow-up of individuals with FH after an AMI. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): University of Oslo and Oslo University Hospital

scholarly journals 2.5-fold increased risk of recurrent acute myocardial infarction with familial hypercholesterolemia

2020 ◽  
Author(s):  
Karianne Svendsen ◽  
Henriette W. Krogh ◽  
Jannicke Igland ◽  
Grethe S. Tell ◽  
Liv J. Mundal ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Familial Hypercholesterolemia ◽  
Increased Risk

scholarly journals Role of diuretics on long-term mortality may differ in volume status in patients with acute myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Kawai ◽  
D Nakatani ◽  
T Yamada ◽  
T Watanabe ◽  
T Morita ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Propensity Score ◽  
Plasma Volume ◽  
Cox Regression ◽  
Volume Status ◽  
Increased Risk ◽  
Long Term Mortality

Abstract Background Diuretics has been reported to have a potential for an activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system, leading to a possibility of poor clinical outcome in patients with cardiovascular disease. However, few data are available on clinical impact of diuretics on long-term outcome in patients with acute myocardial infarction (AMI) based on plasma volume status. Methods To address the issue, a total of 3,416 survived patients with AMI who were registered to a large database of the Osaka Acute Coronary Insufficiency Study (OACIS) were studied. Plasma volume status was assessed with the estimated plasma volume status (ePVS) that was calculated at discharge as follows: actual PV = (1 − hematocrit) × [a + (b × body weight)] (a=1530 in males and a=864 in females, b=41.0 in males and b=47.9 in females); ideal PV = c × body weight (c=39 in males and c=40 in females), and ePVS = [(actual PV − ideal PV)/ideal PV] × 100 (%). Multivariable Cox regression analysis and propensity score matching were performed to account for imbalances in covariates. The endpoint was all-cause of death (ACD) within 5 years. Results During a median follow-up period of 855±656 days, 193 patients had ACD. In whole population, there was no significant difference in long-term mortality risk between patients with and without diuretics in both multivariate cox regression model and propensity score matching population. When patients were divided into 2 groups according to ePVS with a median value of 4.2%, 46 and 147 patients had ACD in groups with low ePVS and high ePVS, respectively. Multivariate Cox analysis showed that use of diuretics was independently associated with an increased risk of ACD in low ePVS group, (HR: 2.63, 95% confidence interval [CI]: 1.22–5.63, p=0.01), but not in high ePVS group (HR: 0.70, 95% CI: 0.44–1.10, p=0.12). These observations were consistent in the propensity-score matched cohorts; the 5-year mortality rate was significantly higher in patients with diuretics than those without among low ePVS group (4.7% vs 1.7%, p=0.041), but not among high ePVS group (8.0% vs 10.3%, p=0.247). Conclusion Prescription of diuretics at discharge was associated with increased risk of 5-year mortality in patients with AMI without PV expansion, but not with PV expansion. The role of diuretics on long-term mortality may differ in plasma volume status. Therefore, prescription of diuretics after AMI may be considered based on plasma volume status. Funding Acknowledgement Type of funding source: None

The ratio of circulating endothelin-1 to endothelin-3 associated with TIMI risk and dynamic TIMI risk score in ST elevation acute myocardial infarction

2020 ◽  
Vol 98 (9) ◽  
pp. 637-643 ◽  
Author(s):  
Anggoro Budi Hartopo ◽  
Ira Puspitawati ◽  
Hasanah Mumpuni
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Risk Score ◽  
Multivariable Analysis ◽  
Primary Objective ◽  
St Segment Elevation ◽  
Timi Score ◽  
Increased Risk ◽  
Timi Risk Score ◽  
Elevation Acute Myocardial Infarction

In ST segment elevation acute myocardial infarction (STEMI), the endothelin (ET) system imbalance, reflected by the circulating ET-1:ET-3 ratio has not been investigated. This study’s primary objective was to measure the circulating ET-1:ET-3 ratio and correlate it with the risk stratification for 1 year mortality of STEMI based on TIMI score. On admission, the TIMI risk score and at discharge, the dynamic TIMI risk score were calculated in 68 consecutive subjects with STEMI. Subjects with high TIMI risk score were associated with higher mean ET-1 level and ET-1:ET-3 ratio. The ET-1:ET-3 ratio more accurately predicted the high on admission TIMI risk score than the ET-1 level. Subjects with high dynamic TIMI risk score were associated with higher mean ET-1 level and ET-1:ET-3 ratio. The ET-1:ET-3 ratio more accurately predicted the high at discharge dynamic TIMI risk score than ET-1 level. From multivariable analysis, the ET-1:ET-3 ratio was not independently associated with high on admission TIMI risk score but independently predicted high at discharge dynamic TIMI risk score (odds ratio = 9.186, p = 0.018). In conclusion, combining the ET-1 and ET-3 levels into the ET-1:ET-3 ratio provided a prognostic value by independently predicting the increased risk to 1 year mortality as indicated by at discharge dynamic TIMI risk score in patients with STEMI.

Abstract 803: Diesel Exhaust Inhalation Enhances Thrombus Formation In Man

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Andrew J Lucking ◽  
Magnus Lundback ◽  
Nicholas L Mills ◽  
Dana Faratian ◽  
Fleming Cassee ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Air Pollution ◽  
Platelet Activation ◽  
Diesel Exhaust ◽  
Intermittent Exercise ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Ex Vivo Model ◽  
Double Blind

Background: Transient exposure to traffic-derived air pollution may be a trigger for acute myocardial infarction although the mechanism is unclear. The aim of this study was to investigate the effect of diesel exhaust inhalation on thrombus formation in man using an ex vivo model of thrombosis. Methods and Results: In a double-blind randomized cross-over study, 20 healthy volunteers were exposed to diluted diesel exhaust (300 μg/m3) or filtered air during intermittent exercise for 1 or 2 hours. Thrombus formation, coagulation, platelet activation and inflammatory markers were measured at 2 and 6 hours after exposure. Thrombus formation was measured using the Badimon ex vivo perfusion chamber at low (212 /s) and high (1,690 /s) shear rates with porcine aortic tunica media as the thrombogenic substrate. Specimens were fixed, stained and thrombus area measured using computerized planimetry. Compared to filtered air, diesel exhaust increased thrombus formation in the low and high shear chambers by 24.2% (p<0.001) and 19.1% (p<0.001) respectively. This increased thrombogenicity was seen at two and six hours, and using two different types of diesel exposure. Although there were no effects on coagulation variables, diesel exhaust inhalation increased platelet-neutrophil (6.5% to 9.2%; P<0.05) and platelet-monocyte (21.0% to 25.0%; P<0.05) aggregates 2 hours following exposure. Conclusions: Inhalation of diesel exhaust increases ex vivo thrombus formation and causes platelet activation in man. These findings provide a potential mechanism that links exposure to traffic-derived air pollution with acute atherothrombotic events including acute myocardial infarction.

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