TAVR: nemesis of NOACs?

Data on non-vitamin K antagonist oral anticoagulants (NOACs) in transcatheter aortic valve replacement (TAVR) patients are controversial. In patients without atrial fibrillation (AF), rivaroxaban showed enhanced ischemia and bleeding as compared to standard of care. ENVISAGE showed enhanced bleeding in AF patients as compared to vitamin K antagonist (VKA). Only apixaban was non-inferior but failed superiority regarding bleeding in AF patients after TAVR. One could hypothesize that this might be due to pharmacokinetics of NOACs. Therefore, we compared outcome in rivaroxaban/edoxaban (once-daily) and apixaban (twice-daily) treated patients. 568 patients with indication for permanent oral anticoagulation due to AF undergoing TAVR were analyzed via inverse probability of treatment weighting. Valve academic research consortium complications during 30-day follow-up were assessed. Bleeding complications were similar in once-daily and twice-daily NOACs (major: 22 (7.5%) vs. 14 (5.3%), p = 0.285; minor: 66 (22.4%) vs. 46 (17.4%), p = 0.133). Complications did not change when splitting the cohort in the different agents apixaban, rivaroxaban and edoxaban. These findings remained robust after multivariate analysis. In summary, twice-daily and once-daily NOACs did not differ regarding bleeding complications in a hypothesis generating real-world cohort of TAVR patients with AF.

High On-Treatment Platelet Reactivity: Aspirin versus Clopidogrel.

BACKGROUND: Antithrombotic regimen in patients on oral anticoagulation (OAC) post-percutaneous coronary intervention (PCI) is challenging. At least, one antiplatelet agent in combination with OAC is recommended after PCI for 6-12 months. Clopidogrel is used most frequently in this setting. However, data comparing P2Y12 inhibition with clopidogrel versus cyclooxygenase inhibition by acetylsalicylic acid (ASA, aspirin) is missing. It is well known that the antiplatelet effects of ASA and clopidogrel are frequently impaired (high on-treatment platelet reactivity [HTPR]). In this pilot investigation, we compared the antiplatelet effects of clopidogrel versus ASA. METHODS: In this retrospective single-center database analysis, we investigated platelet reactivity by light transmission aggregometry in patients under different antiplatelet regimes. Results were presented as maximum of aggregation (MoA). HTPR to ASA and to clopidogrel were assessed. RESULTS: 755 patients were enrolled. 677 were on ASA, 521 were on clopidogrel, and 198 had OAC. Overall mean age was 73 ± 13.4 years, and 458 (60.7%) were male. HTPR to ASA occurred in 94/677 patients (13.9%), and mean arachidonic acid-induced MoA was 14.15 ± 19.04%. HTPR to clopidogrel occurred in 241/521 patients (46.3%), and mean adenosine diphosphate-induced MoA was 50.06 ± 20.42%. HTPR to clopidogrel was significantly more frequent than HTPR to ASA; single antiplatelet therapy (SAPT)-mono ASA: 27/199 (13.6%) versus mono clopidogrel: 6/18 (33.3%); p = 0.037; SAPT with OAC-OAC with ASA: 8/35 (22.9%) versus OAC with clopidogrel: 27/60 (45%); p = 0.046. Same difference in HTPR contingency could be shown in subgroups of dual antiplatelet therapy and ASA + clopidogrel + OAC therapy. CONCLUSION: Impaired pharmacodynamic response to clopidogrel was more frequent as HTPR to ASA. Hence, ASA should be tested in combination with OAC post-PCI.

Rivaroxaban Reduces Arterial Thrombosis by Inhibition of FXa-Driven Platelet Activation via Protease Activated Receptor-1.

RATIONALE: A reduced rate of myocardial infarction has been reported in patients with atrial fibrillation treated with FXa (factor Xa) inhibitors including rivaroxaban compared with vitamin K antagonists. At the same time, low-dose rivaroxaban has been shown to reduce mortality and atherothrombotic events in patients with coronary artery disease. Yet, the mechanisms underlying this reduction remain unknown. OBJECTIVE: In this study, we hypothesized that rivaroxaban's antithrombotic potential is linked to a hitherto unknown rivaroxaban effect that impacts on platelet reactivity and arterial thrombosis. METHODS AND RESULTS: In this study, we identified FXa as potent, direct agonist of the PAR-1 (protease-activated receptor 1), leading to platelet activation and thrombus formation, which can be inhibited by rivaroxaban. We found that rivaroxaban reduced arterial thrombus stability in a mouse model of arterial thrombosis using intravital microscopy. For in vitro studies, atrial fibrillation patients on permanent rivaroxaban treatment for stroke prevention, respective controls, and patients with new-onset atrial fibrillation before and after first intake of rivaroxaban (time series analysis) were recruited. Platelet aggregation responses, as well as thrombus formation under arterial flow conditions on collagen and atherosclerotic plaque material, were attenuated by rivaroxaban. We show that rivaroxaban's antiplatelet effect is plasma dependent but independent of thrombin and rivaroxaban's anticoagulatory capacity. CONCLUSIONS: Here, we identified FXa as potent platelet agonist that acts through PAR-1. Therefore, rivaroxaban exerts an antiplatelet effect that together with its well-known potent anticoagulatory capacity might lead to reduced frequency of atherothrombotic events and improved outcome in patients.

Dapagliflozin reduces thrombin generation and platelet activation: implications for cardiovascular risk reduction in type 2 diabetes mellitus.

AIMS/HYPOTHESIS: People with diabetes have an increased cardiovascular risk with an accelerated development of atherosclerosis and an elevated mortality rate after myocardial infarction. Therefore, cardioprotective effects of glucose-lowering therapies are of major importance for the pharmacotherapy of individuals with type 2 diabetes. For sodium-glucose cotransporter 2 inhibitors (SGLT2is), in addition to a reduction in blood glucose, beneficial effects on atherosclerosis, obesity, renal function and blood pressure have been observed. Recent results showed a reduced risk of worsening heart failure and cardiovascular deaths under dapagliflozin treatment irrespective of the diabetic state. However, the underlying mechanisms are yet unknown. Platelets are known drivers of atherosclerosis and atherothrombosis and disturbed platelet activation has also been suggested to occur in type 2 diabetes. Therefore, the present study investigates the impact of the SGLT2i dapagliflozin on the interplay between platelets and inflammation in atherogenesis. METHODS: Male, 8-week-old LDL-receptor-deficient (Ldlr-/-) mice received a high-fat, high-sucrose diabetogenic diet supplemented without (control) or with dapagliflozin (5 mg/kg body weight per day) for two time periods: 8 and 25 weeks. In a first translational approach, eight healthy volunteers received 10 mg dapagliflozin/day for 4 weeks. RESULTS: Dapagliflozin treatment ameliorated atherosclerotic lesion development, reduced circulating platelet-leucocyte aggregates (glycoprotein [GP]Ib+CD45+: 29.40 ± 5.94 vs 17.00 ± 5.69 cells, p < 0.01; GPIb+lymphocyte antigen 6 complex, locus G+ (Ly6G): 8.00 ± 2.45 vs 4.33 ± 1.75 cells, p < 0.05) and decreased aortic macrophage infiltration (1.31 ± 0.62 vs 0.70 ± 0.58 ×103 cells/aorta, p < 0.01). Deeper analysis revealed that dapagliflozin decreased activated CD62P-positive platelets in Ldlr-/- mice fed a diabetogenic diet (3.78 ± 1.20% vs 2.83 ± 1.06%, p < 0.01) without affecting bleeding time (85.29 ± 37.27 vs 89.25 ± 16.26 s, p = 0.78). While blood glucose was only moderately affected, dapagliflozin further reduced endogenous thrombin generation (581.4 ± 194.6 nmol/l × min) × 10-9 thrombin vs 254.1 ± 106.4 (nmol/l × min) × 10-9 thrombin), thereby decreasing one of the most important platelet activators. We observed a direct inhibitory effect of dapagliflozin on isolated platelets. In addition, dapagliflozin increased HDL-cholesterol levels. Importantly, higher HDL-cholesterol levels (1.70 ± 0.58 vs 3.15 ± 1.67 mmol/l, p < 0.01) likely contribute to dapagliflozin-mediated inhibition of platelet activation and thrombin generation. Accordingly, in line with the results in mice, treatment with dapagliflozin lowered CD62P-positive platelet counts in humans after stimulation by collagen-related peptide (CRP; 88.13 ± 5.37% of platelets vs 77.59 ± 10.70%, p < 0.05) or thrombin receptor activator peptide-6 (TRAP-6; 44.23 ± 15.54% vs 28.96 ± 11.41%, p < 0.01) without affecting haemostasis. CONCLUSIONS/INTERPRETATION: We demonstrate that dapagliflozin-mediated atheroprotection in mice is driven by elevated HDL-cholesterol and ameliorated thrombin-platelet-mediated inflammation without interfering with haemostasis. This glucose-independent mechanism likely contributes to dapagliflozin's beneficial cardiovascular risk profile.

Aspirin I.V. Loading during Elective Percutaneous Coronary Intervention.

Additional loading dose of acetylsalicylic acid (ASA) during percutaneous coronary interventions (PCIs) despite permanent oral ASA medication is frequently applicated. The impact on platelet reactivity and clinical events is not known. In this pilot study, we aimed to analyze high on-treatment platelet reactivity (HTPR) to aspirin in patients undergoing elective PCI. Platelet reactivity was measured using light-transmission aggregometry in 100 patients on permanent low-dose ASA medication undergoing elective PCI. Platelet reactivity measured by arachidonic acid-induced maximum of aggregation (MoA) in patients with versus without additional peri-procedural ASA loading (500 mg i.v.) was compared. HTPR was defined as MoA >20% for ASA. Major adverse cerebro- and cardiovascular events (MACCEs) and bleeding events were evaluated during hospital course. HTPR rate was similar in both groups (HTPR to ASA: loading vs. control 6% vs. 16%, odds ratio [OR] = 0.33, 95% confidence interval [CI] 0.08-1.35, p = 0.12). In-hospital MACCEs were not different between groups (MACCE: loading vs. control: 0 vs. 0 patient, OR = 1.32, 95% CI 0.03-67.95, p = 0.89). Thrombolysis in myocardial infarction minimal bleedings were numerically higher in patients without ASA loading dose. In this pharmacodynamic pilot study, additional ASA loading did not reduce HTPR to ASA. Furthermore, ASA loading did not increase in-hospital MACCE and bleeding complications.

MTX Treatment Does Not Improve Outcome in Mice with AMI.

BACKGROUND: Targeting inflammation in patients with coronary artery disease and/or acute myocardial infarction (AMI) is a matter of debate. Methotrexate (MTX) is one of the most widely used immunosuppressants. Cardiovascular Inflammation Reduction Trial (CIRT) recently failed to demonstrate reduced cardiovascular events in MTX-treated patients. However, it is not known if long-term MTX treatment improves cardiac outcome in AMI. Therefore, in this study, we investigated the postischemic phase in MTX-treated mice undergoing AMI. METHODS: Wild-type mice received MTX medication intraperitoneally for 2 weeks. Afterward, AMI was induced by transient left anterior ascending artery ligation. Postischemic cardiac damage after 24 h was assessed. RESULTS: MTX treatment did not affect infarct size as compared to control (IS/AAR: Con 76.20% ± 12.37%/AAR vs. MTX 73.51 ± 11.72%/AAR, p = 0.64). Moreover, systolic function and structural parameters did not differ between groups (24hejection fraction: Con 36.49 ± 3.23% vs. MTX 32.77 ± 2.29%, p = 0.41; 24hLVID; d: Con 3.57 ± 0.17 mm vs. MTX 3.19 ± 0.13 mm, p = 0.14). Platelets were increased by MTX (Con 1,442 ± 69.20 × 103/mm3 vs. MTX 1,920 ± 68.68 × 103/mm3, p < 0.0001). White blood cell and RBC as well as rate of monocytes, granulocytes, lymphocytes, and serum amyloid P levels were equal. CONCLUSION: MTX medication did not improve postischemic cardiac damage in a murine model of AMI. Future trials are needed to identify and investigate other anti-inflammatory targets to improve cardiovascular outcome.

A novel mechanism of ACE inhibition-associated enhanced platelet reactivity: disproof of the ARB-MI paradox?

PURPOSE: ACE inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are important drugs in cardiovascular disease. However, little is known about which of these drug class is to be preferred. First analyses show that the blockade of the renin-angiotensin-aldosterone system (RAAS) influences platelet reactivity. Therefore, we evaluated the effects of ACEI and ARB on platelet reactivity and thrombin generation. METHODS: We conducted a time series analysis in 34 patients. We performed light transmission aggregometry (LTA) to evaluate platelet reactivity. Results are given as maximum of aggregation (MoA). Thrombin generation was measured as endogenous thrombin potential (ETP) via calibrated automated thrombogram. Flow cytometry was used to analyze protease-activated receptor (PAR)-1 expression. RESULTS: ACEI treatment significantly increased platelet reactivity already 4 h after initiation of treatment (prior vs. 4 h post ACEI: MoA 41.9 ± 16.2% vs. 55.2 ± 16.7%; p = 0.003). After switching from ACEI to ARB treatment, platelet reactivity decreased significantly (3 months after switching: MoA 34.7 ± 20.9%; p = 0.03). ACEI reduced endogenous thrombin potential significantly from before to 3 months after ACEI (ETP 1527 ± 437 nM × min vs. 1088 ± 631 nM × min; p = 0.025). Platelet thrombin receptor (PAR1) expression increased from 37.38 ± 10.97% before to 49.53 ± 6.04% after ACEI treatment (p = 0.036). CONCLUSION: ACEI enhanced platelet reactivity. This can be reversed by changing to ARB. The mechanism behind RAAS influencing platelet function seems to be associated with PAR-1 expression.

Platelet reactivity in patients with chronic kidney disease and hemodialysis.

End stage renal disease requiring hemodialysis (HD) is frequent and coronary artery disease (CAD) is a common comorbidity. It is associated with bleeding and ischemic events. Platelet reactivity is a well-known determinant of both. However, the impact of HD due to end stage chronic kidney disease (CKD) on platelet reactivity is unknown. Therefore in this study, we evaluated platelet reactivity during hemodialysis in patients with CKD and coronary artery disease. 22 patients with CKD, HD and CAD were included in this study. Light transmission aggregometry (LTA) and flow cytometry were used for evaluating platelet function immediately before and 2 h after initiation of HD. Arachidonic acid-induced maximum of aggregation (MoApre HD: 27.36% ± 25.23% vs. MoAduring HD: 28.05% ± 23.50%, p value = 0.822), adenosine diphosphate (ADP)-induced platelet aggregation (MoApre HD: 65.36% ± 12.88% vs. MoAduring HD: 61.55% ± 17.17%, p-value = 0.09) and collagen-induced platelet aggregation (MoApre HD: 62.18% ± 18.14% vs. MoAduring HD: 64.82% ± 18.31%, p-value = 0.375) were not affected by HD. P-selectin expression was significantly lower after 2 h of HD (pre HD: 31.56% ± 18.99%, during HD: 23.97% ± 15.28%, p = 0.026). In this pilot study, HD did not enhance platelet aggregation. Baseline platelet reactivity was decreased during HD.

Enhanced Platelet Reactivity under Aspirin Medication and Major Adverse Cardiac and Cerebrovascular Events in Patients with Coronary Artery Disease.

Aspirin is indispensable in secondary prevention of ischemic events in patients with coronary artery disease (CAD). However, insufficient platelet inhibition despite aspirin medication is frequent. This is referred to as high on-treatment platelet reactivity (HTPR). Nevertheless, if this is associated with clinical outcome instead of only laboratory phenomenon remains unclear so far. In this study, we test whether patients with ischemic events have higher platelet reactivity despite aspirin medication than patients without ischemic events. In this prospective study of 72 CAD patients, we determined pharmacodynamic response to aspirin by arachidonic acid induced aggregation via light-transmission aggregometry and expressed as maximum of aggregation (MoA). During a mean follow-up duration of 3.2 years, major adverse cardiac and cerebrovascular events (MACCE), mortality, non-ST-elevation myocardial infarction (NSTEMI), and stroke were assessed as endpoints via yearly telephone interviews with the treating physician of the patients. Patients who suffered from MACCE, death, and NSTEMI had a significantly higher MoA than those without (MACCE: 5.4 vs. 16.4%, p < 0.05; death: 5.6 vs. 16.8%, p < 0.05; NSTEMI: 1.8 vs. 21%, p < 0.001). MoA did not differ with regard to the occurrence of stroke (10.1 vs. 14.9%, p = 0.59). Patients with MACCE, death, and NSTEMI show enhanced platelet reactivity despite aspirin medication as compared to patients without ischemic events. Hence, insufficient response to aspirin medication should be regarded as risk factor for ischemic events in CAD patients. Further trials are needed to assess options to overcome HTPR to aspirin.

Platelet Reactivity in Patients on Aspirin and Clopidogrel Therapy Measured by a New Bedside Whole-Blood Assay.

Various tests are available for measuring on-treatment platelet reactivity. The pharmacologically most specific assays are time-consuming and elaborate. A highly specific and convenient assay would be desirable for clinical routine. In this pilot study, we aimed to examine the ability of a novel bedside whole-blood assay-ROTEM platelet-to evaluate platelet inhibition compared with established assays. Platelet reactivity was investigated in 93 patients. Forty-Seven patients were on permanent aspirin therapy and 46 on dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. We used ROTEM platelet impedance aggregometry (ROTEM-PTL), light transmission aggregometry (LTA), Multiplate electrode aggregometry (MEA) and vasodilator-stimulated phosphoprotein flow cytometry. Receiver operating characteristic (ROC) analyses showed ROTEM-PTL differentiates well between patients on medication and healthy individuals: aspirin: ROCAUC 0.99 (95% confidence interval, 0.97-1.01); P < 0.0001; DAPT treatment: ROCAUC 0.80 (95% confidence interval, 0.69-0.91); P < 0.001. Pearson regression analyses showed moderate correlations between assays. Aspirin: MEA versus ROTEM-PTL r = 0.435, P ≤ 0.001; LTA versus ROTEM-PTL r = 0.048, P = 0.180. DAPT: MEA versus ROTEM-PTL r = 0.398, P = 0.001; LTA versus ROTEM-PTL r = 0.409, P = 0.001; vasodilator-stimulated phosphoprotein versus ROTEM-PTL r = 0.164, P = 0.055. ROTEM platelet distinguished well between treated and healthy individuals but correlated moderately with other assays. Clinical trials are needed to investigate the ability of this new assay to identify patients at risk of adverse events.

Dose reduction, oral application, and order of intake to preserve aspirin antiplatelet effects in dipyrone co-medicated chronic artery disease patients.

BACKGROUND: Dipyrone comedication in aspirin-treated patients is associated with impaired pharmacodynamic response to aspirin (high on-treatment platelet reactivity [HTPR]). Additionally, in small observational studies, an association with impaired outcome has been described. In this uncontrolled, hypothesis-generating study, we aimed to investigate strategies to prevent this drug-drug interaction in patients with coronary artery disease (CAD). METHODS: We analyzed pharmacodynamic response to aspirin in 80 dipyrone co-medicated CAD patients. Aspirin antiplatelet effects were measured using arachidonic acid (AA)-induced light-transmission aggregometry (LTA). Platelet reactivity was associated with daily dose, administration form, and frequency. Additionally, we conducted a time-series analysis in patients with HTPR to aspirin with re-evaluation of pharmacodynamic response to aspirin after 5 days. RESULTS: Patients' mean age was 75.5 ± 9.8 years. Forty-three (54%) were male, 22 (27.5%) obese, and 38 (47.5%) diabetics. Baseline characteristics, cardiovascular risk factors, comorbidities, comedication, or laboratory parameters did not differ between patients with or without HTPR. HTPR to aspirin occurred in 34 out of 80 patients (42.5%). The incidence of HTPR was associated with dipyrone daily dose (< 1 g/day: HTPR 20% vs. > 3 g/day: HTPR 50%, p > 0.0001) and form of administration (i.v. 87.5% vs. oral 37.5%; p < 0.0001). A strict order of intake (aspirin 30 min prior to dipyrone) restored aspirin antiplatelet effects in all patients (HTPR before 100% vs. HTPR after 0%, p = 0.0002). CONCLUSION: This study shows that dipyrone should be used with caution in aspirin-treated patients. If dipyrone seems indispensable, the lowest effective dose and a strict order of intake seem favorable.

Malondialdehyde Assay in the Evaluation of Aspirin Antiplatelet Effects.

Aspirin is essential in secondary prevention of patients after myocardial infarction and with coronary artery disease. However, impaired pharmacodynamic response to aspirin is frequent (high on-treatment platelet reactivity [HTPR]). This leads to an enhanced prevalence of cardiovascular events and to an impaired clinical outcome. The current specific assays to evaluate aspirin antiplatelet effects are complex, time-consuming and demand for a high laboratory expertise. Therefore, we developed a potentially bedside assay based on the determination of malondialdehyde (MDA). MDA is a by-product of the thromboxane (TX) formation, which is synthesized in equimolar concentrations. In this study, we compared this MDA assay to the conventional assays in determination of pharmacodynamic aspirin response. For this, aspirin antiplatelet effects were measured in 22 healthy individuals and 63 aspirin treated patients using TX B2 formation enzyme-linked antibody assay, arachidonic acid induced light transmission aggregometry (LTA) and the new fluorometric MDA assay. In patients, MDA levels correlated well with TX formation (R = 0.81; 95% CI 0.69-0.88; p < 0.001) and LTA (R = 0.84; CI 0.74-0.91; p < 0.001). Receiver operating characteristic analyses revealed that the MDA assay does detect HTPR to aspirin sufficiently (area under the curve: 0.965; p < 0.001). The optimal cut-off was > 128 nmol/L (sensitivity of 100%, specificity of 91%). The new MDA assay is reliable in detecting HTPR. It is highly specific in the evaluation of antiplatelet effects by aspirin. This promising and potential bedside assay needs to be evaluated in clinical practice.

Safety and Efficacy in Prasugrel- Versus Ticagrelor-Treated Patients With ST-Elevation Myocardial Infarction.

Prasugrel and ticagrelor are recommended over clopidogrel in patients with ST-elevation myocardial infarction (STEMI). In this registry analysis, we compared efficacy and safety of ticagrelor and prasugrel P2Y12 inhibition in patients with STEMI. We included 318 patients in this single-center analysis. Twelve-month follow-up was conducted during ambulatory care at our department. Patients were on dual antiplatelet therapy with aspirin and ticagrelor or prasugrel during the follow-up period. Prescription of prasugrel or ticagrelor, respectively, was according to the preference of the treating physician. Major adverse cardiac and cerebrovascular events (MACCE) [death, myocardial infarction (MI), stroke, and unplanned reintervention] and thrombolysis in myocardial infarction (TIMI) bleeding (major/minor) were registered during hospitalization and follow-up. TIMI bleeding events were more frequent in ticagrelor-treated patients [17 vs. 5 patients, hazard ratio (HR) 2.85, 95% confidence interval (CI) 1.2-6.6; log-rank P value = 0.01]. Prasugrel-treated patients were significantly younger (ticagrelor 63 ± 12 years vs. prasugrel 57 ± 10; P < 0.0001). Besides that, patients' characteristics were similar in both groups. Multivariate analysis revealed that ticagrelor medication was independently associated with bleeding risk after adjustment for age, percutaneous coronary intervention approach (femoral vs. radial), diabetes mellitus, and kidney function (HR 3.01; 95% CI 1.0-7.4; P = 0.043). In patients treated with ticagrelor, 35 MACCE were detected. There was no difference as compared to prasugrel-treated patients (24 events, HR 1.24, 95% CI 0.79-2.09; log-rank P value = 0.41). TIMI bleeding events were more frequent in ticagrelor-treated patients with STEMI during 12-month follow-up. There were no differences in MACCE between groups in this registry analysis.

Heparin dosing in patients with Impella-supported cardiogenic shock.

BACKGROUND: Impella™ is increasingly used in cardiogenic shock. However, thromboembolic and bleeding events are frequent during percutaneous mechanical circulatory support (pMCS). OBJECTIVE: Therefore, we aimed to explore the optimal anticoagulation regime for pMCS to prevent thromboembolism and bleedings. METHODS: This hypothesis-generating multi-center cohort study investigated 170 patients with left-Impella™ support. We (A) compared bleeding/thrombotic events in two centers with therapeutic range (TR-aPTT) activated partial thromboplastin time (60-80s) and (B) compared events of these centers with one center with intermediate range aPTT (40-60s). RESULTS: After matching, there were no differences in patients' characteristics. In centers aiming at TR-aPTT, major bleeding was numerically lower with aPTT <60s within 48 h of left-Impella™ support, versus patients that achieved the aimed aPTT of ≥60s [aPTT ≥60s: 22 (37.3%) vs. aPTT<60s 14 (23.7%); Hazard ratio [HR], 0.62 (95%) CI, 0.28-1.38; p = 0.234]. Major cardiovascular and cerebrovascular adverse events (MACCE) did not differ between groups. In comparison of centers, TR-aPTT strategy showed higher major bleeding rates [TR: 8 (47.1%) vs. intermediate range: 1 (5.9%); HR, 0.06 (95%) CI, 0.01-0.45; p = 0.006]. MACCE were lower in the intermediate range aPTT group as well [TR 12 (70.6%) vs. intermediate range 5 (29.4%) HR, 0.32 (95%) CI, 0.11-0.92; p = 0.034]. CONCLUSION: This pilot analysis showed that lowering UFH-targets in left-Impella™ supported CS patients seems to be a safe and promising strategy for reducing major bleedings without increasing MACCE. This needs to be validated in larger, randomized clinical trials.

Sphingosine-1-phosphate improves outcome of no-reflow acute myocardial infarction via sphingosine-1-phosphate receptor 1.

AIMS: Therapeutic options targeting post-ischaemic cardiac remodelling are sparse. The bioactive sphingolipid sphingosine-1-phosphate (S1P) reduces ischaemia/reperfusion injury. However, its impact on post-ischaemic remodelling independently of its infarct size (IS)-reducing effect is yet unknown and was addressed in this study. METHODS AND RESULTS: Acute myocardial infarction (AMI) in mice was induced by permanent ligation of the left anterior descending artery (LAD). C57Bl6 were treated with the S1P lyase inhibitor 4-deoxypyridoxine (DOP) starting 7 days prior to AMI to increase endogenous S1P concentrations. Cardiac function and myocardial healing were assessed by cardiovascular magnetic resonance imaging (cMRI), murine echocardiography, histomorphology, and gene expression analysis. DOP effects were investigated in cardiomyocyte-specific S1P receptor 1 deficient (S1PR1 Cardio Cre+) and Cre- control mice and S1P concentrations measured by LC-MS/MS. IS and cardiac function did not differ between control and DOP-treated groups on day one after LAD-ligation despite fourfold increase in plasma S1P. In contrast, cardiac function was clearly improved and myocardial scar size reduced, respectively, on Day 21 in DOP-treated mice. The latter also exhibited smaller cardiomyocyte size and reduced embryonic gene expression. The benefit of DOP treatment was abolished in S1PR1 Cardio Cre+. CONCLUSIONS: S1P improves cardiac function and myocardial healing post AMI independently of initial infarct size and accomplishes this via the cardiomyocyte S1PR1. Hence, in addition to its beneficial effects on I/R injury, S1PR1 may be a promising target in post-infarction myocardial remodelling as adjunctive therapy to revascularization as well as in patients not eligible for standard interventional procedures.

Revealing concealed cardioprotection by platelet Mfsd2b-released S1P in human and murine myocardial infarction.

Antiplatelet medication is standard of care in acute myocardial infarction (AMI). However, it may have obscured beneficial properties of the activated platelet secretome. We identify platelets as major source of a sphingosine-1-phosphate (S1P) burst during AMI, and find its magnitude to favorably associate with cardiovascular mortality and infarct size in STEMI patients over 12 months. Experimentally, administration of supernatant from activated platelets reduces infarct size in murine AMI, which is blunted in platelets deficient for S1P export (Mfsd2b) or production (Sphk1) and in mice deficient for cardiomyocyte S1P receptor 1 (S1P1). Our study reveals an exploitable therapeutic window in antiplatelet therapy in AMI as the GPIIb/IIIa antagonist tirofiban preserves S1P release and cardioprotection, whereas the P2Y12 antagonist cangrelor does not. Here, we report that platelet-mediated intrinsic cardioprotection is an exciting therapeutic paradigm reaching beyond AMI, the benefits of which may need to be considered in all antiplatelet therapies.