Dual antiplatelet therapy is associated with high α-tubulin acetylation in circulating platelets from coronary artery disease patients.

Platelet inhibition is the main treatment strategy to prevent atherothrombotic complications after acute coronary syndrome or percutaneous coronary intervention. Despite dual antiplatelet therapy (DAPT) combining aspirin and a P2Y12 receptor inhibitor, high on-treatment platelet reactivity (HPR) persists in some patients due to poor response to treatment and is associated with ischemic risk. Tubulin acetylation has been pointed out as a hallmark of stable microtubules responsible for the discoid shape of resting platelets. However, the impact of antiplatelet treatments on this post-translational modification has never been studied. This study investigated whether tubulin acetylation differs according to antiplatelet therapy and on-treatment platelet reactivity. Platelets were isolated from arterial blood samples of 240 patients admitted for coronary angiography, and levels of α-tubulin acetylation on lysine 40 (α-tubulin K40 acetylation) were assessed by western blot. We show that platelet α-tubulin K40 acetylation was significantly increased in DAPT-treated patients. In addition, the proportion of patients with high levels of α-tubulin K40 acetylation was drastically reduced among DAPT-treated patients with HPR. Multivariate logistic regression confirmed that DAPT resulting in adequate platelet inhibition was strongly associated with elevated α-tubulin K40 acetylation. In conclusion, our study highlights the role of elevated platelet α-tubulin K40 acetylation as a marker of platelet inhibition in response to DAPT.Clinical trial registration: https://clinicaltrials.gov - NCT03034148.

What is the context? High on-treatment platelet reactivity due to dual antiplatelet therapy poor response is associated with thrombotic risk.Acetylation of α-tubulin K40 plays a crucial role in regulating platelet shape.High α-tubulin K40 acetylation is a hallmark of stable microtubules.What is new? α-tubulin K40 acetylation is increased in platelets from dual antiplatelet therapy-treated patients.High platelet α-tubulin K40 acetylation is mainly observed in clopidogrel-responsive patients.What is the impact? Elevated acetylated K40 α-tubulin could be used as a readout of adequate platelet inhibition in response to dual antiplatelet therapy.High α-tubulin K40 acetylation could contribute to maintaining the resting morphology of circulating platelets and therefore modify their capacity to be involved in thrombotic events.

Early thrombogenicity of coronary stents: comparison of bioresorbable polymer sirolimus-eluting and bare metal stents in an aortic rat model.

BACKGROUND: Although 1-month dual antiplatelet therapy (DAPT) in patients treated with bare metal stents (BMS) is well established, the optimal duration of DAPT after implantation of a drug-eluting stent (DES) is still a matter of debate. The safety of shortened DAPT is under investigation due to concern about the risk of stent thrombosis. Data on platelet activation and prothrombotic response in vivo following bioresorbable polymer sirolimus-eluting stent (BP-SES) implantation are scarce. OBJECTIVES: The aim of our study was to compare the early thrombogenicity of BP-SES with that of BMS in an aortic rat model. METHODS AND RESULTS: Overall, 30 rats underwent stent implantation in the abdominal aorta: BMS (Pro-Kinetic Energy; N=15) and BP-SES (Ultimaster Tansei; N=15) were compared in terms of their early thrombogenicity. CD62P exposure at the platelet surface and fibrinogen binding at the integrin receptor were not different between BMS and BP-SES over time. The thrombus coverage of the scaffold (0 vs. 0.1%, P=0.84) was similarly low in both groups at Day 28; thrombotic deposits had totally disappeared at Day 84. The endothelial strut coverage was similarly high at 1 month (90 vs. 95%, P=0.64) and 3 months (87 vs. 97%, P=0.99) following BMS and BP-SES implantation, respectively. CONCLUSIONS: This study demonstrates the low early thrombogenicity of a BP-SES implanted in an aortic rat model, which did not differ from a BMS. These data could be helpful to support the safety of a shortened 1-month DAPT duration following BP-SES implantation in the human coronary artery.

Resheathing of self-expanding bioprosthesis: Impact on procedural results, clinical outcome and prosthetic valve durability after transcatheter aortic valve implantation.

BACKGROUND: New transcatheter aortic valves were recently developed, enabling to resheath and reposition the prosthesis. The aim of the present study was to investigate whether the resheath manoeuvre did not impair the outcome of patients and the bioprosthesis durability after transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: On the 346 consecutive patients (84 ±â€¯7 yrs-old, mean STS 6.7 ±â€¯5%) undergoing a transfemoral TAVI in our institution since January 2008, 170 patients were implanted using a self-expanding valve (SEV). Among those, 39 (Group 1) required resheathing to achieve a successful implantation, while 131 did not require it (Group 2, N = 131). A balloon-expanding valve (BEV) was used in 176 patients (Group 3). Baseline characteristics were similar between groups. Device success was 98%, the rate of in-hospital death was 2%, and the number of procedural complications was similarly low, with no significant difference between groups. The follow-up was complete in 337 of 338 patients undergoing a successful TAVI (781 patients-year). Kaplan-Meier analysis showed that overall survival was 80 ±â€¯2% and 42 ±â€¯3% at 1 and 5 years respectively, with no difference between groups. On multivariate analysis, acute kidney injury, post-dilatation, pulmonary hypertension, porcelain aorta and STS score, but not resheath, were independant predictors of death after TAVI. The annual event rate of structural valve deterioration was 0.6% patients-year, and similar between groups. CONCLUSIONS: Our study shows that SEV resheath did not impair the procedural results, the outcome of patients nor the valve durability at short term after TAVI.

Platelet Acetyl-CoA Carboxylase Phosphorylation: A Risk Stratification Marker That Reveals Platelet-Lipid Interplay in Coronary Artery Disease Patients.

Adenosine monophosphate-activated protein kinase (AMPK) acetyl-CoA carboxylase (ACC) signaling is activated in platelets by atherogenic lipids, particularly by oxidized low-density lipoproteins, through a CD36-dependent pathway. More interestingly, increased platelet AMPK-induced ACC phosphorylation is associated with the severity of coronary artery calcification as well as acute coronary events in coronary artery disease patients. Therefore, AMPK-induced ACC phosphorylation is a potential marker for risk stratification in suspected coronary artery disease patients. The inhibition of ACC resulting from its phosphorylation impacts platelet lipid content by down-regulating triglycerides, which in turn may affect platelet function.

AMPK-ACC signaling modulates platelet phospholipids and potentiates thrombus formation.

AMP-activated protein kinase (AMPK) α1 is activated in platelets on thrombin or collagen stimulation, and as a consequence, phosphorylates and inhibits acetyl-CoA carboxylase (ACC). Because ACC is crucial for the synthesis of fatty acids, which are essential for platelet activation, we hypothesized that this enzyme plays a central regulatory role in platelet function. To investigate this, we used a double knock-in (DKI) mouse model in which the AMPK phosphorylation sites Ser79 on ACC1 and Ser212 on ACC2 were mutated to prevent AMPK signaling to ACC. Suppression of ACC phosphorylation promoted injury-induced arterial thrombosis in vivo and enhanced thrombus growth ex vivo on collagen-coated surfaces under flow. After collagen stimulation, loss of AMPK-ACC signaling was associated with amplified thromboxane generation and dense granule secretion. ACC DKI platelets had increased arachidonic acid-containing phosphatidylethanolamine plasmalogen lipids. In conclusion, AMPK-ACC signaling is coupled to the control of thrombosis by specifically modulating thromboxane and granule release in response to collagen. It appears to achieve this by increasing platelet phospholipid content required for the generation of arachidonic acid, a key mediator of platelet activation.

Greater Efficacy of Total Thyroidectomy versus Radioiodine Therapy on Hyperthyroidism and Thyroid-Stimulating Immunoglobulin Levels in Patients with Graves' Disease Previously Treated with Antithyroid Drugs.

AIMS: We compared the effects of total thyroidectomy (TTx) and radioiodine (RAI) administration on the course of thyroid hormones and thyroid-stimulating immunoglobulins (TSI) in patients with Graves' disease. METHODS: We retrospectively studied 80 patients initially treated with antithyroid drugs and requiring either RAI (8.3 ± 1.7 mCi of (131)I; n = 40) or TTx (n = 40) as second-line therapy. RESULTS: The TTx and RAI groups were not different, except for larger goiter, higher FT3 and more frequent Graves' orbitopathy at diagnosis in the surgery group (p < 0.05). A persistent remission of hyperthyroidism was observed in 97% of operated patients versus 73% of the RAI patients at 3 years (p < 0.01). TTx was followed by a rapid and steady decrease in TSI during the first 9 months, while a surge of antibodies was observed during the first 6 months after RAI, followed by a slow decrease over the next 18 months. At the last visit, high TSI levels were still observed in 18 and 60% of patients in the surgery and RAI groups, respectively (p < 0.001). CONCLUSIONS: TTx is more efficient than RAI to induce a rapid and permanent correction of hyperthyroidism and TSI decrease in patients previously treated with antithyroid drugs.