Effect of CYP2C19*2 and *17 genetic variants on platelet response to clopidogrel and prasugrel maintenance dose and relation to bleeding complications.

The present study was performed to compare the influence of cytochrome P459 2C19 (CYP2C19) *2 and *17 genetic variants on the platelet response to clopidogrel and prasugrel maintenance therapy and to assess the relation between platelet reactivity and bleeding complications. A total of 730 patients were included (517 patients treated with clopidogrel 150 mg/day and 213 discharged with prasugrel 10 mg). Platelet reactivity was assessed at 1 month with the platelet reactivity index vasodilator-stimulated phosphoprotein (PRI VASP). High on-treatment platelet reactivity was defined as PRI VASP >50% and low on-treatment platelet reactivity (LTPR) as PRI VASP <20%. The patients were classified according to their genotypes as poor metabolizers (*2/non *17), intermediate metabolizers (*2/*17 or non *2/non *17) and ultrametabolizers (non *2/*17). At 1 month, the prasugrel response was significantly better than the clopidogrel response in all groups of patients, with a lower incidence of high on-treatment platelet reactivity but a greater incidence of LTPR, regardless of the genetic variants. The genetic distribution had a significant effect on the mean PRI VASP values, the incidence of high on-treatment platelet reactivity, and LTPR with both clopidogrel and prasugrel (p <0.05 for all). LTPR identified a group of patients at a greater risk of bleeding (odds ratio 4.8, 95% confidence interval 2.7 to 8.3; p <0.0001). In conclusion, the present study showed that both clopidogrel and prasugrel have genetic modulation by CYP2C19 *2 and *17 alleles and that prasugrel provides greater platelet inhibition, regardless of the genotypes. In addition, LTPR was associated with a greater risk of bleeding.

Mononuclear cell adenosine deaminase and CD26/dipeptidylpeptidase-IV activities are sensitive markers of reperfusion during percutaneous transluminal angioplasty.

UNLABELLED: During ischaemia, the extracellular level of adenosine increases, which has cytotoxic effects. In endothelium, cell surface adenosine deaminase (ADA) complexing CD26 is coordinately induced during ischaemia as part of an adaptative response by eliminating adenosine. We examined whether a similar mechanism exists for mononuclear cells. We studied mononuclear cell surface ADA (MCADA) and dipeptidyl-peptidase IV activity (DPPIV) of membrane CD26 during percutaneous transluminal coronary angioplasty (PTCA) as a model of ischaemia-reperfusion. Enzymatic activities were compared with levels of ischaemia-modified albumin (IMA), a marker of ischaemia-reperfusion. METHODS AND RESULTS: Patients (15 men and 5 women) with non-ST segment elevation acute coronary syndrome related to a stenosis of proximal left anterior descending artery were prospectively included before revascularization. MCADA, DPPIV and IMA were measured before PTCA (T0) then 15 (T15) and 120 (T120) minutes after reperfusion. Fifteen healthy control subjects were enrolled. At T0, MCADA and IMA levels were higher in patients than in controls. MCADA decreased at T15 (median, IQR: 8.2 [7.6-9.8] IU) relative to T0 (11.25 [10-13.5] IU, p<0.01) and remained low at T120. DPPIV decreased at T15 (0.9 [0.7-1.1] AU) relative to T0 (1.05 [0.99-1.48] AU; p<0.01) and remained low at T120. IMA level increased only at T120. MCADA and DPPIV were correlated. Our findings are that MCADA and DPPIV decreased rapidly after angioplasty, suggesting that both catalysts are early markers of reperfusion. CONCLUSION: MCADA and DPPIV are sensitive and early markers of ischaemia-reperfusion process during PTCA.

Platelet reactivity in diabetic patients undergoing coronary stenting for acute coronary syndrome treated with clopidogrel loading dose followed by prasugrel maintenance therapy.

BACKGROUND: Diabetes has been identified as a risk factor for impaired clopidogrel response, and these patients might have greater benefit with new P2Y12 blockers such as prasugrel. The present study was designed to assess response to thienopyridine in diabetic patients undergoing PCI for ACS. METHODS AND RESULTS: 107 diabetic patients undergoing PCI for ACS were included and treated by clopidogrel 600 mg loading dose and switched to prasugrel 10mg daily after PCI. Platelet reactivity was assessed by PRI VASP. High-on-treatment platelet reactivity (HTPR) was defined by PRI VASP>50% and Low-on-treatment platelet reactivity (LTPR) as PRI VASP below the 75th percentile (PRI VASP<20%). After clopidogrel, mean PRI VASP was 47 ± 21% and 54 patients (50%) were non responders. At one month, mean PRI VASP on prasugrel 10mg daily was 31 ± 13%, 9 patients (8%) had HTPR and 23 patients (22%) had LTPR. In multivariate analysis, factors associated with platelet reactivity were waist circumference for HTPR on clopidogrel and body weight for HTPR and LTPR on prasugrel. 10 patients (9%) suffered from BARC bleeding complications. Patients with bleeding complications had significantly lower PRI VASP values: 22 ± 9 vs. 32 ± 13, p=0.02 and ROC curves identified a cut-off value of VASP=28% to predict bleeding complications. CONCLUSION: The present study confirmed that many diabetic patients treated with clopidogrel for ACS have inadequate platelet inhibition. Switch to prasugrel is effective with acceptable safety in this specific population. We observed a significant relationship between on-treatment platelet reactivity and bleeding complications.

CYP2C19*2 and *17 alleles have a significant impact on platelet response and bleeding risk in patients treated with prasugrel after acute coronary syndrome.

OBJECTIVES: The present study was designed to assess the effect of genetic variants on chronic biological response to prasugrel and bleeding complications. BACKGROUND: CYP2C19*2 loss-of-function allele and CYP2C19*17 gain-of-function allele have been linked with response to clopidogrel, but preliminary data did not show any significant influence of these alleles on prasugrel effect. METHODS: A total of 213 patients undergoing successful coronary stenting for acute coronary syndrome and discharged with prasugrel 10 mg daily were included. Prasugrel response was assessed at 1 month with the platelet reactivity index (PRI) vasodilator-stimulated phosphoprotein (VASP) and high on-treatment platelet reactivity (HTPR) defined as PRI VASP > 50% and hyper-response as PRI VASP <75th percentile (PRI VASP < 17%). CYP2C19*2 and CYP2C19*17 genotyping were performed. RESULTS: Carriers of loss-of-function *2 allele had significantly higher PRI VASP than noncarriers (33 ± 15% vs. 27 ± 14%, p = 0.03) and higher rate of HTPR (16% vs. 4%, p = 0.01). Conversely, carriers of *17 gain-of-function allele had significantly lower PRI VASP than noncarriers (25 ± 13% vs. 31 ± 15%, p = 0.03, p = 0.03), lower rate of HTPR (1% vs. 10%, p = 0.02), higher rate of hyper-response (34% vs. 21%, p = 0.02), and higher rate of bleeding complications than noncarriers: 23% versus 11%, (odds ratio [95% confidence interval]: 2.5 [1.2 to 5.4]; p = 0.02). No significant influence of genotypes on platelet reactivity assessed by adenosine diphosphate-induced platelet aggregation was observed. CONCLUSIONS: The present study shows a significant influence of CYP2C19*2 and *17 alleles on response to chronic treatment by prasugrel 10 mg daily and occurrence of bleeding complications.

Comparison between initial and chronic response to clopidogrel therapy after coronary stenting for acute coronary syndrome and influence on clinical outcomes.

BACKGROUND: Studies have addressed the benefit of tailored therapy based on initial response to clopidogrel loading dose. However, the appropriate timing for platelet testing remains uncertain. METHODS: The present study was performed to compare initial clopidogrel response after 600 mg loading dose and 1-month platelet response and their relationship with ischemic and bleedings events. A total of 475 patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention have been included in the present study. All patients were treated with 600 mg clopidogrel followed by 150 mg daily. Clopidogrel low response was defined by high on-treatment platelet reactivity (HPR) with vasoactive stimulated phosphoprotein >50%, and "hyperresponse," as platelet reactivity index vasoactive stimulated phosphoprotein (PRI VASP) <95th percentile after 600 mg. RESULTS: After 600 mg, 210 patients were identified with HPR (44%), and 23 patients (5%), with hyperresponse (PRI VASP <8%). At 1 month on 150 mg clopidogrel daily, 184 patients (39%) had HPR (39%), 14 patients (3 %) had hyperresponse, and mean PRI VASP was significantly lower (43% ± 19% vs 46% ± 21%, P = .04). At 1 month, among the 210 patients with HPR after 600 mg, 127 (60%) remained, whereas among the 265 patients responders after 600 mg, only 57 (22%) remained with HPR (60% vs 22%, P < .0001). Initial response was significantly associated with risk of stent thrombosis and bleeding complications, whereas 1-month assessment was only linked with bleeding events. CONCLUSION: In conclusion, the present study showed that initial clopidogrel response in patients with acute coronary syndrome is not a reliable predictor of response to maintenance therapy and their values for prediction of clinical outcome are likely to be different.

Epicardial fat volume is associated with coronary microvascular response in healthy subjects: a pilot study.

Epicardial fat (EF) is an active ectopic fat depot, which has been associated with coronary atherosclerosis, and which could early influence endothelial function. We thus investigated the relationship between EF and endothelium-dependent vasoreactivity of the coronary microcirculation, in highly selected healthy volunteers. Myocardial blood flow (MBF) was determined by measuring coronary sinus flow with velocity-encoded cine magnetic resonance imaging (MRI) at 3T. We measured MBF at baseline and in response to sympathetic stimulation by cold pressor testing (CPT) in 30 healthy volunteers with normal left ventricular (LV) function (age 22 ± 4 years, BMI = 21.3 ± 2.8 kg/m(2)). EF volume was volumetrically assessed by manual delineation on short-axis views. CPT was applied by immersing one foot in ice water for 4 min. Mean EF volume was 56 ± 26 ml and mean LV mass 100 ± 28 g. CPT significantly increased heart rate (HR) by 32 ± 19%, systolic blood pressure by 14 ± 10%, and rate-pressure product by 45 ± 25%, P < 0.0001. The increase in HR, reflecting sympathetic stimulation, was not influenced by sex, age or EF volume. CPT induced a decrease in coronary vascular resistance (135 ± 72 vs. 100 ± 42 mm Hg.ml(-1).min.g, P = 0.0006), and a significant increase in MBF (0.81 ± 0.37 vs. 1.24 ± 0.56 ml.min(-1).g(-1), P < 0.0001). Interestingly, we found a significant negative correlation between EF volume and ΔMBF (r= - 0.40, P = 0.03), which remained significant after adjusting for ΔHR. ΔMBF was also associated with adiponectin (r = 0.41, P = 0.046), but not with waist circumference, BMI, C-reactive protein, lipid or glycemic parameters. In multivariate analysis, adiponectin and EF volume remained both independently associated with ΔMBF. A high EF amount is associated with a lower coronary microvascular response, suggesting that EF could early influence endothelial function.

Gender differences in response to cold pressor test assessed with velocity-encoded cardiovascular magnetic resonance of the coronary sinus.

BACKGROUND: Gender-specific differences in cardiovascular risk are well known, and current evidence supports an existing role of endothelium in these differences. The purpose of this study was to assess non invasively coronary endothelial function in male and female young volunteers by myocardial blood flow (MBF) measurement using coronary sinus (CS) flow quantification by velocity encoded cine cardiovascular magnetic resonance (CMR) at rest and during cold pressor test (CPT). METHODS: Twenty-four healthy volunteers (12 men, 12 women) underwent CMR in a 3 Tesla MR imager. Coronary sinus flow was measured at rest and during CPT using non breath-hold velocity encoded phase contrast cine-CMR. Myocardial function and morphology were acquired using a cine steady-state free precession sequence. RESULTS: At baseline, mean MBF was 0.63 ± 0.23 mL·g⁻¹·min⁻¹ in men and 0.79 ± 0.21 mL·g⁻¹·min⁻¹ in women. During CPT, the rate pressure product in men significantly increased by 49 ± 36% (p < 0.0001) and in women by 52 ± 22% (p < 0.0001). MBF increased significantly in both men and women by 0.22 ± 0.19 mL·g⁻¹·min⁻¹ (p = 0.0022) and by 0.73 ± 0.43 mL·g⁻¹·min⁻¹ (p = 0.0001), respectively. The increase in MBF was significantly higher in women than in men (p = 0.0012). CONCLUSION: CMR coronary sinus flow quantification for measuring myocardial blood flow revealed a higher response of MBF to CPT in women than in men. This finding may reflect gender differences in endothelial-dependent vasodilatation in these young subjects. This non invasive rest/stress protocol may become helpful to study endothelial function in normal physiology and in physiopathology.

Acute coronary syndrome and cerebral arterial gas embolism in a scuba diver.

BACKGROUND: Pulmonary barotrauma is a rare but feared complication of scuba diving, with around 30% mortality. OBJECTIVE: We report an uncommon case of pulmonary barotrauma complicated by arterial gas embolism with both coronary and neurological ischemic injuries after scuba diving. CASE REPORT: A 46-year-old-man was admitted to our hospital for acute coronary syndrome and stroke following a scuba dive. After hyperbaric oxygen therapy, the patient recovered fully with a subsequent normal coronary angiogram. CONCLUSION: Myocardial ischemia can be a complication of scuba diving, but does not always reveal significant obstructive coronary artery disease.

Effect of increased aspirin dose after stenting in association with ClOpidogrel: the FIASCO randomized study.

BACKGROUND: Increased doses of antiplatelet therapy have been proposed to overcome the variability of response. However, the chronic dose of aspirin after DES remains controversial. METHODS AND RESULTS: We assessed in a prospective and randomized study the benefit of higher dose of aspirin, in association with clopidogrel, on aspirin response and non COX-specific platelet testing in patients receiving Drug Eluting Stent (DES) for stable angina pectoris. 50 consecutive patients receiving DES for stable angina pectoris were prospectively included. They received loading dose of 250 mg aspirin and 600 mg clopidogrel and antiplatelet response was assessed with Arachidonic Acid-induced aggregation (AA-Ag) and ADP-induced aggregation (ADP-Ag) for aspirin and clopidogrel response respectively. Patients were randomized to either 75 or 160 mg of aspirin with 150 mg clopidogrel and platelet testing were repeated one month after hospital discharge. The two groups (aspirin "75 mg" or "160 mg") had no difference for aspirin response: AA-Ag (5.2 +/- 1.7% vs 6 +/- 2%, p = 0.75) and non COX-specific pathway testing: ADP-Ag (47 +/- 3% vs 49 +/- 4%, p = 0.61). CONCLUSION: The present study did not show any benefit of higher dose of aspirin neither on aspirin responsiveness, nor on inhibition of non COX-specific pathway. These data does not support use of higher dose than 75 mg of aspirin in association with clopidogrel in patients receiving DES, especially while higher doses have been associated with increased bleeding risk.

Glycoprotein IIb/IIIa inhibitors improve outcome after coronary stenting in clopidogrel nonresponders: a prospective, randomized study.

OBJECTIVES: The aim of this study was to assess, in clopidogrel nonresponders undergoing elective percutaneous coronary intervention (PCI), the benefit of adjusted antiplatelet therapy with glycoprotein (GP) IIb/IIIa antagonist administration during PCI for 1-month clinical outcome. BACKGROUND: Numerous biological studies have reported interindividual variability in platelet response to clopidogrel with clinical relevance, and high post-treatment platelet reactivity (adenosine diphosphate-induced aggregation >70%) has been proposed to define nonresponse to clopidogrel. These nonresponders might benefit from tailored antiplatelet therapy. METHODS: One hundred forty-nine clopidogrel nonresponders referred for elective PCI were prospectively included and randomized to "conventional group" (n = 75) or "active group" with GP IIb/IIIa antagonist (n = 74). All patients received 250-mg aspirin and 600-mg clopidogrel before PCI and platelet testing. RESULTS: The rate of cardiovascular events at 1 month was significantly lower in the "active group" than in the "conventional group": 19% (n = 14) versus 40% (n = 30), p = 0.006, odds ratio: 2.8; 95% confidence interval: 1.4 to 6.0. No patient in either group had post-procedural Thrombolysis In Myocardial Infarction major bleeding or required transfusions. CONCLUSIONS: The present study suggested benefit of tailored antiplatelet therapy during elective PCI with GP IIb/IIIa antagonist for clopidogrel nonresponders without increased bleeding risk.

Ventricular arrhythmias during Tako-tsubo syndrome.

Tako-tsubo syndrome is a recently described form of cardiomyopathy. Its pathophysiology remains unknown. However, the main demographic, clinical, electrocardiographic and biologic characteristics of the disease have been described by previous reports. Retrospective studies are essential to help describe this rare disease, although they might have several skews. Previous reports have observed a mortality rate between 0 and 8%. In our serie, demographic, clinical, electrocardiographic and biologic results are similar with those previously reported. However, the mortality rate observed was higher than expected. Refractory ventricular arrhythmias leading to death have been encountered in 15% of patients. Tako-tsubo syndrome may present as sudden death and its mortality rate may have been underestimated in previous reports.