Lipoprotein associated- phospholipase A2 in STEMI vs. NSTE-ACS patients: a marker of cardiovascular atherosclerotic risk rather than thrombosis.

The precise role of Lipoprotein associated phospholipase A2 (Lp-PlA2) in the pathogenesis of acute coronary syndromes (ACS) and in the prediction of future cardiovascular events is still debated. So far, few data exist on the variations of Lp-PlA2 activity in ACS and especially in NSTE-ACS vs. STEMI patients, where thrombotic and atherosclerotic mechanisms could play a differential role. The aim of the present study was, then, to compare Lp-PlA2 activity according to the type of ACS presentation. METHODS: A consecutive cohort of patients undergoing coronary angiography for acute coronary syndrome (ACS) were included and divided according to presentation for non ST-segment elevation-ACS or ST-segment elevation Myocardial Infarction (STEMI). Lp-PLA2 activity was assessed in blood samples drawn at admission using the Diazyme Lp-PlA2 Activity Assay. RESULTS: We included in our study 117 patients, of whom 31 (26.5%) presented with STEMI. STEMI patients were significantly younger (p = 0.05), displayed a lower rate of hypertension (p = 0.002), previous MI (p = 0.001) and PCI (p = 0.01) and used less frequently statins (p = 0.01) and clopidogrel (p = 0.02). White blood cells and admission glycemia were increased in STEMI (p = 0.001, respectively). The prevalence and severity of CAD was not different according to ACS types, but for a higher prevalence of thrombus (p < 0.001) and lower TIMI flow (p = 0.002) in STEMI. The levels of Lp-PlA2 were significantly lower in STEMI as compared to NSTE-ACS patients, (132 ± 41.1 vs. 154.6 ± 40.9 nmol/min/mL, p = 0.01). In fact, the rate of patients with Lp-PlA2 above the median (148 nmol/min/mL) was significantly lower in STEMI patients as compared to NSTE-ACS (32.3% vs. 57%, p = 0.02, adjusted OR[95% CI] = 0.20[0.06-0.68], p = 0.010). Moreover, a direct linear relationship was observed between Lp-PlA2 and LDL-C (r = 0.47, p < 0.001), but not with inflammatory biomarkers. CONCLUSION: The present study shows that among ACS patients, the levels of Lp-PlA2 are inversely associated with STEMI presentation and thrombotic coronary occlusion, being instead increased in NSTE-ACS patients, therefore potentially representing a marker of more aggressive chronic cardiovascular disease with an increased risk of recurrent cardiovascular events.

Short-term dual antiplatelet therapy in diabetic patients admitted for acute coronary syndrome treated with a new-generation drug-eluting stent.

BACKGROUND: The optimal duration of dual antiplatelet therapy (DAPT) in patients with diabetes mellitus (DM) admitted with acute coronary syndrome (ACS) and treated with a drug-eluting stent (DES) remains unclear. This is a prespecified sub-study from the Randomised Evaluation of short-term DUal antiplatelet therapy in patients with acute Coronary syndromE treated with a new generation DES (REDUCE) trial that was designed to determine the efficacy and safety of short-term versus standard 12 months DAPT in diabetic patients with ACS undergoing percutaneous coronary intervention (PCI) using the COMBO stent. METHODS: In this study we included ACS diabetic patients enroled in the REDUCE trial treated with the COMBO stent and randomly assigned to either 3 or 12 months of DAPT. The primary study endpoint was the composite of all-cause mortality, myocardial infarction (MI), stent thrombosis (ST), stroke, target vessel revascularisation (TVR), and bleeding complications at 12 and 24 months follow-up. RESULTS: A total of 307 diabetic patients were included, of which 162 (52.8%) in the 3 months DAPT group and 145 (47.2%) in the 12 months DAPT group. Patient characteristics, PCI success, and number of stents used were similar in the 3 and 12 months DAPT groups. Occurrence of the primary study endpoint at 12 and 24 months follow-up was comparable between the two groups (3.1 vs. 3.5%, p = 0.865, and 15.8 vs. 14.9%, p = 0.824, respectively). Moreover, the prevalence of the specific clinical outcome parameters (all-cause mortality), MI, ST, stroke, TVR, and bleeding was similar in both study groups. CONCLUSIONS: This sub-analysis shows similar clinical outcomes following 3 months DAPT as compared to 12 months DAPT in diabetic patients undergoing PCI for ACS using the COMBO stent. These results suggest that, even in this particular subset of patients, short duration of DAPT might be considered safe. Future larger studies are warranted to provide more precise estimations in terms of safety and efficacy of short term DAPT in these high-risk patients.

Relationship between vitamin D and cholesterol levels in STEMI patients undergoing primary percutaneous coronary intervention.

BACKGROUND AND AIMS: Special interest has been raised on vitamin D association with the metabolic profile, potentially interfering with lipid parameters and lipid-lowering therapies. The aim of the present study was to assess the impact of vitamin D on the cholesterol levels among patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI. METHODS AND RESULTS: A consecutive cohort of 450 patients admitted for STEMI treated with pPCI were retrospectively identified and divided according to tertiles values of 25(OH). The levels of 25(OH)D were assessed at admission by chemiluminescence immunoassay kit LIAISON®Vitamin D assay (Diasorin Inc). Lower vitamin D was associated to a higher use of diuretics (p = 0.03), lower prevalence of lesions on bifurcations (p = 0.001) and smaller diameter of the target coronary vessel (p = 0.03), but higher coronary calcifications (p = 0.007). Total and LDL cholesterol levels were significantly increased in patients with lower vitamin D (p = 0.05 and p = 0.005), inversely relating with total cholesterol (r = -0.09, p = 0.06) and LDL-C (r = -013, p = 0.007), and directly with HDL-C (r = 0.16, p = 0.001). Results were not affected by statin therapy, with a significant relationship being confirmed for atherogenic lipids, but not for HDL-C in statin treated patients. In fact, at multivariate analysis, vitamin D in lower tertiles emerged as an independent predictor of LDL-C elevated or above the target (adjusted OR [95%CI] = 2.6 [1.51-4.44], p = 0.001). CONCLUSION: The present study shows that among patients with STEMI undergoing primary revascularization, lower levels of vitamin D are independently associated with a more atherogenic lipid profile. Similar results were observed in statin treated or naïve patients.

Association of lower vitamin D levels with inflammation and leucocytes parameters in patients with and without diabetes mellitus undergoing coronary angiography.

BACKGROUND: Diabetes mellitus has been associated with a chronic low-grade inflammation and a higher risk of cardiovascular and infectious disease, that could be prevented by the effects of vitamin D. We aimed at evaluating the impact of vitamin D levels on the biomarkers of acute-phase response, inflammation and glucose metabolism in a large cohort of diabetic patients with cardiovascular disease. MATERIALS AND METHODS: Consecutive patients undergoing coronary angiography were included. Diabetes mellitus was defined as previous diagnosis, specific treatment administration (oral drug or insulin), fasting glycaemia >6.99 mmol/L or HbA1c >48 mmol/L. Glucose parameters, white blood cells, Neutrophil-to-Lymphocyte Ratio (NLR), Monocyte-to-Lymphocyte Ratio (MLR), C-reactive protein (CRP) and vitamin D were measured at admission. Vitamin D levels were measured by chemiluminescence immunoassay kit LIAISON® Vitamin D assay (Diasorin Inc). RESULTS: We included 1472 diabetic patients and 2499 non-diabetic patients that were divided according to vitamin D tertiles. Among diabetic patients, lower levels of vitamin D were associated with female gender (P = .02), obesity (P = .004), active smoking and acute presentation (P < .001) and with a more atherogenic metabolic profile. The levels of white blood cells, leucocytes subfamilies, and inflammatory parameters significantly correlated with vitamin D levels in both patients with and without diabetes (diabetic: P = .012 for WBC, P = .004 for NLR and P < .001 for MLR and C-reactive protein, non-diabetic: P < .001 for WBC; NLR, MLR and C-reactive protein, respectively). Among diabetic patients, results were confirmed at multivariate analysis with no significant interaction according to glycaemic control. CONCLUSION: The present study demonstrates that, among patients with cardiovascular disease, vitamin D deficiency is associated with metabolic dysregulation and with an elevation of cellular and humoural inflammatory parameters, especially among diabetics, although not being dependent from glycaemic control.

Low hemoglobin predicts high-platelet reactivity and major cardiovascular ischemic events at long-term follow-up among ACS patients receiving dual antiplatelet therapy with ticagrelor.

BACKGROUND: Reduced levels of hemoglobin (Hb) represent an established marker of impaired outcomes and increased cardiovascular risk in patients with coronary artery disease, challenging the management of dual antiplatelet therapy (DAPT). However, while anemia has emerged as an independent predictor of suboptimal platelet inhibition in patients receiving clopidogrel, no study has so far evaluated the impact of Hb levels on high-on treatment platelet reactivity (HRPR) with ticagrelor and their prognostic consequences, that were the aim of the present study. METHODS: Patients on DAPT with ASA + Ticagrelor (90 mg/twice a day) after percutaneous coronary revascularization for ACS were scheduled for platelet function assessment 30-90 days post-discharge. Aggregation tests were performed by multiple electrode aggregometry. Suboptimal platelet inhibition (HRPR-high residual platelet reactivity was defined if above the lower limit of normality (417 AU*min). The primary study endpoint was defined as the occurrence of major cardiovascular events (a composite of cardiovascular death, recurrent acute coronary syndrome [MI], target vessel revascularization) at longest available follow-up. RESULTS: We included 397 patients that were divided according to tertiles values of Hb (< 12.7, 12-7-14.09, ≥14.1 g/dl). Patients with lower Hb were older and displayed a more severe cardiovascular risk profile. Mean levels of platelet reactivity were enhanced in patients with lower Hb after stimulation with TRAP peptide (TRAP test, p = .03) and ADP (p = .02). Elevated platelet reactivity (HRPR) on Ticagrelor was more frequent among patients with reduced Hb (16.4% vs. 12% vs. 5.4%, p = .005, adjusted OR [95%CI] = 1.71[0.996;3.01], p = .056). At a mean follow-up of 820.9 ± 553.4 days, 21.4% of the patients experienced the primary composite endpoint, with a higher rate of events in patients with lower Hb (27.6% vs. 22.6% vs. 13.5%, p = .006, adjusted HR [95%CI] = 1.51[1.12; 2.03], p = .006), mainly driven by a higher rate of recurrent ACS. After correction for baseline differences lower Hb tertiles but not HRPR emerged as independent predictor of MACE (adjusted HR [95%CI] = 0.98[0.50; 1.92], p = .95). CONCLUSIONS: In the present study, we demonstrated that among patients on DAPT with ASA and ticagrelor after PCI for ACS, lower Hb levels are independently associated with a higher rate of HRPR and an increased rate of major ischemic events, and especially for recurrent ACS, although with no impact on survival. Neutral prognostic effect of HRPR was observed across Hb tertiles.

Impact of renin angiotensin system inhibitors on homocysteine levels and platelets reactivity in patients on dual antiplatelet therapy.

BACKGROUND AND AIMS: Dual antiplatelet therapy (DAPT) and Renin-angiotensin system inhibitors (RASi) represent the cornerstone in the treatment of patients undergoing percutaneous coronary interventions (PCI), mainly after an acute ischemic event. However, high-on treatment residual platelet reactivity (HRPR), is not infrequent despite optimal medical treatment. Homocysteine (Hcy) is a metabolite of methionine catabolism linked to atherothrombosis. Recently, a potential crosstalk between RAS and Hcy has been suggested, potentially favouring platelet aggregation and cardiovascular disease.Therefore, we aimed to investigate the impact of RASi on Hcy levels and platelet aggregation in patients on DAPT after PCI. METHODS AND RESULTS: Patients undergoing PCI on DAPT with ASA plus an ADP-antagonist (clopidogrel, ticagrelor or prasugrel), were included. RASi comprised angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). Aggregation tests were performed by Multiple Electrode Aggregometry. We included 1210 patients, of whom 862 (71.2%) were on treatment with RASi. Overall, DAPT composition was ASA+clopidogrel in 566 (46.8%) patients, ASA+ticagrelor in 428 (35.4%) and ASA+prasugrel in 216 (17.9%). Median values of Hcy were higher in RASi patients (p = 0.006), who displayed a higher percentage of Hcy above the median value (52.4% vs. 44.8%, p = 0.019, adjustedOR [95%CI] = 1.40 [1.04-1.88], p = 0.027). No differences in HRPR rate were found according to RASi use for ASPI test (3.6% vs. 3.3%, p = 0.88) and ADP test (25.6% vs. 24.3%,p = 0.62; adjustedOR [95%CI] = 1.23 [0.89-1.70], p = 0.220) and according to ADP-antagonist type. A direct linear relationship was observed between platelet reactivity and Hcy in both patients receiving RASi and untreated ones, with higher values of platelet aggregation being observed in patients with Hcy above the median, independently from RASi administration and DAPT strategy. CONCLUSION: In patients on DAPT after PCI, RASi treatment did not emerge as an independent predictor of HRPR. However, the levels of Hcy were significantly elevated in patients on RASi and related to higher values of platelet reactivity, independently from the DAPT strategy.

Determinants of vitamin D activation in patients with acute coronary syndromes and its correlation with inflammatory markers.

BACKGROUND AND AIM: Vitamin D deficiency is a pandemic disorder affecting over 1 billion of subjects worldwide. Calcitriol (1,25(OH)2D) represents the perpetrator of the several systemic effects of vitamin D, including the anti-inflammatory, antithrombotic and anti-atherosclerotic actions, potentially preventing acute cardiovascular ischemic events. Variability in the transformation of vitamin D into 1,25(OH)2D has been suggested to modulate its cardioprotective benefits, however, the determinants of the levels of calcitriol and their impact on the cardiovascular risk have been seldom addressed and were, therefore, the aim of the present study. METHODS AND RESULTS: A consecutive cohort of patients undergoing coronary angiography for acute coronary syndrome (ACS) were included. The levels of 25 and 1,25(OH)2 D were assessed at admission by chemiluminescence immunoassay kit LIAISON® Vitamin D assay (Diasorin Inc) and LIAISON® XL. Hypovitaminosis D was defined as 25(OH)D < 10 ng/ml, whereas calcitriol deficiency as 1,25(OH)2D < 19.9 pg/ml. We included in our study 228 patients, divided according to median values of 1,25(OH)2D (

Association between vitamin D deficiency and serum Homocysteine levels and its relationship with coronary artery disease.

Homocysteine (Hcy) elevation and vitamin D deficiency have emerged as potential markers of coronary artery disease (CAD). However, even tough hypovitaminosis D has been suggested to interfere with Hcy catabolism, no study has so far addressed the interaction of vitamin D and Hcy and their impact on CAD, that was the aim of present study. A cohort of consecutive patients undergoing coronary angiography in a single center were included and analyzed within the year 2019. Significant CAD was defined as at least 1 vessel stenosis > 50%, while severe CAD as left main and/or three-vessel disease. Hcy and vitamin D levels were assesssed at admission. We included 3150 patients undergoing coronary angiography at our centre, who were divided according to the quartiles values of vitamin D. Patients with lower levels of Vitamin D displayed a higher cardiovascular risk profile and a higher prevalence of CAD. We observed an inverse linear relationship between lower levels of vitamin D and higher Hcy (r = - 0.092, p < 0.001) and a higher prevalence of hyperhomocysteinemia in patients with lower quartiles values of vitamin D (p < 0.001). By forward conditional regression model, low vitamin D appeared as independent predictors of Homocysteine levels above the median (OR[95%CI] = 1.79[1.37-2.33], p < 0.001). In addition, patients with low vitamin D (below the median) and increased Hcy displayed a non-significantly higher rate of CAD (81% vs 77.7%, p = 0.13, adjusted OR[95%CI] = 1.16[0.88-1.54], p = 0.29) but a significant increase in the rate of severe left main/3-vessel CAD (37.4% vs 30.5%, p = 0.005, adjusted OR[95%CI] = 1.29[1.02-1.67], p = 0.04). Among patients with vitamin D levels above the median, Hcy levels did not impact on the prevalence and extent of CAD (77.7 vs 77.2%, p = 0.81, adjusted OR[95%CI] = 0.94[0.73-1.20], p = 0.60 for CAD and 31.8% vs 27.7%, p = 0.08, adjusted OR[95%CI] = 0.97[0.75-1.25], p = 0.81 for severe left main/3-vessel CAD). No significant interaction between Hcy and vitamin D with CAD or severe CAD was observed. The present study shows an independent inverse linear relationship between vitamin D and Hcy values. Moreover, the association of Hcy with the extent of CAD was significant only among patients with hypovitaminosis D, and not in the cohort of subjects with vitamin D levels above the median, suggesting that a normal vitamin D status can prevent the deleterious effects of hyperhomocysteinemia on coronary atherosclerosis, a hypothesis that certainly needs further confirmation in larger randomized trials.

Impact of active smoking on the immature platelet fraction and its relationship with the extent of coronary artery disease.

INTRODUCTION: Smoking represents a major cardiovascular risk factor, due to the induction of oxidative stress and low-grade, continuous, inflammation that contribute to promote atherothrombosis. However, the mechanisms leading to increased platelet aggregability associated with smoking are only partially defined. A potential role has been hypothesized for immature platelets, a younger and potentially more reactive fraction, previously associated with the main determinants of coronary artery disease (CAD). Therefore, the aim of our study was to define the impact of smoking on the immature platelet fraction (IPF) and its relationship with prevalence and extent of coronary artery disease. METHODS: We enrolled a cohort of consecutive patients undergoing coronary angiography in a single centre. Significant CAD was defined as at least 1 vessel stenosis >50%, while severe CAD was defined as left main and/or three-vessel disease. IPF was measured at admission by routine blood cell count (Sysmex XE-2100). RESULTS: We included in our study 2553 patients who were divided according to smoking status (active smokers: 512; nonactive smokers: 2041). Smokers were younger, more frequent males, with lower rate of diabetes mellitus, previous PCI and previous CABG (P < .001, respectively) and were in treatment less often with ARB, BB, nitrates, statins, ASA, clopidogrel, CCB and diuretics (P < .001, respectively) as compared to nonactive smokers. Higher percentage of smokers was observed in patients with higher IPF values, and at multivariate analysis, active smoking resulted as an independent predictor of higher IPF (adjusted OR [95% CI] = 1.59[1.03-2.45], P = .035). Among smokers, higher IPF was associated with lower ejection fraction (P = .034), percentage of acute coronary syndrome (P = .002) and platelet count (P < .001) compared to ones with lower IPF. However, the IPF (according to quartiles values) was not associated with the prevalence and extent of CAD (82.5%, 80.4%, 86.1% and 80.9%, from 1st to 4th quartile, respectively, adjusted OR[95% CI] = 0.98[0.79-1.23], P = .89) and severe CAD (31%, 31.1%, 39.1% and 35.2%, from 1st to 4th quartile, respectively, adjusted OR[95% CI] = 1.03[0.86-1.23], P = .76). CONCLUSION: The present study shows an independent association between active smoking and the levels of immature platelet fraction in patients undergoing coronary angiography. However, among active smokers, IPF did not result as an independent predictor of CAD or severe CAD.

Impact of diabetes mellitus on immature platelet fraction and its association with coronary artery disease.

BACKGROUND: Higher prothrombotic status and alterations in platelet function and thrombopoiesis are associated with diabetes mellitus (DM). We assessed the impact of diabetes and glucose control on the immature platelet fraction (IPF) and their relationship with prevalence and extent of coronary artery disease (CAD). METHODS: Consecutive patients undergoing coronary angiography were included. Significant CAD was defined as at least one vessel stenosis greater than 50%. IPF levels were measured at admission by routine blood cells count (A Sysmex XE-2100). RESULTS: We included 1781 patients, of whom 660 (37.1%) suffered from diabetes. Diabetes was associated with advanced age and a higher cardiovascular risk profile. No difference in the mean values of IPF were observed between patients with or without DM (3.6 ± 2.5 vs 3.5 ± 2.5, P = 0.39) and neither in the rate of patients with IPF above the median (2.9%) (51.6% vs 50.6%, P = 0.73). In patients with DM, the IPF levels did not relate with glucose control parameters (glycaemia: r = -0.024, P = 0.54, glycosylated haemoglobin: r = 0.11, P = 0.72). The prevalence of CAD was significantly lower in patients with DM and IPF greater than the median (80.5% vs 86.5%, P = 0.04, adjusted odds ratio [OR] [95% confidence interval {CI}] = 0.57[0.36-0.91], P = 0.02), while not left main/three-vessel CAD (36.9% vs 38.2%, P = 0.75, adjusted OR [95%CI] = 0.91[0.64-1.28], P = 0.90). CONCLUSION: In the present study, neither DM nor glucose control are independent predictors of IPF above the median. In patients with DM, higher IPF levels were associated with a lower prevalence of CAD and with a similar extent of severe CAD and angiographic findings. Therefore, until new data become available, elevated IPF should not be systematically applied on a large scale as cardiovascular risk marker in patients with diabetes.

Poly (l-lactic acid) bioresorbable scaffolds versus metallic drug-eluting stents for the treatment of coronary artery disease: A meta-analysis of 11 randomized trials.

BACKGROUND: Bioresorbable vascular scaffolds (BVS) have been proposed for overcoming the long-term limitations of permanent metallic stents, while theoretically warranting similar advantages in plaque stabilization and anti-restenotic drug delivery in the early postrevascularization phase. However, increased rates of malapposition, restenosis, or thrombosis have emerged from initial trials with BVS, that were nevertheless underpowered for the evaluation of the real outcome benefits of these coronary devices. The recent completion of newer randomized clinical trials paves the way to the present meta-analysis, aiming at the comparison of Poly (l-Lactic acid) BVS (PLLA-BVS) versus metallic drug-eluting stents (DES) in the treatment of coronary stenoses. METHODS: Literature and main scientific session abstracts were searched for randomized clinical trials (RCTs) comparing drug-eluting BVS versus metallic DES for the treatment of coronary artery disease (CAD). The primary efficacy endpoint was mortality, secondary endpoints were cardiovascular death, myocardial infarction, target lesion revascularization (TLR), stent thrombosis and the composite of device-oriented target lesion failure (TLF). RESULTS: We included 11 randomized trials, for a total population of 10,707 patients, 54.5% treated with BVS. The major indication for PCI was stable CAD, whereas acute coronary syndrome represented 30% of the patients. At a mean follow-up of 2.64 years (1-5 years), mortality occurred in 2.71% of the patients, with no difference according to the type of implanted stent (OR[95%CI] = 0.94 [0.74, 1.20], p = .62). No interaction was observed according to patients' risk profile or the rate of diabetes and ACS. However, a significant increase in myocardial infarction, stent thrombosis, TLR and TLF was observed with BVS as compared to DES. CONCLUSIONS: The present meta-analysis provides the most updated data on the use of PLLA-BVS for the treatment of CAD. We documented a poorer performance of these new coronary devices, as compared to new generation metallic DES, being associated with an increased rate of recurrent cardiovascular events. However, such ischemic complications did not impact on mortality, with a comparable survival independently from the type of stent.

Vitamin D levels condition the outcome benefits of renin-angiotensin system inhibitors (RASI) among patients undergoing percutaneous coronary intervention.

BACKGROUND: Vitamin D deficiency is estimated as the most common medical condition worldwide, with severe implications on survival and on several inflammatory, immune-mediated and thrombotic disorders, and especially for cardiovascular disease. Recent studies have suggested that vitamin D could directly regulate the Renin-Angiotensin System (RAS) activity, therefore potentially interfering with the pharmacological effects of RAS Inhibitors (RASI), an issue that has seldom been explored. Therefore, the aim of the present study was to evaluate the prognostic impact of the use of RASI according to vitamin D levels among patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). METHODS: Consecutive patients undergoing PCI were included. Main clinical features and chemistry parameters were assessed at admission. Vitamin D levels were measured by chemiluminescence immunoassay kit LIAISON® Vitamin D assay (Diasorin Inc). Severe deficiency was defined for 25(OH)D < 10 ng/mL. The primary study endpoint was defined as the occurrence of major cardiovascular events (MACE, a composite of death, recurrent Myocardial Infarction (MI) and target vessel revascularization) at the longest available follow-up. RESULTS: We included a total of 705 patients, that were divided according to vitamin D tertiles (< 12.7 ng/mL; 12.7-21.59 ng/mL; ≥21.6 ng/mL) and use of RASI. RASI therapy was significantly associated to arterial hypertension, creatinine, lower 25(OH)D, use of statins, diuretics, ASA and ticagrelor across vitamin D tertiles. At a median follow-up of 996 [377-1552] days, MACE occurred in 174 (24.7 %) patients. Severe hypovitaminosis D was significantly associated with a higher rate of MACE (HR[95 %CI] = 0.75[0.62-0.91], p = 0.004). The use of RASI significantly lowered the rate of MACE in patients with lower vitamin D (I tertile: 41.3 % vs 25.9 %, adjusted HR[95 %CI] = 0.43[0.26-0.73], p = 0.002); whilst a non-significant effect was observed for II and III tertiles values (18.6 %vs 29.5 %, adjusted HR[95 %CI] = 1.16[0.57-2.34], p = 0.69, and 21.2 % vs 12.6 %, adjusted HR[95 %CI] = 1.1[0.46-2.62], p = 0.83) (p int = 0.04). A similar prognostic interaction for RASI and vitamin D was observed for cardiovascular mortality and MI (p int = 0.03). CONCLUSION: Among patients undergoing PCI, the use of RASI was associated with lower risk of MACE only among patients with lower levels of vitamin D. Future larger studies are certainly warranted in order to define the prognostic implications of vitamin D supplementation on the RAS system modulation, especially among patients treated with RASI.

Homocysteine levels and platelet reactivity in coronary artery disease patients treated with ticagrelor.

BACKGROUND AND AIM: Recurrent atherothrombotic events have been reported in certain higher risk subsets of patients even with ticagrelor, a potent first-line antiplatelet agent for the management of patients with acute coronary syndrome (ACS). Hyperhomocysteinemia is a known determinant of platelet function abnormalities. Therefore, the aim of our study was to evaluate the impact of homocysteine (Hcy) levels on platelet reactivity in patients receiving Ticagrelor. METHODS AND RESULTS: Patients with ACS undergoing percutaneous coronary revascularization and on dual antiplatelet therapy with ASA + Ticagrelor (90mg/twice a day) were scheduled for platelet function assessment 30-90 days post-discharge. Aggregation tests were performed by Multiple Electrode Aggregometry (MEA). Suboptimal platelet inhibition HRPR-high residual platelet reactivity was defined if above the lower limit of normality (417 AU*min). We included 432 patients, divided according to Hcy tertiles. Higher Hcy levels were associated with age, renal failure, creatinine levels and use diuretics (p < 0.001). Patients with higher Hcy levels displayed a higher platelet reactivity at COL test (p = 0.002), and ADP test (p = 0.04), with a linear relationship between Hcy and platelet aggregation after stimulation with collagen (r = 0.202, p < 0.001), thrombin receptor peptide (r = 0.104, p = 0.05) and ADP (r = 0.145, p = 0.006). However, Hcy levels did not significantly affect the rate of HRPR with Ticagrelor (9.9% vs 13.7% vs 10.7%, p = 0.89; adjusted OR [95% CI] = [0.616-1.51], p = 0.99). CONCLUSIONS: Among patients with ACS, despite the elevated platelet reactivity associated to hyperhomocysteinemia, DAPT with ticagrelor could overcome such phenomenon, achieving an adequate platelet inhibition in the majority of the patients.

Impact of body mass index on clinical outcome among elderly patients with acute coronary syndrome treated with percutaneous coronary intervention: Insights from the ELDERLY ACS 2 trial.

BACKGROUND AND AIM: Elderly patients are at increased risk of hemorrhagic and thrombotic complications after an acute coronary syndrome (ACS). Frailty, comorbidities and low body weight have emerged as conditioning the prognostic impact of dual antiplatelet therapy (DAPT). The aim of the present study was to investigate the prognostic impact of body mass index (BMI) on clinical outcome among patients included in the Elderly-ACS 2 trial, a randomized, open-label, blinded endpoint study comparing low-dose (5 mg) prasugrel vs clopidogrel among elderly patients with ACS. METHODS AND RESULTS: Our population is represented by 1408 patients enrolled in the Elderly-ACS 2 trial. BMI was calculated at admission. The primary endpoint of this analysis was cardiovascular (CV) mortality. Secondary endpoints were all-cause death, recurrent MI, Bleeding Academic Research Consortium (BARC) type 2 or 3 bleeding, and re-hospitalization for cardiovascular reasons or stent thrombosis within 12 months after index admission. Patients were grouped according to median values of BMI (

Impact of gender on immature platelet count and its relationship with coronary artery disease.

The impact of platelet parameters on the cardiovascular risk is still debated. Gender differences in platelet volume indexes and turnover have been previously reported, potentially conditioning their role in the development of coronary artery disease (CAD). However, few studies have addressed, so far, the impact of gender on the immature platelet fraction (IPF) and count (IPC) and their relationship with CAD. We enrolled consecutive patients undergoing coronary angiography in a single centre. IPF and platelet indexes were measured at admission. Significant CAD was defined as the presence of at least one coronary stenosis more than 50%. A total of 2550 patients were included, 1835 (72%) were males, and 715 (28%) were females. Female patients were older (p < 0.001), with lower BMI (p = 0.002), lower prevalence of active smoking (p < 0.001), previous MI, previous PCI and CABG (p = 0.001, p = 0.001, p < 0.001), whilst a higher prevalence of renal failure (p = 0.02), acute presentation (p < 0.001) and CAD (p < 0.001). Platelet count was higher in females (p < 0.001), as well as the IPC levels (838.38 ± 562.05 vs 792.24 ± 535.66, p = 0.05) with no difference in the levels of immature platelet fraction (3.67 ± 2.68% vs 3.74 ± 2.6%, p = 0.55) or the prevalence of patients with IPF ≥ 3rd tertile (33.7% vs 35.2%, p = 0.26). At multivariate analysis, after correction for baseline confounders, gender did not emerge as an independent predictor of higher IPF (adjusted OR [95% CI] = 0.82 [0.64-1.06], p = 0.13). When dividing our patients according to the levels of IPF, in women we observed an inverse association between IPF ≥ 3rd tertile and coronary calcifications (p = 0.025) and a higher prevalence of restenosis (p = 0.003), but no difference in CAD (65.6% vs 66.9%, p = 0.71) or severe CAD (28.1% vs 24.7%, p = 0.31). In males, the IPF ≥ 3rd tertile related with a lower TIMI flow (p = 0.001). Males with lower IPF had a significantly higher percentage of CAD (87.7% vs 83.3%, p = 0.007; adjusted OR: 0.699 [95% CI] = [0.54-0.91], p = 0.008) but not for severe CAD (36.5% vs 39.9%, p = 0.134). The present study shows that among patients undergoing coronary angiography, gender is not associated to the levels of immature platelet fraction. Moreover, we found no association between IPF and the prevalence and extent of CAD in female gender, whereas in male gender the IPF was inversely related with the prevalence of CAD.

Benefits of short-term or prolonged as compared to standard 1 year DAPT in patients with acute coronary syndrome treated with drug-eluting stents: a meta-analysis of 9 randomized trials.

Optimal timepoint for the discontinuation of dual antiplatelet therapy (DAPT) after an acute coronary syndrome is still debated. In fact, despite a shortening of DAPT duration should be advocated, based on the negligible risk of thrombotic complications observed with newer generations of drug-eluting stents (DES), in order to reduce the hemorrhagic risk, a more prolonged anti-ischemic protection would be suitable for certain higher-risk patients, rendering the traditional 12 months strategy outdated. We performed an updated meta-analysis and indirect comparison of randomized trials comparing shorter vs extended DAPT duration in ACS patients undergoing percutaneous coronary interventions with DES. Literature and main scientific session abstracts were searched for studies comparing 3-6 (short-term) or prolonged (> 12 months) DAPT vs traditional 12 months in ACS patients treated with DES. The primary efficacy endpoint was mortality, primary safety endpoint was the occurrence of major bleedings. Secondary endpoints were myocardial infarction and stent thrombosis. We included three randomized clinical trials and six study sub-analysis comparing alternative (short-term or prolonged) DAPT vs 12 months in post-ACS, with a total of 15,738 patients. Mortality occurred in 1.8% of patients, with no difference according to DAPT duration (short-term vs standard DAPT: OR [95% CI] 1.00 [0.72-1.39], p = 0.99; > 12 vs 12 months: OR [95% CI] 0.87 [0.61-1.22], p = 0.41). No difference in the risk of recurrent myocardial infarction and stent thrombosis was observed between short-term and standard DAPT, while a significant reduction was achieved only when extending the duration beyond 12 months (MI: OR [95% CI] 0.49 [0.36-0.67], p < 0.00001; ST: OR [95% CI] 0.40 [0.23-0.70], p = 0.001). However, prolonged DAPT was associated with a significant increase in major bleedings (OR [95% CI] 1.69 [1.17-2.45], p = 0.006). In fact, indirect comparison confirmed a significant interaction between short-term vs prolonged DAPT and the risk of myocardial infarction (p < 0.001), stent thrombosis (p = 0.0006) and major bleeding complications (p = 0.02). Based on the current meta-analysis, among ACS patients treated with percutaneous coronary interventions with DES, a shorter-term (3 or 6 months) DAPT can be safely considered, offering a non-inferior protection from major cardiovascular ischemic events as compared to the standard 12 months strategy. Extending DAPT therapy beyond 12 months enhances the antithrombotic protection, although paying the fee of increasing major bleeding complications, therefore resulting in a null effect on mortality.

Impact of aging on immature platelet count and its relationship with coronary artery disease.

Despite the fact that elderly patients represent a prevalent and challenging population in the current practice, few data exist on the impact of platelet parameters on cardiovascular risk in these patients. Therefore, the aim of the present study was to evaluate the impact of age on the immature platelet count (IPC) and their relationship with CAD. We included a total of 2236 consecutive patients undergoing coronary angiography in a single center. Elderly patients (age ≥ 75 years) were 756 (33.7%). IPC was measured at admission. Elderly patients were more often females (p < .001), with lower BMI and prevalence of smokers (p < .001), and a more complex cardiovascular risk profile and coronary disease (p = .02). Platelet count decreased with aging (p = .05), whereas no difference in the mean IPC was found between patients < or ≥75 years. In fact, advanced age did not emerge as an independent predictor of IPC above III tertile (≥8.6*10^6/ml), (adjusted OR[95%CI] = 0.97[0.78-1.21], p = .79). When considering elderly patients according to tertiles values of IPC (<5.1,5.1-8.59; ≥8.6*10^6/ml), we found no impact of IPC on the prevalence of CAD (81.1% vs 84.5% vs 81.5%, p = .92; adjusted OR[95%CI] = 1.08[0.67-1.72], p = .75) and its extent (37.7% vs 34.5% vs 40.2%, p = .57; adjusted OR[95%CI] = 1.22[0.85-1.73], p = .28). However, we observed a higher rate of calcified and type C lesions in elderly patients with higher IPC (p = .03 and p < .001, respectively). Therefore, advanced age is not associated with higher immature platelet count and the prevalence and severity of CAD. Moreover, IPC does not contribute to explain the higher prevalence and extent of coronary artery disease observed in elderly patients.

Relationship between adenosine A2a receptor polymorphism rs5751876 and fractional flow reserve during percutaneous coronary intervention.

Fractional flow reserve (FFR) assessed during adenosine-induced maximal hyperemia has emerged as a useful tool for the guidance of percutaneous coronary interventions (PCI). However, interindividual variability in the response to adenosine has been claimed as a major limitation to the use of adenosine for the measurement of FFR, carrying the risk of underestimating the severity of coronary stenoses, with potential negative prognostic consequences. Genetic variants of the adenosine receptor A2a (ADORA2A gene), located in the coronary circulation, have been involved in the modulation of the hyperemic response to adenosine. However, no study has so far evaluated the impact of the single nucleotide polymorphism rs5751876 of ADORA2A on the measurement of FFR in patients undergoing percutaneous coronary intervention that was, therefore, the aim of our study. We included patients undergoing coronary angiography and FFR assessment for intermediate (40-70%) coronary lesions. FFR measurement was performed by pressure-recording guidewire (Prime Wire, Volcano), after induction of hyperemia with intracoronary boli of adenosine (from 60 to 1440 µg, with dose doubling at each step). Restriction fragment length polymorphism (RFLP) analysis was performed to assess the presence of rs5751876 C>T polymorphism of ADORA2a receptor. We included 204 patients undergoing FFR measurement of 231 coronary lesions. A total of 134 patients carried the polymorphism (T allele), of whom 41 (30.6%) in homozygosis (T/T).Main clinical and angiographic features did not differ according to ADORA2A genotype. The rs5751876 C>T polymorphism did not affect mean FFR values (p = 0.91), the percentage of positive FFR (p = 0.54) and the duration of maximal hyperemia. However, the time to recovery to baseline FFR values was more prolonged among the T-allele carriers as compared to wild-type patients (p = 0.04). Based on these results, in patients with intermediate coronary stenoses undergoing FFR assessment with adenosine, the polymorphism rs5751876 of ADORA2A does not affect the peak hyperemic response to adenosine and the results of FFR. However, a more prolonged effect of adenosine was observed in T-carriers.

Impact of aging on platelet reactivity in diabetic patients receiving dual antiplatelet therapy.

Advanced age and diabetes represent summative conditions in the determination of cardiovascular risk, and especially for the management of dual antiplatelet therapy (DAPT), often requiring balancing between bleeding and thrombotic complications. However, few studies have so far evaluated the impact of age on platelet reactivity and suboptimal platelet inhibition (high-on treatment platelet reactivity-HRPR) on DAPT among diabetic patients, that was, therefore the aim of the present study. In diabetic patients treated with DAPT (ASA + clopidogrel or ticagrelor) platelet reactivity was assessed at 30-90 days post-discharge for an acute coronary syndrome or elective PCI. Aggregation was assessed by multiple-electrode aggregometry. HRPR was defined for values above the lower limit of normality (in non-treated patients). Elderly patients were considered ≥ 75 years of age. We included 462 patients, among them 149 (32.2%) were ≥ 75 years. Elderly patients were more often females (p = 0.006), with lower body size (p = 0.04), acute coronary syndrome at presentation and renal failure (p < 0.001), non-smokers (p = 0.002), in therapy with insulin (p = 0.02) and diuretics (p < 0.001) and lower rate of betablockers (p = 0.02). Age directly related with C reactive protein (p = 0.01), creatinine levels and inversely with hemoglobin (p < 0.001) and triglycerides (p = 0.003). No association was found at linear regression analysis for platelet reactivity and age with different activating stimuli, but for ASPI test (r = 0.12; p = 0.03). No significant difference in HAPR was found in elderly patients (2.4 vs. 3.2%, p = 0.76, OR[95% CI] = 0.45[0.1-2.11], p = 0.31). HRPR for ADP antagonists was similarly not affected by age (30.1% vs. 35.7%, p = 0.28, adjusted OR[95% CI] = 0.78[0.47-1.29], p = 0.33). Comparable results were obtained when considering separately the DAPT strategies with clopidogrel or ticagrelor, or when adjusting our results according to propensity score values. Among diabetic patients receiving dual antiplatelet therapy for an acute coronary syndrome or elective percutaneous coronary intervention, age does not affect platelet reactivity or the rate of high-on treatment platelet reactivity. Similar results were obtained for ASA and clopidogrel or ticagrelor.

Impact of metabolic syndrome on mean platelet volume and its relationship with coronary artery disease.

Platelets represent one of the main actors involved in pathogenesis of coronary artery disease (CAD). Mean platelet volume (MPV) has been proposed as marker of platelet reactivity and thrombotic risk. However, still debated is whether higher MPV constitutes an independent determinant of CAD or just the consequence of an association with several cardiovascular risk factors. Therefore, the aim of the present study was to assess the impact of metabolic syndrome (MetS), on MPV and its relationship with angiographically defined CAD. Consecutive patients undergoing coronary angiography were included. Admission samples were collected for MPV and chemistry assessment. MetS was defined according to IDF-criteria. Significant CAD was defined as at least 1 vessel stenosis > 50%, while severe CAD as left main and/or 3-vessel disease, as evaluated by quantitative coronary angiography. We included 4730 patients, among them 2167 (45.8%) had MetS. Patients with MetS were older (p < 0.001), more often females (p < 0.001), and displayed higher BMI, higher prevalence of hypercholesterolemia, renal failure, hypertension, diabetes mellitus, history of myocardial infarction (MI), previous PCI (p < 0.001, respectively), previous CABG (p = 0.002),treatment with ACE inhibitors, ARB, beta-blockers, nitrates, statins, ASA, calcium channel blockers, diuretics (p < 0.001, respectively), higher values of glycemia, HbA1c, fibrinogen (p < 0.001, respectively), creatinine (p = 0.01), uric acid (p = 0.02), and lower values of hemoglobin (p = 0.001),total-cholesterol, LDL-cholesterol, and HDL-cholesterol (p < 0.001, respectively). MetS patients showed a higher prevalence of CAD (p = 0.002) and severe CAD (p = 0.01). MPV values were slightly higher in patients with MetS (10.91 ± 1.01 vs. 10.84 ± 1.03 fL, p = 0.02), although MetS did not emerge as an independent predictor of higher MPV values (above 4th quartile; adjusted OR OR[95%CI] = 1.01[0.84-1.22], p = 0.93). When metabolic syndrome patients were analyzed according to MPV quartiles, higher MPV values did not result as an independent predictor of CAD (adjusted OR[95%CI] = 0.79[0.61-1.03], p = 0.08) and severe CAD (adjusted OR[95%CI] = 0.82 [0.65-1.03], p = 0.084). Results did not change when applying the new harmonized definition of MetS. This study shows that among patients undergoing coronary angiography MetS is not an independent predictor of higher MPV. Moreover, among MetS patients, larger-sized platelets are not associated to the prevalence and extent of CAD.