Pharmacodynamic comparison of low-dose ticagrelor to low-dose prasugrel in patients with prior myocardial infarction: the ALTIC-2 study.

Given that patients with prior myocardial infarction and features of high ischemic and low bleeding risk may benefit by extending dual antiplatelet therapy beyond 1 year, we aimed of assessing platelet reactivity provided by ticagrelor 60 mg bid versus prasugrel 5 mg od in 20 such patients participating in a randomized, crossover study. The primary end point of platelet reactivity at the end of the two treatment periods (by VerifyNow, in PRU) was significantly lower for ticagrelor (31.9 PRU [95% CI 12.3-51.4]) compared with prasugrel (132.1 PRU [111.9-152.3]) with a least squares mean difference of -100.2 PRU (72.1-128.3, P < .001). This dedicated pharmacodynamic study showed that in post-myocardial infarction patients with high atherothrombotic risk and receiving P2Y12 receptor antagonist beyond 1 year, low-dose ticagrelor results in a significantly lower platelet reactivity compared to low-dose prasugrel.

Impaired Arterial Elastic Properties and Endothelial Glycocalyx in Patients with Embolic Stroke of Undetermined Source.

BACKGROUND AND PURPOSE: Cardioembolism is a postulated mechanism of embolic stroke of undetermined source (ESUS). We investigated endothelial glycocalyx, aortic elastic properties, oxidative stress, and their association with left atrial (LA) function in ESUS and healthy individuals. METHODS: In 90 ESUS patients (age 50.4 ± 13.2) and 90 controls with similar risk factors, we measured: (1) perfused boundary region (PBR) of the sublingual arterial microvessels (range 5-25 µm), a marker inversely related with glycocalyx thickness, (2) pulse wave velocity (PWV), central systolic blood pressure (cSBP), and augmentation index (AIx), (3) LA volume and strain using speckle-tracking imaging, and (4) malondialdehyde (MDA) and protein carbonyls (PCs), as oxidative stress markers. RESULTS: Compared with controls, ESUS had higher PWV, PBR, MDA, and PC levels as well as higher LA volume and reduced reservoir LA strain (p < 0.05). PBR > 1.2 µm of microvessel ranging from 5 to 9 µm and PWV > 10.2 m/s were associated with ESUS on multivariable analysis (odds ratio: 2.374 and 5.429, p < 0.05, respectively) and increased the c-statistic of the initial model from 0.54 to 0.71. In ESUS, glycocalyx damage (increased PBR) was related with increased PWV (p < 0.01) which was linked with LA reservoir strain after controlling for age, sex, and risk factors (p = 0.03). Increased MDA and PC were related with glycocalyx damage, increased PWV (r = 0.67 and r = 0.52), AIx, cSBP, and aortic atheroma (p < 0.01). CONCLUSION: Arterial function and endothelial glycocalyx are severely impaired in ESUS and are linked to LA dysfunction suggesting their contribution to ESUS pathogenesis. CLINICAL TRIAL REGISTRATION: URL-http://www.clinicaltrials.gov. Unique identifier: NCT03609437.

Ethanol combined with heparin as a locking solution for the prevention of catheter related blood stream infections in hemodialysis patients: A prospective randomized study.

INTRODUCTION: Ethanol lock solution has been mainly administered in paediatric and home parenteral nutrition patients in order to prevent catheter related blood stream infections (CRBSI). Its utility in hemodialysis (HD) patients with non-tunneled-uncuffed catheter (NTC) has been poorly explored. METHODS: We conducted a prospective randomized study in chronic HD patients requiring a newly inserted NTC-while awaiting for the maturation of an already established arteriovenous fistula (AVF) or arteriovenous graft (AVG) or tunneled-cuffed catheter insertion. Patients were randomized in two groups: Group A, where the lock solution was ethanol 70% + unfractionated heparin 2000 U/mL and group B, that received only unfractionated heparin 2000 U/mL. Primary end point was CRBSIs whereas exit site infections, thrombotic and bleeding episodes were the secondary end points. FINDINGS: One hundred three HD patients were enrolled in the study (group A, n = 52; group B, n = 51). The median number of catheter days was 32 for group A (range: 23-39) and 34 (range: 27-40) for group B with no statistically significant difference between the two groups. Group A (ethanol + heparin) demonstrated 4/52 episodes (7.69%) of CRBSI whereas Group B (heparin) 11/51 episodes (21.57%) (P = 0.04). CRBSI rates per 1000 catheter days were 2.53/1000 catheter days for group A and 6.7/1000 catheter days for group B (P = 0.04). Mean cumulative infection-free catheter survival in the ethanol group did not differ significantly compared to the heparin group (log-rank test = 2.99, P = 0.08). Thrombotic episodes did not differ between the two groups. DISCUSSION: Locking of NTCs in HD patients with ethanol 70% + unfractionated heparin reduces CRBSI rates without increasing the thrombotic episodes.

The role of TNF-α, Fas/Fas ligand system and NT-proBNP in the early detection of asymptomatic left ventricular dysfunction in cancer patients treated with anthracyclines.

BACKGROUND: Anthracycline-induced cardiotoxicity typically presents as congestive heart failure (CHF). As immuno-inflammatory activation and apoptosis are important mechanisms in the process of heart failure, the use of biomarkers that could detect cardiovascular toxicity before the clinical presentation is of great importance. We studied whether sTNF-a, sTNF-RI, sTNF-RII, Fas/FasLigand system and NT-proBNP associate with early cardiac dysfunction in patients receiving cardiotoxic drugs. METHODS: Two groups of breast cancer patients-group A with metastatic disease under chemotherapy with epirubicin and group B with no residual disease under a less cardiotoxic regimen-as well as healthy women were included in this prosprective study. NT-proBNP, sTNF-a, sTNF-RI, sTNF-RII, sFas, sFas-Ligand and left ventricular ejection fraction (LVEF) were determined in all patients before and after the completion of chemotherapy. RESULTS: In Group A, an increase in sFas levels (p < 0.001), a decrease in the sFasL levels (p = 0.010), an NT-proBNP increase (p < 0.001) and a significant reduction of LVEF (p < 0.001) was recorded post-chemotherapy. The decrease in LVEF correlated significantly with the increase in sFas, the decrease in sFasL and the rise in NT-proBNP levels. In Group B, TNF-RI levels were higher (p = 0.024) and mean sFas-L levels lower (p = 0.021) post chemotherapy with no LVEF drop. Two of group A (7.6%) patients developed symptomatic CHF 12 and 14 months respectively after the end of chemotherapy. CONCLUSION: SFas, sFas-L and NT-proBNP correlate with reductions in LVEF and could be used as sensitive biochemical indices for the detection of asymptomatic left ventricular dysfunction in cancer patients under cardiotoxic chemotherapy.

Linezolid versus vancomycin antibiotic lock solution for the prevention of nontunneled catheter-related blood stream infections in hemodialysis patients: a prospective randomized study.

The use of antibiotic lock solutions (ALSs) for the prevention of catheter-related blood stream infections (CRBSIs) is a promising option. The efficacy and safety of linezolid as ALS were evaluated in a randomized double-blind prospective study where 131 patients who required nontunneled catheter (NTC) for hemodialysis (HD) were randomized to receive an ALS with either (A) unfractionated heparin (2000 U/ml) alone as a catheter lock control, (B) vancomycin (5 mg/ml) + heparin (2000 U/ml), or (C) linezolid (2 mg/ml) + heparin (2000 U/ml). The primary endpoint of the study was CRBSI. A total of 152 NTCs were inserted in 131 patients. The linezolid-locked group did not present any infective episode (CRBSI rate = 0/1000 catheter days) compared with 2 episodes in the vancomycin-locked group (CRBSI rate = 1.21/1000 catheter days, p = 0.1021) and 11 episodes in the heparin-locked group (CRBSI rate = 6.7/1000 catheter days, p = 0.0001). Median number of catheter days was greater in group C (median = 38) compared with group B (median = 36, p = 0.0415) and with group A (median = 34, p = 0.0036). No side effects and no resistant organisms were recorded with the use of linezolid ALS. Linezolid appears to be a safe and effective ALS, preventing CRBSI and prolonging the survival of the catheter in HD patients.

Additive prognostic value of interleukin-6 at peak phase of dobutamine stress echocardiography in patients with coronary artery disease. A 6-year follow-up study.

BACKGROUND: Interleukin-6 (IL-6) and tissue factor (TF) are elevated after myocardial ischemia during dobutamine stress echo (DSE). We examined the incremental prognostic value of IL-6 or TF measured during DSE over echocardiographic and clinical factors in patients with chronic coronary artery disease (CAD). METHODS: We studied 106 patients with angiographically documented CAD. IL-6 and TF were measured at rest, peak, and during recovery. A wall motion score index was calculated. RESULTS: Fifty-seven (54%) patients had ischemia at DSE. During follow-up (63.7 +/- 20 months), 36 patients (33%) had an adverse event (12 cardiac deaths, 24 acute coronary events). Patients with events had a higher peak IL-6 (P = .02) but similar rest and recovery IL-6 than those without. Patients with peak IL-6 > or =3.14 pg/mL (upper tertile) had a hazard ratio of 2.7 (95% CI 1.44-5.37) (P < .01 for an adverse event). The addition of peak wall motion score index in a multivariable model including risk factors, ejection fraction, revascularization, and multivessel disease increased the model's c statistic from 0.66 to 0.70 (P = .04). The addition of peak IL-6 further increased the model's c statistic to 0.75 (P = .04). Tissue factor was not related with cardiac events. CONCLUSIONS: Interleuikin-6 levels measured during the peak phase of DSE incrementally contribute to risk stratification in patients with chronic CAD.

Incremental value of pulse wave velocity in the determination of coronary microcirculatory dysfunction in never-treated patients with essential hypertension.

BACKGROUND: Coronary microcirculation is disturbed in essential hypertension. We investigated whether arterial stiffness determines coronary flow reserve (CFR) in hypertensive patients. METHODS: We examined 100 never-treated hypertensives and 20 healthy controls. We measured (i) carotid-to-femoral pulse wave velocity (PWV); (ii) Systolic (V (s)) and diastolic (V (d)) coronary flow velocity, time integral (V (TI)-V (d)) of diastolic velocity and CFR after adenosine by transthoracic echocardiography; (iii) ratio of E wave from mitral inflow to Em of mitral annulus, as an index of left ventricular (LV) diastolic pressures using tissue Doppler; (iv) carotid intima-media thickness (IMT), as an index of vascular damage; and (v) 24-h blood pressure parameters using ambulatory blood pressure monitoring. RESULTS: Patients had abnormal PWV, IMT, E/Em, resting V (d)/V (s), and CFR than controls (P < 0.05). In hypertensives, PWV was related to abnormal IMT and E/Em which in turn were related to reduced CFR (P < 0.05). PWV and E/Em were independent determinants of CFR and V (d)/V (s) (P < 0.05) in hypertensives. When added to a model including age, sex, smoking, LV mass (LVM), heart rate, 24-h systolic blood pressure (SBP), and E/Em, PWV had an incremental value in the determination of CFR (r (2) change from 0.25 to 0.46, P < 0.01). PWV >10.7 m/s predicted a CFR <2 with 79 and 75% and a CFR <2.6 with 83 and 82% sensitivity and specificity, respectively, using adjusted-receiver operating characteristic curve (ROC) analysis. CONCLUSIONS: Elevated LV diastolic compressive forces on coronary microcirculation and the presence of generalized vascular damage may explain the association between PWV and CFR. PWV has an incremental value in the determination of impaired coronary microcirculation in hypertensive patients.

Strong correlation of B2-microglobulin (B2-m) with procalcitonin (PCT) in the serum of chronic hemodialysis patients: a role for infections in the dialysis-related amyloidosis?

INTRODUCTION: Infections trigger the activation of defensive cells capable to produce and release B(2)-microglobulin (B(2)-m). Procalcitonin (PCT), secreted by a wide range of human cells, included the aforementioned defensive cells, is generally considered a sensitive and specific marker of infection. In this prospective study, we examined the possibility that infections, as detected by increased levels of PCT, increase the serum levels of B(2)-m in chronic hemodialysis (CHD) patients, possibly affecting the rate of progression of dialysis-related amyloidosis (DRA). METHODS: For a period of four months, 76 CHD patients, 45 men/31 women, mean age 63 +/- 15.7 years, with no residual renal function and in HD for 46 +/- 50 months were studied bimonthly. Blood was drawn, at baseline T(0), two months T(2), and four months T(4), for measuring hematocrit (Ht), white blood cells (WBC), erythrocyte sedimentation rate (ESR), blood urea and serum creatinine, protein (albumin, globulin), C-reactive protein (CRP), and PCT kappa alpha iota B(2)-m. Any events (especially infections) in the preceding 10-day period were recorded. RESULTS: At baseline, 100% of all B(2)-m measurements were abnormal (>2.4 mg/L), 13.4% of PCT values were increased (>1.5 ng/mL), and 49.4% of CRP values exceeded the lower limit of 5 mg/L with no statistically significant differences between the results of the three periods of the study. Statistically significant, in all periods, was the linear positive correlation of B(2)-m with PCT (T[0]: p < 0.001, T[2]: p < 0.004, T[4]: p < 0.001). Also, statistically significant (p < 0.005) was the positive correlation of B(2)-m to HD vintage. CONCLUSIONS: In this study, the strong positive correlation of B(2)-m to PCT probably signifies that the (mainly subclinical) infections increase B(2)-m production in CHD patients intensifying the problem of HD-related amyloidosis.

IgA anticardiolipin antibody is associated with the extent of daily-life ischaemia in patients with chronic coronary artery disease.

BACKGROUND: Circulating anticardiolipin antibodies (aCL) may cause endothelial dysfunction. We investigated whether aCL are related to platelet activation, thrombin generation and daily-life ischaemia in patients with chronic coronary artery disease (CAD). METHODS: We measured (medians 25th-75th percentile) IgG, IgM, IgA aCL serum levels (Arbitrary Elisa Units, AEU), prothrombin fragments (F1+2, nmol/l), 24 h urine excretion of 11-dehydrothromboxane B2 (11-DHTXB2, ng/mg creatinine) creatine kinase (CK) and its cardiac isoenzyme CK-MB (IU/l) in 60 patients with angiographically documented CAD and in 40 age and sex matched controls. Patients underwent a 48 h Holter monitoring for assessment of the number and duration of ischaemic episodes. RESULTS: Patients had higher IgA-aCL levels than controls (3.2 vs 2.4 AEU, p = 0.002). Increased IgA-ACA levels were related to increased number and duration of ischaemic episodes (p<0.01). By ANOVA, patients with >or=10 ischaemic episodes (3rd tertile) or duration of ischaemia >or=32min (3rd tertile) had higher IgA-aCL than those with lower ischaemic burden (4.95 vs 3 vs 2.5 AEU, p = 0.002 and 4.9 vs 3 vs 2.5 AEU, p = 0.001 respectively). Patients with >or=2 ischaemic episodes (2nd and 3rd tertile) had higher 11-DHTXB2, than those with minimal ischaemia (2< episodes, 1st tertile) (p = 0.001). CK and CK-MB were within normal range after Holter monitoring. Receiver operating curve analysis showed a greater area under the curve for IgA-aCL than for 11-DHTXB2 in predicting severe ischaemia (>or=10 ischemic episodes or >or=32 min duration of ischaemia). CONCLUSION: Increasing IgA-aCL levels are associated with increasing ischemic burden in patients with CAD.

ProANP and NT-proBNP levels to prospectively assess cardiac function in breast cancer patients treated with cardiotoxic chemotherapy.

BACKGROUND: Cardiac function impairment is a known side effect of epirubicin-based chemotherapy. Activation of natriuretic peptides is demonstrated in patients with heart failure. AIMS: To identify prospectively the cardiotoxic profile of epirubicin-based chemotherapy in breast cancer patients and to evaluate the sensitivity of proANP and NT-proBNP as early biochemical markers of cardiac dysfunction. METHODS: Forty cancer patients divided in two nonrandomized groups received either epirubicin and paclitaxel (Group A, n=26) or mitoxantrone and docetaxel (Group B, n=14). Control groups, Group C (n=13) and Group D (n=20), consisted of female patients with heart failure and healthy women respectively. Natriuretic peptides and LVEF were determined in all patients. RESULTS: A statistically significant difference was recorded regarding LVEF before and after treatment in Group A patients (p=0.0001). Three patients had a significant LVEF decline between 10% and 18% from baseline values, while three reached an LVEF value below 50%. All of them presented an increase in proANP and NT-proBNP values (mean increase 270.31+/-124 fmol/ml and 303.57+/-108 fmol/ml, respectively). A significant correlation between the increase in plasma proANP (r=0.8, p<0.0001), as well as NT-proBNP (r=0.7, p<0.0001) and the decrease in LVEF was observed. Regarding Group A, levels of proANP increased from 192.25 fmol/ml before treatment to 287.84 fmol/ml after treatment (p=0.0001), whereas NT-proBNP increased from 152.50 to 242 fmol/ml (p<0.0001) respectively. During follow up, two Group A patients developed congestive heart failure twelve and fourteen months after the completion of chemotherapy respectively. A significant LVEF decline was recorded in both patients during the episode. Regarding Group B, no statistically significant differences were demonstrated. CONCLUSION: ProANP and NT-proBNP levels might be used as reliable and sensitive markers in the detection of early cardiac impairment caused by epirubicin-based chemotherapy.

The relative impact of different measures of adiposity on markers of early atherosclerosis.

BACKGROUND: Although there are several methods available to assess adiposity, there is still controversy on the relative clinical utility of each of these methods. This study examines the relative impact of different measures of adiposity on markers of early atherosclerosis. In particular weight changes over time have been poorly assessed in this setting. METHODS: Eighty-six healthy individuals (31 men, age 36.5+/-8.9 years) with a wide range of body-mass index (28.7+/-7.0, 18.9-57.9 kg/m2) without hypertension, diabetes or smoking were examined. In addition to waist circumference and waist-to-hip ratio self-reported weight change since adolescence was also calculated. Ultrasonography was used to measure abdominal fat layers and their ratio. Flow-mediated dilatation of the brachial artery, serum levels of intercellular adhesion molecule (sICAM-1) and mean intima-media thickness of the carotid artery were measured as markers of early atherosclerosis. RESULTS: Stepwise multivariate regression analysis showed waist circumference and waist-to-hip ratio as the only independent predictor of flow-mediated dilatation. Waist circumference and weight change but not current body-mass index were independent predictors of intima-media thickness. These correlations were not influenced by ultrasonographically measured fat layers, C-reactive protein and basal insulin resistance. Body-mass index and weight gain were associated with sICAM-1 but not independently of basal insulin resistance and C-reactive protein. CONCLUSIONS: Waist circumference and weight gain were the strongest predictors of early atherosclerosis in a population of apparently healthy adults. The ultrasonographically measured fat layers did not provide additional information in this population.

Genetic variations of the endothelial nitric oxide synthase gene are related to increased levels of C-reactive protein and macrophage-colony stimulating-factor in patients with coronary artery disease.

It was the objective of this study to investigate the relation between nitric oxide synthase (NOS3) gene polymorphisms, vascular inflammation, endothelial function, and atherosclerosis. We examined the effects of a variable nucleotide tandem repeats (VNTR) in intron 4, G894T in exon 7 and T-786C at the promoter region of NOS3 on i) C-reactive protein (CRP) and macrophage-colony stimulating-factor (MCSF), and ii) augmentation index (AI) measured by pulse-wave analysis , flow-mediated dilation (FMD) of the brachial artery, intima-media thickness (IMT) of the carotid and femoral artery using ultrasonography and ankle-brachial index (ABI) in 122 patients with chronic coronary artery disease (CAD) who underwent coronary angiography. MCSF and CRP were increased in patients withT-786C (77/122) or VNTR (40/122) allele compared to those without (F = 10.8, p = 0.002 and F = 3.8, p = 0.04 for T-786C and F = 3.65, p = 0.04 and F = 3.2 p = 0.049 forVNTR), even after adjustment for traditional risk factors and medication. Patients with combination of VNTR and T-786C (31/122) had higher MCSF or CRP than patients with one or none of these alleles (p < 0.05). Among patients with T-786C, those with MCSF>262 pg/ml or CRP>3.2 mg/l (n = 33/77) had a higher femoral and carotid IMT and number of plaques in the peripheral arteries than those with lower values of these inflammatory indices (p < 0.05). Patients with MCSF >262 pg/ml had also lower FMD and higher Gensini score than those with lower MCSF (p < 0.05). The intron 4-VNTR and T-786C mutation of NOS3 gene enhance the inflammatory process in patients with chronic CAD.

Increased circulating C-reactive protein and macrophage-colony stimulating factor are complementary predictors of long-term outcome in patients with chronic coronary artery disease.

AIMS: We investigated, in a 6 year follow-up study, whether circulating levels of C-reactive protein (CRP) and macrophage colony stimulating factor (MCSF) have an independent or complementary prognostic value in patients with chronic coronary artery disease (CAD). METHODS AND RESULTS: MCSF and CRP were measured in 100 patients with chronic CAD. Of 95 (33%) patients, 31 who completed the 6 year follow-up presented adverse events (death, myocardial infarction, and unstable angina). In multivariable analysis (including traditional risk factors and medications), the upper tertiles of MCSF (> or =814 pg/mL) and CRP (> or =2.5 mg/L) levels were independently associated with a 13- and 6-fold increase in risk of events, respectively (P<0.01). Patients with combined high CRP and MCSF had a higher absolute risk of events than patients with elevated MCSF or CRP alone (75 vs. 59 vs. 32%, respectively, P<0.01). The mean event-free time was 39, 64, and 52 months in patients with elevated MCSF, elevated CRP, and their combination, respectively. CONCLUSION: In patients with chronic CAD, the prognostic value of MCSF is independent and complementary to that of CRP. MCSF is a particularly useful prognostic marker when CRP levels are low, but also provides additional information concerning risk and time-course of events in patients with elevated CRP.