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Prostaglandins are a complex set of biochemical compounds within the body that perform an equally complex array of functions. Two prostaglandins, prostaglandin E2 (PGE2) and prostacyclin (also called prostaglandin I2 or PGI2), have been found to dilate blood vessels. In patients with angina pectoris, the chest pain which results from intermittent oxygen deprivation of the heart muscle, little or no PGI2 or PGE2 can be found. Since normal individuals can increase the production of PGE2 and PGI2 in response to sympathetic stimulation, a test was performed on angina patients under similar conditions. For this test, the stimulation of the sympathetic nervous system, which modulates the body's response to potentially serious or threatening situations, came in the form of immersing the patient's foot in ice water (appropriately called a cold pressor test). The 23 control subjects all responded to the sympathetic stimulation with increased production of PGI2 and PGE2, and a concomitant decrease in the resistance of the coronary arteries to blood flow. In contrast, little or no increase in prostaglandin production could be detected among the 26 patients with angina. Somewhat paradoxically, among the anginal patients, the resistance of the coronary arteries to blood flow actually increased in response to the cold pressor test. It seems clear that prostaglandins play an important role in the response of the heart's circulation to sympathetic stimulation, whether it is in the form of a bucket of cold water or the stresses of everyday life. And, it is equally clear that an abnormal prostaglandin response is part of the inadequate physiological responses that occur in patients with angina. (Consumer Summary produced by Reliance Medical Information, Inc.)

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microangiopathy presenting with variable features, including migraine, psychiatric disorders, stroke, and cognitive decline and variable disability. On neuroimaging, CADASIL is characterized by leukoencephalopathy, multiple lacunar infarcts, and microbleeds. Previous studies suggest a possible role of endothelial impairment in the pathogenesis of the disease.Methods: We assessed plasma levels of von Willebrand factor (vWF) and thrombomodulin (TM) and the blood levels of endothelial progenitor cells (EPCs) and circulating progenitor cells (CPCs) in 49 CADASIL patients and 49 age-matched controls and their association with clinical/functional and neuroimaging features.Results: In multivariate analysis, CADASIL patients had significantly higher vWF and lower EPC levels. TM levels were similar in the 2 groups. CADASIL patients with a more severe clinical phenotype (history of stroke or dementia) presented lower CPC levels in comparison with patients with a milder phenotype. On correlation analysis, lower CPC levels were associated with worse performances on neuropsychological, motor and functional tests, and with higher lesion load on brain magnetic resonance imaging (degree of leukoencephalopathy and number of lacunar infarcts).Conclusions: This is the first CADASIL series in which multiple circulating biomarkers have been studied. Our findings support previous studies on the presence and the possible modulating effect of endothelial impairment in the disease. Furthermore, our research data suggest that blood CPCs may be markers of disease severity. [ABSTRACT FROM AUTHOR]

Background Strong evidence supports an association between high levels of homocysteine (Hcy) and lipoprotein(a) [Lp(a)] and an increased rate of ischemic vascular events. Methods The study population comprised 162 patients (50 women [30.9%]; age, 66.71 ± 12.76 years) having a history of acute coronary syndrome within 1 year who underwent fasting blood sampling, measurement of intima-media thickness and pulse wave velocity at the common carotid and femoral arteries by Doppler ultrasound, and ankle-brachial index measurement. Cutoff values were considered 0.9 mm and 1.2 mm for carotid and femoral intima-media thickness, respectively; 12 m/s for pulse wave velocity; and <0.9 for ankle-brachial index. We included hypertension, dyslipidemia, diabetes, overweight/obesity, smoking, and family history of cardiovascular disease in the count of traditional risk factors (CRFs). Adding Hcy ≥15 μmol/L and Lp(a) ≥500 mg/L to CRFs, we obtained a new score, named TOTAL. Results On univariate analysis, Hcy and Lp(a) were significantly associated with presence of atherosclerotic extracoronary lesions (for Hcy: β = .934; standard error = 0.178; P < .0001; for Lp(a): β = .961; standard error = 0.177; P < .0001) and compliance alterations (for Hcy: odds ratio, 13.3; 95% confidence interval, 3.9-45.3; P < .0001; for Lp(a): odds ratio, 14.6; 95% confidence interval, 5.69-37.62; P < .0001). On multivariate analysis, Lp(a) and Hcy were significantly associated with extracoronary atherosclerosis, even after correction for CRFs. The area under the curve of the TOTAL score for both atherosclerosis and vascular compliance alterations was significantly higher than the area under the curve of traditional CRFs plus only Hcy ≥15 μmol/L or plus Lp(a) ≥500 mg/L, separately added. Conclusions The addition of evaluation of Hcy ≥15 μmol/L and Lp(a) ≥500 mg/L to the traditional CRF count does improve detection of systemic atherosclerotic burden of patients with acute coronary syndrome and can offer a new opportunity to optimize secondary prevention. [ABSTRACT FROM AUTHOR]

Objectives This study sought to investigate the efficacy of prasugrel compared with clopidogrel in clopidogrel nonresponders. Background Clopidogrel nonresponsiveness is a strong marker of the risk of cardiac death and stent thrombosis after a percutaneous coronary intervention (PCI). It is unknown whether clopidogrel nonresponsiveness is a nonmodifiable risk factor or whether prasugrel with more potent and predictable platelet inhibition as measured by ex vivo techniques is associated with a positive effect on clinical outcome. Methods The RECLOSE-3 (REsponsiveness to CLOpidogrel and StEnt thrombosis) study screened clopidogrel nonresponders after a 600-mg loading dose of clopidogrel. Clopidogrel nonresponders switched to prasugrel (10 mg/day) the day of the PCI, and an adenosine diphosphate (ADP) test (10 μmol/l of ADP) was performed 6 days after the PCI. The primary endpoint was 2-year cardiac mortality. Patient outcome was compared with the RECLOSE-2–ACS study. Results We screened 1,550 patients, of whom 302 were clopidogrel nonresponders. The result of the ADP test was 77.6 ± 6.2%. After switching to prasugrel, the ADP test result decreased to 47.1 ± 16.8%. The 2-year cardiac mortality rate was 4% in the RECLOSE-3 study and 9.7% in nonresponders of the RECLOSE-2–ACS study (p = 0.007). The definite and probable stent thrombosis rates were 0.7% and 4.4%, respectively (p = 0.004). On multivariable analysis, prasugrel treatment was related to the risk of 2-year cardiac death (hazard ratio: 0.32, p = 0.036). Conclusions Clopidogrel nonresponsiveness can be overcome by prasugrel (10 mg/day), and optimal platelet aggregation inhibition on prasugrel treatment is associated with a low rate of long-term cardiac mortality and stent thrombosis. [ABSTRACT FROM AUTHOR]

Objective Recently, a large genome-wide association study in patients with abdominal aortic aneurysm (AAA) and control subjects identified nine loci associated with AAA. Besides the significant association of the rs1466535 single nucleotide polymorphism in the low-density lipoprotein receptor-related protein 1 gene ( LRP1 ), two of eight remaining loci, rs6674171 in the tudor domain containing protein 10 ( TDRD10 ) and rs3019885 in solute carrier family 30 zinc transporter member 8 ( SLC30A8 ) gene, showed a weakly significant association with AAA requiring further attention. Therefore, the aim of our study was to evaluate the role of these three polymorphisms in conferring AAA genetic susceptibility. Methods We studied these three polymorphisms in 423 patients and 423 sex- and age-comparable control subjects from Italy. All subjects were genotyped with the use of the real-time TaqMan approach. Multiple logistic regression analysis adjusted for traditional cardiovascular risk factor and chronic obstructive pulmonary disease was used to estimated odds ratios and 95% confidence intervals for AAA risk. Results The prevalence of carriers of the rs3019885 SLC30A8 G allele was higher in control subjects (67.8%) than in patients (60.3%, P = .022), suggesting a protective effect for AAA. The prevalence of carriers of the rs1466535 LRP1 T allele was higher in patients (51.8%) than in control subjects (39.7%, P = .0004), suggesting a risk effect for AAA. rs6674171 polymorphism genotype distribution did not differ between AAA patients and control subjects. In the multiple logistic regression analysis adjusted for traditional AAA risk factors, only the rs1466535 polymorphism remained significantly associated with AAA (odds ratio, 1.85; 95% confidence interval, 1.2-2.84; P = .01). Conclusions Our findings confirm the role as significant and independent susceptibility factor for AAA of the rs1466535 LRP1 polymorphism (T allele) in an Italian population. Nevertheless, our findings consistently differed from previous published data because in the genome-wide association study, the risk allele was the most frequent rs1466535 C allele. Our findings are consistent with literature data of LRP1 knock-out mice developing atherosclerotic lesions and aortic dilatation and association of the T allele with reduced LRP1 gene expression in humans. [ABSTRACT FROM AUTHOR]

Background: In ST-elevation myocardial infarction (STEMI) patients, residual platelet reactivity soon after a loading dose (LD) of prasugrel or ticagrelor is higher than that reported for healthy volunteers or subjects with stable coronary artery disease; and the majority of primary percutaneous coronary intervention (PPCI) procedures with bivalirudin monotherapy are performed without proper platelet inhibition. However, ticagrelor LD is just the daily dose, whereas prasugrel LD is 6-fold the long-term daily dose. We hypothesized that an increased ticagrelor LD may result in a faster and more effective platelet inhibition as compared with the standard prasugrel LD. Methods: Fifty patients with STEMI, pretreated with intravenous aspirin, undergoing PPCI were randomized to receive prasugrel 60-mg LD (n = 25) or ticagrelor 360-mg LD (n = 25). Residual platelet reactivity was assessed by VerifyNow at baseline and 1, 2, 4, and 12 hours after drug LD. Results: At the time of LD, 90% of enrolled patients had an aspirin reactivity unit value <550. P2Y12 reaction units 1 hour after the LD (study primary end point) were 236 (129-289) and 248 (115-304) in the prasugrel and ticagrelor group, respectively (P = .899). High residual platelet reactivity (P2Y12 reaction units ≥240) was found in 43% and 56% of patients (P = .386) at 1 hour and in 30% and 32% of patients (P = .907) at 2 hours, respectively. There was no significant difference in bleeding, arrhythmias, or dyspnea episodes in the 2 groups. Conclusions: In patients with STEMI undergoing PPCI, double (360 mg) ticagrelor LD failed to achieve a faster and more intense platelet inhibition as compared with the standard prasugrel LD. Intravenously administered aspirin allowed to achieve a very early inhibition of acid arachidonic pathway. [Copyright &y& Elsevier]

Objectives: The goal of this study was to investigate the impact of high-dose atorvastatin on the pharmacodynamic (PD) effects of double-dose clopidogrel in statin-naive patients with stable coronary artery disease (CAD) and high-on-treatment platelet reactivity (HTPR) while on standard-dose clopidogrel before percutaneous coronary intervention (PCI). Background: Patients with HTPR are at increased risk of adverse cardiovascular events after PCI. High-dose statins improve prognosis in high-risk patients by lipid- and nonlipid-related mechanisms, including antithrombotic effects. Methods: The ACHIDO (Atorvastatin and Clopidogrel HIgh DOse in stable patients with residual high platelet activity) study was a randomized PD study of high-dose (80 mg) atorvastatin in addition to double-dose (150 mg) clopidogrel (atorvastatin group, n = 38) versus double-dose clopidogrel alone (control group, n = 38) in patients with HTPR. HTPR was defined as P2Y12 reaction units (PRU) ≥235 by the VerifyNow P2Y12 assay. Platelet reactivity was evaluated immediately before PCI and at 10 and 30 days. Results: Patients randomized to atorvastatin had lower PRU values (188 ± 48 vs. 223 ± 53 PRU, p < 0.01; primary endpoint) and HTPR rates (16% vs. 42%, p < 0.01) at 30 days than patients in the control group. Statin treatment (odds ratio [OR]: 3.8, p = 0.011), baseline PRU <298 (OR: 10.7, p = 0.0001), noncarrier status of CYP2C19*2 loss-of-function allele (OR: 2.9, p = 0.043), and age (OR: 0.94, p = 0.032) were variables significantly associated with optimal PD response (PRU <235) at 30 days. No correlations were found between PRU and lipid fractions. Conclusions: High-dose atorvastatin significantly improved the PD effects of double-dose clopidogrel in our stable CAD patients with HTPR undergoing PCI (Atorvastatin and Clopidogrel HIgh DOse in stable patients with residual high platelet activity [ACHIDO]; NCT01335048). [ABSTRACT FROM AUTHOR]

Abstract: Acute coronary syndromes (ACS) represent the main clinical manifestation of atherosclerotic progression in the coronary district. Thrombosis plays a critical role in the patho-anatomical of ACS, as disruption of an atherosclerotic plaque exposes flowing blood to subendothelial collagen, tissue factor, and other procoagulant molecules that trigger activation of platelets and formation of fibrin within the vessel lumen. Endothelial damage/dysfunction, inflammation and coagulation are closely related to the pathophysiology of ACS and may be inter-related. Platelets play key roles in both the formation of the atheromatous plaque and clinical presentation of acute atherothrombotic events following plaque rupture. In the pathogenesis of the ACS, blood clotting activation has a crucial role and thrombin generation and TF may represent useful markers for the identification of patients at high risk of vascular events. Lipoprotein-associated phospholipase A2 (Lp-PLA2) represents the crossroads between lipid metabolism and inflammatory response. [Copyright &y& Elsevier]

Objective: Carotid stenosis is a common manifestation of systemic atherosclerosis. Apart from traditional risk factors, genetic determinants, such as polymorphisms of the renin angiotensin system (RAS), may be relevant in modulating the atherosclerotic process leading to carotid stenosis. In this study, we investigated the role of angiotensin-converting enzyme (ACE) I/D and -240A>T, angiotensinogen (AGT) M235T, and angiotensin type 1 receptor (AGTR1) 1166A > C polymorphisms in modulating the susceptibility to the disease. Methods: Eight hundred twenty-one consecutive patients with severe carotid stenosis (≥70%) and 847 control subjects were investigated. Results: A significant difference in genotype distribution (P < .0001) and allele frequency (P < .0001) between patients and controls for the ACE I/D polymorphism, but not for the other single-nucleotide polymorphisms investigated, was observed. The ACE D allele frequency was significantly higher in patients without traditional risk factors in comparison with that observed in those with at least one risk factor (0.71 vs 0.61; P = .04). The ACE D allele significantly influenced carotid stenosis under dominant, recessive, and additive model of inheritance at both univariate (P < .0001) and multivariate analysis (P < .0001). When the combined effect of RAS unfavorable alleles was considered, patients carrying less than three alleles had a lower risk of carotid stenosis (odds ratio [OR], 0.79 [0.63-0.99]; P = .05), while carriers of more than four unfavorable alleles had an increased risk (OR, 1.44 [1.12-1.84]; P = .004), in comparison with subjects carrying three or four unfavorable alleles. ACE D allele frequency was similar in patients with and without additional atherosclerotic localizations (0.61 vs 0.62, respectively). Conclusions: Our findings evidence a role for ACE I/D polymorphism in influencing the susceptibility to carotid stenosis, even in the absence of traditional risk factors. Interestingly, our findings provided further information concerning the role of this polymorphism in modulating the atherosclerotic process apart from its different localizations. [Copyright &y& Elsevier]

Background: Patients with acute atrial fibrillation with a history of mild structural heart disease could be considered for rhythm conversion. Methods: Patients received intravenous flecainide, propafenone, or amiodarone on presentation and a second dose after 6 hours if atrial fibrillation persisted. No randomization was used, and drugs were given at the discretion of the treating physician. Primary end point was rhythm conversion within the first 6 hours from presentation. Secondary end points included rhythm conversion, time to rhythm conversion, and adverse drug effects within 24 hours. Results: Among the 378 patients enrolled, 37 (10%) recovered sinus rhythm before therapy was given. Of the remaining 341 patients, 43 (13%) received flecainide, 187 (55%) received propafenone, and 111 (32%) received amiodarone. Baseline clinical characteristics were homogeneous among groups. Rhythm conversion was obtained in 87% of treated patients overall. Within 6 hours, the primary end point was achieved in a higher proportion in the flecainide and propafenone groups (72% and 55%, respectively) as compared with the amiodarone group (30%; P < .001). The mean time to the end point overall was shorter in the flecainide and propafenone groups (178 ± 227 and 292 ± 285 minutes, respectively) as compared with the amiodarone group (472 ± 269 minutes; P < .001). Length of in-hospital stay in the amiodarone group was significantly higher (26.1 ± 22.4 hours) compared with the flecainide and propafenone groups (8.9 ± 10.3 and 11.0 ± 13.8 hours; respectively; P = .001). No significant differences were found in adverse drug effects. Conclusions: Flecainide and propafenone achieve rhythm control in a higher proportion of patients as compared with amiodarone within a 6-hour management. [Copyright &y& Elsevier]

Background: Prolongation of the action potential duration, whose major determinants are the delayed-rectifier potassium currents, is a hallmark of failing ventricular myocardium. Genetic variants in the KCNE1 gene, encoding for the β-subunit (minK) of a slowly activated cardiac potassium channel (Iks), may impair myocardial repolarization. Experimental data demonstrated a higher KCNE1 expression in heart failure (HF). Objective: The purpose of this study was to investigate the association between a KCNE1 S38G single-nucleotide polymorphism (SNP) and HF. Methods: We genotyped 197 out of 323 previously investigated patients and 352 healthy controls comparable for age and sex. This study was replicated in 186 HF patients and in 200 healthy subjects comparable for age and sex and recruited from the Department of Cardiovascular Medicine of the National Research Council, Pisa, Italy. Results: A significant difference in genotype distribution and allele frequency between patients and controls was observed for the KCNE1 S38G SNP (P = .002 and P = .0008, respectively). The KCNE1 38G variant was associated with a significant predisposition to HF under a dominant (odds ratio [OR] = 2.22 [1.23–3.28]; P = .008) and additive (OR = 2.13 [1.09–4.15]; P = .03) model, after adjustment for age, sex, and traditional cardiovascular risk factors. No difference in genotype distribution and allele frequency for the KCNE1 S38G SNP according to functional New York Heart Association class was found (P = .4 and P = .3, respectively). In the HF replication study, the KCNE1 38G allele frequency was significantly higher in comparison with that observed in the control population (38G = 0.59 vs. 0.49; P = .004). The 38G allele was associated with HF predisposition under the recessive (OR [95% confidence interval (CI)] = 2.49 [1.45–4.29]; P = .001) and additive models (OR [95% CI] = 2.63 [1.29–5.35]; P = .008), after adjustment for traditional risk factors. Conclusion: KCNE1 S38G SNP is associated with HF predisposition in two study populations. Nevertheless, further studies performed in larger populations and aimed to better define the role of this locus are required. [Copyright &y& Elsevier]

Objective: Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis. Apart from traditional cardiovascular risk factors, several novel biologic mediators and genetic predisposing factors appear relevant in determining the atherogenetic process leading to PAD. Genes encoding for renin angiotensin system (RAS) components have been proposed as candidate in atherosclerosis. This study investigated four polymorphisms in angiotensinogen (AGT), angiotensin converting enzyme (ACE), and angiotensin II receptor type 1 (AGTR1), genes of RAS, in both predicting PAD and modulating the severity of the disease. Methods: The ACE I/D and -240A>T, AGT M235T, and AGTR1 1166A>C polymorphisms were analyzed in 281 PAD patients and in 485 controls comparable for age and sex. Results: The ACE D and -240T alleles both significantly influenced the predisposition to PAD. The ACE D, but not -240 T, allele remained associated with PAD after Bonferroni correction (P = .004) and adjustment for cardiovascular risk factors (P = .03). The ACE D allele influenced PAD predisposition with a dose-dependent effect (odds ratio for ACE ID vs II genotype, 1.77; P = .006; ACE DD vs II genotype, 2.15; P = .001). The haplotype reconstruction analysis for the ACE gene showed that the D/-240T haplotype significantly and independently influenced the predisposition to PAD (P = .02). In 190 PAD patients with no additional atherosclerotic localizations (isolated PAD), a significant association between ACE D and -240T alleles and PAD was observed. Only the ACE D allele remained associated with isolated PAD after Bonferroni correction (P = .02) and after adjustment for cardiovascular risk factors (P = .02). The haplotype reconstruction analysis for the ACE gene showed that the D/-240T, but not the D/-240A haplotype significantly influenced the predisposition to PAD (P = .0003). No influence of the polymorphisms analyzed on the severity of the disease, according to Rutherford categories, was found. Conclusions: The present study contributes data to highlight the role of the ACED/-240T haplotype in predisposing to PAD, also in the absence of other atherosclerotic comorbidities. [Copyright &y& Elsevier]

Abstract: Background: Inflammatory markers are involved in heart failure (HF) pathophysiology. However, the link between these markers and reverse remodeling as well as major adverse cardiac events (HF death, sudden death, and unplanned cardiac rehospitalizations) in patients who undergo cardiac resynchronization therapy (CRT) has not been evaluated. Methods and Results: We recorded major adverse cardiac events of 140 patients (on optimized medical therapy, left ventricular ejection fraction 29.9 ± 9.6%, New York Heart Association Class III-IV, with intraventricular dyssynchrony) who underwent CRT (enrolled since April 2004). Moreover, we evaluated before and after 6 months of CRT: interleukin-6, high-sensitivity C-reactive protein, New York Heart Association class, quality of life (score on Minnesota Living with Heart Failure questionnaire), 6-minute walking test, left ventricular end-diastolic and end-systolic volumes (nonindexed and indexed by body surface area), and left ventricular ejection fraction. Adverse cardiac events were observed in 40 patients (28.6%): 22 deaths and 18 cardiac unplanned rehospitalizations. Only patients without adverse events during follow-up showed a significant reduction of inflammatory markers and left ventricular volumes (reverse remodeling), despite a significant improvement of clinical status observed in both groups of patients. Conclusions: The reduction of inflammatory status seems to be linked to reverse remodeling as well as to a better clinical prognosis in patients with HF who underwent CRT. [Copyright &y& Elsevier]

Background: The mechanism by which high circulating homocysteine concentrations are a risk factor for atherothrombosis is incompletely understood.Aproinflammatory state is related to atherosclerosis, and recent studies suggest that acute phase reactants correlate with circulating concentrations of homocysteine. Objective: We determined whether high concentrations of inflammatory markers are associated with hyperhomocysteinemia independently of dietary vitamin intakes, vitamin concentrations, and cardiovascular disease risk factors in a large, representative sample of the general population. Design: Five hundred eighty-six men and 734 women were randomly selected from the inhabitants of 2 small towns near Florence, Italy. Results: After adjustment for multiple potential confounders, interleukin 1 receptor antagonist (IL-1ra) and interleukin 6 (IL-6) concentrations were significantly (P <0.001) associated with plasma homocysteine concentrations in older (>65 y) populations. Compared with participants in the lowest IL-6 tertile, those in the highest tertile had a higher risk of having homocysteine concentrations that were high (>30 μmol/L; odds ratio: 2.6; 95% CI: 1.1, 5.6; P = 0.024) or in the intermediate range 15-30 μmol/L (odds ratio: 1.6; 95% CI: 1.2, 2.2; P = 0.0014). Sedentary state, intakes of vitamin B-6 and folic acid, and serum folate, vitamin B-12, vitamin B-6, and α-tocopherol concentrations were significant independent correlates of homocysteine. Conclusions: High circulating concentrations of IL-1ra and IL-6 are independent correlates of hyperhomocysteinemia and may explain, at least in part, the association between homocysteine and atherosclerosis. [ABSTRACT FROM AUTHOR]

Thrombin generation is a key event in the pathophysiology of coronary syndromes and provides the rationale for treatment with anticoagulants. Unlike standard heparin, low-molecular-weight heparin (LMWH) has little effect on activated partial thromboplastin time. LMWH treatment has been monitored by measurement of anti-Factor Xa activity, but this may not accurately reflect the anticoagulant action because LMWHs also inhibit Factor II. The Heptest is a clotting assay that is sensitive to both anti-Xa and anti-IIa activity, as well as inhibition of the extrinsic pathway by LMWH-stimulated release of tissue factor pathway inhibitor. The plasma thrombin neutralization assay has also been used to measure LMWH and to detect low concentrations to which chromogenic assays are insensitive. In the clinical setting, monitoring the anti-Xa activity in patients treated with LMWH after acute deep vein thrombosis offered no advantages over a standard weight-adjusted dose. Moreover, in acute coronary syndromes there is no increase in major hemorrhage rates with weight-adjusted LMWH. Monitoring of LMWH concentrations may be advisable in the presence of comorbid conditions carrying an increased risk of hemorrhage, such as renal disease, advanced age, severe over- or underweight, or a history of previous bleeding episodes. [ABSTRACT FROM AUTHOR]

Investigates the prevalence of PLA1/A2 polymorphism in Italians. Association of polymorphism with coronary heart disease; Association with restenosis after PTCA. Roles of platelet glycoprotein IIb/IIIa and the von Willebrand factor in platelet aggregation; Polymorphism as not homogenous among different populations.

Background: Previous data showed decreased low-density lipoprotein receptor-related protein 5 (LRP5) gene expression in peripheral blood cells of abdominal aortic aneurysm (AAA) patients and an association between decreased expression of LRP5 and increased lipoprotein (a) [Lp(a)] levels in AAA. LRP5 gene is involved in bone, lipid, and glucose metabolism, and experimental studies showed that atherosclerotic lesions of ApoE:LRP5 double knockout mice were ∼threefold greater than those in ApoE-knockout mice and were characterized by features of advanced atherosclerosis, with remarkable accumulation of foam cells and destruction of the internal elastic lamina. The aim of this study was to evaluate the role of polymorphisms in LRP5 gene in determining genetic susceptibility to AAA. Methods: A total of 423 AAA patients and 423 controls comparable for sex and age were genotyped for seven polymorphisms within the LRP5 (rs667126, rs3736228, rs4988300, rs3781590, rs312016, rs556442, rs627174) by TaqMan approach. Results: Two polymorphisms were significantly associated with AAA: rs4988300, carriers of the T allele in AAA (74.0% vs 65.3% in controls; P = .007); and rs3781590, carriers of the T allele in AAA (66.5% vs 57.4% in controls; P =.009). At the multiple logistic regression analysis, adjusted for age, sex, dyslipidemia, hypertension, smoking habit, and chronic obstructive pulmonary disease, rs4988300 and rs3781590 polymorphisms remained significant and independent determinants of AAA (OR, 1.62; 95% CI, 1.02-2.56; P = .040, and OR, 1.83; 95% CI, 1.17-2.85; P = .008, respectively). We confirmed that AAA patients had significantly higher Lp(a) levels than control subjects (180.0 mg/L vs 107.6 mg/L; P < .0001). The prevalence of patients with Lp(a) levels ≥300 mg/L was significantly higher in patient carriers of the rs4988300 T allele than in wild-type patients (42.6% vs 30.8%; P = .048). Conclusions: Present data have identified rs4988300 and rs3781590 LPR5 polymorphisms as independent genetic markers of AAA and underlined the need to concentrate our effort in studying the role of these markers in AAA and of LRP5 gene in Lp(a) catabolism and AAA pathophysiology. [Copyright &y& Elsevier]

Background: Abdominal aortic aneurysm (AAA) has a multifactorial etiology and the relevance of genetic factors is getting increasing interest, in particular those related to the destructive remodeling of extracellular matrix. Methods: We performed a candidate gene association study of polymorphisms in genes coding matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs), and elastin (ELN) in AAA. DNA samples from 423 AAA patients and 423 controls were genotyped for 12 polymorphisms in 10 genes: MMP1 (−1607G/GG), MMP2 (−735C/T; −1306C/T; −1575 G/A), MMP3 (5A/6A), MMP9 (−1562C/T), MMP10 (A180G), MMP-12 (−82A/G), MMP-13 (−77A/G), TIMP1 (C434T), TIMP3 (−1296T/C), and ELN (G1355A). Results: Genotype distribution was significantly different between patients and controls for the following polymorphisms: −1306C/T MMP2; 5A/6A MMP3; −77A/G MMP-13; G1355A ELN; and C434T TIMP1. In a multivariable logistic regression analysis adjusted for traditional cardiovascular risk factors and chronic obstructive pulmonary disease, −1306C/T MMP2 (odds ratios [OR] = 0.55 [95% confidence interval, CI .34-.85], P < .007) and G1355A ELN (OR = 0.64 ([95% CI .41-.99], P = .046) polymorphisms resulted in independent protective factors for abdominal aortic aneurysm (AAA), whereas 5A/6A MMP3 (OR = 1.82 [95% CI 1.04-3.12], P = .034) and −77 A/G MMP-13 (OR = 2.14 [95% CI 1.18-3.86], P = .012) polymorphisms resulted in independent risk factors for AAA. In a multivariable logistic regression analysis adjusted for traditional cardiovascular factors and chronic obstructive pulmonary disease, the prevalence of the contemporary presence of three or four genetic risk conditions was a strong and independent determinant of AAA disease (OR = 2.96, 95% CI 1.67-5.24, P < .0001). For those polymorphisms independently associated with AAA in this study (−1306C/T MMP2, 5A/6A MMP3, −77A/G MMP-13, and G1355A ELN polymorphisms), we performed a meta-analysis of the available data (this paper and literature data). We found a significant association with an increased risk of AAA for MMP3 (AAA patients n = 1258, controls n = 1406: OR = 1.48 [95% CI = 1.23-1.78], I 2 = 0%) and MMP-13 (AAA patients n = 800, controls n = 843: OR = 1.37 [95% CI = 1.04-1.82], I 2 = 25%) polymorphisms and a trend that did not reach the statistical significance, toward a decreased risk of AAA for MMP2 (AAA patients n = 1090, controls n = 1077: OR = 0.83 [95% CI = .60-1.15], I 2 =7 1%) and ELN (AAA patients n = 904, controls n = 1069: OR = 0.79 [95% CI = .53-1.18], I 2 = 72%) polymorphisms. Conclusions: These findings suggest that polymorphisms in MMP2, MMP3, MMP-13, and ELN genes may independently contribute to the pathogenesis of AAA. [Copyright &y& Elsevier]

Objective: Several biologic mediators and genetic predisposing factors may contribute to the development of peripheral arterial disease (PAD). The eNOS gene, encoding for endothelial nitric oxide synthase, has been proposed as a candidate gene in the predisposition to the disease. In this study, we evaluated the role of eNOS-786T>C, -894G>T and 4a/4b polymorphisms as markers of PAD per se and in the presence of the ACE D allele in patients previously investigated. Methods: We analyzed 281 consecutive patients (220 men, 61 women; median age, 72 years) with PAD and 562 healthy controls, comparable for sex and age. Results: eNOS-786C, but not -894T and 4a, allele frequency was significantly higher in PAD patients than in controls (P = .03). An association with the predisposition to PAD was found for the eNOS-786C allele (odds ratio [OR], 1.52; 95% confidence interval [CI], 1.11-2.09; P = .009) and the eNOS -786C/4a haplotype (OR, 1.41; 95% CI, 1.02-1.94, P = .04) at univariate analysis but not after adjustment for traditional risk factors. When smoking habit was considered, we observed that eNOS-786C/4a haplotype, but not the eNOS-786C allele, influenced PAD predisposition after adjustment for traditional risk factors in smokers (OR, 2.71; 95% CI, 1.38-5.30; P = .004). The eNOS-786C and eNOS-786C/4a haplotype did not modify the susceptibility to PAD in patients carrying the ACE D allele. Nevertheless, the presence of the eNOS-786C/4a haplotype increased PAD predisposition in smokers also carrying ACE D allele (OR, 2.71 to 3.79; P > .05 for interaction). Conclusions: This study demonstrated an association between eNOS and ACE genes in increasing PAD susceptibility in smokers, thus providing evidence for a gene-environment interaction in modulating predisposition to the disease. [Copyright &y& Elsevier]

Abstract: Background: Clinical and experimental evidence suggests that hepatitis C virus (HCV) infection shows peculiar characteristics that strongly support a role in the development of atherosclerosis. We aimed to investigate whether (a) HCV infection can facilitate asymptomatic carotid lesions and (b) the presence of HCV RNA sequences can be shown in plaque tissues. Methods: The status of carotid arteries, studied as intima-media thickness (IMT) in carotid bifurcation and prevalence and severity of plaques in internal carotid artery, was investigated by high-resolution B-mode ultrasonography in 31 HCV seropositive (HCV+) and in 120 age-matched HCV seronegative (HCV-) subjects evaluated for cardiovascular risk factors. The atherosclerotic risk profile, inflammation markers and main liver function tests were also studied in all patients. HCV RNA sequences were investigated by highly sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) in plaque tissues and serum of 2 HCV+ patients who underwent carotid revascularization. Results: Genomic and antigenomic HCV RNA strands were evidenced within both the carotid plaque tissues examined. The prevalence of an IMT > 1 mm, but not the prevalence and severity of internal carotid plaques, was significantly higher (P < 0.001) in HCV+ than in HCV patients. The atherosclerotic risk profile for traditional and inflammatory factors did not differ between the HCV+ and HCV- groups. Main liver function tests did not differ between the two groups. HCV positivity was significantly associated with >1 mm IMT (P < 0.01) according to univariate analysis, and this association remained significant in multivariate regression analysis. Conclusions: The novel finding of HCV RNA sequences within carotid plaques suggests a local pro-atherogenetic action of the virus inside the plaque. On the whole our data strongly support that HCV infection facilitates the occurrence of carotid atherosclerotic lesions. [Copyright &y& Elsevier]

Introduction Thrombin generation (TG) is a central step of the coagulation system involved in hemostatic and thrombotic roles. Scarce data evaluating in the acute phase the association between TG and the risk of cardiovascular death of acute coronary syndrome (ACS) patients are available, in the era of percutaneous coronary intervention (PCI) and stenting with the use of dual antiplatelet treatment. Materials and methods We investigated TG in 292 ACS patients undergoing PCI with stent implantation on dual antiplatelet treatment. Venous samples were obtained 12–24 h after PCI. TG was assessed using the Calibrated Automated Thrombogram (CAT). Results At two years of follow-up, 57 out of 292 patients (19.5%) died from cardiovascular causes. Higher values of endogenous thrombin potential (ETP) [1115.9 (705–1441.3) vs 940.2 (666.0–1253.1), p = 0.049], peak [176.1 (80.5–259.4) vs 107.3 (59.9–181.1), p = 0.002] and velocity index [61.75 (21.03–97.88) vs 25.64 (11.95–50.90), p < 0.001] were observed in relation to survival patients. At the multivariate model adjusted for the Global Registry of Acute Coronary Events risk score, the association between TG and cardiovascular death remained significant for ETP [OR (95% CI): 2.58 (1.10–6.03), p = 0.029], peak [OR (95%CI): 3.27 (1.35–7.92), p = 0.009] and velocity index [OR (95% CI): 3.06 (1.27–7.39), p = 0.013]. This result was confirmed after adjustment for high on-treatment platelet reactivity [ETP: OR (95% CI) 2.35 (1.11–5.00), p = 0.027; peak: OR (95% CI) 2.42 (1.13–5.15), p = 0.022; velocity index: OR (95% CI) 2.43 (1.14–5.20), p = 0.022]. Conclusions ACS patients with a residual TG after PCI and stent implantation have a significantly higher risk of long-term cardiovascular death. These results might be useful in improving risk stratification for ACS patients and support the need of a tailored antithrombotic therapy. [ABSTRACT FROM AUTHOR]

Introduction: Direct oral anticoagulant (DOAC) intra- and inter-individual variability was previously reported, but its magnitude is still considered negligible for patient management. Objective: To evaluate inter- and intra-individual variability in real-world atrial fibrillation patients on dabigatran, rivaroxaban or apixaban in four Italian anticoagulation clinics and to assess the correlation between DOAC plasma concentration and creatinine-clearance (CrCl). Materials and Methods: A total of 330 consecutive patients were enrolled, of which 160 were on dabigatran (70 and 90 taking 150 mg or 110 mg twice-daily, respectively), 71 on rivaroxaban (37 and 34 taking 20 mg or 15 mg once-daily) and 99 on apixaban (73 and 26 taking 5mg or 2.5 mg twice-daily). Blood was taken at trough and peak within the first month (15-25 days) of treatment. Diluted-thrombin-time (dTT) calibrated for dabigatran and anti-FXa calibrated for rivaroxaban or apixaban was performed. Results: Mean inter-individual variability expressed as overall CV values for all drugs was lower at peak (CV = 46%) than at trough (CV= 63%). Mean CV% intra-individual variability was 36.6% at trough and 34.0% at peak. Correlation with CrCl was poor for all drugs and only dabigatran at trough showed a significant correlation. Conclusion: This multicenter study confirms high DOAC inter-individual variability that cannot be explained by the rate of renal clearance to which the three DOAC were subjected since the correlation with CrCl was relatively poor. This poor correlation suggests caution in using CrCl as the sole laboratory parameter to indirectly evaluate residual circulating DOAC. [ABSTRACT FROM AUTHOR]

Background The study sought to determine the impact of high residual platelet reactivity (HRPR) on long-term cardiac mortality in diabetic patients treated with PCI for CTO. No data exist about the impact of HRPR after 600 mg clopidogrel loading on long-term clinical outcome in patients with diabetes mellitus and treated with percutaneous coronary angioplasty (PCI) for chronic total occlusion (CTO). Methods From the Florence CTO-PCI registry, we identified consecutive diabetic patients with available in vitro platelet reactivity assessment by light transmittance aggregometry after a loading dose of 600 mg of clopidogrel. HRPR was defined as residual platelet aggregation by 10 μmol/L ADP test ≥ 70%. The primary end point of the study was long-term cardiac mortality. Results Two-hundred and three diabetic patients underwent CTO-PCI. The incidence of HRPR was 23%. The 3-year cardiac survival was lower in the HRPR group than the low residual platelet reactivity (LRPR) group (70 ± 7% and 92 ± 3%, respectively; p = 0.001). Within the oral antidiabetic patients there were no significant differences in long-term survival between HRPR and LRPR groups. Conversely, the association of insulin therapy and HRPR was related to a dramatic decrease in survival compared to the LRPR group (34 ± 14% vs. 89 ± 4%; p < 0.001). At multivariable analysis insulin therapy (HR 4.31; p = 0.001) and HRPR (HR 3.26; p = 0.004) were significantly related to long-term mortality, while completeness of revascularization was inversely related to cardiac mortality (HR 0.40; p = 0.029). Conclusion HRPR is a strong marker of increased risk of cardiac death in patients with DM who underwent PCI for CTO. [ABSTRACT FROM AUTHOR]

Background The TIPTOP (Early Short-term Doxycycline Therapy In Patients with Acute Myocardial Infarction and Left Ventricular Dysfunction to Prevent The Ominous Progression to Adverse Remodelling) trial demonstrated that a timely, short-term therapy with doxycycline is able to reduce LV dilation, and both infarct size and severity in patients treated with primary percutaneous intervention (pPCI) for a first ST-elevation myocardial infarction (STEMI) and left ventricular (LV) dysfunction. In this secondary, pre-defined analysis of the TIPTOP trial we evaluated the relationship between doxycycline and plasma levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Methods In 106 of the 110 (96%) patients enrolled in the TIPTOP trial, plasma MMPs and TIMPs were measured at baseline, and at post-STEMI days 1, 7, 30 and 180. To evaluate the remodeling process, 2D-Echo studies were performed at baseline and at 6 months. A 99m Tc-SPECT was performed to evaluate the 6-month infarct size and severity. Results Doxycycline therapy was independently related to higher plasma TIMP-2 levels at day 7 (p < 0.05). Plasma TIMP-2 levels above the median value at day 7 were correlated with the 6-month smaller infarct size (3% [0%–16%] vs. 12% [0%–30%], p = 0.002) and severity (0.55 [0.44–0.64] vs. 0.45 [0.29–0.60], p = 0.002), and LV dilation (− 1 ml/m 2 [from − 7 ml/m 2 to 9 ml/m 2 ] vs. 3 ml/m 2 [from − 2 ml/m 2 to 19 ml/m 2 ], p = 0.04), compared to their counterpart. Conclusions In this clinical setting, doxycycline therapy results in higher plasma levels of TIMP-2 which, in turn, inversely correlate with 6 month infarct size and severity as well as LV dilation. [ABSTRACT FROM AUTHOR]

Introduction: Limited data are available on the natural history of high on treatment platelet reactivity (HPR) by arachidonic acid and ADP - markers of unfavorable prognosis in acute coronary syndrome patients -. Material and methods:In a cohort of acute coronary syndrome male patients (n = 101), we evaluated the time-course of HPR by ADP (platelet aggregation by 10 μM ADP ≥ 70%) and arachidonic acid (platelet aggregation by 1 mmol arachidonic acid ≥ 20%) measuring platelet function in the acute phase (T0), at 6 months (T1) and 1 year (T2). Results: We identified persistent (HPR at T0,T1 and T2), acute non persistent (HPR only at T0), and late (HPR only at T1 or T2). Patients with persistent HPR by ADP were more frequently with higher values of BMI. Patients carrying CYP2C19*2 variant were more prevalent in the group of persistent HPR (33%). Significant higher values of immature platelet fraction and high immature platelet fraction at 6 and 12 months and mean platelet volume were present in patients with late HPR. Immature platelet fraction was the only variable significantly associated with late HPR by ADP at multivariate analysis (OR = 1.6 (1.08-2.3), p = 0.016). Patients with persistent HPR by arachidonic acid were more frequently diabetics. Immature platelet fraction at 6 months and high immature platelet fraction at 6 and 12 months were the parameters associated with late HPR by AA (OR = 1.4 (1.0-1.9), p = 0.036; OR = 1.5 (1.08-2.4), p = 0.05; OR = 4.9 (1.3-18.8), p = 0.018, respectively). Conclusions: About 25% of 101 patients has persistent HPR; they are more frequently diabetics, overweight or carriers of CYP2C19*2. The occurrence of an inflammatory state, indicated by the increase of immature platelet fraction, is associated with the occurrence of late HPR. [ABSTRACT FROM AUTHOR]

Background In acute coronary syndrome (ACS) patients older than 75 years old, prasugrel 10 mg maintenance therapy has shown less clinical efficacy and higher risk of bleeding. In patients older than 75 years, a prasugrel dose of 5 mg should be used if treatment is deemed necessary. Objective The aim of this study was to compare platelet reactivity and outcomes in elderly patients receiving prasugrel 5 mg therapy with non-elderly patients receiving prasugrel 10 mg therapy. Methods and results Consecutive ACS patients undergoing percutaneous coronary intervention (PCI) treated with prasugrel were included. Of 718 patients, 228 (32%) had ≥ 75 years and received prasugrel 5 mg/day. Residual platelet reactivity (RPR) was 47 ± 18% and 36 ± 16% in the elderly and non-elderly group, respectively (p = 0.001). High RPR (≥ 70%) was found in 9% and 2% (p = 0.0001) in elderly and non-elderly patients, respectively. In the 6-month follow-up, there was no difference in mortality, stent thrombosis, and reinfarction rates between the 2 groups but a higher rate of TIMI minor bleeding (7.9% vs 2.4%; p = 0.001) in elderly as compared with younger patients. Age ≥ 75 years was independently associated with bleeding events (HR 2.162 [1.105-4.229]; p = 0.024). Conclusions Elderly patients receiving prasugrel 5 mg are more likely to experience high RPR than younger patients treated by prasugrel 10 mg. Despite the use of a reduced prasugrel maintenance dose and a higher level of RPR, elderly patients show increased risk of bleeding during prasugrel therapy as compared to younger patients. [ABSTRACT FROM AUTHOR]

Background:Data on long term - more than 1-year - prognostic value of global platelet reactivity (G-HPR) - by adenosine diphosphate (ADP) and arachidonic acid (AA) - in patients with STEMI undergoing PCI are limited. High C-reactive protein (CRP) levels have been suggested to be associated with post-PCI atherothrombotic events. Our aim was to evaluate the long-term prognostic impact of G-HPR and CRP levels in STEMI patients.Methods and Results:We evaluated 494 STEMI patients (366M/128F; age: 65.8±12.4yrs) undergoing PCI with stent implantation. At a median follow-up of 2.3years (1.09-4.06), in 58 patients we documented cardiovascular death (11.7%). Platelet reactivity was assessed by light transmission aggregometry by 1mM AA (AA-LTA) and 10 microM ADP (ADP-LTA). By the ROC curve analysis, 17%, 52% and 12mg/L were found to be the values of AA-LTA, ADP-LTA and CRP associated with the highest specificity and sensitivity for death. G-HPR was defined as the presence of both AA-LTA ⩾17% and ADP-LTA ⩾52%. At Cox regression analysis adjusted for age, sex, cardiovascular risk factors, multivessel disease, ejection fraction, renal insufficiency, G-HPR and elevated CRP levels were associated with long-term mortality [HR=1.78 (95%CI 1.04-3.03), p=0.036 and HR=2.91 (1.54-5.52, p=0.001), respectively]. The contemporary presence of G-HPR and elevated CRP levels was associated with the highest risk of death [HR=5.1 (95%CI 1.9-13.4), p=0.001].Conclusion:G-HPR and CRP are independent long-term prognostic markers in STEMI patients. The contemporary presence of G-HPR and CRP identifies a subgroup of patients at significantly higher risk of cardiovascular death. [ABSTRACT FROM AUTHOR]