Serafina Valente

Cardiovascular Death and Nonfatal Myocardial Infarction in Acute Coronary Syndrome Patients Receiving Coronary Stenting Are Predicted by Residual Platelet Reactivity to ADP Detected by a Point-of-Care Assay A 12-Month Follow-Up

Background— The clinical impact of platelet aggregation assessed by point-of-care assays is unknown. We sought to evaluate whether high residual platelet reactivity (RPR) to ADP during clopidogrel therapy, measured by a point-of-care assay, predicts adverse clinical events in acute coronary syndrome patients undergoing percutaneous coronary intervention. Methods and Results— We used the VerifyNow P2Y12 assay (Accumetrics Inc, San Diego, Calif) to determine RPR to ADP in 683 patients with acute coronary syndrome undergoing dual-antiplatelet therapy who underwent percutaneous coronary intervention with bare-metal or drug-eluting stent implantation. All patients received a single 600-mg clopidogrel loading dose followed by 75 mg of clopidogrel daily and 100 to 325 mg of aspirin daily. The end points of the study at follow-up of 12 months were cardiovascular death, nonfatal myocardial infarction (MI), and target-vessel revascularization. At a 12-month follow-up, we found 51 ischemic events (24 cardiovascular deaths [3.5%], 27 nonfatal MIs [3.9%]) and 40 target-vessel revascularizations (5.8%). By receiver operating characteristic curve (ROC) analysis, the optimal cutoff value in predicting 12-month cardiovascular death and nonfatal MI was P2Y12 reaction unit values ≥240. RPR, defined in the presence of P2Y12 reaction unit values above this cutoff, was found to be a significant and independent predictor of cardiovascular death and nonfatal MI in a model that adjusted for cardiovascular risk factors, renal failure, reduced left ventricular ejection fraction, multivessel disease, total stent length, bifurcation lesions, number of lesions treated, type of stent, and use of glycoprotein IIb/IIIa inhibitors (cardiovascular death: hazard ratio 2.55, 95% CI 1.08 to 6.07, P=0.034; nonfatal MI: hazard ratio 3.36, 95% CI 1.49 to 7.58, P=0.004). No significant association was found between high RPR and the risk of target-vessel revascularization. Conclusions— RPR to ADP with clopidogrel therapy, measured by the point-of-care assay VerifyNow P2Y12, is able to detect acute coronary syndrome patients at risk of 12-month cardiovascular death and nonfatal MI. The optimal cutoff value was identified as being 240 P2Y12 reaction units.

Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10 + 12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients.

Objectives The aim of this study was to evaluate the effect of polymorphisms affecting the clopidogrel metabolism (CYP3A4 IVS10+12G/A and CYP2C19*2) and the P2Y12 receptor (P2Y12 T744C) on modulating platelet function in acute coronary syndrome patients on dual antiplatelet treatment. Background Residual platelet reactivity (RPR) phenomenon on antiplatelet therapy requires clarification. P2Y12 T744C, CYP3A4 IVS10+12G/A and, in healthy individuals only, CYP2C19*2 polymorphisms have been investigated; however, the influence on platelet reactivity in a large population of high-risk vascular patients on dual antiplatelet treatment has not yet been elucidated. Methods A total of 1419 acute coronary syndrome patients on dual antiplatelet treatment were studied. Platelet function was evaluated by platelet-rich plasma aggregation. Electronic nanochips and restriction-fragment length polymorphism were used for analysis of polymorphisms. Results Only CYP2C19*2, out of the three investigated polymorphisms, is associated with higher platelet reactivity. Carriers of the *2 allele had significantly higher platelet aggregation values after arachidonic acid (AA; P=0.043), 2 μmol/l adenosine 5′ diphosphate (ADP; P<0.0001) and 10 μmol/l ADP (P=0.001) stimuli. The genotype distribution of CYP2C19*2 polymorphism significantly differed between patients with and without RPR, as evaluated by 10-μmol/l ADP-induced platelet aggregation (P=0.002) and by AA-induced platelet aggregation (P=0.045). At the multivariate linear regression analysis, the CYP2C19*2 polymorphism remained a significant and independent risk factor for dual antiplatelet treatment variability. Conclusions This study demonstrates, for the first time, that the *2 CYP2C19 allele is associated with higher platelet aggregability and RPR in high-risk vascular patients on dual antiplatelet treatment. These findings can have a significant impact on the future design of pharmacogenetic antiaggregant strategies for high-risk vascular patients on dual antiplatelet treatment.

Role of hemodynamic shear stress in cardiovascular disease

Atherosclerosis is the main cause of morbidity and mortality in the Western world. Inflammation and blood flow alterations are new markers emerging as possible determinants for the development of atherosclerotic lesions. In particular, blood flow exerts a shear stress on vessel walls that alters cell physiology. Shear stress arises from the friction between two virtual layers of a fluid and is induced by the difference in motion and viscosity between these layers. Regions of the arterial tree with uniform geometry are exposed to a unidirectional and constant flow, which determines a physiologic shear stress, while arches and bifurcations are exposed to an oscillatory and disturbed flow, which determines a low shear stress. Atherosclerotic lesions develop mainly in areas of low shear stress, while those exposed to a physiologic shear stress are protected. The presence of areas of the arterial tree with different wall shear stress may explain, in part, the different localization of atherosclerotic lesions in both coronary and extracoronary arteries. The measurement of this parameter may help in identifying atherosclerotic plaques at higher risk as well as in evaluating the efficacy of different pharmacological interventions. Moreover, an altered shear stress is associated with the occurrence of both aortic and intracranial aneurysms, possibly leading to their growth and rupture. Finally, the evaluation of shear stress may be useful for predicting the risk of developing restenosis after coronary and peripheral angioplasty and for devising a coronary stent with a strut design less thrombogenic and more conducive to endothelization.

Detection of significant coronary artery disease by noninvasive anatomical and functional imaging.

Background—The choice of imaging techniques in patients with suspected coronary artery disease (CAD) varies between countries, regions, and hospitals. This prospective, multicenter, comparative effectiveness study was designed to assess the relative accuracy of commonly used imaging techniques for identifying patients with significant CAD. Methods and Results—A total of 475 patients with stable chest pain and intermediate likelihood of CAD underwent coronary computed tomographic angiography and stress myocardial perfusion imaging by single photon emission computed tomography or positron emission tomography, and ventricular wall motion imaging by stress echocardiography or cardiac magnetic resonance. If ≥1 test was abnormal, patients underwent invasive coronary angiography. Significant CAD was defined by invasive coronary angiography as >50% stenosis of the left main stem, >70% stenosis in a major coronary vessel, or 30% to 70% stenosis with fractional flow reserve ⩽0.8. Significant CAD was present in 29% of patients. In a patient-based analysis, coronary computed tomographic angiography had the highest diagnostic accuracy, the area under the receiver operating characteristics curve being 0.91 (95% confidence interval, 0.88–0.94), sensitivity being 91%, and specificity being 92%. Myocardial perfusion imaging had good diagnostic accuracy (area under the curve, 0.74; confidence interval, 0.69–0.78), sensitivity 74%, and specificity 73%. Wall motion imaging had similar accuracy (area under the curve, 0.70; confidence interval, 0.65–0.75) but lower sensitivity (49%, P<0.001) and higher specificity (92%, P<0.001). The diagnostic accuracy of myocardial perfusion imaging and wall motion imaging were lower than that of coronary computed tomographic angiography (P<0.001). Conclusions—In a multicenter European population of patients with stable chest pain and low prevalence of CAD, coronary computed tomographic angiography is more accurate than noninvasive functional testing for detecting significant CAD defined invasively. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979199.

Uric acid in the acute phase of ST elevation myocardial infarction submitted to primary PCI: Its prognostic role and relation with inflammatory markers: A single center experience

BACKGROUND AND METHODS Scarce data are available on the prognostic role of uric acid (UA ) in patients with ST elevation myocardial infarction (STEMI). We aimed at assessing the relation between uric acid, measured on Intensive Cardiac Care Unit (ICCU) admission, and mortality at short term follow-up in 466 consecutive STEMI patients submitted to percutaneous coronary intervention (PCI), as well as its relation with inflammatory markers (C-reactive protein, CRP-fibrinogen, erythrocyte sedimentation rate ESR). RESULTS Higher UA were detectable in the 21.5%.. In-hospital mortality was higher in patients with elevated UA (p<0.01 O.R. (95% C.I.): 3.9 (1.5-10.2)). At backward stepwise regression analysis UA resulted an independent predictor for in-hospital mortality (OR 1.82, 95%CI 1.15-2.86; p=0.01). CONCLUSION Our data strongly suggest that in the acute phase of STEMI patients submitted to PCI, uric acid holds a prognostic role for in-hospital mortality.

Effects of ULTRAfiltration vs. DIureticS on clinical, biohumoral and haemodynamic variables in patients with deCOmpensated heart failure: the ULTRADISCO study

To evaluate the clinical, biohumoral, and haemodynamic effects of ultrafiltration vs. intravenous diuretics in patients with decompensated heart failure (HF). Signs and symptoms of volume overload are often present in these patients and standard therapy consists primarily of intravenous diuretics. Increasing evidence suggests that ultrafiltration can be an effective alternative treatment.

Prognostic role of insulin resistance as assessed by homeostatic model assessment index in the acute phase of myocardial infarction in nondiabetic patients submitted to percutaneous coronary intervention

Background and objectives Little information is available on the relation between insulin resistance and acute myocardial infarction. Methods In 253 consecutive nondiabetic patients with ST elevation myocardial infarction (STEMI) submitted to percutaneous coronary intervention, we assessed the prevalence of insulin resistance by homeostatic model assessment (HOMA) index and its prognostic role in early and late mortality. Results Insulin resistance was detectable in 52.9% of patients. Anterior STEMI was more frequent in insulin-resistant patients (P = 0.040), who showed higher values of probrain natriuretic peptide (P = 0.010), creatinine (P < 0.001), creatinine phosphokinase and creatinine phosphokinase-MB (MB, isoenzyme present in the myocardium; P = 0.016 and P = 0.003, respectively). At backward stepwise logistic regression analysis, the following variables were independent predictors for intra-intensive cardiac care unit mortality: HOMA index [hazard ratio 1.40; 95% confidence interval (CI) 1.02–1.95; P = 0.049]; C-peptide (hazard ratio 3.14; 95% CI 1.40–24.80; P = 0.001) and lactic acid (hazard ratio 2.50; 95% CI 1.41–4.44; P = 0.002). At long-term follow-up (Cox regression analysis), neither fasting glycaemia nor HOMA index resulted in predictors for mortality. Conclusion In nondiabetic STEMI patients submitted to percutaneous coronary intervention, insulin resistance, as assessed by HOMA index, is quite common and helps in the early prognostic stratification, as it represents an independent predictor of in-hospital mortality.

NT-proBNP on admission for early risk stratification in STEMI patients submitted to PCI. Relation with extension of STEMI and inflammatory markers

The prognostic implications of NT-proBNP measured on admission in patients with the ST-elevation myocardial infarction (STEMI) are not so far well elucidated. The present investigation, performed in 198 STEMI patients submitted to percutaneous coronary intervention (PCI), was aimed at assessing the prognostic value of NT-proBNP measured on admission to Intensive Cardiac Care Unit (ICCU) and its relation with the extension of myocardial infarction (indicated by cardiac biomarkers and ejection fraction) and inflammatory markers (C-reactive protein - CRP, erythrocyte sedimentation rate - ESR, leucocytes, fibrinogen). All patients who died during ICCU stay had increased values of NT-proBNP. Each quartile of NT-proBNP resulted directly correlated with age, heart rate, peak Tn I, admission creatinine serum levels, ESR, fibrinogen, and inversely correlated with ejection fraction. At backward logistic regression analysis, NT-proBNP values showed a significative correlation with peak Tn I (OR 1.013; 95% CI 1.001-1.025; p=0.036), and CRP positive (OR 6.450; 95% CI 1.714-24.272; p=0.006); age was close to reaching statistical significance (OR 1.043; 95% CI 0.999-1.089; p=0.055). At long term-follow-up NT-proBNP lacks any prognostic role in predicting adverse events such as hospitalization for rePCI, re-infarction and heart failure. Kaplan-Meier curves showed that all patients dead at follow-up were in the highest NT-proBNP quartiles.

Determinants of treatment strategies and survival in acute myocardial infarction: a population-based study in the Florence district, Italy: results of the acute myocardial infarction Florence registry (AMI-Florence).

AIMS The Florence Acute Myocardial Infarction Registry is a prospective, observational study aimed at identifying the determinants of use of primary PCI and of prognosis in patients with STE-AMI, in an unselected population-based setting. METHODS AND RESULTS Nine hundred and thirty cases of STE-AMI (mean age: 70.5 years) were prospectively recorded. Factors associated with use of revascularization, or influencing survival were identified through multivariate analyses (respectively: logistic and Cox regression). Primary PCI was the preferred reperfusion therapy in the study district, with 50% of STE-AMI cases admitted within 24h, and 58% of those admitted within 12h from symptom onset treated; about 5% of patients undergone fibrinolysis (overall revascularization being 55% and 63%, respectively). Availability of PCI facilities at admission hospital was the strongest independent positive predictor of subsequent primary PCI. Advanced age, comorbidities, Killip class 3, delayed hospitalisation and other factors independently reduced the probability of receiving reperfusion. In the whole series, in-hospital mortality was 6.6% for revascularization and 15.6% for conservative therapy, 6-month mortality was 10.1% and 26.0% respectively. The independent, protective effect of primary PCI persisted at the multivariate analysis, being 44% the reduction in the risk of death at 6 months. CONCLUSION In this unselected series of patients, primary PCI, routinely performed in high volume centres, achieved good results in terms of survival even outside the setting of a randomised clinical trial. However, the relatively high number of untreated subjects and the tendency to select less severe cases of AMI for reperfusion treatment confirm the need for an accurate reassessment of behavioural patterns in selecting patients for revascularization.

Comparison of different methods to evaluate the effect of aspirin on platelet function in high-risk patients with ischemic heart disease receiving dual antiplatelet treatment.

Patients with coronary artery disease (CAD) receiving aspirin therapy with a residual platelet reactivity (RPR) may be at increased risk of ischemic vascular events. Point-of-care (POC) methods PFA-100 (Dade-Behring, Marburg, Germany) and VerifyNow (Accumetrics, San Diego, CA) assays have been suggested as rapid tools to evaluate RPR. We compared PFA-100 closure times by collagen/epinephrine and VerifyNow Aspirin assays with light transmission aggregation (LTA) induced by 1 mmol/L of arachidonic acid in 484 patients with CAD undergoing percutaneous coronary intervention and receiving dual antiplatelet therapy. RPR was detected in 30.0% of patients by LTA, in 32.4% by PFA-100, and in 14.3% by VerifyNow. Significant correlations were found among 3 methods (all P < .0001). In relation to the presence or absence of RPR by LTA and PFA-100, by LTA and VerifyNow, and by PFA-100 and VerifyNow, samples were significantly concordant (all P < .0001). Assuming LTA as the reference method, PFA-100 and VerifyNow showed sensitivity of 62.1% and 39.3% and specificity of 80.2% and 96.4%, respectively. The cutoff values for POC methods need to be defined for clinical use.