M. Mariani

Microalbuminuria, an integrated marker of cardiovascular risk in essential hypertension

This paper reviews the existing epidemiological and clinical evidence about the relationships of non-diabetic microalbuminuria with cardiovascular risk factors such as elevated blood pressure (BP), systolic particularly, cardiac hypertrophy, adverse metabolic status, smoking habits, elevated angiotensin II levels, endothelial dysfunction, acute and perhaps subclinical inflammation. Because of that unique property of reflecting the influence of so many clinically relevant parameters, microalbuminuria may legitimately be defined as an integrated marker of cardiovascular risk, an unique profile among the several prognostic predictors available to stratify risk in hypertensive patients. Recent cohort studies also showed associations with cardiovascular morbidity and mortality independently from conventional atherogenic factors. This behaviour, whose understanding still needs further elucidation, suggests to measure albuminuria and to screen patients at a higher absolute risk in whom preventive treatment is expected to be more beneficial than in those with a lower absolute risk.

Impact of gene polymorphisms, platelet reactivity, and the SYNTAX score on 1-year clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention: The GEPRESS study

OBJECTIVESnThe aim of this study was to investigate the association between high on-treatment platelet reactivity (HPR) and the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score (SS) for risk prediction of major adverse cardiovascular events (MACE) in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS) undergoing percutaneous coronary intervention (PCI).nnnBACKGROUNDnPlatelet function testing may be used to optimize antiplatelet therapy in high-risk patients, butxa0identification of this category of patients remains challenging.nnnMETHODSnThe GEPRESS (Gene Polymorphism, Platelet Reactivity, and the Syntax Score) study was a prospective, multicenter, observational study enrolling 1,053 patients with NSTEACS undergoing PCI and treated with clopidogrel. The platelet reactivity index (PRI) was measured at 3 time points: before PCI, at hospital discharge, and 1 month after PCI. Genetic variants of clopidogrel metabolism were determined in 750 patients. Patients were stratified by the presence of HPR (PRI >50%) and by tertile of the SS (upper SS tertilexa0≥15). The primary objective of this study was the risk of MACE in the period between 1 month and 1 year.nnnRESULTSnBetween 1 month and 1 year, 1-month HPR was an independent predictor of MACE in patients with an SSxa0≥15, but not in those with an SSxa0<15, displaying a 5-fold increase in event rates (10.4% vs. 2.5%; pxa0< 0.0001). CYP2C19*2 was the only single nucleotide polymorphism associated with HPR, but it was not associated with MACE. Although there was a significant variability in the PRI across the 1-month period, predischarge HPR and SS effectively stratified the risk of subsequent MACE up to 1-year follow-up.nnnCONCLUSIONSnIn clopidogrel-treated patients with NSTEACS undergoing PCI, HPR was independently associated with an increased risk of MACE only in the presence of a high SS.

Coronary microcirculation into different models of left ventricular hypertrophy—hypertensive and athlete's heart: a contrast echocardiographic study

The study was carried out in two different models of left ventricular hypertrophy: athletes heart and essential arterial hypertension. Three groups of strictly age-matched males were studied: one group of 10 young adult untreated essential hypertensive patients (H), a second group of 10 athletes (A), and a group of 10 healthy individuals as controls (C). A Sonos 5500 echograph with S4 harmonic transducer was used with Levovist (ultrasonic tracer) before and after dipyridamole injection; digitised images of quantitative myocardial contrast echocardiography were collected with Power Harmonic Doppler. Angio images were analysed using dedicated PC software by placing a region-of-interest on the septum. Peak intensity, half-time (HT), the area under the curve of appearance and disappearance of microbubbles at 2/3 of PI, both in absolute and indexed values (/LVMi), were sampled. The per cent increase of PI after dipyridamole was significantly higher in C (+73%, P<0.01) than in H (+31%) and in A (+33%) (P<0.05). The area of appearance was significantly lower in H in comparison with C and A, both at rest and after vasodilatation. The disappearance area after dipyridamole was signifi-cantly higher in C and in A (+124%) than in H (+104%) (P<0.05). Some hypothesis could be made: an impairment in the coronary microcirculatory function in hypertensive patients could be because of an in-crease in the arteriolar resistance. Angiogenesis and several different functional adaptations are the mecha-nisms that allow an optimal distribution of oxygen and of substrates to the hypertrophied myocardium of the athletes.

Neopterin levels in patients with coronary artery disease are independent of chlamydia pneumoniae seropositivity

BACKGROUNDnChronic infection with Chlamydia pneumoniae (Cpn) has been associated with atherosclerotic cardiovascular disease in sero-epidemiological, pathological and animal-model studies. Inflammation and immune activation has been proposed as the pathophysiological link between chronic infection and atherosclerosis. The aim of this study was to assess whether Cpn seropositivity is associated with serum neopterin concentrations, a marker of macrophage activation, in patients with stable and unstable angina pectoris.nnnMETHODSnWe examined 100 patients with angiographically documented coronary artery disease: 60 patients had chronic stable angina and 40 had Braunwald class III unstable angina. Neopterin concentrations were measured with a commercially available immunoassay. Cpn titres were measured with a microimmunofluorescence (MIF) assay.nnnRESULTSnNeopterin concentrations were significantly higher in patients with unstable angina compared to those with chronic stable angina (6.30 [4.85-8.80] nmol/L vs 4.95 [3.35-7.05] nmol/L, P =.004), even after adjustment for variables that were significantly different between the 2 groups on univariate analysis. In contrast, the prevalence of positive Cpn serology did not differ significantly between the 2 angina patient groups (65% v 58%, P =.50). Neopterin levels were similar between Cpn-negative and Cpn-positive patients (P =.40) in both stable and unstable angina groups.nnnCONCLUSIONSnPatients with unstable angina had higher neopterin concentrations than patients with chronic stable angina, probably reflecting the higher degree of immune activation in acute coronary syndromes. Neopterin levels, however, were independent of Cpn serostatus when combining both stable and unstable angina patients. Thus, immune activation in patients with acute coronary syndromes appears to be unrelated to Cpn seropositivity.

Time course changes of cystatin C and inflammatory and biochemical markers in non-ST-elevation acute coronary syndromes.

Background Serum cystatin C (Cys-C), a good marker of renal function, predicts prognosis in non-ST-elevation acute coronary syndromes (NSTE-ACS). However, no data are available on the time course of Cys-C values after discharge. In this study, Cys-C was measured during admission (ACS sample) and 6 weeks after discharge, and was correlated with troponin (c-TNT), high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6) and the N-terminal portion of the pro-brain natriuretic peptide (proBNP) peptide (NT-proBNP) in a highly selected homogeneous group of NSTE-ACS patients. Methods In this prospective, multicentre study, patients with a first NSTE-ACS, single-vessel disease and successful percutaneous coronary interventions (PCIs) had their sera collected, aliquoted and stored at the enrolling site and then shipped for analysis to the clinical chemistry core laboratory. Results Cys-C values slightly, but significantly, increased from the ACS samples to the 6-week samples. In contrast, hsCRP, NT-proBNP and IL-6 values significantly decreased from the ACS to the 6-week sample. Patients with elevated c-TNT levels had higher hsCRP, NT-proBNP and IL-6 values than patients with normal c-TNT levels in the ACS sample, whereas Cys-C levels were similar in patients with and without elevated c-TNT. Cys-C was highly correlated with estimated glomerular filtration rate in both the ACS and 6-week samples. Conclusions In contrast to inflammatory and biochemical stress markers, Cys-C is not affected by the occurrence of myocardial necrosis or by acute left-ventricular impairment, being a reliable marker of renal function during NSTE-ACS.

The bivalirudin paradox: High evidence, low use

A series of trials have shown that bivalirudin, a direct thrombin inhibitor that does not require the cofactor antithrombin III to be effective, is a reasonable alternative to unfractionated heparin (UFH) alone or associated with glycoprotein IIb/IIIa antagonists (GPI) in patients undergoing percutaneous coronary interventions (PCI). Particularly in patients with acute coronary syndromes (ACS), the effects of bivalirudin are striking. In the HORIZONS-AMI trial, patients with persistent ST-segment elevation (STEMI) had lower 30-day rates of net adverse clinical events and major bleeding, largely due to the significantly lower 30-day rate of non-coronary artery bypass grafting major bleeding. Bivalirudin also resulted in significantly lower rates of all-cause mortality and cardiac mortality, a benefit that extended up to 3-year follow-up. The beneficial effects of bivalirudin as compared to UFH associated with abciximab were also observed in 1721 non-ST elevation myocardial infarction (NSTEMI) patients undergoing PCI in the ISAR REACT 4 study. Although no difference was found between the two treatment strategies in the 30-day primary endpoint, bivalirudin use resulted in a lower rate of major bleeding. Despite the abundant evidence of benefit provided by bivalirudin in the treatment of ACS and the high level of recommendation received by the most recent Guidelines, its use is still low. The reasons for this underuse are multifactorial, the most likely being the preference of operators for the use of a low-cost agent, like UFH, that can be associated with a GPI. Countering platelet hyperreactivity is still the main goal of interventional cardiologists treating ACS patients invasively, apparently downplaying the pathogenetic role of thrombin in this clinical condition.

Efficacy and safety of prasugrel compared with clopidogrel in patients with acute coronary syndromes: results of TRITON-TIMI 38 trials.

Current guidelines recommend dual antiplatelet therapy using aspirin and clopidogrel for non-ST elevation acute coronary syndromes (ACS). Despite the established benefits of this approach, many patients continue to have recurrent atherothrombotic events. Moreover, it is often difficult to achieve an adequate inhibition of platelet aggregation with clopidogrel in clinical practice. Prasugrel is an orally administered P2Y12 receptor antagonist that is more potent, more rapid in onset and more consistent in its inhibition of platelet aggregation than currently approved doses of clopidogrel. The trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel – Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) randomized 13,608 moderate-to-high-risk patients with ACS (with or without ST-segment elevation) undergoing percutaneus coronary intervention to compare prasugrel with clopidogrel for a median of follow-up time of 14.5 months. The TRITON-TIMI 38 trial demonstrated a significant reduction in ischemic events in patients randomized to prasugrel compared with those treated with clopidogrel. This beneficial effect, however, was associated with a significant increase in major bleeding.

A comparison of reduced-dose prasugrel and standard-dose clopidogrel in elderly patients with acute coronary syndromes undergoing early percutaneous revascularization: Design and rationale of the randomized Elderly-ACS 2 study

BACKGROUNDnElderly patients display higher on clopidogrel platelet reactivity as compared with younger patients. Treatment with prasugrel 5mg has been shown to provide more predictable and homogenous antiplatelet effect, as compared with clopidogrel, suggesting the possibility of reducing ischemic events after an acute coronary syndrome (ACS) without increasing bleeding.nnnSTUDY DESIGNnThe Elderly-ACS 2 study is a multicenter, randomized, parallel-group, open-label trial designed to demonstrate the superiority of a strategy of dual antiplatelet treatment using a reduced 5-mg daily dose of prasugrel over a standard strategy with a daily clopidogrel dose of 75mg in patients older than 74years with ACS (either ST- or non-ST-elevation myocardial infarction) undergoing early percutaneous revascularization. The primary end point is the composite of all-cause mortality, myocardial reinfarction, disabling stroke, and rehospitalization for cardiovascular causes or bleeding within 1 year. Taking advantage of the planned size of 2,000 patients, the secondary objective is to assess the prognostic impact of selected prerandomization variables (age, sex, diabetic status, serum creatinine level, electrocardiogram changes, abnormal troponin levels, basal and residual SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery [SYNTAX] score).nnnCONCLUSIONnThe Elderly-ACS 2 study is a multicenter, randomized trial comparing a strategy of dual antiplatelet therapy with a reduced dose of prasugrel with a standard dose of clopidogrel in elderly patients with ACS undergoing percutaneous revascularization (the Elderly ACS 2 trial: NCT01777503).

NT pro-B-type natriuretic peptide levels are related to microvascular reperfusion in patients undergoing direct percutaneous transluminal coronary angioplasty for anterior ST-segment elevation myocardial infarction.

Objectives The aim of this study was to describe the time course of NT pro-B-type natriuretic peptide (NT pro-BNP) levels in patients with large anterior ST-segment elevation myocardial infarction (STEMI) treated with primary angioplasty (PPCI) and to investigate the relationship between these values and both microvascular reperfusion and left ventricular (LV) function. Background The clinical efficacy of PPCI is largely dependent on the achievement of microvascular reperfusion. Myocardial blush is an angiographic method to evaluate the presence of effective reperfusion after PPCI. NT pro-BNP is a biomarker of LV stress whose levels are also related to clinical outcome in STEMI. Methods We studied 84 patients with large anterior STEMI treated with PPCI. NT pro-BNP was measured at baseline, after 2 days (day 2) and 7 days (day 7). Echocardiographic LV ejection fraction (LVEF) was measured at baseline, day 7 and after 6 months. Myocardial blush was graded immediately after PPCI. Results NT pro-BNP increased from admission to day 2 and decreased from day 2 to day 7 in patients with significant myocardial blush (grade 2–3) as well as in patients with 0–1 myocardial blush. However, in the latter group median NT pro-BNP levels globally increased from admission to day 7, whereas they decreased in patients with significant myocardial blush. Moreover, in such patients LVEF was higher at all time points than in patients with a grade 0–1 myocardial blush. Conclusion This study shows that the time course of NT pro-BNP in the first week after an anterior STEMI is dependent on the effectiveness of microvascular reperfusion assessed after PPCI and reflects the evolution of LVEF over time.

How to reduce mortality in ST-elevation myocardial infarction patients treated with primary percutaneous coronary interventions: cut the bleeding.

Abstract Background: In-hospital mortality for ST-elevation myocardial infarction (STEMI) has declined thanks to a greater use of primary percutaneous coronary interventions (PCI) associated with more effective antiplatelet and anticoagulant drugs. In this regard, bivalirudin has been shown to decrease total and cardiac mortality as compared to unfractionated heparin (UFH). Objective: The primary purpose of this analysis is to evaluate the hypothesis that the reduction of in-hospital bleeding is the most plausible explanation for the improved survival of STEMI patients treated with bivalirudin during primary PCI. The secondary objective is to reconsider the prognostic significance of the radial access alone or in association with bivalirudin on the basis of the published data. Methods: We have done a comprehensive evaluation of the main and related publications of the HORIZONS-AMI trial in addition to an extensive research by Medline of randomized trials evaluating the prognostic impact of radial access as compared with the femoral one in primary PCI. Results: In the HORIZONS-AMI trial bivalirudin resulted in significantly lower rates of the 30 day primary endpoint (defined as major adverse ischemic outcomes plus major bleeding) over UFH plus GPI, largely due to the significantly lower rate of the protocol-defined major bleeding. All-cause and cardiac mortality were also reduced in the bivalirudin arm at 3 year follow-up. Recent studies have also shown that the use of the radial instead of the femoral approach for primary PCI is associated with reduced bleeding as well as reduced mortality. Conclusions: Our research suggests that decreasing bleeding by either a pharmacologic strategy (use of bivalirudin) or a technical approach (the transradial access) improves survival in STEMI patients undergoing primary PCI. The validity of this hypothesis should be confirmed by specific randomized trials.