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High mannose has previously associated with insulin resistance and cardiovascular disease (CVD). Our objective is to establish whether mannose is associated with anatomical evidence of coronary artery disease (CAD).Plasma mannose concentrations were measured by liquid chromatography/tandem mass spectrometry in a discovery cohort (n = 513) and a validation cohort (n = 221) of carefully phenotyped individuals. In both cohorts CAD was quantitated using state-of-the-art imaging techniques (coronary computed coronary tomography angiography (CCTA), invasive coronary angiography and optical coherence tomography). Information on subsequent CVD events/death was collected. Associations of mannose with angiographic variables and biomarkers were tested using univariate and multivariate regression models. Survival analysis was performed using the Kaplan-Meier estimator.Mannose was related to indices of CAD and features of plaque vulnerability. In the discovery cohort, mannose was a marker of quantity and quality of CCTA-proven CAD and subjects with a mannose level in the top quartile had a significantly higher risk of CVD events/death (p = 3.6e-5). In the validation cohort, mannose was significantly associated with fibrous cap thickness 65 μm (odds ratio = 1.32 per each 10 μmol/L mannose change [95% confidence interval, 1.05-1.65]) and was an independent predictor of death (hazard ratio for mannose≥vs 84.6 μmol/L: 4.0(95%CI, 1.4-11.3), p = 0.006).The current data add novel evidence that high mannose is a signature of CAD with a vulnerable plaque phenotype, consistently across measures of severity of vessel involvement and independent of the traditional correlates of CVD, and that it is an independent predictor of incident adverse outcomes.

BACKGROUND: It is unclear if strategies to rule-out myocardial infarction (MI) based on a single high-sensitivity troponin T (hsTnT) measurement at the emergency department (ED) presentation may also exclude unstable angina. METHODS: We measured hsTnT ex-post on the admission frozen blood sample of 644 subjects with Braunwald IIIB CK-MB-negative unstable angina. This analysis included the 240 patients with hsTnT value ≤99th percentile reference limit (UA). We evaluated the clinical outcome of UA patients and the applicability of two rule-out strategies based on the combination of a non-ischemic ECG with (1) a single hsTnT value below the Limit-of-Detection (LoD), (2) a TIMI risk score ≤1. RESULTS: UA patients with hsTnT ≤99th percentile reference limit had a favorable 30-day outcome [0.8% MI, 0% cardiovascular death (CVD)], but the rate of CVD/MI at 180-day was 4.7%. Sensitivities for UA were 94.6% according to the 'TIMI ≤1-strategy' and 75.4% according to 'hsTnT-below-LoD-strategy', accounting for 5.4 and 24.6% missed diagnoses, respectively. A prognostic risk stratification to guide appropriate outpatient assessment in potential discharged unrecognized UA patients was developed: a risk score based on the combination of age >60 years and C-reactive protein >4.5 mg/L effectively stratified the 180-day CVD/MI occurrence: 0, 2.5 and 12.7% for score 0, 1 and 2 (log-rank = 0.001, C-statistic = 0.776). CONCLUSION: Single measurement hsTnT strategies, successfully tested to rule-out MI, may allow safe ED discharge of patients with a suspected acute coronary syndrome: even if UA may not be excluded, its short-term prognosis is favorable. UA patients with a C-reactive protein >4.5 mg/L and older than 60 years have a substantial medium-term cardiovascular risk and may benefit from a timely outpatient diagnostic assessment.

Atherosclerotic cardiovascular disease still represents the leading cause of death in western countries. A wealth of scientific evidence demonstrates that increased blood cholesterol levels have a major impact on the outbreak and progression of atherosclerotic plaques. Moreover, several cholesterol-lowering pharmacological agents, including statins and ezetimibe, have proven effective in improving clinical outcomes. This document is focused on the clinical management of hypercholesterolemia and has been conceived by 16 Italian medical associations with the support of the Italian National Institute of Health. The authors have considered with particular attention the role of hypercholesterolemia in the genesis of atherosclerotic cardiovascular disease. Besides, the implications of high cholesterol levels in the definition of the individual cardiovascular risk profile have been carefully analyzed, while all available therapeutic options for blood cholesterol reduction and cardiovascular risk mitigation have been considered. Finally, this document outlines the diagnostic and therapeutic pathways for the clinical management of patients with hypercholesterolemia.

Background: High-sensitivity cardiac troponin T (hsTnT) was recently approved for clinical use by the Food and Drug Administration. The transition from contemporary to hsTnT assays requires a thorough understanding of the clinical differences between these assays. Hypothesis: HsTnT may provide a more accurate prognostic stratification than contemporary cardiac troponin I (cTnI) in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS). Methods: HsTnT and cTnI were measured in 644 patients with CK-MB negative NSTE-ACS who were enrolled in the prospective multicenter SPAI (Stratificazione Prognostica dell'Angina Instabile) study. Patients were stratified at the 99th percentile reference limit for each assay. The primary endpoint was cardiovascular death (CVD) or non-fatal myocardial infarction (MI); the secondary endpoint was the occurrence of unstable angina (UA). Follow-up lasted 180 days. Results: Patients with hsTnT ≥99th percentile were at higher risk of CVD/MI (30-day: 5.9% vs 0.8%, p = 0.001; 180-day: 11.1% vs 4.7%, p = 0.004), also after adjusting for TIMI Risk Score. No significant difference in CVD/MI at 180-day was found between hsTnT-positive/cTnI-negative and hsTnT-negative/cTnI-negative patients (adjHR 1.61, 95% CI 0.74–3.49, p = 0.232). Occurrence of UA was not differently distributed between hsTnT groups dichotomized at the 99th percentile (12.4% vs 12.5% p = 0.54). Conclusions: Our investigation on a real-world NSTE-ACS population showed good prognostic performance of hsTnT in the risk stratification of the hard endpoint, but did not demonstrate the improved prognostic ability of hsTnT over contemporary cTn. Neither troponin assay predicted the recurrence of UA, suggesting the acute rise of cardiac troponin as a marker of severity, but not the occurrence of future coronary instability. Keywords: High-sensitivity cardiac troponin, Biomarkers, Acute coronary syndromes, Prognostic risk stratification

OBJECTIVE Coronary artery disease (CAD) is a major challenge in patients with type 2 diabetes (T2D). Coronary computed tomography angiography (CCTA) provides a detailed anatomic map of the coronary circulation. Proteomics are increasingly used to improve diagnostic and therapeutic algorithms. We hypothesized that the protein panel is differentially associated with T2D and CAD. RESEARCH DESIGN AND METHODS In CAPIRE (Coronary Atherosclerosis in Outlier Subjects: Protective and Novel Individual Risk Factors Evaluation—a cohort of 528 individuals with no previous cardiovascular event undergoing CCTA), participants were grouped into CAD− (clean coronaries) and CAD+ (diffuse lumen narrowing or plaques). Plasma proteins were screened by aptamer analysis. Two-way partial least squares was used to simultaneously rank proteins by diabetes status and CAD. RESULTS Though CAD+ was more prevalent among participants with T2D (HbA1c 6.7 ± 1.1%) than those without diabetes (56 vs. 30%, P < 0.0001), CCTA-based atherosclerosis burden did not differ. Of the 20 top-ranking proteins, 15 were associated with both T2D and CAD, and 3 (osteomodulin, cartilage intermediate-layer protein 2, and HTRA1) were selectively associated with T2D only and 2 (epidermal growth factor receptor and contactin-1) with CAD only. Elevated renin and GDF15, and lower adiponectin, were independently associated with both T2D and CAD. In multivariate analysis adjusting for the Framingham risk panel, patients with T2D were “protected” from CAD if female (P = 0.007), younger (P = 0.021), and with lower renin levels (P = 0.02). CONCLUSIONS We concluded that 1) CAD severity and quality do not differ between participants with T2D and without diabetes; 2) renin, GDF15, and adiponectin are shared markers by T2D and CAD; 3) several proteins are specifically associated with T2D or CAD; and 4) in T2D, lower renin levels may protect against CAD.

In the above article, all mentions of “cartilage intermediate-layer protein” refer to “cartilage intermediate-layer protein 2.” The isoform number was misstated in the abstract and one place in the …

Background Despite the association between uric acid and cardiovascular disease has been known for decades, the prognostic value of serum uric acid (UA) in all clinical manifestations of acute coronary syndrome (ACS), namely ST-elevation myocardial infarction (STEMI), NSTEMI and unstable angina, has not been definitively assessed. Methods This retrospective analysis included patients from previous SPAI and FAMI studies with the aim to investigate the association between serum uric acid and major adverse cardiovascular events at 180days from hospital admission. Results 1548 patients were considered and divided in four groups, according UA concentration. Uricemia was significantly associated with gender, BMI, arterial hypertension, HDL-cholesterol, triglycerides, metabolic syndrome and glomerular filtration rate in univariate analysis. Multivariate logistic regression indicated that UA >6.0mg/dL on admission increased the risk of in-hospital mortality in overall population (OR 2.9, 95%CI 1.4–6.1; p =0.0057) and in patients with de novo ACS (OR 3.2, 95%CI 1.5–6.8; p =0.0033). Comparable results were also obtained after adjusting the model for age, gender, body mass index, glomerular filtration rate, metabolic syndrome, acute revascularization and ethnicity. A positive correlation was observed between UA and C reactive protein concentrations in in-hospital deaths only (rho 0.41, p =0.027). Conclusion In patients with acute coronary syndrome, uricemia levels above the current international reference limit (6.0mg/dl) were associated with in-hospital mortality, independently from ethnicity and renal function.

This study sought to assess whether coronary atherosclerosis analysis by coronary computed tomography angiography (CTA) may improve prognostic stratification among patients with diffuse coronary artery disease (CAD) BACKGROUND: Coronary CTA has recently emerged as a promising noninvasive tool for advanced analysis of coronary atherosclerosis.The multicenter CAPIRE (Coronary Atherosclerosis in outlier subjects: Protective and novel Individual Risk factors Evaluation) study is part of the GISSI Outlier Project. A prospective cohort of subjects who underwent coronary CTA for suspected CAD was enrolled. Based on risk factor (RF) burden, patients were defined as having a low clinical risk (0 to 1 RF with the exclusion of patients with diabetes mellitus as single RF) or at high clinical risk (3 or more RFs). Patients with 2 RFs were not enrolled in the study. Coronary CTA advanced plaque assessment was performed. Outcome measures were 3 combined endpoints: acute coronary syndrome (ACS), cardiac death + ACS, and cardiac death + ACS + late revascularization.Among the 544 patients enrolled in the CAPIRE study, in 522 patients, a mean follow-up of 37 ± 10 months was obtained (16 patients were excluded due to 1 segment involvement score 5 at core lab coronary CTA analysis and 6 patients were lost at follow-up). Higher atherosclerotic burden was found in patients with higher clinical risk, but prevalence of elevated noncalcified plaque volume did not significantly differ between low- versus high-risk patients. Quantitative plaque parameters by coronary CTA were associated with composite endpoints at multivariable analysis when corrected for univariate predictors. Elevated noncalcified plaque volume, expressed as dichotomic variable, was associated with all combined endpoints. Even if the low absolute number of events represents a limitation to the present study, patients with low noncalcified plaque volume had similar risk of cardiac events independently from the presence of multivessel disease, while patients with high noncalcified plaque volume had higher rates of cardiac events.The CAPIRE study confirmed the prognostic value of atherosclerosis assessment by coronary CTA, demonstrating high noncalcified plaque volume as the most ACS-predictive parameter in patients with extensive CAD. (GISSE Outliers CAPIRE [CAPIRE]; NCT02157662).

"Several lines of evidence suggest the involvement of infectious agents in the pathogenesis of atherosclerosis. Furthermore, a correlation between infection-driven inflammatory burden and acute manifestation of coronary artery disease has been hypothesized. The aim of this work was to assess whether human herpesvirus (HHV)-6 and HHV-8, two DNA viruses with a distinct tropism for endothelium and lymphocytes, may be associated with coronary instability. An age- and gender-matched cross-sectional study was undertaken in 70 patients with testing of plasma HHV-6 and HHV-8 DNA load in different cardiovascular clinical settings: 29 patients with acute myocardial infarction, 21 patients with stable coronary artery disease, and 20 patients without coronary and carotid artery atherosclerosis subjected to cardiac valve replacement. In all patients, HHV-6 and HHV-8 plasma DNA was tested by using highly sensitive, calibrated quantitative real-time PCR assays which employ a synthetic DNA calibrator to adjust for DNA extraction and amplification efficiency. HHV-8 viremia was undetectable in all three groups. HHV-6 viremia was detected in a substantial fraction of the samples examined (18.6%) without significant differences among the three groups (ST segment elevation myocardial infarction: 17.2%; stable coronary artery disease: 14.3%; patients without coronary and carotid artery atherosclerosis: 25%). Furthermore, no significant differences in plasma HHV-6 load were observed amongst the three groups of patients. These findings indicate that coronary instability is not associated specifically with active HHV-6 or HHV-8 infection. However, an unusually high rate of active HHV-6 infection was documented among patients without atherosclerosis admitted to hospital with cardiac disease. "

Several studies have evaluated the influence of different dietary habits on the risk of acute myocardial infarction and on the long-term prognosis after a coronary event, whilst no clear data are available on the in-hospital and short-term prognosis. We assessed the role of dietary habits and, in

anemia is significantly associated with cardiovascular disease (CVD) after adjustment for other risk factors in patients with established disease as well as in the general population ([21][1], [23][2]). The main proposed mechanisms linking anemia to CVD involve the reduction of oxygen delivery to

Aims: Von Willebrand factor (VWF), a key player in hemostasis and thrombosis, is released from endothelial cells during inflammation. Upon release, VWF is processed by ADAMTS13 into an inactive conformation. The aim of our study was to investigate whether plasma levels of active VWF, total VWF, ADAMTS13, osteoprotegerin (OPG) and the ratios between VWF and ADAMTS13 are risk factors for first ST-segment elevation myocardial infarction (STEMI). Methods and results: We assessed 1026 patients with confirmed first STEMI and 652 control subjects from China, Italy and Scotland, within six hours after their cardiovascular event. Median plasma levels of total VWF, active VWF, OPG and ratios VWF/ADAMTS13 were increased, while plasma levels of ADAMTS13 were decreased in patients compared to controls. The odds ratio (OR) of STEMI in patients with high plasma levels of active VWF was 2.3 (interquartile range (IQR): 1.8–2.9), total VWF was 1.8 (1.4–2.3), ADAMTS13 was 0.6 (05–0.8), OPG was 1.6 (1.2–2.0) and high VWF/ADAMTS13 ratios was 1.5 (1.2–2.0). The OR for total VWF, active VWF and ratios VWF/ADAMTS13 remained significant after adjustment for established risk factors, medical treatment, C-reactive protein, total VWF, ADAMTS13 and OPG. When we adjusted for levels of active VWF, the significance of the OR for VWF and ratios VWF/ADAMTS13 disappeared while the OR for active VWF remained significant. Conclusions: We found evidence that plasma levels of active VWF are an independent risk factor for first STEMI in patients from three different ethnic groups. Our findings confirm the presence of VWF abnormalities in patients with STEMI and may be used to develop new therapeutic approaches.

Heart rate variability (HRV) and systemic markers of inflammation have prognostic value in patients with unstable angina pectoris (UAP). However, it is unknown whether any relation exists between HRV parameters and indexes of inflammation in this clinical context. We assessed HRV on 24-hour electrocardiographic Holter recordings, performed within 24 hours of admission, and measured C-reactive protein (CRP) serum levels by a high-sensitivity assay on admission, in 531 patients with UAP (65 +/- 10 years of age; 347 men) who were enrolled in the prospective multicenter study Stratificazione Prognostica dell'Angina Instabile (SPAI). A significant inverse correlation was found between CRP levels and all HRV parameters, with the highest r coefficient shown with SD of all RR intervals (r = -0.23; p < 0.001) in the time domain and with very low-frequency amplitude (r = -0.22; p < 0.001) in the frequency domain. When patients were categorized into 4 groups according to CRP quartile levels, statistically significant lower HRV values were observed in the upper CRP quartile. On separate multiple regression analyses, including the most important clinical and laboratory variables, SD of all RR intervals and very low-frequency amplitude were the most significant predictors of increasing CRP levels (p < 0.001 for the 2 comparisons). In contrast, in models with SD of all RR intervals and very low-frequency amplitude as dependent variables, CRP was a strong predictor of impaired cardiac autonomic function (p < 0.001 for the 2 comparisons). Thus, our data show that, in patients with UAP, high levels of serum CRP levels are significantly associated with decreased HRV, suggesting a possible pathophysiologic link between cardiac autonomic dysfunction and inflammatory activity. (c) 2006 Elsevier Inc. All rights reserved.

A previously unreported case of a complex congenital cardiac anomaly consisting of coronary and valvular angiodysplasia, complicated by an eosinophilic endomyocardial disease, is described. The disorder presented clinically with congestive heart failure, which was characterized by evidence of floating masses causing severe pulmonary stenosis and dysfunction of the mitral and aortic valves. Symptoms of cardiac failure disappeared following pulmonary valve replacement and steroid therapy.

Rationale: At the onset of ST-elevation acute myocardial infarction (STEMI), patients can present with very high circulating interleukin-6 (IL-6 + ) levels or very low-IL-6 – levels. Objective: We compared these 2 groups of patients to understand whether it is possible to define specific STEMI phenotypes associated with outcome based on the cytokine response. Methods and Results: We compared 109 patients with STEMI in the top IL-6 level (median, 15.6 pg/mL; IL-6 + STEMI) with 96 in the bottom IL-6 level (median, 1.7 pg/mL; IL-6 − STEMI) and 103 matched controls extracted from the multiethnic First Acute Myocardial Infarction study. We found minimal clinical differences between IL-6 + STEMI and IL-6 − STEMI. We assessed the inflammatory profiles of the 2 STEMI groups and the controls by measuring 18 cytokines in blood samples. We exploited clustering analysis algorithms to infer the functional modules of interacting cytokines. IL-6 + STEMI patients were characterized by the activation of 2 modules of interacting signals comprising IL-10, IL-8, macrophage inflammatory protein-1α, and C-reactive protein, and monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and monokine induced by interferon-γ. IL-10 was increased both in IL-6 + STEMI and IL-6 − STEMI patients compared with controls. IL-6 + IL-10 + STEMI patients had an increased risk of systolic dysfunction at discharge and an increased risk of death at 6 months in comparison with IL-6 − IL-10 + STEMI patients. We combined IL-10 and monokine induced by interferon-γ (derived from the 2 identified cytokine modules) with IL-6 in a formula yielding a risk index that outperformed any single cytokine in the prediction of systolic dysfunction and death. Conclusions: We have identified a characteristic circulating inflammatory cytokine pattern in STEMI patients, which is not related to the extent of myocardial damage. The simultaneous elevation of IL-6 and IL-10 levels distinguishes STEMI patients with worse clinical outcomes from other STEMI patients. These observations could have potential implications for risk-oriented patient stratification and immune-modulating therapies.

Novel high-sensitivity assay can detect very low levels of circulating cardiac troponin (hs-cTnT) in apparently healthy subjects. Within normal range, higher levels are associated with coronary artery disease (CAD) and cardiac abnormalities commonly associated to traditional risk factors (RFs) for CAD. Therefore, we investigated the relation between circulating hs-cTnT and CAD in patients with a spectrum of RF burden aiming to assess the added value of hs-cTnT to identify "outlier" patients with CAD despite a low RF burden. Hs-cTnT was measured in 525 stable patients without previous diagnosis of ischemic heart disease with 0 to 1 RF, excluded diabetes, (low-RF group, n = 263) or ≥2 RFs (multiple-RF group, n = 262) and without CAD (segment involvement score = 0) or diffuse CAD (segment involvement score5) at coronary computed tomography angiography. Outlier patients with diffuse CAD despite low-RF burden had similar extent, severity, and plaque composition than patients with multiple RFs. Overall, hs-cTnT was measurable in 81% of patients with median value of 6.0 ng/L. In both groups, hs-cTnT concentration was higher in patients with CAD than in patients with normal coronary arteries (p0.0001). Hs-cTnT was more accurate to detect patients with CAD in the low-RF group than in the multiple-RF group (p = 0.04). In multivariate analysis, higher level of hs-cTnT (6 ng/L) was independently associated with CAD in low-RF group only. Despite very low circulating concentrations, hs-cTnT may identify with a good accuracy the outlier patients with diffuse CAD despite low-RF burden.

Objectives This study sought to assess the prevalence of normal levels of high sensitivity C-reactive protein (hsCRP) at the very onset of ST-segment elevation myocardial infarction (STEMI). Background Levels of hsCRP ≥2 mg/l identify individuals who benefit from lipid lowering and possibly anti-inflammatory agents, but how many patients develop infarction in spite of hsCRP levels Methods We studied 887 patients with unequivocally documented STEMI as the first manifestation of coronary disease and 887 matched control subjects from urban areas of Italy, Scotland, and China. Blood samples were obtained before reperfusion strategies Results hsCRP values were similar in samples obtained Conclusions The measurement of hsCRP, with a 2 mg/l cutoff, would not have predicted 41% of unequivocally documented STEMIs in 3 ethnic groups without evidence of previous coronary disease, thus indicating both its limitations as an individual prognostic marker and as an indicator of a generalized inflammatory pathogenetic component of STEMI. New specific prognostic and therapeutic approaches should be found for such a large fraction of patients at risk.

Prinzmetal's variant angina (VA) and cardiac syndrome X (CSX) are two distinct, usually easily recognizable, forms of angina syndromes, caused by epicardial spasm, usually responsible for transient transmural myocardial ischemia at rest and by coronary microvascular dysfunction (CMVD), usually responsible for effort induced subendocardial ischemia, respectively. In this article we report clinical evidence in three patients of the simultaneous occurrence of angina episodes typical of both VA and CSX, suggesting that common pathogenetic factors may be responsible for clinical manifestations both of functional macrovascular and microvascular coronary artery abnormalities in some angina patients. Copyright © 2009 Wiley Periodicals, Inc.

Non-compaction of the ventricular myocardium (NCVM) is a rare disorder of myocardial morphogenesis usually diagnosed in paediatric age associated with high mortality rates. Among reported cases, NCVM has been described in only six patients >= 70 years. We describe the case of a 74-year-old male with NCVM involving the left ventricle, representing one of the oldest patients ever reported in the literature. Of note, this case was characterized by late appearance of NCVM and rapid deterioration of clinical conditions. The wide age range of symptom onset from prenatal to geriatric age supports the hypothesis that NCVM is a multifactorial rather than a simple congenital disorder. J Cardiovasc Med 7:714-716 (C) 2006 Italian Federation of Cardiology.

To evalutate whether Holter electrocardiographic monitoring may improve the detection of ST-segment depression in patients with anginal chest pain and normal coronary arteries, we performed symptom-limited exercise testing and 24-hour Holter monitoring in a group of 38 such patients (27 women, age 54 +/- 8 years). Patients were divided into 2 groups: group X1 included 28 patients with and group X2 10 patients without significant ST-segment depression during exercise testing. There were no significant differences between the 2 groups in age, gender, characteristics of chest pain, exercise duration, heart rate (HR), and blood pressure at peak exercise, but anginal pain during exercise testing was reported by 10 patients of group X1 (36%) and 9 of group X2 (90%) (p < 0.01). Episodes of ST-segment depression on Holter monitoring were found in 17 patients of group X1 (61%) and in 5 patients of group X2 (50%) (p = NS). There were no differences between the 2 groups in daily number of ST episodes (3.6 +/- 4 vs 2.8 +/- 5 episodes per patient), symptomatic episodes (8% vs 18%), and duration of the episodes. On average, HR increased significantly, in a similar way, from 15 minutes before ST-segment depression to 1-mm ST in both groups, and its value at the onset of ischemia was similar in the 2 groups (102 +/- 22 vs 109 +/- 18 beats/min, p = NS). Finally, HR at 1-mm ST during Holter monitoring was significantly lower than that observed at 1-mm ST during exercise testing (127 +/- 16 beats/min, p less than or equal to 0.01) in group X1, and it was also lower than that observed at peak exercise (136 +/- 22 beats/min, p less than or equal to 0.01) in group X2. In conclusion, Holter monitoring can significantly Increase the detection of ST-segment depression in patients with anginal pain and normal coronary arteries, indicating a cardiac, although not necessarily ischemic, origin of the pain. Indeed, 50% of our patients with negative symptom-limited exercise testing showed spontaneous ST changes, compatible with transient myocardial ischemia, during daily activities. Differences in the response of coronary microvascular tone to exercise testing and to stimuli operating during daily life are likely to play a significant role in determining these findings. (C) 1997 by Excerpta Medica, Inc.

Background Clinical characteristics and outcome of patients with variant angina were assessed in the 1970–1980s of the past Century. The recent progress in prevention, diagnosis and treatment of coronary artery disease may have significantly modified clinical characteristics and prognosis of these patients. Methods From January 1991 to December 2002, 202 patients (57.1±12 years; 166 men) were diagnosed to have variant angina at our Institute. Detailed clinical findings and clinical events were prospectively collected for each patient. Results The median time from the first angina attack to diagnosis was 2 months (range 1–276), with diagnosis requiring >6 months in 31.7% of patients. Coronary angiography ( n =183) showed normal coronary arteries in 42.1% of patients and significant coronary stenoses (>50%) in 44.3%, with multi-vessel disease in 8.7%. Diagnosis of variant angina was done during coronary angiography in 3% of cases during the first half of the study period, but in 42% of patients in the second half of the study period. Major cardiac events (MCE, i.e., death, resuscitation from cardiac arrest, myocardial infarction) occurred in 41 patients (20.3%), with 43.9% of events occurring within 1 month of symptom onset. The only variable significantly associated with MCE was the detection during angina of ST segment elevation in both anterior and inferior ECG leads (odds ratio 3.24; 95% confidence interval 1.43–7.36; P =0.005). Conclusion Our data suggest that variant angina is still a frequently overlooked diagnosis, and a timely diagnosis would be crucial to prevent early life-threatening events. Patients with diffuse ST segment elevation on ECG are those at the highest risk of MCE, independently of angiographic findings.

Although it is generally accepted that cardiac ischemic events develop when coronary atherosclerosis (coronary artery disease [CAD]) has reached a critical threshold, this is true only to a first approximation. Indeed, there are patients with severe CAD who do not develop ischemic events; conversely, at the other extreme, individuals with minimal CAD may do. Similar exceptions to this paradigm include patients with diffuse CAD with a low risk factor (RF) profile and others with multiple RFs who develop only mild or no CAD. Therefore, the CAPIRE project was designed to investigate whether the specific study of these extreme outlier populations could provide clues for identification of yet unknown risk or protective factors for CAD and ischemic events. In the CAPIRE study, 481 subjects without previous symptoms or history of ischemic heart disease and normal left ventricular systolic function undergoing coronary computed tomography angiography have been selected based on coronary computed tomography angiography findings and cardiovascular RF profile. Therefore, in the whole population, 2 extreme outlier populations have been identified: (1) subjects with no CAD despite multiple RFs, and (2) at the opposite extreme, subjects with diffuse CAD despite a low-risk profile. Each subject has been characterized by clinical, anatomical imaging variables of CAD and baseline circulating biomarkers. Blood samples were collected and stored in a biological bank for further advanced investigations. The project is designed as a prospective, observational, international multicenter study with an initial cross-sectional analysis of clinical, imaging, and biomolecular variables in the selected groups and a longitudinal 5-year follow-up.

Rationale: Four monocentric studies reported that circadian rhythms can affect left ventricular infarct size after ST-segment–elevation acute myocardial infarction (STEMI). Objective: To further validate the circadian dependence of infarct size after STEMI in a multicentric and multiethnic population. Methods and Results: We analyzed a prospective cohort of subjects with first STEMI from the First Acute Myocardial Infarction study that enrolled 1099 patients (ischemic time Conclusions: Although the circadian dependence of infarct size supported by previous studies poses an intriguing hypothesis, we were unable to converge toward their conclusions in a multicentric and multiethnic setting. Parameters that vary as a function of latitude could potentially obscure the circadian variations observed in monocentric studies. We believe that, to assess whether circadian rhythms can affect the infarct size, future study design should not only include larger samples but also aim to untangle the molecular time–dynamic mechanisms underlying such a relation.

Background/objectives Bicuspid aortic valve (BAV) is the most common congenital heart disorder, affecting up to 2% of the population. Involvement of aortic root and ascending aorta (aneurysm or, eventually, dissection) is frequent in patients with pathologic or normal functioning BAV. Unfortunately, there are no well-known correlations between valvular and vascular diseases. In VAR protocol, with a new strategy of research, we analysemultiple aspects of BAV disease through correlation between surgical, echo, histologic and genetic findings in phenotypically homogeneous outlier cases. Methods VAR protocol is a prospective, longitudinal, multicenter study. It observes 4 homogeneous small groups of BAV surgical patients (15 patients each): isolated aortic regurgitation, isolated ascending aortic aneurysm, aortic regurgitation associated with aortic aneurysm, isolated aortic stenosis in older patients (>60years). Echo analysis is extended to first-degree relatives and, in case of BAV, genetic test is performed. Patients and relatives are enrolled in 10 cardiac surgery/cardiologic centers throughout Italy. Conclusions The aim of the study is to identify predictors of favorable or unfavorable evolution of BAV in terms of valvular dysfunction and/or aortic aneurysm. Correlations between different features could help in identification of various BAV risk groups, rationalizing follow-up and treatment.

Atherosclerotic plaque fissuring or ulceration generally cause the development of the acute coronary artery disease syndromes. Vulnerable or “unstable” atherosclerotic plaques have temperature and pH heterogeneity, thin fibrous caps, inflammatory cells primarily macrophages, and activated T cells on their surface, and an adjacent lipid pool. Some patients have multiple unstable atherosclerotic plaques simultaneously. Several serum markers when elevated help identify patients at increased risk for future vascular events, including C-reactive protein (CRP), CD40SL, pregnancyassociated protein, serum amyloid protein (SAP), brain natriuretic peptide (BNP), vascular cell adhesion molecule (VCAM), intracellular adhesion molecule (ICAM), and interleukin-6. Unstable angina and non-ST segment elevation myocardial infarction (NSTEMI) are associated with atherosclerotic plaque fissuring or ulceration, adherence of platelets at the same sites, the accumulation of thromboxane A2, serotonin, adenosine diphosphate (ADP), thrombin, tissue factor, oxygen-derived free radicals, and endothelin promoting growth of the thrombus and dynamic vasoconstriction with transient (unstable angina or NSTEMI) or permanent coronary artery occlusion (ST segment elevation MI, STEMI). The functional absence or diminished effect of nitric oxide (NO), tissue-type plasminogen activator (t-PA), and prostacyclin at sites of vascular injury contributes to dynamic thrombosis, vasoconstriction, fibroproliferation, and inflammation at sites of coronary artery atherosclerosis and plaque fissuring and ulceration. Unstable angina, NSTEMI, and STEMI represent a continuum of thrombosis and vasoconstriction in that unstable angina is often caused by transient and recurrent coronary artery thrombosis and vasoconstriction, NSTEMI by slightly more prolonged but still usually transient thrombosis and vasoconstriction or subtotal coronary artery occlusion, and STEMI by prolonged and usually permanent coronary artery occlusion. Power failure complications of MIs occur in patients with ≥40% irreversible damage to the left ventricle (LV) and include cardiogenic shock, medically refractory congestive heart failure (CHF), and medically refractory arrhythmias. Even with relatively small MIs, mechanical problems, such as acute mitral regurgitation (MR), ventricular septal defects (VSDs), and ventricular aneurysms may lead to shock and CHF.

Intracoronary infusion of serotonin has been reported to induce varying degrees of coronary vasoconstriction in different coronary syndromes, but it has never been studied in patients after myocardial infarction. In patients with recent myocardial infarction, we found a low incidence (11%) of serotonin-induced occlusive spasm only in the infarct-related artery (IRA), and a significantly higher vasoconstriction in the distal segment of the IRA than in the same segment of the non-IRA.

Location, severity, duration, and time course of pain were assessed in 104 consecutive patients with either first or second, anterior or inferior Q-wave acute myocardial infarction (AMI). Pain severity was assessed using a visual analog scale. Pain location and radiation were similar in 48 patients with anterior and 56 patients with inferior wall AMI. Pain duration (6.1 +/- 6.4 vs 6.5 +/- 5.4 hours, p = NS) and severity (68 +/- 21 vs 61 +/- 21 mm, p = NS) were also similar. The pain was continuous in 34 patients with anterior (71%) and in 42 with inferior (75%) wall AMI. Among the 41 patients who did not receive thrombolytic therapy, 18 patients with continuous pain had a higher creatine kinase peak level than the remaining 23 patients with intermittent pain or preinfarction angina, or both (2,065 +/- 1,017 vs 1,162 +/- 994 IU, p 1 AMI, different locations of the infarction pain were highly predictive of ischemia occurring in different myocardial regions. Finally, patients with preinfarction angina or intermittent pain tended to have smaller infarcts.

A group of investigators met for two days in Santorini, Greece, to discuss progress in the field of identification and treatment of high risk/vulnerable atherosclerotic plaques and patients. Many differences in the manner in which terms are being utilized were noted. It was recognized that increased understanding of the pathophysiology of coronary thrombosis and onset of acute coronary syndromes has created the need for agreement on nomenclature. The participants spent considerable time discussing the topic and reached agreement on their own usage of the terms as described below. It is the hope that this usage might be of value to the larger community of scientists working in this field, and that widespread adoption of a common nomenclature would accelerate progress in the prevention of acute coronary events.

The identification of potential triggers of acute coronary syndromes (ACS) represented by unstable angina (UA), myocardial infarction (MI) (preceded or not by UA), and sudden coronary death (SCD) is a rapidly growing area of research. Coronary plaque disruption and subsequent thrombosis is the major recognized pathogenetic component of “unstable plaques,” which characterize the transition from stable coronary artery disease (CAD) to ACS. However, in the presence of unstable or even stable plaques, a thrombogenic state or “high-risk blood” may contribute, at least in some cases, to the development of ACS.1 Furthermore, thrombosis is also an integral component of the chronic atherothrombotic progression of atherosclerosis. Although the observation that plaque disruption leads to ACS goes back a number of decades, the notion of “vulnerable plaques” was first developed a little over a decade ago on the basis of post-mortem observations in patients with ACS.2 At the site of culprit coronary lesions, a rupture was often found at the shoulder of atheromatous plaques with a large pultaceous lipid core and a thin fibrous cap. Such rupture was originally thought to be the result of localized mechanical shear stress forces.3 However, on the basis of emerging evidence of a prevalent inflammatory component in ACS, inflammatory mechanisms of plaque instability began to receive considerable attention.4 The acquisition of knowledge does not necessarily makes things more comprehensible, but rather often adds novel complexities. Yet, when confronted with a pressing issue, such as predicting major future adverse events, there is a natural inclination to accept generalizations not yet justified by available data. The intriguing concept of a vulnerable plaque, as a potential short-term precursor of unstable plaques, derives from the theoretical possibility of identifying those coronary atherosclerotic plaques that might become unstable and thus trigger ACS. The notion of vulnerable plaques is …

Background— Platelet reactivity is increased by exercise in patients with obstructive coronary artery disease (CAD) but not in patients with syndrome X. In this study, we prospectively investigated whether the platelet response to exercise might help distinguish, among patients with angina, those with obstructive CAD from those with normal coronary arteries (NCAs). Methods and Results— Venous blood samples were collected before and 5 minutes after exercise from 194 consecutive patients with stable angina. Platelet reactivity was measured by the platelet function analyzer (PFA)-100 system as the time for flowing whole blood to occlude a collagen-adenosine diphosphate ring (closure time). Coronary angiography showed CAD in 163 patients (84%) and NCA in 31 patients (16%). Baseline closure time was shorter in NCA patients (78.0±16 versus 95.5±23 seconds, P P P =0.0004). An increase in closure time with exercise ≥10 seconds had 100% specificity and positive predictive value for NCAs. Similarly, a decrease ≥10 seconds had 100% specificity and positive predictive value for CAD. A closure time change (increase or decrease) ≥10 seconds allowed a correct classification of 55% of all patients. Conclusions— Among patients with stable angina, the response of platelet reactivity to exercise was predictive of normal or stenosed coronary arteries at angiography. Specifically, an increase in closure time with exercise ≥10 seconds was invariably associated with the presence of NCA.

Inflammation is a common component of atherosclerotic plaques, and is an established consequence of myocardial ischaemia and necrosis, but it appears also to be a possible pathogenetic component that is responsible for the sudden onset of coronary instability. Systemically detectable signs of inflammation, typically represented by elevated levels of circulating C-reactive protein (CRP), are commonly detected in acute coronary syndromes. Elevated values of CRP are observed in approximately 70% of patients with severe unstable angina and are correlated with risk for developing an acute infarction in the short term. Indeed, CRP is elevated before the appearance of signs of necrosis in over 90% of patients with acute infarction preceded by unstable angina, but in fewer than 50% of those in whom infarction was totally unheralded. The very episodic nature and the common short duration of acute coronary syndromes suggest that the inflammatory stimuli that cause the systemically detectable inflammatory process could be unrelated to the chronic inflammatory component of the atherosclerotic background. Causes of the inflammation may be multiple and not necessarily the same in all patients, and their effect is probably modulated by the individual immunological and inflammatory response.

Background— Patients undergoing revascularization procedures for peripheral vascular disease (PVD) have a greatly increased risk for coronary artery disease (CAD) that is predicted only partly by clinical data and cardiovascular risk factors. We investigated whether the prognostic assessment in PVD patients could be improved by preoperative measurements of C-reactive protein (CRP). Methods and Results— We assessed clinical and risk factors profiles, Eagle clinical scores, and preoperative CRP serum levels in 51 patients with PVD at Fontaine-Leriche stages II to IV without severe rest ventricular dysfunction or ischemia. During 24 months of follow-up, 17 patients (34%) had fatal (11) or nonfatal (6) myocardial infarction (MI). With univariate logistic regression analysis, only previous history of CAD, Eagle score, and CRP were independently related to MI. At multivariate logistic regression analysis, only CRP values in the upper tertile (P Conclusions— The high incidence of MI in patients with PVD severe enough to require revascularization is strongly predicted by preprocedural measurements of serum CRP, independent of previous CAD, Eagle score index, and traditional cardiovascular risk factors. These patients may benefit from therapy modulating the inflammatory response.

Objectives: The aims of this study were to compare the efficacy of a 2- versus a 3 RF lesions ablation procedure in the RA in patients with paroxysmal AF, and to map right atrial activation during AF. Background: RF catheter-mediated ablation lines mimicking the Maze operation have been proposed as a novel curative approach for AF. The relationship between this type of ablation and right atrial mapping has not been extensively studied. Methods: Twenty-four patients with recurrent, drug-refractory, paroxysmal AF underwent an extensive mapping of the RA before attempting linear lesion RF ablation. Patients were divided into two groups: 15 patients received two linear lesions (Group 1), 9 patients three linear lesions (Group 2). Results: One-month success rate AF did not recur in 40% of Group 1 patients (6/15) and in 66% (6/9) of Group 2 patients. 27% of patients in Group 1 and 11% of patients in Group 2 had recurrences controlled by drugs. No benefit in 33% of Group 1 patients and 22% of Group 2. Long-term follow-up In the absence of any drug treatment, no AF recurrences were observed in 26% of Group 1 patients (FU: 23 to 47 months) and 55% of Group 2 (FU: 14 to 23 months). No complications were reported. Conclusions: Right atrial linear ablation is safe and may be proposed for AF treatment in selected patients.

Background: To better understand the mechanisms linking C reactive protein (CRP) to the risk of coronary thrombosis, we investigated the relation between inflammatory state and hemostatic response to coronary angioplasty in patients with either stable or unstable angina.