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Background: The impact of incident sudden cardiac death (SCD) on the predictive accuracy of prognostic risk scores for patients with chronic heart failure (HF) has rarely been examined. We assessed the relationship between estimated probability of death and modes of death in this population, as well as the predictors of death and survival in prognostic outliers.Methods and Results: The MAGGIC 3-year probability of death was estimated in 6,859 participants of the GISSI-HF trial (mean age 67±11 years, 78% men, 91% with ejection fraction <40%, mean follow-up 3.5±1.3 years, observed mortality 28.4%). The incidence of SCD progressively decreased with increased probability of death, and occurred in 52.5% of patients estimated at low-risk (N = 61 with probability <14%) vs. in 23.5% of the high-risk ones (N = 375 with probability >56%, P < .0001). On the contrary, death from worsening HF was significantly more frequent in the latter group (19.7% vs. 46.1%, P < .0001). The overall predictive accuracy of the MAGGIC model improved after excluding deaths from SCD (AUC from 0.731 to 0.760, P = .0034). Among patients estimated at low-risk (N = 61 dead, 743 alive), independent predictors of death were older age, longer history of HF, higher serum uric acid and chronic obstructive pulmonary disease. The only predictor of survival in patients estimated at high-risk (N = 210 alive, 375 dead) was higher systolic blood pressure.Conclusions: The MAGGIC risk score demonstrated its scarce ability to capture SCD, particularly in chronic HF patients estimated at low risk of death. Newer and better prognostic tools in the evolving horizon of HF are needed. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) is a common arrhythmia that frequently recurs after restoration of sinus rhythm. In a consistent percentage of cases, AF recurrences are asymptomatic, thus making its clinical management difficult in relation to both therapeutic efficacy and thromboembolic risk. Methods: The GISSI-AF trial enrolled 1,442 patients in sinus rhythm with previous AF episodes. Patients were randomized to valsartan or placebo and followed for 12 months. To improve the likelihood of detecting arrhythmic recurrences, arrhythmic follow-up was based on both programmed or symptom-related control visits and transtelephonic electrocardiographic transmissions. The present post hoc analysis was performed on 1,638 arrhythmic episodes that occurred in 623 patients. Results: Asymptomatic AF recurrences were present in 49.5% of patients. In multivariable analysis, asymptomatic AF recurrences were significantly associated with a longer duration of qualifying arrhythmias (odds ratio [95% CI] 1.57 (1.26-1.97), P < .0001). A lower ventricular response (P < .001) and a longer duration of the arrhythmic recurrence (P < .001) characterized asymptomatic episodes. Patients with asymptomatic events were more likely to be in AF at the time of electrocardiographic control at the end of the 12-month follow-up (adjusted odds ratio [95% CI] 4.9 (2.8-8.4), P < .001). Moreover, a higher CHADS2 (Congestive heart failure, history of Hypertension, Age≥75 years, Diabetes mellitus, and past history of Stroke or TIA doubled) score and a more frequent use of amiodarone, calcium-channel blockers, and digitalis characterized patients with asymptomatic, whereas 1C drugs were more often used in subjects with symptomatic recurrences. Conclusion: Asymptomatic AF recurrences were frequent in the GISSI-AF study population in patients who were more likely to develop persistent-permanent AF and were characterized by an increased thromboembolic risk. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) is a common arrhythmia that frequently recurs after restoration of sinus rhythm (SR). Identifying risk factors for recurrence may help define the best strategy for secondary prevention. Methods: The GISSI-AF trial enrolled 1,442 patients in SR with at least 2 documented AF episodes in the previous 6 months or after cardioversion in the last 2 weeks. Patients were randomized to valsartan or placebo; all other treatments for AF or underlying heart diseases were allowed. Primary end points were time to first recurrence of AF and proportion of patients with >1 AF episode during 1-year follow-up. We evaluated clinical and electrocardiographic baseline characteristics of all patients to identify independent predictors for AF recurrence using a Cox multivariable model. Results: Risk factors for AF recurrence were a history of 2 or more AF episodes in the previous 6 months, independent of the modality of SR restoration, spontaneous (HR 1.42, 95% CI 1.14-1.77, P = .002), or by cardioversion (HR 1.19, 95% CI 1.01-1.40, P = .038), and a lower heart rate during SR (HR 0.99, 95% CI 0.99-1.00, P = .052). The risk factors were the same for >1 AF recurrence. Patients treated with amiodarone had a lower risk for both end points (P < .0001 and P = .017), whereas those on diuretics had a greater risk (P = .009 and P = .003). Conclusions: In the GISSI-AF study population, AF history had significant prognostic value independent of the modality of SR restoration. Amiodarone and diuretic treatment affected the rate of AF recurrence. [Copyright &y& Elsevier]

Background: The OASIS-5 (Organization to Assess Strategies in Ischemic Syndromes-5) trial demonstrated that fondaparinux was noninferior to enoxaparin while reducing the risk of bleeding by 50%. The objectives of our study were to assess the effects of fondaparinux compared to enoxaparin in patients stratified by their Global Registry of Acute Coronary Events (GRACE) score and to examine the ability of the GRACE score to predict bleeding in patients with acute coronary syndromes (ACS). Methods: We analyzed efficacy and safety according to the GRACE admission risk score. Results: The impact of fondaparinux versus enoxaparin on the primary outcome of death, myocardial infarction, and refractory ischemia at 180 days was similar in the low-, intermediate-, and high-risk groups: 7.0% versus 7.7% (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.75-1.08), 10.2% versus 11.3% (HR 0.89, 95% CI 0.77-1.03), and 20.1% versus 21.1% (HR 0.95, 95% CI 0.85-1.06). Major bleeding rates were higher with increasing GRACE risk scores: 2.2%, 3.2%, and 4.1% in the low, intermediate, and high-risk groups. Six-month mortality was 2.2%, 4.2%, and 12.3% in the 3 groups. The risk of major bleeding was substantially lower with fondaparinux in all groups: 1.6% versus 2.9% (HR 0.55, 95% CI 0.39-0.77), 2.2% versus 4.1% (HR 0.53, 95% CI 0.40-0.70), 2.8% versus 5.5% (HR 0.50, 95% CI 0.38-0.64). Conclusion: The GRACE score predicted both bleeding and mortality in patients with ACS. The efficacy and safety of fondaparinux were consistent in all risk groups supporting its use in a broad range of ACS patients. [Copyright &y& Elsevier]

Background: The causes of death occurring in clinical trials of myocardial infarction (MI) are scarcely reported in the literature. The present analysis is aimed to describe the inhospital causes of death in patients with acute MI stratified to angiotensin converting enzyme (ACE) inhibitor treatment/no treatment, as described in the GISSI-3 trial. Furthermore, the 5-year survival analysis of GISSI-3 patients is reported. Methods and Results: An independent committee assigned the definition of causes of death of GISSI-3 based on clinical and/or anatomical data. Univariate and multivariable analyses were performed to identify the predictors of early and late deaths. Kaplan-Meier mortality curves were used to describe the effects of ACE-I treatment on mortality on a median follow-up period of 56 months. Patients receiving lisinopril had fewer inhospital cardiac deaths than patients allocated to the no-lisinopril group (4.7% vs 5.3%, P = .052), corresponding to a 12% relative risk reduction. The risk of dying from cardiac rupture was reduced by 39% by lisinopril treatment. The improvement in survival associated with the lisinopril treatment was mainly due to a reduction in cardiac rupture, electromechanical dissociation, and pump failure occurring early (within 4 days) from the onset of MI symptoms. The beneficial effects of lisinopril observed at 6 weeks (8 fewer deaths per 1000 treated patients) were maintained up to nearly 5 years (10 fewer deaths per 1000). Conclusions: Early administration of ACE inhibitors in unselected patients with acute MI should be considered standard therapy to reduce early deaths, specifically those due to cardiac rupture. The early beneficial effect persisted up to nearly 5 years. [Copyright &y& Elsevier]

: ObjectivesWe evaluated the prognostic relevance of the extent of myocardial injury, as measured by a standard electrocardiographic (ECG) method, on the patients’ long-term prognosis, its time dependence and its relation to fibrinolytic therapy efficacy.: BackgroundMany clinical and instrumental variables influence the short- and long-term prognoses of patients with acute myocardial infarction (MI). The extent of myocardial injury is relevant to predict both the short-term prognosis and the benefit of fibrinolytic treatment.: MethodsIn 8,731 patients with MI enrolled in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto (GISSI-1) study, the number of ECG leads with ST-segment elevation was used to define the extent of myocardial injury and four different severity groups: A, B, C and D, with ST-segment elevation in two or three leads, four or five leads, six or seven leads and more than eight leads, respectively.: ResultsAt 10 years, the mortality rates were 36.6%, 41.0%, 47.9% and 51.2% in groups A, B, C and D, respectively. At 30 days, according to the extent of myocardial injury, the relative risk (RR) of death was significantly higher for groups B, C and D, compared with group A (RR 1.19 and 95% confidence interval [CI] 1.06 to 1.34 for group B; RR 1.54 and 95% CI 1.31 to 1.80 for group C; RR 2.01 and 95% CI 1.69 to 2.39 for group D). At one-year follow-up, the RR of death remained higher for groups C and D, whereas, subsequently, the extent of myocardial injury did not influence the RR of death. At 10 years, the differences in fibrinolytic treatment benefit between the four groups were similar to those at hospital discharge.: ConclusionsAt 10 years, the survival rate appears to be related to the extent of myocardial injury, as evaluated by ST-segment elevation on the admission ECG. [Copyright &y& Elsevier]

Background: Metabolic syndrome (MS) is associated with late-onset diabetes. However, diagnostic criteria for individual components of MS are based on categorical/arbitrary cut points and, therefore, do not exploit the information yield of each factor. We aimed to generate a diagnostic score for MS (MS-Score), aimed at predicting diabetes by giving appropriate weight to the individual components of MS. Methods: Of 11323 patients with prior myocardial infarction and followed up for 3.5 years in the GISSI-Prevenzione study, 3855 subjects with diabetes at baseline or missing information for relevant variables were excluded. A Cox proportional hazards model including age, sex, glycemia, high-density lipoprotein cholesterol, triglycerides, hypertension, and body mass index was fitted to create a diagnostic score. A cutoff point of 28 of the score was the best compromise between sensitivity and specificity for MS diagnosis (MS-Score). The prognostic performance of the MS-Score was compared with that of the diagnostic criteria of MS, as defined by National Cholesterol Education Program Adult Treatment Panel III (MS-ATP). Results: Of 7468 patients, 940 developed diabetes. The risk of getting diabetes significantly and progressively increased in the quintiles of the score reaching >6-fold higher risk in the last one. The predictive capability of MS-Score was significantly higher than that of the MS-ATP (AUC = 0.650 vs 0.587, sensitivity 67% vs 52%, specificity 63% vs 66%, P = .0002). The MS-Score, but not the MS-ATP, was significantly associated with mortality. Conclusion: MS-Score improves the prediction of diabetes development by using the full informative content of individual components for diagnosis of MS. [Copyright &y& Elsevier]

Abstract: Background: To date uric acid (UA) is not considered a cardiovascular risk factor, although evidence about a relationship between UA and cardiovascular diseases has been reported. Methods: Information from 10,840 patients enrolled in the GISSI-Prevenzione trial was used to evaluate the relationship between UA and risk for total mortality and cardiovascular events (CVE). UA levels were categorized in quintiles, as ≤4.5 (Q1), 4.6 to 5.3 (Q2), 5.4 to 6.0 (Q3), 6.1 to 6.8 (Q4) and >6.8 (Q5) mg/dL. Multivariable analysis was used to estimate the relative risks (HR) of outcome measures across categories of UA. The analysis of the area under the receiver operating characteristic curve (AUC), the net reclassification improvement (NRI), and the integrated discrimination improvement (IDI) tests were used to evaluate the incremental prognostic information of UA. Results: During 36,802 person-years of follow-up, 974 deaths and 1120 cardiovascular events occurred. We found a statistically significant association between high UA and total mortality [HR, P value]: Q1 [reference category, 1.00]; Q2 [1.13, 0.267]; Q3 [1.06, 0.619]; Q4 [1.23, 0.063]; Q5 [1.63, <0.0001], test for trend P<0.0001. Similar results were obtained for cardiovascular events [HR, P value]: Q1 [reference category, 1.00]; Q2 [1.12, 0.271]; Q3 [1.19, 0.094]; Q4 [1.25, 0.031]; Q5 [1.38, 0.002], test for trend P=0.0009. The prognostic accuracy of prediction models for CVE was significantly increased by adding UA to classical cardiovascular risk factors (AUC P=0.0041; NRI P=0.0004; IDI P<0.0001). Conclusion: High UA may be considered a risk factor for death and CVE. [Copyright &y& Elsevier]

Background: The APO B gene is characterised by numerous polymorphic sites, three of which (XbaI, EcoRI, SpIns/Del) are related to levels of total cholesterol (TC), low-density lipoproteins, apo B and tryglicerides, and to coronary artery disease (CAD) and/or myocardial infarction (MI). Moreover, conflicting results emerge from literature. To assess how each polymorphism of the APO B gene was associated with CAD and MI risk, we carried out a meta-analysis of all published studies. Methods and results: Thirty case-control studies were considered, for a total of 6077, 3870 and 11 616 individuals, respectively, for XbaI, EcoRI and SpIns/Del polymorphisms. For each polymorphism we calculated the risk of CAD/MI on the overall sample and for large and small studies separately. No evidence of increased risk emerged for XbaI polymorphism. Whereas, positive associations were detected for EcoRI, SpIns/Del and risk of CAD and MI, with odds ratio (OR) of 1.73 (95% CI, 1.19–2.50) and 1.19 (95% CI, 1.05–1.35) for carriers of AA and DD, respectively. Conclusions: Despite the small size of most studies and the incomplete understanding of the effects of these polymorphisms on lipid metabolism and on final clinical implications, the findings suggest that EcoRI and SpIns/Del polymorphisms significantly increase the risk of CAD and MI. Despite the rarity of the allelic variant of EcoRI polymorphism, its presence is strongly related to the occurrence of CAD/MI. Moreover, there is a high consistency between small and large studies. The results on SpIns/Del polymorphism seem the most interesting and reliable, considering both the number of subjects analysed and the consistency of the evidence of its effect on lipid levels. These results need to be confirmed by larger and appropriately powered studies. [Copyright &y& Elsevier]

Background Troponin changes over time have been suggested to allow for an early diagnosis of cardiac injury ensuing cancer chemotherapy; cancer patients with troponin elevation may benefit of therapy with enalapril. It is unknown whether a preventive treatment with enalapril may further increase the benefit. Methods The International CardioOncology Society-one trial (ICOS-ONE) was a controlled, open-label trial conducted in 21 Italian hospitals. Patients were randomly assigned to two strategies: enalapril in all patients started before chemotherapy (CT; ‘prevention’ arm), and enalapril started only in patients with an increase in troponin during or after CT (‘troponin-triggered’ arm). Troponin was assayed locally in 2596 blood samples, before and after each anthracycline-containing CT cycle and at each study visit; electrocardiogram and echocardiogram were done at baseline, and at 1, 3, 6 and 12-month follow-up. Primary outcome was the incidence of troponin elevation above the threshold. Findings Of the 273 patients, 88% were women, mean age 51 ± 12 years. The majority (76%) had breast cancer, 3% had a history of hypertension and 4% were diabetic. Epirubicin and doxorubicin were most commonly prescribed, with median cumulative doses of 360 [270–360] and 240 [240–240] mg/m 2 , respectively. The incidence of troponin elevation was 23% in the prevention and 26% in the troponin-triggered group (p = 0.50). Three patients (1.1%) -two in the prevention, one in the troponin-triggered group-developed cardiotoxicity, defined as 10% point reduction of LV ejection fraction, with values lower than 50%. Interpretation Low cumulative doses of anthracyclines in adult patients with low cardiovascular risk can raise troponins, without differences between the two strategies of giving enalapril. Considering a benefit of enalapril in the prevention of LV dysfunction, a troponin-triggered strategy may be more convenient. [ABSTRACT FROM AUTHOR]

The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico–Heart Failure (GISSI-HF) study reported benefits of n-3 fatty acid (FA) treatment on cardiovascular (CV) events, but the effects of treatment on a putative CV disease risk factor, the red blood cell (RBC) n-3 FA level (the omega-3 index), have not been examined in this context. We hypothesized that treatment with prescription omega-3 acid ethyl esters (O3AEE) would increase the omega-3 index to the proposed cardioprotective value of 8%. RBCs were collected from a subset of patients participating in the GISSI-HF study (n = 461 out of 6975 randomized), at baseline and after 3 months of treatment with either an olive oil placebo or O3AEE (1 g/d). RBC FA levels were expressed as a percentage of total FA. Patients also reported their typical olive oil and fish intakes. RBC oleic acid levels were directly correlated with reported frequency of olive oil consumption, and the omega-3 index was correlated with reported fish intake ( P for trends <0.001 for both). After treatment, the omega-3 index increased from 4.8 ± 1.7% to 6.7 ± 1.9% but was unchanged in the placebo group (4.7 ± 1.7 to 4.8 ± 1.5%) ( P < .0001 for changes between groups). At 3 months, more patients reached the proposed target omega-3 index level of 8%-12% in the treated vs placebo group (22.6% vs. 1.3%, P < .0001), however, what omega-3 index levels were ultimately achieved after four years in this trial are unknown. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this research was to determine if sex and gender differences in the management of acute coronary syndromes (ACS) are associated with differences in prognosis after ACS. Background: Previous investigators have reported sex/gender differences in the management of patients with ACS, but the impact of these differences on prognosis is unclear. Methods: We analyzed data from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, which enrolled 4,836 women and 7,726 men with ACS. Patients were classified into risk strata using the Thrombolysis In Myocardial Infarction (TIMI) score. Results: Women underwent fewer invasive procedures including angiography, angioplasty, and coronary artery bypass graft (CABG) surgery (47.6% vs. 60.5%; p = 0.0001) compared to men. No significant differences in cardiovascular death, myocardial infarction (MI), or stroke were observed (9.8% vs. 10.9%; p = 0.04), although women were more likely than men to develop refractory ischemia and to be rehospitalized for chest pain during follow-up (16.6% vs. 13.9%; p = 0.0001). These differences were particularly evident among TIMI high-risk women. A significant interaction between TIMI risk and gender for the outcome of refractory angina and rehospitalization for angina was present. Conclusions: Compared to men, high-risk women with ACS undergo less coronary angiography, angioplasty, and CABG surgery, and while they do not have higher incidence cardiovascular death, recurrent MI, or stroke, they suffer an increased rate of refractory ischemia and rehospitalization. All high-risk women and men with ACS should receive optimal medical management, and be considered for coronary angiography with possible revascularization if their coronary anatomy warrants it. [Copyright &y& Elsevier]

Bicuspid aortic valve (BAV) formation is genetically determined, with reduced penetrance and variable expressivity. NOTCH1 is a proven candidate gene and its mutations have been found in familial and sporadic cases of BAV. 66 BAV patients from the GISSI VAR study were genotyped for the NOTCH1 gene. We identified 63 variants, in heterozygous and homozygous states. Fifty-two are common polymorphisms present in almost all patients. Eleven variants are new and never yet reported: two are non-synonymous substitutions, Gly540Asp in exon 10 and Glu851Gln in exon 16; one is in the 3'UTR region and seven in introns, one corresponds to a T allele insertion in intron 27. We selected four statistically noteworthy and seven new variants identified in six BAV patients and correlated them with clinical and demographic variables and with imaging and histological parameters. Preliminary data show that four were BAV patients with isolated stenosis in patients over 60 aged. These variants may correlate with a later need for surgery for the presence of stenosis and not aortic valve regurgitation or ascending aortic aneurysm. Completing the genotyping of 62 BAV patients we found 11 new variants in the NOTCH1 gene never yet reported. These findings confirm that the identification of new, clinically remarkable biomarkers for BAV requires a deeper genetic understanding of the NOTCH1 gene variants, which could be targeted by future diagnostic and therapeutic strategies. • Our preliminary genetic characterization of the BAV population of the GISSI VAR study corroborates the role of NOTCH1 gene mutations as proven candidate for familial and sporadic cases of BAV. • The GISSI VAR study is first study with 4 groups based on echographic BAV classification and aortic disease. • Among the 63 identified variants in the NOTCH1 gene, eleven are new and never yet reported in literature. • New variants may correlate with a later need for surgery for the presence of stenosis. [ABSTRACT FROM AUTHOR]