Search

Background: The risk of sudden death has changed over time among patients with symptomatic\ud heart failure and reduced ejection fraction with the sequential introduction of medications\ud including angiotensin-converting–enzyme inhibitors, angiotensin-receptor\ud blockers, beta-blockers, and mineralocorticoid-receptor antagonists. We sought to\ud examine this trend in detail.\ud \ud Methods: We analyzed data from 40,195 patients who had heart failure with reduced ejection\ud fraction and were enrolled in any of 12 clinical trials spanning the period from\ud 1995 through 2014. Patients who had an implantable cardioverter–defibrillator at\ud the time of trial enrollment were excluded. Weighted multivariable regression was\ud used to examine trends in rates of sudden death over time. Adjusted hazard ratios\ud for sudden death in each trial group were calculated with the use of Cox regression\ud models. The cumulative incidence rates of sudden death were assessed at different\ud time points after randomization and according to the length of time between the\ud diagnosis of heart failure and randomization.\ud \ud Results: Sudden death was reported in 3583 patients. Such patients were older and were\ud more often male, with an ischemic cause of heart failure and worse cardiac function,\ud than those in whom sudden death did not occur. There was a 44% decline in the rate\ud of sudden death across the trials (P=0.03). The cumulative incidence of sudden\ud death at 90 days after randomization was 2.4% in the earliest trial and 1.0% in\ud the most recent trial. The rate of sudden death was not higher among patients\ud with a recent diagnosis of heart failure than among those with a longer-standing\ud diagnosis.\ud \ud Conclusions: Rates of sudden death declined substantially over time among ambulatory patients\ud with heart failure with reduced ejection fraction who were enrolled in clinical trials,\ud a finding that is consistent with a cumulative benefit of evidence-based medications\ud on this cause of death. (Funded by the China Scholarship Council and the\ud University of Glasgow.)

Background Dysregulation of the vitamin D system promotes renal dysfunction and has direct detrimental effects on the heart. Progressive deterioration of renal function is common in patients with chronic heart failure (HF) and is invariably associated with unfavorable outcomes which can be improved by early identification and timely interventions. We examined the relation between two plasma markers of vitamin D metabolism and worsening of renal function (WRF) in a large cohort of patients with chronic HF. Methods Plasma levels of 1,25-dihydroxyvitamin D (1,25(OH) 2 D) and parathyroid hormone PTH (1–84) were measured in 1237 patients with clinical evidence of chronic and stable HF enrolled in the multicentre GISSI-HF trial and followed for 3.9years. We examined the relation of 1,25(OH) 2 D, PTH(1–84), and their ratio with WRF, defined as first increase in serum creatinine concentration ≥0.3mg/dL and ≥25% at two consecutive measurements at any time during the study. Results Lower 1,25(OH) 2 D/PTH(1–84) ratio was associated with a higher baseline serum concentration of creatinine, winter season, female sex and older age; 335 patients (29.6%) experienced an episode of WRF. After adjustment, a lower 1,25(OH) 2 D/PTH(1–84) ratio remained significantly associated with a higher risk of WRF (HR=0.75 [0.62–0.90], p=0.002) and correctly reclassified events. This ratio also independently predicted mortality and admission to hospital for cardiovascular reasons. Conclusions The plasma 1,25(OH) 2 D/PTH(1–84) ratio is a promising indicator of future risk of deterioration of renal function in patients with chronic HF and mild renal impairment, that may serve to optimize therapies and improve outcomes.

A population in a natural crossroad within Europe reveals multiple ancient contributions and substantial population structure., European populations display low genetic differentiation as the result of long-term blending of their ancient founding ancestries. However, it is unclear how the combination of ancient ancestries related to early foragers, Neolithic farmers, and Bronze Age nomadic pastoralists can explain the distribution of genetic variation across Europe. Populations in natural crossroads like the Italian peninsula are expected to recapitulate the continental diversity, but have been systematically understudied. Here, we characterize the ancestry profiles of Italian populations using a genome-wide dataset representative of modern and ancient samples from across Italy, Europe, and the rest of the world. Italian genomes capture several ancient signatures, including a non–steppe contribution derived ultimately from the Caucasus. Differences in ancestry composition, as the result of migration and admixture, have generated in Italy the largest degree of population structure detected so far in the continent, as well as shaping the amount of Neanderthal DNA in modern-day populations.

European populations display low genetic diversity as the result of long term blending of the small number of ancient founding ancestries. However it is still unclear how the combination of ancient ancestries related to early European foragers, Neolithic farmers and Bronze Age nomadic pastoralists can fully explain genetic variation across Europe. Populations in natural crossroads like the Italian peninsula are expected to recapitulate the overall continental diversity, but to date have been systematically understudied. Here we characterised the ancestry profiles of modern-day Italian populations using a genome-wide dataset representative of modern and ancient samples from across Italy, Europe and the rest of the world. Italian genomes captured several ancient signatures, including a non-steppe related substantial ancestry contribution ultimately from the Caucasus. Differences in ancestry composition as the result of migration and admixture generated in Italy the largest degree of population structure detected so far in the continent and shaped the amount of Neanderthal DNA present in modern-day populations. One sentence summary Ancient and historical admixture events shaped the genetic structure of modern-day Italians, the ancestry profile of Southern European populations and the continental distribution of Neanderthal legacy.

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

Aims Uncertainties remain on the biological and prognostic significance and therapeutic implications of loss in body weight (W-LOSS) in chronic heart failure (HF) patients. We assessed whether W-LOSS added additional prognostic value to classical clinical risk factors in two separate and large cohorts of patients with chronic HF. The factors associated with W-LOSS were studied. Methods and results W-LOSS and estimated plasma volume changes were measured serially in the GISSI-HF (n = 6820) and Val-HeFT trials (n = 4892). In both studies, experiencing at least one episode of ≥5% W-LOSS during the first year of follow-up was considered a sign of wasting. In GISSI-HF, self-reported unintentional W-LOSS ≥2 kg between two consecutive clinical visits within 1 year was also considered a sign of wasting. W-LOSS occurred in 16.4% and 15.7% of the patients enrolled in GISSI-HF and Val-HeFT, respectively (unintentional ≥2 kg W-LOSS occurred in 18.9% in GISSI-HF). In multivariable analyses adjusting for a number of baseline covariates as well as for plasma volume changes, W-LOSS was found to be independently associated with mortality and adverse cardiovascular and non-cardiovascular outcomes, with a significant net reclassification improvement (cfNRI) and an increase in integrated discrimination improvement (IDI). W-LOSS was independently associated with several features representing the severity of HF, including baseline NT-proBNP and high sensitivity C-reactive protein (hsCRP) in Val-HeFT. Conclusions W-LOSS was a frequent finding in the GISSI-HF and Val-HeFT trials, associated with multiple patient features, and added additional prognostic information beyond clinical variables of HF severity, including estimated plasma volume changes.

Background Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery and predicts increased morbidity and mortality. Identification of patients at high risk of POAF with the help of circulating biomarkers may enable early preventive treatment but data are limited, especially in contemporary surgical patients. Methods Plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) were measured at enrolment, on the morning of cardiac surgery, at end surgery, and 2 days postsurgery in 562 patients undergoing cardiac surgery, randomized to perioperative supplementation with oral fish oil or placebo in the Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation trial (OPERA). The primary endpoint was incident POAF lasting ≥ 30 s, centrally adjudicated and confirmed electrocardiographically. Results Higher levels of NT-proBNP and hs-cTnT before surgery were associated with older age, renal or cardiac dysfunction and EuroSCORE. NT-proBNP peaked on postoperative day 2 (2172 [1238–3758] ng/L, median [Q1–Q3]), while hs-cTnT peaked at the end of surgery (373 [188–660] ng/L). Fish oil supplementation did not alter the time course of the cardiac biomarkers (P > 0·05). Concentrations of NT-proBNP or hs-cTnT, on the morning of surgery, or changes in their level between morning of surgery and postsurgery, were not significantly associated with POAF after adjustment for clinical and surgical characteristics. Conclusion Among patients undergoing cardiac surgery, NT-proBNP and hs-cTnT are related to clinical and surgical characteristics, have different perioperative time courses but are not independently associated with risk of POAF.

Background The independent prognostic impact of diabetes mellitus ( DM ) and prediabetes mellitus (pre‐ DM ) on survival outcomes in patients with chronic heart failure has been investigated in observational registries and randomized, clinical trials, but the results have been often inconclusive or conflicting. We examined the independent prognostic impact of DM and pre‐ DM on survival outcomes in the GISSI ‐HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca‐Heart Failure) trial. Methods and Results We assessed the risk of all‐cause death and the composite of all‐cause death or cardiovascular hospitalization over a median follow‐up period of 3.9 years among the 6935 chronic heart failure participants of the GISSI ‐ HF trial, who were stratified by presence of DM (n=2852), pre‐ DM (n=2013), and non‐ DM (n=2070) at baseline. Compared with non‐ DM patients, those with DM had remarkably higher incidence rates of all‐cause death (34.5% versus 24.6%) and the composite end point (63.6% versus 54.7%). Conversely, both event rates were similar between non‐ DM patients and those with pre‐ DM . Cox regression analysis showed that DM , but not pre‐ DM , was associated with an increased risk of all‐cause death (adjusted hazard ratio, 1.43; 95% CI , 1.28–1.60) and of the composite end point (adjusted hazard ratio, 1.23; 95% CI , 1.13–1.32), independently of established risk factors. In the DM subgroup, higher hemoglobin A1c was also independently associated with increased risk of both study outcomes (all‐cause death: adjusted hazard ratio, 1.21; 95% CI , 1.02–1.43; and composite end point: adjusted hazard ratio, 1.14; 95% CI , 1.01–1.29, respectively). Conclusions Presence of DM was independently associated with poor long‐term survival outcomes in patients with chronic heart failure. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00336336.

515 Background: The ETNA study showed that substituting P with nab-P did not significantly increase the overall rate of pathological complete response (pCR) (P 18.6%, nab-P 22.5%, p = 0.19). The multivariate analysis revealed that tumor subtype (triple negative vs luminal B-like) was the most significant factor (OR 4.85) influencing treatment outcome (Gianni L et al, JAMA Oncol 2018). Methods: This multicenter open label study (NCT01822314) in collaboration with GEICAM and BCRC-WA randomized 695 patients with centrally-confirmed HER2-negative breast cancer to nab-P 125 mg/m2 (346 patients) or P 90 mg/m2 (349 patients). The two drugs were given on weeks 1, 2 and 3 followed by 1-week rest for 4 cycles before 4 cycles of an anthracycline regimen as per investigator choice. The primary endpoint was pCR (absence of invasive cells in breast and nodes). A secondary endpoint is event-free survival (EFS) defined as the time from randomization to the first date of disease progression while on primary therapy or disease recurrence (local, regional, distant, invasive contralateral breast cancer) after surgery or death due to any cause. Results: The ITT analysis of the secondary endpoint EFS at 5 years is reported below: Clinical trial information: NCT01822314. Overall 5-year survival was 84.8% after P and 87.3% for nab-P. No serious adverse events were documented during the follow-up. Conclusions: The improved 5-year EFS after nab-P failed to reach statistical significance (unadjusted P = 0.245). In the analysis by subgroup the numerical improvement was almost exclusively observed in luminal B and not in TN tumors. So far the data do not support substitution of P with nab-P in the schedule and doses adopted in the ETNA trial. Additional analyses will be based on ongoing molecular studies.[Table: see text]

527 Background: Downregulation of Ki67 by neoadjuvant endocrine therapy predicts activity of endocrine treatments in hormone receptors positive breast cancer. NA-PHER2 is an exploratory phase II study (NCT02530424) assessing Ki67 changes in patients with HER2+ and ER+ breast cancer undergoing dual HER2 block and palbociclib. Cohort A of the NA-PHER2 showed significant decrease of Ki67 at week 2 and at surgery and pathological complete response (pCR) in 27% of patients (Lancet Oncol 2018). Methods: After completing cohort A two additional cohorts were started. In Cohort B cases with HER2 3+ or amplified unilateral breast cancer received therapy with dual block and palbociclib without fulvestrant. In Cohort C tumors with Ki67 >20% and HER2 low (1+/2+, no amplification) received also fulvestrant. Trastuzumab and pertuzumab q3 wks were dosed for 6 cycles and palbociclib for 5 cycles (125 mg po q.d. 3q4 wks). Fulvestrant in Cohort C was given im 500 mg q4 wks for 5 cycles. Primary endpoint was Ki67 change from baseline to 2 weeks and at surgery. Results: 26 eligible patients in cohort B and 23 in cohort C with centrally confirmed HER2 and ER status were recruited. Ki67 was centrally assessed. Main results are reported in the table. Clinical trial information: NCT02530424. The most frequent G >=3 adverse events were neutropenia (36%) and gastrointestinal disorders (12%). Conclusions: Dual block of HER2 and palbociclib caused robust persistent decrease of Ki67 as in cohort A. In cohort B without endocrine therapy there also were pCR and high objective response rate. Effects on Ki67 and ORR were similar in HER2 low tumors. The chemo-free approach of NA-PHER2 leads to promising therapeutic effects and deserves investigation in ER+ HER2+ tumors to spare the toxicity of chemotherapy, and in HER2-low tumors, in which functional activation of HER2 may lead to resistance to endocrine therapy. Supported in part by unrestricted grants of Pfizer Italia S.r.l. and Roche S.p.a. Italia.[Table: see text]

n-3 Polyunsaturated fatty acid (n-3PUFA) supplementation in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca (GISSI-HF) study reduced total mortality in patients with heart failure (HF), but the mechanism of action is still debated. The hypothesis of the present GISSI-HF substudy was that n-3PUFA may have beneficial effects on cardiac autonomic control.To evaluate the effect of 1 g/day of n-3PUFA vs placebo on heart rate variability variables, deceleration capacity, and turbulence slope.The GISSI-HF study enrolled patients with HF of any cause and severity. Twenty-four-hour (range 16-24 hours) Holter recordings were performed and analyzed in 388 patients at baseline, 3 months, and 12 months. Baseline characteristics were compared by using the χ(2) test, t test, or nonparametric Wilcoxon 2-sample test. Changes over time were tested by using the analysis of covariance adjusted by baseline values.At baseline, 36% of the patients were older than 70 years, 82% were men, 92% presented a left ventricular ejection fraction40%, and 80% were in New York Heart Association class II. An increase in mean RR interval, standard deviation of all normal-to-normal RR intervals, very low frequency power (all P.05), and turbulence slope (P = .05) was observed after 3 months in the n-3PUFA group compared to the placebo group, independently of the frequency of dietary fish consumption or beta-blocker treatment. These differences between study groups were no longer statistically significant at 12 months. A per-protocol analysis in patients compliant with study treatment showed similar results.n-3PUFA supplementation partially restored autonomic modulation in patients with chronic HF; this effect was maximal after 3 months of treatment.

Background An intense systemic inflammatory response is observed following reperfusion after cardiac arrest. Heparin-binding protein (HBP) is a granule protein released by neutrophils that intervenes in endothelial permeability regulation. In the present study, we investigated plasma levels of HBP in a large population of patients resuscitated from out-of-hospital cardiac arrest. We hypothesized that high circulating levels of HBP are associated with severity of post-cardiac arrest syndrome and poor outcome. Methods Plasma was obtained from 278 patients enrolled in a prospective multicenter observational study in 21 intensive care units (ICU) in Finland. HBP was assayed at ICU admission and 48 h later. Multiple organ dysfunction syndrome (MODS) was defined as the 24 h Sequential Organ Failure Assessment (SOFA) score ≥ 12. ICU death and 12-month Cerebral Performance Category (CPC) were evaluated. Multiple linear and logistic regression tests and receiver operating characteristic curves with area under the curve (AUC) were performed. Results Eighty-two percent of patients (229 of 278) survived to ICU discharge and 48 % (133 of 276) to 1 year with a favorable neurological outcome (CPC 1 or 2). At ICU admission, median plasma levels of HBP were markedly elevated, 15.4 [9.6–31.3] ng/mL, and persisted high 48 h later, 14.8 [9.8–31.1] ng/mL. Admission levels of HBP were higher in patients who had higher 24 h SOFA and cardiovascular SOFA score (p

Study Hypothesis Recently, genome-wide association studies (GWAS) have identified several common variants associated with increased risk of coronary artery disease (CAD) and myocardial infarction (MI) by 10% to 30%. The authors state that these loci explain only a small proportion of the predicted genetic risk and that all of the current loci for CAD and MI by GWAS have been discovered in European populations. The authors hypothesized that discovery of new susceptibility loci of smaller effect sizes would be aided by conducting much larger studies in addition to an emphasis on early-onset CAD and clearly defined clinical end points. Therefore, they assembled the Coronary Artery Disease (C4D) Genetics Consortium.1 ### How Was the Hypothesis Tested? The authors performed a meta-analysis of 4 large GWAS of CAD, 2 of European ancestry (PROCARDIS and HPS) and 2 of South Asian ancestry (PROMIS and LOLLIPOP), with ≈575 000 genotyped single-nucleotide polymorphisms (SNPs) in a discovery data set comprising 15 420 individuals with CAD (cases) (8424 Europeans and 6996 South Asians) and 15 062 control subjects. They observed little evidence for ancestry-specific associations, supporting the use of combined analyses. Furthermore, the authors state that because all individuals were genotyped on the same platform (whole-genome Illumina BeadChips), a meta-analysis of actual genotypes rather than imputed data enabled analysis of low-frequency variants (1% to 5%), which have been excluded from GWAS either because of sample size or because imputation has been required to combine data from different genotyping platforms. After the meta-analysis, they selected 59 SNPs from 50 loci that showed potential new associations from the meta-analysis of the European and South Asian studies (41 SNPs; P

Total plasma homocysteine concentration (tHcy) is a biomarker for atherothrombotic disease, but causality remains uncertain. Polymorphisms in the genes involved in methionine metabolism explain only a small fraction of the heritability of tHcy levels. In a genome-wide association study, we examined the genetic determinants of tHcy using a 2-stage design. First, 283 437 single nucleotide polymorphisms (SNPs) were tested for association with tHcy in 387 persons recruited from 21 large Spanish families. Of those, 17 SNPs showed equal or stronger association with tHcy level compared with the MTHFR 677C>T SNP (β = 0.10, P = .0001). Second, a replication analysis of these 17 SNPs was performed in patients with premature myocardial infarction (n = 1238). Novel associations were found for SNPs near the ZNF366 gene (lead SNP rs7445013; discovery stage: adjusted β = −0.12, P = 5.30 × 10−6, replication stage: adjusted β = −0.13, P = .004) and the PTPRD gene (lead SNP rs973117; discovery stage: adjusted β = 0.11, P = 5.5 × 10−6, replication stage: adjusted β = 0.10, P = .005). These associations were independent of known confounders, including creatinine clearance and plasma fibrinogen concentration. Our findings implicate novel pathways in homocysteine metabolism, and highlight the need for investigation of the associated genes in the etiology of vascular diseases.

Dysregulation of the vitamin D system promotes renal dysfunction and has direct detrimental effects on the heart. Progressive deterioration of renal function is common in patients with chronic heart failure (HF) and is invariably associated with unfavorable outcomes which can be improved by early identification and timely interventions. We examined the relation between two plasma markers of vitamin D metabolism and worsening of renal function (WRF) in a large cohort of patients with chronic HF.Plasma levels of 1,25-dihydroxyvitamin D (1,25(OH)Lower 1,25(OH)The plasma 1,25(OH)

Atrial fibrillation (AF) is the most common arrhythmia and has an increasing impact on public health because of its morbidity and mortality. Clinical and diagnostic tests to predict the recurrence of arrhythmia and clinical events before AF becomes permanent are still an open issue. 307 out of 1442 patients in sinus rhythm, at high risk of recurrence of AF enrolled in the GISSI-AF study, participated in a substudy with echocardiographic and biohumoral evaluation at baseline and at 12-month follow-up. The relations between biomarker concentrations and echocardiographic parameters with study endpoints in 1 year, were analysed by a stepwise multivariable Cox model (entry criteria p

Background The genetic structure of human populations is the outcome of the combined action of different processes such as demographic dynamics and natural selection. Several efforts toward the characterization of population genetic architectures and the identification of adaptation signatures were recently made. In this study, we provide a genome-wide depiction of the Italian population structure and the analysis of the major determinants of the current existing genetic variation. Results We defined and characterized 210 genomic loci associated with the first Principal Component calculated on the Italian genotypic data and correlated to the North–south genetic gradient. Using a gene-enrichment approach we identified the immune function as primarily involved in the Italian population differentiation and we described a locus on chromosome 13 showing combined evidence of North–south diversification in allele frequencies and signs of recent positive selection. In this region our bioinformatics analysis pinpointed an uncharacterized long intergenic non-coding (lincRNA), whose expression appeared specific for immune-related tissues suggesting its relevance for the immune function. Conclusions Our study, combining population genetic analyses with biological insights provides a description of the Italian genetic structure that in future could contribute to the evaluation of complex diseases risk in the population context. Electronic supplementary material The online version of this article (doi:10.1186/s12863-015-0293-x) contains supplementary material, which is available to authorized users.

To analyze the published data on the role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II-receptor blockers (ARBs) in secondary prevention of AF. Some post-hoc analyses from trials in different clinical scenarios suggested the efficacy of ACEIs and ARBs in the prevention of new onset atrial fibrillation (AF), while their efficacy in preventing AF recurrences is notably controversial.The authors reviewed all published prospective, randomized vs. placebo or no-treatment studies, concerning the effect of ACEIs and ARBs in the prevention of AF recurrences. Four ACEIs studies accounting for a total of 355 patients and six ARBs studies comprising 4.040 patients were analyzed.The pooled ACEIs data showed a statistical significant effect in preventing AF recurrences. However, the studies did not have a robust follow-up algorithm to recognize AF episodes, and were individually very small. On the contrary, pooled ARBs data did not show any effect in preventing AF recurrences (RR 0.90; 95% CI, 0.75-1.08; p = 0.24). The ARBs analyzed population was much larger in three large prospective, randomized, double-blind, placebo-control trials with transtelephoning monitoring of AF recurrences and neutral results. The meta-analysis of ACEIs and ARBs trials together could suggest a publication bias that may result in an overestimation of the treatment effect.Currently there is no role for ARBs in secondary prevention of AF. With regard to ACEIs, the data are not strong enough for a conclusion, although the efficacy is expected to be the same as that of ARBs.

Eur J Clin Invest 2011; 41 (12): 1330–1338 Abstract Background We hypothesized that, besides type 2 diabetes (T2D) and body mass index (BMI), circulating adiponectin concentration would be associated with variants of the ADIPOQ gene in patients with chronic heart failure (CHF). We also assessed the influence of these confounders on the prognostic value of adiponectin. Methods Plasma adiponectin was measured at entry and after 3 months in approximately 1200 patients with CHF enrolled in the GISSI-HF trial. Four common single-nucleotide polymorphisms (SNPs) spanning the ADIPOQ gene were studied: rs17300539 (−11391GA), rs266729 (−11377CG), rs2241766 (+45TG) and rs1501299 (+276GT). Associations with clinical characteristics and mortality were evaluated in patients with or without T2D. Results Adiponectin concentrations were negatively related to BMI, higher in women and older persons, but lower in patients with diabetes. T-allele carriers for rs1501299 and A-allele carriers for rs17300539 had significantly elevated adiponectin concentrations. Irrespective of diabetes, baseline plasma adiponectin was independently associated with mortality (adjusted HR [95%CI] per 1 SD increase in adiponectin concentration = 1·24[1·12–1·37], P

Atrial (ANP) and B-type natriuretic peptides (BNP) are cardiac hormones released by the heart in response to myocardial stretch and volume overload (1). ANP and BNP induce vasodilation, natriuresis and suppress the renin-angiotensin-aldosterone system. In heart failure (HF), ANP and BNP are highly produced and secreted from the atria and ventricles in the attempt to compensate the increased cardiac filling pressures. Natriuretic peptides exert also a metabolic action, indeed, ANP and BNP induce lipolysis in vitro and vivo (2). In consideration of the metabolic properties of natriuretic peptides, it is still debated whether these hormones play a role in weight loss observed in cardiac cachexia. Previous studies conducted in general populations from Massachusetts, Sweden, Finland, Minnesota and Italy reported that the ANP genetic variant rs5068 is associated with higher circulating levels of ANP, BNP and lower blood pressure values, body mass index (BMI), waist circumference, prevalence of hypertension, obesity and metabolic syndrome (3-5). To date no studies have described the phenotype related to rs5068 in the clinical context of chronic heart failure. Hence, the aim of our study was to characterize in-depth the cardiovascular and metabolic phenotype associated with rs5068 in a cohort of heart failure patients.

Latini R, Masson S, Pirelli S, Barlera S, Pulitano G, Carbonieri E, Gulizia M, Vago T, Favero C, Zdunek D, Struck J, Staszewsky L, Maggioni AP, Franzosi MG, Disertori M on the behalf of the GISSI-AF Investigators (Istituto di Ricerche Farmacologiche “Mario Negri”, Milan; Istituti Ospitalieri, Cremona; POL Madonna della Consolazione, Reggio Calabria; Ospedale Nuovo Girolimo Fracastoro, San Bonifacio; Ospedale Garibaldi-Nesima, Catania; Ospedale Luigi Sacco, Milan, Italy; Roche Diagnostics, Rotkreuz, Switzerland; B.R.A.H.M.S. AG, Henningsdorf, Germany; ANMCO Research Center, Florence; and Ospedale Santa Chiara, Trento, Italy). Circulating cardiovascular biomarkers in recurrent atrial fibrillation: data from the GISSI-Atrial Fibrillation Trial. J Intern Med 2011; 269: 160–171. Objective. We evaluated the prognostic role of circulating cardiovascular biomarkers in patients with a history of recent atrial fibrillation (AF). Background. Predicting long-term maintenance of sinus rhythm in patients with AF is difficult. Methods. Plasma concentrations of three specific cardiac markers [high-sensitivity troponin T (hsTnT), N-terminal probrain natriuretic peptide (NT-proBNP) and mid-regional proatrial natriuretic peptide (MR-proANP)] and three stable fragments of vasoactive peptides [mid-regional proadrenomedullin (MR-proADM), copeptin (CT-proAVP) and CT-proendothelin-1 (CT-proET-1)] were measured at baseline and after 6 and 12 months in 382 patients enrolled in the GISSI-AF study, a prospective randomized trial to determine the effect of valsartan to reduce the recurrence of AF. The association between these markers, clinical characteristics and recurrence of AF was tested by univariate and multivariate Cox models. Results. Mean patient age was 68 ± 9 years (37.2% females). A total of 84.8% of patients had a history of hypertension. In total, 59.7% qualified for history of AF because of successful cardioversion, 11.8% because of two or more episodes of AF in the 6 months preceding randomization and 28.5% because of both. Patients in AF at 6 or 12 months (203 (53.1%) with first recurrence) had significantly higher concentrations of most biomarkers. Despite low baseline levels, higher concentrations of hsTnT {adjusted hazard ratio (HR) [95% confidence intervals (CIs) for 1 SD increment] (1.15 [1.04–1.28], P = 0.007), MR-proANP (1.15 [1.01–1.30], P = 0.04), NT-proBNP (1.24 [1.11–1.39], P = 0.0001) and CT-proET-1 (1.16 [1.01–1.33], P = 0.03) independently predicted higher risk of a first recurrence of AF. Changes over time of MR-proANP tended to predict subsequent recurrence (adjusted HR [95%CI]) (1.53 [0.98–2.37], P = 0.06). Conclusion. Circulating markers of cardiomyocyte injury/strain and endothelin are related to recurrence of AF in patients in sinus rhythm with a history of recent AF.

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 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.

Epidemiological, experimental studies and post hoc analyses of randomized trials suggested that n-3 polyunsaturated fatty acids (PUFA) and statins could be beneficial in chronic heart failure. Two double-blind, placebo-controlled, randomized clinical trials investigated the efficacy and safety of n-3 PUFA 1 g daily (R1) and rosuvastatin 10 mg daily (R2) in patients with heart failure. In total, 6975 and 4574 patients were randomized in R1 and R2, respectively; the main reason for excluding patients from R2 being the open-label administration of statin treatment. Primary end points were death, and death or admission to hospital for cardiovascular reasons. n-3 PUFA, but not rosuvastatin, significantly decreased the two coprimary end points: 56 and 44 patients needed to be treated with n-3 PUFA for a median duration of 3.9 years to avoid one death or one cumulative event. Both drugs were safe and were tolerated. A simple and safe treatment with n-3 PUFA provides a beneficial advantage in patients with heart failure in a context of usual care.

Objectives This study sought to evaluate the association between changes over time of N-terminal pro-brain natriuretic peptide (NT-proBNP) expressed in different ways and outcome in patients with stable and chronic heart failure (HF). Background Although previous studies examined the prognostic value of repeated determinations of BNP in HF, there are only limited data on the clinical utility of serial measurements of the inactive peptide NT-proBNP in a large population of ambulatory patients with chronic HF with sufficient follow-up time. Methods The NT-proBNP was measured at randomization and after 4 months in 1,742 patients enrolled in the placebo arm of Val-HeFT (Valsartan Heart Failure Trial). Changes in NT-proBNP concentrations over 4 months were expressed as absolute change from baseline, percent relative changes, or categorical changes across a threshold value and related to subsequent mortality. Results A single determination of NT-proBNP (area under the curve at 4 months: 0.702, 95% confidence interval [CI]: 0.669 to 0.735) showed a higher prognostic discrimination than continuous changes of concentrations, expressed either as absolute (0.592, 95% CI: 0.549 to 0.634) or relative changes (0.602, 95% CI: 0.566 to 0.639). A Cox proportional hazards model showed that stratification of patients into 4 categories according to NT-proBNP levels at 2 time points 4 months apart with respect to a threshold concentration provided prognostic information in patients with chronic HF beyond that of a single determination. Conclusions Serial determinations of NT-proBNP concentration and classification into few categories of changes according to threshold levels may be a superior strategy for risk stratification of patients with chronic and stable HF.

Chronic obstructive pulmonary disease (COPD) and heart failure are major causes of death and disability. Because little information is available about the population of patients with both syndromes, we assessed the characteristics and the independent contribution of COPD to outcomes in patients with stable chronic heart failure.The clinical, neurohormonal, and echocardiographic characteristics of the 5010 patients enrolled in the Valsartan Heart Failure Trial were compared in patients with or without COPD. The prognostic value of COPD was tested by multivariate Cox proportional hazard models.Patients with COPD were older, more symptomatic, and less likely to be receiving beta-blocker therapy, and had a higher mortality (27.4% vs. 18.4%, P.0001). Echocardiographic parameters were not different, and brain natriuretic peptide was only minimally increased. Norepinephrine, inflammatory markers, cardiac troponin T, and creatinine values were significantly higher. After adjustment, COPD no longer predicted all-cause mortality but remained predictive of noncardiovascular mortality (hazard ratio 2.50; 95% confidence interval: 1.58-3.96; P.0001) and hospitalizations, especially noncardiovascular (hazard ratio 1.71; 95% confidence interval; 1.43-2.06; P.0001).Patients with COPD are more symptomatic and have worse outcomes that are not explained by poorer left ventricular function. After adjustment for demographic, clinical, biohumoral, and treatment variables, COPD is a weak predictor of all-cause mortality but a strong predictor of noncardiovascular events. Awareness and optimized treatment of heart failure and COPD may reduce the clinical burden of these patients.

To assess the relationship between body mass index (BMI), mortality and mode of death in chronic heart failure (CHF) patients; to define the shape of the relationship between BMI and mortality.We performed a post-hoc analysis of 5010 patients from the Valsartan Heart Failure Trial. The end-points of the study were all-cause and cardiovascular mortality. Mortality rate was 27.2% in underweight patients (BMI22 kg/m2), 21.7% in normal weight patients (BMI 22-24.9 kg/m2), 17.9% in overweight patients (BMI 25-29.9 kg/m2) and 16.5% in obese patients (BMI30 kg/m2) (p0.0001). The rates of non-cardiovascular death did not differ among groups. The risk of death due to progressive heart failure was 3.4-fold higher in the underweight than in the obese patients (p0.0001). Normal weight, overweight and obese patients had lower risk of death as compared with underweight patients (p=0.019, HR 0.76, 95% CI 0.61-0.96; p=0.0005, HR 0.68, 95% CI 0.55-0.84; p=0.003, HR 0.67, 95% CI 0.52-0.88, respectively) independently of symptoms, ventricular function, beta-blocker use, C-reactive protein and brain natriuretic peptide levels.In CHF patients a higher BMI is associated with a better prognosis independently of other clinical variables. The relationship between mortality and BMI is monotonically decreasing.

Whether cyclosporine A (CsA) has beneficial effects in reperfused myocardial infarction (MI) is debated.This study investigated whether CsA improved ST-segment resolution in a randomized, multicenter phase II study.The authors randomly assigned 410 patients from 31 cardiac care units, age 63 ± 12 years, with large ST-segment elevation MI within 6 h of symptom onset, Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 to 1 in the infarct-related artery, and committed to primary percutaneous coronary intervention, to 2.5 mg/kg intravenous CsA (n = 207) or control (n = 203) groups. The primary endpoint was incidence of ≥70% ST-segment resolution 60 min after TIMI flow grade 3. Secondary endpoints included high-sensitivity cardiac troponin T (hs-cTnT) on day 4, left ventricular (LV) remodeling, and clinical events at 6-month follow-up.Time from symptom onset to first antegrade flow was 180 ± 67 min; a median of 5 electrocardiography leads showed ST-segment deviation (quartile [Q]1 to Q3: 4 to 6); 49.8% of MIs were anterior. ST-segment resolution ≥70% was found in 52.0% of CsA patients and 49.0% of controls (p = 0.55). Median hs-cTnT on day 4 was 2,160 (Q1 to Q3: 1,087 to 3,274) ng/l in CsA and 2,068 (1,117 to 3,690) ng/l in controls (p = 0.85). The 2 groups did not differ in LV ejection fraction on day 4 and at 6 months. Infarct site did not influence CsA efficacy. There were no acute allergic reactions or nonsignificant excesses of 6-month mortality (5.7% CsA vs. 3.2% controls, p = 0.17) or cardiogenic shock (2.4% CsA vs. 1.5% controls, p = 0.33).In the CYCLE (CYCLosporinE A in Reperfused Acute Myocardial Infarction) trial, a single intravenous CsA bolus just before primary percutaneous coronary intervention had no effect on ST-segment resolution or hs-cTnT, and did not improve clinical outcomes or LV remodeling up to 6 months. (CYCLosporinE A in Reperfused Acute Myocardial Infarction [CYCLE]; NCT01650662; EudraCT number 2011-002876-18).

Although high cardiovascular risk patients should be the main target of preventive strategies, modifiable risk factors are often inadequately controlled.To assess feasibility and results of a comprehensive personalized method for cardiovascular prevention in high risk patients followed by their general practitioner.Between 2004 and 2007, 12,513 patients (mean age 64.0 ± 9.5 years; 61.5% males) with multiple cardiovascular risk factors or history of atherosclerotic disease were identified and followed for five years. If control of major modifiable cardiovascular risk factors (hypertension, hypercholesterolaemia, diabetes, obesity, smoking, unhealthy diet, physical inactivity) was sub-optimal, at baseline and yearly thereafter general practitioners planned with patients, with the help of a brief checklist, preventive interventions to improve the global risk profile. Main outcome was the control of the seven major modifiable cardiovascular risk factors during follow-up. Secondary outcome was the incidence of cardiovascular deaths and hospitalization for cardiovascular reasons according to the improvement in global cardiovascular risk profile during the first year.Control of all major modifiable risk factors except physical inactivity improved gradually and significantly (p 0.0001) during follow-up.The improvement in the global cardiovascular risk profile during the first year was independently and significantly associated with a lower rate of major cardiovascular events in the following years (hazard ratio 0.939; 95% confidence interval 0.887-0.994, p = 0.03).Our comprehensive, personalized method for cardiovascular risk prevention in people at high risk appears feasible in general practice. The improvement in the global cardiovascular risk profile was associated with a better prognosis.

A systemic inflammatory response is observed after cardiopulmonary resuscitation. We investigated two novel inflammatory markers, pentraxin 3 (PTX3) and soluble suppression of tumorigenicity 2 (sST2), in comparison with the classic high-sensitivity C-reactive protein (hsCRP), for prediction of early multiple organ dysfunction syndrome (MODS), early death, and long-term outcome after out-of-hospital cardiac arrest.PTX3, sST2, and hsCRP were assayed at ICU admission and 48 h later in 278 patients. MODS was defined as the 24 h non-neurological Sequential Organ Failure Assessment (SOFA) score ≥12. Intensive care unit (ICU) death and 12-month Cerebral Performance Category (CPC) were evaluated.In total, 82% of patients survived to ICU discharge and 48% had favorable neurological outcome at 1 year (CPC 1 or 2). At ICU admission, median plasma levels of hsCRP (2.8 mg/L) were normal, while levels of PTX3 (19.1 ng/mL) and sST2 (117 ng/mL) were markedly elevated. PTX3 and sST2 were higher in patients who developed MODS (pHigher plasma levels of PTX3 and sST2, but not of hsCRP, at ICU admission were associated with higher risk of MODS and early death.

Laparoscopic cholecystectomy (LC) is the gold standard technique for gallbladder diseases in both acute and elective surgery. Nevertheless, reports from national surveys still seem to represent some doubts regarding its diffusion. There is neither a wide consensus on its indications nor on its possible related morbidity. On the other hand, more than 25 years have passed since the introduction of LC, and we have all witnessed the exponential growth of knowledge, skill and technology that has followed it. In 1995, the EAES published its consensus statement on laparoscopic cholecystectomy in which seven main questions were answered, according to the available evidence. During the following 20 years, there have been several additional guidelines on LC, mainly focused on some particular aspect, such as emergency or concomitant biliary tract surgery. In 2012, several Italian surgical societies decided to revisit the clinical recommendations for the role of laparoscopy in the treatment of gallbladder diseases in adults, to update and supplement the existing guidelines with recommendations that reflect what is known and what constitutes good practice concerning LC.

Background: Clinical trials emphasize mortality and morbidity endpoints. Aims: To bring relevance of trial results to point of care by examining the prognostic and therapeutic value of individual signs and symptoms (S&S). Methods: We analysed data from 5010 patients with stable chronic heart failure and left ventricular dysfunction who were participants in the Val-HeFT study. Individual S&S were stratified by severity. Treatment differences between valsartan and placebo were analysed by S&S strata at baseline and endpoint by logistical regression, and an overall S&S score by ANCOVA. Hazard ratios of S&S strata were calculated for mortality and heart failure hospitalisation. Prognostic contributions of S&S to other variables were determined by multivariate analysis. Results: At endpoint, there were significantly fewer valsartan and more placebo patients with severe symptoms. Over time, improvement in the S&S overall score was significantly more favourable for valsartan than placebo. S&S strata were significantly predictive of risk for hospitalisation and death. S&S were each independent and incremental predictors of mortality compared to other variables. Symptom strata separated out moderately symptomatic patients with a mortality rate which was intermediate between that for NYHA Class II and III. Conclusion: Risk stratification of individual S&S defined prognosis, identified patients with an intermediate mortality between Class II and III, and treatment benefits of valsartan over placebo.

Endothelin is elevated in heart failure and contributes to neurohormonal activation, hemodynamic deterioration, and cardiovascular remodeling. Here, we examined its prognostic value in a large population of patients with chronic heart failure.Big endothelin-1 (Big ET-1) and 4 other neurohormones were measured at study entry in 2359 patients enrolled in the Valsartan Heart Failure Trial (Val-HeFT) and their concentrations related to outcome over a median follow-up of 23 months. Baseline concentration of Big ET-1 (median 0.80 pmol/L) was proportional to severity of disease (New York Heart Association class, left ventricular structure and function). High circulating concentrations of brain natriuretic peptide (BNP), creatinine and bilirubin, advanced New York Heart Association class, elevated body mass index, and the presence of atrial fibrillation were independently associated to higher concentrations of Big ET-1. Big ET-1 (ranking second just behind BNP among neurohormonal factors) was an independent predictor of outcome defined as all-cause mortality (hazard ratio 1.49, 95% CI 1.20-1.84, P = .0003) or the combined endpoint of mortality and morbidity (hazard ratio 1.43, 95% CI 1.20-1.69, P.0001) and provided incremental prognostic value compared with BNP.In a large population of patients with symptomatic heart failure, the circulating concentration of Big ET-1, a precursor of the paracrine and bioactive peptide ET-1, was an independent marker of mortality and morbidity. In this setting, BNP remained the strongest neurohormonal prognostic factor.

Objectives: Post-operative atrial fibrillation (POAF) is a common complication after cardiac surgery and predicts increased morbidity and mortality. Identification of patients at high risk of POAF with the help of circulating biomarkers may enable early preventive treatment but data are limited, especially in contemporary surgical patients. Methods: Plasma concentrations of N-terminal probrain natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin T (hs-cTnT) and C-reactive protein (hsCRP) were measured at enrollment, on the morning of cardiac surgery, at end-surgery, and 2 days post-surgery in 562 patients undergoing cardiac surgery, randomized to perioperative supplementation with oral fish oil or placebo in the international clinical trial Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation trial (OPERA). The primary endpoint was incident POAF lasting ≥ 30 seconds, centrally adjudicated and confirmed electrocardiographically. Results: Higher levels of NT-proBNP and hs-cTnT before surgery were associated with older age, renal or cardiac dysfunction and higher EuroSCORE, while hsCRP correlated positively with BMI. NT-proBNP (2172 [1238-3758] ng/L) and hsCRP (118 [75-165] mg/L) peaked on post-operative day 2, while hs-cTnT peaked at the end of surgery (373 [188-660] ng/L). Fish oil supplementation did not alter the time course of the cardiac or inflammatory biomarkers. Concentrations of the 3 biomarkers, on the morning of surgery, or changes in their level between morning of surgery and post-surgery, were not significantly associated with POAF after adjustment for clinical and surgical characteristics. Conclusions: Among patients undergoing cardiac surgery, cardiac markers are related to clinical and surgical characteristics, have different perioperative time courses but do not help in predicting the risk of POAF.

Aims of the present study were (1) to confirm the prognostic role of anemia in patients with heart failure (HF) and (2) to analyze this aspect in relatively unselected patients with HF monitored prospectively in a community setting (IN-CHF), and in patients selected for enrollment into the Valsartan Heart Failure Trial (Val-HeFT).In both Val-HeFT and IN-CHF Registry, anemia was defined as a hemoglobin (Hb) levelor = 11 g/dL in women andor = 12 g/dL in men. Of the 2411 patients of the IN-CHF Registry, 15.5% had anemia, whereas in the 5010 patients of the Val-HeFT trial, the prevalence was 9.9%. In the IN-CHF registry, 1-year all-cause mortality was significantly higher in anemic patients (25.9%) than in patients without anemia (13.2%) (P.0001). The association of anemia with mortality was confirmed by the multivariable analysis (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.20-1.97). The risk of death decreased by 9.7% for each gram of Hb. The Val-HeFT trial showed an all-cause mortality rate for anemic patients of 29.6% over a mean follow-up period of 22.4 months versus 18.5% (P.0001) in patients without anemia. After adjustment, anemia retained its negative independent prognostic role (HR 1.26, 95% CI 1.04-1.52). When Hb was considered as a continuous variable, the risk of death decreased by 7.8% for each gram of Hb.Anemia was confirmed to be an independent negative prognostic factor in patients with HF. This finding is consistent in 2 different clinical contexts, a controlled trial and a registry in clinical practice, in which patient characteristics and outcome are largely different.

The objective of this study was to investigate the effect of trapidil 200 mg t.i.d. in preventing the occurrence of death, of myocardial infarction and the need for repeat revascularization at 12 months after balloon PTCA with or without stenting. Coronary restenosis after stenting is still a major drawback of percutaneous coronary interventions (PCI) for 30-40% of patients. Trapidil has been shown to prevent restenosis after PTCA. Eligible patients were randomized to placebo or oral trapidil 200 mg t.i.d. at least 48 hr before PCI and continuing 6 months after a successful balloon angioplasty or stent implantation. Aspirin was given to all patients, and ticlopidine 250 mg b.i.d. to those who received a stent for 4 weeks. In a randomized subgroup of 216 patients, quantitative coronary angiography was performed also at 6-month follow-up. Out of the 933 patients enrolled, primary endpoint incidence was 20.3% in trapidil and 18.0% in placebo (P = 0.37). When recurrence or deterioration of angina was added to the combined endpoint, incidence was 27.4% in trapidil and 23.0% in placebo (P = 0.12). Restenosis rate in patients with 6-month angiography was 25.0% in trapidil arm vs. 30.1% in placebo (P = 0.43). Stent restenosis rate was similar in patients randomized to trapidil or placebo (30.2% vs. 23.8%, respectively; P = 0.44), while in patients treated with balloon angioplasty, it was lower in trapidil (17.1%) than in placebo (40.0%; P = 0.03). Oral trapidil 200 mg t.i.d. for 6 months in addition to aspirin did not influence the occurrence of major cardiac events after coronary angioplasty with or without stenting. In a prespecified subgroup of 191 patients treated with balloon angioplasty only, trapidil reduced angiographic restenosis.

Although risk assessment charts have been proposed to identify patients at high cardiovascular risk, in everyday practice general practitioners (GPs) often use their knowledge of the patients to estimate the risk subjectively.A cross-sectional study aimed to describe how GPs perceive, qualify and grade cardiovascular risk in everyday practice.General practitioners had to identify in a random sample of 10% of their contacts the first 20 consecutive patients perceived as being at cardiovascular risk. For each patient essential data were collected on clinical history, physical examination and laboratory tests, for the qualification of risk. At the end of the process GPs subjectively estimated the overall patient's level of risk. General practitioners grading was compared with the risk estimate from a reference chart.Over a mean time of 25 days 3120 patients perceived as being at cardiovascular risk were enrolled. According to the inclusion scheme each GP had contact with more than 200 patients at cardiovascular risk every month. Thirty percent of these patients had atherosclerotic diseases. Up to 72% of patients without any history of atherosclerotic diseases but perceived to be at risk could be classified according to a reference chart as being at moderate to very high risk. Comparing GPs' grading of risk with a chart estimate there was agreement in 42% of the cases. Major determinants of GPs' underestimation of risk were age, sex and smoking habits, while obesity and family history were independently associated with overestimation.On the basis of their perception GPs properly identify patients at cardiovascular risk in the majority of cases. General practitioners subjective grading of risk level only partially agreed with that given by a chart.

Aims Plasma levels of individual neurohormones (NH) have been proposed as reliable indicators for risk stratification of patients with heart failure (HF). Mainly because of small sample size, the predictive value of different NH has never been compared, while taking into account demographic, clinical and echocardiographic markers of risk in HF. Methods and results Plasma brain natriuretic peptide (BNP), norepinephrine (NE), renin activity (PRA), aldosterone (aldo) and endothelin were measured in 4300 patients before randomization in Val-HeFT. Univariate and multivariate Cox proportional hazard analyses were performed to investigate the relationship between NH and two primary study outcomes, mortality and combined mortality and morbidity (M/M). Higher baseline values for all NH were related to mortality and M/M, with univariate hazard ratios ranging from 1.13 \[95% CI 0.99–1.30\] (aldo) to 2.47 \[2.13–2.87\] (BNP) for mortality, and from 1.24 \[1.11–1.39\] (aldo) to 2.56 \[2.28–2.89\] (BNP) for M/M. In multivariate analyses, BNP had the strongest association with outcome, followed by NE and PRA. Patients with more activation of renin-angiotensin-aldosterone system tended to show greater benefit from valsartan; but the trend was not statistically significant. Conclusion All the NHs evaluated in 4300 patients with stable moderate to severe HF were found to be significant markers of outcome, despite therapy with ACEi, BB and randomization to an angiotensin receptor blocker or placebo. Several of these markers have been implicated as contributors to progression of HF, but BNP, which is thought to be protective, was the most powerful indicator for poor outcome.

Background: Outdoor air pollution is hazardous to human pulmonary health. Airway inflammation is an important cause of bronchial hyperresponsiveness. Information is not univocal about the potential effects of prolonged exposure to environmental air pollutants on lung function. Objectives: A cross-sectional study was performed to assess bronchial responsiveness to methacholine in children living in an air-polluted area. Afterwards, the same study protocol was repeated in children of similar age living in mountain valleys with virtually no air pollution. Methods: Every child underwent a lung function test, skin tests to common allergens, total serum levels of IgE, and a challenge to methacholine at increasing doses (PD20 FEV1). Subjects were 246 children 11–12 years old living in an air-polluted area, and 285 children 11–13 years old living in mountain valleys. Respectively, 156 and 161 were negative to skin tests and had serum total IgE Results: Lung function data, adjusted for the effect of potential confounders showed significantly lower FVC, and even more so FEV1, in the children from the polluted area. After the exclusion of subjects with positive skin tests and serum total IgE >100 IU/ml and those with history of asthma or respiratory disorders, there were higher percentages of positive responses in the challenge to methacholine in children from the polluted area (28.9 vs. 15.5%, p < 0.001). Conclusions: These data may corroborate the possible importance of long exposure to air pollutants on the prevalence of bronchial aspecific hyperresponsiveness in otherwise normal children.

Aims To predict the long-term left ventricular volume index early after myocardial infarction and to investigate the relationship between long-term left ventricular dilatation risk and clinical outcome.Methods and Results By applying a previously developed dilatation model, we predicted the 6-month left ventricular volume index early after myocardial infarction (median 9 days) in 13 679 GISSI-3 patients, to identify patients at high risk of long-term left ventricular dilatation. The left ventricular systolic and diastolic volume indexes at 6 months were predicted with r=0.72 and r=0.68. respectively. in the subgroup of patients in whom a pre-discharge echo was available (n=7842). Patients predicted to be at risk for long-term left ventricular dilatation had an increased risk of mortality (R.R. 1.87. 95% CI: 1.48 to 2.36) and heart failure at 6 months (RR 2.59, 95% CI:2.04 to 3.28), but no increased risk of reinfarction at 6 months (RR 1.12, 95% CI: 0.87 to 1.45) or of angina pectoris (RR 1.07, 95% CI: 0.95 to 1.20).Conclusion Our prediction of long-term left ventricular dilatation, obtained by applying our new dilatation model in over 13 000 GISSI-3 patients, correlated well with mortality and heart failure after myocardial infarction, Therefore, our new dilatation model may contribute to more efficient risk stratification early after myocardial infarction. (C) 2001 The European Society of Cardiology.

Background The kynurenine pathway ( KP ) is the major route of tryptophan ( TRP ) catabolism and is activated by inflammation and after cardiac arrest in animals. We hypothesized that the KP activation level correlates with severity of post–cardiac arrest shock, early death, and long‐term outcome. Methods and Results Plasma was obtained from 245 patients enrolled in a prospective multicenter observational study in 21 intensive care units in Finland. Time to return of spontaneous circulation, lowest systolic arterial pressure, and bicarbonate during the first 24 hours were collected. A cerebral performance category of 3 to 5 defined 12‐month poor outcome. Plasma TRP and KP metabolites, kynurenine ( KYN ), kynurenic acid, 3‐hydroxyanthranilic acid, and the ratio of KYN to TRP were measured by liquid chromatography and mass spectrometry. All KP metabolites at intensive care unit admission were significantly higher in cardiac arrest patients with a nonshockable rhythm compared to those with a shockable rhythm, and kynurenic acid and 3‐hydroxyanthranilic acid correlated with time to return of spontaneous circulation . Patients with higher levels of KYN , KYN to TRP , kynurenic acid , and 3‐hydroxyanthranilic acid had lower 24‐hour systolic arterial pressure and bicarbonate. All KP metabolites and the ratio of KYN to TRP , but not TRP , were significantly higher in patients who died in the intensive care unit in comparison to those who survived. Multivariable logistic regression showed that high kynurenic acid (odds ratio: 1.004; 95% confidence interval: 1.001 to 1.008; P =0.014), and 3‐hydroxyanthranilic acid ( odds ratio: 1.011; 95% confidence interval: 1.001 to 1.022; P =0.03) were independently associated with 12‐month poor outcome and significantly improved risk reclassification. Conclusions KP is activated early after cardiac arrest and is associated with severity of post– cardiac arrest shock, early death, and poor long‐term outcome.

Objectives: Adiponectin has insulin-sensitizing, anti-inflammatory and anti-atherogenic properties. There are few and controversial data on the role of ADIPOQ variants in heart failure (HF) pathogenesis. We planned this large association study to investigate the potential association of four selected ADIPOQ polymorphisms with HF in a population of Italian origin. Methods: We genotyped 1173 cases with symptomatic HF and 1136 controls for alleles rs17300539, rs266729, rs1501299 and rs2241766. Cases were patients enrolled in the GISSI-Heart Failure genetic sub-study, with a long-term follow up (median 3.9 years). Controls were blood donors with no history of diabetes or cardiovascular disease (CVD). Genotype and allele frequencies of the four single nucleotide polymorphisms (SNPs) were compared between the two groups. Results: Clinical characteristics were significantly different between HF patients and controls. No significant differences were reported in the allelic and genotypic distribution, with the exception of rs266729 G allele, which showed a significant association with an increased risk of HF [odds ratio (OR) = 1.26; 95% confidence interval (CI) = 1.07–1.48; p = 0.006). We divided the GISSI-HF population according to HF etiology (ischemic and nonischemic) and presence of diabetes. For rs266729 G allele, a significant association with HF was confirmed in both ischemic (OR = 1.29; 95% CI = 1.06–1.56; p = 0.009) and nonischemic patients (OR = 1.2; 95% CI = 1.02–1.42; p = 0.03) as well as in nondiabetic patients (OR = 1.25; 95% CI = 1.05–1.49; p = 0.012). rs2241766 G allele showed a significant reduction of risk of HF in nonischemic (OR = 0.77; 95% CI = 0.62–0.95; p = 0.02) and diabetic patients (OR = 0.62; 95% CI = 0.45–0.84; p = 0.0025). Conclusions: We confirm the association between rs266729 G allele and an increased risk of HF and between rs2241766 G allele and decreased risk of HF. Our study extends the knowledge on the influence of ADIPOQ variants on CVD.

Background There is little epidemiologic information from large multicenter databases on sustained monomorphic ventricular tachycardia occurring after the initial 48 hours of myocardial infarction. Methods We reassessed its incidence and short-term prognosis in 16,842 patients with a definite myocardial infarction enrolled in the Gruppo Italiano per lo Studio della Soprovvivenza nell'Infarto Miocardico (GISSI-3) trial. Results The incidence rate of late sustained ventricular tachycardia by 6 weeks was around 1%. Older age, a history of hypertension, diabetes, and myocardial infarction, nonadministration of lytic therapy, Killip class >I, ≥6 leads with ST-segment elevation, higher heart rate, and bundle branch block on admission were significantly more frequent among patients with than without late sustained ventricular tachycardia. Patients with ventricular tachycardia had a more complicated course in-hospital and posthospital to 6 weeks than the reference group did. The arrhythmia was associated with a significant excess of pump failure, atrial flutter-fibrillation, asystole, atrioventricular block, ventricular fibrillation within the first 48 hours of myocardial infarction, and recurrent ischemic events. Larger left ventricular end-systolic volumes and lower ejection fractions were more frequent among ventricular tachycardia patients than in the reference group by 6 weeks. Death rates by 6 weeks were 35% for patients with ventricular tachycardia and 5% for those without the arrhythmia. Irrespective of the stratification of patients by site and type of infarct and presence/absence of bundle branch block, the occurrence of the arrhythmia was associated with reduced 6-week survival. Conclusion In a proportional hazard regression model late sustained ventricular tachycardia was retained as a strong, independent predictor of 6-week mortality after myocardial infarction (hazard ratio 6.13, 95% confidence interval 4.56-8.25). (Am Heart J 2001;142:87-92.)

Background The aim of this study was to evaluate the prognostic significance of the pressure-rate product (PRP) obtained during exercise stress testing and of its change from rest to maximal exercise (dPRP) in a population of survivors of acute myocardial infarction treated with thrombolytic agents. Methods And Results Survivors of acute myocardial infarction (n = 6251) from the GISSI-2 database, who underwent a maximal symptom-limited exercise test with either bicycle ergometer or treadmill, were followed up for 6 months. PRP and dPRP values were dichotomized (≤21,700 and >21,700, ≤11,600 and >11,600, respectively) and analyzed in a multivariate Cox model individually and simultaneously with other ergometric variables. Six-month mortality rate was 0.8% in the high PRP group and 2.0% in the low PRP group. Low PRP was an independent predictor of 6-month mortality rate (relative risk [RR] 1.97, 95% confidence interval [CI] 1.24 to 3.13). Patients with low dPRP had mortality rates higher than patients with high dPRP (2.1% vs 0.8%). At the multivariate analysis, low dPRP showed negative predictive value (RR 1.97, 95% CI 1.23 to 3.16). A further multivariate analysis was performed with PRP and dPRP, also adjusting for low work capacity, abnormal systolic blood pressure response to exercise, and symptomatic-induced ischemia. The results showed that low work capacity, low PRP, and symptomatic exercise-induced ischemia were still significantly associated with higher 6-month mortality rate ( P = .04, .02, and .05; RR = 1.68, 1.71, and 1.78 respectively). Conclusions PRP is a predictive index to assess prognosis in survivors of acute myocardial infarction treated with thrombolytic agents able to perform an exercise test after acute myocardial infarction, but its usefulness appears to be limited, considering that these patients were at low risk. (Am Heart J 1999;137:443-52.)

Background: in acute inferior myocardial infarction (AIMI), the ST depression from V1 to V4 has been the subject of many papers, while the ST changes in other leads, their association, and the right ventricular (RV) involvement have been studied less. Hypothesis: This study was performed to contribute to the meaning of the ST changes and RV involvement in AIMI. Methods: Seventy-one patients, admitted within 6 h from symptom onset, all thrombolysed, were enrolled. We classified them according to ST patterns and RV involvement. We divided the right coronary artery into three segments, considering the origin of RV branch and the crux as dividing points. We established a coronary score attributing 2 points to each terminal branch. Comparisons were performed between the electrocardiographic (ECG) findings at onset, the creatine phosphokinase (CPK) peaks, the radionuclide ejection fractions, and the coronary angiographies. Results: We found that the ST changes give indications regarding the site, extension, and extent of AIMI; RV involvement can mask posterior extension, points to the right coronary as the culprit vessel (100%), and, with high probability, indicates the proximal segment as the site of the lesion; the ECG signs of isolated AIMI indicate a peripheral obstruction; and a collateral circulation may appear relatively early. Conclusions: Our findings prove the diagnostic and prognostic value of the ST changes and RV involvement at the onset of AIMI and suggest that the higher in-hospital mortality and complication rates found with RV involvement and reported in the literature are related more to posterior extension, masked by RV involvement than to this involvement per se. Furthermore, these findings prove the clinical value of our classification of the AIMIs and distinction in segments of the right coronary artery.

Background Few data on the thromboembolic (TE) risk of paroxysmal and persistent atrial fibrillation (AF) are available. This study aimed to assess the incidence of TE events in paroxysmal and persistent AF. Methods We performed a subset post hoc analysis of 771 patients with paroxysmal and 463 with persistent AF enrolled in the multicenter, prospective, randomized, double-blind, placebo-controlled GISSI-AF trial - comparing the efficacy of valsartan versus placebo in preventing AF recurrences – where the choice of antithrombotic treatment was left to the judgment of the referring physician. TE and major outcome events were centrally validated. AF recurrences were detected by frequent clinic visits and a transtelephonic monitoring device with weekly and symptomatic transmissions. Results Eighty-five percent of patients had a history of hypertension, and the 7.7% had heart failure, left ventricular dysfunction, or both. The mean CHADS2 score was 1.41±0.84. TE and major bleeding events were observed at a low incidence among the overall population at 1-year follow-up (0.97% and 0.81%, respectively). The univariate and multivariable analyses revealed no statistically significant differences in the incidence of TE, major bleeding events or mortality in paroxysmal and persistent AF patients. TE events were more common among women than men (p=0.02). The follow-up examination showed under- or overtreatment with warfarin in many patients, according to guideline suggestions. Warfarin was more frequently prescribed to patients with persistent AF (p

Background— We developed a prognostic model to assess the risk of all-cause mortality in patients with chronic heart failure. Methods and Results— We examined 6975 patients with chronic heart failure enrolled in the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico-Heart Failure (GISSI-HF) trial (3.9 years follow-up). Multivariable Cox regression models were developed to predict mortality (1969 deaths). By stepwise selection, the full final model included 25 predictors. A reduced model, considering the most significant variables ranked according to the Wald χ 2 ( P Conclusions— In a large contemporary population with chronic heart failure, this model offers good ability to assess the risk of death, confirming most of the risk factors that have emerged in recent trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00336336.

Aims To investigate the prognostic value of autonomic variables in patients with symptomatic chronic heart failure (HF) treated according to current recommendations. Methods and results We analysed 24 h time-domain [standard deviation of all normal-to-normal RR intervals (SDNN)], frequency-domain [very low frequency and low frequency power (VFLP and LFP)], and non-linear [detrended fluctuation analysis (DFA)] heart rate variability, deceleration capacity (DC), and heart rate turbulence (HRT) in 388 sinus rhythm HF patients enrolled in the GISSI-HF Holter substudy [82% males, age 65 ±10 years, New York Heart Association (NYHA) functional class III–IV 20%, left ventricular ejection fraction (LVEF) 33 ±8%]. Cardiovascular (CV) mortality and combined sudden death + implantable cardioverter defibrillator (ICD) discharge were assessed as a function of continuous variables in the entire population and in patients with LVEF >30% in univariate and multivariable Cox proportional hazards models. After a median of 47 months, 57 patients died of CV causes and 47 experienced the arrhythmic endpoint. For CV mortality, VLFP, LFP, and turbulence slope (TS) improved predictive discrimination (c-index) and risk classification [integrated discrimination improvement (IDI)] when added to clinical variables [age ≥70 years, LVEF, non-sustained ventricular tachycardia (NSVT), serum creatinine], while for arrhythmic mortality although the c-index increased in all three autonomic markers, the results of the IDI were statistically significant only for TS when added to NSVT, serum creatinine, and ischaemic aetiology. In 194 patients with LVEF >30% (20 arrhythmic events), the hazard ratio of an impaired TS (30% at increased arrhythmic risk. Trial registration NCT00336336