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Randomized cardiovascular trials aimed to reduce the excessive residual risk in high‐risk patients through a more aggressive low‐density lipoprotein‐cholesterol control or targeting triglycerides or high‐density lipoprotein‐cholesterol levels have shown a null or, at best, limited incremental benefit. In some cases, the treatment produced meaningful effects only in study subgroups. As a consequence, some compounds were withdrawn (e.g., nicotinic acid derivatives and cholesteryl ester transfer protein inhibitors), whereas others (fibrates) are utilized with reluctance due to the low level of evidence‐based data. By reviewing these trials analytically, we identified a common feature that might explain their meager results: most of them involved patients generically at high cardiovascular risk with normal or near normal lipid levels and not patients with “true” dyslipidemia, who would receive the treatment if it were part of usual care. These observations may warrant re‐examining a central criterion of pragmatism, eligibility, in the outline of forthcoming cardiovascular trials with novel lipid‐modifying drugs.

Aims: Exercise-derived parameters, specifically peak exercise oxygen uptake (peak VO2) and minute ventilation/carbon dioxide relationship slope (VE/VCO2 slope), have a pivotal prognostic value in heart failure (HF). It is unknown how the prognostic threshold of peak VO2 and VE/VCO2 slope has changed over the last 20 years in parallel with HF prognosis improvement. Methods and results: Data from 6083 HF patients (81% male, age 61 ± 13 years), enrolled in the MECKI score database between 1993 and 2015, were retrospectively analysed. By enrolment year, four groups were generated: group 1 1993–2000 (n = 440), group 2 2001–2005 (n = 1288), group 3 2006–2010 (n = 2368), and group 4 2011–2015 (n = 1987). We compared the 10-year survival of groups and analysed how the overall risk (cardiovascular death, urgent heart transplantation, or left ventricular assist device implantation) changed over time according to peak VO2 and VE/VCO2 slope and to major clinical and therapeutic variables. At 10 years, a progressively higher survival from group 1 to group 3 was observed, with no further improvement afterwards. A 20% risk for peak VO2 15 mL/min/kg (95% confidence interval 16–13), 9 (11–8), 4 (4–2) and 5 (7–4) was observed in group 1, 2, 3, and 4, respectively, while the VE/VCO2 slope value for a 20% risk was 32 (37–29), 47 (51–43), 59 (64–55), and 57 (63–52), respectively. Conclusions: Heart failure prognosis improved over time up to 2010 in a HF population followed by experienced centres. The peak VO2 and VE/VCO2 slope cut-offs identifying a definite risk progressively decreased and increased over time, respectively. The prognostic threshold of peak VO2 and VE/VCO2 slope must be updated whenever HF prognosis improves.

AIMS Mineralocorticoid receptor antagonists (MRAs) have been demonstrated to improve outcomes in reduced ejection fraction heart failure (HFrEF) patients. However, MRAs added to conventional treatment may lead to worsening of renal function and hyperkalaemia. We investigated, in a population-based analysis, the long-term effects of MRA treatment in HFrEF patients. METHODS AND RESULTS We analysed data of 6046 patients included in the Metabolic Exercise Cardiac Kidney Index score dataset. Analysis was performed in patients treated (n = 3163) and not treated (n = 2883) with MRA. The study endpoint was a composite of cardiovascular death, urgent heart transplantation, or left ventricular assist device implantation. Ten years' survival was analysed through Kaplan-Meier, compared by log-rank test and propensity score matching. At 10 years' follow-up, the MRA-untreated group had a significantly lower number of events than the MRA-treated group (P

Aims Risk stratification in heart failure (HF) is crucial for clinical and therapeutic management. A multiparametric approach is the best method to stratify prognosis. In 2012, the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score was proposed to assess the risk of cardiovascular mortality and urgent heart transplantation. The aim of the present study was to compare the prognostic accuracy of MECKI score to that of HF Survival Score (HFSS) and Seattle HF Model (SHFM) in a large, multicentre cohort of HF patients with reduced ejection fraction. Methods and results We collected data on 6112 HF patients and compared the prognostic accuracy of MECKI score, HFSS, and SHFM at 2- and 4-year follow-up for the combined endpoint of cardiovascular death, urgent cardiac transplantation, or ventricular assist device implantation. Patients were followed up for a median of 3.67 years, and 931 cardiovascular deaths, 160 urgent heart transplantations, and 12 ventricular assist device implantations were recorded. At 2-year follow-up, the prognostic accuracy of MECKI score was significantly superior [area under the curve (AUC) 0.781] to that of SHFM (AUC 0.739) and HFSS (AUC 0.723), and this relationship was also confirmed at 4 years (AUC 0.764, 0.725, and 0.720, respectively). Conclusion In this cohort, the prognostic accuracy of the MECKI score was superior to that of HFSS and SHFM at 2- and 4-year follow-up in HF patients in stable clinical condition. The MECKI score may be useful to improve resource allocation and patient outcome, but prospective evaluation is needed.

On-pump cardiac surgery may trigger inflammation and accelerate platelet cyclooxygenase-1 renewal, thereby modifying low-dose aspirin pharmacodynamics. Thirty-seven patients on standard aspirin 100 mg once-daily were studied before surgery and randomized within 36 hours postsurgery to 100 mg once-daily, 100 mg twice-daily, or 200 mg once-daily for 90 days. On day 7 postsurgery, immature and mature platelets, platelet mass, thrombopoietin, glycocalicin, leukocytes, C-reactive protein, and interleukin-6 significantly increased. Interleukin-6 significantly correlated with immature platelets. At day 7, patients randomized to 100 mg once-daily showed a significant increase in serum thromboxane (TX)B2 within the 24-hour dosing interval and urinary TXA2 metabolite (TXM) excretion. Aspirin 100 mg twice-daily lowered serum TXB2 and prevented postsurgery TXM increase (P < 0.01), without affecting prostacyclin metabolite excretion. After cardiac surgery, shortening the dosing interval, but not doubling the once-daily dose, rescues the impaired antiplatelet effect of low-dose aspirin and prevents platelet activation associated with acute inflammation and enhanced platelet turnover.

Aims: The use of β-blockers represents a milestone in the treatment of heart failure with reduced ejection fraction (HFrEF). Few studies have compared β-blockers in HFrEF, and there is little data on the effects of different doses. The present study aimed to investigate in a large database of HFrEF patients (MECKI score database) the association of β-blocker treatment with a composite outcome of cardiovascular death, urgent heart transplantation or left ventricular assist device implantation, addressing the role of β-selectivity and dosage regimens. Methods and results: In 5242 HFrEF patients, we investigated the role of: (i) β-blocker treatment vs. non-β-blocker treatment, (ii) β1-/β2-receptor-blockers vs. β1-selective blockers, and (iii) daily β-blocker dose. Patients were followed for 3.58 years, and 1101 events (18.3%) were observed; 4435 patients (86.8%) were on β-blockers, while 807 (13.2%) were not. At 5 years, β-blocker-patients showed a better outcome than non-β-blocker-subjects [hazard ratio (HR) 0.48, P 2 5 mg carvedilol equivalent daily dose, n = 1005) patients than in both medium dose (12.5–25 mg, n = 1431) and low dose (

Aims Obesity has been found to be protective in heart failure (HF), a finding leading to the concept of an obesity paradox. We hypothesized that a preserved cardiorespiratory fitness in obese HF patients may affect the relationship between survival and body mass index (BMI) and explain the obesity paradox in HF. Methods and results A total of 4623 systolic HF patients (LVEF 31.5 ± 9.5%, BMI 26.2 ± 3.6 kg/m2) were recruited and prospectively followed in 24 Italian HF centres belonging to the MECKI Score Research Group. Besides full clinical examination, patients underwent maximal cardiopulmonary exercise test at study enrolment. Median follow-up was 1113 (553–1803) days. The study population was divided according to BMI ( 30 to ≤35 kg/m2) and predicted peak oxygen consumption (peak VO2, 80%). Study endpoints were all-cause and cardiovascular deaths including urgent cardiac transplant. All-cause and cardiovascular deaths occurred in 951 (28.6%, 57.4 per person-years) and 802 cases (17.4%, 48.4 per 1000 person-years), respectively. In the high BMI groups, several prognostic parameters presented better values [LVEF, peak VO2, ventilation/carbon dioxide slope, renal function, and haemoglobin (P < 0.01)] compared with the lower BMI groups. Both BMI and peak VO2 were significant positive predictors of longer survival: both higher BMI and peak VO2 groups showed lower mortality (P < 0.001). At multivariable analysis and using a matching procedure (age, gender, LVEF, and peak VO2), the protective role of BMI disappeared. Conclusion Exercise tolerance affects the relationship between BMI and survival. Cardiorespiratory fitness mitigates the obesity paradox observed in HF patients.

Objectives We investigated the use of a 3-hr treatment with hemodiafiltration, initiated soon after emergency or urgent coronary angiography in acute coronary syndrome (ACS) patients with associated severe renal and cardiac dysfunction. Background Patients with ACS and severe combined renal and cardiac dysfunction have a particularly high mortality risk. In them, the ideal strategy to both optimize treatment of coronary disease and minimize renal injury risk is currently unknown. Methods This was an interventional study. ACS patients (STEMI and NSTEMI) with associated severe renal (eGFR ≤30 ml/min/1.73 m2) and cardiac (LVEF ≤40%) dysfunction, admitted at La Spezia Hospital

Objective To investigate the impact of intermittent interleukin-2 (IL-2) plus combination antiretroviral therapy (cART) on HIV-1 entry co-receptor use. Methods Primary HIV-1 isolates were obtained from 54 HIV-1-positive individuals at baseline and after 12 months using co-cultivation of peripheral blood mononuclear cells (PBMC) with activated PBMC of HIV-negative healthy donors. HIV-1 co-receptor use was determined on U87-CD4 cells. Results Fourteen out of the 21 (67%) IL-2-treated individuals harbouring a primary CCR5-dependent (R5) HIV-1 isolate at baseline confirmed an R5 virus isolation after 12 months in contrast to 3 out of 7 (43%) of those receiving cART only. After 12 months, only 1 R5X4 HIV-1 isolate was obtained from 21 cART+IL-2-treated individuals infected with an R5 virus at entry (5%) vs. 2/7 (29%) patients receiving cART alone, as confirmed by a 5-year follow-up on some individuals. Conclusions Intermittent IL-2 administration plus cART may prevent evolution towards CXCR4 usage in individuals infected with R5 HIV-1.

Background: Oxidative stress is increased in the failing heart, and this might contribute to the pathogenesis of myocardial remodelling and heart failure (HF). Aim: To identify the oxidized proteins in plasma of chronic HF patients and to evaluate their possible role in endothelial damage. Methods: Plasma levels of oxidized proteins were measured by immunoassay and by analysis in albumin and immunoglobulin depleted plasma using a proteomic approach, in 40 HF patients and in 20 age-matched normal subjects. Analysis of the effects of proteins oxidized in vitro on human endothelial cell (EC) viability was also performed. Results: Plasma levels of oxidized proteins were significantly higher in HF patients than in controls (p < 0.01). We identified two proteins, α-1-antitrypsin and fibrinogen, which underwent oxidation. Oxidation of α-1-antitrypsin resulted in loss of its protease inhibitor activity, thus leading to EC death in the presence of elastase. Fibrinogen, when oxidized, became otherwise cytotoxic and induced apoptosis in EC. Conclusions: This study shows that plasma levels of oxidized proteins are increased in HF, and permitted the identification of two proteins, namely α-1-antitrypsin and fibrinogen, which underwent oxidation. In vitro results highlighted the potential role of oxidized proteins in the EC damage that occurs in HF.

CYP1A1 is involved in the metabolism of benzopyrene, a suspected lung carcinogen; it is therefore conceivable that genetically determined variations in its activity modify individual susceptibility to lung cancer. The role of the CYP1A1 MspI polymorphism in lung cancer has been widely studied but has not been fully clarified. We have included 2,451 cases and 3,358 controls in a pooled analysis of 22 case-control studies on CYP1A1 and lung cancer risk. We found a clear association between the CYP1A1 homozygous MspI restriction fragment length polymorphism (RFLP) and lung cancer risk in Caucasians (age- and gender-adjusted odds ratio = 2.36; 95% confidence interval 1.16-4.81); other associations were weaker or not statistically significant. The association with the homozygous variant was equally strong for squamous cell carcinomas and adenocarcinomas among Caucasians. We analyzed the risk by duration of smoking: for Caucasian subjects with the MspI RFLP combined variants (homozygotes plus heterozygotes), the increase in the risk of lung cancer was steeper than among the individuals with the homozygous reference allele. Our analysis suggests that Caucasians with homozygous variant CYP1A1 polymorphism have a higher risk of lung cancer. The data were more consistent among Caucasians, with a strong association between the homozygous variant in both squamous cell carcinomas and adenocarcinomas, and a stronger association in men than in women. The analyses were more inconsistent and failed to reach statistical significance in Asians. This observation might be due to design specificities or unknown effect modifiers in the Asian studies.

Recent studies have demonstrated that the incidence of cardiovascular events occurring with renal transplantation is higher than that in the general population. Renal transplantation modifies the characteristic dyslipidemia of chronic renal failure. In this study the change in lipoprotein and lipid values of 103 transplant recipients after transplantation was investigated. The aim of our work was to examine the short-term and long-term variations in lipid metabolism. The major lipoprotein fractions (VLDL, LDL, HDL) were separated by preparative ultracentrifugation, and TG and cholesterol concentrations were determined in plasma and lipoprotein fractions. Whole plasma apolipoproteins were determined by a rate immunonephelometric technique. In the pretransplant period the patients displayed the typical picture of uremics. After transplantation the most evident alterations in the lipoprotein profile occurred in our case series after 3 mon. The major finding was a 35% reduction in plasma TG. The modifications in the TG-rich lipoproteins of our transplant recipients persisted throughout the observation period. In the initial 3-mon period, total cholesterol remained steady, whereas LDL-cholesterol and total apolipoprotein B showed a significant increase. No significant changes were found in total and transported TG and cholesterol between the 3-mon and the 6-yr values. The substantial stability of cholesterol levels after transplantation and in subsequent reports, as well as a higher incidence of cardiovascular complications, may suggest that the mechanisms responsible for vessel damage must be sought mainly in the structural and physicochemical alterations of the individual lipoprotein fractions or in other risk factors.

Plasma levels of alpha1-antichymotrypsin (ACT) and interleukin-1beta (IL-1beta) were increased in patients with probable Alzheimer's disease (AD). A common polymorphism within ACT and IL-1beta genes affected plasma levels of ACT or IL-1beta, and AD patients with the ACT T,T or IL-1beta T,T genotype showed the highest levels of plasma ACT or IL-1beta, respectively. The concomitant presence of the ACT T,T and IL-1beta T,T genotypes increased the risk of AD (odds ratio: 5.606, confidence interval: 1.654-18.996) and decreased the age at onset of the disease.

Overexpression of the pluripotent cytokine interleukin-1 (IL-1) by microglial cells correlates with formation of neuritic beta-amyloid plaques in Alzheimer's disease (AD). We evaluated polymorphisms in the genes coding for the IL-1alpha, IL-1beta, and IL-1 receptor antagonist cytokines, and tested their association with the occurrence and age at onset of sporadic AD. We found a strong association between the IL-1A T/T genotype and AD onset before 65 years of age (odds ratio, 4.86), with carriers of this genotype showing an onset of disease 9 years earlier than IL-1A C/C carriers. A weaker association with the age at onset was also shown for the IL-1B and IL-1RN genes. These data suggest either a direct effect of the IL-1 gene family, mainly IL-1A, on the clinical onset of AD, or a linkage dysequilibrium with an unknown locus relevant to AD on chromosome 2.

Epidemiology and Medical Statistics Unit, San Raffaele Scientific Institute, Milano, ItalyThe U937-derived chronically HIV-infected U1 cell line and uninfected U937 cell clones wereefficiently lysed by both unstimulated (NK) and IL-2-stimulated (lymphokine-activated killer;LAK) peripheral blood mononuclear cells (PBMC) of healthy HIV-seronegative donors. Pre-treatment of target cells with IFN- down-modulated killing of both U1 cells and two U937cell clones, and up-regulated MHC class I expression. In contrast, TNF- ¼ enhanced the sen-sitivity of infected U1 cells, but not of U937 cell clones to NK/LAK cell lysis. Co-cultivation ofIL-2-stimulated PBMC with U1 cells triggered expression and replication of HIV by cell-cellcontact, and this effect was inhibited by anti-TNF- ¼ antibodies (Ab); virus production waspartially inhibited by zidovudine. Of interest, anti-TNF- ¼ Ab protected U1 cells from LAK cellactivity. Thus, TNF- ¼ can induce HIV expression from chronically infected U1 cells, but alsoplays an important role in sensitizing these cells to lysis.

Summary Background The impact of diet on cow's milk allergy (CMA) duration and whether exposure to residual amounts of cow's milk protein influences the onset of tolerance are unknown. Objective To prospectively assess the dietary factors influencing disease duration in a randomized cohort. Methods We randomly switched the formula of symptomatic patients from the Milan Cow's Milk Allergy Cohort to one of three treatment groups according to the quarterly rotation of rice hydrolysate formula, extensively hydrolysed cow's milk formula and soy-based formula. In this intention-to-treat, randomized analysis, a hazard ratio (HR) estimation model was used to analyse dietary impact on disease duration. Results Seventy-two children aged a mean of 14.1±8.6 months at diagnosis were followed up for a median of 26 months. Fifty-one reached tolerance at a mean of 34.1±15.2 months. The mean duration of disease was 40.2±4.8 months with milk hydrolysate, 24.3±3.6 months with rice and 24.3±2.6 months with soy. Dietary choice independently predicted shorter duration of disease [adjusted HRs 3.09 (P=0.007) for rice, 2.54 (P=0.02) for soy, both against milk hydrolysate]. In 50 children not co-sensitized to soy, diet choice impacted the duration of disease more strongly [adjusted HRs 8.02 (P=0.006) for rice, 6.53 (P=0.015) for soy, both against milk hydrolysate]. Discussion Patients not exposed to cow's milk protein residue achieve cow's milk tolerance earlier than patients who follow an extensively hydrolysed cow's milk diet. This may be due to residual antigenicity in hydrolysed milks. As the effect of dietary intervention is stronger in patients not sensitized to soy, we infer that when atopic disease has progressed to multiple sensitizations, the elimination of allergenic exposure may not be sufficient to reduce the duration of CMA. Cite this as: L. Terracciano, G. R. Bouygue, T. Sarratud, F. Veglia, A. Martelli and A. Fiocchi, Clinical & Experimental Allergy, 2010 (40) 637–642.