Effects of hyperoxemia in patients with sepsis - A post-hoc analysis of a multicentre randomized clinical trial.

BACKGROUND: Administration of supplemental oxygen is a life-saving treatment in critically ill patients. Still, optimal dosing remains unclear during sepsis. The aim of this post-hoc analysis was to assess the association between hyperoxemia and 90-day mortality in a large cohort of septic patients. METHODS: This is a post-hoc analysis of the Albumin Italian Outcome Sepsis (ALBIOS) randomized controlled trial (RCT). Patients with sepsis who survived the first 48 h since randomization were included and stratified into two groups according to their average PaO2 levels during the first 48 h (PaO2 0-48 h). The cut-off value was established at 100 mmHg (average PaO2 0-48 h >100 mmHg: hyperoxemia group; PaO2 0-48h≤100: normoxemia group). The primary outcome was 90-day mortality. RESULTS: 1632 patients were included in this analysis (661 patients in the hyperoxemia group, 971 patients in the normoxemia group). Concerning the primary outcome, 344 (35.4%) patients in the hyperoxemia group vs. 236 (35.7%) in the normoxemia group had died within 90 days from randomization (p = 0.909). No association was found after adjusting for confounders (HR 0.87; CI [95%] 0.736-1.028, p = 0.102) or after excluding patients with hypoxemia at enrollment, patients with lung infection or including post-surgical patients only. Conversely, we found an association between lower risk of 90-day mortality and hyperoxemia in the subgroup including patients who had the lung as primary site of infection (HR 0.72; CI [95%] 0.565-0.918). Mortality at 28 days, ICU mortality, incidence of acute kidney injury, use of renal replacement therapy, days to suspension of vasopressor or inotropic agents, and resolution of primary and secondary infections did not differ significantly. Duration of mechanical ventilation and length of stay in ICU were significantly longer in patients with hyperoxemia. CONCLUSIONS: In a post-hoc analysis of a RCT enrolling septic patients, hyperoxemia as average PaO2>100 mmHg during the first 48 h was not associated with patients' survival.

Neurofilament light compared to neuron-specific enolase as a predictor of unfavourable outcome after out-of-hospital cardiac arrest.

AIM: We compared the prognostic abilities of neurofilament light (NfL) and neuron-specific enolase (NSE) in patients resuscitated from out-of-hospital cardiac arrest (OHCA) of various aetiologies. METHODS: We analysed frozen blood samples obtained at 24 and 48 hours from OHCA patients treated in 21 Finnish intensive care units in 2010 and 2011. We defined unfavourable outcome as Cerebral Performance Category (CPC) 3-5 at 12 months after OHCA. We evaluated the prognostic ability of the biomarkers by calculating the area under the receiver operating characteristic curves (AUROCs [95% confidence intervals]) and compared these with a bootstrap method. RESULTS: Out of 248 adult patients, 12-month outcome was unfavourable in 120 (48.4%). The median (interquartile range) NfL concentrations for patients with unfavourable and those with favourable outcome, respectively, were 689 (146-1804) pg/mL vs. 31 (17-61) pg/mL at 24 h and 1162 (147-4360) pg/mL vs. 36 (21-87) pg/mL at 48 h, p < 0.001 for both. The corresponding NSE concentrations were 13.3 (7.2-27.3) µg/L vs. 8.5 (5.8-13.2) µg/L at 24 h and 20.4 (8.1-56.6) µg/L vs. 8.2 (5.9-12.1) µg/L at 48 h, p < 0.001 for both. The AUROCs to predict an unfavourable outcome were 0.90 (0.86-0.94) for NfL vs. 0.65 (0.58-0.72) for NSE at 24 h, p < 0.001 and 0.88 (0.83-0.93) for NfL and 0.73 (0.66-0.81) for NSE at 48 h, p < 0.001. CONCLUSION: Compared to NSE, NfL demonstrated superior accuracy in predicting long-term unfavourable outcome after OHCA.

PCSK9 is associated with mortality in patients with septic shock: data from the ALBIOS study.

BACKGROUND: Pro-protein convertase subtilisin/kexin 9 (PCSK9) is a proenzyme primarily known to regulate low-density lipoprotein receptor re-uptake on hepatocytes. Whether PCSK9 can concurrently trigger inflammation or not remains unclear. Here, we investigated the potential association between circulating levels of PCSK9 and mortality in patients with severe sepsis or septic shock. METHODS: Plasma PCSK9 levels at days 1, 2 and 7 were measured in 958 patients with severe sepsis or septic shock previously enrolled in the Albumin Italian Outcome Sepsis (ALBIOS) trial. Correlations between levels of PCSK9 and pentraxin 3 (PTX3), a biomarker of disease severity, were evaluated with ranked Spearman's coefficients. Cox proportional hazards models were used to assess the association of PCSK9 levels at day 1 with 28- and 90-day mortality. RESULTS: Median plasma PCSK9 levels were 278 [182-452] ng mL-1 on day 1. PCSK9 correlated positively with PTX3 at the three time-points, and patients with septic shock within the first quartile of PCSK9 showed higher levels of PTX3. Similar mortality rates were observed in patients with severe sepsis across PCSK9 quartiles. Patients with septic shock with lower PCSK9 levels on day 1 (within the first quartile) showed the highest 28- and 90-day mortality rate as compared to other quartiles. CONCLUSION: In our sub-analysis of the ALBIOS trial, we found that patients with septic shock presenting with lower plasma PCSK9 levels experienced higher mortality rate. Further studies are warranted to better evaluate the pathophysiological role of PCSK9 in sepsis.

Incretin-based drugs and hospitalization for heart failure in the clinical practice: A nested case-control study.

BACKGROUND AND AIMS: There are concerns that incretin-based antidiabetic drugs - including dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists - increase the risk of hospitalization for heart failure (HF). To further analyse this issue, we conducted a nested case-control study within a cohort of antidiabetic users in a real world setting. METHODS AND RESULTS: Within a cohort of 133,639 subjects with a first prescription of an antidiabetic drug (new-users) between 2010 and 2016 in Lombardy, Italy, and were followed-up to 2016, we identified 4057 subjects with a first hospitalization for HF and 80,450 controls matched on sex, age, and date of cohort-entry. The multivariate odds ratios (ORs) of HF in relation to current use of incretin-based drugs as compared to current use of two or more oral antidiabetics was 1.06 (95% confidence interval, CI, 0.83-1.35), with no evidence of a trend in risk with increasing duration of use. The corresponding ORs were 1.10 (95% CI 0.85-1.41) for DPP-4 inhibitors and 0.84 (95% CI 0.48-1.47) for GLP-1 receptor agonists. Estimates were consistent in various sensitivity analyses. CONCLUSIONS: This study indicates that incretin-based drugs are not associated with an increased risk of hospitalization for HF, thus providing further reassurance on the cardiovascular safety of these antidiabetic drugs in the clinical practice.

Screening for unknown atrial fibrillation in older people: a feasibility study in community pharmacies.

INTRODUCTION: Atrial fibrillation (AF) is the most common heart arrhythmia. It is associated with an increased risk of morbidity and mortality and its prevalence rises with age. The arrhythmia is often asymptomatic, and systematic AF screening could help identify asymptomatic individuals to implement therapeutic and preventive strategies. The main study aims were to test the technical feasibility and citizens' acceptance of a freely offered service in older people using community pharmacies. MATERIALS AND METHODS: During 2 months, a 30-s single-lead electrocardiogram (ECG) with a telemedicine device was used for screening in 20 pharmacies in a mixed rural-urban health district of Northern Italy. RESULTS: A total of 289/335 older adults 70 years old or more agreed to participate in the study. A cardiologist considered 80% of the ECG tracings readable and unknown AF was identified in 1.3%. CONCLUSIONS: The screening scheme appears technically feasible and acceptable both to professionals and citizens/participants. Training the pharmacists could ensure broader participation and substantially improve the pharmacies' overall performance.

The fibroblast growth factor-23 and Vitamin D emerge as nontraditional risk factors and may affect cardiovascular risk.

OBJECTIVES: Fibroblast growth factor-23 (FGF-23) and vitamin D are hormones involved in phosphate homoeostasis. They also directly influence cardiomyocyte hypertrophy. We examined whether the relationships between levels of vitamin D or FGF-23, cardiac phenotype and outcome were independent of established cardiac biomarkers in a large cohort of community-dwelling elderly subjects. DESIGN AND SETTING: Plasma levels of FGF-23 and vitamin D were measured in 1851 men and women (65-84 years) resident in the Lazio region of Italy. Participants were referred to eight cardiology centres for clinical examination, electrocardiography, comprehensive Doppler echocardiography and blood sampling. All-cause mortality or hospitalizations were available after a median follow-up of 47 months with record linkage of administrative data. RESULTS: Vitamin D deficiency (<20 ng mL(-1) ) was found in 72.3% of subjects, but FGF-23 levels were normal [74 (58-97) RU per mL]. After adjustment for cardiovascular risk factors and morbidities, low concentrations of vitamin D and high levels of FGF-23 were associated with a higher left ventricular (LV) mass index. Levels of FGF-23 [hazard ratio (HR) (95% confidence interval (CI)) 1.71 (1.28-2.28), P < 0.0001] but not vitamin D [0.76 (0.57-1.01), P = 0.08] were independently associated with mortality after adjustment for clinical risk factors and two cardiac markers together (N-terminal pro-brain natriuretic peptide and high-sensitivity cardiac troponin T), but did not predict hospital admission. People with above median values of FGF-23 and below median values of vitamin D had greater LV hypertrophy and higher mortality. CONCLUSIONS: In community-dwelling elderly individuals with highly prevalent vitamin D deficiency, FGF-23 levels were associated with LV hypertrophy and predicted mortality independently of two robust cardiac biomarkers. A causal relationship was not demonstrated, but the hormones involved in mineral metabolism emerged as nontraditional risk factors and may affect cardiovascular risk.

Autonomic cardiovascular modulation with three different anesthetic strategies during neurosurgical procedures.

BACKGROUND: Autonomic cardiovascular modulation during surgery might be affected by different anesthetic strategies. Aim of the present study was to assess autonomic control during three different anesthetic strategies in the course of neurosurgical procedures by the linear and non-linear analysis of two cardiovascular signals. METHODS: Heart rate (EKG-RR intervals) and systolic arterial pressure (SAP) signals were analyzed in 93 patients during elective neurosurgical procedures at fixed points: anesthetic induction, dura mater opening, first and second hour of surgery, dura mater and skin closure. Patients were randomly assigned to three anesthetic strategies: sevoflurane+fentanyl (S-F), sevoflurane+remifentanil (S-R) and propofol+remifentanil (P-R). RESULTS: All the three anesthetic strategies were characterized by a reduction of RR and SAP variability. A more active autonomic sympathetic modulation, as ratio of low to high frequency spectral components of RR variability (LF/HF), was present in the P-R group vs. S-R group. This is confirmed by non-linear symbolic analysis of RR series and SAP variability analysis. In addition, an increased parasympathetic modulation was suggested by symbolic analysis of RR series during the second hour of surgery in S-F group. CONCLUSION: Despite an important reduction of cardiovascular signal variability, the analysis of RR and SAP signals were capable to detect information about autonomic control during anesthesia. Symbolic analysis (non-linear) seems to be able to highlight the differences of both the sympathetic (slow) and vagal (fast) modulation among anesthetics, while spectral analysis (linear) underlines the same differences but only in terms of balance between the two neural control systems.

The cardiokine secreted Frizzled-related protein 3, a modulator of Wnt signalling, in clinical and experimental heart failure.

OBJECTIVES: Experimental studies have shown involvement of Wnt signalling in heart failure (HF). We hypothesized that secreted frizzled-related protein 3 (sFRP3), a modulator of Wnt signalling, is related to the progression of HF. DESIGN: Circulating sFRP3 was measured in 153 HF patients and compared with 25 healthy controls. The association of sFRP3 with mortality was evaluated in 1202 patients (GISSI-HF trial). sFRP3 mRNA expression was assessed in failing human and murine left ventricles (LV), and cellular localization was determined after fractioning of myocardial tissue. In vitro studies were carried out in cardiac fibroblasts subjected to cyclic mechanical stretch. RESULTS: (i) Heart failure patients had significantly raised serum sFRP3 levels compared with controls, (ii) during a median follow-up of 47 months, 315 patients died in the GISSI-HF substudy. In univariable Cox regression, tertiles of baseline sFRP3 concentration were significantly associated with all-cause and cardiovascular mortality. After adjustment for demographic and clinical variables, but not for CRP and NT-proBNP, the associations with mortality remained significant for the third tertile (all-cause, HR 1.45, P = 0.011; cardiovascular, HR 1.66, P = 0.003), (iii) sFRP3 mRNA expression was increased in failing human LV, with a decline following LV assist device therapy. LV from post-MI mice showed an increased sFRP3 mRNA level, particularly in cardiac fibroblasts, and (iv) mechanical stretch enhanced sFRP3 expression and release in myocardial fibroblasts. CONCLUSION: There is an association between increased sFRP3 expression and adverse outcome in HF, suggesting that the failing myocardium itself contributes to an increase in circulating sFRP3.

High-sensitivity cardiac troponin T for detection of subtle abnormalities of cardiac phenotype in a general population of elderly individuals.

OBJECTIVE: To investigate the association between circulating cardiac biomarkers and minor abnormalities in cardiac phenotype [left ventricular (LV) mass and midwall fractional shortening (MFS)] in elderly individuals in a general population sample. DESIGN AND SETTING: We examined the relationship between plasma concentrations of high-sensitivity cardiac troponin T (hs-cTnT) or N-terminal probrain natriuretic peptide (NT-proBNP) and elevated LV mass (LV mass/body surface area >95 g m(-2) for women and 115 g m(-2) for men), reduced MFS (<15%) or isolated LV diastolic dysfunction in 1973 elderly subjects (mean age 73 ± 5 years, range 65-84) resident in the Lazio region of Italy and enrolled in the PREDICTOR study. RESULTS: Overall, 24.8% of subjects had elevated LV mass, and 30.4% had reduced MFS. Median [quartile 1-3] plasma concentrations of hs-cTnT and NT-proBNP were higher in individuals with elevated than those with normal LV mass: 6.6 [3.5-11.6] and 147 [64-296] ng L(-1) vs. 4.6 [3.0-8.1] and 79 [41-151] ng L(-1) respectively (P < 0.001). There was a graded increase in median hs-cTnT concentrations across clinical categories of LV hypertrophy: 4.6 [3.0-8.1], 5.8 [3.1-10.2], 7.6 [3.8-13.7] and 8.4 [3.8-17.6] ng L(-1) for subjects with normal LV mass and mild, moderate or severe LV hypertrophy respectively (P < 0.0001); hs-cTnT also increased with increasing quartiles of MFS or grades of isolated LV diastolic dysfunction. CONCLUSIONS: Within an extremely low range of concentrations, increased hs-cTnT amongst community-dwelling elderly subjects is associated with subtle alterations in cardiac phenotype, suggesting that minor injury to cardiac myocytes and subsequent release of troponin reflect subclinical pathophysiological LV deterioration in this population.

Telomere/telomerase system impairment in circulating angiogenic cells of geriatric patients with heart failure.

BACKGROUND: The functional characteristics of circulating angiogenic cells (CACs) are impaired in congestive heart failure (CHF) patients, suggesting that CAC dysfunction could contribute to CHF pathogenesis. However, the underlying mechanisms are only partly unraveled. No data are currently available regarding telomere/telomerase system in CACs of CHF patients. METHODS: CACs were obtained from 80 subjects: 40 healthy control subjects (CTR) [median age (IQR), 80 (76-85 yrs)] and 40 patients affected by post-ischemic cardiomyopathy CHF [median age (IQR), 82 (77-89)]. CAC and leukocyte telomere length, assessed as T/S ratio, and telomerase (TERT) activity were determined in all the enrolled subjects. Specificity and sensitivity of CAC and leukocyte T/S in discriminating between CHF and CTR were evaluated using Receiver Operator Characteristic (ROC) curve analysis and reported as AUC values. CD34+/VEGFR2+ number and pro-inflammatory cytokines plasma levels, such as IL-6 and TNF-α, were also measured. RESULTS: CAC T/S and TERT activity were significantly reduced in CHF patients compared to CTR subjects. In leukocytes, only a significant T/S reduction was observed. AUC values were higher for CAC T/S with respect to leukocyte T/S (AUC=0.89, and AUC=0.73, P<0.01, respectively). In multivariate analysis, leukocyte T/S, CAC T/S, CAC TERT activity and NT-proBNP levels were confirmed as parameters significantly associated with CHF. CD34+/VEGFR2+ number, IL-6 and TNF-α plasma levels were significantly increased in CHF patients. CONCLUSIONS: CACs from CHF patients are characterized by telomere/telomerase system impairment, providing new insight into the clinical relevance of CACs in CHF pathogenesis.

Adjusted indirect comparison of new oral anticoagulants for stroke prevention in atrial fibrillation.

BACKGROUND: Vit-K antagonists are the therapy of choice to prevent thromboembolic events due to atrial fibrillation since many years. New oral anticoagulants (NOA) showed encouraging results vs. warfarin but there are no data directly comparing different NOA. We performed an adjusted indirect meta-analysis. METHODS: Randomized controlled trials (RCTs) were searched. Efficacy end points were the cumulative rate of thomboembolic stroke (TES) and systemic embolism (SE). Main safety end point was the rate of hemorrhagic stroke (HS). RESULTS: Three RCTs (50578 patients) were included. Overall, NOA were comparable to warfarin according to the cumulative risk of TES and SE, as well as for TES alone. NOA were associated with a reduced rate of SE [OR 0.64 (0.44, 0.94], P=0.02]. Compared to warfarin, NOA were associated with a significantly reduced risk of HS [OR 0.43 (0.34, 0.55), P<0.001, NNT to avoid a HS 153] and all cause death [OR 0.90 [0.84, 0.96], P=0.03, NNT to save one fatality 43]. Head to head comparison showed that in terms of cumulative rate of TES/SE, as well as of TES, none of the NOA was significantly superior to the others (all Ps>0.05). Rivaroxaban showed superiority in the prevention of SE. Dabigatran 150 mg/twice daily was associated with the largest reduction in the risk of HS vs. warfarin and vs. other NOA. Overall mortality was quite comparable across NOA. CONCLUSION: Overall superiority of NOA over warfarin is largely influenced by the reduction of HS. Dabigatran 150 mg/twice daily seems to have the best risk/benefit profile.

L-selectin and SDF-1 enhance the migration of mouse and human cardiac mesoangioblasts.

Efficient delivery of stem cells to heart regions is still a major problem for cell therapy. Here, we report experiments aimed to improve migration of mouse and human cardiac mesoangioblasts to the damaged heart. Cardiac mesoangioblasts were induced to transmigrate through the endothelium by factors released by cardiomyocytes or cytokines, among which stromal-derived factor 1 (SDF-1) was the most potent. Cardiac mesoangioblasts were also delivered into the left ventricular (LV) chamber of mice after coronary artery ligation (CAL), and their in vivo homing to the damaged heart was found to be quite modest. Pretreatment of cardiac mesoangioblasts with SDF-1 or transient expression of L-selectin induced a two- to three-fold increase in their transmigration and homing to the damaged heart. Therefore, combined pretreatment with SDF-1 and L-selectin generated modified cardiac mesoangioblasts, 50% of which, after injection into the LV chamber of mice early after CAL, home directly to the damaged free wall of the heart. Finally, modified mouse cardiac mesoangioblasts, injected into the LV chamber regenerate a larger surface of the ventricle in long-term experiments in comparison with their control counterparts. This study defines the requirements for efficient homing of cardiac mesoangioblasts to the damaged heart and offers a new potent tool to optimize efficiency of future cell therapy protocols for cardiovascular diseases.

Multi-Link Vision stent vs. first-generation drug-eluting stents: systematic review and meta-analysis.

BACKGROUND: Since its introduction, the cobalt chromium alloy MULTI-LINK VISION stent (MLV) has been extensively investigated thus leading to the largest amount of data so far available for a bare metal stent. Aim and METHODS: Systematic review and meta-analysis (according to Cochrane collaboration guidelines) aiming at summarizing the real world safety and efficacy of MLV stent. Endpoints of interest were: major adverse events [(MAE) combination of overall death and non-fatal myocardial infarction, MI], and target vessel revascularization (TVR). Rate of stent thrombosis was also assessed. RESULTS: Eleven studies finally retrieved totalling 5539 patients [7 study registries, 4243 patients and 4 randomized controlled trials (RCTs) comparing MLV vs. first generation of drug-eluting stent (DES) (paclitaxel or sirolimus eluting), (RCTs) 1296 patients]. Across study registries, at a mean follow-up of 11.1 months, MLV was associated with a 5.3% risk of MAE, 3% of death, 2.3% of MI and a 9% of TVR. Risk of ST was 0.5%. Compared to first generation of DES in RCTs, at a mean follow-up of 10.5 months, MLV achieved similar results in terms of MAE, death and MI. On the other hand, MLV was associated with a double risk of TVR [OR 2.01 (1.34-3.01), P < 0.001, number needed to treat 18 (13-40)]. Overall, in stent late loss with MLV was 0.81 mm (±0.51), while the in segment late loss was 0.61 mm (±0.5). Risk of stent thrombosis was equivalent. Of note, performance of MLV in terms of safety, efficacy and risk of repeat revascularization was quite consistent across all the published studies, despite inherent differences in study design, clinical setting, complexity of the lesions and ethnicity. CONCLUSION: Compared to first-generation DES, MLV showed substantial equivalence with respect to hard clinical endpoints. Data are consistent in study registries and RCTs meaning that the overall performance of MLV is quite predictable and reproducible into the wide spectrum of clinical settings.

Effect of canrenone on left ventricular mechanics in patients with mild systolic heart failure and metabolic syndrome: the AREA-in-CHF study.

BACKGROUND AND AIM: We analyzed the effect of the mineralocorticoid receptor antagonist canrenone on LV mechanics in patients with or without metabolic syndrome (MetS) and compensated (Class II NYHA) heart failure (HF) with reduced ejection fraction (EF≤45%) on optimal therapy (including ACE-i or ARB, and ß-blockers). METHODS AND RESULTS: From a randomized, double-blind placebo-controlled trial (AREA-in-CHF), patients with (73 on canrenone [Can] and 77 on placebo [Pla]), based on modified ATPIII definition (BMI≥30kg/m(2) instead of waist girth) or without MetS (146 by arm). In addition to traditional echocardiographic parameters, we also evaluated myocardial mechano-energetic efficiency (MME) based on a previously reported method. At baseline, Can and Pla did not differ in age, BMI, blood pressure (BP), metabolic profile, BNP, and PIIINP. Compared with MetS-Pla, and controlling for age, sex and diabetes, at the final control MetS-Can exhibited increased MME, preserved E/A ratio, and decreased atrial dimensions (0.04

Circulating cardiovascular biomarkers in recurrent atrial fibrillation: data from the GISSI-atrial fibrillation trial.

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.

Current concepts on antiplatelet therapy: focus on the novel thienopyridine and non-thienopyridine agents.

Thienopyridines are a class of drug targeting the platelet adenosine diphosphate (ADP) 2 receptor. They significantly reduce platelet activity and are therefore clinically beneficial in settings where platelet activation is a key pathophysiological feature, particularly myocardial infarction. Ticlopidine, the first of the class introduced to clinical practice, was soon challenged and almost completely replaced by clopidogrel for its better tolerability. More recently, prasugrel and ticagrelor have been shown to provide a more powerful antiplatelet action compared to clopidogrel but at a cost of higher risk of bleeding complications. Cangrelor, a molecule very similar to ticagrelor, is currently being evaluated against clopidogrel. Considering the key balance of ischemic protection and bleeding risk, this paper discusses the background to the development of prasugrel, ticagrelor, and cangrelor and aims to characterise their risk-benefit profile and possible implementation in daily practice.

Modeling the potential distribution of the invasive golden mussel Limnoperna fortunei in the Upper Paraguay River system using limnological variables.

The invasive golden mussel, Limnoperna fortunei (Dunker, 1857), was introduced into the La Plata River estuary and quickly expanded upstream to the North, into the Paraguay and Paraná rivers. An ecological niche modeling approach, based on limnological variables, was used to predict the expansion of the golden mussel in the Paraguay River and its tributaries. We used three approaches to predict the geographic distribution: 1) the spatial distribution of calcium concentration and the saturation index for calcium carbonate (calcite); 2) the Genetic Algorithm for Rule-Set Production (GARP) model; and the 3) Maximum Entropy Method (Maxent) model. Other limnological variables such as temperature, dissolved oxygen, pH, and Total Suspended Solids (TSS) were used in the latter two cases. Important tributaries of the Paraguay River such as the Cuiabá and Miranda/Aquidauana rivers exhibit high risk of invasion, while lower risk was observed in the chemically dilute waters of the middle basin where shell calcification may be limited by low calcium concentrations and carbonate mineral undersaturation.

What is the risk of intensifying platelet inhibition beyond clopidogrel? A systematic review and a critical appraisal of the role of prasugrel.

Thienopyridines are a class of drug targeting the platelet adenosine diphosphate 2 receptor. They have been shown to significantly reduce platelet activity exerting an important role in those clinical settings in which such an effect is beneficial. Ticlopidine was first to be introduced several years ago but it was quickly replaced by clopidogrel as it had a better risk/benefit profile. Recently, prasugrel has been developed and tested in several ex vivo studies and clinical trials showing able to provide a more powerful antiplatelet effect at the expense of a higher risk of bleeding complications. Great debate rose around its recent approval in the US as well as in Europe. This review aims at exploring the development and available clinical data of this third-generation thienopyridine while discussing its practical implementation in routine practice.

Aldosterone status associated with insulin resistance in patients with heart failure--data from the ALOFT study.

BACKGROUND: Aldosterone has a key role in the pathophysiology of heart failure. In around 50% of such patients, aldosterone "escapes" from inhibition by drugs that interrupt the renin-angiotensin axis; such patients have a worse clinical outcome. Insulin resistance is a risk factor in heart failure and cardiovascular disease. The relation between aldosterone status and insulin sensitivity was investigated in a cohort of heart failure patients. METHODS: 302 patients with New York Heart Association (NYHA) class II-IV heart failure on conventional therapy were randomised in the ALiskiren Observation of heart Failure Treatment study (ALOFT), designed to test the safety of a directly acting renin inhibitor. Plasma aldosterone and 24-hour urinary aldosterone excretion, as well as fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. Subjects with aldosterone escape and high urinary aldosterone were identified according to previously accepted definitions. RESULTS: 20% of subjects demonstrated aldosterone escape and 34% had high urinary aldosterone levels. At baseline, there was a positive correlation between fasting insulin and plasma (r = 0.22 p<0.01) and urinary aldosterone(r = 0.19 p<0.03). Aldosterone escape and high urinary aldosterone subjects both demonstrated higher levels of fasting insulin (p<0.008, p<0.03), HOMA-IR (p<0.06, p<0.03) and insulin-glucose ratios (p<0.006, p<0.06) when compared to low aldosterone counterparts. All associations remained significant when adjusted for potential confounders. CONCLUSIONS: This study demonstrates a novel direct relation between aldosterone status and insulin resistance in heart failure. This observation merits further study and may identify an additional mechanism that contributes to the adverse clinical outcome associated with aldosterone escape.