AimsCirculating biomarkers of collagen turnover reflect extracellular cardiac matrix (ECCM) remodelling. The extent to which the success of cardiac resynchronization therapy (CRT) is influenced by the degree of cardiac fibrosis and whether CRT can influence matrix remodelling has yet to be studied. Our aim was to determine, in patients with heart failure (HF) and cardiac dyssynchrony, whether ECCM biomarkers are influenced by CRT and can predict cardiovascular outcomes and response to CRT. Methods and resultsSerum levels of ECCM biomarkers , N-terminal propeptides of type I and III procollagens (PINP and PIIINP), type I collagen telopeptide (ICTP), and matrix metalloproteinase 1 (MMP-1)] were measured in 260 patients, in a substudy of CARE-HF, a randomized controlled trial which evaluated the effects of CRT in patients with left ventricular systolic dysfunction and cardiac dyssynchrony. ECCM biomarkers did not change throughout the 18-month follow-up period. In age-and gender-adjusted analyses, Gal-3 and PIIINP were associated with death or HF hospitalization. In a further multivariate model, Gal-3 .30 ng/mL was associated [OR (95% CI): 2.98 (1.43-6.22), P ¼ 0.004] with death or HF hospitalization, along with left ventricular end-systolic volume .200 mL [3.42 (OR: 1.65 -7.10), P ¼ 0.001]. The outcome death or left ventricular ejection fraction (LVEF) ≤35% was associated with MMP-1 [≤3 ng/mL: 3.04 (1.37-6.71), P ¼ 0.006]. No significant interaction was observed between the tested biomarkers and the treatment group. ConclusionsIncreased Gal-3 and PIIINP, and low MMP-1 are associated with adverse long-term cardiovascular outcomes but did not predict response to CRT. CRT did not favourably affect serum concentrations of ECCM markers.--

Background and Purpose-Arterial stiffening and thickening and endothelial dysfunction may be associated with cognitive decline or white matter hyperintensities (WMH) independently of blood pressure level. We aimed to investigate, using an integrative approach, the relative contributions of structural and functional vascular factors to the degree of cognitive impairment (primary outcome) and the severity of WMH (secondary outcome) in elderly hypertensive patients with subjective memory complaints, a group prone to dementia. Methods-A prospective, dedicated, cross-sectional population of 198 elderly hypertensive patients (mean age 69.3Ϯ6.2 years) with subjective memory complaints underwent a full set of cognitive function assessments, brain MRI with semiquantification of WMH, carotid ultrasonography, carotid-femoral pulse wave velocity, brachial endothelial function, and plasma von Willebrand Factor measurements. Results-After adjustment for the usual cardiovascular risk factors, increased arterial stiffness (as assessed by pulse wave velocity) was significantly and independently associated with memory impairment in men. The severity of WMH was independently associated with increased carotid intima media thickness and stiffness (as assessed by augmentation index) as well as with increased age and plasma levels of von Willebrand Factor, a biomarker of endothelial dysfunction. Conclusions-Our data suggest that vascular abnormalities, independently of blood pressure levels, may play a role in the setting of subjective memory complaints as well as of WMH in elderly hypertensive patients. Arterial thickness and stiffness as well as endothelial function should be assessed simultaneously and may represent additional targets for the prevention of subjective memory complaints and WMH.

Background-Aldosterone stimulates cardiac collagen synthesis. Circulating biomarkers of collagen turnover provide a useful tool for the assessment of cardiac remodeling in patients with congestive heart failure and left ventricular systolic dysfunction after acute myocardial infarction. Methods and Results-In a substudy of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), which evaluated the effects of the selective aldosterone receptor antagonist eplerenone versus placebo, serum levels of collagen biomarkers were measured in 476 patients with congestive heart failure after acute myocardial infarction complicated with left ventricular systolic dysfunction. The combination of the type I collagen telopeptide and brain natriuretic peptide levels above median at baseline was associated with all-cause mortality and the composite end point of cardiovascular death or heart failure hospitalization, with hazard ratios of 2.49 (Pϭ0.039) and 3.03 (Pϭ0.002), respectively. During follow-up, levels of aminoterminal propeptide of type I and type III procollagen were found to be consistently lower in the eplerenone group and significantly lower beginning at 6 months. Conclusions-Changes in biomarkers of collagen synthesis and degradation suggest that extracellular matrix remodeling is an active process in patients with congestive heart failure and left ventricular systolic dysfunction after acute myocardial infarction. High type I collagen telopeptide and high brain natriuretic peptide serum levels are associated with the highest event rate. Eplerenone suppresses post-acute myocardial infarction collagen turnover changes.

IMPORTANCE Clinical evidence supports the beneficial effects of lowering blood pressure (BP) levels in community-living, robust, hypertensive individuals older than 80 years. However, observational studies in frail elderly patients have shown no or even an inverse relationship between BP and morbidity and mortality. OBJECTIVE To assess all-cause mortality in institutionalized individuals older than 80 years according to systolic BP (SBP) levels and number of antihypertensive drugs. DESIGN, SETTING, AND PARTICIPANTS This longitudinal study included elderly residents of nursing homes. The interaction between low (<130 mm Hg) SBP and the presence of combination antihypertensive treatment on 2-year all-cause mortality was analyzed. A total of 1127 women and men older than 80 years (mean, 87.6 years; 78.1% women) living in nursing homes in France and Italy were recruited, examined, and monitored for 2 years. Blood pressure was measured with assisted self-measurements in the nursing home during 3 consecutive days (mean, 18 measurements). Patients with an SBP less than 130 mm Hg who were receiving combination antihypertensive treatment were compared with all other participants. MAIN OUTCOMES AND MEASURES All-cause mortality over a 2-year follow-up period. RESULTS A significant interaction was found between low SBP and treatment with 2 or more BP-lowering agents, resulting in a higher risk of mortality (unadjusted hazard ratio [HR], 1.81; 95% CI, 1.36-2.41); adjusted HR, 1.78; 95% CI, 1.34-2.37; both P < .001) in patients with low SBP who were receiving multiple BP medicines compared with the other participants. Three sensitivity analyses confirmed the significant excess of risk: propensity score-matched subsets (unadjusted HR, 1.97; 95% CI, 1.32-2.93; P < .001; adjusted HR, 2.05; 95% CI, 1.37-3.06; P < .001), adjustment for cardiovascular comorbidities (HR, 1.73; 95% CI, 1.29-2.32; P < .001), and exclusion of patients without a history of hypertension who were receiving BP-lowering agents (unadjusted HR, 1.82; 95% CI, 1.33-2.48; P < .001; adjusted HR, 1.76; 95% CI, 1.28-2.41; P < .001). CONCLUSIONS AND RELEVANCE The findings of this study raise a cautionary note regarding the safety of using combination antihypertensive therapy in frail elderly patients with low SBP (<130 mm Hg). Dedicated, controlled interventional studies are warranted to assess the corresponding benefit to risk ratio in this growing population.

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BackgroundData are sparse regarding the effects of prolonged prone positioning (PP) during VV-ECMO. Previous studies, using short sessions (<12 h), failed to find any effects on respiratory system compliance. In the present analysis, the effects of prolonged PP sessions (24 h) were retrospectively studied with regard to safety data, oxygenation and respiratory system compliance.MethodsRetrospective review of 17 consecutive patients who required both VV-ECMO and prone positioning. PP under VV-ECMO was considered when the patient presented at least one unsuccessful ECMO weaning attempt after day 7 or refractory hypoxemia combined or not with persistent high plateau pressure. PP sessions had a duration of 24 h with fixed ECMO and respiratory settings. PP was not performed in patients under vasopressor treatment and in cases of recent open chest cardiac surgery.ResultsDespite optimized protective mechanical ventilation and other adjuvant treatment (i.e. PP, inhaled nitric oxide, recruitment maneuvers), 44 patients received VV-ECMO during the study period for refractory acute respiratory distress syndrome. Global survival rate was 66 %. Among the latter, 17 patients underwent PP during VV-ECMO for a total of 27 sessions. After 24 h in prone position, PaO2/FiO2 ratio significantly increased from 111 (84–128) to 173 (120–203) mmHg (p < 0.0001) while respiratory system compliance increased from 18 (12–36) to 32 (15–36) ml/cmH2O (p < 0.0001). Twenty-four hours after the return to supine position, tidal volume was increased from 3.0 (2.2–4.0) to 3.7 (2.8–5.0) ml/kg (p < 0.005). PaO2/FiO2 ratio increased by over 20 % in 14/14 sessions for late sessions (≥7 days) and in 7/13 sessions for early sessions (<7 days) (p = 0.01). Quantitative CT scan revealed a high percentage of non-aerated or poorly-aerated lung parenchyma [52 % (41–62)] in all patients. No correlation was found between CT scan data and respiratory parameter changes. Hemodynamics did not vary and side effects were rare (one membrane thrombosis and one drop in ECMO blood flow).ConclusionWhen used in combination with VV-ECMO, 24 h of prone positioning improves both oxygenation and respiratory system compliance. Moreover, our study confirms the absence of serious adverse events.Electronic supplementary materialThe online version of this article (doi:10.1186/s13613-015-0078-4) contains supplementary material, which is available to authorized users.

A ldosterone via the activation of the mineralocorticoid receptor (MR) is a main actor of renal sodium reabsorption and water homeostasis. Extra-renal effects of the mineralocorticoid pathway have now been characterized, especially in the cardiovascular system, opening on new dimensions of the aldosterone/MR pathway in physiology, pathophysiology, and diseases. In the cardiovascular system, mineralocorticoid signaling has been shown to play an important role in the progression of cardiovascular diseases (CVDs). Previous reports using transgenic mouse models or pharmacological approaches demonstrated adverse effects of aldosterone on cardiac remodeling and fibrosis, inflammation, and hypertension.1 These features are prevented by the pharmacological blockade of the MR. In humans, several clinical studies showed the beneficial effects of MR antagonism in addition to standard care, to reduce mortality and morbidity in patients with severe 2 or mild heart failure (HF) 3 or after acute myocardial infarction. 4 Understanding the molecular mechanisms of mineralocorticoid activation pathway in cardiovascular pathophysiology remains incomplete. Indeed, a better knowledge of the underlying mechanisms may highlight novel mediators of the MR signaling cascade. These newly identified intermediates could be good candidates as biotargets for novel pharmacological approaches, especially in diseases where the aldosterone/MR pathway is involved. Moreover, these biotargets may as well be considered as potent biomarkers of MR activation, Abstract-Activation of the mineralocorticoid receptor has been shown to be deleterious in cardiovascular diseases (CVDs).We have recently shown that lipocalin 2 (Lcn2), or neutrophil gelatinase-associated lipocalin (NGAL), is a primary target of aldosterone/mineralocorticoid receptor in the cardiovascular system. Lcn2 is a circulating protein, which binds matrix metalloproteinase 9 and modulates its stability. We hypothesized that Lcn2 could be a mediator of aldosterone/ mineralocorticoid receptor profibrotic effects in the cardiovascular system. Correlations between aldosterone and profibrotic markers, such as procollagen type I N-terminal peptide, were investigated in healthy subjects and subjects with abdominal obesity. The implication of Lcn2 in the mineralocorticoid pathway was studied using Lcn2 knockout mice subjected to a nephrectomy/aldosterone/salt (NAS) challenge for 4 weeks. In human subjects, NGAL/matrix metalloproteinase 9 was positively correlated with plasma aldosterone and fibrosis biomarkers. In mice, loss of Lcn2 prevented the NAS-induced increase of plasma procollagen type I N-terminal peptide, as well as the increase of collagen fibers deposition and collagen I expression in the coronary vessels and the aorta. The lack of Lcn2 also blunted the NAS-induced increase in systolic blood pressure. Ex vivo, treatment of human fibroblasts with recombinant Lcn2 induced the expression of collagen I and the profibrotic galectin-3 and cardiotrophin-1 molecules. allowing a better selectio...

Results of the HepZero study comparing heparin-grafted membrane and standard care show that heparin-grafted dialyzer is safe and easy to use for heparin-free dialysis Gambro-Hospal, Meyzieu, FranceHeparin is used to prevent clotting during hemodialysis, but heparin-free hemodialysis is sometimes needed to decrease the risk of bleeding. The HepZero study is a randomized, multicenter international controlled open-label trial comparing no-heparin hemodialysis strategies designed to assess non-inferiority of a heparin grafted dialyzer (NCT01318486). A total of 251 maintenance hemodialysis patients at increased risk of hemorrhage were randomly allocated for up to three heparin-free hemodialysis sessions using a heparin-grafted dialyzer or the center standardof-care consisting of regular saline flushes or pre-dilution. The first heparin-free hemodialysis session was considered successful when there was neither complete occlusion of air traps or dialyzer, nor additional saline flushes, changes of dialyzer or bloodlines, or premature termination. The current standard-of-care resulted in high failure rates (50%). The success rate in the heparin-grafted membrane arm was significantly higher than in the control group (68.5% versus 50.4%), which was consistent for both standardof-care modalities. The absolute difference between the heparin-grafted membrane and the controls was 18.2%, with a lower bound of the 90% confidence interval equal to plus 7.9%. The hypothesis of the non-inferiority at the minus 15% level was accepted, although superiority at the plus 15% level was not reached. Thus, use of a heparin-grafted membrane is a safe, helpful, and easy-to-use method for heparin-free hemodialysis in patients at increased risk of hemorrhage.