Low-Dose Colchicine in Patients With Type 2 Diabetes and Recent Myocardial Infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT).

OBJECTIVE: The cardiovascular benefits of low-dose colchicine have been demonstrated in patients with coronary disease. Its effects were evaluated in this prespecified analysis in patients with type 2 diabetes (T2D) from the Colchicine Cardiovascular Outcomes Trial (COLCOT). RESEARCH DESIGN AND METHODS: COLCOT was a randomized, double-blinded trial of colchicine, 0.5 mg daily, versus placebo initiated within 30 days after a myocardial infarction. RESULTS: There were 959 patients with T2D enrolled and monitored for a median of 22.6 months. A primary end point event occurred in 8.7% of patients in the colchicine group and in 13.1% in the placebo group (hazard ratio 0.65; 95% CI 0.44-0.96; P = 0.03). Nausea was reported in 2.7% and 0.8% in the study groups (P = 0.03), and pneumonia occurred in 2.4% and 0.4% (P = 0.008). CONCLUSIONS: Among patients with T2D and a recent myocardial infarction, colchicine, 0.5 mg daily, leads to a large reduction of cardiovascular events. These results support the conduct of the COLCOT-T2D trial in primary prevention.

Adenylate cyclase type 9 antagonizes cAMP accumulation and regulates endothelial signalling involved in atheroprotection.

AIMS: The adenylate cyclase type 9 (ADCY9) gene appears to determine atherosclerotic outcomes in patients treated with dalcetrapib. In mice, we recently demonstrated that Adcy9 inactivation potentiates endothelial function and inhibits atherogenesis. The objective of this study was to characterize the contribution of ADCY9 to the regulation of endothelial signalling pathways involved in atherosclerosis. METHODS AND RESULTS: We show that ADCY9 is expressed in the endothelium of mouse aorta and femoral arteries. We demonstrate that ADCY9 inactivation in cultured endothelial cells paradoxically increases cAMP accumulation in response to the adenylate cyclase activators forskolin and vasoactive intestinal peptide (VIP). Reciprocally, ADCY9 overexpression decreases cAMP production. Using mouse femoral artery arteriography, we show that Adcy9 inactivation potentiates VIP-induced endothelial-dependent vasodilation. Moreover, Adcy9 inactivation reduces mouse atheroma endothelial permeability in different vascular beds. ADCY9 overexpression reduces forskolin-induced phosphorylation of Ser157-vasodilator-stimulated phosphoprotein (VASP) and worsens thrombin-induced fall of RAP1 activity, both leading to increased endothelial permeability. ADCY9 inactivation in thrombin-stimulated human coronary artery endothelial cells results in cAMP accumulation, increases p-Ser157-VASP, and inhibits endothelial permeability. MLC2 phosphorylation and actin stress fibre increases in response to thrombin were reduced by ADCY9 inactivation, suggesting actin cytoskeleton regulation. Finally, using the Miles assay, we demonstrate that Adcy9 regulates thrombin-induced endothelial permeability in vivo in normal and atherosclerotic animals. CONCLUSION: Adcy9 is expressed in endothelial cells and regulates local cAMP and endothelial functions including permeability relevant to atherogenesis.

Are Operando Measurements of Rechargeable Batteries Always Reliable? An Example of Beam Effect with a Mg Battery.

Operando and in situ techniques are becoming mandatory to study Li-ion, post Li-ion, and solid-state batteries. They are essential for monitoring the (electro)chemical and dynamic processes in the battery environment and for providing understanding at different spatial and temporal scales. While operando measurements are becoming more and more routine, scientists have to keep in mind that such experiments are not always harmless for the battery operation, especially when using synchrotron techniques. This is the case in the example described herein with Mg batteries. We show that the electrode reactivity in a InSb/organohaluminate electrolyte/Mg cell is strongly retarded during operando synchrotron X-ray absorption acquisition. Through comparison of ex situ, operando, and in situ data, we demonstrate that this effect occurred only on the samples' volumes exposed to the X-ray radiation. This study illustrates how incorrect conclusions might be drawn from operando measurements, especially when looking at new battery chemistries, and calls for extreme caution when designing and interpreting operando data.

Influence of Electrolyte on the Electrode/Electrolyte Interface Formation on InSb Electrode in Mg-Ion Batteries.

Achieving the full potential of magnesium-ion batteries (MIBs) is still a challenge due to the lack of adequate electrodes or electrolytes. Grignard-based electrolytes show excellent Mg plating/stripping, but their incompatibility with oxide cathodes restricts their use. Conventional electrolytes like bis(trifluoromethanesulfonyl)imide ((Mg(TFSI)2) solutions are incompatible with Mg metal, which hinders their application in high-energy Mg batteries. In this regard, alloys can be game changers. The insertion/extraction of Mg2+ in alloys is possible in conventional electrolytes, suggesting the absence of a passivation layer or the formation of a conductive surface layer. Yet, the role and influence of this layer on the alloys performance have been studied only scarcely. To evaluate the reactivity of alloys, we studied InSb as a model material. Ex situ X-ray photoelectron spectroscopy (XPS) and electrochemical impedance spectroscopy were used to investigate the surface behavior of InSb in both Grignard and conventional Mg(TFSI)2/DME electrolytes. For the Grignard electrolyte, we discovered an intrinsic instability of both solvent and salt against InSb. XPS showed the formation of a thick surface layer consisting of hydrocarbon species and degradation products from the solvent (THF) and salt (C2H5MgCl-(C2H5)2AlCl). On the contrary, this study highlighted the stability of InSb in Mg(TFSI)2 electrolyte.

Operando NMR characterization of a metal-air battery using a double-compartment cell design.

Applying operando investigations is becoming essential for acquiring fundamental insights into the reaction mechanisms and phenomena at stake in batteries currently under development. The capability of a real-time characterization of the charge/discharge electrochemical pathways and the reactivity of the electrolyte is critical to decipher the underlying chemistries and improve the battery performance. Yet, adapting operando techniques for new chemistries such as metal-oxygen (i.e. metal-air) batteries introduces challenges in the cell design due notably to the requirements of an oxygen gas supply at the cathode. Herein a simple operando cell is presented with a two-compartment cylindrical cell design for NMR spectroscopy. The design is discussed and evaluated. Operando7Li static NMR characterization on a Li-O2 battery was performed as a proof-of-concept. The productions of Li2O2, mossy Li/Li dendrites and other irreversible parasitic lithium compounds were captured in the charge/discharge processes, demonstrating the capability of tracking the evolution of the anodic and cathodic chemistry in metal-oxygen batteries.

Pharmacogenomics of the Efficacy and Safety of Colchicine in COLCOT.

BACKGROUND: The randomized, placebo-controlled COLCOT (Colchicine Cardiovascular Outcomes Trial) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine. METHODS: There were 1522 participants of European ancestry from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study's primary cardiovascular end point was defined as for the main trial, as time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina requiring coronary revascularization. The safety end point was time to the first report of gastrointestinal events. Patients' DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study in colchicine-treated patients. RESULTS: None of the genetic variants passed the genome-wide association study significance threshold for the primary cardiovascular end point conducted in 702 patients in the colchicine arm who were compliant to medication. The genome-wide association study for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found 2 significant association signals, one with lead variant rs6916345 (hazard ratio, 1.89 [95% CI, 1.52-2.35], P=7.41×10-9) in a locus which colocalizes with Crohn disease, and one with lead variant rs74795203 (hazard ratio, 2.51 [95% CI, 1.82-3.47]; P=2.70×10-8), an intronic variant in gene SEPHS1. The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant. CONCLUSIONS: We found 2 genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.

ApoA-I mimetic does not improve left ventricular diastolic dysfunction in rabbits without aortic valve stenosis.

BACKGROUND: We previously demonstrated that high-density lipoprotein (HDL) infusions may improve left ventricular diastolic dysfunction (LVDD) in an aortic valve stenosis (AVS) model. Whether the benefit was direct or mediated by the observed reduction in AVS severity is not clear. Here, we aimed to test the direct effect of an ApoA-I mimetic on LVDD in the absence of AVS. METHODS: Rabbits were exposed to three different protocols to develop LVDD. First, rabbits were exposed to 0.5% cholesterol-rich diet for an average of 17 weeks. Second, rabbits were subjected to surgical ascending aortic constriction (AAC), to mimic the effect of fixed reduced aortic valve area, and studied after 10 weeks. The third model combined both cholesterol-enriched diet (for 12 weeks) and surgical AAC. The control group consisted of age-matched rabbits under normal diet. After development of LVDD, rabbits were randomized to receive infusions of saline or apoA-I mimetic (25 mg/kg) 3 times per week for 4 weeks. Detailed cardiac structure and function measurements were assessed at baseline and weekly during treatment period. Histological and molecular analyses were performed on LV samples. RESULTS: In the three models, echocardiographic results showed development of LVDD over time, with preserved LV systolic and aortic valve functions versus controls. ApoA-I mimetic infusions did not significantly improve echocardiographic parameters nor molecular markers of cardiac inflammation, oxidative stress and fibrosis. CONCLUSION: ApoA-I mimetic therapy did not directly improve LVDD. These results indicate that previously observed changes of LVDD were caused by AVS improvement induced by this treatment.

Colchicine for Secondary Prevention of Cardiovascular Disease: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Reduction of inflammation with colchicine has emerged as a therapeutic option for secondary prevention of cardiovascular disease (CVD) in patients with coronary artery disease (CAD). Our objective was to consolidate evidence from randomized controlled trials (RCTs) evaluating the efficacy and safety of low-dose colchicine for secondary prevention of CVD among patients with CAD on standard medical therapy. METHODS: RCTs comparing the incidence of cardiovascular (CV) events between patients with clinically manifest CAD randomized to colchicine vs placebo (or no colchicine) were included. The primary composite efficacy endpoint included CV mortality, myocardial infarction (MI), ischemic stroke, and urgent coronary revascularization. The DerSimonian and Laird random-effects model was used to calculate pooled hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Four RCTs, with a pooled sample size of 11,594 patients, were included (colchicine n = 5774; placebo/no colchicine n = 5820). Included RCTs studied populations with stable CAD (N = 2) and acute coronary syndrome (N = 2). Compared with placebo or no colchicine, colchicine was associated with a statistically significant reduction in the incidence of the primary composite endpoint (pooled HR, 0.68; 95% CI, 0.54-0.81; I2 = 37.7%). The reduction in CV events among patients randomized to colchicine was driven by statistically significant reductions in MIs, ischemic strokes, and urgent coronary revascularizations (P < 0.05 for all) and was relatively consistent among subgroups. The incidence of safety outcomes did not differ between groups (P > 0.05). CONCLUSIONS: In secondary prevention of CV events, the addition of low-dose colchicine to standard medical therapy reduces the incidence of major CV events-except CV mortality-when compared with standard medical therapy alone.

Cost-effectiveness of low-dose colchicine after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT).

AIMS: In the randomized, placebo-controlled Colchicine Cardiovascular Outcomes Trial (COLCOT) of 4745 patients enrolled within 30 days after myocardial infarction (MI), low-dose colchicine (0.5 mg once daily) reduced the incidence of the primary composite endpoint of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization. To assess the in-trial period and lifetime cost-effectiveness of low-dose colchicine therapy compared to placebo in post-MI patients on standard-of-care therapy. METHODS AND RESULTS: A multistate Markov model was developed incorporating the primary efficacy and safety results from COLCOT, as well as healthcare costs and utilities from the Canadian healthcare system perspective. All components of the primary outcome, non-cardiovascular deaths, and pneumonia were included as health states in the model as both primary and recurrent events. In the main analysis, a deterministic approach was used to estimate the incremental cost-effectiveness ratio (ICER) for the trial period (24 months) and lifetime (20 years). Over the in-trial period, the addition of colchicine to post-MI standard-of-care treatment decreased the mean overall per-patient costs by 47%, from $502 to $265 Canadian dollar (CAD), and increased the quality-adjusted life years (QALYs) from 1.30 to 1.34. The lifetime per-patient costs were further reduced (69%) and QALYs increased with colchicine therapy (from 8.82 to 11.68). As a result, both in-trial and lifetime ICERs indicated colchicine therapy was a dominant strategy. CONCLUSION: Cost-effectiveness analyses indicate that the addition of colchicine to standard-of-care therapy after MI is economically dominant and therefore generates cost savings.

Cardiorespiratory Fitness Mediates Cognitive Performance in Chronic Heart Failure Patients and Heart Transplant Recipients.

We compared cognitive profiles in chronic heart failure patients (HF), heart transplant recipients (HT) and healthy controls (HC) and examined the relationship between cardiorespiratory fitness (V˙O2peak), peak cardiac output (COpeak) and cognitive performance. Stable HT patients (n = 11), HF patients (n = 11) and HC (n = 13) (61.5 ± 8.5 years) were recruited. Four cognitive composite scores targeting different cognitive functions were computed from neuropsychological tests: working memory, processing speed, executive functions and verbal memory. Processing speed and executive function scores were higher, which indicates lower performances in HF and HT compared to HC (p < 0.05). V˙O2peak and first ventilatory threshold (VT1) were lower in HF and HT vs. HC (p < 0.01). COpeak was lower in HF vs. HT and HC (p < 0.01). Processing speed, executive function and verbal memory performances were correlated with V˙O2peak, VT1 and peak cardiac hemodynamics (p < 0.05). Mediation analyses showed that V˙O2peak and VT1 mediated the relationship between group and processing speed and executive function performances in HF and HT. COpeak fully mediated executive function and processing speed performances in HF only. V˙O2peak and COpeak were related to cognitive performance in the entire sample. In addition, V˙O2peak and VT1 fully mediated the relationship between group and executive function and processing speed performances.

Time-to-treatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT).

AIMS: The COLchicine Cardiovascular Outcomes Trial (COLCOT) demonstrated the benefits of targeting inflammation after myocardial infarction (MI). We aimed to determine whether time-to-treatment initiation (TTI) influences the beneficial impact of colchicine. METHODS AND RESULTS: In COLCOT, patients were randomly assigned to receive colchicine or placebo within 30 days post-MI. Time-to-treatment initiation was defined as the length of time between the index MI and the initiation of study medication. The primary efficacy endpoint was a composite of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring coronary revascularization. The relationship between endpoints and various TTI (<3, 4-7 and >8 days) was examined using multivariable Cox regression models. Amongst the 4661 patients included in this analysis, there were 1193, 720, and 2748 patients, respectively, in the three TTI strata. After a median follow-up of 22.7 months, there was a significant reduction in the incidence of the primary endpoint for patients in whom colchicine was initiated < Day 3 compared with placebo [hazard ratios (HR) = 0.52, 95% confidence intervals (CI) 0.32-0.84], in contrast to patients in whom colchicine was initiated between Days 4 and 7 (HR = 0.96, 95% CI 0.53-1.75) or > Day 8 (HR = 0.82, 95% CI 0.61-1.11). The beneficial effects of early initiation of colchicine were also demonstrated for urgent hospitalization for angina requiring revascularization (HR = 0.35), all coronary revascularization (HR = 0.63), and the composite of cardiovascular death, resuscitated cardiac arrest, MI, or stroke (HR = 0.55, all P < 0.05). CONCLUSION: Patients benefit from early, in-hospital initiation of colchicine after MI. TRIAL REGISTRATION: COLCOT ClinicalTrials.gov number, NCT02551094.

Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction.

BACKGROUND: Experimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis. METHODS: We performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed. RESULTS: A total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group. Patients were followed for a median of 22.6 months. The primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P = 0.02). The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization. Diarrhea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group (P = 0.35). Pneumonia was reported as a serious adverse event in 0.9% of the patients in the colchicine group and in 0.4% of those in the placebo group (P = 0.03). CONCLUSIONS: Among patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo. (Funded by the Government of Quebec and others; COLCOT ClinicalTrials.gov number, NCT02551094.).

Cardiopulmonary, biomarkers, and vascular responses to acute hypoxia following cardiac transplantation.

Previous studies have suggested good adaptation of cardiac transplant (CTx) recipients to exposure to a high altitude. No studies have investigated the cardiopulmonary and biomarker responses to acute hypoxic challenges following CTx. Thirty-six CTx recipients and 17 age-matched healthy controls (HC) were recruited. Sixteen (16) patients (42%) had cardiac allograft vasculopathy (CAV). Cardiopulmonary responses to maximal and submaximal exercise at 21% O2 , 20-minutes hypoxia (11.5% O2 ), and following a 10-minute exposure to 11.5% O2 using 30% of peak power output were completed. Vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), suppression of tumorigenicity 2 (ST2) were measured at baseline and at peak stress. Endothelial peripheral function was assessed using near-infrared spectroscopy. Compared with HC, CTx presented a lesser O2 desaturation both at rest (-19.4 ± 6.8 [CTx] vs -24.2 ± 6.0% O2 [HC], P < 0.05) and following exercise (-23.2 ± 4.9 [CTx] vs -26.2 ± 4.7% O2 [HC], P < 0.05). CTx patients exhibited a significant decrease in peak oxygen uptake. IL-6 and VEGF levels were significantly higher in CTx recipients in basal conditions but did not change in response to acute stress. CTx patients exhibit a favorable ventilatory and overall response to hypoxic stress. These data provide further insights on the good adaptability of CTx to exposure to high altitude.

Investigation of the local structure of nanosized rhodium hydride.

The local structure and the thermal stability of small and well-dispersed RhHx nanoparticles (average size of 1.4 nm) were studied by in situ X-ray Absorption Spectroscopy. The RhHx nanoparticles are stable at room temperature and undergo a structural transition from hydride (fcc) to metal phase (fcc) with a shrinking of the lattice volume due to the desorption of hydrogen. This phase transition occurs in the temperature range of 150-180 °C, in good agreement with the results from thermo-desorption spectroscopy. Above 180 °C, the desorbed nanoparticles undertake important coalescence. In situ transmission electron microscopy performed up to 300 °C proves that this process cannot be only thermal, thus it may be ascribed to a X-ray beam effect.

Factors associated with failure of emergency department management in children with acute moderate or severe asthma: a prospective, multicentre, cohort study.

BACKGROUND: The management of paediatric asthma exacerbations is based on trials in children of all ages. Recent studies from 2009 raised the possibility that preschoolers (younger than 6 years) with viral-induced wheezing and children exposed to tobacco smoke might be at an increased risk of treatment failure. The study objective was to identify factors associated with management failure in children presenting to the emergency department with moderate or severe asthma exacerbations. METHODS: We undertook a prospective, multicentre cohort study of children aged 1-17 years presenting to five emergency departments with moderate or severe asthma (defined as a Pediatric Respiratory Assessment Measure [PRAM] of 4 to 12). Children received oral corticosteroids and severity-specific inhaled bronchodilator therapy. The primary outcome was emergency department management failure (hospital admission, prolonged emergency department therapy [≥8 h], or relapse within 72 h of discharge from the emergency department with admission to hospital or prolonged emergency department stay). Viral cause was ascertained by PCR on nasopharyngeal specimens and environmental tobacco smoke exposure by salivary cotinine concentration. This study is registered at ClinicalTrials.gov (NCT02013076). FINDINGS: Between Feb 14, 2011, and Dec 20, 2013, we screened 1893 children and enrolled 1012 eligible children. Of those eligible children, 973 participants were included in the analysis. 165 (17%) of 965 children experienced management failure in the emergency department, which was significantly associated with viral detection (110 [19%] of 579 participants with virus detection vs 46 [13%] of 354 participants without viral detection, odds ratio [OR] 1·57; 95% CI 1·04-2·37), fever (24% vs 15%, 1·96; 1·32-2·92), baseline PRAM (OR 1·38 per 1-point increase; 1·22-1·56), oxygen saturation of less than 92% (50% vs 12%, 3·94; 1·97-7·89), and presence of symptoms between exacerbations (21% vs 16%, 1·73; 1·13-2·64). Age, salivary cotinine concentration, and oral corticosteroids dose were not significantly associated with management failure. Viral detection (67% vs 46%, p<0·0001) and fever (31% vs 16%, p<0·0001) occurred more frequently in preschoolers than in older children. Viral detection was also associated with reduced speed of recovery over the 10 days after discharge. INTERPRETATION: In children presenting with moderate or severe asthma, viral detection, but not age, was associated with failure of symptom management, independently from exacerbation severity (ie, baseline PRAM and oxygen saturation), fever, and symptom chronicity (viral detection). Although it did not reach statistical significance, the association between treatment management failure and exposure to tobacco smoke warrants further investigation. FUNDING: Canadian Institutes of Health Research.

Efficacy of amiodarone in patients with atrial fibrillation with and without left ventricular dysfunction: a pooled analysis of AFFIRM and AF-CHF trials.

INTRODUCTION: Despite amiodarone's established safety profile in the setting of heart failure, it is unknown whether its impact on cardiovascular outcomes in patients with atrial fibrillation is modulated by left ventricular function. METHODS AND RESULTS: A pooled analysis of 3,307 patients (age 68.0 ± 0.2 years; 31.1% female) enrolled in AFFIRM and AF-CHF trials was conducted to assess the effect of rhythm control with amiodarone on cardiovascular outcomes, according to left ventricular systolic function. In amiodarone-treated patients (N = 1,107), freedom from recurrent atrial fibrillation was 84% and 45% at 1 and 5 years, respectively, with no differences according to left ventricular function (P = 0.8754). Similarly, the adjusted proportion of time spent in atrial fibrillation (15.0 ± 1.8%) did not vary according to ventricular function (P = 0.6094). Over 40.0 ± 0.3 months of follow-up, 1,963 (59.4%) patients required at least one hospitalization, 1,401 (42.6%) of whom had cardiovascular-related hospitalizations. Adjusted all-cause and cardiovascular hospitalization rates were similar with amiodarone versus rate control in all patients and in subgroups with and without severe left ventricular dysfunction. A total of 729 (22.0%) patients died, 498 (15.1%) from cardiovascular causes. Adjusted all-cause and cardiovascular mortality rates were similar with amiodarone versus rate control overall and in subgroups with and without severe left ventricular dysfunction. CONCLUSION: Amiodarone's efficacy in maintaining sinus rhythm and reducing the burden of atrial fibrillation is similar in the presence or absence of severe left ventricular dysfunction. Rhythm control with amiodarone is associated with comparable hospitalization and mortality rates to rate control in patients with and without left ventricular dysfunction.

Heart failure with anemia: novel findings on the roles of renal disease, interleukins, and specific left ventricular remodeling processes.

BACKGROUND: Anemia is a highly prevalent and strong independent prognostic marker in heart failure (HF), yet this association is not completely understood. Whether anemia is simply a marker of disease severity and concomitant chronic kidney disease or represents the activation of other detrimental pathways remains uncertain. We sought to determine which pathophysiological pathways are exacerbated in patients with HF, reduced ejection fraction (HFrEF) and anemia in comparison with those without anemia. METHODS AND RESULTS: In a prospective study involving 151 patients, selected biomarkers were analyzed, each representing proposed contributive mechanisms in the pathophysiology of anemia in HF. We compared clinical, echocardiographic, and circulating biomarkers profiles among patients with HFrEF and anemia (group 1), HFrEF without anemia (group 2), and chronic kidney disease with preserved EF, without established HF (chronic kidney disease control group 3). We demonstrate here that many processes other than those related to chronic kidney disease are involved in the anemia-HF relationship. These are linked to the pathophysiological mechanisms pertaining to left ventricular systolic dysfunction and remodeling, systemic inflammation and volume overload. We found that levels of interleukin-6 and interleukin-10, specific markers of cardiac remodeling (procollagen type III N-terminal peptide, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase 1, left atrial volume), myocardial stretch (NT-proBNP [N-terminal probrain natriuretic peptide]), and myocyte death (troponin T) are related to anemia in HFrEF. CONCLUSIONS: Anemia is strongly associated not only with markers of more advanced and active heart disease but also with the level of renal dysfunction in HFrEF. Increased myocardial remodeling, inflammation, and volume overload are the hallmarks of patients with anemia and HF. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00834691.