Degree of multilingual engagement modulates resting state oscillatory activity across the lifespan.

Multilingualism has been demonstrated to lead to a more favorable trajectory of neurocognitive aging, yet our understanding of its effect on neurocognition across the lifespan remains limited. We collected resting state EEG recordings from a sample of multilingual individuals across a wide age range. Additionally, we obtained data on participant multilingual language use patterns alongside other known lifestyle enrichment factors. Language experience was operationalized via a modified multilingual diversity (MLD) score. Generalized additive modeling was employed to examine the effects and interactions of age and MLD on resting state oscillatory power and coherence. The data suggest an independent modulatory effect of individualized multilingual engagement on age-related differences in whole brain resting state power across alpha and theta bands, and an interaction between age and MLD on resting state coherence in alpha, theta, and low beta. These results provide evidence of multilingual engagement as an independent correlational factor related to differences in resting state EEG power, consistent with the claim that multilingualism can serve as a protective factor in neurocognitive aging.

Safety, Tolerability, and Pharmacodynamics of AZD3366 (Optimized Human CD39L3 Apyrase) Alone and in Combination With Ticagrelor and Acetylsalicylic Acid: A Phase 1, Randomized, Placebo-Controlled Study.

BACKGROUND: ADP and ATP are importantly involved in vascular and thrombotic homeostasis, via multiple receptor pathways. Blockade of ADP P2Y12 receptors inhibits platelet aggregation and represents an effective cardiovascular disease prevention strategy. AZD3366 (APT102), a long-acting recombinant form of an optimized CD39L3 human apyrase, has effectively reduced ATP, ADP, and platelet aggregation and provided tissue protection in preclinical models, features that could be very beneficial in treating patients with cardiovascular disease. METHODS AND RESULTS: We conducted this phase 1, first-in-human study of single ascending doses of intravenous AZD3366 or placebo, including doses added to dual antiplatelet therapy with ticagrelor and acetylsalicylic acid. The primary objective was safety and tolerability; secondary and exploratory objectives included pharmacokinetics, pharmacodynamics (measured as inhibition of platelet aggregation), adenosine diphosphatase (ADPase) activity, and ATP/ADP metabolism. In total, 104 participants were randomized. AZD3366 was generally well tolerated, with no major safety concerns observed. ADPase activity increased in a dose-dependent manner with a strong correlation to AZD3366 exposure. Inhibition of ADP-stimulated platelet aggregation was immediate, substantial, and durable. In addition, there was a prompt decrease in systemic ATP concentration and an increase in adenosine monophosphate concentrations, whereas ADP concentration appeared generally unaltered. At higher doses, there was a prolongation of capillary bleeding time without detectable changes in the ex vivo thromboelastometric parameters. CONCLUSIONS: AZD3366 was well tolerated in healthy participants and demonstrated substantial and durable inhibition of platelet aggregation after single dosing. Higher doses prolonged capillary bleeding time without detectable changes in ex vivo thromboelastometric parameters. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04588727.

Balcinrenone plus dapagliflozin in patients with heart failure and chronic kidney disease: Results from the phase 2b MIRACLE trial.

AIMS: Many patients with heart failure (HF) have chronic kidney disease (CKD) and may not tolerate mineralocorticoid receptor antagonists. We investigated the efficacy and safety of the novel mineralocorticoid receptor modulator balcinrenone in combination with dapagliflozin in a phase 2b study. METHODS AND RESULTS: From January 2021 to October 2023, we randomized 133 adults with symptomatic HF, ejection fraction <60%, estimated glomerular filtration rate (eGFR) ≥30 to ≤60 ml/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) ≥30 to <3000 mg/g, to receive balcinrenone 15, 50 or 150 mg/day plus dapagliflozin 10 mg/day, or dapagliflozin 10 mg/day plus placebo, for 12 weeks. Enrolment was stopped early because of slow recruitment. Relative reductions in UACR from baseline to week 12 (primary endpoint) were not significantly different between the balcinrenone plus dapagliflozin groups versus dapagliflozin plus placebo. There was no clear balcinrenone dose-response relationship. There were possible dose-dependent increases in serum potassium levels, reduced eGFR in the highest dose group, and non-significant trends towards reduced N-terminal pro-B-type natriuretic peptide levels. Hyperkalaemia adverse events led to discontinuation in two participants receiving balcinrenone plus dapagliflozin and none in those receiving dapagliflozin plus placebo. CONCLUSION: While the smaller than planned sample size limits interpretation, we did not see significant reduction in UACR in patients treated with balcinrenone plus dapagliflozin compared with dapagliflozin plus placebo.

Recombinant human soluble domain of CD39L3 and ticagrelor: cardioprotective effects in experimental myocardial infarction.

BACKGROUND AND AIMS: The ecto-nucleoside triphosphate diphosphohydrolases of the CD39 family degrade ATP and ADP into AMP, which is converted into adenosine by the extracellular CD73/ecto-5-nucleotidase. This pathway has been explored in antithrombotic treatments but little in myocardial protection. We have investigated whether the administration of solCD39L3 (AZD3366) confers additional cardioprotection to that of ticagrelor alone in a pre-clinical model of myocardial infarction (MI). METHODS: Ticagrelor-treated pigs underwent balloon-induced MI (90 min) and, before reperfusion, received intravenously either vehicle, 1 mg/kg AZD3366 or 3 mg/kg AZD3366. All animals received ticagrelor twice daily for 42 days. A non-treated MI group was run as a control. Serial cardiac magnetic resonance (baseline, Day 3 and Day 42 post-MI), light transmittance aggregometry, bleeding time, and histological and molecular analyses were performed. RESULTS: Ticagrelor reduced oedema formation and infarct size at Day 3 post-MI vs. controls. A 3 mg/kg AZD3366 provided an additional 45% reduction in oedema and infarct size compared with ticagrelor and a 70% reduction vs. controls (P < .05). At Day 42, infarct size declined in all ticagrelor-administered pigs, particularly in 3 mg/kg AZD3366-treated pigs (P < .05). Left ventricular ejection fraction was diminished at Day 3 in placebo pigs and worsened at Day 42, whereas it remained unaltered in ticagrelor ± AZD3366-administered animals. Pigs administered with 3 mg/kg AZD3366 displayed higher left ventricular ejection fraction upon dobutamine stress at Day 3 and minimal dysfunctional segmental contraction at Day 42 (χ2P < .05 vs. all). Cardiac and systemic molecular readouts supported these benefits. Interestingly, AZD3366 abolished ADP-induced light transmittance aggregometry without affecting bleeding time. CONCLUSIONS: Infusion of AZD3366 on top of ticagrelor leads to enhanced cardioprotection compared with ticagrelor alone.

Myeloperoxidase Inhibition in Heart Failure With Preserved or Mildly Reduced Ejection Fraction: SATELLITE Trial Results.

BACKGROUND: Inflammation is a key driver of heart failure with preserved left ventricular ejection fraction. AZD4831 inhibits extracellular myeloperoxidase, decreases inflammation, and improves microvascular function in preclinical disease models. METHODS AND RESULTS: In this double-blind phase 2a study (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure [SATELLITE]; NCT03756285), patients with symptomatic heart failure, left ventricular ejection fraction of ≥40%, and elevated B-type natriuretic peptides were randomized 2:1 to once-daily oral AZD4831 5 mg or placebo for 90 days. We aimed to assess target engagement (primary end point: myeloperoxidase specific activity) and safety of AZD4831. Owing to coronavirus disease 2019, the study was terminated early after randomizing 41 patients (median age 74.0 years, 53.7% male). Myeloperoxidase activity was decreased by more than 50% from baseline to day 30 and day 90 in the AZD4831 group, with a placebo-adjusted decreased of 75% (95% confidence interval, 48, 88, nominal P < .001). No improvements were noted in secondary or exploratory end points, apart from a trend in Kansas City Cardiomyopathy Questionnaire overall summary score. No deaths or treatment-related serious adverse events occurred. AZD4831 treatment-related adverse events were generalized maculopapular rash, pruritus, and diarrhea (all n = 1). CONCLUSIONS: AZD4831 inhibited myeloperoxidase and was well tolerated in patients with heart failure and left ventricular ejection fraction of 40% or greater. Efficacy findings were exploratory owing to early termination, but warrant further clinical investigation of AZD4831. LAY SUMMARY: Few treatments are available for patients with the forms of heart failure known as heart failure with preserved or mildly reduced ejection fraction. Current treatments do not target inflammation, which may play an important role in this condition. We tested a new drug called AZD4831 (mitiperstat), which decreases inflammation by inhibiting the enzyme myeloperoxidase. Among the 41 patients in our clinical trial, AZD4831 had a good safety profile and inhibited myeloperoxidase by the expected amount. Results mean we can conduct further trials to see whether AZD4831 decreases the symptoms of heart failure and improves patients' ability to participate in physical exercise.

Rationale and design of ENDEAVOR: A sequential phase 2b-3 randomized clinical trial to evaluate the effect of myeloperoxidase inhibition on symptoms and exercise capacity in heart failure with preserved or mildly reduced ejection fraction.

AIMS: Mitiperstat (formerly AZD4831) is a novel selective myeloperoxidase inhibitor. Currently, no effective therapies target comorbidity-induced systemic inflammation, which may be a key mechanism underlying heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). Circulating neutrophils secrete myeloperoxidase, causing oxidative stress, microvascular endothelial dysfunction, interstitial fibrosis, cardiomyocyte remodelling and diastolic dysfunction. Mitiperstat may therefore improve function of the heart and other organs, and ameliorate heart failure symptoms and exercise intolerance. ENDEAVOR is a combined, seamless phase 2b-3 study of the efficacy and safety of mitiperstat in patients with HFpEF/HFmrEF. METHODS: In phase 2b, approximately 660 patients with heart failure and ejection fraction >40% are being randomized 1:1:1 to mitiperstat 2.5 mg, 5 mg or placebo for 48 weeks. Eligible patients have baseline 6-min walk distance (6MWD) of 30-400 m with a <50 m difference between screening and randomization and Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) ≤90 points at screening and randomization. The dual primary endpoints are change from baseline to week 16 in 6MWD and KCCQ-TSS. The sample size provides 85% power to detect placebo-adjusted improvements of 21 m in 6MWD and 6.0 points in KCCQ-TSS at overall two-sided alpha of 0.05. Safety is monitored throughout treatment, with a focus on maculopapular rash. In phase 3 of ENDEAVOR, approximately 820 patients will be randomized 1:1 to mitiperstat or placebo. CONCLUSION: ENDEAVOR is the first phase 2b-3 study to evaluate whether myeloperoxidase inhibition can improve symptoms and exercise capacity in patients with HFpEF/HFmrEF.

Myeloperoxidase Inhibition Reverses Biomarker Profiles Associated With Clinical Outcomes in HFpEF.

BACKGROUND: Systemic microvascular dysfunction and inflammation are postulated to play a pathophysiologic role in heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: This study aimed to identify biomarker profiles associated with clinical outcomes in HFpEF and investigate how inhibition of the neutrophil-derived reactive oxygen species-producing enzyme, myeloperoxidase, affects these biomarkers. METHODS: Using supervised principal component analyses, the investigators assessed the associations between baseline plasma proteomic Olink biomarkers and clinical outcomes in 3 independent observational HFpEF cohorts (n = 86, n = 216, and n = 242). These profiles were then compared with the biomarker profiles discriminating patients treated with active drug vs placebo in SATELLITE (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure), a double-blind randomized 3-month trial evaluating safety and tolerability of the myeloperoxidase inhibitor AZD4831 in HFpEF (n = 41). Pathophysiological pathways were inferred from the biomarker profiles by interrogation of the Ingenuity Knowledge Database. RESULTS: TNF-R1, TRAIL-R2, GDF15, U-PAR, and ADM were the top individual biomarkers associated with heart failure hospitalization or death, and FABP4, HGF, RARRES2, CSTB, and FGF23 were associated with lower functional capacity and poorer quality of life. AZD4831 downregulated many markers (most significantly CDCP1, PRELP, CX3CL1, LIFR, VSIG2). There was remarkable consistency among pathways associated with clinical outcomes in the observational HFpEF cohorts, the top canonical pathways being associated with tumor microenvironments, wound healing signaling, and cardiac hypertrophy signaling. These pathways were predicted to be downregulated in AZD4831 relative to placebo-treated patients. CONCLUSIONS: Biomarker pathways that were most strongly associated with clinical outcomes were also the ones reduced by AZD4831. These results support the further investigation of myeloperoxidase inhibition in HFpEF.

Effect of AZD9977 and spironolactone on serum potassium in heart failure with preserved or mildly reduced ejection fraction, and renal impairment: A randomized trial.

This phase Ib study compared the effects of AZD9977, a selective mineralocorticoid receptor modulator with predicted low hyperkalemia risk, with spironolactone on serum potassium (sK+ ) in patients with heart failure (HF) with preserved or mildly reduced ejection fraction (EF; ≥40%), and renal impairment. Patients with HF with EF greater than or equal to 40% and estimated glomerular filtration rate of 40-70 ml/min/1.73 m2 were randomized to once-daily AZD9977 100 mg or spironolactone 25 mg for 14 days, up-titrated to AZD9977 200 mg or spironolactone 50 mg for another 14 days. The primary end point was relative change (%) in sK+ for AZD9977 versus spironolactone (baseline to day 28). Serum/urinary electrolytes, fractional excretion (FE) of Na+ /K+ , plasma aldosterone, cortisol, and renin, and safety were also assessed. Sixty-eight patients were randomized (AZD9977, n = 33; spironolactone, n = 35). Mean (SD) age was 73.0 (8.5) years, 51.5% men. Mean sK+ change from baseline to day 28 was 5.7% (AZD9977) and 4.2% (spironolactone), and 1.5% and 4.2% at day 14. Relative change (95% confidence interval) in sK+ with AZD9977 versus spironolactone was -0.3% (-5.3% to 4.4%; day 28), and 3.4% (-0.8% to 7.5%; day 14). Median increase from baseline in plasma aldosterone at day 28 was 89.8 pmol/L for AZD9977 and 67.4 pmol/L for spironolactone. Median FE of K+ was 12.9% (AZD9977) and 10.1% (spironolactone). AZD9977 was well-tolerated. No discontinuations due to hyperkalemia occurred with either treatment. Evidence of target engagement for AZD9977 with a favorable safety profile, supports further evaluation of AZD9977 in patients with HF and renal impairment.

Safety and efficacy of the 5-lipoxygenase-activating protein inhibitor AZD5718 in patients with recent myocardial infarction: The phase 2a FLAVOUR study.

BACKGROUND: Leukotrienes are pro-inflammatory vasoactive lipid mediators implicated in the pathophysiology of atherosclerotic cardiovascular disease. We studied the effect of the 5-lipoxygenase-activating protein inhibitor AZD5718 on leukotriene biosynthesis and coronary microvascular function in a single-blind, phase 2a study. METHODS: Patients 7-28 days after myocardial infarction (±ST elevation), with <50% left anterior descending coronary artery stenosis and Thrombolysis in Myocardial Infarction flow grade ≥ 2 after percutaneous coronary intervention, were randomized 2:1:2 to once-daily AZD5718 200 mg or 50 mg, or placebo, in 4- and 12-week cohorts. Change in urine leukotriene E4 (uLTE4) was the primary endpoint, and coronary flow velocity reserve (CFVR; via echocardiography) was the key secondary endpoint. RESULTS: Of 129 randomized patients, 128 received treatment (200 mg, n = 52; 50 mg, n = 25; placebo, n = 51). Statistically significant reductions in uLTE4 levels of >80% were observed in both AZD5718 groups versus the placebo group at 4 and 12 weeks. No significant changes in CFVR were observed for AZD5718 versus placebo. Adverse events (AEs) occurred in 12/18, 3/6 and 6/13 patients receiving 200 mg, 50 mg and placebo, respectively, in the 4-week cohort, and in 27/34, 14/19 and 24/38 patients, respectively, in the 12-week cohort. Serious AEs in seven patients receiving AZD5718 and four receiving placebo were not treatment-related, and there were no deaths. CONCLUSIONS: In patients with recent myocardial infarction, AZD5718 was well tolerated, and leukotriene biosynthesis was dose-dependently inhibited. No significant changes in CFVR were detected. CLINICALTRIALS: gov identifier: NCT03317002.

Pharmacokinetics, Pharmacodynamics, and Tolerability of AZD5718, an Oral 5-Lipoxygenase-Activating Protein (FLAP) Inhibitor, in Healthy Japanese Male Subjects.

BACKGROUND AND OBJECTIVE: AZD5718, a 5-lipoxygenase-activating protein (FLAP) inhibitor, is in clinical development for treatment of coronary artery disease (CAD) and chronic kidney disease (CKD). This study evaluated AZD5718 pharmacokinetics, pharmacodynamics, and tolerability in healthy male Japanese subjects. METHODS: Four cohorts of eight Japanese subjects were randomized to receive oral doses of AZD5718 (60, 180, 360, and 600 mg) or matching placebo administered as a single dose on Day 1 and as once-daily doses from Day 3 to Day 10 in fasted conditions. Pharmacokinetic, pharmacodynamic, and safety data were collected. RESULTS: The pharmacokinetics characteristics of AZD5718 in Japanese male subjects were similar to those reported in a previous study, and the pharmacokinetics were characterized as rapid absorption with median time to reach maximum concentration (Tmax) of 1-2 h Creatine-normalized urine maximum concentration (Cmax) with mean half-lives ranging from 8 to 21 h, and supra-proportional increase in exposure over the 60-600 mg dose range evaluated. Also, an increase in steady-state area under the concentration-time curve (AUC) compared to the first dose was observed. After both single and multiple doses of AZD5718, a clear dose/concentration-effect relationship was shown for urinary leukotriene E4 (LTE4) versus AZD5718 exposure with > 80 % inhibition at plasma concentrations in the lower nM range. No clinically relevant safety and tolerability findings were observed. CONCLUSIONS: The observed pharmacokinetics and pharmacodynamics were similar to reported data for non-Japanese healthy subjects, which support further evaluation of AZD5718 at similar doses/exposures in Japanese and non-Japanese subjects for future evaluation in patients with CAD and CKD.

Arginase 1 is upregulated at admission in patients with ST-elevation myocardial infarction.

BACKGROUND: The mechanisms underlying rupture of a coronary atherosclerotic plaque and development of myocardial ischemia-reperfusion injury in ST-elevation myocardial infarction (STEMI) remain unresolved. Increased arginase 1 activity leads to reduced nitric oxide (NO) production and increased formation of reactive oxygen species due to uncoupling of the NO-producing enzyme endothelial NO synthase (eNOS). This contributes to endothelial dysfunction, plaque instability and increased susceptibility to ischemia-reperfusion injury in acute myocardial infarction. OBJECTIVE: The purpose of this study was to test the hypothesis that arginase gene and protein expression are upregulated in patients with STEMI. METHODS: Two cohorts of patients with STEMI were included. In the first cohort (n = 51), expression of arginase and NO-synthases as well as arginase 1 protein levels were determined and compared to a healthy control group (n = 45). In a second cohort (n = 68), plasma arginase 1 levels and infarct size were determined using cardiac magnetic resonance imaging. RESULTS: Expression of the gene encoding arginase 1 was significantly elevated at admission and 24-48 h after STEMI but not 3 months post STEMI, in comparison with the control group. Expression of the genes encoding arginase 2 and endothelial NO synthase (NOS3) were unaltered. Arginase 1 protein levels were elevated at admission, 24 h post STEMI and remained elevated for up to 6 months. No significant correlation between plasma arginase 1 protein levels and infarct size was observed. CONCLUSION: The markedly increased gene and protein expression of arginase 1 already at admission indicates a role of arginase 1 in the development of STEMI.

Endothelin-1 increases expression and activity of arginase 2 via ETB receptors and is co-expressed with arginase 2 in human atherosclerotic plaques.

BACKGROUND AND AIMS: Endothelin-1 (ET-1) and arginase are both suggested to be involved in the inflammatory processes and development of endothelial dysfunction in atherosclerosis. However, information regarding the roles of ET-1 and arginase, as well as the interactions between the two in human atherosclerosis, is scarce. We investigated the expression of ET-1 and its receptors, ETA and ETB, as well as arginase in human carotid atherosclerotic plaques and determined the functional interactions between ET-1 and arginase in endothelial cells and THP-1-derived macrophages. METHODS: Carotid plaques and blood samples were retreived from patients undergoing surgery for symptomatic or asymptomatic carotid stenosis. Plaque gene and protein expression was determined and related to clinical characteristics. Functional interactions between ET-1 and arginase were investigated in endothelial cells and THP-1 cells. RESULTS: Expression of ET-1 and ETB receptors was increased in plaques from patients with symptomatic carotid artery disease. ET-1 was co-localized with arginase 1 and arginase 2 in the necrotic core, together with macrophage markers CD163 and CD68. Arginase 2, ET-1 and ETB receptors were expressed in endothelial cells as well as in smooth muscle cells in the fibrous cap. ET-1 increased arginase 2 mRNA expression and arginase activity in endothelial cells and arginase activity in macrophages. Moreover, ET-1 stimulated formation of reactive oxygen species (ROS) in THP-1-derived macrophages via an arginase-dependent mechanism. CONCLUSIONS: This is the first study that demonstrates co-localization of ET-1 and arginase 2 in human atherosclerotic plaques. ET-1 stimulated arginase 2 expression and activity in endothelial cells, as well as arginase activity and ROS formation in macrophages via an arginase-dependent mechanism. These results indicate an important interaction between the ET pathway and arginase in human atherosclerotic plaques.

High-sensitivity C-reactive protein and the risk of chronic kidney disease progression or acute kidney injury in post-myocardial infarction patients.

BACKGROUND: Persistent, low-grade inflammation likely participates in the pathophysiology of both atherosclerosis and kidney disease. Although high-sensitivity C-reactive protein (hsCRP) predicts future cardiovascular risk in patients with chronic kidney disease (CKD), it is unknown whether hsCRP levels predict adverse renal outcomes in patients with cardiovascular disease. METHODS: We studied all myocardial infarction (MI) survivors undergoing hsCRP testing >30 days after their MI during routine health care in Stockholm, Sweden (2006-2011), with available information on estimated glomerular filtration rate (eGFR). HsCRP tests measured during hospitalization/emergency room visits, followed by antibiotics or indicative of acute illness, were excluded, together with patients with ongoing/recent cancer, chronic infections, or immunosuppression. Inflammation was defined over a 3-month baseline window. Study outcomes were CKD progression (composite of doubling plasma creatinine, renal replacement therapy, or renal death) and acute kidney injury (AKI, acute creatinine peaks according to Kidney Disease: Improving Global Outcomes criteria). Multivariable Cox regression was used to adjust for age, sex, eGFR, hemoglobin, time since MI, comorbidities, undertaken procedures, and medications. RESULTS: A total of 12,905 patients (62% men, mean age 73 years and 3 years since MI) were included, of whom 35% had an eGFR<60 mL/min/1.73 m2. The mean (SD) hsCRP was 3.0 (4.4) mg/L. Baseline hsCRP levels were increasingly higher across lower eGFR categories. During a median follow-up of 3.2 years, 1,019 CKD progressions and 1,481 AKI events were recorded. Patients with hsCRP ≥2 mg/L were at higher risk of both CKD progression (adjusted hazard ratio 1.42; 95% CI 1.21-1.66) and AKI (1.29; 1.13-1.47) compared to those with hsCRP <2 mg/L. This association persisted across single CKD severity stages and after further hsCRP categorization into 4 groups (≤1, 1-3, 3-10, >10 mg/L). Results were robust across subgroups of patients and after exclusion of events occurring during the first 6-12 months. CONCLUSIONS: In post-MI patients undergoing routine health care, elevated hsCRP was associated with subsequent risk of AKI and progression of CKD, irrespective of baseline kidney function.

hsCRP Level and the Risk of Death or Recurrent Cardiovascular Events in Patients With Myocardial Infarction: a Healthcare-Based Study.

Background Beyond the controlled setting of trials, scarce information exists on the burden, predictors, and outcomes associated with elevated hs CRP (high-sensitivity C-reactive protein) in "real-world" patients with myocardial infarction ( MI ). Methods and Results We included all-coming MI survivors undergoing hs CRP testing >30 days after an MI during routine health care in Stockholm, Sweden (2006-2011). hs CRP tests measured during hospitalization/emergency department visits, followed by antibiotics or indicative of acute illness, were excluded, together with patients with ongoing/recent cancer, chronic infections, or immunosuppression. Inflammation was defined over a 3-month baseline window and associated with subsequent death and major adverse cardiovascular events (composite of MI, ischemic stroke, or cardiovascular death). Included were 17 464 patients (63% men; mean age, 72.6 years) with a median hs CRP level of 2.2 (interquartile range, 1.0-6.0) mg/L and a median of 2.2 (interquartile range, 0.8-4.9) years since their MI . Most (66%) had hs CRP ≥2 mg/L, and 40% had hs CRP >3 mg/L. Lower hemoglobin, lower estimated glomerular filtration rate, and comorbidities (eg, heart failure, peripheral vascular disease, stroke, atrial fibrillation, diabetes mellitus, and rheumatoid diseases) were associated with higher odds of hs CRP ≥2 mg/L. Conversely, previous percutaneous coronary intervention, ongoing renin-angiotensin blockade, and statins were associated with lower hs CRP ≥2 mg/L odds. Patients with hs CRP ≥2 mg/L were at higher risk of major adverse cardiovascular events (n=3900; adjusted hazard ratio, 1.28; 95% CI, 1.18-1.38) and death (n=4138; adjusted hazard ratio, 1.42; 95% CI, 1.31-1.53). Results were robust across subgroups of patients and after exclusion of events occurring during the first 6 to 12 months. On a continuous scale, the association between hs CRP and outcomes was linear until hs CRP >5 mg/L, plateauing thereafter. Conclusions Most patients with MI exhibit elevated hs CRP levels. Besides identifying populations at high-inflammatory risk, this study extends the prognostic validity of this biomarker from trial evidence to real-world healthcare settings.

Diagnostic approach for cardiac involvement in sarcoidosis.

AIMS: Cardiac sarcoidosis (CS) is a potentially life-threatening condition. Early detection of CS is therefore important. The aim of this study was to eludicate the usefulness of different investigations in a subgroup of patients with sarcoidosis regarded as having an increased risk for cardiac involvement. METHODS: 42 sarcoidosis patients, who had an abnormal resting electrocardiogram (ECG) and/or symptoms indicating possible cardiac involvement (i.e. palpitations, pre-syncope or syncope), were included in the study. They were identified in a consecutive manner among patients followed-up at outpatient clinics for respiratory disorders. Holter monitoring, exercise test, transthoracic echocardiogram (TTE), cardiovascular magnetic resonance (CMR) and analysis of N-terminal pro B-type natriuretic peptide (NT-pro-BNP) in serum were performed. Note, that the role of FDG-PET was not investigated in this study. RESULTS: In the group with a pathologic ECG 11/25 (44%) were ultimately diagnosed with CS (all with pathologic CMR). However, in the group with only symptoms but a normal ECG just 1/17 got the diagnosis CS (p<0.05). This patient had a pathologic Holter monitoring. The risk for CS was increased if serum NT-pro-BNP was elevated (i.e. NT-pro-BNP>125 ng/L), sensitivity 78% (p<0.05), specificity 67%. By adding a pathologic ECG to an elevated NT-pro-BNP increased specificity to 93% and sensitivity remained at 78%. CONCLUSION: Our findings indicate that CMR should be performed at an early stage in sarcoidosis patients with an abnormal resting ECG. Holter monitoring and elevated levels of NT-pro-BNP may enhance the diagnostic accuracy whereas exercise testing and TTE in this study had less impact on the identification of CS.

Copeptin in Heart Failure, Post-Left Ventricular Assist Device and Post-Heart Transplantation.

BACKGROUND: Heart failure (HF) is associated with pathological activation of arginine vasopressin, measured in plasma by the pre-hormone fragment copeptin. We hypothesised that copeptin is elevated and associated with worse prognosis in HF, and that left ventricular assist device (LVAD) therapy and heart transplantation (HTx) are associated with lower levels of copeptin. METHODS: We measured copeptin in groups of 49 patients with advanced HF, 13 patients one year post-LVAD and 22 patients one year post-HTx and correlated with clinical data and cardiac output. In HF we also assessed the prognostic role of copeptin with Kaplan-Meier analysis and multivariate Cox regression. RESULTS: In HF, median (interquartile range) copeptin was 28 (18-45) pmol/L, after LVAD 16 (6-27) pmol/L, and after HTx 12 (5-20) pmol/L (p overall <0.001). In HF, copeptin was an independent predictor of death, LVAD or HTx (hazard ratio for log copeptin, 3.28 [95% confidence interval: 1.66-6.50], p=0.001). CONCLUSIONS: Copeptin was elevated in, and independently predicted prognosis in, HF. Copeptin was progressively lower after LVAD and HTx. This suggests that improvement in cardiac output with LVAD and HTx may induce progressively reduced activation of vasopressin, which may be a marker for the beneficial effects of LVAD and HTx.

MicroRNA 486-3P as a stability marker in acute coronary syndrome.

Easily accessible biomarkers are needed to diagnose cardiovascular disease precisely-particularly, to distinguish between disease subtypes that are encountered in clinical practice. Per the hypothesis that plasma miRNA is valuable for this purpose, we performed complete transcriptional profiling of an miRNA discovery-set in 14 samples: three patients with ST-elevated acute myocardial infarction (STEMI) at baseline and after three months of follow-up, four with stable ischaemic heart disease (stable-IHD) and four healthy age-matched volunteers. Our aim was to determine whether we could distinguish patients with unstable plaques from stable patients following a STEMI event. After analysing miRNA profiles, we conducted a validation study comparing three-month STEMI (n=40) with stable-IHD (n=35), which confirmed that miR-486-3P differentiates patients with three-month STEMI from those with stable-IHD (P=0.019).

Adaptive cardiovascular hormones in a spectrum of heart failure phenotypes.

BACKGROUND/OBJECTIVES: In heart failure (HF), activation of brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and adrenomedullin (ADM) is adaptive. The activation of these peptides in relation to different HF phenotypes such as HF with preserved ejection fraction (HFpEF), reduced ejection fraction (HFrEF) and after left ventricular assist device (LVAD) and heart transplantation (HTx) remains poorly characterized. METHODS: We measured and compared N-terminal (NT)-proBNP, mid-regional (MR)-proANP and mid-regional (MR)-proADM in 86 patients with HFpEF, 49 patients with HFrEF, 13 patients one year post-LVAD and 22 patients one year post-HTx. We assessed their prognostic impact using Kaplan-Meier analysis and multivariable Cox regression. RESULTS: In HFpEF, HFrEF, LVAD and HTx, NT-proBNP, median (inter-quartile range), was 1000 (465-2335), 3145 (1475-5190), 1430 (986-2570), and 208 (127-353) pmol/L, p < 0.001. MR-proANP was 313 (192-381), 449 (325-596), 276 (216-305), and 118 (96-163) pmol/L, p < 0.001. MR-proADM was 1.2 (0.9-1.6), 1.3 (0.9-2.0), 0.9 (0.7-1.4), and 0.7 (0.6-0.9) nmol/L, p < 0.001 overall and p = 0.212 HFpEF versus HFrEF. In both HFpEF and HFrEF, NT-proBNP and MR-proANP predicted survival free from HTx or LVAD, independent of age, gender, NYHA class and eGFR, whereas MR-proADM did not. CONCLUSIONS: Patterns of the cardiomyocyte stress hormones NT-proBNP and MR-proANP suggest that compared to HFrEF, HFpEF may represent milder disease and LVAD and HTx may represent progressive resolution of HF severity. NT-proBNP and MR-proANP independently predicted prognosis in both HFpEF and HFrEF. In contrast, MR-proADM did not distinguish between HFpEF and HFrEF, did not predict prognosis in either, and may be more non-specific in HF.

Gender differences in myocardial function and arterio-ventricular coupling in response to maximal exercise in adolescent floor-ball players.

BACKGROUND: The hemodynamic and cardiac responses to exercise have been widely investigated in adults. However, little is known regarding myocardial performance in response to a short bout of maximal exercise in adolescents. We therefore sought to study alterations in myocardial function and investigate sex-influences in young athletes after maximal cardiopulmonary testing. METHODS: 51 adolescent (13-19 years old) floor-ball players (24 females) were recruited. All subjects underwent a maximal exercise test to determine maximal oxygen uptake (VO2max) and cardiac output. Cardiac performance was investigated using conventional and tissue velocity imaging, as well as 2D strain echocardiography before and 30 minutes following exercise. Arterio-ventricular coupling was evaluated by means of single beat ventricular elastance and arterial elastance. RESULTS: Compared to baseline the early diastolic myocardial velocity (E'LV) at the basal left ventricular (LV) segments declined significantly (females: E'LV: 14.7 +/- 2.6 to 13.6 +/- 2.9 cm/s; males: 15.2 +/- 2.2 to 13.9 +/- 2.3 cm/s, p < 0.001 for both). Similarly, 2D strain decreased significantly following exercise (2D strain LV: from 21.5 +/- 2.4 to 20.2 +/- 2.7% in females, and from 20 +/- 1 to 17.9 +/- 1.5% in males, p < 0.05 for both). However, there were no significant changes in LV contractility estimated by elastance in either sex following exercise (p > 0.05). Arterial elastance) Ea) at baseline was identified as the only predictor of VO2max in males (r = 0.76, p < 0.001) but not in females (p > 0.05). CONCLUSIONS: The present study demonstrates that vigorous exercise of short duration results in a significant decrease of longitudinal myocardial motion in both sexes. However, in view of unaltered end systolic LV elastance (Ees), these reductions most probably reflect changes in the loading conditions and not an attenuation of myocardial function per se. Importantly, we show that arterial load at rest acts as a strong predictor of VO2max in males but not in female subjects.