Ferric Carboxymaltose in Heart Failure with Iron Deficiency.

BACKGROUND: Ferric carboxymaltose therapy reduces symptoms and improves quality of life in patients who have heart failure with a reduced ejection fraction and iron deficiency. Additional evidence about the effects of ferric carboxymaltose on clinical events is needed. METHODS: In this double-blind, randomized trial, we assigned ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency, in a 1:1 ratio, to receive intravenous ferric carboxymaltose or placebo, in addition to standard therapy for heart failure. Ferric carboxymaltose or placebo was given every 6 months as needed on the basis of iron indexes and hemoglobin levels. The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. The significance level was set at 0.01. RESULTS: We enrolled 3065 patients, of whom 1532 were randomly assigned to the ferric carboxymaltose group and 1533 to the placebo group. Death by month 12 occurred in 131 patients (8.6%) in the ferric carboxymaltose group and 158 (10.3%) in the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean (±SD) change from baseline to 6 months in the 6-minute walk distance was 8±60 and 4±59 m, respectively (Wilcoxon-Mann-Whitney P = 0.02; unmatched win ratio, 1.10; 99% confidence interval, 0.99 to 1.23). Repeated dosing of ferric carboxymaltose appeared to be safe with an acceptable adverse-event profile in the majority of patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (413 patients [27.0%] in the ferric carboxymaltose group and 401 [26.2%] in the placebo group). CONCLUSIONS: Among ambulatory patients who had heart failure with a reduced ejection fraction and iron deficiency, there was no apparent difference between ferric carboxymaltose and placebo with respect to the hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance. (Funded by American Regent, a Daiichi Sankyo Group company; HEART-FID ClinicalTrials.gov number, NCT03037931.).

Determination of Clinically Acceptable Analytical Variation of Cardiac Troponin at Decision Thresholds.

BACKGROUND: Clinical decision-making for risk stratification for possible myocardial infarction (MI) uses high-sensitivity cardiac troponin (hs-cTn) thresholds that range from the limit of detection to several-fold higher than the upper reference limit (URL). To establish a minimum analytical variation standard, we can quantify the effect of variation on the population clinical measures of safety (sensitivity) and effectiveness [proportion below threshold, or positive predictive value (PPV)]. METHODS: From large datasets of patients investigated for possible MI with the Abbott hs-cTnI and Roche hs-cTnT assays, we synthesized datasets of 1 000 000 simulated patients. Troponin concentrations were randomly varied several times based on absolute deviations of 0.5 to 3 ng/L and relative changes of 2% to 20% around the low-risk threshold (5 ng/L) and URLs, respectively. RESULTS: For both assays at the low-risk thresholds, there were negligible differences in sensitivity (<0.3%) with increasing analytical variation. The proportion of patients characterized as low risk reduced by 30% to 29% (Roche) and 53% to 44% (Abbott). At the URL, increasing analytical variation also did not change sensitivity; the PPV fell by less than 3%. For risk stratification, increased delta thresholds (change between serial troponin concentrations) increased sensitivity at the cost of a decreased percentage of patients below the delta threshold, with the largest changes at the greatest analytical variation. CONCLUSIONS: At the low-risk threshold, analytical variation up to 3 ng/L minimally impacted the safety metric (sensitivity) but marginally reduced effectiveness. Similarly, at the URL even relative variation up to 25% minimally impacted safety metrics and effectiveness. Analytical variation for delta thresholds did not negatively impact sensitivity but decreased effectiveness.

Dietary Sodium Intake and Outcomes: a Secondary Analysis From Sodium-HF.

OBJECTIVES: This post hoc analysis of SODIUM-HF (Study of Dietary Intervention under 100 mmol in Heart Failure) assessed the association between baseline dietary sodium intake and change at 6 months with a composite of cardiovascular (CV) hospitalizations, emergency department visits and all-cause death at 12 and 24 months. BACKGROUND: Dietary sodium restriction is common advice for patients with heart failure (HF). Randomized clinical trials have not shown a beneficial effect of dietary sodium restriction on clinical outcomes. METHODS: A multivariable Cox proportional hazard regression model was used to assess the association of dietary sodium intake measured at randomization with primary and secondary endpoints. RESULTS: The study included 792 participants. Baseline sodium intake was ≤ 1500 mg/day in 19.9% (n = 158), 1501-3000 mg/day in 56.5% (n = 448) and > 3000 mg/day in 23.4% (n = 186) of participants. The factors associated with higher baseline sodium intake were higher calorie consumption, higher body mass index and recruitment from Canada. Multivariable analyses showed no association between baseline sodium intake nor magnitude of 6-month change or 12- or 24-month outcomes. In a responder analysis, participants achieving a sodium intake < 1500 mg at 6 months showed an association with a decreased risk for the composite outcome (adjusted HR 0.52 [95% CI 0.25, 1.07] P = 0.08) and CV hospitalization (adjusted HR 0.51 [95% CI 0.24, 1.09] P = 0.08) at 12 months. CONCLUSION: There was no association between dietary sodium intake and clinical outcomes over 24 months in patients with HF. Responder analyses suggest the need for further investigation of the effects of sodium reduction in those who achieve the targeted dietary sodium-reduction level.

Baseline characteristics of patients in the randomized study to investigate the efficacy and safety of ferric carboxymaltose as treatment for heart failure with iron deficiency: HEART-FID trial.

BACKGROUND: Prior clinical trials have investigated intravenous iron in patients with heart failure (HF) and iron deficiency, but the safety and efficacy of this therapy remains unclear. METHODS: We report the baseline demographics and clinical characteristics of patients enrolled in the HEART-FID study and compare HEART-FID participants with patients within other contemporary clinical trials of patients with HF with reduced ejection fraction (HFrEF), including other intravenous iron trials. RESULTS: In the 3,065 participants randomized in HEART-FID, median (IQR) age was 69.7 (62.0-76.5) years, 1,037 (33.8%) were female, 322 (10.5%) were Black, median ejection fraction was 32% (25%-37%), 1,837 (60.0%) had ischemic etiology, and baseline median NT-proBNP was 1,462 (721-2,966) pg/mL. Median baseline hemoglobin was 12.6 (11.6-13.6) g/dL, and median 6-minute walk test distance was 272 (196-350) m, similar to prior intravenous iron HFrEF trials. Common comorbidities included atrial fibrillation/flutter (43.7%), and type 2 diabetes (45.2%). Compared with several recent HFrEF trials, patients enrolled in HEART-FID had similar baseline demographics and clinical characteristics, though a greater proportion of women and Black participants were recruited in HEART-FID. In HEART-FID, HFrEF therapy included a beta-blocker in 92.5%, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitors (ARNI) in 86.1% (with 29.7% ARNI), and a mineralocorticoid antagonist (MRA) in 55.6%. CONCLUSIONS: Patients enrolled in HEART-FID were similar to those enrolled in other contemporary HFrEF trials and registries, including trials of intravenous iron in HFrEF. However, the HEART-FID cohort is substantially larger and more racially diverse than prior trials of intravenous iron in HFrEF. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03037931).

Application of High-Sensitivity Troponin in Suspected Myocardial Infarction.

BACKGROUND: Data regarding high-sensitivity troponin concentrations in patients presenting to the emergency department with symptoms suggestive of myocardial infarction may be useful in determining the probability of myocardial infarction and subsequent 30-day outcomes. METHODS: In 15 international cohorts of patients presenting to the emergency department with symptoms suggestive of myocardial infarction, we determined the concentrations of high-sensitivity troponin I or high-sensitivity troponin T at presentation and after early or late serial sampling. The diagnostic and prognostic performance of multiple high-sensitivity troponin cutoff combinations was assessed with the use of a derivation-validation design. A risk-assessment tool that was based on these data was developed to estimate the risk of index myocardial infarction and of subsequent myocardial infarction or death at 30 days. RESULTS: Among 22,651 patients (9604 in the derivation data set and 13,047 in the validation data set), the prevalence of myocardial infarction was 15.3%. Lower high-sensitivity troponin concentrations at presentation and smaller absolute changes during serial sampling were associated with a lower likelihood of myocardial infarction and a lower short-term risk of cardiovascular events. For example, high-sensitivity troponin I concentrations of less than 6 ng per liter and an absolute change of less than 4 ng per liter after 45 to 120 minutes (early serial sampling) resulted in a negative predictive value of 99.5% for myocardial infarction, with an associated 30-day risk of subsequent myocardial infarction or death of 0.2%; a total of 56.5% of the patients would be classified as being at low risk. These findings were confirmed in an external validation data set. CONCLUSIONS: A risk-assessment tool, which we developed to integrate the high-sensitivity troponin I or troponin T concentration at emergency department presentation, its dynamic change during serial sampling, and the time between the obtaining of samples, was used to estimate the probability of myocardial infarction on emergency department presentation and 30-day outcomes. (Funded by the German Center for Cardiovascular Research [DZHK]; ClinicalTrials.gov numbers, NCT00470587, NCT02355457, NCT01852123, NCT01994577, and NCT03227159; and Australian New Zealand Clinical Trials Registry numbers, ACTRN12611001069943, ACTRN12610000766011, ACTRN12613000745741, and ACTRN12611000206921.).

Presentation, Treatment and Long-Term Outcomes of a Multidisciplinary Acute Atrial Fibrillation Pathway: A 12-Month Follow-Up Study.

AIM: Atrial fibrillation/flutter (AF/AFL) is associated with high rates of emergency department (ED) visits and acute hospitalisation. A recently established multidisciplinary acute AF treatment pathway seeks to avoid hospital admissions by early discharge of haemodynamically stable, low risk patients from the ED with next-working-day return to a ward-based AF clinic for further assessment. We conducted a preliminary analysis of the clinical outcomes of this pathway. METHODS: We retrospectively reviewed clinical records of all patients assessed at the AF clinic at Christchurch Hospital, New Zealand, over a 12-month period. Data related to presentation, patient characteristics, treatment, and 12-month outcomes were analysed. RESULTS: A total of 143 patients (median age 65, interquartile range: 57-74 years, 59% male, 87% European) were assessed. Of these, 87 (60.8%) presented with their first episode of AF/AFL. Spontaneous cardioversion occurred in 41% at ED discharge, and this increased to 73% at AF clinic review. Electrical cardioversion was subsequently performed in 16 patients (11.2%), and 16 (11.2%) ultimately required hospital admission (eight to facilitate electrical cardioversion). At a median of 1 day, 83.9% were discharged from the AF clinic in sinus rhythm. During 12-month follow-up, there were 25 AF-related hospitalisations (20 patients, 14%) and one patient underwent electrical cardioversion; additionally, one patient had had a stroke and eight had bleeding complications giving a combined outcome rate of 6.3%. CONCLUSION: Utilising a rate-control strategy with ED discharge and early return to a dedicated AF clinic can safely prevent the majority of hospitalisations, avert unnecessary procedures, and facilitate longitudinal care.

Trends in the Detection, Management and 30-Day Outcomes of Spontaneous Coronary Artery Dissection: A Six-Year, New Zealand Centre Experience.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an important but under-recognised cause of acute coronary syndrome (ACS), particularly in younger women. We assessed trends in the detection, management and outcomes of all patients with SCAD over 6 consecutive years. METHODS: All patients with first diagnosis of SCAD at Christchurch Public Hospital, New Zealand, between January 2014 and January 2020 were included. Patient management and outcomes were determined by retrospective review of medical records. SCAD presentations were compared to total ACS presentations, obtained from a national ACS (ANZACS-QI) database. RESULTS: We identified 113 patients with angiographic diagnosis of SCAD. Median age was 54 years (88% female). The detection of SCAD increased over the period, both as a total number (Kendall's τ 0.87, p=0.015) and as a proportion of all ACS (p value for trend <0.0001). In 2019, SCAD represented 2.4% of all ACS and 18% of ACS in females aged less than 60 years. The most common presentation was non-ST elevation myocardial infarction (NSTEMI) in 72%; and, there was an increase in NSTEMI compared with STEMI over the period (p=0.023). Initial strategy of percutaneous coronary intervention (PCI) was undertaken in 12% of patients, with a significant trend towards a more conservative approach over the study period (p=0.019). The rate of 30-day major adverse cardiovascular events (MACE) was 8.8% overall, and significantly reduced over the study period to 3% in 2019 (p value for trend, 0.006). CONCLUSIONS: The detection of SCAD has increased and is a particularly important cause of ACS in younger women. This increase has been largely driven by an increasing number of NSTEMI patients diagnosed with SCAD, associated with a significant improvement in 30-day MACE.

ICare-ACS (Improving Care Processes for Patients With Suspected Acute Coronary Syndrome): A Study of Cross-System Implementation of a National Clinical Pathway.

BACKGROUND: Efforts to safely reduce length of stay for emergency department patients with symptoms suggestive of acute coronary syndrome (ACS) have had mixed success. Few system-wide efforts affecting multiple hospital emergency departments have ever been evaluated. We evaluated the effectiveness of a nationwide implementation of clinical pathways for potential ACS in disparate hospitals. METHODS: This was a multicenter pragmatic stepped-wedge before-and-after trial in 7 New Zealand acute care hospitals with 31 332 patients investigated for suspected ACS with serial troponin measurements. The implementation was a clinical pathway for the assessment of patients with suspected ACS that included a clinical pathway document in paper or electronic format, structured risk stratification, specified time points for electrocardiographic and serial troponin testing within 3 hours of arrival, and directions for combining risk stratification and electrocardiographic and troponin testing in an accelerated diagnostic protocol. Implementation was monitored for >4 months and compared with usual care over the preceding 6 months. The main outcome measure was the odds of discharge within 6 hours of presentation RESULTS: There were 11 529 participants in the preimplementation phase (range, 284-3465) and 19 803 in the postimplementation phase (range, 395-5039). Overall, the mean 6-hour discharge rate increased from 8.3% (range, 2.7%-37.7%) to 18.4% (6.8%-43.8%). The odds of being discharged within 6 hours increased after clinical pathway implementation. The odds ratio was 2.4 (95% confidence interval, 2.3-2.6). In patients without ACS, the median length of hospital stays decreased by 2.9 hours (95% confidence interval, 2.4-3.4). For patients discharged within 6 hours, there was no change in 30-day major adverse cardiac event rates (0.52% versus 0.44%; P=0.96). In these patients, no adverse event occurred when clinical pathways were correctly followed. CONCLUSIONS: Implementation of clinical pathways for suspected ACS reduced the length of stay and increased the proportions of patients safely discharged within 6 hours. CLINICAL TRIAL REGISTRATION: URL: https://www.anzctr.org.au/ (Australian and New Zealand Clinical Trials Registry). Unique identifier: ACTRN12617000381381.

Prognostic Implications of Changes in Amino-Terminal Pro-B-Type Natriuretic Peptide in Acute Decompensated Heart Failure: Insights From ASCEND-HF.

BACKGROUND: Amino-terminal pro-B-type natriuretic peptide (NTproBNP) is closely associated with prognosis in acute decompensated heart failure (ADHF). As a result, there has been great interest measuring it during the course of treatment. The prognostic implications in both short-term and follow-up changes in NTproBNP need further clarification. METHODS: Baseline, 48-72 hour, and 30-day NTproBNP levels were measured in 795 subjects in the ASCEND-HF trial. Multivariable logistic and Cox-proportional hazards models were used to test the association between static, relative, and absolute changes in NTproBNP with outcomes during and after ADHF. RESULTS: The median NTproBNP at baseline was 5773 (2981-11,579) pg/mL; at 48-72 hours was 3036 (1191-6479) pg/mL; and at 30 days was 2914 (1364-6667) pg/mL. Absolute changes in NTproBNP by 48-72 hours were not associated with 30-day heart failure rehospitalization or mortality (P = .065), relative changes in NTproBNP were nominally associated (P = .046). In contrast, both absolute and relative changes in NTproBNP from baseline to 48-72 hours and to 30 days were closely associated with 180-day mortality (P < .02 for all) with increased discrimination compared to the multivariable models with baseline NTproBNP (P <.05 for models with relative and absolute change at both time points). CONCLUSIONS: Although the degree of absolute change in NTproBNP was dependent on baseline levels, both short-term absolute and relative changes in NTproBNP were independently and incrementally associated with long-term clinical outcomes. Changes in NTproBNP levels at 30-days were particularly well associated with long-term clinical outcomes.

New Insights into Cardiac and Vascular Natriuretic Peptides: Findings from Young Adults Born with Very Low Birth Weight.

BACKGROUND: In community studies, plasma B-type natriuretic peptide (BNP) is positively associated with cardiovascular disorders. Those born with very low birth weight (VLBW) have increased risk of metabolic and vascular disorders in later life, but plasma concentrations of natriuretic peptides have not been studied. The objectives here were to evaluate BNP and C-type natriuretic peptide (CNP)-a putative marker of vascular risk-in young adults born with VLBW. METHODS: In all, 220 VLBW cases and 97 matched controls were studied 28 years after birth during a 2-day period at 1 research center. Aminoterminal (NT) products (NTproBNP, NTproCNP) and a range of conventional vascular risk factors including echocardiographic indices were measured along with genetic polymorphisms known to increase plasma NTproBNP. RESULTS: VLBW individuals were smaller, had smaller hearts, reduced stroke volume and endothelial function, and higher systolic blood pressure and arterial elastance. Of the many humoral vascular and metabolic risk factors measured, including NTproBNP, only plasma NTproCNP (higher in VLBW individuals) differed significantly. Across all individuals, associations of NTproCNP with each of 7 conventional risk factors, as well as with arterial elastance, were positive, whereas associations of NTproBNP with risk were all inverse. In multivariate analysis, the genetic variant rs198358 was independently associated with NTproBNP. CONCLUSIONS: In young adults at increased risk of cardiovascular disease, higher NTproCNP likely reflects a compensatory vascular response to vascular stress, whereas the negative link with NTproBNP likely reflects beneficial genetic mutations. The ratio of NTproBNP to NTproCNP may provide a novel index of ideal cardiovascular health.

Detectable High-Sensitivity Cardiac Troponin within the Population Reference Interval Conveys High 5-Year Cardiovascular Risk: An Observational Study.

BACKGROUND: Increased cardiac troponin I or T detected by high-sensitivity assays (hs-cTnI or hs-cTnT) confers an increased risk of adverse prognosis. We determined whether patients presenting with putatively normal, detectable cTn concentrations [> limit of detection and < upper reference limit (URL)] have increased risk of major adverse cardiovascular events (MACE) or all-cause mortality. METHODS: A prospective 5-year follow-up of patients recruited in the emergency department with possible acute coronary syndrome (ACS) and cTn concentrations measured with hs-cTnI (Abbott) and hs-cTnT (Roche) assays. Cox regression models were generated with adjustment for covariates in those without MACE on presentation. Hazard ratios (HRs) for hs-cTn were calculated relative to the HRs at the median concentration. RESULTS: Of 1113 patients, 836 were without presentation MACE. Of these, 138 incurred a MACE and 169 died during a median 5.8-year follow-up. HRs for MACE at the URLs were 2.3 (95% CI, 1.7-3.2) for hs-cTnI and 1.8 (95% CI, 1.3-2.4) for hs-cTnT. Corresponding HRs for mortality were 1.7 (95% CI, 1.2-2.2) for hs-cTnI and 2.3 (95 % CI, 1.7-3.1) for hs-cTnT. The HR for MACE increased with increasing hs-cTn concentration similarly for both assays, but the HR for mortality increased at approximately twice the rate for hs-cTnT than hs-cTnI. Patients with hs-cTnI ≥10 ng/L or hs-cTnT ≥16 ng/L had the same percentage of MACE at 5-year follow-up (33%) as patients with presentation MACE. CONCLUSIONS: Many patients with ACS ruled out and putatively normal but detectable hs-cTnI concentrations are at similar long-term risk as those with MACE. hs-cTnT concentrations are more strongly associated with 5-year mortality than hs-cTnI.

Plasma levels of soluble VEGF receptor isoforms, circulating pterins and VEGF system SNPs as prognostic biomarkers in patients with acute coronary syndromes.

BACKGROUND: Development of collateral circulation in coronary artery disease is cardio-protective. A key process in forming new blood vessels is attraction to occluded arteries of monocytes with their subsequent activation as macrophages. In patients from a prospectively recruited post-acute coronary syndromes cohort we investigated the prognostic performance of three products of activated macrophages, soluble vascular endothelial growth factor (VEGF) receptors (sFlt-1 and sKDR) and pterins, alongside genetic variants in VEGF receptor genes, VEGFR-1 and VEGFR-2. METHODS: Baseline levels of sFlt-1 (VEGFR1), sKDR (VEGFR2) and pterins were measured in plasma samples from subgroups (n = 513; 211; 144, respectively) of the Coronary Disease Cohort Study (CDCS, n = 2067). DNA samples from the cohort were genotyped for polymorphisms from the VEGFR-1 gene SNPs (rs748252 n = 2027, rs9513070 n = 2048) and VEGFR-2 gene SNPs (rs2071559 n = 2050, rs2305948 n = 2066, rs1870377 n = 2042). RESULTS: At baseline, levels of sFlt-1 were significantly correlated with age, alcohol consumption, NTproBNP, BNP and other covariates relevant to cardiovascular pathophysiology. Total neopterin levels were associated with alcohol consumption at baseline. 7,8 dihydroneopterin was associated with BMI. The A allele of VEGFR-2 variant rs1870377 was associated with higher plasma sFlt-1 and lower levels of sKDR at baseline. Baseline plasma sFlt-1 was univariately associated with all cause mortality with (p < 0.001) and in a Cox's proportional hazards regression model sFlt-1 and pterins were both associated with mortality independent of established predictors (p < 0.027). CONCLUSIONS: sFlt-1 and pterins may have potential as prognostic biomarkers in acute coronary syndromes patients. Genetic markers from VEGF system genes warrant further investigation as markers of levels of VEGF system components in these patients. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. ACTRN12605000431628 . 16 September 2005, Retrospectively registered.

C-Type Natriuretic Peptides in Coronary Disease.

AIMS: C-type natriuretic peptide (CNP) is a paracrine growth factor expressed in the vascular endothelium. Although upregulated in atheromatous arteries, the predictive value of plasma CNP products for outcome in coronary disease is unknown. This study aimed to compare the prognostic value of plasma CNP products with those of other natriuretic peptides in individuals with coronary artery disease, and investigate their associations with cardiac and renal function. METHODS AND RESULTS: Plasma concentrations of CNP and amino-terminal proCNP (NT-proCNP) were measured at baseline in 2129 individuals after an index acute coronary syndrome admission and related to cardiac and renal function, other natriuretic peptides [atrial NP (ANP) and B-type NP (BNP)] and prognosis (primary end point, mortality; secondary end point, cardiac readmission). Median follow-up was 4 years. At baseline, and in contrast to CNP, ANP, and BNP, plasma NT-proCNP was higher in males and weakly related to cardiac function but strongly correlated to plasma creatinine. All NPs were univariately associated with mortality. Resampling at 4 and 12 months in survivors showed stable concentrations of NT-proCNP whereas all other peptides declined. When studied by diagnosis (myocardial infarction, unstable angina) at index admission using a multivariate model, NT-proBNP predicted mortality and readmission in myocardial infarction. In unstable angina, only NT-proCNP predicted both mortality and cardiac readmission. CONCLUSIONS: In contrast to the close association of NT-proBNP with cardiac function, and predictive value for outcome after myocardial infarction, plasma NT-proCNP is highly correlated with renal function and is an independent predictor of mortality and cardiac readmission in individuals with unstable angina.

Effectiveness of EDACS Versus ADAPT Accelerated Diagnostic Pathways for Chest Pain: A Pragmatic Randomized Controlled Trial Embedded Within Practice.

STUDY OBJECTIVE: A 2-hour accelerated diagnostic pathway based on the Thrombolysis in Myocardial Infarction score, ECG, and troponin measures (ADAPT-ADP) increased early discharge of patients with suspected acute myocardial infarction presenting to the emergency department compared with standard care (from 11% to 19.3%). Observational studies suggest that an accelerated diagnostic pathway using the Emergency Department Assessment of Chest Pain Score (EDACS-ADP) may further increase this proportion. This trial tests for the existence and size of any beneficial effect of using the EDACS-ADP in routine clinical care. METHODS: This was a pragmatic randomized controlled trial of adults with suspected acute myocardial infarction, comparing the ADAPT-ADP and the EDACS-ADP. The primary outcome was the proportion of patients discharged to outpatient care within 6 hours of attendance, without subsequent major adverse cardiac event within 30 days. RESULTS: Five hundred fifty-eight patients were recruited, 279 in each arm. Sixty-six patients (11.8%) had a major adverse cardiac event within 30 days (ADAPT-ADP 29; EDACS-ADP 37); 11.1% more patients (95% confidence interval 2.8% to 19.4%) were identified as low risk in EDACS-ADP (41.6%) than in ADAPT-ADP (30.5%). No low-risk patients had a major adverse cardiac event within 30 days (0.0% [0.0% to 1.9%]). There was no difference in the primary outcome of proportion discharged within 6 hours (EDACS-ADP 32.3%; ADAPT-ADP 34.4%; difference -2.1% [-10.3% to 6.0%], P=.65). CONCLUSION: There was no difference in the proportion of patients discharged early despite more patients being classified as low risk by the EDACS-ADP than the ADAPT-ADP. Both accelerated diagnostic pathways are effective strategies for chest pain assessment and resulted in an increased rate of early discharges compared with previously reported rates.

Heart Fatty Acid Binding Protein and cardiac troponin: development of an optimal rule-out strategy for acute myocardial infarction.

BACKGROUND: Improved ability to rapidly rule-out Acute Myocardial Infarction (AMI) in patients presenting with chest pain will promote decongestion of the Emergency Department (ED) and reduce unnecessary hospital admissions. We assessed a new commercial Heart Fatty Acid Binding Protein (H-FABP) assay for additional diagnostic value when combined with cardiac troponin (using a high sensitivity assay). METHODS: H-FABP and high-sensitivity troponins I (hs-cTnI) and T (hs-cTnT) were measured in samples taken on-presentation from patients, attending the ED, with symptoms triggering investigation for possible acute coronary syndrome. The optimal combination of H-FABP with each hs-cTn was defined as that which maximized the proportion of patients with a negative test (low-risk) whilst maintaining at least 99 % sensitivity for AMI. A negative test comprised both H-FABP and hs-cTn below the chosen threshold in the absence of ischemic changes on the ECG. RESULTS: One thousand seventy-nine patients were recruited including 248 with AMI. H-FABP < 4.3 ng/mL plus hs-cTnI < 10.0 ng/L together with a negative ECG maintained >99 % sensitivity for AMI whilst classifying 40.9 % of patients as low-risk. The combination of H-FABP < 3.9 ng/mL and hs-cTnT < 7.6 ng/L with a negative ECG maintained the same sensitivity whilst classifying 32.1 % of patients as low risk. CONCLUSIONS: In patients requiring rule-out of AMI, the addition of H-FABP to hs-cTn at presentation (in the absence of new ischaemic ECG findings) may accelerate clinical diagnostic decision making by identifying up to 40 % of such patients as low-risk for AMI on the basis of blood tests performed on presentation. If implemented this has the potential to significantly accelerate triaging of patients for early discharge from the ED.

Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure.

BACKGROUND: Trimethylamine-N-oxide (TMAO) has been linked to increased cardiovascular risk. We aimed to determine the prognostic value of TMAO and its dietary precursors, choline and betaine, in heart failure (HF). METHODS AND RESULTS: In 112 patients with chronic systolic HF with comprehensive echocardiographic evaluation, we measured plasma TMAO, choline, and betaine by mass spectrometry. Median (interquartile range) TMAO levels, choline, and betaine levels were 5.8 (3.6-12.1) µmol/L, 10.9 (8.4-14.0) µmol/L, and 43.8 (37.1-53.0) µmol/L, respectively, and were correlated with each other (all P < .0001 for both). TMAO levels were significantly higher in patients with diabetes mellitus (9.4 [4.9-13.2] vs 4.8 [3.4-9.8] µmol/L; P = .005) and in subjects with New York Heart Association functional class III or greater (7.0 [4.7-14.8] vs 4.7 [3.4-11.3] µmol/L; P = .02). Elevated TMAO, choline, and betaine levels were each associated with higher plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and more advanced left ventricular diastolic dysfunction, but not systolic dysfunction or inflammatory and endothelial biomarkers. Higher choline (hazard ratio [HR] 1.64, 95% CI 1.22-2.20; P = .001), betaine (HR 1.51, 95% CI 1.10-2.08; P = .01), and TMAO (HR 1.48, 95% CI 1.10-1.96; P = .01) predicted increased risk for 5-year adverse clinical events (death/transplantation). Only higher TMAO levels predicted incident adverse clinical events independently from age, estimated glomerular filtration rate, mitral E/septal Ea, and NT-proBNP levels (HR 1.46, 95% CI 1.03-2.14; P = .03). CONCLUSION: Elevated plasma TMAO, choline, and betaine levels are each associated with more advanced left ventricular diastolic dysfunction and portend poorer long-term adverse clinical outcomes in chronic systolic HF. However, only higher plasma TMAO was associated with poor prognosis after adjustment for cardiorenal indices.

Human muscle sympathetic nerve responses to urocortin-2 in health and stable heart failure.

Sympatholytic and vasodilator drugs have been of major therapeutic benefit in patients with heart failure (HF). Urocortin-2 (Ucn2) is a small corticotrophin-related peptide distributed throughout the cardiovascular system which inhibits cardiac sympathetic nerve activity (CSNA) and is also a powerful vasodilator. This study analysed the effects of a 60-min infusion of Ucn2 (25 µg) on muscle sympathetic nerve activity (MSNA) recorded from the lower limb in eight healthy men and four men with stable HF. During Ucn2 infusion, mean arterial pressure fell to a nadir of 84 ± 2 compared to 95 ± 2 mmHg during placebo (P = 0.001) and heart rate increased to a maximum of 74 ± 1 compared to 64 ± 1 b.p.m. (P < 0.001). Total peripheral resistance fell by 23 ± 4% compared with an increase of 23 ± 4% (P < 0.001) and cardiac output increased by 22 ± 4 compared to 4 ± 4% (P = 0.001). The MSNA burst frequency increased by 9 ± 2 compared to 1 ± 2 burst/min (P = 0.005) and burst area/min by 133 ± 7 vs 107 ± 7% (P = 0.01). Burst incidence and baroreflex sensitivity were not significantly altered. Qualitatively similar changes were observed in stable HF patients. Ucn2-induced vasodilatation increased MSNA in humans, as opposed to the decrease in CSNA we observed in sheep. Therefore, if Ucn2 has a central inhibitory effect on MSNA, it was over-run by off-loading the cardiovagal baroreflex. Alternatively, CSNA may be less responsive to baroreflex off-loading than MSNA.

The New Zealand 1986 very low birth weight cohort as young adults: mapping the road ahead.

BACKGROUND: Very low birth weight (less than 1500 g) is associated with increased morbidity and costs of health care in childhood. Emerging evidence suggests these infants face a range of health and social problems as young adults. We studied all New Zealand very low birth weight infants born in 1986 (when 58% were exposed to antenatal corticosteroids) in infancy, with later follow-up at 7 to 8 years and 23 to 24 years. We now aim to assess the cohort at 26-28 years compared with controls. METHODS/DESIGN: The case sample will comprise a minimum of 250 members of the 1986 New Zealand national very low birth weight cohort (77% of survivors). Outcomes will be compared with a control group of 100 young adults born at term in 1986. Following written informed consent, participants will travel to Christchurch for 2 days of assessments undertaken by experienced staff. Medical assessments include growth measures, vision, respiratory function, blood pressure and echocardiogram, renal function, dental examination and blood tests. Cognitive and neuropsychological functioning will be assessed with standard tests, and mental health and social functioning by participant interview. A telephone interview will be conducted with a parent or significant other person nominated by the respondent to gain a further perspective on the young person's health and functioning. All those born at less than 28 weeks' gestation, plus a random subset of the cohort to a total of 150 cases and 50 controls, will be offered cranial magnetic-resonance imaging. Statistical analysis will examine comparison with controls and long-term trajectories for the very low birth weight cohort. DISCUSSION: The research will provide crucial New Zealand data on the young adult outcomes for very low birth weight infants and address gaps in the international literature, particularly regarding cardiovascular, respiratory, visual and neurocognitive outcomes. These data will inform future neonatal care, provide evidence-based guidelines for care of preterm graduates transitioning to adult care, and help shape health education and social policies for this high risk group. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000995875 . Registered 1 October 2012.

Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis.

AIMS: Natriuretic peptide-guided (NP-guided) treatment of heart failure has been tested against standard clinically guided care in multiple studies, but findings have been limited by study size. We sought to perform an individual patient data meta-analysis to evaluate the effect of NP-guided treatment of heart failure on all-cause mortality. METHODS AND RESULTS: Eligible randomized clinical trials were identified from searches of Medline and EMBASE databases and the Cochrane Clinical Trials Register. The primary pre-specified outcome, all-cause mortality was tested using a Cox proportional hazards regression model that included study of origin, age (<75 or ≥75 years), and left ventricular ejection fraction (LVEF, ≤45 or >45%) as covariates. Secondary endpoints included heart failure or cardiovascular hospitalization. Of 11 eligible studies, 9 provided individual patient data and 2 aggregate data. For the primary endpoint individual data from 2000 patients were included, 994 randomized to clinically guided care and 1006 to NP-guided care. All-cause mortality was significantly reduced by NP-guided treatment [hazard ratio = 0.62 (0.45-0.86); P = 0.004] with no heterogeneity between studies or interaction with LVEF. The survival benefit from NP-guided therapy was seen in younger (<75 years) patients [0.62 (0.45-0.85); P = 0.004] but not older (≥75 years) patients [0.98 (0.75-1.27); P = 0.96]. Hospitalization due to heart failure [0.80 (0.67-0.94); P = 0.009] or cardiovascular disease [0.82 (0.67-0.99); P = 0.048] was significantly lower in NP-guided patients with no heterogeneity between studies and no interaction with age or LVEF. CONCLUSION: Natriuretic peptide-guided treatment of heart failure reduces all-cause mortality in patients aged <75 years and overall reduces heart failure and cardiovascular hospitalization.

Thoracic impedance measures tissue characteristics in the vicinity of the electrodes, not intervening lung water: implications for heart failure monitoring.

The rationale for intrathoracic impedance (Z) detection of worsening heart failure (HF) presupposes that changes in Z reflect changes in pulmonary congestion, but is confounded by poor specificity in clinical trials. We therefore tested the hypothesis that Z is primarily affected by tissue/water content in proximity to electrodes rather than by lung water distribution between electrodes through the use of a new computational model for deriving the near-field impedance contributions from the various electrodes. Six sheep were implanted with a left atrial pressure (LAP) monitor and a cardiac resynchronization therapy device which measured Z from six vectors comprising of five electrodes. The vector-based Z was modelled as the summation of the near-field impedances of the two electrodes forming the vector. During volume expansion an acute increase in LAP resulted in simultaneous reductions in the near-field impedances of the intra-cardiac electrodes, while the subcutaneous electrode showed several hours of lag (all p<0.001). In contrast, during the simulated formation of device-pocket edema (induced by fluid injection) the near-field impedance of the subcutaneous electrode had an instantaneous response, while the intra-cardiac electrodes had a minimal inconsistent response. This study suggests that the primary contribution to the vector based Z is from the tissue/water in proximity to the individual electrodes. This novel finding may help explain the limited utility of Z for detecting worsening HF.