AIMS:Metabolic dysregulation accompanies heart failure (HF), yet coordinated biochemical shifts are rarely quantified for prognostication. We investigated whether early metabolic profiles predict morbidity and mortality in HF with preserved (HFpEF) or reduced ejection fraction (HFrEF). METHODS AND RESULTS:In the PEOPLE and SHOP cohorts (n = 1520), 288 plasma metabolites were quantified by tandem mass spectrometry. Weighted co-expression network analysis produced metabolic indices that were regressed against all-cause mortality and composite outcomes (death or readmission) using multivariable proportional hazards and win-ratio models. In HFpEF, metabolic indices of nitric oxide signalling and glycaemic control (netNO-pEF) and purine metabolism (netPurine-pEF) predicted outcomes. In HFrEF, indices of acylcarnitine (netACa-rEF) and amino acids (netAA-rEF) predicted outcomes. Every 20% higher netNO-pEF was associated with adjusted hazard ratios (HR20%higher) of 0.64 [95% CI 0.49-0.84] in PEOPLE-HFpEF and 0.40 [0.20-0.83] in SHOP-HFpEF; HR20%higher for netPurine-pEF were 1.71 [1.30-2.24] in PEOPLE-HFpEF and 1.96 [1.08-3.55] in SHOP-HFpEF; HR20%higher for netACa-rEF were 1.48 [1.23-1.79] in PEOPLE-HFrEF and 1.39 [1.15-1.68] in SHOP-HFrEF; HR20%higher for netAA-rEF were 0.75 [0.62-0.91] in PEOPLE-HFrEF and 0.51 [0.39-0.67] in SHOP-HFrEF. Adjusted inverse win-ratios were concordant: 1/WR20%higher for netACa-rEF were 1.40 [1.19-1.64] in PEOPLE-HFrEF and 1.17 [1.02-1.34] in SHOP-HFrEF; 1/WR20%higher for netNO-pEF were 0.74 [0.54-1.00] in PEOPLE-HFrEF and 0.55 [0.33-0.89] in SHOP-HFrEF. netNO-pEF was negatively associated with body surface area among HFpEF with concomitant hypertension and diabetes, but only in SHOP-HFpEF. Adding orotic acid, a constituent metabolite of netNO-pEF, to a base model containing five risk indices (MAGGIC score, NT-proBNP, hsTnT, GDF15, and E/e' ratio) incrementally improved 2-year mortality prediction (AUROC: 0.82→0.83 in PEOPLE; 0.74→0.79 in SHOP). CONCLUSION:Differential metabolic signatures tied to metabolic inflammation in HFpEF and impaired energy metabolism in HFrEF enhance risk stratification and point to therapeutic targets.

INTRODUCTION:The prognostic value of cardiac troponins in revascularized patients with myocardial infarction (MI) is uncertain. This study examined the relationship between peak troponin levels and adverse outcomes in a revascularized cohort from the Multi-Ethnic New Zealand Study of Acute Coronary Syndromes (MENZACS). METHODS:MENZACS enrolled patients with a first-time acute coronary syndrome from 2015 to 2019. Peak high sensitivity troponin was standardized by dividing the observed peak troponin by the upper limit of normal. The primary outcome was a composite of all-cause death or cardiovascular readmission, determined through national datasets. Troponin's relationship with outcomes was analysed using penalized spline Cox regression. RESULTS:Among 1,645 revascularized patients (81% male, mean age 61, 74% European, 14% Māori, 5% Pacific, 5% Indian, 3% Other; 46% ST-elevation MI (STEMI), 54% non-STEMI), higher peak troponin was associated with male sex, STEMI, current smoking, and elevated N-terminal pro-B-type natriuretic peptide levels. Over a median of 4.9 years, 402 (24%) people experienced the primary outcome. Peak troponin levels were not significantly associated with this outcome. CONCLUSION:In this revascularized cohort surviving a first-time MI, the magnitude of peak troponin elevation was not associated with all-cause death or cardiovascular readmission.

AIMS:Plasma concentrations of the heart failure (HF) biomarker N-terminal B-type natriuretic peptide (NT-proBNP) vary by ethnicity. We investigated whether NT-proBNP concentrations differed in HF between Pacific peoples, Māori (the Indigenous people), and New Zealand (NZ) Europeans, in patients with HF. METHODS:Plasma NT-proBNP was measured in patients with HF participating in two prospective NZ based multicentre studies [PEOPLE: n = 836, 30% female, median age 71, interquartile interval (IQI) 60, 80; IMPERATIVE-HF: n = 413, 30% female, median age 66, IQI 55, 76]. Regression analyses were used to understand predictors of NT-proBNP taking into account age, sex, body mass index (BMI), estimated glomerular filtration rate (eGFR), left ventricular ejection fraction (LVEF) and presence of atrial fibrillation (AF). RESULTS:Median NT-proBNP concentrations were significantly lower in both Pacific (930 pg/mL; P < 0.001, IQI 409-1,473; n = 127) and Māori (1,387 pg/mL, IQI 685-2,393; P < 0.001; n = 221) compared with NZ Europeans (2,055 pg/mL, IQI 973-3,865; n = 901) in unadjusted comparisons. NT-proBNP was independently associated with ethnicity, age, sex, BMI, eGFR, LVEF and presence of AF. The significant differences in plasma NT-proBNP between Pacific peoples, but not Māori, and NZ Europeans remained after adjusting for these clinical and demographic factors. The effect of age on NT-proBNP concentrations differed significantly between Pacific peoples and NZ Europeans, but not between Māori and NZ European (Pinteraction = 0.0109). For each decade of life over 60 years, plasma NT-proBNP in patients with HF was on average, 67% lower in a Pacific person than that of an aged-matched NZ European. CONCLUSIONS:In HF, Pacific and Māori people had significantly lower median plasma concentrations of NT-proBNP than NZ Europeans. This difference remained after adjusting for clinical and demographic factors in patients with Pacific ethnicity. Pacific peoples also had a significantly lower rate of increase of NT-proBNP with age compared with NZ Europeans and Māori.

BACKGROUND AND AIMS:Lipoprotein(a) (Lp[a]) is an established predictor of cardiovascular risk but associations with secondary events are less certain, and data on understudied ethnic groups are scarce. This study aimed to assess the association between Lp(a) and secondary events and explore variation in Lp(a) levels by ethnicity in first-time acute coronary syndrome (ACS) patients, to inform future risk prediction models. METHODS:The Multi-Ethnic New Zealand Study of Acute Coronary Syndromes (MENZACS) is a longitudinal multi-centre cohort study of 1900 patients enrolled during their ACS admission. Baseline plasma Lp(a) concentrations were measured using an isoform-insensitive assay measured in nmol/L. The primary outcome was a composite of all-cause mortality or cardiovascular readmission, ascertained through national health datasets. Cox regression models were used to assess the association between Lp(a) levels and outcomes, adjusted for clinical risk factors. RESULTS:The mean age was 61 years, 20 % were female, and 73 % were European, 14 % Māori, 5 % Pacific peoples, 4 % Indian and 3 % other ethnicities. Of 1890 alive at discharge, 493 (26 %) experienced the primary outcome over a median follow-up of 4.9 years. Higher Lp(a) levels were associated with increased risk of secondary events. Compared to the lowest quartile (≤7 nmol/L), the adjusted hazard ratio for the highest quartile (>92 nmol/L) was 1.46 (95 %CI 1.12-1.89, p = 0.004). In this ACS cohort, Lp(a) concentrations varied by ethnicity, being highest amongst Indian participants (median 27 nmol/L) and lowest amongst Māori participants (median 12 nmol/L). CONCLUSIONS:Elevated Lp(a) concentrations are associated with secondary events following ACS. Further research is needed to define optimal thresholds for increased risk and explore ethnic-specific implications for secondary prevention.

[This corrects the article DOI: 10.1371/journal.pone.0318656.].

OBJECTIVE:To evaluate the relative strengths of 3 frailty assessment instruments for predicting mortality and prolonged hospitalization in acute coronary syndrome patients. DESIGN:Prospective cohort study. SETTING:Acute cardiac care units in New Zealand. PARTICIPANTS:1174 patients >70 years of age hospitalized with an acute coronary syndrome. INTERVENTIONS:The Clinical Frailty Scale (CFS), Edmonton Frail Scale (EFS) and Fried Criteria (Fried), were completed during hospital admission following an acute coronary syndrome when the patient was clinically stable. PRIMARY AND SECONDARY OUTCOME MEASURES:All-cause mortality over the next ~5 years and hospitalization for >10 days in the next year determined from national administrative data. RESULTS:During median follow-up of 5.1 years there were 353 deaths. Harrell's C-statistic for mortality for EFS was 0.663, Fried 0.648 and CFS 0.640 (p<0.001 for all). C-statistics for hospitalization >10 days (n = 267, 22%) were EFS 0.649, Fried 0.628, and CFS 0.584 (p<0.001 for all). Associations between increase in frailty scores and mortality were graded including in patients not classified as frail. The hazard ratio (HR) for mortality, adjusted for age and sex, for patients with an EFS score ≥9 (n = 197) compared to ≤2 (n = 331) was 5.0 (95% CI: 3.4-7.4). In models which included the Euroscore II or GRACE risk scores the EFS improved risk discrimination for both mortality and prolonged hospitalization more than the CFS and Fried. CONCLUSION:In older patients assessed following an acute coronary syndrome the EFS discriminated the risk of all cause mortality and prolonged hospitalization better than the CFS and Fried tests, and improved risk discrimination when added to clinical risk scores.

BACKGROUND AND AIMS:In Aotearoa-New Zealand (NZ) approximately 8000 people are admitted with a first-time acute coronary syndrome (ACS) annually. In this cross-sectional analysis, we describe the dietary patterns of patients who present with their first ACS and examine their associations with socio-demographic and clinical characteristics. METHODS AND RESULTS:The Multi-Ethnic NZ study of Acute Coronary Syndromes (MENZACS) is a multi-centre, longitudinal cohort study of patients with first-time ACS. At study enrolment, patients (n = 1914) completed a validated short food frequency questionnaire asking about dietary intakes in the 12 months preceding their ACS. Three dietary patterns were identified using Principal Component Analysis. The Convenience pattern was characterised by high intakes of take-aways, and participants with higher scores were on average younger, more likely to be male, live in the most deprived areas, and current smokers (all p for trend<0.001). The Harvest pattern was characterised by high intakes of vegetables and fruit, and participants with higher scores were on average older, less likely to be male, more likely to live in the least deprived areas, and have a history of hypertension, and less likely to be current smokers (all p for trend<0.05). The Comfort pattern was characterised by high intakes of potatoes, biscuits, tea/coffee, meat, and jam, and participants with higher scores were on average older and more likely to be male (both p for trend<0.05). CONCLUSION:Three distinct dietary patterns were found in patients presenting with first-time ACS in NZ and these patterns were associated with various socio-demographic and clinical factors.

Heart failure is a major healthcare problem in New Zealand. The Acute Decompensated Heart Failure (ADHF) Registry was introduced in 2015, and has identified the need for quality improvement strategies to improve care of patients hospitalised with heart failure. In this paper, we describe the implementation of the revised ANZACS-QI Heart Failure Registry, which has a primary aim to support evidence-based management of and quality improvement measures for patients who are hospitalised with heart failure in New Zealand. Taking the learnings from the initial experience with the ADHF Registry, the revised ANZACS-QI Heart Failure Registry i) utilises age-stratified sampling of hospital discharge coding to identify a representative heart failure cohort, ii) utilises existing ANZACS-QI infrastructure for data-linkage to reduce the burden of manual data entry, iii) receives governance from the Heart Failure Working Group, and iv) focusses on established quality improvement indicators for heart failure management.

Background The relationship of serial NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) measurements with changes in cardiac features and outcomes in heart failure (HF) remains incompletely understood. We determined whether common clinical covariates impact these relationships. Methods and Results In 2 nationwide observational populations with HF, the relationship of serial NT‐proBNP measurements with serial echocardiographic parameters and outcomes was analyzed, further stratified by HF with reduced versus preserved left ventricular ejection fraction, inpatient versus outpatient enrollment, age, obesity, chronic kidney disease, atrial fibrillation, and attainment of ≥50% guideline‐recommended doses of renin‐angiotensin system inhibitors and β‐blockers. Among 1911 patients (mean±SD age, 65.1±13.4 years; 26.6% women; 62% inpatient and 38% outpatient), NT‐proBNP declined overall, with more rapid declines among inpatients, those with obesity, those with atrial fibrillation, and those attaining ≥50% guideline‐recommended doses. Each doubling of NT‐proBNP was associated with increases in left ventricular volume (by 6.1 mL), E/e′ (transmitral to mitral annular early diastolic velocity ratio) (by 1.4 points), left atrial volume (by 3.6 mL), and reduced left ventricular ejection fraction (by −2.1%). The effect sizes of these associations were lower among patients with HF with preserved ejection fraction, atrial fibrillation, or advanced age ( P interaction <0.001). A landmark analysis identified that an SD increase in NT‐proBNP over 6 months was associated with a 27% increase in the risk of the composite event of HF hospitalization or all‐cause death between 6 months and 2 years (adjusted hazard ratio, 1.27 [95% CI, 1.15–1.40]; P <0.001). Conclusions The relationships between NT‐proBNP and structural/functional remodeling differed by age, presence of atrial fibrillation, and HF phenotypes. The association of increased NT‐proBNP with increased risk of adverse outcomes was consistent in all subgroups.

Heart failure affects 1–3% of the population and remains a major public health problem, with high rates of hospitalisation and mortality. Health inequities in the incidence of heart failure have widened over the last 13 years in Aotearoa New Zealand. Urgent action is required to address the inequitable burden of heart failure among Māori and Pasifika. Regional and international heart failure guidelines now provide clear and consistent guidance on the contemporary approach to management for patients with heart failure. The purpose of this position statement is to ensure that all people in Aotearoa New Zealand have access to optimal healthcare delivery and pharmacotherapy for contemporary management of heart failure. Three main areas are addressed, including: 1) access to evidence-based pharmacotherapy for patients with heart failure, 2) the importance of early initiation and titration of pharmacotherapy, and 3) the workforce required to ensure timely delivery of heart failure therapies. Implementation of evidence-based healthcare will ensure all patients with heart failure in Aotearoa New Zealand have opportunity for substantial improvement in health.

Heart failure is a major healthcare problem in New Zealand. The Acute Decompensated Heart Failure (ADHF) Registry was introduced in 2015, and has identified the need for quality improvement strategies to improve care of patients hospitalised with heart failure. In this paper, we describe the implementation of the revised ANZACS-QI Heart Failure Registry, which has a primary aim to support evidence-based management of and quality improvement measures for patients who are hospitalised with heart failure in New Zealand. Taking the learnings from the initial experience with the ADHF Registry, the revised ANZACS-QI Heart Failure Registry i) utilises age-stratified sampling of hospital discharge coding to identify a representative heart failure cohort, ii) utilises existing ANZACS-QI infrastructure for data-linkage to reduce the burden of manual data entry, iii) receives governance from the Heart Failure Working Group, and iv) focusses on established quality improvement indicators for heart failure management.

Aims This study investigated age-specific sex differences in short- and long-term clinical outcomes following hospitalization for a first-time acute coronary syndrome (ACS) in New Zealand (NZ).Methods and results Using linked national health datasets, people admitted to hospital for a first-time ACS between January 2010 and December 2016 were included. Analyses were stratified by sex and 10-year age groups. Logistic and Cox regression were used to assess in-hospital death and from discharge the primary outcome of time to first cardiovascular (CV) readmission or death and other secondary outcomes at 30 days and 2 years. Among 63 245 people (mean age 69 years, 40% women), women were older than men at the time of the ACS admission (mean age 73 vs. 66 years), with a higher comorbidity burden. Overall compared with men, women experienced higher rates of unadjusted in-hospital death (10% vs. 7%), 30-day (16% vs. 12%) and 2-year (44% vs. 34%) death, or CV readmission (all P < 0.001). Age group-specific analyses showed sex differences in outcomes varied with age, with younger women (<65 years) at higher risk than men and older women (>= 85 years) at lower risk than men: unadjusted hazard ratio of 2-year death or CV readmission for women aged 18-44 years = 1.51 [95% confidence interval (CI) 1.21-1.84] and aged >= 85 years = 0.88 (95% CI 0.83-0.93). The increased risk for younger women was no longer significant after multivariable adjustment whereas the increased risk for older men remained.Conclusion Men and women admitted with first-time ACS have differing age and comorbidity profiles, resulting in contrasting age-specific sex differences in the risk of adverse outcomes between the youngest and oldest age groups.

Objective The Multi-Ethnic New Zealand Study of Acute Coronary Syndromes (MENZACS) was established to investigate the drivers of secondary events after first-time acute coronary syndrome (ACS), including addressing inequitable outcomes by ethnicity. Herein, the first clinical outcomes and prognostic modelling approach are reported. Methods First, in 28 176 New Zealanders with first-time ACS from a national registry, a clinical summary score for predicting 1-year death/cardiovascular readmission was created using Cox regression of 20 clinical variables. This score was then calculated in the 2015 participant MENZACS study to represent clinical risk. In MENZACS, Cox regression was used to assess N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a prognostic marker for death/cardiovascular readmission in four models, adjusting for (1) age and sex; (2) age, sex, ethnicity; (3) clinical summary score; (4) clinical summary score and ethnicity. Results Of the 2015 MENZACS participants (mean age 61 years, 79% male, 73% European, 14% Māori, 5% Pacific people), 2003 were alive at discharge. Of the 2003, 416 (20.8%) experienced all-cause death/cardiovascular readmission over a median of 3.5 years. In a simple model, age, male sex, Māori ethnicity and NT-proBNP levels were significant predictors of outcome. After adjustment for the clinical summary score, which includes age and sex, NT-proBNP and ethnicity were no longer statistically significant: log2(NT-proBNP) hazard ratio (HR) 1.03, 95% confidence interval (95% CI) 0.98 to 1.08, p=0.305; Māori ethnicity HR 1.26, 95% CI 0.97 to 1.62, p=0.084. Conclusions In 2015 patients with first-time ACS, recurrent events were common (20.8%). Increasing NT-proBNP levels and Māori ethnicity were predictors of death/cardiovascular readmission, but not after adjustment for the 20 clinical risk factors represented by the clinical summary score. Trial registration number ACTRN12615000676516.

Cardiovascular diseases are responsible for almost 10,000 deaths annually in Aotearoa New Zealand. Almost a quarter of these are avoidable, increasing to half of all cardiovascular deaths for Māori and Pacific people. Health system reforms are an opportunity to set clear ambitious goals for improved heart health. This has been done for smoking, a cancer plan, mental health and diabetes among other health conditions. Given the scale of avoidable heart disease and avoidable heart health inequity, much of it due to people simply not accessing existing treatment options, there is no excuse not to deliver a national heart health action plan and we urge health policy makers to put it on the agenda.

Objective The recommended duration of dual anti-platelet therapy (DAPT) following acute coronary syndrome (ACS) varies from 1 month to 1 year depending on the balance of risks of ischaemia and major bleeding. We designed paired ischaemic and major bleeding risk scores to inform this decision. Methods New Zealand (NZ) patients with ACS investigated with coronary angiography are recorded in the All NZ ACS Quality Improvement registry and linked to national health datasets. Patients were aged 18–84 years (2012–2020), event free at 28 days postdischarge and without atrial fibrillation. Two 28-day to 1-year postdischarge multivariable risk prediction scores were developed: (1) cardiovascular mortality/rehospitalisation with myocardial infarction or ischaemic stroke (ischaemic score) and (2) bleeding mortality/rehospitalisation with bleeding (bleeding score). Findings In 27 755 patients, there were 1200 (4.3%) ischaemic and 548 (2.0%) major bleeding events. Both scores were well calibrated with moderate discrimination performance (Harrell’s c-statistic 0.75 (95% CI, 0.74 to 0.77) and 0.69 (95% CI, 0.67 to 0 .71), respectively). Applying these scores to the 2020 European Society of Cardiology ACS antithrombotic treatment algorithm, the 31% of the cohort at elevated (>2%) bleeding and ischaemic risk would be considered for an abbreviated DAPT duration. For those at low bleeding risk, but elevated ischaemic risk (37% of the cohort), prolonged DAPT may be appropriate, and for those with low bleeding and ischaemic risk (29% of the cohort) short duration DAPT may be justified. Conclusion We present a pair of ischaemic and bleeding risk scores specifically to assist clinicians and their patients in deciding on DAPT duration beyond the first month post-ACS.

Background Recognising frailty is important to guide clinical decisions in older patients with cardiac disease. The relative strengths of different frailty instruments to predict mortality and hospitalization risk are uncertain. Methods The Edmonton Frail Scale (EFS), Fried Criteria (Fried), Clinical Frailty Scale (CFS), Katz score (Katz), GP Cognition test (GPCog), and Euroscore II, a non-frailty risk score, were completed in 1174 clinically stable inpatients >70 years of age admitted with suspected acute coronary syndrome. Associations with all cause mortality (n=353, 29%) during a median follow-up of 5.1 (IQR: 4.6-5.5) years and hospitalization for > 10 days in the next year (n=267, 22%) were evaluated. Results There were graded associations between increasing frailty assessed by each tool and all cause mortality. For the EFS, which scores up to 17 points on different dimensions of frailty, hazard ratios for high (score 9-17, n=197) compared to low frailty (score 0-2, n=331) were 5.0 (95%CI: 3.4-7.4) for mortality, and 5.3 (3.4-8.3) for hospitalization. Discrimination for all-cause mortality according to Harrell's C-index were EFS 0.663, Euroscore II 0.654, Fried 0.648, CFS 0.640, GPCog 0.608, and Katz 0.593, P<0.001 for all. C-statistics for hospitalization >10 days were EFS 0.649, Fried 0.628, Katz 0.602, Euroscore II 0.589, CFS 0.584, and GPCog 0.552, P<0.001 for all. When combining tools integrated discrimination improvement for both mortality and hospitalization were greater for EFS than for other frailty instruments. Conclusion In acute coronary syndrome patients the Edmonton Frail Scale discriminated the risk of mortality and hospitalization as well or better than other frailty instruments. ### Competing Interest Statement AL; JB; AK; KB; GD; AS; DS; AT; GW; RAHS had nothing to disclose HDW: received grant support paid to the institution and fees for serving on a steering committee for the ODYSSEY study from Sanofi-Aventis and Regeneron Pharmaceuticals, for the HEART-FID study from American Regent; for the dal-GenE study from DalCor Pharma UK Inc, for the AEGIS-II study from CSL Behring, for the SCORED trial and the SOLOIST-WHF trial from Sanofi-Aventis Australia Pty Ltd, and for the CLEAR Outcomes Study from Esperion Therapeutics Inc. He has served on an Advisory Board for Genentech, Inc. and received lecture fees from AstraZeneca outside the submitted work. ### Clinical Trial Was not a clinical trial ### Funding Statement Anne Langsted was supported by the Research Fund for the Capital Region of Denmark (A7160), the Beckett Foundation (21-2-7785), the Augustinus Foundation (21-2056), and the Reinholdt W. Jorck and Wife Foundation (21-JU-0053). This research was supported by a grant form the Health Research Council of New Zealand ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the New Zealand Health and disciplinary Ethics Committee (number 14/NTB/207). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The Data will be made available on request

BACKGROUND Regional handling and the prognostic performance of insulin-like growth factor binding protein (IGFBP)-7, in contrast or in combination with other candidate biomarkers, in chronic heart failure (CHF) remain uncertain. OBJECTIVES The authors investigated the regional handling of plasma IGFBP-7 and its association with long-term outcomes in CHF in comparison with selected circulating biomarkers. METHODS Plasma concentrations of IGFBP-7, N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin-T, growth differentiation factor-15, and high-sensitivity C-reactive protein were measured prospectively in a cohort with CHF (n = 863). The primary outcome was the composite of heart failure (HF) hospitalization or all-cause mortality. In a separate non-HF cohort (n = 66) undergoing cardiac catheterization, transorgan gradients of plasma IGFBP-7 concentrations were evaluated. RESULTS Among 863 patients (age 69 +/- 14 years, 30% female, 36% HF with preserved ejection fraction), IGFBP-7 (median: 121 [IQR: 99-156] ng/mL) related inversely to left ventricular volumes but directly to diastolic function. Above the optimal cutoff, IGFBP-7 >= 110 ng/mL was independently associated with 32% increased hazard of the primary outcome: 1.32 (95% CI: 1.06-1.64). Among the 5 markers, IGFBP-7 had the highest hazard for a proportional increment in plasma concentrations independent of HF phenotype in single- and double-biomarker models, and provided incremental prognostic value beyond clinical predictors plus NT-proBNP, high-sensitivity troponin-T, and high-sensitivity C-reactive protein (P < 0.05). Assessment of regional concentrations indicated renal secretion of IGFBP-7 in contrast to renal extraction of NT-proBNP, possible cardiac extraction of IGFBP-7 in contrast to secretion of NT-proBNP, and common hepatic extraction of both peptides. CONCLUSIONS Transorgan regulation of IGFBP-7 is distinct from NT-proBNP. Circulating IGFBP-7 independently predicts adverse outcomes in CHF with a strong prognostic performance when compared with other well-recognized cardiac-specific or noncardiac prognostic markers. (C) 2023 by the American College of Cardiology Foundation.

Background: Iron deficiency (ID) is highly prevalent in patients with heart failure (HF) but its impact on prognosis in HF with preserved ejection fraction (HFpEF) remains unclear. We assessed whether ID defined by soluble transferrin receptor (sTfR) criteria is independently associated with all-cause mortality in patients with HFpEF, and evaluated its comparative prognostic performance to ID definitions in common clinical use. Methods and Results: Data were analyzed from 788 patients (36% HFpEF) in a prospective multicenter HF cohort study. Baseline plasma samples were analyzed with respect to 4 definitions of ID: sTfR of >= 1.59 mg/L (IDsTfR1), sTfR of >= 1.76 mg/L (IDsTfR2), ferritin of < 100 mu g/L, or ferritin of 100-300 mu g/L + transferrin saturation of < 20% (IDFerritin), and transferrin saturation of < 20% (IDTsat). In multivariable Cox models IDsTfR2 (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.23-2.75) and IDTsat (HR, 1.69, 95% CI 1.10-2.59) were both independently associated with all-cause mortality in patients with HFpEF, whereas IDsTfR1 (HR 1.41, 95% CI 0.92-2.16) and IDFerritin (HR 1.19, 95% CI 0.77-1.85) were not. On inclusion of patients with HF with reduced EF, IDsTfR1 (HR 1.45, 95% CI 1.13-1.86) gained significance, but IDFerritin (HR 1.21, 95% CI 0.95-1.54) did not. For each pair of definitions intra-patient concordance was approximately 65%. Conclusion: ID defined by sTfR criteria is independently associated with all-cause mortality in patients with HFpEF. Poor concordance between ID definitions suggests that iron biomarkers do not reflect the same pathological process in the complex relationship between iron and HF. Therefore, which definition should guide iron replacement needs further evaluation. (J Cardiac Fail 2022;28:1255-1263)