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.

Longitudinal NT-proBNP: Associations With Echocardiographic Changes and Outcomes in Heart Failure.

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 ß-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 (Pinteraction<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.

Convalescent Growth Differentiation Factor-15 and Long-Term Outcomes after an Acute Coronary Syndrome.

BACKGROUND: Growth differentiation factor-15 (GDF-15) has been shown to be associated with adverse clinical outcomes in patients after an acute coronary syndrome when measured soon after an event. Although dynamic in the acute phase after myocardial injury, GDF-15 has been shown to remain stable during convalescence. In this study, we aimed to assess the value of GDF-15 as a long-term prognostic marker for clinical outcomes when measured in the convalescent phase following an acute coronary syndrome. METHODS: GDF-15 concentrations were measured in 1945 patients who were recruited between 2002 and 2009 to the Coronary Disease Cohort Study. For this analysis, follow-up was curtailed at 10 years and association of GDF-15 with all-cause death, cardiovascular death, recurrent myocardial infarction, and heart failure hospitalizations were assessed with multivariate Cox proportional hazard regression analysis. RESULTS: After 10 years of follow-up, there were 648 deaths (348 from cardiovascular causes), 500 admissions for myocardial infarction, and 436 for heart failure. Four-month convalescent GDF-15 demonstrated a robust independent association with all endpoints, which remained after adjustment for Global Registry of Acute Coronary Events score and other convalescent biomarkers. When compared to the lowest quartile of GDF-15 concentrations, those in the highest quartile had a 3-fold increased risk of all-cause death. CONCLUSIONS: Convalescent plasma GDF-15 is a strong and independent predictor of 10-year all-cause death, cardiovascular death, recurrent myocardial infarction, and heart failure admission following an acute coronary syndrome. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY TRIAL ID: ACTRN12605000431628.

Utilizing Quality of Life Adjusted Days Alive and Out of Hospital in Heart Failure Clinical Trials.

BACKGROUND: In heart failure (HF) trials, there has been an emphasis on utilizing more patient-centered outcomes, including quality of life (QoL) and days alive and out of hospital. We aimed to explore the impact of QoL adjusted days alive and out of hospital as an outcome in 2 HF clinical trials. METHODS: Using data from 2 trials in HF (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT] and Study of Dietary Intervention under 100 mmol in Heart Failure [SODIUM-HF]), we determined treatment differences using percentage days alive and out of hospital (%DAOH) adjusted for QoL at 18 months as the primary outcome. For each participant, %DAOH was calculated as a ratio between days alive and out of hospital/total follow-up. Using a regression model, %DAOH was subsequently adjusted for QoL measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score. RESULTS: In the GUIDE-IT trial, 847 participants had a median baseline Kansas City Cardiomyopathy Questionnaire Overall Summary Score of 59.0 (interquartile range, 40.8-74.3), which did not change over 18 months. %DAOH was 90.76%±22.09% in the biomarker-guided arm and 88.56%±25.27% in the usual care arm. No significant difference in QoL adjusted %DAOH was observed (1.09% [95% CI, -1.57% to 3.97%]). In the SODIUM-HF trial, 796 participants had a median baseline Kansas City Cardiomyopathy Questionnaire Overall Summary Score of 69.8 (interquartile range, 49.3-84.3), which did not change over 18 months. %DAOH was 95.69%±16.31% in the low-sodium arm and 95.95%±14.76% in the usual care arm. No significant difference was observed (1.91% [95% CI, -0.85% to 4.77%]). CONCLUSIONS: In 2 large HF clinical trials, adjusting %DAOH for QoL was feasible and may provide complementary information on treatment effects in clinical trials.

Derivation and Validation of Thresholds Using Synthetic Data Methods for Single-Test Screening of Emergency Department Patients with Possible Acute Myocardial Infarction Using a Point-of-Care Troponin Assay.

BACKGROUND: Single-sample (screening) rule-out of acute myocardial infarction (AMI) with troponin requires derivation of a single-test screening threshold. In data sets with small event numbers, the lowest one or two concentrations of myocardial infarction (MI) patients dictate the threshold. This is not optimal. We aimed to demonstrate a process incorporating both real and synthetic data for deriving such thresholds using a novel pre-production high-precision point-of-care assay. METHODS: cTnI concentrations were measured from thawed plasma using the Troponin I Next (TnI-Nx) assay (i-STAT; Abbott) in adults on arrival to the emergency department with symptoms suggestive of AMI. The primary outcome was an AMI or cardiac death within 30 days. We used internal-external validation with synthetic data production based on clinical and demographic data, plus the measured TnI-Nx concentration, to derive and validate decision thresholds for TnI-Nx. The target low-risk threshold was a sensitivity of 99% and a high-risk threshold specificity of >95%. RESULTS: In total, 1356 patients were included, of whom 191 (14.1%) had the primary outcome. A total of 500 synthetic data sets were constructed. The mean low-risk threshold was determined to be 5 ng/L. This categorized 38% (95% CI, 6%-68%) to low-risk with a sensitivity of 99.0% (95% CI, 98.6%-99.5%) and a negative predictive value of 99.4% (95% CI, 97.6%-99.8%). A similarly derived high-risk threshold of 25 ng/L had a specificity of 95.0% (95% CI, 94.8%-95.1%) and a positive predictive value of 74.8% (95% CI, 71.5%-78.0%). CONCLUSIONS: With the TnI-Nx assay, we successfully demonstrated an approach using synthetic data generation to derive low-risk thresholds for safe and effective screening.

Hierarchical End Points in Prior Heart Failure Trials and the HEART-FID Trial.

BACKGROUND: Clinical trials in heart failure (HF) traditionally use time-to-event analyses focusing on death and hospitalization for HF. These time-to-first event analyses may have more limited abilities to assess the probability of benefiting from a therapy, especially if that benefit manifests as improved functional status rather than reduced risk of death or HF hospitalization. Hierarchical end points including clinical outcomes and patient status measures allow for ranked evaluation of outcomes in 1 metric assessing whether patients randomized to intervention or control are more likely to derive an overall benefit while also allowing more patients to contribute to the primary outcome. METHODS: We review the rationale for using hierarchical end points in HF trials, provide examples of HF trials that used this type of end point, and discuss its use in the HEART-FID trial (Randomized Placebo-Controlled Trial of Ferric Carboxymaltose as Treatment for Heart Failure With Iron Deficiency), the largest HF trial to date implementing a hierarchical end point analysis for the primary outcome. RESULTS: Using a hierarchical end point as the primary outcome allows for the inclusion of different types of outcomes in 1 ranked end point, making it possible to more holistically assess the potential utility of a new therapy on patient well-being and outcomes. CONCLUSIONS: Hierarchical end points assess the potential utility of a new therapy on patient well-being and outcome more holistically than time-to-first event analysis. Trials that would not have been feasible due to decreasing rates of death and hospitalization in the HF population can use hierarchical end points to successfully power studies to identify promising HF therapies. The HEART-FID trial used hierarchical end points to better determine the role of intravenous ferric carboxymaltose in patients with HF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931.

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).

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.).

Evolution of NT-proBNP During Prerandomization Screening in VICTORIA: Implications for Clinical Outcomes and Efficacy of Vericiguat.

BACKGROUND: Selecting high-risk patients with heart failure with potentially modifiable cardiovascular events is a priority. Our objective was to evaluate NT-proBNP (N-terminal pro-B-type natriuretic peptide) changes during a 30-day screening to establish (1) the frequency and direction of changes; (2) whether a relationship exists between changes in NT-proBNP and the primary composite outcome of cardiovascular death and heart failure hospitalization; and (3) whether changes in NT-proBNP relate to vericiguat's clinical benefit. METHODS: VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) randomized 5050 patients with heart failure with reduced ejection fraction and a recent worsening heart failure event. We studied 3821 patients who had NT-proBNP measured during screening and at randomization. RESULTS: Sixteen hundred exhibited a >20% reduction, 1412 had ≤20% change, and 809 showed a >20% rise in NT-proBNP levels. As compared with the primary composite outcome of 28.4/100 patient-years (497 events; 31.1%) in patients with a >20% decline in NT-proBNP, those with >20% during screening had worse outcomes; 48.8/100 patient-years (359 events; 44.4%); adjusted hazard ratio, 1.61 (95% CI, 1.39-1.85). Those patients with a ≤20% change in NT-proBNP had intermediate outcomes; 39.2/100 patient-years (564 events; 39.9%); adjusted hazard ratio, 1.33 (95% CI, 1.17-1.51). No relationship existed between NT-proBNP changes during screening and vericiguat's effect on cardiovascular death and heart failure hospitalization. CONCLUSIONS: Substantial differences occurred in the rates of cardiovascular death and heart failure hospitalization, especially in patients with a >20% change in NT-proBNP levels during screening interval. Sequential NT-proBNP levels add important prognostic information meriting consideration in future heart failure trials. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02861534.

Personalized diagnosis in suspected myocardial infarction.

BACKGROUND: In suspected myocardial infarction (MI), guidelines recommend using high-sensitivity cardiac troponin (hs-cTn)-based approaches. These require fixed assay-specific thresholds and timepoints, without directly integrating clinical information. Using machine-learning techniques including hs-cTn and clinical routine variables, we aimed to build a digital tool to directly estimate the individual probability of MI, allowing for numerous hs-cTn assays. METHODS: In 2,575 patients presenting to the emergency department with suspected MI, two ensembles of machine-learning models using single or serial concentrations of six different hs-cTn assays were derived to estimate the individual MI probability (ARTEMIS model). Discriminative performance of the models was assessed using area under the receiver operating characteristic curve (AUC) and logLoss. Model performance was validated in an external cohort with 1688 patients and tested for global generalizability in 13 international cohorts with 23,411 patients. RESULTS: Eleven routinely available variables including age, sex, cardiovascular risk factors, electrocardiography, and hs-cTn were included in the ARTEMIS models. In the validation and generalization cohorts, excellent discriminative performance was confirmed, superior to hs-cTn only. For the serial hs-cTn measurement model, AUC ranged from 0.92 to 0.98. Good calibration was observed. Using a single hs-cTn measurement, the ARTEMIS model allowed direct rule-out of MI with very high and similar safety but up to tripled efficiency compared to the guideline-recommended strategy. CONCLUSION: We developed and validated diagnostic models to accurately estimate the individual probability of MI, which allow for variable hs-cTn use and flexible timing of resampling. Their digital application may provide rapid, safe and efficient personalized patient care. TRIAL REGISTRATION NUMBERS: Data of following cohorts were used for this project: BACC ( www. CLINICALTRIALS: gov ; NCT02355457), stenoCardia ( www. CLINICALTRIALS: gov ; NCT03227159), ADAPT-BSN ( www.australianclinicaltrials.gov.au ; ACTRN12611001069943), IMPACT ( www.australianclinicaltrials.gov.au , ACTRN12611000206921), ADAPT-RCT ( www.anzctr.org.au ; ANZCTR12610000766011), EDACS-RCT ( www.anzctr.org.au ; ANZCTR12613000745741); DROP-ACS ( https://www.umin.ac.jp , UMIN000030668); High-STEACS ( www. CLINICALTRIALS: gov ; NCT01852123), LUND ( www. CLINICALTRIALS: gov ; NCT05484544), RAPID-CPU ( www. CLINICALTRIALS: gov ; NCT03111862), ROMI ( www. CLINICALTRIALS: gov ; NCT01994577), SAMIE ( https://anzctr.org.au ; ACTRN12621000053820), SEIGE and SAFETY ( www. CLINICALTRIALS: gov ; NCT04772157), STOP-CP ( www. CLINICALTRIALS: gov ; NCT02984436), UTROPIA ( www. CLINICALTRIALS: gov ; NCT02060760).

DNA methylation patterns at birth predict health outcomes in young adults born very low birthweight.

BACKGROUND: Individuals born very low birthweight (VLBW) are at increased risk of impaired cardiovascular and respiratory function in adulthood. To identify markers to predict future risk for VLBW individuals, we analyzed DNA methylation at birth and at 28 years in the New Zealand (NZ) VLBW cohort (all infants born < 1500 g in NZ in 1986) compared with age-matched, normal birthweight controls. Associations between neonatal methylation and cardiac structure and function (echocardiography), vascular function and respiratory outcomes at age 28 years were documented. RESULTS: Genomic DNA from archived newborn heel-prick blood (n = 109 VLBW, 51 controls) and from peripheral blood at ~ 28 years (n = 215 VLBW, 96 controls) was analyzed on Illumina Infinium MethylationEPIC 850 K arrays. Following quality assurance and normalization, methylation levels were compared between VLBW cases and controls at both ages by linear regression, with genome-wide significance set to p < 0.05 adjusted for false discovery rate (FDR, Benjamini-Hochberg). In neonates, methylation at over 16,400 CpG methylation sites differed between VLBW cases and controls and the canonical pathway most enriched for these CpGs was Cardiac Hypertrophy Signaling (p = 3.44E-11). The top 20 CpGs that differed most between VLBW cases and controls featured clusters in ARID3A, SPATA33, and PLCH1 and these 3 genes, along with MCF2L, TRBJ2-1 and SRC, led the list of 15,000 differentially methylated regions (DMRs) reaching FDR-adj significance. Fifteen of the 20 top CpGs in the neonate EWAS showed associations between methylation at birth and adult cardiovascular traits (particularly LnRHI). In 28-year-old adults, twelve CpGs differed between VLBW cases and controls at FDR-adjusted significance, including hypermethylation in EBF4 (four CpGs), CFI and UNC119B and hypomethylation at three CpGs in HIF3A and one in KCNQ1. DNA methylation GrimAge scores at 28 years were significantly greater in VLBW cases versus controls and weakly associated with cardiovascular traits. Four CpGs were identified where methylation differed between VLBW cases and controls in both neonates and adults, three reversing directions with age (two CpGs in EBF4, one in SNAI1 were hypomethylated in neonates, hypermethylated in adults). Of these, cg16426670 in EBF4 at birth showed associations with several cardiovascular traits in adults. CONCLUSIONS: These findings suggest that methylation patterns in VLBW neonates may be informative about future adult cardiovascular and respiratory outcomes and have value in guiding early preventative care to improve adult health.

Prognostic modelling of clinical outcomes after first-time acute coronary syndrome in New Zealand.

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% Maori, 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, Maori 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; Maori 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 Maori 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.

The Predictive Value of A, B, and C-Type Natriuretic Peptides in People at Risk of Heart Disease: Protocol for a Longitudinal Observational Study.

BACKGROUND: Heart disease and stroke are major and often unheralded causes of serious morbidity and premature death in middle age. Early detection of those most at risk is an urgent unmet need for instituting preventative measures. In an earlier community study (Canterbury Health, Ageing and Life Course [CHALICE]) of healthy people aged 50 years, contrary to previous reports, low levels of the heart hormone B-type natriuretic peptide (BNP) were associated with reduced measures of heart function and higher markers of vascular risk. A specific gene variant (rs198358) was found to be an independent contributor to higher BNP levels. A closely related vascular hormone (C-type natriuretic peptide [CNP]) showed opposite associations-higher levels were correlated with higher vascular risk and reduced cardiac function. To determine whether these novel findings predict serious heart or vascular disease in later life, this proposal re-examines the same CHALICE participants 15 years later. OBJECTIVE: The primary objective is to determine the predictive value of (1) low plasma concentrations of the circulating cardiac hormones (atrial natriuretic peptide [ANP] and BNP) and (2) high levels of the vascular hormone CNP at age 50 years in detecting impaired cardiac and vascular function 15 years later. Secondary objectives are to determine specific associations of individual analytes (ANP, BNP, CNP, cyclic guanosine monophosphate [cGMP]) with echo-derived changes in cardiac performance at ages 50 years and 65 years. METHODS: All of the 348 participants (205/348, 58.9% female; 53/348, 15.2% Maori or Pacifica ethnicity) participating in the original CHALICE study-free of history of heart or renal disease at age 50 years and who consented to further study-will be contacted, recruited, and restudied as previously described. Data will include intervening health history, physical examination, heart function (speckle-tracking echocardiography), vascular status (carotid intimal thickness), and genetic status (genome-wide genotyping). Laboratory measures will include fasting blood sampling and routine biochemistry, ANP, BNP, CNP, their downstream effector (cGMP), and their bio-inactive products. Humoral metabolic-cardiovascular risk factors will be measured after an overnight fast. Primary outcomes will be analyzed using multiple linear regression. RESULTS: The study will commence in 2022 and be completed in 2024. CONCLUSIONS: Proving our hypothesis-that low BNP and high CNP at any age in healthy people predict premature aging of heart and blood vessels, respectively-opens the way to early detection and improved outcomes for those most at risk. Confirmation of our hypotheses would improve current methods of screening and, in appropriate cases, enable interventions aimed at increasing natriuretic hormones and reducing risk of serious cardiovascular complications using drugs already available. Such advances in detection, and from interventional corrections, have the potential to not only improve health in the community but also reduce the high costs inevitably associated with heart failure. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/37011.

Diagnostic and prognostic performance of the ratio between high-sensitivity cardiac troponin I and troponin T in patients with chest pain.

BACKGROUND: Elevations of high-sensitivity cardiac troponin (hs-cTn) concentrations not related to type 1 myocardial infarction are common in chest pain patients presenting to emergency departments. The discrimination of these patients from those with type 1 myocardial infarction (MI) is challenging and resource-consuming. We aimed to investigate whether the hs-cTn I/T ratio might provide diagnostic and prognostic increment in this context. METHODS: We calculated the hs-cTn I/T ratio in 888 chest pain patients having hs-cTnI (Abbott Laboratories) or hs-cTnT (Roche Diagnostics) concentrations above the respective 99th percentile at 2 hours from presentation. All patients were followed for one year regarding mortality. RESULTS: The median hs-cTn I/T ratio was 3.45 (25th, 75th percentiles 1.80-6.59) in type 1 MI patients (n = 408 ☯46.0%]), 1.18 (0.81-1.90) in type 2 MI patients (n = 56 ☯6.3%]) and 0.67 (0.39-1.12) in patients without MI. The hs-cTn I/T ratio provided good discrimination of type 1 MI from no type 1 MI (area under the receiver-operator characteristic curve 0.89 ☯95% confidence interval 0.86-0.91]), of type 1 MI from type 2 MI (area under the curve 0.81 ☯95% confidence interval 0.74-0.87]), and was associated with type 1 MI in adjusted analyses. The hs-cTn I/T ratio provided no consistent prognostic value. CONCLUSIONS: The hs-cTn I/T ratio appears to be useful for early diagnosis of type 1 MI and its discrimination from type 2 MI in chest pain patients presenting with elevated hs-cTn. Differences in hs-cTn I/T ratio values may reflect variations in hs-cTn release mechanisms in response to different types of myocardial injury.

Identifying Candidate Circulating RNA Markers for Coronary Artery Disease by Deep RNA-Sequencing in Human Plasma.

Advances in RNA sequencing (RNA-Seq) have facilitated transcriptomic analysis of plasma for the discovery of new diagnostic and prognostic markers for disease. We aimed to develop a short-read RNA-Seq protocol to detect mRNAs, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in plasma for the discovery of novel markers for coronary artery disease (CAD) and heart failure (HF). Circulating cell-free RNA from 59 patients with stable CAD (half of whom developed HF within 3 years) and 30 controls was sequenced to a median depth of 108 paired reads per sample. We identified fragments from 3986 messenger RNAs (mRNAs), 164 long non-coding RNAs (lncRNAs), 405 putative novel lncRNAs and 227 circular RNAs in plasma. Circulating levels of 160 mRNAs, 10 lncRNAs and 2 putative novel lncRNAs were altered in patients compared with controls (absolute fold change >1.2, p < 0.01 adjusted for multiple comparisons). The most differentially abundant transcripts were enriched in mRNAs encoded by the mitochondrial genome. We did not detect any differences in the plasma RNA profile between patients who developed HF compared with those who did not. In summary, we show that mRNAs, lncRNAs and circular RNAs can be reliably detected in plasma by deep RNA-Seq. Multiple coding and non-coding transcripts were altered in association with CAD, including several mitochondrial mRNAs, which may indicate underlying myocardial ischaemia and oxidative stress. If validated, circulating levels of these transcripts could potentially be used to help identify asymptomatic individuals with established CAD prior to an acute coronary event.

Sequential Evaluation of NT-proBNP in Heart Failure: Insights Into Clinical Outcomes and Efficacy of Vericiguat.

BACKGROUND: The effect of vericiguat on sequential N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and influence of this relationship on clinical outcomes is unknown. OBJECTIVES: This study assessed the relationship between changes in NT-proBNP and the primary outcome (cardiovascular death or heart failure hospitalization); evaluated the effect of vericiguat on changes in NT-proBNP; and explored the association between the efficacy of vericiguat and changes in NT-proBNP. METHODS: NT-proBNP was measured at randomization and at 16, 32, 48, and 96 weeks in 4,805 of 5,050 patients. The association between NT-proBNP change at week 16 and the primary outcome was assessed. The relationship between changes in NT-proBNP and the primary outcome according to treatment group was assessed by using joint modeling and mediation analysis. RESULTS: A significant and sustained decline in NT-proBNP levels was seen in both treatment groups. After week 16, NT-proBNP levels decreased more with vericiguat vs placebo (any reduction: odds ratio [OR]: 1.45 [95% CI: 1.28-1.65]; P < 0.001; ≥50% reduction: OR: 1.27 [95% CI: 1.10-1.47]; P = 0.001) and were less likely to increase (≥20% increase: OR: 0.68 [95% CI: 0.59-0.78]; P < 0.001; ≥50% increase: OR: 0.70 [95% CI: 0.59-0.82]; P < 0.001). The treatment effect related to serial NT-proBNP on the primary composite outcome was HR: 0.96 (95% CI: 0.95-0.99) at week 16, which increased to HR: 0.90 (95% CI: 0.85-0.96) at week 48; the average extent of mediation of the composite outcome related to NT-proBNP was 45%. CONCLUSIONS: In patients with worsening HFrEF, vericiguat significantly decreased NT-proBNP levels compared with placebo. This change appeared associated with a modest relative improvement in the primary outcome of cardiovascular death or heart failure hospitalization. (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534).

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.

Preterm birth and cardiac function in adulthood.

Preterm birth affects 1 in 10 pregnancies worldwide, with increasing survival rates over the last 30 years. However, as this new generation of long-term survivors approaches middle age, recent studies have revealed increased cardiovascular risk factors and higher rates of ischaemic heart disease and heart failure. Cardiovascular imaging has identified smaller cardiac chamber size, changes in myocardial mass and impaired ventricular function, particularly under physiological stress. Accordingly, this population should be recognised as having a higher risk of heart failure as they age. In this review, we present current evidence for increased rates of heart failure and evidence of alterations in cardiac structure and function in those born preterm. We discuss potential mechanisms to explain this risk including greater frequency of co-morbidities known to be associated with heart failure. We also explore potential mechanistic links specific to the preterm-born population, including the impact of premature birth on myocardial and vascular development and the effects of perinatal haemodynamic changes and chronic lung disease on the developing heart. We highlight gaps in our knowledge and consider implications for patient management relevant to the adult physician.

Vascular endothelial growth factor-A promoter polymorphisms, circulating VEGF-A and survival in acute coronary syndromes.

BACKGROUND: Development of a competent collateral circulation in established coronary artery disease is cardio-protective. The vascular endothelial growth factor (VEGF) system plays a key role in this process. We investigated the prognostic performance of circulating VEGF-A and three genetic variants in the VEGFA gene in a clinical coronary cohort. METHODS AND RESULTS: The Coronary Disease Cohort Study (CDCS) recruited 2,140 patients, with a diagnosis of acute coronary syndrome (ACS), after admission to Christchurch or Auckland City Hospitals between July 2002 and January 2009. We present data for 1927 patients from the cohort genotyped for three SNPs in the VEGF-A gene, rs699947 (C-2578A), rs2010963 (C405G) and rs3025039 (C936T). Plasma VEGF-A concentrations were assayed in a subgroup (n = 550) of CDCS patients (geometric mean 36.6 [34.7-38.5] pg/ml). VEGF-A levels correlated with patient heart rate at baseline (p = 0.034). None of rs699947, rs3025039, nor rs2010963 genotypes were significantly associated with VEGF-A levels, but rs3025039 genotype was positively associated with collateral vessels perfusion according to the Rentrop classification (p = 0.01) and baseline natriuretic peptide levels (p<0.05). Survival in the CDCS cohort was independently associated with baseline VEGF-A levels and (in males) with rs699947 genotype. CONCLUSIONS: This study is strongly suggestive that VEGF-A levels have value as a prognostic biomarker in coronary heart disease patients and SNPs in VEGF-A deserve further investigation as prognostic markers and indicators of angiogenic potential influencing the formation of collateral circulation.