N-terminal pro-B-type natriuretic peptide levels vary by ethnicity and are associated with insulin sensitivity after gestational diabetes mellitus.

BACKGROUND: Individuals of South Asian origin have a greater risk of cardiovascular disease after gestational diabetes mellitus (GDM) than European individuals. B-type natriuretic peptide (BNP) and the amino-terminal fragment of its prohormone (NT-proBNP) are commonly used for heart failure screening and diagnosis, but biologically BNP exerts several beneficial cardiovascular effects primarily by counteracting the renin-angiotensin-aldosterone-system. We asked whether ethnic differences in circulating NT-proBNP levels could be explained by the differences in cardiometabolic and inflammatory risk markers? METHODS: We examined 162 South Asian and 107 Nordic women in Norway 1-3 years after GDM with a clinical examination, fasting blood samples and an oral glucose tolerance test. We measured the levels of NT-proBNP, high-sensitivity cardiac troponin T, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), leptin, adiponectin and markers of insulin sensitivity, such as the Matsuda insulin sensitivity index (ISI). Finally, we tried to identify which independent covariate best mediated the ethnic differences in NT-proBNP. RESULTS: The mean (SD) age was 35.3 (4.5) years, BMI 29.1 (6.0) kg/m2, waist-height ratio 0.60 (0.08) and 164 women (61%) had prediabetes/diabetes. Notably, South Asian women had lower levels of NT-proBNP than Nordic women in both the normoglycemic and prediabetes/diabetes groups (median (IQR) 26  (15-38)  vs. 42 (22-66) ng/L, p < 0.001). Higher NT-proBNP levels were associated with greater insulin sensitivity in both South Asian and Nordic women (p = 0.005 and p < 0.001). South Asian women had higher levels of hsCRP (median (IQR) 2.2 (1.1-4.4) vs. 1.2 (0.3-4.2) mg/L), IL-6 (2.3 (1.5-3.2) vs. 1.5 (1.5-2.5) pg/mL), leptin (1647 (1176-2480) vs. 1223 (876-2313) pmol/L), and lower adiponectin levels (7.2 (5.3-9.3) vs. 10.0 (7.2-13.5) mg/L) and Matsuda ISI (2.4 (1.7-3.7) vs. 4.2 (2.9-6.1), pall<0.01) than Nordic women. Even after adjusting for these differences, higher NT-proBNP levels remained associated with insulin sensitivity (22% higher NT-proBNP per SD Matsuda ISI, p = 0.015). Insulin sensitivity and adiponectin mediated 53% and 41% of the ethnic difference in NT-proBNP. CONCLUSIONS: NT-proBNP levels are lower in South Asian than in Nordic women after GDM. Lower NT-proBNP levels correlate with impaired insulin sensitivity. Lower NT-proBNP levels in South Asian women could, therefore, be attributed to impaired insulin sensitivity rather than total body fat.

Clinical and Analytical Performance of a Novel Point-of-Care High-Sensitivity Cardiac Troponin I Assay.

BACKGROUND: Point-of-care (POC) high-sensitivity cardiac troponin assays may further accelerate the diagnosis of myocardial infarction (MI). OBJECTIVES: This study sought to assess the clinical and analytical performance of the novel high-sensitivity cardiac troponin I (hs-cTnI)-SPINCHIP POC test. METHODS: Adult patients presenting with acute chest discomfort to the emergency department were enrolled in an international, diagnostic, multicenter study. The final diagnosis was centrally adjudicated by 2 independent cardiologists using all clinical information. We compared the discriminatory performance of hs-cTnI-SPINCHIP with current established central laboratory assays and derived an assay-specific hs-cTnI-SPINCHIP 0/1-hour algorithm. Secondary analyses included sample type comparisons (whole blood, fresh/frozen plasma, and capillary finger prick) and precision analysis. RESULTS: MI was the adjudicated final diagnosis in 214 (19%) of 1,102 patients. Area under the receiver-operating characteristic curve was 0.94 (95% CI: 0.92-0.95) for hs-cTnI-SPINCHIP vs 0.94 (95% CI: 0.92-0.95) for hs-cTnI-Architect (P = 0.907) and 0.93 (95% CI: 0.91-0.95) for high-sensitivity cardiac troponin T Elecsys (P = 0.305). A cutoff <7 ng/L at presentation (if chest pain onset was >3 hours) or <7 ng/L together with a 0/1-hour delta of <4 ng/L ruled out 51% with a sensitivity and negative predictive value of 100% (95% CI: 97.7%-100%) and 100% (95% CI: 99.0%-100%), respectively. A hs-cTnI-SPINCHIP concentration ≥36 ng/L or a 0/1-hour delta ≥11 ng/L ruled in 27% with a specificity and positive predictive value of 90.9% (95% CI: 88.3%-92.9%) and 72.9% (95% CI: 66.4%-78.6%), respectively. Bootstrap internal validation confirmed excellent diagnostic performance. High agreement was observed between different sample types. CONCLUSIONS: The SPINCHIP hs-cTnI POC test has very high diagnostic accuracy. Its assay-specific 0/1-hour algorithm achieved very high sensitivity/negative predictive value and specificity/positive predictive value for rule-out/in MI. (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE] Study [APACE]; NCT00470587).

Diagnosing Myocardial Injury in an Acute Chest Pain Cohort; Long-Term Prognostic Implications of Cardiac Troponin T and I.

BACKGROUND: There are limited data regarding the utility of follow-up cardiac troponin (cTn) measurements after admission for acute chest pain and how long-term stability of myocardial injury and prognostic value differ when using cardiac troponin T (cTnT) or I (cTnI). METHODS: We measured high-sensitivity (hs)-cTnT (Roche Diagnostics) and hs-cTnI (Siemens Healthineers) during hospitalization for acute chest pain and after 3 months. Acute myocardial injury was defined as concentrations > sex-specific upper reference limit (URL) during hospitalization and ≤URL at 3-months. Chronic myocardial injury (CMI) was defined as concentrations > URL at both time points. Patients were followed from the 3-month sampling point for a median of 1586 (IQR 1161-1786) days for a primary composite endpoint of all-cause mortality, myocardial infarction (MI), revascularization, and heart failure, and a secondary endpoint of all-cause mortality. RESULTS: Among 754 patients, 33.8% (hs-cTnT) and 19.2% (hs-cTnI) had myocardial injury during hospitalization. The rate of CMI was 5 times higher by hs-cTnT (20%) assay than hs-cTnI (4%), while acute myocardial injury was equally common; 14% (hs-cTnT) and 15% (hs-cTnI), respectively (6% and 5% when excluding index non-ST-elevation MI (NSTEMI). For hs-cTnT, peak index concentration, 3-month concentration and classification of CMI predicted the primary endpoint; hazard ratios (HRs) 1.38 (95% CI 1.20-1.58), 2.34 (1.70-3.20), and 2.31 (1.30-4.12), respectively. For hs-cTnI, peak index concentration predicted the primary endpoint; HR 1.14 (1.03-1.25). This association was nonsignificant after excluding index NSTEMI. CONCLUSIONS: Acute myocardial injury is equally frequent, whereas CMI is more prevalent using hs-cTnT assay than hs-cTnI. Measuring hs-cTnT 3 months after an acute chest pain episode could assist in further long-term risk assessment. ClinicalTrials.gov Registration Number: NCT02620202.

Associations Between Biomarkers of Myocardial Injury and Systemic Inflammation and Risk of Incident Ventricular Arrhythmia.

BACKGROUND: Cardiac troponins (cTns) and biomarkers of inflammation are elevated in heart failure (HF) and predict cardiovascular risk. Whether these biomarkers associate with risk of ventricular arrhythmias (VAs) is unclear. OBJECTIVES: This study sought to assess whether cTnT, growth differentiation factor 15 (GDF-15), interleukin-6 (IL-6), and C-reactive protein (CRP) concentrations are associated with incident VA. METHODS: In a prospective, observational study of patients treated with implantable cardioverter-defibrillator, cTnT, GDF-15, IL-6, and CRP were measured at baseline and after 1.4 ± 0.5 years and were associated with implantable cardioverter-defibrillator-detected incident VA, HF hospitalizations, and mortality. RESULTS: This study included 489 patients aged 66 ± 12 years and 83% were men. Median concentrations of cTnT were 15 (Q1-Q3: 9-25) ng/L at inclusion, and higher concentrations were associated with higher age, male sex, diabetes mellitus, coronary artery disease, and HF. During 3.1 ± 0.7 years of follow-up, 137 patients (28%) had ≥1 VA. cTnT concentrations were associated with an increased VA risk (per log-unit, HR: 1.63; 95% CI: 1.31-2.01; P < 0.001), also after adjustment for age, sex, body mass index, coronary artery disease, HF, renal function, and left ventricular ejection fraction (P < 0.001). GDF-15, IL-6, and CRP concentrations were not associated with incident VA, but all (including cTnT) were associated with HF hospitalization and mortality. Changes in cTnT, GDF-15, IL-6, and CRP from baseline to 1.4 years were not associated with subsequent VA. CONCLUSIONS: Higher concentrations of cTnT, GDF-15, IL-6, and CRP associate with HF hospitalization and death, but only cTnT predict incident VA. These findings suggest that myocardial injury rather than inflammation may play a pathophysiological role in VA and sudden cardiac death.

Individual and Joint Associations of High-Sensitivity Troponin I and High-Sensitivity Troponin T with Cardiac Phenotypes and Outcomes in the General Population: An Analysis From the Dallas Heart Study.

BACKGROUND: High-sensitivity troponin I (hs-cTnI) and T (hs-cTnT) provide complementary information regarding cardiovascular disease risk. The explanation for their distinct risk profiles is incompletely understood. METHODS AND RESULTS: hs-cTnI and hs-cTnT were measured in Dallas Heart Study participants. Associations of hs-cTnI and hs-cTnT with demographics and phenotypes were assessed using linear regression. Associations with incident heart failure, atherosclerotic cardiovascular disease, global cardiovascular disease, and cardiovascular and all-cause mortality were assessed using Cox models. Among 3276 participants (56% women, 50% Black persons, median age 43 years), the correlation between hs-cTnI and hs-cTnT was modest (Spearman rho=0.35). Variables associated with hs-cTnI but not hs-cTnT included hypertension, higher body mass index and total cholesterol, and lower high-density lipoprotein and cholesterol efflux capacity. Older age, male sex, and diabetes were positively associated, and smoking was negatively associated, with hs-cTnT but not hs-cTnI. Hs-cTnI and hs-cTnT were associated with heart failure (hazard ratio [HR] per SD log hs-cTnI 1.53 [95% CI, 1.30-1.81] and HR per SD log hs-cTnT 1.65 [95% CI, 1.40-1.95]), global cardiovascular disease (HR, 1.22 [95% CI, 1.10-1.34] and HR, 1.27 [95% CI, 1.15-1.32]), and all-cause mortality (HR, 1.12 [95% CI, 1.01-1.25], and HR, 1.17 [95% CI, 1.06-1.29]). After adjustment for N-terminal pro-B-type natriuretic peptide and the alternative troponin, both remained associated with heart failure (HR per SD log hs-cTnI 1.32 [95% CI, 1.1-1.58] and HR per log hs-cTnT 1.27 [95% CI, 1.06-1.51]). CONCLUSIONS: Hs-cTnI and hs-cTnT are modestly correlated, demonstrate differential associations with cardiac and metabolic phenotypes, and provide complementary information regarding heart failure risk.

Prognostic Value of Cardiovascular Biomarkers in the Population.

Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies. Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors. Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years. Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein. Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses. Results: The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people. Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.

Trans-Cardiac Gradient of Secretoneurin in Patients with Takotsubo Syndrome.

INTRODUCTION: Secretoneurin (SN) is a novel biomarker that provides prognostic information in patients with cardiovascular disease. In experimental models, SN production is increased in the failing myocardium. Currently, no information is available on SN production in human myocardium. Accordingly, we wanted to determine the trans-cardiac gradient of SN in patients with Takotsubo syndrome (TTS), and to correlate circulating SN concentrations with indices of cardiac structure and function. METHODS: We included 15 women diagnosed with TTS according to established criteria. Plasma SN concentrations were measured in blood samples obtained simultaneously from the aortic root and the coronary sinus. Coronary physiology was assessed by invasive measurements, and we used cardiac magnetic resonance imaging to determine left ventricular ejection fraction (LVEF) and cardiac mass. RESULTS: Median age was 65 years and median LVEF was 45%. Median SN concentration was 39 (25th-75th percentile 31-44) pmol/L in the coronary sinus and 37 (30-41) pmol/L in the aortic root (p = 0.02 for difference). SN concentrations in the aortic root showed the highest correlations with N-terminal B-type natriuretic peptide (rho = 0.47) and estimated glomerular filtration rate (rho = -0.41). In contrast, we found weak correlations between SN concentrations and index of myocardial resistance (rho = 0.12), LVEF (rho = 0.08), and cardiac mass (rho = -0.09). CONCLUSION: We demonstrate a positive trans-cardiac gradient of SN in patients with TTS, which supports the hypothesis that SN is produced and released in the human myocardium in situations of myocardial dysfunction and stress.

Reference intervals of circulating secretoneurin concentrations determined in a large cohort of community dwellers: the HUNT study.

OBJECTIVES: Secretoneurin (SN) is a novel cardiac biomarker that associates with the risk of mortality and dysfunctional cardiomyocyte Ca2+ handling in heart failure patients. Reference intervals for SN are unknown. METHODS: SN was measured with a CE-marked ELISA in healthy community dwellers from the fourth wave of the Trøndelag Health Study (HUNT4) conducted in 2017-2019. The common, sex and age specific 90th, 95th, 97.5th and 99th percentiles were calculated using the non-parametric method and outlier exclusion according to the Reed test. The applicability of sex and age specific reference intervals were investigated using Harris and Boyd test. We also estimated the percentiles in a subset with normal findings on echocardiographic screening. RESULTS: The total cohort included 887 persons (56.4 % women). After echocardiographic screening 122 persons were excluded, leaving a total of 765 persons (57.8 % women). The 97.5th percentile (95 % CI in brackets) of SN was 59.7 (57.5-62.1) pmol/L in the total population and 58.6 (57.1-62.1) pmol/L after echocardiography screening. In general, slightly higher percentiles were found in women and elderly participants, but less than 4 % in these subgroups had concentrations deviating from the common 97.5th percentile. Low BMI or eGFR was also associated with higher concentrations of SN. CONCLUSIONS: Upper reference limits for SN were similar amongst healthy adult community dwellers regardless of prescreening including cardiac echocardiography or not. Women and elderly showed higher concentrations of SN, but the differences were not sufficiently large to justify age and sex stratified upper reference limits.

Trajectory of cardiac troponin T following moderate-to-severe COVID-19 and the association with cardiac abnormalities.

BACKGROUND: COVID-19 has been associated with cardiac troponin T (cTnT) elevations and changes in cardiac structure and function, but the link between cardiac dysfunction and high-sensitive cardiac troponin T (hs-cTnT) in the acute and convalescent phase is unclear. OBJECTIVE: To assess whether hs-cTnT concentrations are associated with cardiac dysfunction and structural abnormalities after hospitalization for COVID-19, and to evaluate the performance of hs-cTnT to rule out cardiac pathology. METHODS: Patients hospitalized with COVID-19 had hs-cTnT measured during the index hospitalization and after 3-and 12 months, when they also underwent an echocardiographic study. A subset also underwent cardiovascular magnetic resonance imaging (CMR) after 6 months. Cardiac abnormalities were defined as left ventricular hypertrophy or dysfunction, right ventricular dysfunction, or CMR late gadolinium. RESULTS: We included 189 patients with hs-cTnT concentrations measured during hospitalization for COVID-19, and after 3-and 12 months: Geometric mean (95%CI) 13 (11-15) ng/L, 7 (6-8) ng/L and 7 (6-8) ng/L, respectively. Cardiac abnormalities after 3 months were present in 45 (30%) and 3 (8%) of patients with hs-cTnT ≥ and < 5 ng/L at 3 months, respectively (negative predictive value 92.3% [95%CI 88.5-96.1%]). The performance was similar in patients with and without dyspnea. Hs-cTnT decreased from hospitalization to 3 months (more pronounced in intensive care unit-treated patients) and remained unchanged from 3 to 12 months, regardless of the presence of cardiac abnormalities. CONCLUSION: Higher hs-cTnT concentrations in the convalescent phase of COVID-19 are associated with the presence of cardiac pathology and low concentrations (< 5 ng/L) may support in ruling out cardiac pathology following the infection.

Systolic Blood Pressure, Diastolic Blood Pressure and Pulse Pressure and the Risk of Subclinical Myocardial Injury: The HUNT Study.

BACKGROUND: Subclinical myocardial injury expressed as higher cardiac troponin concentrations may represent an important intermediary between hypertension and the risk of cardiovascular disease. The study aimed to assess the relative strength of associations between systolic blood pressure (BP), diastolic BP, and pulse pressure, and subclinical myocardial injury, and how change in BP variables over time associates with subclinical myocardial injury. METHODS AND RESULTS: cTnl (cardiac troponin I) was measured in 32 968 participants of the fourth wave of the population-based cohort HUNT4 (Trøndelag Health Study) without a history of cardiovascular disease. An additional longitudinal analysis included participants from HUNT4 with BP measurements from HUNT3 (n=18 681). Associations between BP variables and cTnI concentrations were assessed by linear and logistic regression analyses. The median cTnI concentration was 1.6 ng/L (25th-75th percentiles, 0.6-3.1 ng/L), median age was 52 years (39.1-65.6 years), and 57% were female subjects. Cross-sectionally, only systolic BP categories ≥130 mm Hg associated with higher cTnI concentrations, compared with a reference systolic BP of <110 mm Hg. All categories of diastolic BP and pulse pressure were positively associated with higher cTnI concentrations when diastolic BP 70 to 79 mm Hg and pulse pressure <40 mm Hg were used as references, respectively. When comparing systolic BP, diastolic BP, and pulse pressure as continuous variables, cross-sectionally, pulse pressure most strongly associated with cTnI concentrations (P for all comparisons <0.001), whereas longitudinally, change in diastolic BP was most strongly associated with cTnI concentrations (P for all comparisons <0.05). CONCLUSIONS: Subjects with high pulse pressure and longitudinal increase in diastolic BP are at higher risk for subclinical myocardial injury.

Impact of the ESC Cardio-Oncology Guidelines Biomarker Criteria on Incidence of Cancer Therapy-Related Cardiac Dysfunction.

Background: The impact of recent consensus definitions of cancer therapy-related cardiac dysfunction (CTRCD) from the European Society of Cardiology cardio-oncology guidelines on the reported incidence of CTRCD has not yet been assessed. Objectives: The aim of this study was to assess the: 1) cumulative incidence; 2) point prevalence during and after adjuvant therapy; and 3) prognostic value of CTRCD as defined by different asymptomatic CTRCD guideline criteria. Methods: The cumulative incidence and point prevalence of CTRCD were retrospectively assessed in 118 patients participating in the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial. Asymptomatic CTRCD was assessed using alternative cardiac troponin (cTn) 99th percentile upper reference limits (URLs) to define cTnT and cTnI elevation. Results: The cumulative incidence of moderate or severe CTRCD was low (1.7%), whereas the cumulative incidence of mild asymptomatic CTRCD was higher and differed markedly according to the biomarker criteria applied, ranging from 49.2% of patients when cTnT greater than the sex-specific 99th percentile URL was used to define cTn elevation to 9.3% when sex-neutral cTnI was used. The point prevalence of CTRCD was highest at the end of anthracycline therapy (47.8%) and was driven primarily by asymptomatic cTn elevation. CTRCD during adjuvant therapy was not prognostic for CTRCD at extended follow-up of 24 months (Q1-Q3: 21-29 months) after randomization. Conclusions: Mild asymptomatic CTRCD during adjuvant breast cancer therapy was frequent and driven mainly by cTn elevation and was not prognostic of subsequent CTRCD. The incidence of mild, asymptomatic CTRCD differed markedly depending on the cTn assay and whether sex-neutral or sex-dependent URLs were applied. (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy [PRADA]; NCT01434134).

Exercise training and high-sensitivity cardiac troponin-I in patients with heart failure with reduced ejection fraction.

AIMS: The aims of this sub-study of the SMARTEX trial were (1) to evaluate the effects of a 12-week exercise training programme on serum levels of high sensitivity cardiac troponin I (hs-cTnI) in patients with moderate chronic heart failure (CHF), in New York Heart Association class II-III with reduced ejection fraction (HFrEF) and (2) to explore the associations with left ventricular remodelling, functional capacity and filling pressures measured with N-terminal pro brain natriuretic peptide (NT-proBNP). METHODS AND RESULTS: In this sub-study, 196 patients were randomly assigned to high intensity interval training (HIIT, n = 70), moderate continuous training (MCT, n = 59) or recommendation of regular exercise (RRE), (n = 67) for 12 weeks. To reveal potential difference between structured intervention and control, HIIT and MCT groups were merged and named supervised exercise training (SET) group. The RRE group constituted the control group (CG). To avoid contributing factors to myocardial injury, we also evaluated changes in patients without additional co-morbidities (atrial fibrillation, hypertension, diabetes mellitus, and chronic obstructive pulmonary disease). The relationship between hs-cTnI and left ventricular end-diastolic diameter (LVEDD), VO2peak, and NT-proBNP was analysed by linear mixed models. At 12 weeks, Hs-cTnI levels were modestly but significantly reduced in the SET group from median 11.9 ng/L (interquartile ratio, IQR 7.1-21.8) to 11.5 ng/L (IQR 7.0-20.7), P = 0.030. There was no between-group difference (SET vs. CG, P = 0.116). There was a numerical but not significant reduction in hs-cTnI for the whole population (P = 0.067) after 12 weeks. For the sub-group of patients without additional co-morbidities, there was a significant between-group difference: SET group (delta -1.2 ng/L, IQR -2.7 to 0.1) versus CG (delta -0.1 ng/L, IQR -0.4 to 0.7), P = 0.007. In the SET group, hs-cTnI changed from 10.9 ng/L (IQR 6.0-22.7) to 9.2 ng/L (IQR 5.2-20.5) (P = 0.002), whereas there was no change in the CG (6.4 to 5.8 ng/L, P = 0.64). Changes in hs-cTnI (all patients) were significantly associated with changes in; LVEDD, VO2peak, and NT-proBNP, respectively. CONCLUSIONS: In patients with stable HFrEF, 12 weeks of structured exercise intervention was associated with a modest, but significant reduction of hs-cTnI. There was no significant difference between intervention group and control group. In the sub-group of patients without additional co-morbidities, this difference was highly significant. The alterations in hs-cTnI were associated with reduction of LVEDD and natriuretic peptide concentrations as well as improved functional capacity.

Large scale plasma proteomics identifies novel proteins and protein networks associated with heart failure development.

Heart failure (HF) causes substantial morbidity and mortality but its pathobiology is incompletely understood. The proteome is a promising intermediate phenotype for discovery of novel mechanisms. We measured 4877 plasma proteins in 13,900 HF-free individuals across three analysis sets with diverse age, geography, and HF ascertainment to identify circulating proteins and protein networks associated with HF development. Parallel analyses in Atherosclerosis Risk in Communities study participants in mid-life and late-life and in Trøndelag Health Study participants identified 37 proteins consistently associated with incident HF independent of traditional risk factors. Mendelian randomization supported causal effects of 10 on HF, HF risk factors, or left ventricular size and function, including matricellular (e.g. SPON1, MFAP4), senescence-associated (FSTL3, IGFBP7), and inflammatory (SVEP1, CCL15, ITIH3) proteins. Protein co-regulation network analyses identified 5 modules associated with HF risk, two of which were influenced by genetic variants that implicated trans hotspots within the VTN and CFH genes.

Prognostic significance of chronic myocardial injury diagnosed by three different cardiac troponin assays in patients admitted with suspected acute coronary syndrome.

OBJECTIVES: Chronic myocardial injury (CMI) is defined as stable concentrations of cardiac troponin T or I (cTnT or cTnI) above the assay-specific 99th percentile upper reference limit (URL) and signals poor outcome. The clinical implications of diagnosing CMI are unclear. We aimed to assess prevalence and association of CMI with long-term prognosis using three different high-sensitivity cTn (hs-cTn) assays. METHODS: A total of 1,292 hospitalized patients without acute myocardial injury had cTn concentrations quantified by hs-cTn assays by Roche Diagnostics, Abbott Diagnostics and Siemens Healthineers. The median follow-up time was 4.1 years. The prevalence of CMI and hazard ratios for mortality and cardiovascular (CV) events were calculated based on the URL provided by the manufacturers and compared to the prognostic accuracy when lower percentiles of cTn (97.5, 95 or 90), limit of detection or the estimated bioequivalent concentrations between assays were used as cutoff values. RESULTS: There was no major difference in prognostic accuracy between cTnT and cTnI analyzed as continuous variables. The correlation between cTnT and cTnI was high (r=0.724-0.785), but the cTnT assay diagnosed 3.9-4.5 times more patients with having CMI based on the sex-specific URLs (TnT, n=207; TnI Abbott, n=46, TnI Siemens, n=53) and had higher clinical sensitivity and AUC at the URL. CONCLUSIONS: The prevalence of CMI is highly assay-dependent. cTnT and cTnI have similar prognostic accuracy for mortality or CV events when measured as continuous variables. However, a CMI diagnosis according to cTnT has higher prognostic accuracy compared to a CMI diagnosis according to cTnI.

Prognostic value of growth differentiation factor-15 3 months after an acute chest pain admission.

OBJECTIVE: Growth differentiation factor-15 (GDF-15) is a predictor of death and cardiovascular events when measured during index hospitalisation in patients with acute chest pain. This study investigated the prognostic utility of measuring GDF-15 3 months after an admission with suspected non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS: GDF-15 was measured at baseline and 3 months after admission in 758 patients admitted with suspected NSTE-ACS. Patients were followed for a median of 1540 (IQR: 1087-1776) days after the 3-month visit. The primary endpoint was all-cause mortality, while the secondary composite endpoint included all-cause mortality, incident myocardial infarction and heart failure hospitalisation during follow-up. RESULTS: In patients with GDF-15 ≥1200 pg/mL (n=248), 18% died and 25% met the composite endpoint. In patients with GDF-15 <1200 pg/mL (n=510), 1.7% died and 4% met the composite endpoint. The GDF-15 concentration (log2 transformed) at 3 months was significantly associated with all-cause mortality (adjusted HR: 2.2, 95% CI: 1.4 to 3.3, p<0.001) and the composite endpoint (adjusted HR: 1.9, 95% CI: 1.4 to 2.7, p<0.001), independently of traditional risk factors and baseline troponin T. A 10% change in GDF-15 concentration from baseline to the 3-month visit was associated with increased risk of all-cause mortality (HR: 1.06, 95% CI: 1.01 to 1.13, p=0.031), adjusting for baseline GDF-15 concentrations. CONCLUSIONS: High GDF-15 concentrations 3 months after admission for suspected NSTE-ACS are associated with long-term mortality and cardiovascular events, independent of traditional risk factors and troponin T. A change in GDF-15 concentration can provide prognostic information.

Aiming toWards Evidence baSed inTerpretation of Cardiac biOmarkers in patients pResenting with chest pain using Point of Care Testing (WESTCOR-POC): study design.

OBJECTIVES: Patients presenting with symptoms suggestive of acute coronary syndrome (ACS) contribute to a high workload and overcrowding in the Emergency Department (ED). Accelerated diagnostic protocols for non-ST-elevation myocardial infarction have proved challenging to implement. One obstacle is the turnaround time for analyzing high-sensitivity cardiac troponin (hs-cTn). In the WESTCOR-POC study (Clinical Trials number NCT05354804) we aim to evaluate safety and efficiency of a 0/1 h hs-cTn algorithm utilizing a hs-cTnI point of care (POC) instrument in comparison to central laboratory hs-cTnT measurements. DESIGN: This is a prospective single-center randomized clinical trial aiming to include 1500 patients admitted to the ED with symptoms suggestive of ACS. Patients will receive standard investigations following the European Society of Cardiology 0/1h protocols for centralized hs-cTnT measurements or the intervention using a 0/1h POC hs-cTnI algorithm. Primary end-points are 1) Safety; death, myocardial infarction or acute revascularization within 30 days 2) Efficiency; length of stay in the ED, 3) Cost- effectiveness; total episode cost, 4) Patient satisfaction, 5) Patient symptom burden and 6) Patients quality of life. Secondary outcomes are 12-months death, myocardial infarction or acute revascularization, percentage discharged after 3 and 6 h, total length of hospital stay and all costs related to hospital contact within 12 months. CONCLUSION: Results from this study may facilitate implementation of POC hs-cTn testing assays and accelerated diagnostic protocols in EDs, and may serve as a valuable resource for guiding future investigations for the use of POC high sensitivity troponin assays in outpatient clinics and prehospital settings.

Recent successes in heart failure treatment.

Remarkable recent advances have revolutionized the field of heart failure. Survival has improved among individuals with heart failure and a reduced ejection fraction and for the first time, new therapies have been shown to improve outcomes across the entire ejection fraction spectrum of heart failure. Great strides have been taken in the treatment of specific cardiomyopathies such as cardiac amyloidosis and hypertrophic cardiomyopathy, whereby conditions once considered incurable can now be effectively managed with novel genetic and molecular approaches. Yet there remain substantial residual unmet needs in heart failure. The translation of successful clinical trials to improved patient outcomes is limited by large gaps in implementation of care, widespread lack of disease awareness and poor understanding of the socioeconomic determinants of outcomes and how to address disparities. Ongoing clinical trials, advances in phenotype segmentation for precision medicine and the rise in technology solutions all offer hope for the future.