Plasma soluble fms-like tyrosine kinase-1, placental growth factor, and vascular endothelial growth factor system gene variants as predictors of survival in heart failure.

AIMS: Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), components of the vascular endothelial growth factor (VEGF) system, play key roles in angiogenesis. Reports of elevated plasma levels of sFlt-1 and PlGF in coronary heart disease and heart failure (HF) led us to investigate their utility, and VEGF system gene single nucleotide polymorphisms (SNPs), as prognostic biomarkers in HF. METHODS AND RESULTS: ELISA assays for sFlt-1, PlGF and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were performed on baseline plasma samples from the PEOPLE cohort (n = 890), a study of outcomes among patients after an episode of acute decompensated HF. Eight SNPs potentially associated with sFlt-1 or PlGF levels were genotyped. sFlt-1 and PlGF were assayed in 201 subjects from the Canterbury Healthy Volunteers Study (CHVS) matched to PEOPLE participants. All-cause death was the major endpoint for clinical outcome considered. In PEOPLE participants, mean plasma levels for both sFlt-1 (125 ± 2.01 pg/ml) and PlGF (17.5 ± 0.21 pg/ml) were higher (both p < 0.044) than in the CHVS cohort (81.2 ± 1.31 pg/ml and 15.5 ± 0.32 pg/ml, respectively). sFlt-1 was higher in HF with reduced ejection fraction compared to HF with preserved ejection fraction (p = 0.005). The PGF gene SNP rs2268616 was univariately associated with death (p = 0.016), and was also associated with PlGF levels, as was rs2268614 genotype. Cox proportional hazards modelling (n = 695, 246 deaths) showed plasma sFlt-1, but not PlGF, predicted survival (hazard ratio 6.44, 95% confidence interval 2.57-16.1; p < 0.001) in PEOPLE, independent of age, NT-proBNP, ischaemic aetiology, diabetic status and beta-blocker therapy. CONCLUSIONS: Plasma sFlt-1 concentrations have potential as an independent predictor of survival and may be complementary to established prognostic biomarkers in HF.

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.

Regional Handling and Prognostic Performance of Circulating Insulin-Like Growth Factor Binding Protein-7 in Heart Failure.

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.

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.

Circulating Forms of B-Type Natriuretic Peptide in Very Preterm Infants.

BACKGROUND: B-type natriuretic peptide (BNP) is a cardiac hormone released with an N-terminal fragment (NTproBNP) under conditions of ventricular pressure or volume overload. BNP has been proposed for use as a biomarker of cardiac dysfunction in premature infants in the setting of hemodynamically significant patent ductus arteriosus (HsPDA) and bronchopulmonary dysplasia (BPD). In adult settings the presence of proBNP and glycosylated isoforms may affect assay interpretation. However, there are limited data on how immature preterm physiology may affect BNP or NTproBNP levels and no published data on post-translational BNP processing in premature infants. METHODS: Pooled serial plasma samples from preterm infants born at less than 30 weeks gestation were analyzed for BNP congeners using Luminex® assay and high performance liquid chromatography. Samples were grouped according to clinical status: Group 1, no HsPDA and no BPD, Group 2 HsPDA and no/mild BPD, Group 3 HsPDA and moderate/severe BPD. RESULTS: Plasma from 15 infants was analyzed, and across all three groups NTproBNP predominated with minimal amounts of other isoforms; no glycosylation was detected. CONCLUSIONS: NTproBNP appears to be the predominant isoform across each of our clinical groups in our pooled sample analysis with no evidence of significant glycosylation. This suggests NTproBNP is likely to be a robust marker in this clinical setting.

Mid-regional pro-adrenomedullin outperforms N-terminal pro-B-type natriuretic peptide for the diagnosis of acute heart failure in the presence of atrial fibrillation.

AIMS: The performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in diagnosing acute decompensated heart failure (ADHF) among patients presenting with breathlessness is markedly impaired in the presence of atrial fibrillation (AF). We evaluated the diagnostic performance of mid-regional pro-adrenomedullin (MR-proADM) and cardiac troponin T as possible alternative markers for discrimination of ADHF in this setting. METHODS AND RESULTS: Breathless patients (n = 1107) were prospectively and contemporaneously recruited in emergency departments in Singapore and New Zealand. The diagnoses of ADHF and presence of AF were adjudicated by two clinician specialists, blinded to MR-proADM, NT-proBNP and high-sensitivity cardiac troponin T (hs-cTnT) results. MR-proADM exhibited strong discrimination of ADHF with little change in performance irrespective of the presence of AF (area under the curve 0.83 in non-AF vs. 0.76 in AF) compared to NT-proBNP (0.91 vs. 0.71) and hs-cTnT (0.83 vs. 0.62), respectively. The accuracy of MR-proADM (73.3%) for diagnosing ADHF among patients with AF was superior to both NT-proBNP (61.6%) and hs-cTnT (64.6%). The superior performance of MR-proADM remained apparent when data from Singapore and New Zealand were analysed separately. CONCLUSION: In the presence of AF, MR-proADM showed greater discrimination and accuracy, and less impairment in performance compared to that in non-AF cases, for the diagnosis of ADHF, compared to the guideline-endorsed NT-proBNP.

Convalescent troponin and cardiovascular death following acute coronary syndrome.

OBJECTIVES: High-sensitivity cardiac troponin testing is used in the diagnosis of acute coronary syndromes but its role during convalescence is unknown. We investigated the long-term prognostic significance of serial convalescent high-sensitivity cardiac troponin concentrations following acute coronary syndrome. METHODS: In a prospective multicentre observational cohort study of 2140 patients with acute coronary syndrome, cardiac troponin I concentrations were measured in 1776 patients at 4 and 12 months following the index event. Patients were stratified into three groups according to the troponin concentration at 4 months using the 99th centile (women>16 ng/L, men>34 ng/L) and median concentration of those within the reference range. The primary outcome was cardiovascular death. RESULTS: Troponin concentrations at 4 months were measurable in 99.0% (1759/1776) of patients (67±12 years, 72% male), and were ≤5 ng/L (median) and >99th centile in 44.8% (795) and 9.3% (166), respectively. There were 202 (11.4%) cardiovascular deaths after a median of 4.8 years. After adjusting for the Global Registry of Acute Coronary Events score, troponin remained an independent predictor of cardiovascular death (HR 1.4, 95% CI 1.3 to 1.5 per doubling) with the highest risk observed in those with increasing concentrations at 12 months. Patients with 4-month troponin concentrations >99th centile were at increased risk of cardiovascular death compared with those ≤5 ng/L (29.5% (49/166) vs 4.3% (34/795); adjusted HR 4.9, 95% CI 3.8 to 23.7). CONCLUSIONS: Convalescent cardiac troponin concentrations predict long-term cardiovascular death following acute coronary syndrome. Recognising this risk by monitoring troponin may improve targeting of therapeutic interventions. TRIAL REGISTRATION NUMBER: ACTRN12605000431628;Results.

Clinical chemistry score versus high-sensitivity cardiac troponin I and T tests alone to identify patients at low or high risk for myocardial infarction or death at presentation to the emergency department.

BACKGROUND: Testing for high-sensitivity cardiac troponin (hs-cTn) may assist triage and clinical decision-making in patients presenting to the emergency department with symptoms of acute coronary syndrome; however, this could result in the misclassification of risk because of analytical variation or laboratory error. We sought to evaluate a new laboratory-based risk-stratification tool that incorporates tests for hs-cTn, glucose level and estimated glomerular filtration rate to identify patients at risk of myocardial infarction or death when presenting to the emergency department. METHODS: We constructed the clinical chemistry score (CCS) (range 0-5 points) and validated it as a predictor of 30-day myocardial infarction (MI) or death using data from 4 cohort studies involving patients who presented to the emergency department with symptoms suggestive of acute coronary syndrome. We calculated diagnostic parameters for the CCS score separately using high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT). RESULTS: For the combined cohorts (n = 4245), 17.1% of participants had an MI or died within 30 days. A CCS score of 0 points best identified low-risk participants: the hs-cTnI CCS had a sensitivity of 100% (95% confidence interval [CI] 99.5%-100%), with 8.9% (95% CI 8.1%-9.8%) of the population classified as being at low risk of MI or death within 30 days; the hs-cTnT CCS had a sensitivity of 99.9% (95% CI 99.2%-100%), with 10.5% (95% CI 9.6%-11.4%) of the population classified as being at low risk. The CCS had better sensitivity than hs-cTn alone (hs-cTnI < 5 ng/L: 96.6%, 95% CI 95.0%-97.8%; hs-cTnT < 6 ng/L: 98.2%, 95% CI 97.0%-99.0%). A CCS score of 5 points best identified patients at high risk (hs-cTnI CCS: specificity 96.6%, 95% CI 96.0%-97.2%; 11.2% [95% CI 10.3%-12.2%] of the population classified as being at high risk; hs-cTnT CCS: specificity 94.0%, 95% CI 93.1%-94.7%; 13.1% [95% CI 12.1%-14.1%] of the population classified as being at high risk) compared with using the overall 99th percentiles for the hs-cTn assays (specificity of hs-cTnI 93.2%, 95% CI 92.3-94.0; specificity of hs-cTnT 73.8%, 95% CI 72.3-75.2). INTERPRETATION: The CCS score at the chosen cut-offs was more sensitive and specific than hs-cTn alone for risk stratification of patients presenting to the emergency department with suspected acute coronary syndrome. Study registration: ClinicalTrials.gov, nos. NCT01994577; NCT02355457.

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

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

Factors affecting N-terminal pro-B-type natriuretic peptide levels in preterm infants and use in determination of haemodynamic significance of patent ductus arteriosus.

This study aimed to investigate factors affecting N-terminal pro-B-type natriuretic peptide (NTproBNP) in preterm infants and the ability of NTproBNP to predict haemodynamically significant patent ductus arteriosus (HsPDA). Prospective cohort study of 51 infants < 30 weeks gestation. Blood NTproBNP and heart ultrasound were performed on day of life 3, 10, 28 and 36 weeks corrected age. NTproBNP levels analysed for prediction of HsPDA. The effect of gestational age, ventilation, hypoxia, bronchopulmonary dysplasia (BPD), creatinine and haemoglobin levels on NTproBNP levels were investigated. Infants with HsPDA had higher mean (SD) day 3 NTproBNP (1840 pmol/L (1058) versus 178 pmol/L (140) p < 0.001). Receiver operator curves of day 3 NTproBNP for prediction of day 3 and day 10 HsPDA had an area under the curve of 0.98 and 0.94, respectively. A chosen day 3 NTproBNP value of ≥ 287 pmol/L for the prediction of day 3 HsPDA correctly classified 92% (sensitivity 92%, specificity 92%). NTproBNP demonstrated only modest ability to predict severe BPD. Chronological but not gestational age affected NTproBNP. Ventilation, hypoxia and haemoglobin levels did not influence NTproBNP but creatinine level was positively correlated. CONCLUSION: Day 3 NTproBNP is a useful biomarker to predict HsPDA and may be a valuable tool in future trial design. What is Known: • NTproBNP is a cardiac hormone used to diagnose and monitor cardiac dysfunction in adults and has been shown to be higher in premature infants with haemodynamically significant ductus arteriosus (HsPDA). What is new: • NTproBNP is highly predictive of ultrasound-defined HsPDA and may be a useful tool for further triage • Early NTproBNP higher in infants who develop severe BPD and with renal impairment but not affected by gestational age, recent exposure to hypoxia or haemoglobin levels while late levels unexpectedly higher in those without BPD or HsPDA.

The heart regulates the endocrine response to heart failure: cardiac contribution to circulating neprilysin.

Aims: Heart failure (HF) is accompanied by major neuroendocrine changes including the activation of the natriuretic peptide (NP) pathway. Using the unique model of patients undergoing implantation of the CARMAT total artificial heart and investigating regional differences in soluble neprilysin (sNEP) in patients with reduced or preserved systolic function, we studied the regulation of the NP pathway in HF. Methods and results: Venous blood samples from two patients undergoing replacement of the failing ventricles with a total artificial heart were collected before implantation and weekly thereafter until post-operative week 6. The ventricular removal was associated with an immediate drop in circulating NPs, a nearly total disappearance of circulating glycosylated proBNP and furin activity and a marked decrease in sNEP. From post-operative week 1 onwards, NP concentrations remained overall unchanged. In contrast, partial recoveries in glycosylated proBNP, furin activity, and sNEP were observed. Furthermore, while in patients with preserved systolic function (n = 6), sNEP concentrations in the coronary sinus and systemic vessels were similar (all P > 0.05), in patients with reduced left-ventricular systolic function, sNEP concentration, and activity were ∼three-fold higher in coronary sinus compared to systemic vessels (n = 21, all P < 0.0001), while the trans-pulmonary gradient was neutral (n = 5, P = 1.0). Conclusion: The heart plays a pivotal role as a regulator of the endocrine response in systolic dysfunction, not only by directly releasing NPs but also by contributing to circulating sNEP, which in turn determines the bioavailability of other numerous vasoactive peptides.

Superior performance of N-terminal pro brain natriuretic peptide for diagnosis of acute decompensated heart failure in an Asian compared with a Western setting.

AIMS: This study was conducted to test the diagnostic performance of NT-proBNP for discrimination of acute decompensated heart failure (ADHF) among breathless patients presenting in an Asian compared with a Western centre. METHODS AND RESULTS: Patients with breathlessness were prospectively and contemporaneously recruited in Emergency Departments in Singapore and New Zealand (NZ). The diagnosis of ADHF was adjudicated by two clinician specialists. A total of 606 patients were recruited in Singapore and 500 in NZ. The discriminative power of NT-proBNP for ADHF was superior in Singapore compared with NZ [area under the curve (AUC) 0.926 vs. 0.866; P = 0.012] both overall and among selected subgroups stratified according to age, renal function, body mass index, and presence or absence of AF or diabetes. Previously established cut-off point values of plasma NT-proBNP yielded comparable sensitivity and negative predictive values, but superior specificity and accuracy in Singapore compared with NZ. The difference in test performance was driven by the younger age (median age 56 years vs. 73 years; P < 0.001), associated with better renal function (estimated glomerular filtration rate 89 vs. 62 mL/min/1.73 m2 ; P < 0.001), and lower prevalence of AF (9.7% vs. 25.7%; P < 0.001) in acutely breathless patients in Singapore. CONCLUSION: Considering emerging evidence of a lower average age of presentation with ADHF over most of Asia compared with Western countries, NT-proBNP is likely to be more accurate when applied in Asian centres than in the West.

Release kinetics of high-sensitivity cardiac troponins I and T and troponin T upstream open reading frame peptide (TnTuORF) in clinically induced acute myocardial infarction.

CONTEXT: Troponin T upstream open reading frame peptide (TnTuORF) may be useful as a novel biomarker in acute cardiac syndromes. OBJECTIVE: The study examined the early release kinetics of TnTuORF. MATERIALS AND METHODS: We analyzed the time course of the release of cardiac troponins I and T and TnTuORF in patients (n = 31) with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy (TASH). RESULTS: Fifteen minutes after TASH, the levels of both troponins increased significantly (cTnT median: 18 ng/L versus 27 ng/L; cTnI median: 15 ng/L versus 25 ng/L). TnTuORF showed no variation. DISCUSSION: We observed a significantly greater increase in cTnI compared with cTnT. CONCLUSION: Our results demonstrate that troponin assays allow early detection of myocardial injury, whereas TnTuORF levels remain unchanged in this setting.

B-type natriuretic peptide signal peptide (BNPsp) in patients presenting with chest pain.

OBJECTIVES: We assessed the ability of B-type natriuretic peptide signal peptide (BNPsp) to assist with the identification of patients with myocardial infarction (MI) and unstable angina pectoris (UAP). DESIGN AND METHODS: We studied 505 patients who presented to hospital within 4h of onset of chest pain suspicious of ACS. Blood samples were drawn at 0, 1, 2 and 24h from presentation and assayed for BNPsp, NT-proBNP, TnI and high sensitivity TnT. The ability of BNPsp and other markers to diagnose acute myocardial infarction (MI) and unstable angina pectoris (UAP) and predict subsequent events within one year was assessed. Statistical analysis was made using ROC AUC in SPSS, v.22. RESULTS: Receiver operator area under the curve (AUC) data for the discrimination of MI was 0.69 for BNPsp and 0.97 for troponin, with BNPsp failing to add to troponin. However, in non-MI patients, BNPsp had discriminative power for UAP (p<0.05), and when combined with presentation values of NT-proBNP, white cell count and potassium into a unique parameter (UARatio), generated an AUC of 0.76 for UAP in patients with normal ECG results (p<0.001). In non-MI patients, the UARatio was significantly predictive of subsequent stroke (AUC=0.70, p<0.05) and heart failure (AUC=0.82, p<0.01) within one year. CONCLUSIONS: In patients with chest pain, BNPsp is predictive of MI but is not a useful adjunct to troponin. However, the ability of BNPsp, in conjunction with NT-proBNP and key analytes, to diagnose UAP and other ischemic syndromes merits further investigation.

CNP Signal Peptide in Patients with Cardiovascular Disease.

We have previously reported that signal peptide fragments of C-type natriuretic peptide (CNP) are present in the human circulation. Here, we provide the first preliminary assessment of the potential utility of CNP signal peptide (CNPsp) measurement in acute cardiovascular disease. Utilizing our specific and sensitive immunoassay, we assessed the potential of CNPsp measurement to assist in the identification of acute coronary syndromes in 494 patients presenting consecutively with chest pain. The diagnostic and prognostic potential of CNPsp were assessed in conjunction with a contemporary clinical troponin I assay, an investigational highly sensitive troponin T assay and NT-proBNP measurement. Utility was assessed via receiver operator curve characteristic analysis. CNPsp did not identify patients with myocardial infarction (MI) or those with unstable angina, nor did it assist the diagnostic ability of clinical or investigational troponin measurement. CNPsp levels were significantly elevated in patients presenting with atrial fibrillation (P < 0.05) and were significantly lower in those with a history of previous MI (P < 0.05). CNPsp could identify those at risk of mortality within 1 year (P < 0.05) and also could identify those at risk of death or re-infarction within 1 year (P < 0.01). This is the first exploratory report describing the potential of CNPsp measurement in acute cardiovascular disease. While CNPsp does not have utility in acute diagnosis, it may have potential in assisting risk prognosis with respect to mortality and re-infarction.

Reference Values and Release Kinetics of B-Type Natriuretic Peptide Signal Peptide in Patients with Acute Myocardial Infarction.

BACKGROUND: The signal peptide for human B-type natriuretic peptide preprohormone (BNPsp), which is released from cardiomyocytes, is increased in plasma of patients with acute myocardial infarction (AMI); however, its exact release kinetics have not been defined. METHODS: We measured BNPsp and high-sensitivity cardiac troponin T (hs-cTnT) in a reference group of individuals without structural heart disease (n = 285) and determined the release kinetics of these biomarkers in patients (n = 29) with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy (TASH), a procedure allowing exact timing of onset of iatrogenic AMI. Blood samples were collected before TASH and at numerous preselected time points after TASH. RESULTS: The reference median BNPsp concentration was 53.4 pmol/L [interquartile range (IQR) 47.0-61.0; 95th percentile 85.9 pmol/L; 99th percentile 116.3 pmol/L]. Baseline concentrations in patients undergoing TASH were higher than in the reference group [91.9 pmol/L (IQR 62.9-116.4); P < 0.0001]. BNPsp increased significantly, peaking at 15 min after induction of AMI [149.6 pmol/L (109.5-204.9) vs baseline; P = 0.004] and declining slowly thereafter, falling below the preprocedural value after 8 h (P = 0.014). hs-cTnT increased significantly 15 min after induction of AMI [26 ng/L (19-39) vs 18 ng/L (11-29); P = 0.001] and remained high at all later time points. CONCLUSIONS: BNPsp concentrations increased immediately after AMI induction, providing early evidence of myocardial injury. The release kinetics of BNPsp differed from those of hs-cTnT. These findings provide information that should help in establishing the diagnostic value of BNPsp in the setting of early AMI.

Signal peptides: new markers in cardiovascular disease?

Proteins and peptides are well-documented as useful marker adjuncts to cardiovascular clinical decision-making. Most markers measured derive from a defined, stable proprotein region of their respective gene. However, a neglected portion of preproproteins known as the signal peptide (SP) is also present in the circulation and may also present as a measurable marker. SPs were assumed to be degraded intracellularly after directing secretion, but a small, growing body of evidence is identifying SPs as not being degraded within and without cells. In this article, evidence for the persistence of SPs after translation is presented and their role as potential cardiovascular biomarkers is discussed.