Activation of a novel natriuretic endocrine system in humans with heart failure

Proguanylin and prouroguanylin are the inactive precursors of guanylin and uroguanylin, natriuretic peptides involved in the regulation of sodium balance. Urinary uroguanylin levels have been found previously to be elevated in patients with HF (heart failure). The aim of the present study was to investigate whether plasma proguanylin and prouroguanylin levels are increased in patients with HF and to evaluate their relationship with cardiac and renal function. In this prospective observational study, we recruited 243 patients with HF (151 men) and 72 healthy controls. In patients with HF, plasma levels of proguanylin [median, 7.2 (range, 0.9–79.0) μg/l] and prouroguanylin [8.3 (1.7–53.0 μg/l)] were both significantly (P<0.0005) higher compared with levels in healthy controls [5.5 (0.4–22.3 μg/l) for proguanylin and 6.3 (2.5–16.9) μg/l for prouroguanylin]. In patients with HF, increased age, a history of hypertension, diabetes and atrial fibrillation, use of diuretics, a higher NYHA (New York Heart Association) class and a lower eGFR (estimated glomerular filtration rate) were significant univariate predictors of proguanylin and prouroguanylin levels. In multivariate analysis, a history of hypertension and low eGFR both had strong independent associations with proguanylin and prouroguanylin levels. Proguanylin and prouroguanylin varied significantly between NYHA class with a trend of increasing plasma concentrations with worsening severity of symptoms. In conclusion, plasma proguanylin and prouroguanylin are elevated in patients with HF. Elevated plasma proguanylin and prouroguanylin levels are associated with hypertension, renal impairment and increasing severity of HF. This novel endocrine system may contribute to the pathophysiology of HF

Using matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling in order to predict clinical outcomes of patients with heart failure

Background Current risk prediction models in heart failure (HF) including clinical characteristics and biomarkers only have moderate predictive value. The aim of this study was to use matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling to determine if a combination of peptides identified with MALDI-MS will better predict clinical outcomes of patients with HF. Methods A cohort of 100 patients with HF were recruited in the biomarker discovery phase (50 patients who died or had a HF hospital admission vs. 50 patients who did not have an event). The peptide extraction from plasma samples was performed using reversed phase C18. Then samples were analysed using MALDI-MS. A multiple peptide biomarker model was discovered that was able to predict clinical outcomes for patients with HF. Finally, this model was validated in an independent cohort with 100 patients with HF. Results After normalisation and alignment of all the processed spectra, a total of 11,389 peptides (m/z) were detected using MALDI-MS. A multiple biomarker model was developed from 14 plasma peptides that was able to predict clinical outcomes in HF patients with an area under the receiver operating characteristic curve (AUC) of 1.000 (p = 0.0005). This model was validated in an independent cohort with 100 HF patients that yielded an AUC of 0.817 (p = 0.0005) in the biomarker validation phase. Addition of this model to the BIOSTAT risk prediction model increased the predictive probability for clinical outcomes of HF from an AUC value of 0.643 to an AUC of 0.823 (p = 0.0021). Moreover, using the prediction model of fourteen peptides and the composite model of the multiple biomarker of fourteen peptides with the BIOSTAT risk prediction model achieved a better predictive probability of time-to-event in prediction of clinical events in patients with HF (p = 0.0005). Conclusions The results obtained in this study suggest that a cluster of plasma peptides using MALDI-MS can reliably predict clinical outcomes in HF that may help enable precision medicine in HF

Plasma proteomic approach in patients with heart failure:insights into pathogenesis of disease progression and potential novel treatment targets

Aims To provide insights into pathogenesis of disease progression and potential novel treatment targets for patients with heart failure by investigation of the plasma proteome using network analysis. Methods and results The plasma proteome of 50 patients with heart failure who died or were rehospitalised were compared with 50 patients with heart failure, matched for age and sex, who did not have an event. Peptides were analysed on two‐dimensional liquid chromatography coupled to tandem mass spectrometry (2D LC ESI‐MS/MS) in high definition mode (HDMSE). We identified and quantified 3001 proteins, of which 51 were significantly up‐regulated and 46 down‐regulated with more than two‐fold expression changes in those who experienced death or rehospitalisation. Gene ontology enrichment analysis and protein–protein interaction networks of significant differentially expressed proteins discovered the central role of metabolic processes in clinical outcomes of patients with heart failure. The findings revealed that a cluster of proteins related to glutathione metabolism, arginine and proline metabolism, and pyruvate metabolism in the pathogenesis of poor outcome in patients with heart failure who died or were rehospitalised. Conclusions Our findings show that in patients with heart failure who died or were rehospitalised, the glutathione, arginine and proline, and pyruvate pathways were activated. These pathways might be potential targets for therapies to improve poor outcomes in patients with heart failure

Myotrophin is a more powerful predictor of major adverse cardiac events following acute coronary syndrome than N terminal pro B type natriuretic peptide

Myotrophin is a 12 kD protein initially isolated from hypertrophied hearts of spontaneously hypertensive rats and acts by modulating NFκB activity. We have reported the presence of myotrophin in patients with human systolic heart failure. However its role as a predictor of major adverse cardiac events (MACE) in patients with acute coronary syndrome (ACS) is unclear. We sought to investigate this and compared it to N-terminal pro B type natriuretic peptide (NTproBNP), a marker of MACE. We studied 356 ACS patients (276 men, mean age 63.0 ± 12.8 years, 80.8% STEMI, 19.2% NSTEMI). Blood measurement was made at 25-48hrs after the onset of chest pain. The plasma concentration of myotrophin and NTproBNP was determined using in-house non-competitive immunoassays. Patients were followed-up for the combined endpoint of death, MI or need for urgent revascularisation. Over the median follow up period of 355 days (range 0-645) there were 28 deaths, 27 non-fatal MI and 73 patients required urgent revascularisation. Myotrophin was raised in patients with MACE compared to survivors (Median [Range], fmol/ml, 510.7; [116.0–7445.6] vs. 371.5; [51.8– 6990.4] fmol/ml; p=0.001). Using a Cox proportional hazards model myotrophin (HR 1.64, 95% CI: 0.97-2.76, p=0.05) and Killip class above 1 (HR 1.52, 95% CI: 0.93-2.42, p=0.10) were the only independent predictors of MACE. The Kaplan-Meier survival curve revealed a significantly better clinical outcome in patients with myotrophin below the median compared with those with myotrophin above the median (log rank 7.63, p=0.006). After an ACS, levels of myotrophin are more informative at predicting MACE than NTproBNP and may be useful to risk stratify patients

Oxygen-regulated protein 150 and prognosis following myocardial infarction.

ORP150 (oxygen-regulated protein 150) is a chaperonin expressed in tissues undergoing hypoxic or endoplasmic reticulum stress. In the present study, we investigated plasma levels of ORP150 in patients with AMI (acute myocardial infarction) and its relationship with prognosis, together with a known risk marker N-BNP (N-terminal pro-B-type natriuretic peptide). Plasma from 396 consecutive patients with AMI was obtained for measurement of ORP150 and N-BNP. Mortality and cardiovascular morbidity (acute coronary syndromes/heart failure) was determined during follow-up. A specific ORP150 assay detected the 150 kDa protein in plasma extracts, including 3 and 7 kDa fragments. During follow-up (median, 455 days), 43 (10.9%) patients died. Both N-BNP and ORP150 levels were higher in those who died compared with the survivors [N-BNP, 724 (14.5-28840) compared with 6167 (154.9-33884) pmol/l (P<0.0005); ORP150, 257 (5.9-870.9) compared with 331 (93.3-831.8) pmol/l (P<0.001); values are medians (range)]. In a Cox regression model for mortality prediction, both N-BNP (odds ratio, 5.06; P<0.001) and ORP150 (odds ratio, 2.39; P<0.01) added prognostic information beyond creatinine and the use of thrombolytics. A Kaplan-Meier survival analysis revealed that ORP150 added prognostic information to N-BNP, especially in those with supra-median N-BNP levels. A simplified dual-marker approach with both markers below and either above or both above their respective medians effectively stratified mortality risk (log rank statistic for trend, 32.7; P<0.00005). ORP150 levels were not predictive of other cardiovascular morbidity (acute coronary syndromes or heart failure). In conclusion, ORP150 and peptide fragments derived from it are secreted following AMI and provide independent prognostic information on mortality. High levels associated with endoplasmic reticulum/hypoxic stress predict a poor outcome

Urotensin II Is Raised In Acute Myocardial Infarction And Low Levels Predict Risk Of Adverse Clinical Outcome In Humans.

Background: UII is elevated in patients with heart failure; however its role in acute myocardial infarction (AMI) is unknown. We sought to compare levels of UII in patients with AMI to controls. We also compared UII to N terminal pro B type natriuretic peptide (NT-BNP) to evaluate whether levels of UII can be used to predict the risk of adverse clinical outcome (ACO). Methods and Results 129 patients were studied with serial blood measurements and echocardiogram during their index admission. Plasma concentration of median UII was significantly elevated in AMI compared to controls (median 1.40 vs. 0.42 fmol/ml p<0.012). Over the median follow up of 102 days (range 0-189) there were 14 deaths and 14 readmissions with AMI or heart failure. Using a Cox proportional hazards model the only independent predictors of ACO were UII (OR 0.29, p=0.046) and NT-BNP (OR 4.78, p=0.012) between 73-96hr. The Kaplan-Meier survival curve revealed a significantly better clinical outcome in patients with UII above the median compared with UII below the median. Conclusions UII levels are raised in AMI and is an independent predictor of ACO. Patients with a poor outcome mount a lower UII response suggesting a possible cardioprotective role for this peptide

Prognostic Significance of Adrenomedullin in Patients With Heart Failure and With Myocardial Infarction.

We undertook this systematic review to determine the prognostic significance of adrenomedullin (ADM) in patients with heart failure and acute myocardial infarction (AMI). Given the difficulty in measuring mature ADM, its surrogate, midregional proadrenomedullin (MRproADM) has been used in most studies. Systematic search of original published studies through MEDLINE and the Cochrane Collaboration databases restricted to reports in English from January 1, 1993, to June 30, 2014, in humans was undertaken. Heterogeneity of studies prohibited a meta-analysis. In patients with heart failure, the area under the curve for prediction of mortality by MRproADM ranged from 0.68 to 0.81 (95% confidence intervals [CI] 0.63 to 0.91) across studies. One nmol/l increase in MRproADM was associated with hazard ratios (HRs) ranging from 1.77 to 2.79 (95% CI 1.29 to 5.95) for death in patients with heart failure. In patients with AMI, the area under the curve for MRproADM predicting MACE ranged from 0.64 to 0.80 (CI 0.51 to 0.87) across studies and death 0.79 to 0.84 (CI 0.73 to 0.90). One nmol/l increase in MRproADM was associated with HR for MACE ranging from 1.78 to 4.10 (CI 1.20 to 10.12), whereas log10 of MRproADM had HRs of 3.63 to 9.75 (CI 1.48 to 26.16) for MACE and 4.86 to 16.68 (CI 4.56 to 60.99) for death across studies in patients with AMI. In conclusion, adrenomedullin is an independent predictor of death in patients with heart failure and of MACE and death in patients who have suffered an AMI. Quantification of this peptide might contribute to improved risk stratification in settings of heart failure and myocardial infarction