Jenny P.C. Chong

Growth differentiation factor 15, ST2, high‐sensitivity troponin T, and N‐terminal pro brain natriuretic peptide in heart failure with preserved vs. reduced ejection fraction

Growth differentiation factor 15 (GDF15), ST2, high‐sensitivity troponin T (hsTnT), and N‐terminal pro brain natriuretic peptide (NT‐proBNP) are biomarkers of distinct mechanisms that may contribute to the pathophysiology of heart failure (HF) [inflammation (GDF15); ventricular remodelling (ST2); myonecrosis (hsTnT); and wall stress (NT‐proBNP)].

Growth differentiation factor 15 in heart failure with preserved vs. reduced ejection fraction.

Growth differentiation factor 15 (GDF15) is a cytokine highly expressed in states of inflammatory stress. We aimed to study the clinical correlates and prognostic significance of plasma GDF15 in heart failure with preserved ejection fraction (HFpEF) vs. reduced ejection fraction(HFrEF), compared with N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), an indicator of haemodynamic wall stress.

Markers of cardiac dysfunction in cognitive impairment and dementia.

AbstractMarkers of cardiac dysfunction such as amino terminal pro-brain natriuretic peptide (NTpro-BNP) and high sensitivity cardiac troponin T (hs-cTnT) may be associated with dementia. However, limited data exist on their association with either pre-dementia stages, that is, cognitive impairment no dementia (CIND), or the burden of cerebrovascular diseases (CeVD).We therefore, examined the association of these biomarkers of cardiac dysfunction with CeVD in both CIND and dementia.A case–control study, with cases recruited from memory clinics and controls from memory clinics and community. All subjects underwent collection of blood samples, neuropsychological assessment, and neuroimaging. Subjects were classified as CIND and dementia based on clinical criteria whilst significant CeVD was defined as the presence of cortical infarcts and/or more than 2 lacunes and/or confluent white matter lesions in two regions of brain on Age-Related White Matter Changes Scale.We included a total of 35 controls (mean age: 65.9 years), 78 CIND (mean age: 70.2 years) and 80 cases with dementia (mean age: 75.6 years). Plasma concentrations of hs-cTnT were associated significantly with CeVD in both CIND (odds ratios [OR]: 9.05; 95% confidence interval [CI]: 1.64–49.79) and dementia (OR: 16.89; 95%CI: 2.02–142.67). In addition, NTpro-BNP was associated with dementia with CeVD (OR: 7.74; 95%CI: 1.23–48.58). These associations were independent of other vascular risk factors.In this study, we showed that plasma NTproBNP and hs-cTnT are associated with dementia and CIND, only when accompanied by presence of CeVD.

Natriuretic peptide receptor 3 (NPR3) is regulated by microRNA-100

Natriuretic peptide receptor 3 (NPR3) is the clearance receptor for the cardiac natriuretic peptides (NPs). By modulating the level of NPs, NPR3 plays an important role in cardiovascular homeostasis. Although the physiological functions of NPR3 have been explored, little is known about its regulation in health or disease. MicroRNAs play an essential role in the post-transcriptional expression of many genes. Our aim was to investigate potential microRNA-based regulation of NPR3 in multiple models. Hypoxic challenge elevated levels of NPPB and ADM mRNA, as well as NT-proBNP and MR-proADM in human left ventricle derived cardiac cells (HCMa), and in the corresponding conditioned medium, as revealed by qRT-PCR and ELISA. NPR3 was decreased while NPR1 was increased by hypoxia at mRNA and protein levels in HCMa. Down-regulation of NPR3 mRNA was also observed in infarct and peri-infarct cardiac tissue from rats undergoing myocardial infarction. From microRNA microarray analyses and microRNA target predictive databases, miR-100 was selected as a candidate regulator of NPR3 expression. Further analyses confirmed up-regulation of miR-100 in hypoxic cells and associated conditioned media. Antagomir-based silencing of miR-100 enhanced NPR3 expression in HCMa. Furthermore, miR-100 levels were markedly up-regulated in rat hearts and in peripheral blood after myocardial infarction and in the blood from heart failure patients. Results from this study point to a role for miR-100 in the regulation of NPR3 expression, and suggest a possible therapeutic target for modulation of NP bioactivity in heart disease.

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

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.

High-Sensitivity Sandwich ELISA for Plasma NT-proUcn2: Plasma Concentrations and Relationship to Mortality in Heart Failure

BACKGROUND Urocortin 2 (Ucn2) has powerful hemodynamic, renal, and neurohormonal actions and likely participates in normal circulatory homeostasis and the compensatory response to heart failure (HF). A validated assay for endogenous circulating Ucn2 would facilitate investigations into Ucn2 physiology and elucidate its derangement and potential as a biomarker in heart disease. METHOD We developed a chemiluminescence-based sandwich ELISA to measure plasma N-terminal (NT)-proUcn2 in non-HF patients (control; n = 160) and HF patients with reduced (HFREF; n = 134) and preserved (HFPEF; n = 121) left ventricular ejection fraction (LVEF). RESULTS The ELISA had a limit of detection of 8.47 ng/L (1.52 pmol/L) and working range of 23.8-572 ng/L. Intra- and interassay CV and total error were 4.8, 16.2, and 17.7%, respectively. The median (interquartile range) plasma NT-proUcn2 concentration in controls was 112 (86-132) ng/L. HFREF, HFPEF, and all HF plasma concentrations were significantly increased [117 (98-141) ng/L, P = 0.0007; 119 (93-136) ng/L, P = 0.0376, and 119 (97-140) ng/L, P = 0.001] compared with controls but did not differ significantly between HFREF and HFPEF. NT-proUcn2 was modestly related to age (r = 0.264, P = 0.001) and cardiac troponin T (r = 0.258, P = 0.001) but not N-terminal pro-B-type natriuretic peptide, body mass index, LVEF, or estimated glomerular filtration rate. On multivariate analysis, plasma NT-proUcn2 was independently and inversely related to 2-year mortality in HF. CONCLUSIONS The validated ELISA measured human NT-proUcn2 in plasma and showed modest but significant increases in HF patients compared with controls. In HF, the unusual inverse relationship between plasma NT-proUcn2 and 2-year mortality portends potential prognostic value but requires further corroboration.

The prognostic value of highly sensitive cardiac troponin assays for adverse events in men and women with stable heart failure and a preserved vs. reduced ejection fraction

Circulating biomarkers are important in the diagnosis, risk stratification and management of patients with heart failure (HF). Given the current lack of biomarkers in HF with preserved ejection fraction (HFpEF), we aimed to investigate the prognostic performance of the newly developed high‐sensitivity (hs) assays for cardiac troponin I (hsTnI) compared with troponin T (hsTnT) for adverse events in HFpEF vs. HF with reduced ejection fraction (HFrEF). Findings in these two HF subgroups were also compared with those in the recently defined HF with mid‐range ejection fraction (HFmrEF) subgroup.

Thymosin Beta‐4 Is Elevated in Women With Heart Failure With Preserved Ejection Fraction

Background Thymosin beta‐4 (TB4) is an X‐linked gene product with cardioprotective properties. Little is known about plasma concentration of TB4 in heart failure (HF), and its relationship with other cardiovascular biomarkers. We sought to evaluate circulating TB4 in HF patients with preserved (HFpEF) or reduced (HFrEF) ejection fraction compared to non‐HF controls. Methods and Results TB4 was measured using a liquid chromatography and mass spectrometry assay in age‐ and sex‐matched HFpEF (n=219), HFrEF (n=219) patients, and controls (n=219) from a prospective nationwide study. Additionally, a 92‐marker multiplex proximity extension assay was measured to identify biomarker covariates. Compared with controls, plasma TB4 was elevated in HFpEF (985 [421–1723] ng/mL versus 1401 [720–2379] ng/mL, P<0.001), but not in HFrEF (1106 [556–1955] ng/mL, P=0.642). Stratifying by sex, only women (1623 [1040–2625] ng/mL versus 942 [386–1891] ng/mL, P<0.001), but not men (1238.5 [586–1967] ng/mL versus 1004 [451–1538] ng/mL, P=1.0), had significantly elevated TB4 in the setting of HFpEF. Adjusted for New York Heart Association class, N‐terminal pro B‐type natriuretic peptide, age, and myocardial infarction, hazard ratio to all‐cause mortality is significantly higher in women with elevated TB4 (1.668, P=0.036), but not in men (0.791, P=0.456) with HF. TB4 is strongly correlated with a cluster of 7 markers from the proximity extension assay panel, which are either X‐linked, regulated by sex hormones, or involved with NF‐κB signaling. Conclusions We show that plasma TB4 is elevated in women with HFpEF and has prognostic information. Because TB4 can preserve EF in animal studies of cardiac injury, the relation of endogenous, circulating TB4 to X chromosome biology and differential outcomes in female heart disease warrants further study.

Growth differentiation factor-15 and white matter hyperintensities in cognitive impairment and dementia

Abstract Vascular pathology plays an important role in the development of cognitive decline and dementia. In this context, growth differentiation factor-15 (GDF-15) has been suggested to be a biomarker due to its regulatory roles in inflammatory and trophic responses during tissue injury. However, limited data exist on the associations of GDF-15 with either cerebrovascular disease (CeVD) burden or the spectrum of cognitive impairment. Therefore, we aimed to study peripheral levels of GDF-15 incognitive impairment no dementia (CIND) or Alzheimer disease (AD) subjects assessed for CeVD using a case–control cohort design, with cases recruited from memory clinics and controls from memory clinics and the community. All subjects underwent detailed neuropsychological assessment, 3-Tesla magnetic resonance imaging, and venous blood draw. Subjects were classified as CIND or AD based on clinical criteria, while significant CeVD was defined as the presence of cortical infarcts and/or 2 lacunes or more, and/or confluent white matter hyperintensities (WMHs) in 2 or more brain regions. A total of 324 subjects were included in the study, of whom 80 had no cognitive impairment, 144 CIND and 100with AD. Higher GDF-15 levels were significantly associated with disease groups, especially in the presence of CeVD, namely, CIND with CeVD (odds ratios [OR]: 7.21; 95% confidence interval [CI]: 2.14–24.27) and AD with CeVD (OR: 21.87; 95% CI: 2.01–237.43). Among the different CeVD markers, only WMH was associated with higher GDF-15 levels (OR: 3.97; 95% CI: 1.79–8.83). The associations between GDF-15 and cognitive impairment as well as with WMH remained significant after excluding subjects with cardiovascular diseases. In conclusion, we showed that increased GDF-15 may be a biomarker for CIND and AD in subjects with WMH.

Plasma mid-regional pro-atrial natriuretic peptide and N-terminal pro-brain natriuretic peptide improve discrimination of lone atrial fibrillation

a Cardiovascular Division, Department of Medicine, University of Minnesota, 420 Delaware Street SE, MMC 508, Minneapolis, MN, USA b Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, Singapore c Division of Biostatistics, School of Public Health, University of Minnesota, 420 Delaware Street SE, MMC 303, Minneapolis, MN, USA d Christchurch Heart Institute, University of Otago, 2 Riccarton Avenue, Dunedin, New Zealand e Cardiac Department, 5 Lower Kent Ridge Road, National University Heart Centre, Singapore