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Adrenomedullin and arterial stiffness: integrative approach combining monocyte ADM expression, plasma MR-Pro-ADM, and genome-wide association study.

ABSTRACT: BACKGROUND:Adrenomedullin (ADM) is a circulating vasoactive peptide involved in vascular homeostasis and endothelial function. Single nucleotide polymorphisms of the ADM gene are associated with blood pressure variability, and elevated levels of plasma midregional proadrenomedullin (MR-pro-ADM) are associated with cardiovascular diseases. METHODS AND RESULTS:We investigated the sources of variability of ADM gene expression and plasma MR-pro-ADM concentrations in the general population, and their relationship with markers of atherosclerosis. MR-pro-ADM levels were assessed in 4155 individuals who underwent evaluation of carotid intima-media thickness and arterial rigidity (reflection index and stiffness index). In a subsample of 1372 individuals, ADM gene expression was assessed as part of a transcriptomic study of circulating monocytes. Nongenetic factors explained 45.8% and 7.5% of MR-pro-ADM and ADM expression variability, respectively. ADM expression correlated with plasma C-reactive protein, interleukin-receptor 1A, and myeloperoxidase, whereas MR-pro-ADM levels correlated with C-terminal proendothelin-1, creatinine, and N-terminal pro-B-type natriuretic peptide. Genome-wide association study of ADM expression and MR-pro-ADM levels both identified a single locus encompassing the ADM gene. ADM expression was associated with 1 single nucleotide polymorphism rs11042717 (P=2.36×10(-12)), whereas MR-pro-ADM was associated with 2 single nucleotide polymorphisms with additive effects, rs2957692 (P=1.54×10(-13)) and rs2957717 (P=4.24×10(-8)). Reflection index was independently associated with rs11042717 (P<10(-4)) and ADM expression (P=0.0002) but not with MR-pro-ADM. Weaker associations were observed for stiffness index. Intima-media thickness was not related to ADM single nucleotide polymorphisms or expression. CONCLUSIONS:These results support an involvement of the ADM gene in the modulation of peripheral vascular tone.

SUBMITTER: Beygui F

PROVIDER: S-EPMC5865635 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Adrenomedullin and arterial stiffness: integrative approach combining monocyte ADM expression, plasma MR-Pro-ADM, and genome-wide association study.

Beygui Farzin F Wild Philipp S PS Zeller Tanja T Germain Marine M Castagné Raphaele R Lackner Karl J KJ Münzel Thomas T Montalescot Gilles G Mitchell Gary F GF Verwoert Germaine C GC Tarasov Kirill V KV Trégouët David-Alexandre DA Cambien François F Blankenberg Stefan S Tiret Laurence L

Circulation. Cardiovascular genetics 20140722 5

<h4>Background</h4>Adrenomedullin (ADM) is a circulating vasoactive peptide involved in vascular homeostasis and endothelial function. Single nucleotide polymorphisms of the ADM gene are associated with blood pressure variability, and elevated levels of plasma midregional proadrenomedullin (MR-pro-ADM) are associated with cardiovascular diseases.<h4>Methods and results</h4>We investigated the sources of variability of ADM gene expression and plasma MR-pro-ADM concentrations in the general popula ...[more]

PMID: 25053723

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Project description:Adrenomedullin is a potent vasodilatory peptide, linked to pulmonary arterial hypertension pathology. Proximity extension assays were utilized to study plasma biomarkers related to vasoregulation, with focus on adrenomedullin peptides and precursor levels, collectively referred to as ADM. ADM was measured in 48 treatment-naïve pulmonary arterial hypertension patients at diagnosis, and in 31 of them at an early treatment follow-up. Plasma ADM was additionally assessed in patients with chronic thromboembolic pulmonary hypertension (n = 20) and pulmonary hypertension due to heart failure with preserved (HFpEF(PH)) (n = 33) or reduced (HFrEF(PH)) (n = 36) ejection fraction, as well as healthy controls (n = 16). ADM was studied in relation to pulmonary arterial hypertension hemodynamics, risk assessment, prognosis, treatment response, and differentiation. Plasma ADM levels in pulmonary arterial hypertension patients at diagnosis were higher than in healthy controls (p < 0.001), similar as in chronic thromboembolic pulmonary hypertension patients (p = ns), but lower compared to HFpEF(PH) (p < 0.03) and HFrEF(PH) (p < 0.001). In pulmonary arterial hypertension, specifically, plasma ADM at diagnosis correlated mainly to mean right atrial pressure (r = 0.73, p < 0.001), N-terminal prohormone of brain natriuretic peptide (r = 0.75, p < 0.001), six-minute walking distance (r = -0.57, p < 0.001), and venous oxygen saturation (r = -0.57, p < 0.001). ADM also correlated to the ECS/ERS- (r = 0.74, p < 0.001) and REVEAL risk scores (r = 0.54, p < 0.001) at pulmonary arterial hypertension diagnosis. Plasma ADM in pulmonary arterial hypertension patients was unaltered at early treatment follow-up compared to baseline (p = ns). Pulmonary arterial hypertension patients with supra-median ADM at diagnosis showed worse overall survival than those with infra-median levels (median survival 34 versus 66 months, p = 0.0077). In conclusion, the present results suggest that baseline plasma ADM levels mirror disease severity, correlating to both ECS/ERS- and the REVEAL risk scores.

Project description:(i) evaluate the performance of MR-pro-ADM in reflecting the outcome and risk for CAP patients in the emergency department, and (ii) compare the prognostic performance of MR-pro-ADM with that of clinical scores PSI and CURB65.Observational prospective, single-center study in patients with suspected community acquired pneumonia (CAP). Eighty one patients underwent full clinical and laboratory assessment as by protocol, and were followed up a 28 days. Primary endpoints measured were: death, death at 14 days, non-invasive mechanical ventilation (NIMV), endotracheal intubation (EI), ICU admission, overall hospital stay >10 days, emergency department stay >4 days. The discriminative performance of MR-pro-ADM and clinical scores was assessed by AUROC analysis.The distribution for MR-pro-ADM followed an upward trend, increasing with the increase of both PSI (p<0.001) and CURB65 (p<0.001) classes. However, the difference between MRproADM values and score classes was significant only in the case of CURB65 classes 0 and 1 (p = 0.046), 2 (p = 0.013), and 3 (p = 0.011); and with PSI classes 5, 3 (p = 0.044), and 1 (p = 0.020). As to the differences among variables for the six end-points, MR-pro-ADM values in the two groups selected for each considered end-point differed in a statistically significant manner for all endpoints. Both PSI and CURB65 differed significantly for all end-points, except for stay in the ED longer than 4 days and the hospital stay longer than 10 days and endotracheal intubation (only PSI classes differed with statistical significance). ROC analyses evidenced that MR-pro-ADM values gave the greatest AUC for the prediction of death, endotracheal intubation, hospital stay >10 days and DE stay >4 days, compared to the PSI and CURB (though difference not statistically significant). For each endpoint measured, the best thresholds values for Mr-pro-ADM were: 1.6 (specificity 76.5%; sensitivity 77.8%) for death; 2.5 (specificity 88.9%; sensitivity 80.0%) for death at 14 days; 1.5 (specificity 77.0%; sensitivity 87.5%) for NIMV; 2.4 (specificity 88.7%; sensitivity 83.3%) for endotracheal intubation; 0.9 (specificity 53.5%; sensitivity 70.6%) for DE stay greater than 4 days; 1.9 (specificity 82.1%; sensitivity 55.3%) for hospital stay greater than 10 days. The AUC for the combination of MR-pro-ADM and PSI was 81.29% [63.41%-99.17%], but not in a statistically significant manner compared to the AUCs of the single predictors. Conversely, the AUC for the combination of MR-pro-ADM and CURB65 was 87.58% [75.54%-99.62%], which was significantly greater than the AUC of CURB65 (p = 0.047) or PSI (p = 0.017) alone.The present study confirms that assessment of MR-pro-ADM levels in CAP patients in addition to CURB scores increases the prognostic accuracy of CURB alone and may help rule out discrepancies arising from flawed clinical severity classification. With particular reference to patients scoring in the upper classes of CURB and PSI, MR-pro-ADM values provided additional information towards a better risk stratification of those patients. In particular, our results pointed towards two MR-pro-ADM threshold values that appear to predict with a good degree of accuracy the patient's need for non-invasive mechanical ventilation, endotracheal intubation, or intensive care. This aspect, however, deserves further investigation.

Dataset Information

Adrenomedullin and arterial stiffness: integrative approach combining monocyte ADM expression, plasma MR-Pro-ADM, and genome-wide association study.

Publications

Adrenomedullin and arterial stiffness: integrative approach combining monocyte ADM expression, plasma MR-Pro-ADM, and genome-wide association study.

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