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Bioactive adrenomedullin in plasma is associated with biventricular filling pressures in patients with advanced heart failure

Assessment of cardiac function by right heart catheterization remains a key examination in patients with advanced heart failure. The procedure, however, comes with a risk of adverse events. Identification of blood-borne biomarkers that can be used as proxy measures of intra-cardiac pressure measures would be beneficial. A fragment of the molecular precursor to adrenomedullin (ADM), namely mid-regional pro-ADM, has earlier been associated with outcome in most diseases including heart failure.1–3 An assay for bioactive ADM (bio-ADM) has been developed where bio-ADM may represent a more time-dependent relation to fluctuating parameters such as cardiac pressures.4–6 Blood-borne biomarkers associated with intra-cardiac pressures would be beneficial in screening patients prior to invasive examination or as an adjunct measure together with the haemodynamic variables. Here, we hypothesized that circulating concentrations of bio-ADM may be associated with intracardiac pressures in patients with advanced heart failure undergoing right heart catheterization. An altogether 65 patients referred for right heart catheterization for possible heart transplantation or implantation of a left ventricular assist device were included. Plasma was obtained on the day of examination prior to the procedure. Bio-ADM was measured at a research laboratory at Sphingotec GmbH (Hennigsdorf, Germany) using a method previously described.7 Intra-assay and inter-assay variation was <10% and <8%, respectively. In 200 healthy adults, the median concentration has earlier been reported to be 20.7 pg/mL.8 Patient characteristics have been reported previously.9 Notably, left ventricular ejection fraction as evaluated by echocardiography was 19± 8%. Only two patients did not display severely impaired systolic function, and we, therefore, did not further divide the patients into functional groups based on reduced or preserved left ventricular systolic function. The median concentration of bio-ADM in all patients was 27.4 pg/mL (range 8–145 pg/mL), thus elevated in comparison with the aforementioned reference interval. When comparing bio-ADM (log) concentrations to clinical measures of disease severity, we found associations to pulmonary rales (P < 0.001), hepatomegaly (P = 0.022), oedema (P = 0.005) and presence of ascites (P = 0.049). On the other hand, no significant association was noted between bio-ADM concentrations and left ventricular ejection fraction, cardiac index, or estimated glomerular filtration rate (data not shown). However, bio-ADM concentrations were moderately associated with intra-cardiac pressures, namely mean pressures in the right atrium, pulmonary artery, and the pulmonary capillary wedge pressure (Figure 1A–C). BioADM also was associated with N-terminal pro-B-type natriuretic peptide (NT-proBNP) (Figure 1D). In univariable analysis, right atrial pressure, pulmonary capillary wedge pressure, mean pulmonary artery pressure, estimated glomerular filtration rate, body mass index, and NT-proBNP concentrations all were found significantly associated with bio-ADM concentrations (data not shown). In addition, in multivariable analysis including right atrial pressure, left ventricular ejection fraction, cardiac index, age, gender, estimated glomerular filtration rate, body mass index, and NT-proBNP concentrations, bio-ADM concentrations only correlated with right atrial pressure (P = 0.002), body mass index (0.002), and NT-proBNP (P = 0.020). To test whether right atrial pressure and left ventricular function associated with other measures than bio-ADM and NT-proBNP, univariable and multivariable analyses were performed including age, gender, body mass index, left ventricular ejection fraction, and estimated glomerular filtration rate. For right atrial pressure, only log bio-ADM and log NT-proBNP were significantly associated in univariable analysis (P < 0.001 for both analyses); for left ventricular ejection fraction, only NT-proBNP were found to be significantly associated (P = 0.002). On Cox regression analyses using a single endpoint defined as all-cause mortality (21 events), we found increased bio-ADM concentrations (≥27 pg/mL) to be associated with increased risk of mortality (hazard ratio 3.3, 95% confidence interval 1.3–8.6; P = 0.014), even when adjusting for pulmonary capillary wedge pressure, right atrial pressure, age, gender, and NT-proBNP (hazard ratio 3.3, 95% confidence interval 1.2–9.8; P = 0.022). In this short communication, we report that bio-ADM measurement in plasma prior to right heart catheterization is associated with intra-cardiac pressures recorded during the invasive procedure. Our results thus expand the findings in a recent report on bio-ADM in patients with worsening signs and symptoms of heart failure.10 In this study, the authors showed that bio-ADM is associated with the degree of clinical congestion as assessed by peripheral oedema, jugular venous pressure and orthopnoea. However, the study did not include haemodynamic measures, where such association so far has only been reported in patients with cardiogenic shock.11 Our results using invasive assessment of haemodynamic changes suggest that the mechanism for increased bio-ADM could be directly related to measures of pulmonary congestion and flow. Interestingly, a recent study has shown that ADM secretion from endothelial cells is markedly affected by increased flow-induced shear stress and vascular pressure.12 While our study remains descriptive in nature, our data do suggest that pulmonary ADM may be of further clinical relevance, which should be further pursued in patients with pulmonary hypertension or valvular disease. While measurement of bio-ADM is a potentially new biomarker for clinical studies, the association of ADM to cardiovascular disease is not entirely new.13 The early studies, however, often evaluated ADM measurement vs. natriuretic peptide measurement, which may not be ideal. ADM is mainly expressed in the right atrium and the pulmonary artery tree, and in the adrenals (hence the name). A future task will therefore be to test for a net release from the heart and/or the lungs using blood samples from selected vessels – including the coronary sinus. From a clinical point of view, ADM measurement for now should focus on the right