Plasma Levels of Adrenomedullin in Primary and Secondary Pulmonary Hypertension in Patients <20 Years of Age

Pulmonary arterial hypertension (PAH) is a vascular disorder associated with high morbidity and mortality rate and is characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance, ultimately resulting in right ventricular failure and death. Over the past few decades, significant advances in the understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary arterial hypertension have occured. This has led to the development of disease specific treatment including prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, and soluble guanylate cyclase stimulators. These therapies significantly improve exercise capacity, quality of life, pulmonary hemodynamics, but none of the current treatments are actually curative and long-term prognosis remains poor. Thus, there is a clear need to develop new therapies.

Several potential pharmacologic agents for the treatment of pulmonary arterial hypertension are under clinical development and some promising results with these treatments have been reported. These agents include tyrosine protein kinase inhibitors, rho-kinase inhibitors, synthetically produced vasoactive intestinal peptide, antagonists of the 5-HT2 receptors, and others. This article will review several of these promising new therapies and will discuss the current evidence regarding their potential benefit in pulmonary arterial hypertension.

Adrenomedullin (AM) is a pluripotent peptide hormone with contradictory effects in human health and disease. In chronic inflammatory lung diseases, such as asthma and COPD, AM has been shown to inhibit inflammation and cell proliferation. In the present study, we aimed to investigate the effect of AM on pro-angiogenic and pro-inflammatory cytokines in asthma and COPD.

Serum levels of pro-AM were measured in patients with asthma, COPD and matched controls. The effect of AM on intracellular signaling proteins and cytokine secretion was assessed in primary cultures of epithelial cells (EC) and airway smooth muscle cells (ASMC) established from endo-bronchial biopsies of patients with asthma, COPD and controls.

Serum pro-AM was higher in patients with asthma and COPD, compared to controls. AM stimulated cAMP in ASMC but not in EC. In EC, AM decreased Erk1/2 MAPK expression and activation but in ASMC, AM activated Erk1/2. This effect was similar in asthma, COPD and controls. AM stimulated the secretion of pro-angiogenic CXCL1 by EC of controls and CXCL5 by EC of asthma patients. AM did not affect the secretion of IL-6 or IL-8 by EC but stimulated the secretion of IL-6 by ASMC. In EC, AM inhibited the stimulatory effect of TGF-β and IL-4 on the secretion of IL-6 and IL-8 but had an additive stimulatory effect with TGF-β in ASMC.

These data suggest that AM mediates the secretion of pro-angiogenic and pro-inflammatory cytokines in a cell-type and/or a disease-specific way, explaining its association with clinical outcomes in COPD.

Congenital Heart Disease (CHD) constitutes a common cause of major congenital abnormalities with prevalence around 8.2 per 1000 live births in Europe. Despite the important advances in the diagnosis, treatment and management of CHD patients throughout the years, it remains a challenge how to better manage the children with CHD using the biomarkers. However, in the last decade, B-type Natriuretic Peptide (BNP) and less often Adrenomedullin (ADM) and Urotensin II (UT II) have become the focus of research, in view of the improvement in the management of patients with CHD. Moreover, despite crescent evidences supporting the use of BNP as diagnostic and prognostic marker in children with CHD, its use remains limited and guidelines/expert consensus recommendations are lacking. Adrenomedullin (ADM) and Urotensin II (UT II) are two potent vasoactive peptides that might play a role in the development of pulmonary hypertension. Future studies are needed to explore the role of both peptides as biomarkers of pulmonary hypertension and their prognostic significance on the development of pulmonary hypertension in CHD patients.

Pulmonary arterial hypertension (PAH) is a complex disease with a poor prognosis. In recent years, great advances have occurred in our understanding of the pathophysiologic mechanisms underlying the characteristic vascular proliferative lesions, thus allowing the development of several specific drugs. Nevertheless, PAH still presents a high mortality; therefore, early diagnosis and prognostic stratification seem to be of paramount importance in order to choose the best therapeutic strategies. Circulating biomarkers have been proposed as potentially noninvasive and objective parameters for diagnosis, prognosis, and response to therapy. The molecules evaluated to date, including markers of dysfunction and neurohormonal activation, myocardial injury, inflammation and oxidative stress, vascular damage and remodelling, end-organ failure, and gene expression, reflect the complex pathophysiology of PAH. However, not one of these shows all the characteristics of the ideal biomarker; thus, a multiparameter approach is probably desirable. Moreover, future direction could be research of structural proteins specifically expressed in the pathologic tissue that act as disease-specific markers. This report presents an extensive review of circulating biomarkers in PAH and some consideration about potential future direction in this area.

Collagen accumulation is one of the important pathologic changes in the development of pulmonary hypertension. Previous research showed that adrenomedullin (ADM) mitigates the development of pulmonary hypertension. The present study explored the role of ADM in the development of pulmonary artery collagen accumulation induced by high pulmonary blood flow, by investigating the effect of ADM [1.5 μg/(kg h)] subcutaneously administered by mini-osmotic pump on pulmonary hemodynamics, pulmonary vascular structure and pulmonary artery collagen accumulation and synthesis in rats with high pulmonary blood flow induced by aortocaval shunting. The results showed that ADM significantly decreased mean pulmonary artery pressure (mPAP) and the ratio of right ventricular mass to left ventricular plus septal mass [RV/(LV + SP)], attenuated the muscularization of small pulmonary vessels and relative medial thickness (RMT) of pulmonary arteries in rats with high pulmonary blood flow. Meanwhile, ADM ameliorated pulmonary artery collagen deposition represented by a decrease in lung tissue hydroxyproline, collagens I and III content and pulmonary artery collagens I and III expression, reduced collagen synthesis represented by a decrease in lung tissue procollagens I and III mRNA expression. The results suggest that ADM plays a protective role in the development of pulmonary hypertension induced by high blood flow, by inhibiting pulmonary procollagen synthesis and alleviating pulmonary artery collagen accumulation.

Midrange-proadrenomedullin (MR-proADM) has been shown to be elevated in patients hospitalized for an acute exacerbation of COPD (AECOPD) and in patients with community-acquired pneumonia. When measured during AECOPDs, MR-proADM has also been shown to be a predictor of mortality. We hypothesized that MR-proADM levels measured in a stable state could also predict mortality.

We included 181 patients in whom we had paired plasma samples for MR-proADM determinations during a stable state and at hospitalization for an AECOPD when they also produced sputum. Time to death or censoring was compared between patients with MR-proADM above or below the median of 0.71 nmol/L. The predictive value of MR-proADM for survival was determined by calculating the C statistic.

Patients with COPD and MR-proADM levels > 0.71 nmol/L in the stable state had a threefold-higher risk of dying than did patients with MR-proADM levels < 0.71 nmol/L (hazard ratio, 2.98 [95% CI, 1.51-5.90]; C statistic, 0.76). The corrected OR for 1-year mortality was 8.90 (95% CI, 1.94-44.6) in patients with high MR-proADM levels measured in the stable state, compared with patients with low levels measured in the stable state.

MR-proADM measured in the stable state appeared to be a strong predictor of mortality in patients with COPD. MR-proADM is far easier to measure than other predictors of mortality in COPD, such as BMI, airflow obstruction, dyspnea, and exercise capacity score.