Modest elevation in BNP in asymptomatic hypertensive patients reflects sub-clinical cardiac remodeling, inflammation and extracellular matrix changes

In asymptomatic subjects B-type natriuretic peptide (BNP) is associated with adverse cardiovascular outcomes even at levels well below contemporary thresholds used for the diagnosis of heart failure. The mechanisms behind these observations are unclear. We examined the hypothesis that in an asymptomatic hypertensive population BNP would be associated with sub-clinical evidence of cardiac remodeling, inflammation and extracellular matrix (ECM) alterations. We performed transthoracic echocardiography and sampled coronary sinus (CS) and peripheral serum from patients with low (n = 14) and high BNP (n = 27). Peripheral BNP was closely associated with CS levels (r = 0.92, p<0.001). CS BNP correlated significantly with CS levels of markers of collagen type I and III turnover including: PINP (r = 0.44, p = 0.008), CITP (r = 0.35, p = 0.03) and PIIINP (r = 0.35, p = 0.001), and with CS levels of inflammatory cytokines including: TNF-α (r = 0.49, p = 0.002), IL-6 (r = 0.35, p = 0.04), and IL-8 (r = 0.54, p<0.001). The high BNP group had greater CS expression of fibro-inflammatory biomarkers including: CITP (3.8±0.7 versus 5.1±1.9, p = 0.007), TNF-α (3.2±0.5 versus 3.7±1.1, p = 003), IL-6 (1.9±1.3 versus 3.4±2.7, p = 0.02) and hsCRP (1.2±1.1 versus 2.4±1.1, p = 0.04), and greater left ventricular mass index (97±20 versus 118±26 g/m(2), p = 0.03) and left atrial volume index (18±2 versus 21±4, p = 0.008). Our data provide insight into the mechanisms behind the observed negative prognostic impact of modest elevations in BNP and suggest that in an asymptomatic hypertensive cohort a peripheral BNP measurement may be a useful marker of an early, sub-clinical pathological process characterized by cardiac remodeling, inflammation and ECM alterations.

Task sharing within a managed clinical network to improve child health in Malawi

BACKGROUND: Eighty per cent of Malawi's 8 million children live in rural areas, and there is an extensive tiered health system infrastructure from village health clinics to district hospitals which refers patients to one of the four central hospitals. The clinics and district hospitals are staffed by nurses, non-physician clinicians and recently qualified doctors. There are 16 paediatric specialists working in two of the four central hospitals which serve the urban population as well as accepting referrals from district hospitals. In order to provide expert paediatric care as close to home as possible, we describe our plan to task share within a managed clinical network and our hypothesis that this will improve paediatric care and child health.

PRESENTATION OF THE HYPOTHESIS: Managed clinical networks have been found to improve equity of care in rural districts and to ensure that the correct care is provided as close to home as possible. A network for paediatric care in Malawi with mentoring of non-physician clinicians based in a district hospital by paediatricians based at the central hospitals will establish and sustain clinical referral pathways in both directions. Ultimately, the plan envisages four managed paediatric clinical networks, each radiating from one of Malawi's four central hospitals and covering the entire country. This model of task sharing within four hub-and-spoke networks may facilitate wider dissemination of scarce expertise and improve child healthcare in Malawi close to the child's home.

TESTING THE HYPOTHESIS: Funding has been secured to train sufficient personnel to staff all central and district hospitals in Malawi with teams of paediatric specialists in the central hospitals and specialist non-physician clinicians in each government district hospital. The hypothesis will be tested using a natural experiment model. Data routinely collected by the Ministry of Health will be corroborated at the district. This will include case fatality rates for common childhood illness, perinatal mortality and process indicators. Data from different districts will be compared at baseline and annually until 2020 as the specialists of both cadres take up posts.

IMPLICATIONS OF THE HYPOTHESIS: If a managed clinical network improves child healthcare in Malawi, it may be a potential model for the other countries in sub-Saharan Africa with similar cadres in their healthcare system and face similar challenges in terms of scarcity of specialists.

Exchange protein directly activated by cyclic AMP (EPAC) activation reverses neutrophil dysfunction induced by β2-agonists, corticosteroids, and critical illness

Background Neutrophils play a role in the pathogenesis of asthma, chronic obstructive pulmonary disease, and pulmonary infection. Impaired neutrophil phagocytosis predicts hospital-acquired infection. Despite this, remarkably few neutrophil-specific treatments exist. 

Objectives We sought to identify novel pathways for the restoration of effective neutrophil phagocytosis and to activate such pathways effectively in neutrophils from patients with impaired neutrophil phagocytosis. 

Methods Blood neutrophils were isolated from healthy volunteers and patients with impaired neutrophil function. In healthy neutrophils phagocytic impairment was induced experimentally by using β₂-agonists. Inhibitors and activators of cyclic AMP (cAMP)-dependent pathways were used to assess the influence on neutrophil phagocytosis in vitro. 

Results β₂-Agonists and corticosteroids inhibited neutrophil phagocytosis. Impairment of neutrophil phagocytosis by β₂-agonists was associated with significantly reduced RhoA activity. Inhibition of protein kinase A (PKA) restored phagocytosis and RhoA activity, suggesting that cAMP signals through PKA to drive phagocytic impairment. However, cAMP can signal through effectors other than PKA, such as exchange protein directly activated by cyclic AMP (EPAC). An EPAC-activating analog of cAMP (8CPT-2Me-cAMP) reversed neutrophil dysfunction induced by β₂-agonists or corticosteroids but did not increase RhoA activity. 8CPT-2Me-cAMP reversed phagocytic impairment induced by Rho kinase inhibition but was ineffective in the presence of Rap-1 GTPase inhibitors. 8CPT-2Me-cAMP restored function to neutrophils from patients with known acquired impairment of neutrophil phagocytosis. 

Conclusions EPAC activation consistently reverses clinical and experimental impairment of neutrophil phagocytosis. EPAC signals through Rap-1 and bypasses RhoA. EPAC activation represents a novel potential means by which to reverse impaired neutrophil phagocytosis.