Targeted therapies in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of small pulmonary arteries that leads to elevated pulmonary arterial pressure and right heart failure. During the last decades, an improved understanding of the pathophysiology of the disease has resulted in the development of effective therapies targeting endothelial dysfunction (epoprostenol and derivatives, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors). These drugs allow clinical, functional and hemodynamic improvement. Even though, no cure exists for PAH and prognosis remains poor. Recently, several additional pathways have been suggested to be involved in the pathogenesis of PAH, and may represent innovative therapies. In this summary, we review conventional therapy, pharmacological agents currently available for the treatment of PAH and the benefit/risk ratio of potential future therapies.     

In Vitro Activity of AZD5847 against Geographically Diverse Clinical Isolates of Mycobacterium tuberculosis

The MIC of the novel antituberculosis (anti-TB) drug AZD5847 was determined against 146 clinical isolates from diverse geographical regions, including eastern Europe, North America, Africa, and Asia, using the automated Bactec Mycobacterial Growth Indicator Tube (MGIT) 960 system. These isolates originated from specimen sources such as sputum, bronchial alveolar lavage fluid, pleural fluid, abscess material, lung biopsies, and feces. The overall MIC₉₀ was 1.0 mg/liter (range, 0.125 to 4 mg/liter). The MICs of AZD5847 for isolates of Mycobacterium tuberculosis were similar among drug-sensitive strains, multidrug-resistant (MDR) strains, and extensively drug resistant (XDR) strains. The good in vitro activity of AZD5847 against M. tuberculosis and the lack of cross-resistance make this agent a promising anti-TB drug candidate.     

Phrenic nerve stimulation in CRT patients and benefits of electronic lead repositioning: the ERACE trial

Purpose

Despite novel left ventricular (LV) lead technologies, phrenic nerve stimulation (PNS) remains an adverse effect observed in many patients with cardiac resynchronization therapy (CRT). Beyond anatomic repositioning, modern CRT devices allow avoidance of PNS also by software-based adaption of the pacing configuration. The Electronic Repositioning With Acuity and Easytrak Leads study evaluated the incidence of PNS in a CRT population and examined how often LV lead relocation can be avoided by “electronic repositioning” (ER).

Methods

Patients who had an indication for implantation of a first CRT defibrillator with the option of ER were enrolled. Primary endpoint was the efficiency of ER determined by the frequency of PNS with the standard pacing configuration (LV tip to RV coil) avoidable by ER. PNS and pacing parameters were evaluated during implant, predischarge, and first routine follow-up (FU) using four different pacing configurations available by ER.

Results

In total, 292 patients were enrolled and provided with a transvenous LV lead (82.2 % male, 65.5?±?9.2 years old). The majority of the population was in NYHA III (84.2 %) with a LV ejection fraction of 25.3?±?6.8 % and mean QRS width of 155?±?27 ms, ischemic cardiomyopathy was present in 43.6 %. Median FU was 116 days. In the standard pacing configuration, PNS was inducible in 19.0/25.6/24.6 % at implant/predischarge/FU, respectively, resulting in 32.2 % of the patients presenting at least once with PNS. The safety margin for the standard pacing configuration between LV and PNS threshold was <1.0 V at 0.5 ms in 5.6/7.0/5.0 % of the patients, corresponding with a total rate of 11.6 % during the FU. In the finally chosen configuration, clinically relevant PNS occurred in 1.0/2.2/1.3 %. The four vector configurations allowed all but 6 of 292 (2 %) patients to be reprogrammed using ER without reoperation.

Conclusions

The incidence of inducible PNS in CRT patients is considerable. In this study, PNS could be avoided in the majority of the patients by means of electronic repositioning. Thus, the use of ER should be considered for CRT patients.     

Prediction of non-alcoholic fatty-liver disease and liver fat content by serum molecular lipids

Aims/hypothesis

We examined whether analysis of lipids by ultra-performance liquid chromatography (UPLC) coupled to MS allows the development of a laboratory test for non-alcoholic fatty-liver disease (NAFLD), and how a lipid-profile biomarker compares with the prediction of NAFLD and liver-fat content based on routinely available clinical and laboratory data.

Methods

We analysed the concentrations of molecular lipids by UPLC-MS in blood samples of 679 well-characterised individuals in whom liver-fat content was measured using proton magnetic resonance spectroscopy (¹H-MRS) or liver biopsy. The participants were divided into biomarker-discovery (n?=?287) and validation (n?=?392) groups to build and validate the diagnostic models, respectively.

Results

Individuals with NAFLD had increased triacylglycerols with low carbon number and double-bond content while lysophosphatidylcholines and ether phospholipids were diminished in those with NAFLD. A serum-lipid signature comprising three molecular lipids (‘lipid triplet’) was developed to estimate the percentage of liver fat. It had a sensitivity of 69.1% and specificity of 73.8% when applied for diagnosis of NAFLD in the validation series. The usefulness of the lipid triplet was demonstrated in a weight-loss intervention study.

Conclusions/interpretation

The liver-fat-biomarker signature based on molecular lipids may provide a non-invasive tool to diagnose NAFLD, in addition to highlighting lipid molecular pathways involved in the disease.