This study highlights the influence of age on phenotypes of incident pulmonary arterial hypertension and has shown the changes in demographics and epidemiology over the past decade in a national setting. The results suggest that there may be two subtypes of patients: the younger subtype with more severe hemodynamic impairment but better survival, compared with the older subtype who has more comorbidities.

Objectives: Acute muscle wasting in the critically ill is common, and causes significant morbidity. In a novel human model of acute muscle wasting following cardiac surgery, known or potential circulating modulators of muscle mass: insulin-like growth factor-1 (IGF-1), myostatin and growth and differentiation factor-15 (GDF-15), were measured over a week. It was hypothesised that patients who developed acute muscle wasting would show distinct patterns of change in these mediators.Design: A prospective longitudinal observational study of high-risk elective cardiac surgical patients identifying, by ultrasound, those developing muscle wasting.Setting: Tertiary cardiothoracic referral centre: Royal Brompton Hospital, London, UK.Patients: 42 patients undergoing elective high-risk cardiothoracic surgery.Interventions: Circulating IGF-1, myostatin and GDF-15 were assayed pre-operatively and over the first week post-operatively. The ability of GDF-15 to cause muscle wasting in vitro was determined in C2C12 myotubes. Measurements and main results: 23 of 42 patients (55%) developed quadriceps atrophy. There wasan acute decrease in IGF-1 and unexpectedly myostatin, known mediators of muscle hypertrophy and atrophy, respectively. By contrast, plasma GDF-15 concentrations increased in all patients. This increase in GDF-15 was sustained at day 7 in those who developed muscle wasting (day 7 compared with baseline, p<0.01), but recovered in the non-wasting group (p>0.05). IGF-1 did not recover in those who developed muscle wasting (day 7 compared with baseline, p<0.01) but did in the nonwasting group (p>0.05). Finally, we demonstrated that GDF-15 caused atrophy of myotubes in vitro. Conclusion:These data support the hypothesis that acute muscle loss occurs as a result of an imbalance between drivers of muscle atrophy and hypertrophy. GDF-15 is a potential novel factor associated with muscle atrophy, which may become a therapeutic target in patients with Intensive care unit acquired paresis and other forms of acute muscle wasting.Abstract word count: 292

Background and objectiveNuclear factor kappa B (NF‐kB)‐mediated inflammatory gene expression and vascular endothelial cell proliferation/remodelling are implicated in the pathophysiology of the fatal disease, pulmonary arterial hypertension (PAH). Bromodomain and extra‐terminal (BET) proteins are essential for the expression of a subset of NF‐kB‐induced inflammatory genes. BET mimics including JQ1+ prevent binding of BETs to acetylated histones and down‐regulate the expression of selected genes.MethodsThe effects of JQ1+ on the proliferation of primary human pulmonary microvascular endothelial cells (HPMECs) from healthy subjects were measured by bromodeoxyuridine (BrdU) incorporation. Cell cycle progression was assessed by flow cytometry; mRNA and protein levels of cyclin‐dependent kinases (CDKs), inhibitors and cytokines were determined by reverse transcription‐quantitative PCR (RT‐qPCR), Western blotting or ELISA. Histone acetyltransferase (HAT) and deacetylase (HDAC) activities were determined in nuclear extracts from whole lung of PAH and control patients.Results JQ1+ significantly inhibited IL6 and IL8 (IL6 and CXCL8) mRNA and protein in HPMECs compared with its inactive enantiomer JQ1−. JQ1+ decreased NF‐kB p65 recruitment to native IL6 and IL8 promoters. JQ1+ showed a concentration‐dependent decrease in HPMEC proliferation compared with JQ1−‐treated cells. JQ1+ induced G1 cell cycle arrest by increasing the expression of the CDK inhibitors (CDKN) 1A (p21cip) and CDKN2D (p19INK4D) and decreasing that of CDK2, CDK4 and CDK6. JQ1+ also inhibited serum‐stimulated migration of HPMECs. Finally, HAT activity was significantly increased in the lung of PAH patients.ConclusionInhibition of BETs in primary HPMECs decreases inflammation and remodelling. BET proteins could be a target for future therapies for PAH.

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