Targeting myocardial remodelling to develop novel therapies for heart failure: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology

The failing heart is characterized by complex tissue remodelling involving increased cardiomyocyte death, and impairment of sarcomere function, metabolic activity, endothelial and vascular function, together with increased inflammation and interstitial fibrosis. For years, therapeutic approaches for heart failure (HF) relied on vasodilators and diuretics which relieve cardiac workload and HF symptoms. The introduction in the clinic of drugs interfering with beta-adrenergic and angiotensin signalling have ameliorated survival by interfering with the intimate mechanism of cardiac compensation. Current therapy, though, still has a limited capacity to restore muscle function fully, and the development of novel therapeutic targets is still an important medical need. Recent progress in understanding the molecular basis of myocardial dysfunction in HF is paving the way for development of new treatments capable of restoring muscle function and targeting specific pathological subsets of LV dysfunction. These include potentiating cardiomyocyte contractility, increasing cardiomyocyte survival and adaptive hypertrophy, increasing oxygen and nutrition supply by sustaining vessel formation, and reducing ventricular stiffness by favourable extracellular matrix remodelling. Here, we consider drugs such as omecamtiv mecarbil, nitroxyl donors, cyclosporin A, SERCA2a (sarcoplasmic/endoplasmic Ca(2 +) ATPase 2a), neuregulin, and bromocriptine, all of which are currently in clinical trials as potential HF therapies, and discuss novel molecular targets with potential therapeutic impact that are in the pre-clinical phases of investigation. Finally, we consider conceptual changes in basic science approaches to improve their translation into successful clinical applications.

Ungulate behavioral responses to the heterogeneous road-network of a touristic protected area in Africa

Understanding how wildlife responds to road and traffic is essential for effective conservation. Yet, not many studies have evaluated how roads influence wildlife in protected areas, particularly within the large iconic African National Parks where tourism is mainly based on sightings from motorized vehicles with the consequent development and intense use of roads. To reduce this knowledge gap, we studied the behavioral response and local spatial distribution of impala Aepyceros melampus along the heterogeneous (with variation in road surface type and traffic intensity) road-network of Kruger National Park (KNP, South Africa). We surveyed different types of roads (paved and unpaved) recording the occurrence of flight responses among sighted impala and describing their local spatial distribution (in relation to the roads). We observed relatively few flight responses (19.5% of 118 observations), suggesting impalas could be partly habituated to vehicles in KNP. In addition, impala local distribution is apparently unaffected by unpaved roads, yet animals seem to avoid the close proximity of paved roads. Overall, our results suggest a negative, albeit small, effect of traffic intensity, and of presence of pavement on roads on the behavior of impala at KNP. Future studies would be necessary to understand how roads influence other species, but our results show that even within a protected area that has been well-visited for a long time, wildlife can still be affected by roads and traffic. This result has ecological (e.g., changes in spatial distribution of fauna) and management implications (e.g., challenges of facilitating wildlife sightings while minimizing disturbance) for protected areas where touristic activities are largely based on driving.