Cyclic strain has antifibrotic effects on the human cardiac fibroblast transcriptome in a human cardiac fibrosis-on-a-chip platform.

In cardiac fibrosis, in response to stress or injury, cardiac fibroblasts deposit excessive amounts of collagens which contribute to the development of heart failure. The biochemical stimuli in this process have been extensively studied, but the influence of cyclic deformation on the fibrogenic behavior of cardiac fibroblasts in the ever-beating heart is not fully understood. In fact, most investigated mechanotransduction pathways in cardiac fibroblasts seem to ultimately have profibrotic effects, which leaves an important question in cardiac fibrosis research unanswered: how do cardiac fibroblasts stay quiescent in the ever-beating human heart? In this study, we developed a human cardiac fibrosis-on-a-chip platform and utilized it to investigate if and how cyclic strain affects fibrogenic signaling. The pneumatically actuated platform can expose engineered tissues to controlled strain magnitudes of 0-25% - which covers the entire physiological and pathological strain range in the human heart - and to biochemical stimuli and enables high-throughput screening of multiple samples. Microtissues of human fetal cardiac fibroblasts (hfCF) embedded in gelatin methacryloyl (GelMA) were 3D-cultured on this platform and exposed to strain conditions which mimic the healthy human heart. The results provide evidence of an antifibrotic effect of the applied strain conditions on cardiac fibroblast behavior, emphasizing the influence of biomechanical stimuli on the fibrogenic process and giving a detailed overview of the mechanosensitive pathways and genes involved, which can be used in the development of novel therapies against cardiac fibrosis.

Myocardial Disease and Long-Distance Space Travel: Solving the Radiation Problem.

Radiation-induced cardiovascular disease is a well-known complication of radiation exposure. Over the last few years, planning for deep space missions has increased interest in the effects of space radiation on the cardiovascular system, as an increasing number of astronauts will be exposed to space radiation for longer periods of time. Research has shown that exposure to different types of particles found in space radiation can lead to the development of diverse cardiovascular disease via fibrotic myocardial remodeling, accelerated atherosclerosis and microvascular damage. Several underlying mechanisms for radiation-induced cardiovascular disease have been identified, but many aspects of the pathophysiology remain unclear. Existing pharmacological compounds have been evaluated to protect the cardiovascular system from space radiation-induced damage, but currently no radioprotective compounds have been approved. This review critically analyzes the effects of space radiation on the cardiovascular system, the underlying mechanisms and potential countermeasures to space radiation-induced cardiovascular disease.

Anti-fibrotic Effects of Cardiac Progenitor Cells in a 3D-Model of Human Cardiac Fibrosis.

Cardiac fibroblasts play a key role in chronic heart failure. The conversion from cardiac fibroblast to myofibroblast as a result of cardiac injury, will lead to excessive matrix deposition and a perpetuation of pro-fibrotic signaling. Cardiac cell therapy for chronic heart failure may be able to target fibroblast behavior in a paracrine fashion. However, no reliable human fibrotic tissue model exists to evaluate this potential effect of cardiac cell therapy. Using a gelatin methacryloyl hydrogel and human fetal cardiac fibroblasts (hfCF), we created a 3D in vitro model of human cardiac fibrosis. This model was used to study the possibility to modulate cellular fibrotic responses. Our approach demonstrated paracrine inhibitory effects of cardiac progenitor cells (CPC) on both cardiac fibroblast activation and collagen synthesis in vitro and revealed that continuous cross-talk between hfCF and CPC seems to be indispensable for the observed anti-fibrotic effect.

Outcome of a Step-Up Treatment Strategy for Chyle Leakage After Esophagectomy.

BACKGROUND: Thoracic chyle leakage is a major complication of esophagectomy. In this study our treatment strategy for chyle leakage was evaluated and its risk factors were identified. METHODS: According to the Esophagectomy Complications Consensus Group recommendations, chyle leakage was classified as follows: I, enteric dietary modifications; II, total parenteral nutrition (TPN); and III, interventional or surgical therapy. It was graded as A, less than 1,000 mL per day; or B, more than 1,000 mL per day. In our protocol, chyle leakage less than 500 mL per day was treated with a low-fat diet; more than 1,000 mL per day, with TPN, and 500 to 1,000 mL per day, with a low-fat diet or TPN depending on whether the chyle leakage was increasing or decreasing at diagnosis and the clinical condition. Surgery was reserved for refractory leakages. RESULTS: In total 371 patients were included. Chyle leakage incidence was 21%, consisting of 51% grade A and 49% grade B leakage. Chyle leakage severity was associated with length of stay (grade A, median 17 days versus B, 25 days; p = 0.006). Independent risk factors were a transthoracic approach (odds ratio 4.8, p = 0.002), neoadjuvant chemoradiotherapy (odds ratio 2.6, p = 0.002), and preoperative body mass index (exp(B) 0.92, p = 0.031). Treatment consisted of low-fat diet in 53%, TPN in 37%, and surgery in 10% of the patients. Low-fat diet and TPN successfully treated 87% of chyle leaks. Chyle leakages treated by TPN first were significantly more severe compared with those treated first by low-fat diet, and were significantly associated with electrolyte deficiencies, increased complication severity, and length of stay, but not with 90-day mortality. CONCLUSIONS: A step-up treatment strategy, starting with dietary modifications, solved nearly 90% of chyle leaks conservatively. A minority of chyle leaks required surgery.