Cardiac fibroblasts support cardiac inflammation in heart failure

Abstract

Cardiac remodeling and inflammation are hallmarks of cardiac failure and correlate with outcome in patients. However, the basis for the development of both remains unclear. We have previously reported that cardiac inflammation triggers transdifferentiation of fibroblasts to myofibroblasts and therefore increase accumulation of cardiac collagen, one key pathology in cardiac remodeling. Hence, identifying key pathways for inflammation would be beneficial for patients suffering from heart failure also. Besides their well-characterized function in matrix regulation, we here investigate the role of fibroblasts in the inflammatory process. We address for the first time the role of fibroblasts as inflammatory supporter cells in heart failure. Using endomyocardial biopsies from patients with heart failure and dilated cardiomyopathy, we created a primary human cardiac fibroblast cell culture system. We found that mechanical stretch mimicking cardiac dilation in heart failure induces activation of fibroblasts and not only stimulates production of extracellular matrix but more interestingly up-regulates chemokine production and triggers typical inflammatory pathways in vitro. Moreover, the cell culture supernatant of stretched fibroblasts activates inflammatory cells and induces further recruitment of monocytes by allowing transendothelial migration into the cardiac tissue. Our findings reveal that cardiac fibroblasts provide pro-inflammatory mediators and may act as sentinel cells activated by mechanical stress. Those cells are able to recruit inflammatory cells into the cardiac tissue, a process known to aggravate outcome of patients. This might be important in different forms of heart failure and therefore may be one general mechanism specific for fibroblasts.

Inflammation – Cause or Consequence of Heart Failure or Both?

“…Obesity for example can lead to inflammation, whereas chronic inflammation can induce obesity-associated diabetes in part by inducing insulin resistance [21]. With respect to pathophysiological processes in the heart, there is accumulating evidence that inflammation-triggered myofibroblasts are capable of inducing the inflammatory response by their own via (1) expressing chemokines, attracting immune cells to the heart, (2) inducing adhesion molecules on the endothelium, (3) stimulating monocytes to express gelatinases, facilitating transmigration of immune cells through the basolateral membrane [23, 24], and (4) NLRP3 inflammasome activity and IL-1ß release [25]. In this manner, a vicious circle is induced supporting chronic inflammation in the heart [24].…”

Challenges and opportunities in treating inflammation associated with pulmonary hypertension

“…Experimentally, over-expression of various cytokines has been demonstrated in heart failure models. While data derived from heart tissue of PAH patients are presently lacking, it is not farfetched to postulate that effective treatment of patients with severe PAH decreases the activity of inflammatory cells in the myocardium and the activation of cardiomyocytes and fibroblasts (36, 158). Alternatively, a reduction of the degree of systemic inflammation may also reduce the inflammatory response in the stressed heart.…”

Intermittent pacing therapy favorably modulates infarct remodeling

“…However, it is well known that LV pacing results in considerable changes in LV contraction patterns, even in the peri-infarct zone [25, 45], resulting in alterations in regional stretch and loading conditions [17, 33, 36, 46]. Since mechanical tension is an important stimulus for cardiac fibroblast to myofibroblast differentiation [11, 15, 16, 26], it is likely that regional alterations in myocardial stretch produced by IPTVVI stimulated resident fibroblasts to differentiate into myofibroblasts.…”