Correcting dilated cardiomyopathy with fibroblast-targeted p38 deficiency

Abstract

Inherited mutations in contractile and structural genes, which decrease cardiomyocyte tension generation, are principal drivers of dilated cardiomyopathy (DCM) - the leading cause of heart failure. Progress towards developing precision therapeutics for and defining the underlying determinants of DCM has been cardiomyocyte centric with negligible attention directed towards fibroblasts despite their role in regulating the best predictor of DCM severity, cardiac fibrosis. Given that failure to reverse fibrosis is a major limitation of both standard of care and first in class precision therapeutics for DCM, this study examined whether cardiac fibroblast-mediated regulation of the heart's material properties is essential for the DCM phenotype. Here we report in a mouse model of inherited DCM that prior to the onset of fibrosis and dilated myocardial remodeling both the myocardium and extracellular matrix (ECM) stiffen from switches in titin isoform expression, enhanced collagen fiber alignment, and expansion of the cardiac fibroblast population, which we blocked by genetically suppressing p38a in cardiac fibroblasts. This fibroblast-targeted intervention unexpectedly improved the primary cardiomyocyte defect in contractile function and reversed ECM and dilated myocardial remodeling. Together these findings challenge the long-standing paradigm that ECM remodeling is a secondary complication to inherited defects in cardiomyocyte contractile function and instead demonstrate cardiac fibroblasts are essential contributors to the DCM phenotype, thus suggesting DCM-specific therapeutics will require fibroblast-specific strategies.

Regulatory and Communication Shifts in Dilated Cardiomyopathy: A Multimodal Single-Cell Analysis

“…However, some studies have suggested that broblast activity may not be directly correlated with cardiac brosis in DCM. Bretherton et al [19] reported that studies on precision therapeutics and the etiological factors of DCM have predominantly focused on cardiomyocytes with minimal emphasis on broblasts despite their crucial role in modulating cardiac brosis, a key indicator of DCM severity. Modifying broblast activity can markedly enhance cardiomyocyte contractile function and myocardial remodeling.…”

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

“…A question relating to the therapeutic efficacy of OM and other myosin activators is whether their use not only increases tension in DCM but also reduces fibrosis. [4,112]. This is an important issue as fibrosis has been known for some time to be a predictor of mortality and hospitalization in DCM [1,113,114].…”

“…This is an important issue as fibrosis has been known for some time to be a predictor of mortality and hospitalization in DCM [1,113,114]. In view of lack of evidence that myosin activators reverse fibrosis in systolic HF, it has been argued that a fibroblast specific therapeutic approach is necessary [4]. This make sense as fibroblast proliferation occurs with an avoidance of cell death Even so the per cent of patients with mid-wall fibrosis, the most common manifestation, is less than half the population.…”

“…This make sense as fibroblast proliferation occurs with an avoidance of cell death Even so the per cent of patients with mid-wall fibrosis, the most common manifestation, is less than half the population. The argument has been made that inhibition in fibrosis by expression of p38 in fibroblasts indicates that there is feedback by which loss of tension at the sarcomere level is reduced in a DCM model [4]. This is not surprising as it is expected that mechano signaling occurs not only within cells but from cell to cell.…”

“…2 specific therapeutic strategies [1][2][3][4]. Progression of the disorder to heart failure (HF) includes an exacerbating wall thinning, fibrosis, arrythmias, dyspnea, exercise intolerance, and in some cases sudden death.…”