Heart failure is the name given to a category of dysfunctions in which the heart cannot pump enough blood to sustain the body. It is characterized by structural changes in heart muscle, some of which are maladaptive, some of which are compensatory, and a range of increasingly unpleasant consequences throughout the body and brain as the condition progresses in severity. The most prevalent cause of heart failure is the narrowing of important blood vessels by atherosclerotic plaque. The rupture of plaque to cause a transient blockage and heart attack can also sufficiently injure and weaken the heart in survivors to cross the threshold into heart failure. Hypertension is another common cause, as long-term disruption of the feedback mechanisms controlling blood pressure and heart activity causes enlargement and weakening of heart muscle, and thereby heart failure. There are other common contributing causes of heart failure that can in principle be sufficient on their own, such as severe atrial fibrillation and pulmonary hypertension, but in older people these issues are more usually coincident with atherosclerosis and hypertension.
In today's open access paper, researchers identify a harmful population of fibroblasts resident in heart tissue that only emerges in the state of heart failure. Fibroblasts are primarily responsible for generating extracellular matrix structures, and in an aged or damaged heart they also produce the scarring of fibrosis that reduces function. Fibroblasts have other capabilities, however, and the particular population of harmful fibroblasts engages in signaling that detrimentally changes the behavior of cardiomyocyte cells making up heart muscle. Interfering in this signaling may be a basis for therapies to reduce the progression of heart failure, preventing some fraction of the maladaptive changes in cell function that contribute to the condition.
Heart failure (HF) is a growing global health issue. While most studies focus on cardiomyocytes, here we highlight the role of cardiac fibroblasts (CFs) in HF. Although CFs are thought to maintain cardiac homeostasis primarily by producing extracellular matrices, CFs communicate with other cell types, including cardiomyocytes, via direct interactions and paracrine signaling. In response to diverse stresses under pathological conditions, CFs dynamically alter their phenotype, transitioning from resident fibroblasts to myofibroblasts and eventually matrifibrocytes after myocardial infarction (MI).
Single-cell RNA sequencing of mouse hearts under pressure overload identified heterogeneity in CFs across sham hearts, pressure-overload-induced hypertrophic hearts, and failing hearts, revealing an HF-specific subpopulation of fibroblasts, here designated as HF-Fibro. HF-Fibro expressed Postn, which is expressed in fibroblasts activated by MI, but not Acta2 or the osteochondral gene Chad, suggesting that HF-Fibro are different from myofibroblasts or matrifibrocytes that appear in MI hearts.
The HF-Fibro population also highly expresses the transcription factor Myc. Deleting Myc in CFs improves cardiac function without reducing fibrosis. MYC directly regulates the expression of the chemokine CXCL1, which is elevated in HF-Fibro CFs and downregulated in Myc-deficient CFs. The CXCL1 receptor, CXCR2, is expressed in cardiomyocytes and blocking the CXCL1-CXCR2 axis mitigates HF. Additionally, CXCL1 impairs contractility in neonatal rat and human iPSC-derived cardiomyocytes. Human CFs from failing hearts also express MYC and CXCL1, unlike those from controls.
These findings reveal that HF-Fibro cells contribute to HF via the MYC-CXCL1-CXCR2 pathway, offering a promising therapeutic target beyond cardiomyocytes.
View the full article at FightAging
