*2.2. Cardiac Fibrosis*

In CKD patients, myocardial fibrosis is a pathologic process that occurs together with LVH. One hallmark of myocardial fibrosis is a marked increase in the production of extracellular matrix, especially collagens, which impair diastolic filling due to increased sti ffness of the left ventricle, but they may also a ffect systolic function since functional myocytes are replaced by fibrotic scar tissue [22,23].

The main causes of myocardial fibrosis are hemodynamic alterations and disturbed secretion of various systemic soluble factors. A primary factor leading to myocardial fibrosis in CKD patients is hypertension, which is mainly associated with pressure overload. Factors related to hemodynamic alterations in CKD patients like senescence, ischemia, catecholamines, angiotensin II and aldosterone further promote the development of cardiac fibrosis [21]. Arterial sti ffening is accelerated in the presence of CKD and is caused by a loss of elastic fibers and vascular calcification [24]. Increased vascular sti ffness leads to increased cardiac afterload, which promotes cardiac hypertrophy and fibrosis [21,25].

However, during CKD progression, left ventricular remodeling has been found to occur even earlier than changes in large arteries [26]. This might be explained by a range of factors and mechanisms including uremic toxins, TGF-β and other growth factors. In addition to the role of hemodynamic changes in the development of cardiac fibrosis, non-hemodynamic factors related to the uremic milieu, such as overactivity of the renin-angiotensin-aldosterone system, FGF-23, parathyroid hormone, endothelin, increased sympathetic nerve discharge and increased plasma catecholamines might also play an important role [21,27].

Perivascular mesenchymal cells surround the VSMC layer in the so-called adventitia of larger arteries but are also present as pericytes around the vasa vasorum and in direct contact with endothelial cells of both the large arteries and micro-vessels. They play a role in vasomotion, homeostasis and permeability of the vasculature [11]. The heterogeneity of perivascular cells has been unclear for many years, but recent single-cell RNA-sequencing data sugges<sup>t</sup> that various, previously unknown, perivascular mesenchymal populations exist [28,29]. We have reported that Gli1 marks a specific perivascular cell type that drives cardiac fibrosis and vascular calcification [30,31]. Gli1+ cells are a subset of cardiac interstitial PDGFRβ+ cells, but are mostly distinct from cardiac NG2+ pericytes [31]. However, the complex system of the cardiac perivascular cell types remains unclear, and single-cell experiments are needed to shed light on their heterogeneity and the role they play in homeostasis and disease.
