*Cellular Crosstalk in the Heart*

The mammalian heart is a highly interactive complex of cardiac muscle cells, extracellular matrix (ECM) and vessels. Other essential cell types include endothelial cells, fibroblasts, vascular smooth muscle cells and perivascular cells [6,7]. Studies, using state-of-the-art methods such as single-cell transcriptomics, sugges<sup>t</sup> that all cardiac cell types communicate vigorously with one another in homeostasis and disease [8–10]. Each cardiomyocyte is in physical contact with at least one capillary, allowing mechanical and paracrine crosstalk between at least four key cell types, namely, cardiomyocytes, endothelial cells, vascular smooth muscle cells (VSMCs) and pericytes/fibroblasts [11]. Cardiomyocytes crosstalk with endothelial cells and fibroblasts by secreting various specific growth factors [7]. Various lines of evidence sugges<sup>t</sup> that endothelial cells crosstalk with cardiomyocytes and are key players in angiogenesis and vasomotor tone control by secreting angiocrine factors such as nitric oxide or endothelin-1 [12]. One example of paracrine intercellular crosstalk inside the myocardium is vasomotion. Endothelial cells are directly exposed to shear stress, contrary to VSMCs. To facilitate vasomotion, endothelial cells release nitric oxide in response to shear stress, thus signaling to the VSMCs to dilate. The cardiac morphology and function can be affected by further external and internal stimuli.

### **2. Pathology and Pathophysiology of the Cardiorenal Syndrome**

Kidney and cardiac health are highly linked to each other, with diseases of either organ affecting the other organ. In the following, we aim to give an overview of the mechanisms and relevant factors that have been reported to be involved in cardiac remodeling due to kidney injury, i.e., cardiorenal syndrome.

The presence of CKD and end-stage renal disease (ESRD) leads to cardiac remodeling with hypertrophy, fibrosis and capillary loss [13]. Uremic cardiomyopathy affects about 80% of hemodialysis patients [14] and is the main cause of death in this cohort. A similar prevalence has even been reported in pediatric uremic patients [15] who presumably lack traditional atherosclerotic risk factors. The comorbidities in CKD patients that contribute to cardiovascular remodeling are atherosclerosis, hyperlipidemia, diabetes and/or hypertension, but also include a plethora of so-called non-traditional cardiovascular risk factors such as those discussed below and summarized in Table 1. These stimuli exacerbate the pathophysiological cardiac changes, including left-ventricular hypertrophy (LVH), diffuse interstitial fibrosis and capillary rarefaction leading to systolic and diastolic dysfunction. In this review, we consider these cardiac abnormalities that frequently occur in patients with CKD as uremic cardiomyopathy.
