Background: Chronic kidney disease (CKD) affects more than 10% of the population worldwide and is associated with increased mortality and morbidity. In patients with CKD, cardiovascular diseases are the most common cause of death. The pathophysiologic interaction between heart and kidney pathologies is summarized under the term cardiorenal syndrome. The effects of CKD on cellular mechanisms in cardiomyocytes remain only partially understood. Thus, our goal was to investigate the influence of CKD on human myocardium to better understand the pathomechanism of cardiorenal syndrome. 

Methods: Experiments were conducted using human left ventricular myocardium, which was acquired from patients with aortic stenosis and preserved LV function (EF ≥50%) undergoing surgical valve replacement. Based on the glomerular filtration rate (GFR), patients were divided into a control (C) group (GFR>60 ml/min/1,73m²) or CKD group (GFR<60 ml/min/1,73m²). Cell isolation was performed to obtain single cardiomyocytes and direct experiments were carried out. Epifluorescence microscopy for measurements of Ca²⁺ homeostasis was performed using the ratiometric Ca²⁺ dye Fura-2 AM. Action potential measurements were conducted using ruptured-patch whole-cell current clamp technique. A stimulation frequency of 30 bpm was used during experiments. 

Results: Ventricular myocardium was obtained from 11 patients with normal kidney function and 8 patients with CKD. Patients in the CKD group had markedly impaired GFR (35.1±15.8 ml/min/1,73m² CKD vs. 87.0±11.5 ml/min/1,73m² C, p<0,0001) and higher levels of potassium (4.5±0.6 mmol/l CKD vs. 4.1±0.3 mmol/l C, p=0,044), phosphate (1.4±0.4 mmol/l CKD vs. 0.9±0.2 mmol/l C, p=0,014) and urea (66.4±34.4 ml/dl CKD vs. 31.5±5.5 mg/dl C, p=0,004). LVEF was persevered in both groups (52.5±3.6% CKD vs. 54.1±4.7% C, p=0.474). There were no significant differences regarding age, gender, pre-existing conditions or medication.

Epifluorescence microscopy demonstrated that a significant Ca²⁺ transient amplitude reduction could be observed in the CKD group which points to negative inotropic effects. In addition, action potential measurements revealed an action potential duration (APD) prolongation when the CKD group was compared to the control group. Longer APD represents a potential arrhythmic trigger and may explain the increased amount of rhythm disorders seen in patients with impaired renal function (figure 1). Both reduced Ca²⁺ transient amplitudes and prolonged APD are also known as typical hallmarks of heart failure. Diastolic Ca²⁺ levels, decay kinetic of Ca²⁺ transients, resting membrane potential and action potential amplitudes did not show any significant changes.

Fig. 1: Effects of CKD on Ca²⁺ transients (A) and APD90 (B) at 30 bpm. Cells per group: (A) 43 vs. 55, (B) 23 vs. 14. Data are presented with SEM, Student t test was performed, ***p<0,001. 

Conclusion: We could demonstrate for the first time that human ventricular cardiomyocytes isolated from patients with CKD show impaired cellular electrophysiological function. These findings have translational importance as in an aging population, CKD and cardiovascular diseases will further increase. Thus, our results may be the first step in understanding the development of cardiorenal syndrome on a cellular myocardial level and developing new therapeutic approaches. Further experiments will be available soon to provide mechanistic insight into the described alterations.