Background The myocardial cytoskeleton functions as the fundamental framework critical for organelle function, bioenergetics and myocardial remodeling. To date, impairment of the myocardial cytoskeleton occurring in the failing heart in patients with advanced
chronic kidney disease has been largely undescribed. Methods and Results We conducted a 3-arm cross-sectional cohort study of explanted human heart tissues from patients who are dependent on
hemodialysis (n=19),
hypertension (n=10) with preserved renal function, and healthy controls (n=21). Left ventricular tissues were subjected to pathologic examination and next-generation
RNA sequencing. Mechanistic and interference RNA studies utilizing in vitro human cardiac fibroblast models were performed. Left ventricular tissues from patients undergoing
hemodialysis exhibited increased myocardial wall thickness and significantly greater
fibrosis compared with
hypertension patients (P<0.05) and control (P<0.01). Transcriptomic analysis revealed that the focal adhesion pathway was significantly enriched in hearts from patients undergoing
hemodialysis. Hearts from patients undergoing
hemodialysis exhibited dysregulated components of the focal adhesion pathway including reduced β-actin (P<0.01), β-
tubulin (P<0.01),
vimentin (P<0.05), and increased expression of
vinculin (P<0.05) compared with controls. Cytoskeletal adaptations in hearts from the
hemodialysis group were associated with impaired mitochondrial bioenergetics, including dysregulated mitochondrial dynamics and fusion, and loss of cell survival pathways. Mechanistic studies revealed that cytoskeletal changes can be driven by uremic and metabolic abnormalities of
chronic kidney disease, in vitro. Furthermore,
focal adhesion kinase silencing via interference RNA suppressed major
cytoskeletal proteins synergistically with
mineral stressors found in
chronic kidney disease in vitro. Conclusions
Myocardial failure in advanced
chronic kidney disease is characterized by impairment of the cytoskeleton involving disruption of the focal adhesion pathway, mitochondrial failure, and loss of cell survival pathways.