Increased concentration of circulating angiogenesis and nitric oxide inhibitors induces endothelial to mesenchymal transition and myocardial fibrosis in patients with chronic kidney disease
Introduction
Individuals with chronic kidney disease (CKD) have high risks of developing and dying from cardiovascular (CV) disease and these risks are not fully explained by traditional risk factors [1]. Strong associations of novel factors with CV events, a failure of standard therapies to substantively impact mortality in advanced CKD, and an outsize risk of sudden death relative to myocardial infarction suggest that unique features underlie CVD in the setting of uremia [2].
Experimental models of uremia are characterized by myocardial fibrosis, loss of myocardial capillaries, and inhibition of ischemia driven neo-angiogenesis [3], [4]. These changes increase capillary to myocyte distance, alter oxygen delivery, and disrupt myocardial conduction, thereby facilitating propagation of arrhythmias. Experimental studies also demonstrate altered nitric oxide (NO) bioavailability in uremia [5] which may induce secondary changes in the activity and concentration of additional angiogenesis inhibitors [6], [7], [8] thereby contributing to the observed myocardial fibrosis and capillary rarefaction. However, similar data in human disease remains sparse. We undertook this study to characterize for the first time changes in human myocardial pathology across the spectrum of CKD and assess associations with NO-related circulating angiogenesis inhibitors and their effects on human coronary artery endothelial cells (HCAECs).
Section snippets
Autopsy cohort
Autopsies performed at Brigham & Women's Hospital (BWH) between 2004 and 2006 (n = 45) were included. Cases without sufficient data to estimate kidney function, history of acute kidney injury lasting > 1 week, cardiac transplant, active cancer, prior thoracic irradiation, treatment with anthracyclines, congenital heart disease, idiopathic or viral cardiomyopathy, or insufficient tissue were excluded. Medical history and laboratory data were extracted from clinical records. Kidney function was
Evaluation of cardiac fibrosis
The risk of sudden cardiac death increases dramatically as GFR declines [13]. Sudden cardiac death and overall mortality on the other hand are strongly associated with the presence of cardiac fibrosis [14]. We therefore aimed to systematically evaluate amount of cardiac fibrosis over various stages of CKD by analyzing heart tissue obtained from autopsy.
Among our autopsy cohort of 45 individuals, we identified 21 subjects with preserved kidney function, 17 with stage 3–4 CKD, and 7 with ESRD (
Discussion
We found that myocardial fibrosis and EndMT increased while microvascular supply decreased significantly with CKD severity. In addition, the concentration of circulating angiogenesis and NO inhibitors increased with CKD severity while serum from patients with more severe CKD inhibited proliferation and increased apoptosis of cultured coronary endothelial cells. Finally, ADMA, ANG, TSP and END had qualitatively similar effects on cultured endothelial cells as uremic serum.
CKD is strongly
Funding
This work was supported by funds of the University Medical Center of Göttingen (EMZ and MZ); the Paul Teschan Research Fund; the Carl Gottschalk Award of the American Society of Nephrology; the American Heart Association Scientist Development Grant [0735638N] (DMC), NIH RO1 HL070938 (JH), grants ZE523/3-1 and ZE523/2-1 by the Deutsche Forschungsgemeinschaft (MZ), the Cancer Prevention and Research Institute of Texas, the Metastasis Research Center at MD Anderson Cancer Center, and NIH grants
Conflict of interest
None declared. Author contributions—DMC and EMZ—study design, conduct of experiments, analysis of data, and drafting of manuscript. RP, RK, AMH—study design, conduct of experiments, and analysis of study. MZ and JH—analysis of data and drafting of manuscripts. AC, XX, XL—conduct of experiments and analysis of data. All authors approved the final draft.
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