Comparison of surgically removed cardiac valves of patients with ESRD with those of the general population
ABSTRACT Patients with end-stage renal disease (ESRD) have increased vascular and valvular calcification compared with the general population. Recently, 44% of renal transplant recipients were found to have vascular calcification of the medial layer of the inferior epigastric artery that was associated with deposition of bone matrix proteins. Similar findings have been reported for native and bioprosthetic cardiac valves surgically removed from patients without ESRD.
To determine whether valvular calcification in patients with ESRD is similar to that in patients without ESRD, we retrospectively examined surgically excised native cardiac valves of all hemodialysis patients and compared them pathologically with those of matched controls without renal failure. Valves were examined by using routine stains and immunohistochemistry for markers to endothelial cells, macrophages, B and T lymphocytes, alkaline phosphatase, osteopontin, and bone morphogenic protein 4.
Histologically, 7 of 10 valves from patients with ESRD had moderate to severe inflammation compared with 1 of 10 valves from control patients. Patients with ESRD had more endothelial cells/vascularity (P = 0.002) and macrophages (P = 0.069). There was no difference between the 2 groups with respect to B and T lymphocytes, alkaline phosphatase, osteopontin, or bone morphogenic protein 4.
The noncollagenous proteins bone morphogenic protein and osteopontin have been shown in surgically removed cardiac valves of patients with ESRD and the general population. However, valvular calcification in patients with ESRD is associated with enhanced inflammation, consistent with the previously reported greater C-reactive protein levels in this patient population and their increased risk for death.
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ABSTRACT: A high prevalence and a rapid progression of aortic valve stenosis (AS) in patients undergoing hemodialysis (HD) has been reported. In these circumstances, intraleaflet hemorrhage of aortic valve may be related to the development of AS in HD patients. We immunohistochemically examined the relationship among intraleaflet hemorrhage, neovascularization, hemoglobin scavenger receptor (CD163), and heme oxygenase-1 (HO-1) using surgically resected aortic valve specimens from AS patients undergoing HD. The study population consisted of 26 HD patients and 25 non-HD patients with severe AS who had undergone aortic valve replacement. Frozen aortic valve samples surgically obtained from AS patients were stained immunohistochemically with antibodies against smooth muscle cells, macrophages, glycophorin-A (a protein specific to erythrocyte membranes), CD31, CD163, and HO-1. Morphometric analysis demonstrated that the CD163-positive macrophage score, the number of CD31-positive microvessels, and the percentage of glycophorin-A and HO-1-positive area were significantly higher in HD patients than in non-HD patients (CD163-positive macrophage score, P < 0.0001; CD31-positive microvessels, P < 0.0001; glycophorin-A, P < 0.0001; HO-1, P < 0.0001). Double immunostaining for CD163 or HO-1 and macrophages revealed that the majority of CD163- or HO-1-positive cells were macrophages. Furthermore, CD163-positive macrophage score was positively correlated with glycophorin-A, HO-1-positive area, and the number of CD31-positive microvessels (glycophorin-A, R = 0.66, P < 0.0001; HO-1, R = 0.50, P < 0.0005; microvessels, R = 0.38, P < 0.01). These findings suggest a positive association among intraleaflet hemorrhage, neovascularization, and enhanced expression of CD163 and HO-1 as a response to intraleaflet hemorrhage in stenotic aortic valves in AS patients undergoing HD.Hemodialysis International 02/2014; DOI:10.1111/hdi.12147 · 1.36 Impact Factor
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ABSTRACT: The aim of this study was to determine the effects of advanced chronic kidney disease (CKD) on early and late outcomes after transcatheter aortic valve implantation (TAVI), and to evaluate the predictive factors of poorer outcomes in such patients. This was a multicentre study including a total of 2075 consecutive patients who had undergone TAVI. Patients were grouped according the estimated glomerular filtration rate as follows: CKD stage 1-2 (≥60 mL/min/1.73 m(2); n = 950), stage 3 (30-59 mL/min/1.73 m(2); n = 924), stage 4 (15-29 mL/min/1.73 m(2); n = 134) and stage 5 (<15 mL/min/1.73 m² or dialysis; n = 67). Clinical outcomes were evaluated at 30-days and at follow-up (median of 15 [6-29] months) and defined according to the VARC criteria. Advanced CKD (stage 4-5) was an independent predictor of 30-day major/life-threatening bleeding (P = 0.001) and mortality (P = 0.027), and late overall, cardiovascular and non-cardiovascular mortality (P < 0.01 for all). Pre-existing atrial fibrillation (HR: 2.29, 95% CI: 1.47-3.58, P = 0.001) and dialysis therapy (HR: 1.86, 95% CI: 1.17-2.97, P = 0.009) were the predictors of mortality in advanced CKD patients, with a mortality rate as high as 71% at 1-year follow-up in those patients with these 2 factors. Advanced CKD patients who had survived at 1-year follow-up exhibited both a significant improvement in NYHA class (P < 0.001) and no deterioration in valve hemodynamics (P = NS for changes in mean gradient and valve area over time). Advanced CKD was associated with a higher rate of early and late mortality and bleeding events following TAVI, with AF and dialysis therapy determining a higher risk in these patients. The mortality rate of patients with both factors was unacceptably high and this should be taken into account in the clinical decision-making process in this challenging group of patients.European Heart Journal 05/2014; DOI:10.1093/eurheartj/ehu175 · 14.72 Impact Factor
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ABSTRACT: Calcific aortic valve disease (CAVD) is an active process presumably triggered by interplays between cardiovascular risk factors, molecular signaling networks and hemodynamic cues. While earlier studies demonstrated that alterations in fluid shear stress (FSS) on the fibrosa could trigger inflammation, the mechanisms of CAVD pathogenesis secondary to side-specific FSS abnormalities are poorly understood. This knowledge could be critical to the elucidation of key CAVD risk factors such as congenital valve defects, aging and hypertension, which are known to generate FSS disturbances. The objective of this study was to characterize ex vivo the contribution of isolated and combined abnormalities in FSS magnitude and frequency to early valvular pathogenesis. The ventricularis and fibrosa of porcine aortic valve leaflets were exposed simultaneously to different combinations of sub-physiologic/physiologic/supra-physiologic levels of FSS magnitude and frequency for 24, 48 and 72 hours in a double cone-and-plate device. Endothelial activation and paracrine signaling were investigated by measuring cell-adhesion molecule (ICAM-1, VCAM-1) and cytokine (BMP-4, TGF-β1) expressions, respectively. Extracellular matrix (ECM) degradation was characterized by measuring the expression and activity of the proteases MMP-2, MMP-9, cathepsin L and cathepsin S. The effect of the FSS treatment yielding the most significant pathological response was examined over a 72-hour period to characterize the time-dependence of FSS mechano-transduction. While cytokine expression was stimulated under elevated FSS magnitude at normal frequency, ECM degradation was stimulated under both elevated FSS magnitude at normal frequency and physiologic FSS magnitude at abnormal frequency. In contrast, combined FSS magnitude and frequency abnormalities essentially maintained valvular homeostasis. The pathological response under supra-physiologic FSS magnitude peaked at 48 hours but was then maintained until the 72-hour time point. This study confirms the sensitivity of valve leaflets to both FSS magnitude and frequency and suggests the ability of supra-physiologic FSS levels or abnormal FSS frequencies to initiate CAVD mechanisms.PLoS ONE 12/2013; 8(12):e84433. DOI:10.1371/journal.pone.0084433 · 3.53 Impact Factor