Objectives The aim of this study was to determine whether oxidative stress is increased in calcified, stenotic aortic valves and to examine mechanisms that might contribute to increased oxidative stress. Background Oxidative stress is increased in atherosclerotic lesions and might play an important role in plaque progression and calcification. The role of oxidative stress in valve disease is not clear. Methods Superoxide (dihydroethidium fluorescence and lucigenin-enhanced chemiluminescence), hydrogen peroxide (H2O2) (dichlorofluorescein fluorescence), and expression and activity of pro- and anti-oxidant enzymes were measured in normal valves from hearts not suitable for transplantation and stenotic aortic valves that were removed during surgical replacement of the valve. Results In normal valves, superoxide levels were relatively low and distributed homogeneously throughout the valve. In stenotic valves, superoxide levels were increased 2-fold near the calcified regions of the valve (p < 0.05); noncalcified regions did not differ significantly from normal valves. Hydrogen peroxide levels were also markedly elevated in calcified regions of stenotic valves. Nicotinamide adenine dinucleotide phosphate oxidase activity was not increased in calcified regions of stenotic valves. Superoxide levels in stenotic valves were significantly reduced by inhibition of nitric oxide synthases (NOS), which suggests uncoupling of the enzyme. Antioxidant mechanisms were reduced in calcified regions of the aortic valve, because total superoxide dismutase (SOD) activity and expression of all 3 SOD isoforms was significantly decreased. Catalase expression also was reduced in pericalcific regions. Conclusions This study provides the first evidence that oxidative stress is increased in calcified regions of stenotic aortic valves from humans. Increased oxidative stress is due at least in part to reduction in expression and activity of antioxidant enzymes and perhaps to uncoupled NOS activity. Thus, mechanisms of oxidative stress differ greatly between stenotic aortic valves and atherosclerotic arteries.

The prophylactic administration of ganciclovir after heart transplantation is safe, and in CMV-seropositive patients it reduces the incidence of CMV-induced illness.

Background-Short-term variability of RR interval and blood pressure occurs predominantly at low frequency (LF; Ϸ0.1 Hz) and high frequency (Ϸ0.25 Hz). The arterial baroreflex is thought to be the predominant determinant of the LF component of RR variability. Patients with severe congestive heart failure (CHF) have an attenuated or absent LF oscillation in RR variability. The left ventricular assist device (LVAD) offers a unique possibility for analysis of spectral oscillations in RR interval independent of any effects of blood pressure that influence these oscillations via the baroreflex. Methods and Results-We performed spectral analysis of RR, blood pressure, and respiration in 2 patients with CHF before and after LVAD implantation. LF components of the RR-interval and blood pressure variability were absent in both CHF patients before LVAD implantation. After LVAD implantation, spectral analysis of the RR interval showed restoration of a clear and predominant LF oscillation in the native hearts of both patients, with no such oscillation evident in the blood pressure profile. Conclusions-During total circulatory support with the LVAD, the LF oscillation in RR interval of the native heart, absent in CHF, is restored. This LF oscillation in RR interval occurs in the absence of LF oscillations in blood pressure and thus is unlikely to be explained by baroreflex mechanisms. Hence, the absence of LF oscillation in the RR interval in CHF is functional and is reversible by LVAD circulation. The presence of a predominant LF oscillation in RR interval independent of any oscillation in blood pressure suggests that the LF oscillation is a fundamental property of central autonomic outflow. (Circulation. 1998;98:556-561.)

Background-Low-level endotoxemia (ie, Ն50 pg/mL) in apparently healthy subjects was recently identified as a powerful, independent risk factor for atherosclerosis. Methods and Results-We treated human saphenous veins (HSVs) with low levels of endotoxin. Release of the proinflammatory chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) was measured by ELISA. Superoxide was determined by using the fluorescent probe dihydroethidium (HE), and monocyte binding was assessed with calcein-labeled U-937 cells. Three-to 4-fold increases in MCP-1 and IL-8 release were observed at endotoxin concentrations of 100 pg/mL; these increases were inhibited by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin. Studies in cultured endothelial cells suggest that the mechanism is related to inhibition of isoprenylation (ie, geranylgeranylation) rather than cholesterol formation. Endotoxin produced dose-dependent increases in HE fluorescence that were inhibited by the superoxide dismutase mimics Tiron and MnTBAP. Endotoxin potently induced U-937 cell binding to HSV; binding was inhibited by both Tiron and atorvastatin. Toll-like receptor-4 expression was detected in cultured HSV endothelial and smooth muscle cells and in intact HSV. Key Words: toll-like receptor-4 Ⅲ superoxide Ⅲ monocytes Ⅲ saphenous veins Ⅲ atorvastatin A therosclerosis of coronary arteries and coronary bypass grafts frequently occurs in patients without traditional cardiac risk factors. 1 Inflammatory markers have been correlated with increased risk of cardiovascular events, 2 suggesting that chronic inflammation might play a major role in the development of atherosclerosis and restenosis in many patients. 3,4 The factors responsible for vascular inflammation in atherosclerosis, however, are largely unknown. Conclusions-ClinicallyOne potentially important proatherosclerotic factor is circulating endotoxin, a unique glycolipid that comprises most of the outer leaflet of the outer wall of Gram-negative bacteria (GNB 1 ). 5 This complex molecule, found exclusively in GNB, consists of a highly variable carbohydrate portion and a unique lipid A region that is highly conserved across many GNB species. 5 Epidemiologic evidence suggests that endotoxemia at levels of Ն50 pg/mL constitutes a strong risk factor for the development of atherosclerosis, particularly among smokers. 6,7 Moreover, chronic infections conferred an increased risk of atherosclerosis even in low-risk subjects who lacked conventional vascular disease risk factors. 6,7 Low levels of endotoxemia in apparently healthy subjects might result from chronic or recurrent infection associated with the breaching of epithelial barrier function (eg, periodontitis, smoker's bronchitis, diverticulitis, etc). The circulating endotoxin activates inflammatory cells (ie, macrophages and neutrophils) by binding to CD14 through a process that is modulated by lipopolysaccharide-binding protein. 8 CD14 has no intracellular domain and interacts with Toll-like receptor-4 (TLR-4) ...

The cost of long-term LVAD implantation is commensurate with other life-saving organ transplantation procedures like liver transplantation. As an evolving technology, there are a number of opportunities for improvement that will likely reduce costs in the future.