. Apoptosis in the left ventricle of chronic volume overload causes endocardial endothelial dysfunction in rats. Am J Physiol Heart Circ Physiol 282: H1197-H1205, 2002. First published November 29, 2001 10.1152/ajpheart.00483.2001.-The hypothesis is that chronic increases in left ventricular (LV) load induce oxidative stress and latent matrix metalloproteinase (MMP) is activated, allowing the heart to dilate in the absence of endothelial nitric oxide (NO) and thereby reduce filling pressure. To create volume overload, an arteriovenous (A-V) fistula was placed in male Sprague-Dawley rats. To decrease oxidative stress and apoptosis, 0.08 mg/ml nicotinamide (Nic) was administered in drinking water 2 days before surgery. The rats were divided into the following groups: 1) A-V fistula, 2) A-V fistula ϩ Nic, 3) sham operated, 4) sham ϩ Nic, and 5) control (unoperated); n ϭ 6 rats/group. After 4 wk, hemodynamic parameters were measured in anesthetized rats. The heart was removed and weighed, and LV tissue homogeneates were prepared. A-V fistula caused an increase in heart weight, lung weight, and end-diastolic pressure compared with the sham group. The levels of malondialdehyde (MDA; a marker of oxidative stress) was 6.60 Ϯ 0.23 ng/mg protein and NO was 6.87 Ϯ 1.21 nmol/l in the LV of A-V fistula rats by spectrophometry. Nic treatment increased NO to 13.88 Ϯ 2.5 nmol/l and decreased MDA to 3.54 Ϯ 0.34 ng/mg protein (P ϭ 0.005). Zymographic levels of MMP-2 were increased, as were protein levels of nitrotyrosine and collagen fragments by Western blot analysis. The inhibition of oxidative stress by Nic decreased nitrotyrosine content and MMP activity. The levels of tissue inhibitor of metalloproteinase-4 mRNA were decreased in A-V fistula rats and increased in A-V fistula rats treated with Nic by Northern blot analysis. TdT-mediated dUTP nick-end labeling-positive cells were increased in A-V fistula rats and decreased in fistula rats treated with Nic. Acetylcholine and nitroprusside responses in cardiac rings prepared from the above groups of rats suggest impaired endothelial-dependent cardiac relaxation. Treatment with Nic improves cardiac relaxation. The results suggest that an increase in the oxidative stress and generation of nitrotyrosine are, in part, responsible for the activation of metalloproteinase and decreased endocardial endothelial function in chronic LV volume overload. nitric oxide; malondialdehyde; collagen degradation; tissue inhibitor of metalloproteinase; arteriovenous fistula; nicotinamide; NADH oxidase; nitrotyrosine; TUNEL; cardiac ring; acetylcholine; nitroprusside; stretch; contraction; relaxation; heart failure THE EXTRACELLULAR MATRIX (ECM), particularly type I fibrillar collagen surrounding the cardiomyocytes, helps the cardiac muscle to synchronize contraction and relaxation during systole and diastole, respectively (22,53,62). To compensate for the increase in workload and to reduce the wall stress, the cardiac muscle undergoes hypertrophy. This leads to remodeling of the ECM (54). Remodelin...
The HITECH Act has stimulated unprecedented, multi-stakeholder interest in HIT. Early experiences indicate that the resulting digital infrastructure is being used to improve quality of care and curtail costs. Reform efforts are however severely limited by problems with usability, limited interoperability and the persistence of the fee-for-service paradigm-addressing these issues therefore needs to be the federal government's main policy target.
The hypothesis is that homocysteine decreases endothelial nitric oxide (NO) availability by generating nitrotyrosine. In the absence of NO, and in an attempt to reduce endocardial load by dilatation, the matrix metalloproteinase (MMP) is activated. To address this hypothesis, homocysteine (0.67 mg/ml) was administered in drinking water of Sprague-Dawley rats for 8 weeks. To elicit the reversible effects of homocysteine, homocysteine was removed from the water after 8 weeks. The plasma levels of homocysteine were 2.79 +/- 0.5 microM in control (n = 6), measured by spectrofluorometry. The levels of homocysteine increased to 22 +/- 1.3 and 17 +/- 2.8 microM following 4 (n = 6) and 8 (n = 6) weeks of homocysteine treatment, respectively. The level of homocysteine decreased to 5.8 +/- 1.0 microM (n = 6) when homocysteine was removed from the drinking water. The mean arterial pressure (MAP) of control rats was 108 +/- 10 mm Hg and increased to 128 +/- 2 and 130 +/- 3 mm Hg following 4 and 8 weeks of homocysteine treatment, respectively. When homocysteine was removed from the drinking water, the MAP was decreased to 118 +/- 3 mm Hg. Left ventricle (LV) parameters were measured by a catheter in the LV through right common carotid artery in anesthetized rats. The LV tissue was analyzed for MMP activity by zymography. Levels of nitrotyrosine and cardiospecific tissue inhibitor of metalloproteinase-4 (TIMP-4/CIMP) were measured by western blot analysis using the respective antibodies. The specific bands in zymographic gel and western blot were scanned and normalized with beta-actin. The results suggest a continuous increase in nitrotyrosine levels at 4 and 8 weeks after homocysteine administration. The removal of homocysteine did not decrease the levels of nitrotyrosine. The zymographic analysis revealed a temporal increase in MMP-2 activity from 4 to 8 weeks post homocysteine administration. However, removal of homocysteine did not decrease the MMP-2 activity. The cardiac active diastolic function, -dP/dt, was decreased at 4 weeks and stayed depressed up to 12 weeks. The end-diastolic pressure started increasing at 8 weeks; at this point the MMP-2 activity was also increased. The results suggest that in the absence of endothelial NO, and in an attempt to reduce LV load, MMP-2 is activated and CIMP is inactivated, by increasing nitrotyrosine.
With increasing digitization of healthcare, real-world data (RWD) are available in greater quantity and scope than ever before. Since the 2016 United States 21st Century Cures Act, innovations in the RWD life cycle have taken tremendous strides forward, largely driven by demand for regulatory-grade real-world evidence from the biopharmaceutical sector. However, use cases for RWD continue to grow in number, moving beyond drug development, to population health and direct clinical applications pertinent to payors, providers, and health systems. Effective RWD utilization requires disparate data sources to be turned into high-quality datasets. To harness the potential of RWD for emerging use cases, providers and organizations must accelerate life cycle improvements that support this process. We build on examples obtained from the academic literature and author experience of data curation practices across a diverse range of sectors to describe a standardized RWD life cycle containing key steps in production of useful data for analysis and insights. We delineate best practices that will add value to current data pipelines. Seven themes are highlighted that ensure sustainability and scalability for RWD life cycles: data standards adherence, tailored quality assurance, data entry incentivization, deploying natural language processing, data platform solutions, RWD governance, and ensuring equity and representation in data.
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