Background-Sympathetic tone is consistently raised in patients with end-stage renal disease (ESRD). We therefore tested the hypothesis that sympathetic activation is associated with mortality and cardiovascular events in a cohort of 228 patients undergoing chronic hemodialysis who did not have congestive heart failure at baseline and who had left ventricular ejection fraction Ͼ35%. Methods and Results-The plasma concentration of norepinephrine (NE) was used as a measure of sympathetic activity. Plasma NE exceeded the upper limit of the normal range (cutoff 3.54 nmol/L) in 102 dialysis patients (45%). In a multivariate Cox regression model that included all univariate predictors of death as well as the use of sympathicoplegic agents and -blockers, plasma NE proved to be an independent predictor of this outcome (hazard ratio [1-nmol/L increase in plasma NE]: 1.07, 95% CI 1.01 to 1.14, Pϭ0.03). Similarly, plasma NE emerged as an independent predictor of fatal and nonfatal cardiovascular events (hazard ratio [1-nmol/L increase in plasma NE] 1.08, 95% CI 1.02 to 1.15, Pϭ0.01) in a model that included previous cardiovascular events, pulse pressure, age, diabetes, smoking, and use of sympathicoplegic agents and -blockers. The adjusted relative risk for cardiovascular complications in patients with plasma NE Ͼ75th percentile was 1.92 (95% CI 1.20 to 3.07) times higher than in those below this threshold (Pϭ0.006). Conclusions-Sympathetic nerve overactivity is associated with mortality and cardiovascular outcomes in ESRD.Controlled trials with antiadrenergic drugs are needed to determine whether interference with the sympathetic system could reduce the high cardiovascular morbidity and mortality in dialysis patients.
Changes in LVMI have an independent prognostic value for cardiovascular events and provide scientific support to the use of repeated echocardiographic studies for monitoring cardiovascular risk in dialysis patients.
Abstract-Cardiac fibroblasts (CFs) produce extracellular matrix proteins and participate in the remodeling of the heart.It is unknown if brain natriuretic peptide (BNP) is synthesized by CFs and if BNP participates in the regulation of extracellular matrix turnover. In this study, we examined the production of BNP in adult canine CFs and the role of BNP and its signaling system on collagen synthesis and on the activation of matrix metalloproteinases (MMPs Key Words: cardiac fibroblasts Ⅲ extracellular matrix Ⅲ remodeling Ⅲ cGMP Ⅲ protein kinase G T he cardiac interstitium is a dynamic structure, as reflected by continuous synthesis and degradation of matrix proteins. The family of matrix metalloproteinases (MMPs) consists of more than 20 different zinc-containing, Ca 2ϩ -dependent endopeptidases. 1,2 They degrade matrix proteins and therefore play an important role in the physiological regulation of the interstitium. The interstitial collagenases (MMP-1 and MMP-13), the stromelysin (MMP-3), the gelatinases (MMP-2 and MMP-9), and membranous-type 1 MMPs (MMP-14; MT1-MMP) have been demonstrated within the mammalian myocardium. 2 Furthermore, dysregulation of MMP proteins and their endogenous inhibitor, tissue inhibitors of MMP (TIMP), has been observed in the hypertensive and the failing heart, suggesting an important role of MMP in the process of ventricular remodeling. [3][4][5][6][7] Cardiac fibroblasts (CFs) play a crucial role in the regulation of the extracellular matrix (ECM) of the heart by synthesizing collagen and other matrix proteins as well as promoting their degradation by secreting MMP proteins. In response to myocardial injury, activation of CFs occurs. These activated CFs (myofibroblasts) have special morphological and functional characteristics. 8,9 The natriuretic peptides (NPs) atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) play important roles in maintaining cardiorenal homeostasis under physiological and pathological conditions. 10 ANP and BNP are synthesized by cardiomyocytes, and their production is stimulated in pathologic conditions such as myocardial infarction (MI), cardiac hypertrophy, and heart failure (HF). 11-13 ANP and BNP have natriuretic, vasodilating, and lusitropic properties, and they inhibit the sympathetic and renin-angiotensin-aldosterone system. 14,15 These actions are primarily mediated by the second messenger cGMP. 16 Cameron et al 17 have recently reported that ANP is produced in CFs after MI, indicating that fibroblasts, like cardiomyocytes, can be a source of NPs. However, it remains unknown if BNP is produced by CFs.Although it is well established that BNP has growthinhibiting properties in the heart, 18 -21 the role of BNP on the regulation of the cardiac interstitium remains undefined. Given the widespread cross-talk of the NPs with other systems that are activated in cardiorenal disorders, we aimed to investigate whether CFs are a source of BNP and whether BNP and its signaling system contribute to the regulation of Original
Hypertension and heart failure (HF) are common diseases that, despite advances in medical therapy, continue to be associated with high morbidity and mortality. Therefore, innovative therapeutic strategies are needed. Inhibition of the neutral endopeptidase (NEPinh) had been investigated as a potential novel therapeutic approach because of its ability to increase the plasma concentrations of the natriuretic peptides (NPs). Indeed, the NPs have potent natriuretic and vasodilator properties, inhibit the activity of the renin-angiotensin-aldosterone system, lower sympathetic drive, and have antiproliferative and antihypertrophic effects. Such potentially beneficial effects can be theoretically achieved by the use of NEPinh. However, studies have shown that NEPinh alone does not result in clinically meaningful blood pressure-lowering actions. More recently, NEPinh has been used in combination with other cardiovascular agents, such as angiotensin-converting enzyme inhibitors, and antagonists of the angiotensin receptor. Another future possible combination would be the use of NEPinh with NPs or their newly developed chimeric peptides. This review summarizes the current knowledge of the use and effects of NEPinh alone or in combination with other therapeutic agents for the treatment of human cardiovascular disease such as HF and hypertension.
There is a clear association between hyperhomocysteinemia and incident cardiovascular mortality and atherothrombotic events in hemodialysis patients. Intervention studies are needed to determine whether the accumulation of this substance has a causal role in the pathogenesis of cardiovascular damage in patients undergoing hemodialysis.
Reduced cardiac contractility during heart failure (HF) is linked to impaired Ca2+ release from Ryanodine Receptors (RyRs). We investigated whether this deficit can be traced to nanoscale RyR reorganization. Using super-resolution imaging, we observed dispersion of RyR clusters in cardiomyocytes from post-infarction HF rats, resulting in more numerous, smaller clusters. Functional groupings of RyR clusters which produce Ca2+ sparks (Ca2+ release units, CRUs) also became less solid. An increased fraction of small CRUs in HF was linked to augmented ‘silent’ Ca2+ leak, not visible as sparks. Larger multi-cluster CRUs common in HF also exhibited low fidelity spark generation. When successfully triggered, sparks in failing cells displayed slow kinetics as Ca2+ spread across dispersed CRUs. During the action potential, these slow sparks protracted and desynchronized the overall Ca2+ transient. Thus, nanoscale RyR reorganization during HF augments Ca2+ leak and slows Ca2+ release kinetics, leading to weakened contraction in this disease.
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