Upregulated microRNAs in membranous glomerulonephropathy are associated with significant downregulation of IL6 and MYC mRNAs.

Membranous glomerulonephropathy (MGN) is a glomerulopathy characterized by subepithelial deposits of immune complexes on the extracapillary side of the glomerular basement membrane. Insertion of C5b-9 (complement membrane-attack complex) into the membrane leads to functional impairment of the glomerular capillary wall. Knowledge of the molecular pathogenesis of MGN is actually scanty. MicroRNA (miRNA) profiling in MGN and unaffected tissues was performed by TaqMan Low-Density Arrays. Expression of miRNAs and miRNA targets was evaluated in Real-Time polymerase chain reaction (PCR). In vitro transient silencing of miRNAs was achieved through transfection with miRNA inhibitors. Ten miRNAs (let-7a-5p, let-7b-5p, let-7c-5p, let-7d-5p, miR-107, miR-129-3p, miR-423-5p, miR-516-3p, miR-532-3p, and miR-1275) were differentially expressed (DE) in MGN biopsies compared to unaffected controls. Interleukin 6 (IL6) and MYC messenger RNAs (mRNAs; targets of DE miRNAs) were significantly downregulated in biopsies from MGN patients, and upregulated in A498 cells following let-7a-5p or let-7c-5p transient silencing. Gene ontology analysis showed that DE miRNAs regulate pathways associated with MGN pathogenesis, including cell cycle, proliferation, and apoptosis. A significant correlation between DE miRNAs and mRNAs and clinical parameters (i.e., antiphospholipid antibodies, serum creatinine, estimated glomerular filtration, proteinuria, and serum cholesterol) has been detected. Based on our data, we propose that DE miRNAs and their downstream network may be involved in MGN pathogenesis and could be considered as potential diagnostic biomarkers of MGN.

Pulse wave velocity differs between ulcerative colitis and chronic kidney disease.

BACKGROUND: We hypothesized that a reversal of the physiological stiffness gradient, previously reported in end-stage renal disease, begins in the early stages of chronic kidney disease (CKD) and that chronic inflammation produces a different arterial phenotype in patients with ulcerative colitis (UC). OBJECTIVES: To assess the extent of arterial stiffening in the central (carotid-femoral pulse wave velocity, cf.-PWV) and peripheral arteries (carotid-radial pulse wave velocity, cr-PWV) and to explore the determinants of the stiffness gradient in UC and in CKD. METHODS: We enrolled 45 patients with UC, 45 patients with stage 3-4 CKD and 45 matched controls. RESULTS: Despite the comparable cf.-PWV, the cr-PWV was higher in patients with UC than in those with CKD (median: 8.7 vs. 7.5m/s; p<0.001) and, consequently, the PWV ratio was lower (median: 0.97 vs. 1.12; p<0.001). In patients with CKD a stiffness mismatch was reported starting from stage 3B. The PWV ratio was associated with age and C-reactive protein (beta: 0.08 z-score, 95%CI 0.02-0.14; p=0.01) or active disease (beta: 0.43 z-score, 95%CI 0.003-0.857; p=0.048) in patients with UC and with age and glomerular filtration rate (beta: -0.56 z-score, 95%CI -1.05 to -0.07; p=0.02) in patients with CKD. CONCLUSIONS: The arterial phenotype differed between UC and CKD. The reversal of the arterial stiffness gradient is evident in CKD patients starting from stage 3B but not in patients with UC and comparable cf.-PWV. In patients with UC, the stiffness of both elastic and muscular arteries is increased as a consequence of inflammation.

Phosphodiesterase type 5 inhibition improves arterial stiffness after exercise but not exercise capacity in hypertensive men.

BACKGROUND: Established hypertension is associated with abnormal exercise hemodynamics and reduced exercise capacity through mechanisms that may include contributions from arterial stiffness and endothelial vasomotor dysfunction. Phosphodiesterase type 5 (PDE5) inhibitors prolong nitric oxide-mediated cyclic guanosine monophosphate (cGMP) signaling in vascular smooth muscle, and have beneficial effects on exercise tolerance in pulmonary hypertension and heart failure. Recent studies suggest they may also be useful antihypertensive agents. We hypothesized they would reduce arterial stiffness and increase exercise capacity in hypertensive men. METHODS: In a 3-way, randomized, placebo-controlled study, 15 untreated hypertensive and 15 matched normotensive male subjects received 50mg sildenafil (PDE5 inhibitor), 25mg hydralazine (control, cGMP-independent vasodilator) or placebo, 3 times daily for 1 week, and the effects on exercise blood pressure (during modest and maximal exercise), peak oxygen uptake, and arterial stiffness were investigated. RESULTS: Peak oxygen uptake was significantly lower in hypertensive than normotensive subjects (analysis of variance [ANOVA] P < 0.0001), but not affected by sildenafil in either group. However, while pulse wave velocity, as a measure of arterial stiffness, increased after exercise in hypertensive men following placebo, sildenafil reversed these changes, significantly reducing pulse wave velocity compared with both placebo and hydralazine (ANOVA P = 0.0001). CONCLUSIONS: PDE5 inhibition with sildenafil did not improve exercise capacity in hypertensive men. Nevertheless, our findings suggest that sildenafil may reduce arterial stiffness in the recovery period after exercise.

Long-term cardiac pro-B-type natriuretic peptide gene delivery prevents the development of hypertensive heart disease in spontaneously hypertensive rats.

BACKGROUND: Diastolic dysfunction associated with high blood pressure (BP) leads to cardiac remodeling and fibrosis and progression to congestive heart failure. B-type natriuretic peptide (BNP) has BP-lowering, antifibrotic, and antihypertrophic properties, which makes BNP an attractive agent for attenuating the adverse cardiac remodeling associated with hypertension. In the current study, we tested the effects of sustained cardiac proBNP gene delivery on BP, cardiac function, and remodeling in spontaneously hypertensive rats (SHR). METHODS AND RESULTS: We used the myocardium-tropic adeno-associated virus serotype 9 (AAV9) vector to achieve continuously enhanced cardiac rat proBNP expression. In SHR, a single systemic administration of AAV9 vector allowed long-term cardiac BNP overexpression, resulting in reductions in systolic and diastolic BP for 9 months after injection. Left ventricular (LV) thickness, LV end-systolic dimensions, and LV mass were reduced, whereas ejection fraction was significantly increased, in BNP-treated compared with untreated SHR. Circumferential systolic strain and strain rate of the early phase of diastole were improved in BNP-treated compared with untreated SHR. Noncardiac overexpression of BNP via AAV2 vector was not associated with changes in BP and plasma BNP in SHR. Furthermore, normal Wistar rats injected with AAV9 proBNP vector showed significantly reduced heart weights 4 weeks after injection without BP reduction. CONCLUSIONS: AAV9 vector facilitates sustained cardiac proBNP overexpression and improves LV function in hypertensive heart disease. Long-term proBNP delivery improved both systolic and diastolic function. The effects on cardiac structure and function occurred independently of BP-lowering effects in normal Wistar rats.

Neuropeptide Y receptor Y2 gene polymorphism interacts with plasma neuropeptide Y levels in predicting left ventricular hypertrophy in dialysis patients.

BACKGROUND: Neuropeptide Y (NPY) is a sympathetic neurotransmitter that acts on multiple receptors involved in cardiovascular remodelling and angiogenesis. Plasma levels of NPY are increased in patients with end-stage renal disease (ESRD) and are independently related to left ventricular hypertrophy (LVH) and incident cardiovascular events in these patients. OBJECTIVE: To investigate the relationship between NPY receptor Y2 gene polymorphism and left ventricular mass index (LVMI) as well as the interaction between this polymorphism and plasma NPY in determining LVH in 189 ESRD patients. RESULTS: LVMI was significantly higher (+12%, P = 0.03) in patients carrying the C allele than in those without C allele and was linearly associated with plasma NPY (P = 0.01). Interaction analysis showed a significant NPY-LVMI relationship in patients with the C allele, both at univariate (r = 0.27, P = 0.001) and multivariate (r = 0.21, P = 0.01) analyses, whereas no such relationship existed in patients without this allele. In fully adjusted analyses, a 10 pmol/l increase in plasma NPY entailed a 4.9 g/m increase in LVMI in patients with C allele, whereas the same change in NPY levels did not modify the NPY-LVMI link in patients without such allele (P = 0.009). CONCLUSION: NPY receptor Y2 polymorphism is independently associated with LVMI and interacts with plasma levels of NPY in explaining the variability of LVH in ESRD. These results offer a genetic basis to the hypothesis that NPY is causally implicated in the pathogenetic pathway leading to LVH in ESRD patients.

The prevalence of the cardiac origin of chest pain: the experience of a rural area of southeast Italy.

This study was designed to assess the application of diagnostic guidelines to the management of chest pain by an observational study carried out in a small town (Ragusa) of southeast Sicily. This study was an attempt to compare a Sicilian experience with the literature. In this observational study, we examined all the patients referred for chest pain to the Emergency Department (ED) of "Civile-M. P. Arezzo" Hospital during a period of 6 months (from January 1st 2008 to June 30th 2008). As much as 857 patients were studied. The results of our study show that musculoskeletal chest pain is the most common final diagnosis (49%), followed by cardiac chest pain (26.3%), gastrointestinal chest pain (13%), pulmonary chest pain (7%) and psychiatric chest pain (4%). The majority of patients (95%) never made contact with their primary care providers, and came straight to ED. These results emphasize the need for reworking a strategy to avoid the situation in which all cases of non-emergency chest pain, such as musculoskeletal ones, come to the hospital for evaluation, thereby overwhelming the ED, particularly in rural areas where the management of any emergency is centralized in a single hospital.

Soluble e-selectin is an inverse and independent predictor of left ventricular wall thickness in end-stage renal disease patients.

BACKGROUND: E-selectin is a specific endothelial cell product involved in leukocyte recruitment on the endothelium, which is an important early step in the reparative process following vascular damage. In end-stage renal disease (ESRD), the relationship of E-selectin with left ventricular function has been so far neglected. METHODS: We studied 237 patients on chronic dialysis (200 on hemodialysis, 37 on continuous ambulatory peritoneal dialysis) for at least 6 months, without clinical evidence of heart failure. On a mid-week non-dialysis day, fasting blood sampling and echocardiography were performed. RESULTS: Left ventricular mass index (LVMI, corrected for height) was inversely related to E-selectin levels, increasing from 56.8 +/- 18.9 (>75th percentile E-selectin tertile) to 66.7 +/- 20.1 g/m(2.7) (<50th percentile E-selectin tertile) (p = 0.002). However, in multiple regression models, including traditional (age, sex, smoking, diabetes, systolic blood pressure, hemoglobin, albumin, previous cardiovascular events) and emerging (asymmetric dimethylarginine, interleukin-6) risk factors associated with ESRD, soluble E-selectin has proved to be a significant inverse and independent predictor of mean wall thickness, but not of LVMI. CONCLUSION: This study demonstrates that soluble E-selectin is inversely associated with the muscular component of the left ventricle, thereby suggesting that the lack of such a reparative factor may be associated with cardiac remodeling in ESRD patients.

Vascular endothelial growth factor, left ventricular dysfunction and mortality in hemodialysis patients.

OBJECTIVES: Vascular endothelial growth factor induces nitric oxide-dependent angiogenic effects and participates in the inflammatory response. This cytokine is over-expressed in the myocardium in experimental models of pressure overload and renal mass ablation, and vascular endothelial growth factor is increased in end-stage renal disease. We investigated the relationship between vascular endothelial growth factor, left ventricular function (by midwall fractional shortening) and mortality in a prospective cohort study in 228 hemodialysis patients. RESULTS: Serum vascular endothelial growth factor concentration was associated directly with interleukin-6 and tumor necrosis factor-alpha (P < 0.01) and inversely with albumin (P = 0.007) but was independent of the endogenous inhibitor of nitric oxide synthesis, asymmetric dimethylarginine. Vascular endothelial growth factor was inversely related with midwall fractional shortening (P = 0.002) and predicted mortality (P = 0.02). In multivariate analyses testing the involvement of this angiogenic cytokine in left ventricular dysfunction and death, these links remained substantially unmodified after adjustment for Framingham risk factors, risk factors peculiar to end-stage renal disease (Hb, Ca, P) and previous cardiovascular complications. However, these links became weaker and not significant when biomarkers of inflammation and asymmetric dimethylarginine were sequentially introduced into the multivariate models. In crude and adjusted analyses, left ventricular function was lowest in patients who displayed both high vascular endothelial growth factor and high asymmetric dimethylarginine, intermediate in patients with either high vascular endothelial growth factor or high asymmetric dimethylarginine and highest in those with low asymmetric dimethylarginine and low vascular endothelial growth factor (P = 0.001). CONCLUSION: Vascular endothelial growth factor is associated with left ventricular systolic dysfunction and mortality in hemodialysis patients. Vascular endothelial growth factor appears to be in the pathway whereby inflammation and nitric oxide inhibition lead to cardiomyopathy and death in hemodialysis patients.

Coronary heart disease extension as a predictor of atherosclerotic renal artery stenosis.

BACKGROUND: Although the association of renal artery stenosis with coronary artery disease is well established, the best cutoff of diseased coronary vessels predicting atherosclerotic narrowing of renal artery remains still undefined. METHODS: In 109 consecutive patients (78/31 M/F) submitted to elective coronary angiography because of effort angina, renal angiography was also performed in the same session. We considered only renal artery stenosis > or =60% to be of clinical relevance. RESULTS: Coronary artery stenosis was present in 87 patients (80%), while significant narrowing of renal arteries was found in 42 patients (39%). On univariate analysis, the odds ratio (OR) of renal artery stenosis associated with 1 stenotic coronary vessel was 1.76 (95% confidence interval [95% CI], 1.34-2.33, p<0.001). This estimate was confirmed in a multiple logistic regression model adjusting for a series of potential confounders (OR=1.83, 95% CI, 1.34-2.48, p<0.001). On receiver operating characteristic curve analysis (area under the curve: 0.74 +/- 0.05, p<0.001), the presence of 3 diseased coronary vessels provided the best cutoff for the diagnosis of concomitant renal artery stenosis (positive predictive value: 63%; negative predictive value: 76%). CONCLUSIONS: There is a strong parallelism between the number of diseased coronary vessels and the occurrence of renal vascular disease. The presence of 3 diseased coronary vessels may corroborate the decision of performing renal angiography in patients with ischemic heart disease.

Contribution of the M3 muscarinic receptors to the vasodilator response to acetylcholine in the human forearm vascular bed.

AIMS: Acetylcholine (ACh) is a muscarinic agonist that causes receptor-mediated, endothelium-dependent vasodilatation in the forearm vasculature. Previous indirect evidence suggests this effect may be mediated by muscarinic M(3) receptors. Darifenacin is a recently developed antimuscarinic drug with greater M(3) selectivity, and our main objective was to investigate whether darifenacin affects dose-dependent vasodilatation to ACh in the forearm circulation. METHODS: Healthy subjects were enrolled in two studies designed to assess the effects of atropine and darifenacin on the forearm blood flow (FBF) response to ACh. RESULTS: In both studies ACh caused similar dose-dependent vasodilation in the forearm vasculature. In study I (5 subjects), the FBF response to ACh was largely attenuated by pretreatment with the nonselective muscarinic antagonist atropine. In study II (10 subjects), oral administration of darifenacin 15 mg for 1 week significantly reduced the FBF dose-dependent response to ACh 20 microg min(-1) (mean difference from placebo 5.8 [95% confidence interval (CI) 3.1, 8.7] ml min(-1) per 100 ml of forearm volume, P < 0.001) and to ACh 60 microg min(-1)[mean difference from placebo 5.9 (95% CI 3.1, 8.7) ml min(-1) per 100 ml of forearm volume, P < 0.001]. After darifenacin, the AUC of change in FBF from baseline was reduced by almost 50% compared with placebo. CONCLUSIONS: These results suggest that, in the forearm vasculature, muscarinic M(3) receptors play a major role in ACh-induced endothelium-mediated vasodilatation.

Phosphodiesterase type 5 inhibition reverses impaired forearm exercise-induced vasodilatation in hypertensive patients.

OBJECTIVE: Established hypertension is characterized by increased peripheral vascular resistance and endothelial dysfunction, features that may underlie the reduced exercise-induced vasodilatation seen in hypertensive patients. Sildenafil citrate is a phosphodiesterase type 5 (PDE5) inhibitor used clinically for the treatment of male erectile dysfunction. Its vasodilating properties are due to the inhibition of cyclic guanosine monophosphate (cGMP) breakdown and prolongation of the signalling actions of the nitric oxide (NO)-cGMP pathway in vascular smooth muscle cells. Sildenafil has beneficial effects on endothelial function and exercise tolerance in congestive heart failure and pulmonary hypertension, and we hypothesized that it would improve exercise-induced vasodilatation in hypertensive patients. METHODS AND RESULTS: Ten hypertensive patients and ten matched normotensive subjects were studied in a three-way, randomized, single-blind and placebo-controlled study. On each study day, forearm blood flow (FBF) responses to handgrip exercise were assessed before and after intra-arterial (brachial) infusion of sildenafil, verapamil (a control, cGMP-independent vasodilator), and saline (placebo). Preinfusion exercise-induced vasodilatation was significantly reduced in hypertensive patients compared to normotensive controls. Sildenafil and verapamil infusions both caused a similar increase in baseline FBF. However, while verapamil did not affect the vasodilator response to handgrip exercise in either group, sildenafil substantially enhanced this response in hypertensive patients, but not in normotensive subjects. CONCLUSIONS: Our data suggest that sildenafil, through an increase in cGMP levels in the vasculature, substantially and selectively improves the vasodilator response to handgrip exercise in hypertensive patients. These findings represent an essential first step in support of further studies exploring the potentially beneficial effects of PDE5 inhibition on impaired exercise capacity in hypertension.

Pulse pressure is an independent predictor of aortic stiffness in patients with mild to moderate chronic kidney disease.

BACKGROUND: In patients with end-stage renal disease pulse wave velocity (PWV) has been widely assessed, but its behavior in mild to moderate chronic kidney disease (CKD) has been less investigated. We evaluated PWV in mild to moderate CKD. METHODS: We studied 31 patients with grade II-IV CKD. Aortic PWV (aPWV), aortic and upper limb augmentation index, creatinine clearance, C-reactive protein, serum fibrinogen, interleukin-1, interleukin-6, tumor necrosis factor, albumin, total and high-density lipoprotein cholesterol and blood pressure were evaluated. RESULTS: aPWV (7.95 +/- 0.64 m/s), but not augmentation index was significantly higher (p = 0.03) in CKD patients than age-matched healthy subjects (aPWV: 6.24 +/- 0.43 m/s; upper limb: 32.8 +/- 1.9; aortic: 27.7 +/- 1.9). At univariate regression analysis, aPWV was significantly correlated with age (r = 0.44; p = 0.013), interleukin-6 (r = 0.43; p = 0.027), pulse (r = 0.39; p = 0.029), systolic blood pressure (r = 0.37; p = 0.038) and tumor necrosis factor (r = 0.39; p = 0.029). At multivariate analysis, pulse pressure was the only significant independent determinant (beta = 0.37; p = 0.05) of aPWV. CONCLUSION: The results of this study confirm an aPWV increase in mild to moderate CKD and emphasize association between pulse pressure and PWV, independently of renal failure.

Lack of activation of molecular forms of the BNP system in human grade 1 hypertension and relationship to cardiac hypertrophy.

We evaluated relationships among two circulating molecular forms of brain natriuretic peptide (BNP32 and NT-proBNP), severity of hypertension (HTN), and cardiac hypertrophy in subjects with mild, moderate, and severe HTN. We prospectively studied 78 patients (43 males; mean age 51.4 +/- 11 yr) with essential HTN and 28 age- and sex-matched controls. BNP32 and NT-proBNP were measured by radioimmunoassay. In grade 1 HTN, BNP32 was not elevated and NT-proBNP was reduced (P = 0.030) compared with controls. However, log-transformed values of BNP32 and NT-proBNP were both increased with severity of HTN from grade 1 to 3 (P <0.0001 and P = 0.003, respectively). By multivariate analysis, log BNP32 was independently predicted by age (beta = 0.210, P = 0.026) and HTN grade (beta = 0.274, P = 0.004), whereas log NT-proBNP was independently predicted by sex (beta = 0.235, P = 0.012) and HTN grade (beta = 0.218, P = 0.0023). Two forms of BNP were measured in normal subjects and patients with essential HTN. In grade 1 HTN, BNP32 was unchanged and NT-proBNP was significantly reduced compared with controls. As severity increased in humans with grade 1 to 3 HTN, both BNP32 and NT-proBNP levels were increased while not being affected by the presence of left ventricular hypertrophy. The lack of activation of BNP32 together with the reduction of NT-proBNP in grade 1 HTN may represent an impaired response of the BNP system in the early phase of HTN. The later activation of both forms of BNP may be a late compensatory effect, because it correlates with severity of HTN rather than cardiac hypertrophy/remodeling.

Left ventricular systolic function monitoring in asymptomatic dialysis patients: a prospective cohort study.

Although it is well established that compromised systolic function predicts cardiovascular (CV) complications in symptomatic and asymptomatic patients with ESRD, it still is unknown whether repeated echocardiographic measurements of systolic function in asymptomatic patients with ESRD is useful for monitoring the evolution of cardiomyopathy in these patients. The prognostic value for CV events of changes in systolic function, as measured by midwall fractional shortening (mwFS) in a cohort of 191 dialysis patients, was tested. Echocardiography was performed twice, 17 +/- 2 mo apart. Changes in mwFS (ch-mwFS) that occurred between the second and the first echocardiographic studies then were used to predict CV events during the ensuing 27 +/- 13 mo. After the second echocardiographic study, 85 patients had incident CV events. In a Kaplan-Meier analysis, there was a graded increase in the risk for fatal and nonfatal CV events across ch-mwFS quartiles (P = 0.005). On multivariate Cox regression analysis, ch-mwFS maintained an independent association with CV outcomes. In this analysis, the risk for CV events was 51% lower in patients who manifested an increase in mwFS (hazard ratio 0.49; 95% confidence interval 0.27 to 0.88; P = 0.02) than in those who had a decrease in mwFS. Changes in mwFS have an independent prognostic value for CV events, and periodic echocardiographic studies of systolic function are useful for monitoring asymptomatic dialysis patients.

The E-selectin gene polymorphism and carotid atherosclerosis in end-stage renal disease.

BACKGROUND: E-selectin is a cell surface glycoprotein that mediates the adhesion of leucocytes to vessels endothelium, an important early step in the atherosclerotic process. End-stage renal disease (ESRD) is a highly atherogenic disease but it is unknown whether genetic polymorphism(s) in the E-selectin gene plays a role in the severity of arterial damage in this condition. Method. In this study, we tested whether the Leu554Phe variant in the E-selectin gene is linked to carotid atherosclerosis in 134 well-characterized ESRD patients. The frequency of this polymorphism was also measured in a population sample of the same geographical area. RESULTS: A total of 84% patients had the CC genotype, 13% had the CT genotype, 3% had the TT genotype and this distribution did not differ from that in the control population. Intima-media thickness (IMT) (P = 0.01) and cross-sectional area (P = 0.02) were significantly higher in patients with the T-allele than in those without this allele. Furthermore, the degree of carotid stenosis was significantly higher (P = 0.02) in patients with T-allele than in CC patients. On multivariate analyses including the traditional and non-traditional risk factors, the Leu554Phe polymorphism was confirmed as an independent correlate of IMT (P = 0.02), cross-sectional area (P = 0.03) and carotid stenosis (P = 0.02). CONCLUSION: In ESRD, the Leu554Phe polymorphism of E-selectin gene is associated with the severity of carotid atherosclerosis, suggesting that genetically-determined alterations in the E-selectin molecule may render ESRD patients with this gene variant particularly susceptible to the detrimental effects of inflammation on the arterial wall.

Prognostic value of combined use of biomarkers of inflammation, endothelial dysfunction, and myocardiopathy in patients with ESRD.

BACKGROUND: Cardiovascular risk stratification is important in the clinical management of patients with end-stage renal diseases (ESRD) and biomarkers are increasingly used in these patients. METHODS: In a cohort of 246 dialysis patients without heart failure at baseline we tested the combined prognostic power of three well-established biomarkers: brain natriuretic peptide (BNP), C-reactive protein (CRP), and asymmetric dimethyl arginine (ADMA). The independent prognostic value of individual and combined biomarkers was estimated in separate Cox models, including standard risk factors in dialysis patients and comorbidities. RESULTS: When the prediction power of the three biomarkers was evaluated individually, BNP, ADMA, and CRP added significant predictive value (P< or = 0.01) to all-cause and cardiovascular mortality models and the explanatory gain attributable to these biomarkers were of similar degree (ranging from 3.3% to 5.7%). When the biomarkers were evaluated jointly, a score based on the BNP-CRP combination, increased by 9.9% (all-cause) and by 10.5% (cardiovascular) the explained mortality variance of standard Cox models and such gain in power was similar to that achieved by the CRP-ADMA combination (all-cause death 9.0% and cardiovascular death 8.4%). Of note, the explanatory gain derived by the simultaneous use of the three biomarkers was very similar (all-cause death 11.6% and cardiovascular death 10.5%) to that achieved by the use of two biomarkers. CONCLUSION: These findings indicate a potential role for CRP, BNP, and ADMA to be incorporated into diagnostic and therapeutic strategies aimed at detection and treatment of atherosclerotic complications and at preventing heart failure in the dialysis population.

Left ventricular mass monitoring in the follow-up of dialysis patients: prognostic value of left ventricular hypertrophy progression.

BACKGROUND: Regression of left ventricular hypertrophy (LVH) in the setting of a well-planned intervention study has been associated with longer survival in hemodialysis patients. Whether changes in left ventricular mass (LVM) in clinical practice predict survival and cardiovascular events in these patients is still unknown. METHODS: In a prospective study in 161 hemodialysis patients we tested the prognostic value of changes in LVM on survival and incident cardiovascular events. Echocardiography was performed twice, 18 +/- 2 SD months apart. Changes in LVM occurring between the first and the second echocardiographic study were then used to predict mortality and cardiovascular events during the ensuing 29 +/- 13 months. The prognostic value of LVM changes was tested in a multivariate Cox's model with LVM index (LVMI) [expressed as LVM/height(2.71)], included as a covariate to control for regression to the mean. RESULTS: The rate of increase of LVMI was significantly (P= 0.029) higher in patients with incident cardiovascular events than in those without such events. Accordingly, cardiovascular event-free survival in patients with changes in LVMI below the 25th percentile was significantly (P= 0.004) higher than in those with changes above the 75th percentile. In a multiple Cox regression analysis, including age, diabetes, smoking, homocysteine, 1 g/m(2.7)/month increase in LVMI was associated with a 62% increase in the incident risk of fatal and nonfatal cardiovascular events [hazard ratio 1.62 (95% CI 1.13-2.33), P= 0.009]. CONCLUSION: 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.

Prognostic value of echocardiographic indicators of left ventricular systolic function in asymptomatic dialysis patients.

Patients with end-stage renal disease (ESRD) are at high risk for heart failure, but the prevalence and the prognostic value of asymptomatic systolic dysfunction in these patients are unknown. In this prospective cohort study, the authors have therefore assessed by echocardiography the prevalence and the prognostic value of systolic function as estimated by ejection fraction (EF), fractional shortening at endocardial level (endoFS), and at midwall (mwFS), in a cohort of 254 asymptomatic dialysis patients. Systolic dysfunction had a prevalence rate of 26% by endoFS and of 48% by mwFS. During the follow-up period, 125 patients had one or more fatal and nonfatal CV events. On multivariate COX regression analysis, the three LV systolic function indicators were independently associated with incident fatal and nonfatal CV events, and there were no differences in the predictive power of these indicators (P > 0.30). The prediction power of LV function indicators was largely independent of traditional and novel risk factors in ESRD such as C-reactive protein and asymmetric dimethyl arginine (ADMA). ADMA was significantly related with LV function indicators as well as with mortality and incident CV events, but these links were much reduced (P = NS) in models including LV function indicators. Of note, the risk of CV events was minimal in patients with normal LV mass and function, intermediate in patients with either LVH or systolic dysfunction, and maximal in patients displaying both alterations. The study of myocardial contractility by echocardiography provides prognostic information independently of LV mass and other risk factors in ESRD. Risk stratification by simple systolic function parameters may prove useful in secondary prevention strategies in these patients.

Brain natriuretic peptide enhances renal actions of furosemide and suppresses furosemide-induced aldosterone activation in experimental heart failure.

BACKGROUND: The renal actions of brain natriuretic peptide (BNP) in congestive heart failure (CHF) are associated with increased diuresis and natriuresis, preserved glomerular filtration rate (GFR), and lack of activation of the renin-angiotensin-aldosterone system (RAAS). In contrast, diuretic-induced natriuresis may be associated with reduced GFR and RAAS activation. The objective of this study was to test the hypothesis that exogenous BNP enhances the renal diuretic and natriuretic actions of furosemide (Fs) and retards the activation of aldosterone in a model of CHF. METHODS AND RESULTS: CHF was produced in 2 groups of dogs by ventricular pacing. One group received continuous (90-minute) intravenous Fs (1 mg x kg(-1) x h(-1)). A second group (Fs+BNP) received 45-minute intravenous coinfusion of Fs (1 mg x kg(-1) x h(-1)) and low-dose (2 pmol x kg(-1) x min(-1)) BNP followed by 45-minute coinfusion of Fs (1 mg x kg(-1) x h(-1)) and high-dose (10 pmol x kg(-1) x min(-1)) BNP. Fs increased urinary flow, but the effect of Fs+BNP was greater. Similarly, urinary sodium excretion was higher in the Fs+BNP group. Although GFR tended to decrease in the Fs group, it increased in the Fs+BNP group (35+/-3 to 56+/-4*) (* indicates P<0.05 versus baseline) (P<0.0001 between groups). Plasma aldosterone increased with Fs (41+/-10 to 100+/-11* ng/dL) but was attenuated in the Fs+BNP group (44+/-11 to 54+/-9 ng/dL low-dose and to 47+/-7 ng/dL high-dose) (P=0.0007 between groups). CONCLUSIONS: Fs+BNP has more profound diuretic and natriuretic responses than Fs alone and also increases GFR without activation of aldosterone. Coadministration of BNP and loop diuretic is effective in maximizing natriuresis and diuresis while preserving renal function and inhibiting activation of aldosterone.