[show abstract][hide abstract] ABSTRACT: Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P=2.58 · 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P=1.032 · 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.
[show abstract][hide abstract] ABSTRACT: End stage renal disease (ESRD) patients exhibit a higher risk of cerebrovascular events as compared with the general population. In 283 ESRD patients followed up for 10 years, we investigated the long-term predictive value for stroke and transient ischemic attacks of traditional and nontraditional risk factors. Data analysis was performed by a modified Cox regression analysis for repeated events and by a competing risks analysis.
During the follow-up, 61 cerebrovascular events occurred in 47 patients. On univariate Cox analysis, the risk of cerebrovascular outcomes was directly related to age, smoking, diabetes, BMI, systolic and pulse pressures, triglycerides, hemoglobin, history of stroke/transient ischemic attacks, arrhythmia and left ventricular mass index. Nontraditional risk factors in ESRD such as norepinephrine, homocysteine, interleukin-6 and asymmetric dimethylarginine failed to predict these events. In a multivariate Cox model for repeated events only smoking [hazard ratio: 2.45, 95% confidence interval (CI): 1.29-4.65], age (hazard ratio: 1.05, 95% CI: 1.01-1.08), hemoglobin (hazard ratio: 1.28, 95% CI 1.06-1.54), triglycerides (hazard ratio: 1.04, 95% CI 1.01-1.08), pulse pressure (hazard ratio: 1.53, 95% CI 1.01-2.23) and left ventricular mass index (hazard ratio: 1.02, 95% CI 1.01-1.04) maintained an independent relationship with cerebrovascular events. The direct link between hemoglobin and cerebrovascular events was significantly stronger (P < 0.05) than that of the same variable and death.
The risk of stroke in ESRD depends mainly on traditional risk factors, high hemoglobin and left ventricular hypertrophy. Multiple interventions aimed to reduce arterial stiffness, left ventricular mass and smoking as well as to maintain hemoglobin within the recommended therapeutic range may have beneficial effects on the risk of cerebrovascular events in ESRD patients.
Journal of hypertension 12/2010; 28(12):2468-74. · 4.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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).
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.
Journal of hypertension 08/2010; 28(8):1745-51. · 4.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Internal and Emergency Medicine 05/2010; 5(5):427-32. · 2.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
Nephron Clinical Practice 10/2009; 114(1):c74-80. · 1.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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).
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.
Journal of Hypertension 09/2008; 26(9):1875-82. · 3.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: To clarify the role of gene polymorphisms on the effect of losartan and losartan plus hydrochlorothiazide on blood pressure (primary end point) and on cardiac, vascular and metabolic phenotypes (secondary end point) after 4, 8, 12, 16 and 48 weeks treatment, an Italian collaborative study - The Study of the Pharmacogenomics in Italian hypertensive patients treated with the Angiotensin receptor blocker losartan (SOPHIA) - on never-treated essential hypertensives (n = 800) was planned. After an 8 week run-in, losartan 50 mg once daily will be given and doubled to 100 mg at week +4 if blood pressure is more than 140/90 mmHg. Hydroclorothiazide 25 mg once daily at week +8 and amlodipine 5 mg at week +16 will be added if blood pressure is more than 140/90 mmHg. Cardiac mass (echocardiography), carotid intima-media thickness, 24 h ambulatory blood pressure, homeostatic model assessment (HOMA) index, microalbuminuria, plasma renin activity and aldosterone, endogenous lithium clearance, brain natriuretic peptide and losartan metabolites will be evaluated. Genes of the renin-angiotensin-aldosterone system, salt sensitivity, the beta-adrenergic system and losartan metabolism will be studied (Illumina custom arrays). A whole-genome scan will also be performed in half of the study cohort (1M array, Illumina 500 GX beadstation).
[show abstract][hide abstract] ABSTRACT: E-selectin is a key adhesion molecule which plays a fundamental role in endothelial progenitor cell-dependent reparative mechanisms in experimental ischaemia and it serves to anchor leucocytes to the endothelium in inflammatory processes. Inflammation is one of the strongest risk factors for death and cardiovascular (CV) events in end-stage renal disease (ESRD).
The objective of the current study was to evaluate whether E-selectin is a useful biomarker of clinical outcome in ESRD patients. We tested the prediction power of circulating E-selectin for mortality and CV events in a cohort of 265 ESRD patients.
During the follow-up, 59 patients died and 58 had CV events. All-cause mortality was inversely related to serum E-selectin, the risk of death being the lowest in patients in the third E-selectin tertile (HR: 1, reference group), intermediate in those in the second tertile (HR: 1.30) and the highest in patients in the first tertile (HR: 2.02, P = 0.01). Similarly, the risk of fatal and nonfatal CV events followed an inverse pattern being lowest in the third tertile (reference group) and highest in the first tertile (HR: 1.73, P = 0.03). The prediction power of E-selectin for death and CV events was confirmed in a Cox regression analysis where E-selectin emerged as an inverse predictor of these outcomes, particularly so in patients with severe inflammation.
These data are in keeping with the hypothesis that in systemic inflammation altered E-selectin shedding may play a role in arterial damage and implicates this adhesion molecule in atherosclerotic complications in a high-risk condition like ESRD.
Journal of Internal Medicine 11/2007; 262(4):479-87. · 6.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
Kidney and Blood Pressure Research 02/2007; 30(5):283-8. · 1.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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].
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.
Kidney International 05/2004; 65(4):1492-8. · 7.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Journal of the American Society of Nephrology 04/2004; 15(4):1029-37. · 8.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: Fibrinogen is an established predictor of cardiovascular events in the general population but the relationship between fibrinogen, mortality and incident cardiovascular complications has been very little investigated in patients with end-stage renal disease (ESRD).
We investigated the relationship between fibrinogen and all cause mortality and cardiovascular outcomes in a prospective cohort study in 192 patients on chronic haemodialysis treatment (follow-up: 34 +/- 16 months).
Fibrinogen was significantly higher in patients who died during the follow-up than in those who survived. Similarly, fibrinogen was higher in patients who had fatal or nonfatal cardiovascular events than in event free patients. On multivariate Cox regression analysis fibrinogen was an independent predictor of survival [hazard ratio (1 g x L(-1) increase in plasma fibrinogen): 1.19, 95% confidence interval (CI): 1.05-1.35, P = 0.006] and a highly significant (P = 0.0008), independent predictor of fatal and nonfatal cardiovascular events [hazard ratio (1 g x L(-1) increase in plasma fibrinogen): 1.25, 95% CI: 1.10-1.43] in a model including traditional risk factors and serum C-reactive protein (CRP) and plasma homocysteine.
Fibrinogen is as an independent risk factor for overall and cardiovascular mortality in patients with ESRD. Intervention studies are required to see whether reducing plasma fibrinogen may help to curb the exceedingly high cardiovascular risk of the uremic population.
Journal of Internal Medicine 09/2003; 254(2):132-9. · 6.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hepatocyte growth factor is a pleiotropic cytokine with cardioprotective properties. Its serum concentration is markedly raised in end-stage renal disease. This study assessed the relation of hepatocyte growth factor (HGF) with left ventricular mass and geometry in end-stage renal disease. Serum HGF measurements and echocardiographic studies were performed in 185 patients receiving hemodialysis. Patients with serum HGF above the median (1.85 ng/mL) had more frequent cardiovascular complications. This cytokine was directly related to mean left ventricular wall thickness (r=0.23, P=0.002) and relative wall thickness (r=0.25, P=0.0001); a multivariate analysis showed that this relation was independent of other risk factors. Accordingly, the prevalence of left ventricular concentric geometry (either concentric left ventricular hypertrophy or remodeling) was much higher (n=49, 53%) among patients with HGF values above the median that in those with values < or =1.85 ng/mL (n=31, 34%). Furthermore, the risk for left ventricular concentric geometry was higher in patients with HGF values above the median (odds ratio, 2.57; 95% CI, 1.33 to 4.98; P=0.005), and multiple logistic regression analysis confirmed that this association was independent of other risk factors. In patients receiving hemodialysis, elevated serum HGF is associated with concentric left ventricular geometry. This is consistent with reports that link this cytokine to arterial remodeling and survival in patients with end-stage renal disease and suggests that it is part of a counterregulatory response aimed at attenuating cardiovascular damage in this high-risk population.
[show abstract][hide abstract] ABSTRACT: Cardiac troponin T (cTnT) is related to left ventricular (LV) mass in patients with end-stage renal disease (ESRD). Furthermore, cTnT reflects the severity of systolic dysfunction in patients with heart diseases. We tested the diagnostic value of cTnT for left ventricular hypertrophy (LVH) and LV systolic dysfunction in a large group of clinically stable hemodialysis patients without heart failure.
CTnT was significantly (P < 0.001) higher in patients with LVH than in those with normal LV mass. In a multiple logistic regression model, adjusting for potential confounders (including cardiac ischemia), systolic pressure and cTnT (both P = 0.003) were the strongest correlates of LVH. Similarly, cTnT was significantly higher (P = 0.005) in patients with systolic dysfunction than in those with normal LV function and in a multiple logistic regression model cTnT ranked as the second independent correlate of this alteration after male sex. Serum cTnT had a high positive prediction value for the diagnosis of LVH (87%) but its negative prediction value was relatively low (44%). The positive predictive value of cTnT for LV dysfunction was low (25%) while its negative predictive value was high (93%). A combined analysis including systolic pressure (for the diagnosis of LVH) and sex (for the diagnosis of LV systolic dysfunction) augmented the diagnostic estimates to an important extent (95% positive prediction value for LVH and 98% negative prediction value for LV systolic dysfunction).
CTnT has a fairly good diagnostic potential for the identification of LVH and for the exclusion of LV systolic dysfunction in patients with ESRD without heart failure. This marker may be useful for the screening of alterations in LV mass and function in clinically stable hemodialysis patients.
Kidney International 12/2002; 62(5):1884-90. · 7.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: Diagnostic value of troponin T for alterations in left ventricular mass and function in dialysis patients.Background Cardiac troponin T (cTnT) is related to left ventricular (LV) mass in patients with end-stage renal disease (ESRD). Furthermore, cTnT reflects the severity of systolic dysfunction in patients with heart diseases. We tested the diagnostic value of cTnT for left ventricular hypertrophy (LVH) and LV systolic dysfunction in a large group of clinically stable hemodialysis patients without heart failure.
Kidney International 10/2002; 62(5):1884-1890. · 7.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cardiac troponin T (cTnT) predicts death and cardiovascular outcomes in clinically stable patients with end-stage renal disease. Because this protein is synthesized exclusively in myocardial cells, its predictive power for these outcomes may be because it reflects, besides cardiac ischemia, left ventricular (LV) mass, which is a strong predictor of cardiovascular death in this population per se. We tested the relationship between cTnT level and LV mass and the predictive power of this cardiac protein for all-cause and cardiovascular mortality in a cohort of hemodialysis patients (n = 199) without acute coronary syndrome and heart failure followed up for an average of 35 months (range, 0.8 to 52 months). cTnT was measured by means of a third-generation electrochemiluminescence immunoassay. cTnT level was related directly to interventricular septum (r = 0.36; P < 0.001) and posterior wall thickness (r = 0.40; P < 0.001), as well as LV mass (r = 0.45; P < 0.001). On multivariate analysis, after age, LV mass was the strongest independent predictor of cTnT level (beta = 0.28; P < 0.001). Serum cTnT level was significantly related to all-cause and cardiovascular mortality on univariate analysis (P < 0.001). On multivariate Cox regression analysis, the adjusted risk for all-cause death was 2.39 times (95% confidence interval [CI], 1.13 to 5.06; P = 0.02) greater in patients in the third cTnT tertile than the first tertile, and a similar pattern emerged for cardiovascular mortality (hazard ratio, 2.35; 95% CI, 1.01 to 5.49; P = 0.048). In hemodialysis patients, plasma cTnT level is independently related to LV mass and predicts all-cause and cardiovascular mortality. These data support the hypothesis that this marker can be usefully applied for risk stratification in clinically stable dialysis patients.
American Journal of Kidney Diseases 08/2002; 40(1):68-75. · 5.29 Impact Factor