Giuseppe Seminara

Circulating Natriuretic Peptide Concentrations in Patients With End-Stage Renal Disease: Role of Brain Natriuretic Peptide as a Biomarker for Ventricular Remodeling

OBJECTIVES To determine levels of natriuretic peptides (NPs) in patients with end-stage renal disease (ESRD) and to examine the relationship of these cardiovascular peptides to left ventricular hypertrophy (LVH) and to cardiac mortality. PATIENTS AND METHODS One hundred twelve dialysis patients without clinical evidence of congestive heart failure underwent plasma measurement of NP concentrations and echocardiographic investigation for left ventricular mass index (LVMI). RESULTS Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations correlated positively with LVMI and inversely with left ventricular ejection fraction, whereas C-type NP and Dendroaspis NP levels did not correlate with LVMI. In dialysis patients with LVH (LVMI >125 g/m2), plasma ANP and BNP concentrations were increased compared with those in dialysis patients without LVH (both P<001). In a subset of 15 dialysis patients without LVH or other concomitant diseases, plasma BNP concentrations were not significantly increased compared with those in 35 controls (mean +/- SD, 20.1+/-13.4 vs 13.5+/-9.6 pg/mL; P=.06), demonstrating that the BNP concentration was not increased by renal dysfunction alone. Furthermore, the BNP level was significantly higher in the 16 patients who died from cardiovascular causes compared with survivors (mean +/- SD, 129+/-13 vs 57+/-7 pg/mL; P<.003) and was significantly associated with greater risk of cardiovascular death in Cox regression analysis (P<.001), as was the ANP level (P=.002). CONCLUSIONS Elevation of the plasma BNP concentration is more specifically related to LVH compared with the other NP levels in patients with ESRD independent of congestive heart failure. Thus, BNP serves as an important plasma biomarker for ventricular hypertrophy in dialysis patients with ESRD.

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.

Fibrinogen, mortality and incident cardiovascular complications in end-stage renal failure.

Abstract. Zoccali C, Mallamaci F, Tripepi G, Cutrupi S, Parlongo S, Malatino LS, Bonanno G, Rapisarda F, Fatuzzo P, Seminara G, Stancanelli B, Nicocia G, Buemi M (Institute of Biomedicine, Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Reggio Cal; University of Catania; and University of Messina, Italy). Fibrinogen, mortality and incident cardiovascular complications in end‐stage renal failure. J Intern Med 2003; 254: 132–139.

Low triiodothyronine and cardiomyopathy in patients with end-stage renal disease.

Objectives and methods Low free plasma triiodothyronine (fT3) is associated with inflammation and cardiovascular damage in patients with end-stage renal disease (ESRD). We investigated the relationship between fT3, left ventricular systolic function and left ventricular mass in a group of 234 dialysis patients, and modelled the association between fT3 and cardiomyopathy in statistical analyses including both direct (interleukin-6 and C-reactive protein) and inverse (serum albumin) acute phase inflammation markers. Results Plasma fT3 concentration in dialysis patients was significantly (P < 0.001) reduced in comparison with healthy participants and clinically euthyroid patients with normal renal function. Left ventricular systolic function was depressed (P ≤ 0.003) and left ventricular mass increased (P < 0.001) in patients in the first fT3 quartile as compared with patients in other quartiles. In multiple regression analyses these associations remained significant also after adjustment for Framingham risk factors and antihypertensive therapy (P ≤ 0.01), and for risk factors peculiar to ESRD (P = 0.03). Adjustments for interleukin-6 or for albumin, however, abrogated these relationships. Conclusions Low triiodothyronine is associated with left ventricular dysfunction and left ventricular hypertrophy in ESRD patients. These associations appear largely mediated by inflammation. Low fT3 may be an intermediate mechanism implicated in the adverse cardiac effects of inflammation in patients with ESRD.

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.

Prospective Study of Neuropeptide Y as an Adverse Cardiovascular Risk Factor in End-Stage Renal Disease

Chronic renal insufficiency is a situation characterized by high plasma concentration of neuropeptide Y (NPY). Because this neuropeptide interferes with cardiovascular (CV) function, it is possible that it is involved in the high CV-related morbidity and mortality of these patients. To test this hypothesis, a follow-up study was performed (average duration, 34 mo; range 0.2 to 52.0 mo) in a cohort of 277 patients with end-stage renal disease receiving chronic dialysis. Univariate analysis revealed that plasma NPY was directly related to plasma norepinephrine (r = 0.37, P < 0.001) and epinephrine (r = 0.17, P = 0.005), exceeding the upper limit of the normal range in the majority of patients with end-stage renal disease (170 of 277, 61%). One hundred thirteen patients had one or more fatal and nonfatal CV events; 112 patients died, 66 of them (59%) of CV causes. Plasma NPY failed to predict all-cause mortality but was an independent predictor of adverse CV outcomes (hazard ratio [10 pmol/L increase in plasma NPY], 1.32; 95% confidence interval, 1.09 to 1.60; P = 0.004) in a Cox proportional-hazard model that included a series of traditional and nontraditional CV risk factors. Plasma NPY maintained its predictive power for CV events in statistical model including plasma norepinephrine. Plasma NPY predicts incident CV complications in end-stage renal disease. Controlled trials are needed to establish whether interference with the sympathetic system, NPY, or both may reduce the high CV morbidity and mortality of dialysis patients.

Fibrinogen, inflammation and concentric left ventricular hypertrophy in chronic renal failure

Background We investigated the relationship between fibrinogen and echocardiographic measurements of left ventricular (LV) geometry and LV function in a group of 192 patients with end stage renal disease (ESRD).

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-α (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.

Neuropeptide Y, left ventricular mass and function in patients with end stage renal disease.

Objective Neuropeptide Y (NPY) is released during sympathetic stimulation and mediates the central effects of the adipostatic hormone leptin. The plasma concentration of NPY and leptin is increased in patients with end stage renal disease (ESRD), but it is unknown whether these substances are related to biochemical markers of sympathetic activity and to alterations in left ventricular (LV) mass and function in these patients. Design We investigated the relationship between NPY, norepinephrine (NE), leptin and echocardiographic measurements in a cross-sectional study in 198 patients with ESRD. Results NPY was directly related to plasma NE and heart rate but it was largely independent of arterial pressure and of retention of metabolic waste products. NPY was significantly higher in patients with LV hypertrophy and in those with LV systolic dysfunction than in those without these alterations. Of note, NPY emerged as an independent correlate of LV mass index and of LV ejection fraction (LVEF) (both P ⩽ 0.002) in multiple linear regression analyses including a series of cardiovascular risk factors. Furthermore in a multiple logistic regression model patients in the top NPY tertile had a risk for LV concentric hypertrophy that was 18.10 (95% confidence interval: 5.87–55.83) times higher than in those in the first tertile (P < 0.001). Leptin was unrelated to NPY as well as to LV mass and to systolic function. Conclusions Elevated NPY is independently associated with LV concentric hypertrophy and systolic dysfunction in ESRD. It remains to be seen whether these links contribute to the high cardiovascular mortality in these patients.

Extension of a Pelvic Tumor into the Right Atrium

To the Editor: Secondary localization of intrathoracic tumors in the heart is often due to metastatic spread or neoplastic infiltration of veins. Renal, adrenal, and hepatic carcinomas as well as l...