Francesco A. Benedetto

Inflammation is associated with carotid atherosclerosis in dialysis patients

Objective To investigate the relationship between inflammatory processes and atherosclerosis in uraemic patients on chronic dialysis. Design A cross-sectional study in 138 dialysis patients (92 on haemodialysis and 46 on continuous ambulatory peritoneal dialysis). Methods Serum C-reactive protein (CRP), IgG anti-Chlamydia pneumoniae antibodies, lipoprotein (a), fibrinogen and plasma homocysteine as well as the intima–media thickness and the number of atherosclerotic plaques of the carotid arteries (by Echo-Colour-Doppler) were measured in each patient. Results One hundred and eight patients had at least one plaque and 26 had more than six plaques. Serum CRP was above the upper limit of the normal range (5 mg/l) in 85 of 138 patients (62%). IgG anti-Chlamydia pneumoniae antibodies were detectable in 64% of patients (high level in 24%, intermediate in 33% and low in 7%) and undetectable in the remaining 36% of patients. In a multiple regression model age (β = 0.35), serum CRP (β = 0.23), plasma homocysteine (β = 0.19), duration of dialysis (β = 0.19) and pulse pressure (β = 0.18) were independent predictors of intima–media thickness (R = 0.54, P < 0.0001). Similarly, age (β = 0.33), serum CRP (β = 0.29), plasma homocysteine (β = 0.20) and serum albumin (β = −0.18) were independent correlates of the number of atherosclerotic plaques (R = 0.55, P < 0.0001). Furthermore, in smokers, the interaction serum CRP–IgG anti–Chlamydia pneumoniae antibodies was the stronger independent predictor (β = 0.43, P = 0.0001) of the number of atherosclerotic plaques while no such relationship (P = 0.73) was found in non-smokers. Conclusions In patients on chronic dialysis treatment CRP is independently associated to carotid atherosclerosis and appears at least in part to be explained by IgG anti-Chlamydia pneumoniae antibodies level. These data lend support to the hypothesis that inflammation plays a role in the pathogenesis of atherosclerosis in these 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.

Detection of Pulmonary Congestion by Chest Ultrasound in Dialysis Patients

OBJECTIVES This study sought to investigate clinical and echocardiographic correlates of the lung comets score. BACKGROUND Early detection of pulmonary congestion is a fundamental goal for the prevention of congestive heart failure in high-risk patients. METHODS We undertook an inclusive survey by a validated ultrasound (US) technique in a hemodialysis center to estimate the prevalence of pulmonary congestion and its reversibility after dialysis in a population of 75 hemodialysis patients. RESULTS Chest US examinations were successfully completed in all patients (N = 75). Before dialysis, 47 patients (63%) exhibited moderate to severe lung congestion. This alteration was commonly observed in patients with heart failure but also in the majority of asymptomatic (32 of 56, 57%) and normohydrated (19 of 38, 50%) patients. Lung water excess was unrelated with hydration status but it was strongly associated with New York Heart Association functional class (p < 0.0001), left ventricular ejection fraction (r = -0.55, p < 0.001), early filling to early diastolic mitral annular velocity (r = 0.48, p < 0.001), left atrial volume (r = 0.39, p = 0.001), and pulmonary pressure (r = 0.36, p = 0.002). Lung water reduced after dialysis, but 23 patients (31%) still had pulmonary congestion of moderate to severe degree. Lung water after dialysis maintained a strong association with left ventricular ejection fraction (r = -0.59, p < 0.001), left atrial volume (r = 0.30, p = 0.01), and pulmonary pressure (r = 0.32, p = 0.006) denoting the critical role of cardiac performance in the control of this water compartment in end-stage renal disease. In a multiple regression model including traditional and nontraditional risk factors only left ventricular ejection fraction maintained an independent link with lung water excess (beta = -0.61, p < 0.001). Repeatability studies of the chest US technique (Bland-Altman plots) showed good interobserver and inter-US probes reproducibility. CONCLUSIONS Pulmonary congestion is highly prevalent in symptomatic (New York Heart Association functional class III to IV) and asymptomatic dialysis patients. Chest ultrasound is a reliable technique that detects pulmonary congestion at a pre-clinical stage in end-stage renal disease.

Norepinephrine and Concentric Hypertrophy in Patients With End-Stage Renal Disease

We have recently observed that in patients with end-stage renal disease (ESRD) raised plasma norepinephrine (NE) is an independent predictor of incident cardiovascular events but that its prognostic power is reduced when this sympathetic marker is tested in statistical models including also left ventricular mass. Because left ventricular hypertrophy (LVH) may be a mechanism whereby NE contributes to the high rate of cardiovascular events in ESRD, we examined the relationship between plasma NE and echocardiographic parameters of left ventricle mass in a large group of ESRD patients. Mean wall thickness (MWT) was higher in patients in the third NE tertile than in the other 2 tertiles (P =0.001), and such an increase was paralleled by a rise in relative wall thickness (RWT) (P =0.006). Concentric LVH was more prevalent in patients in the third NE tertile (46%) than in the second (38%) and first (25%) NE tertiles. Multivariate regression analysis confirmed that the association of plasma NE with the muscular component of left ventricle (MWT) and with RWT was independent (P ≤0.001) of other cardiovascular risk factors, and in these models, plasma NE ranked as the second correlate of MWT and RWT. Similarly, multiple logistic regression analysis showed that the association of plasma NE with concentric LVH was strong and again independent of other risk factors (P =0.003). Plasma NE is associated to concentric LVH in ESRD patients. These observations constitute a sound basis for testing the effect of anti-adrenergic drugs on left ventricle mass and on cardiovascular outcomes in patients with ESRD.

Left atrial volume in end-stage renal disease: a prospective cohort study.

Background End-stage renal disease (ESRD) is a high-risk condition and left ventricular hypertrophy (LVH) is the strongest risk factor in this population. Objective and methods Since the prognostic value of left atrial (LA) size in ESRD is still unknown, we performed a prospective cohort study aimed at testing the prognostic value of LA volume in a cohort of 249 ESRD patients. Results Both un-indexed and indexed LA volume (LAV) was significantly higher in dialysis patients than in healthy subjects (P < 0.001). On multivariate analysis only left ventricular mass index (LVMI), LV ejection fraction (LVEF), ratio of early (E) to late atrial (A) mitral Doppler peak flow velocity (E/A ratio) and antihypertensive treatment maintained an independent association with LAV. During the follow-up 113 patients died. LAV added significant prognostic power to a multivariate Cox model of all-cause death and the model based on height2.7 provided the best data fit. Notably, this index maintained an independent predictive value for death (P = 0.03) also when LVMI and LVEF were jointly forced into the Coxs model. Neither crude nor body surface area (BSA)-adjusted LAV had an independent association with death when tested in the Cox model including LVMI and LVEF. Conclusions In patients with ESRD, LAV indexed for height2.7 displays prognostic value beyond and above that provided by LV mass and function.

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 hypertrophy and nocturnal hypoxemia in hemodialysis patients.

Objective Nocturnal hypoxemia has recently been proposed as a cardiovascular risk factor in patients with chronic renal failure. In this study we have tested the hypothesis that this disturbance is associated with left ventricular hypertrophy (LVH) in dialysis patients. Methods During a mid-week non-dialysis day, 38 hemodialysis patients underwent continuous monitoring of arterial O2 saturation (SaO2) during night-time as well as 24 h ambulatory blood pressure monitoring and echocardiography. Results Eighteen patients had one or more episodes of O2 desaturation during night-time (average: 21 episodes; range 1 to 120) while the other 20 had no episode. Neither day-time arterial pressure nor heart rate were significantly associated with nocturnal hypoxemia. However there was a significant correlation between the night/day systolic ratio and the severity of hypoxemia during night-time (r = 0.36, P = 0.03). On multivariate analysis, nocturnal hypoxemia proved to be the stronger independent predictor of relative wall thickness, mean wall thickness and left ventricular mass index, suggesting that nocturnal O2 desaturation is linked to concentric hypertrophy and to concentric geometry of the left ventricle. Accordingly, the proportion of patients with such geometric alteration was higher (χ2 = 4.1, P = 0.04) in patients with a pulse oximetry severity score > 50th percentile [15 of 19 (79%)] than in those below this threshold [nine of 19 (47%)]. Conclusions Nocturnal hypoxemia is an important correlate of LVH in hemodialysis patients. Such an association is largely independent of arterial pressure. These data further underscore the importance of disturbed respiratory control as a cardiovascular risk factor in dialysis patients.

Left Atrial Volume Monitoring and Cardiovascular Risk in Patients with End-Stage Renal Disease: A Prospective Cohort Study

Left atrial volume (LAV), as indexed by height(2.7), has recently emerged as an useful echocardiographic measurement to refine the estimate of cardiovascular (CV) risk in ESRD. Whether progression or regression in LAV has prognostic value in patients with ESRD is still unknown. The prognostic value for CV events of changes in LAV was tested in a cohort of 191 dialysis patients. Echocardiography was performed twice, 17 +/- 2 mo apart. Changes in LAV that occurred between the second and the first echocardiographic studies were used to predict CV events during the ensuing 27 +/- 13 mo. During the follow-up, there was a significant increase in LAV (from 10.5 +/- 5.0 to 11.6 +/- 5.6 ml/m(2.7); P < 0.001). After the second echocardiographic study, 76 patients died (52 [68%] of CV causes) and 33 had nonfatal CV events. The independent association between changes in LAV and CV events was analyzed in a multiple Cox regression model taking into account a series of potential confounders, including baseline LAV and left ventricular mass and geometry. In these models, a 1-ml/m(2.7) per yr increase in LAV was associated with a 12% increase in the relative risk for fatal and nonfatal CV events (P < 0.001). Changes in LAV predict incident CV events in dialysis patients independent of the corresponding baseline measurement and of left ventricular mass. Monitoring LA size by echocardiography is useful for monitoring CV risk in patients with ESRD.

Vitamin D receptor (VDR) gene polymorphism is associated with left ventricular (LV) mass and predicts left ventricular hypertrophy (LVH) progression in end-stage renal disease (ESRD) patients.

Left ventricular hypertrophy (LVH) is a strong cardiovascular risk marker in end‐stage renal disease (ESRD) patients. Vitamin D deficiency and/or disturbed vitamin D signaling has been implicated in LVH in experimental models. Because the BsmI vitamin D receptor VDR gene polymorphism may alter VDR function, we performed a cross‐sectional and longitudinal study in a cohort of 182 dialysis patients to investigate (1) the relationship between BsmI VDR gene polymorphism and left ventricular mass index (LVMI) measured by echocardiography and (2) the predictive power of this polymorphism for progression in LVH over a 18 ± 2 months of follow‐up. As a reference group, we used 175 healthy subjects matched to the study population as for age and sex. The distribution of BsmI genotypes did not significantly deviate from Hardy‐Weinberg equilibrium either in patients or in the control group of healthy subjects. The frequency of the B allele of BsmI polymorphism (40.4%) in dialysis patients was similar to that of healthy control subjects (38.6%), and the number of B alleles was directly related to LVMI (r = 0.20, P = .007). This relationship remained robust (β = 0.19, P = .006) in multivariate analysis adjusting for traditional and nontraditional risk factors and antihypertensive and calcitriol treatment. In the longitudinal study, LVMI rose from 60.1 ± 17.9 to 64.2 ± 19.3 g/m2.7 (P < .001), and again, the number of B alleles was associated with LVMI changes both in crude and in fully adjusted analyses. These cross‐sectional and longitudinal observations coherently support the hypothesis that altered vitamin D signaling is implicated in LVH in ESRD patients.

Noncardiac consequences of hypertension in hemodialysis patients.

Hypertension in end‐stage renal disease (ESRD) is an important risk factor for left ventricular hypertrophy (LVH), cardiac failure, coronary artery disease (CAD), and arrhythmia. LVH is generally considered an integrator of the long‐term effects of hypertension and other cardiovascular (CV) risk factors and represents the strongest predictor of adverse CV outcomes in ESRD patients. The risk of heart failure is higher in patients with a history of hypertensive renal disease than in those with other diagnoses. Both coronary heart disease (CHD) and LVH predict congestive heart failure, which is often the ultimate cause of death in patients with cardiac ischemia or LVH. A history of long‐standing hypertension is associated with ischemic heart disease both in cross‐sectional and prospective studies in ESRD. Atrial fibrillation and ventricular arrhythmias are highly prevalent in dialysis patients and are implicated in mortality and sudden death in this population. Despite the lack of evidence from randomized controlled trials, it appears reasonable that interventions aimed at curbing the high CV mortality of ESRD should be targeted to both hypertension and LVH.