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Cardiorenal syndrome type 4 (CRS type 4), or chronic renocardiac syndrome, has been defined as "chronic abnormalities in renal function leading to cardiac disease" and recognizes the extreme burden of cardiovascular disease (CVD) risk in patients with chronic kidney disease (CKD). CKD is common and increasingly recognized as a risk factor for CVD. Even though the treatment for CVD has dramatically improved over the past decades, it still takes responsibility for up to 50% of deaths in CKD patients. For this reason, patients with CKD should be thoroughly evaluated for cardiovascular risk factors that require careful management, given the significant burden of CRS type 4 on the healthcare system. This review focuses on the most significant conventional and non-conventional CVD risk factors related to CKD., (Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: The prognostic role of left ventricular remodeling and renal function in elderly hypertensive patients has been so far scarcely investigated., Aims: We assessed the impact of left ventricular geometry and renal function on 24h-Holter electrocardiogram (ECG) recordings and outcome in elderly hypertensive patients., Methods: We enrolled 251 asymptomatic hypertensive elderly patients (>65year-old). Left ventricular remodeling was evaluated by 2-D echocardiogram. Lown's class, mean QTc and standard deviation of all normal R-R intervals (SDNN) were assessed by 24-h Holter-ECG recordings. Data on all-cause and cardiovascular mortality were collected for 2years., Results: Mean age was 76.2±11.4years. High Lown's classes were more frequently observed in the presence of left ventricular hypertrophy (LVH) (57.3% vs. 23.7%; p<0.001). Mean QTc was 444.8±34.8ms and resulted directly correlated with indexed left ventricular mass (r=0.228; p=0.001). Patients with Chronic Kidney Disease (CKD) showed lower SDNN as compared with those with preserved renal function (92.02±36.11ms vs. 103.84±33.96ms, respectively; p=0.017). At 2years, all-cause and cardiovascular mortality rates were 38.0% and 21.1%, respectively. Diabetes mellitus (HR: 2.40; 95% C.I.1.16 to 4.99; p=0.019), CKD (HR: 2.22; 95% C.I.1.10 to 4.52; p=0.028), prolonged QTc (HR: 2.18; 95% C.I.1.07 to 4.41; p=0.030) and SDNN<96ms (HR: 1.98; 95% C.I.1.03 to 4.13; p=0.048) were independent predictors of cardiovascular death at 2year follow-up., Conclusions: CKD and left ventricular remodeling predicted altered ventricular batmotropism. Diabetes, CKD, heart rate variability and QTc are important predictors of cardiovascular death in elderly hypertensive patients., (Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

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.

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 (beta = 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/m(2.7) (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., (Copyright 2010 American Society for Bone and Mineral Research.)

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

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.

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

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.

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., Results: 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)., Conclusions: 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.

Background: The endogenous inhibitor of nitric oxide (NO), asymmetric dimethylarginine (ADMA), is a strong predictor of adverse cardiovascular outcomes in patients with end-stage renal disease (ESRD)., Methods: Since arterial and cardiac remodeling is associated with altered endothelial microcirculatory responses to forearm ischemia (a NO-dependent response), interference of ADMA with the NO system may be important for the pathogenesis of left ventricular hypertrophy (LVH) in these patients. This study sought to identify the relationship between plasma ADMA and LV geometry and function in a cohort of 198 hemodialysis patients., Results: Plasma ADMA was significantly higher (P = 0.008) in patients with LVH (median 3.00 micromol/L, inter-quartile range 1.73 to 3.97 micromol/L) than in those without this alteration (1.88 micromol/L, 1.15 to 3.56 micromol/L) and was significantly related to left ventricular (LV) mass (r = 0.26, P < 0.001). Interestingly, ADMA was much higher (P < 0.001) in patients with concentric LVH (3.60 micromol/L, 2.90 to 4.33 micromol/L) than in patients with eccentric LVH (2.17 micromol/L, 1.47 to 3.24 micromol/L) or normal LV mass (1.76 micromol/L, 1.13 to 2.65 micromol/L). Furthermore, plasma ADMA was higher (P = 0.02) in patients with systolic dysfunction (3.52 micromol/L, 2.08 to 5.87 micromol/L) than in those with normal LV function (2.58 micromol/L, 1.53 to 3.84 micromol/L) and inversely related to ejection fraction (EF; r = -0.25, P < 0.001). The link between ADMA and LV mass and EF was confirmed by multivariate analysis (ADMA vs. LVMI, beta = 0.17, P = 0.006; ADMA vs. EF, beta = -0.24, P < 0.001)., Conclusions: Overall, this study indicates that raised plasma concentration of ADMA is associated to concentric LVH and LV dysfunction. Intervention studies are needed to see whether the link between ADMA and concentric LVH remodeling and LV dysfunction is a causal one.

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< or =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 ventricular hypertrophy (LVH) is exceedingly frequent in patients undergoing dialysis. Cardiac mass is proportional to body size, but the influence of various indexing methods has not been studied in patients with end-stage renal disease. The issue is important because malnutrition and volume expansion would both tend to distort the estimate of LV mass (LVM) in these patients. In a cohort of 254 patients, the prognostic impact on all-cause mortality and cardiovascular outcomes of LVH values, calculated according to two established methods of indexing, either body surface area (BSA) or height(2.7), was assessed prospectively. When LVM was analyzed as a categorical variable, the height(2.7)-based method identified a larger number of patients with LVH than the corresponding BSA-based method. One hundred and thirty-seven fatal and nonfatal cardiovascular events occurred during the follow-up period. Overall, 90 patients died, 51 of cardiovascular causes. In separate Cox models, both the LVM/height(2.7) and the LVM/BSA index independently predicted total and cardiovascular mortality (P < 0.001). However, the height(2.7)-based method coherently produced a closer-fitting model (P < or = 0.02) than did the BSA-based method. The height(2.7) index was also important for the subcategorization of patients according to the presence of concentric or eccentric LVH because the prognostic value of such subcategorization was apparent only when the height(2.7)-based criterion was applied. In conclusion, LVM is a strong and independent predictor of survival and cardiovascular events in patients undergoing dialysis. The indexing of LVM by height(2.7) provides more powerful prediction of mortality and cardiovascular outcomes than the BSA-based method, and the use of this index appears to be appropriate in patients undergoing dialysis.