Subclinical markers of cardiovascular disease predict adverse outcomes in chronic kidney disease patients with normal left ventricular ejection fraction.

Emerging cardiovascular biomarkers, such as speckle tracking echocardiography (STE) and aortic pulse wave velocity (aPWV), have recently demonstrated the presence of subclinical left ventricular dysfunction and arterial stiffening in patients with chronic kidney disease (CKD) and no previous cardiovascular history. However, limited information exists on the prognostic impact of these biomarkers. We aimed to investigate whether STE and aPWV predict major adverse cardiac events (MACE) in this patient population. In this cohort study we prospectively analysed 106 CKD patients with no overt cardiovascular disease (CVD) and normal left ventricular ejection fraction. Cardiac deformation was measured using STE while aPWV was measured using arterial tonometry. The primary end-point was the composite of all-cause mortality, acute coronary syndrome, stable angina requiring revascularization (either using percutaneous coronary intervention or coronary artery bypass surgery), hospitalization for heart failure and stroke. Over a median follow up period of 49 months (interquartile range 11-63 months), 26 patients (24.5%) reached the primary endpoint. In a multivariable Cox hazards model, global longitudinal strain (GLS) (HR 1.12, 95% CI 1.02-1.29, p = 0.041) and aPWV (HR 1.31, 95% CI 1.05-1.41, p = 0.021) were significant, independent predictors of MACE. GLS and aPWV independently predict MACE in CKD patients with normal EF and no clinically overt CVD.

Left ventricular twist mechanics and its relation with aortic stiffness in chronic kidney disease patients without overt cardiovascular disease.

BACKGROUND: Recent studies hypothesized left ventricular (LV) twist as a potential biomarker for evaluation of sub clinical myocardial disease, however its relationship with aortic stiffness has yet to be investigated. Chronic kidney disease (CKD) has been identified as a risk factor for both myocardial and arterial disease. As such we sought to explore the relationship between aortic stiffness and LV twist in CKD patients without known cardiovascular disease (CVD). METHODS: In this prospective, observational study we enrolled 106 CKD patients (Stages 1 to 5) with normal LVEF as assessed by conventional echocardiography. Aortic stiffness was measured using aortic pulse wave velocity (aPWV). We defined increased aPWV as ≥10 m/s. LV Twist was measured using two-dimensional speckle tracking echocardiography. RESULTS: Patients with increased aPWV had higher LV twist (p = 0.002) but similar LVEF (p = 0.486). Aortic PWV correlated crudely with age (p < 0.001), the presence of diabetes (p < 0.001), hypertension (p < 0.001), eGFR (p < 0.001), LVMI (p = 0.01), e/e' (p < 0.001) and LV twist (p = 0.003). In multivariable analyses after adjusting for age, gender, cardiovascular risk factors and hypertensive medication, aPWV was independently associated with LV twist (ß = 0.163, p = 0.025). CONCLUSIONS: Aortic stiffness independently associates with LV Twist in asymptomatic CKD patients. These findings suggest a close interaction between LV twist mechanics and arterial remodeling even before CVD becomes clinically relevant.

Early detection of subclinical left ventricular myocardial dysfunction in patients with chronic kidney disease.

AIMS: To identify subclinical left ventricular (LV) myocardial dysfunction using speckle tracking echocardiography (STE) in patients with chronic kidney disease (CKD), preserved LV ejection fraction (LVEF), and no cardiovascular history or symptoms. METHODS AND RESULTS: Cross-sectional comparisons of conventional and STE parameters were performed between controls and patients with different stages of CKD. CKD patients were followed up for major adverse cardiovascular events (MACEs). We recruited 106 CKD patients and 38 controls. Mean age was 54.4 ± 15.1 and 36.9 ± 11.5 years, respectively (P < 0.001), with 49.1 vs. 52.6% being female (P = 0.705). There were 29 (27.4%) patients with CKD stages 1/2, 38 (35.8%) with stage 3, and 39 (36.8%) with stages 4/5. Global longitudinal strain (GLS) was more impaired when moving from controls to CKD stages 4/5 (-20.67 ± 3.06, -20.39 ± 2.29, -18.33 ± 3.81, -18.01 ± 2.64, controls vs. CKD stages 1/2, vs. CKD stage 3, vs. CKD stages 4/5, respectively, Padjusted = 0.016), whereas LV twist (16.2 ± 4.8, 18.51 ± 4.36, 19.91 ± 5.35, 24.6 ± 5.35, Padjusted < 0.001) and LV twist rate (101.7 ± 30.3, 110.4 ± 30.1, 121 ± 31.4, 154.8 ± 36.7, Padjusted < 0.001) increased. Risk factor-adjusted GLS (standardized beta ß = -0.245, P = 0.025), strain rate (SR) [global longitudinal strain rates (GLSRs); ß = -0.236, P = 0.019], and early diastolic longitudinal strain rate (GLSRe; ß = 0.247, P = 0.019) were significantly associated with estimated glomerular filtration rate (eGFR), whereas LV twist (ß = -0.432, P < 0.001), LV twist rate (ß = -0.433, P < 0.001), and number of segments with diastolic dysfunction (ß = -340, P < 0.001) were inversely and independently associated with eGFR. Impaired GLS (more than -16%) was observed in almost a quarter of CKD patients and associated with a reduced estimated MACE-free survival at 12-month follow-up (88.5 vs 93.7%, Plogrank = 0.038). CONCLUSION: In CKD patients with no cardiovascular symptoms or history and preserved LVEF, STE can identify subclinical abnormalities of both systolic (decreased GLS and GLSR, increased LV twist, and twist rate) and diastolic (decreased GLSRe and increased number of segments with diastolic dysfunction) LV function.

Cardiovascular repercussions of the pseudoexfoliation syndrome.

Pseudoexfoliation syndrome is a primarily ophthalmological disorder caused by deposition of whitish-gray protein on the lens, iris, and multiple other eye tissues. There is increasing evidence over the previous years that pseudoexfoliation syndrome is a systemic disorder with various extraocular manifestations and has recently been linked to several cardiovascular disorders. The present article aims to summarize the current knowledge on cardiovascular implications of this well-described clinical entity.

Pericardial effusion in a young patient with newly diagnosed systemic lupus erythematosus and a mediastinal mass.

We present the case of a 32-year-old-woman who was admitted to the hospital for evaluation of pericardial effusion. The subsequent diagnostic workup revealed the presence of a mediastinal mass along with systemic lupus erythematosus (SLE). The patient underwent thymectomy, and histological evaluation of the resected mass revealed thymic follicular hyperplasia without evidence of malignancy. SLE disease activity was promptly controlled by corticoids. Clinicians should be aware of the occasional association of autoimmune disorders with focal thymic hyperplasia, which might be confused with thymomas or thymocarcinomas.

Association of serum uric acid level with aortic stiffness and arterial wave reflections in newly diagnosed, never-treated hypertension.

BACKGROUND: Serum uric acid (UA) plays a key role in the development and progression of hypertension. We investigated the association of UA levels and indices of arterial function in a cohort of newly diagnosed, never-treated hypertensive subjects. METHODS: One thousand two hundred and twenty-five patients with a new diagnosis of mild to moderate arterial hypertension for which they had never received treatment were enrolled in the study (mean age 52.9 years, 728 men). Serum UA, carotid-femoral pulse-wave velocity (cfPWV), an index of aortic stiffness and augmentation index (AIx), a composite marker of wave reflections and arterial stiffness were measured. RESULTS: In univariable analysis, UA levels correlated with cfPWV (r = 0.23, P < 0.001) and AIx (r = -0.24, P < 0.001). In multiple linear regression analysis, an independent positive association of cfPWV with UA levels was observed after adjusting for confounders (standardized regression coefficient ß = 0.169, P < 0.001, adjusted R² = 0.402), indicating an increase in aortic stiffness with higher values of UA. In contrast, an independent negative association of AIx with UA levels was observed after adjusting for confounders (standardized regression coefficient ß = -0.064, P = 0.011, adjusted R² = 0.557), indicating a decrease in wave reflections with higher values of UA. In gender-specific analyses, UA positively correlated with cfPWV in both genders, whereas a negative correlation with AIx existed only in females. CONCLUSIONS: Serum UA levels are independently associated with aortic stiffening and wave reflections in never-treated hypertensives. Future studies are warranted in order to explore its exact role on arterial function in the hypertensive setting.

Amino-terminal pro-C-type natriuretic peptide is associated with arterial stiffness, endothelial function and early atherosclerosis.

OBJECTIVE: C-type natriuretic peptide (CNP) is a paracrine molecule with effects on endothelial integrity, vascular tone and atherosclerotic process. Arterial stiffness, wave reflections, endothelial dysfunction and carotid intima-media thickness (IMT) are predictors of cardiovascular events. We investigated whether CNP is related to arterial structure and function in men. METHODS: We evaluated arterial structural and functional characteristics in 117 consecutive men (mean age 57.3 + or - 9.2 years), with and without cardiovascular risk factors, who had no established cardiovascular disease. Arterial elastic properties were evaluated with carotid-femoral pulse wave velocity (PWV), wave reflections with augmentation index (AIx), endothelial function with flow-mediated dilatation of the brachial artery (FMD) and early atherosclerosis with carotid IMT. Amino-terminal proCNP (NT-proCNP) was assessed in venous blood. RESULTS: The number of cardiovascular risk factors was inversely related to levels of NT-proCNP (P<0.01) and there was a progressive increase in Framingham risk score according to decreasing tertiles of NT-proCNP (P<0.001). In multivariable regression analysis NT-proCNP exhibited significant negative associations with PWV and IMT and positive association with FMD (all P<0.05) that were independent of age, blood pressure, smoking habits, body mass index, blood glucose, total triglycerides, low-density lipoprotein and endothelin-1 or high-sensitivity C-reactive protein. There was no relation between NT-proCNP and AIx. CONCLUSION: The present study is the first to demonstrate in a global arterial approach relationship between CNP and functional and early structural arterial changes. These findings elucidate pathophysiological links and may have important clinical implications for the estimation of cardiovascular risk in men.

Association of interleukin-18 levels with global arterial function and early structural changes in men without cardiovascular disease.

BACKGROUND: Increased levels of interleukin-18 (IL-18) have been related to plaque progression and vulnerability and cardiovascular outcomes. Arterial functional and structural characteristics and endothelial/inflammatory activation are important determinants of cardiovascular performance and predictors of risk. We investigated whether IL-18 is a determinant of global arterial function and early structural changes in men. METHODS: We evaluated arterial structural and functional characteristics (carotid-femoral pulse wave velocity (PWV), central aortic pressures, wave reflection indexes, flow-mediated dilation of the brachial artery, and common carotid intima-media thickness (IMT)) and we measured systemic inflammatory markers in 97 men (mean age 57.8 +/- 8.6 years) without manifest cardiovascular/atherosclerotic disease. RESULTS: Multivariable analysis adjusting for age, mean pressure, other risk factors, high-sensitivity C-reactive protein (hsCRP), and treatment showed independent associations between IL-18 level and carotid-femoral PWV (P < 0.01) and IMT (P = 0.03). On the other hand, no relationship between IL-18 and flow-mediated dilation, central pressures or augmentation index (AIx) was found. The combination of higher IL-18 level with higher carotid-femoral PWV and carotid IMT values showed greater effect on 10-year risk of a cardiovascular event. CONCLUSIONS: IL-18 level is independently associated with aortic stiffening and carotid early atherosclerosis. This finding underlines the important role of IL-18 as a marker of arterial damage, and implies a contribution of this compound to the pathophysiology of cardiovascular disease.

Amino-terminal pro-C-type natriuretic peptide is associated with the presence, severity, and duration of vasculogenic erectile dysfunction.

BACKGROUND: Endothelial dysfunction is a key event in the pathophysiology of erectile dysfunction (ED) and generalized vascular disease. C-type natriuretic peptide (CNP) is a paracrine molecule that effects endothelial integrity and vascular tone. OBJECTIVE: To determine the role of CNP in men with vasculogenic ED. DESIGN, SETTING, AND PARTICIPANTS: Fifty-two consecutive men (age: 57+/-10 yr) with nonpsychogenic and nonhormonal ED for >6 mo and free of cardiovascular disease who were referred to the Cardiovascular Diseases and Sexual Health Unit of our Department for evaluation of ED were compared with 31 subjects with normal erectile function matched for age, body mass index, and traditional risk factors. MEASUREMENTS: Vasculogenic ED was diagnosed according to comprehensive history, physical examination, Sexual Health Inventory for Men (SHIM-5) scoring, hormonal testing, and penile color-Doppler ultrasound. Amino-terminal proCNP (NT-proCNP) was measured in plasma with enzyme-linked immunosorbent assay (ELISA). RESULTS AND LIMITATIONS: Compared to controls, ED patients had significantly lower NT-proCNP levels (0.21+/-0.08 pmol/l in ED patients vs 0.34+/-0.07 pmol/l in control subjects; p<0.001). NT-proCNP levels were associated with erectile performance as expressed by SHIM-5 score (r=0.57; p<0.001), even after adjusting for confounders. There was also an inverse linear relationship between ED duration and NT-proCNP levels (p<0.05). In patients with arteriogenic ED, there was a positive correlation of NT-proCNP levels with peak systolic velocity (PSV) (r=0.51; p=0.01). CONCLUSIONS: CNP levels are associated with the presence, severity, and duration of ED. These findings provide further insight into the role of CNP in the pathophysiology of ED.

Usefulness of dobutamine stress echocardiography with Tissue Doppler imaging for the evaluation and follow-up of patients with repaired tetralogy of Fallot.

BACKGROUND: The longstanding pulmonary regurgitation in patients with repaired tetralogy of Fallot (RTOF) results in right ventricular (RV) failure. The estimation of RV function and reserve in these patients is of great importance, especially for the determination of the proper timing of pulmonary valve replacement. Tissue Doppler imaging (TDI) of the tricuspid annulus has been proved a valuable tool in the evaluation of these patients. Dobutamine stress echocardiography (DSE) in low doses detects the contractility reserve of cardiac myocytes. The aim of our study was to estimate RV reserve in patients with RTOF with the use of DSE and TDI and to examine whether this is related to baseline TDI indices of the tricuspid annulus. METHODS: We studied 21 patients with RTOF and 21 age- and gender-matched controls with TDI Doppler at the tricuspid annulus during DSE. TDI measurements were made at baseline and at infusion rates of 10 and 20 microg x kg x min. RESULTS: Patients with RTOF had lower values of TDI indices at baseline and during dobutamine infusion and smaller dobutamine-induced increase of Sa (DeltaSa) (3.8 +/- 1.2 vs. 10.8 +/- 3.6 cm/sec, P < .001) and Aa (3.5 +/- 2.2 vs. 10.0 +/- 3.2 cm/sec, P < .001). A value of DeltaSa < or = 6 cm/sec clearly discriminated patients from controls and could be predicted by values of Sa < 11.5 cm/sec with sensitivity of 95% and specificity of 100%. CONCLUSIONS: In patients with RTOF, impaired RV contractile reserve can be documented with TDI of tricuspid annular motion during DSE and is predicted by TDI indices at rest. Its serial estimation may contribute to optimal timing of reoperation.

Relationship of fibrinogen with arterial stiffness and wave reflections.

INTRODUCTION: Increased levels of fibrinogen have been related to target organ damage and cardiovascular outcomes. Arterial elastic properties are important determinants of cardiovascular performance and predictors of the corresponding risk. This study investigated whether the fibrinogen level is associated with arterial stiffness and wave reflections. METHODS: We studied 229 consecutive, non-diabetic patients with uncomplicated, never-treated essential hypertension (mean age 51 years, 149 men) and an age-matched control group of 159 normotensive individuals (mean age 50 years, 83 men). Carotid-femoral and carotid-radial pulse wave velocity (PWVc-f and PWVc-r) were measured as indices of elastic-type, aortic stiffness and muscular type, medium-sized arterial stiffness, respectively. The heart rate-corrected augmentation index (AIx75) was estimated as a composite marker of wave reflections and arterial stiffness. Plasma fibrinogen was measured using immunonephelometry. RESULTS: The fibrinogen level and arterial function indices (PWVc-f, PWVc-r, AIx75) were significantly higher in hypertensive patients than controls. In the whole population, fibrinogen level correlated with PWVc-f and AIx75 in univariable analysis, but not with PWVc-r. In multivariable analysis, an independent association was established between fibrinogen level and PWVc-f after adjusting for age, sex, mean pressure, heart rate, height, body mass index, smoking status, and total cholesterol. In contrast, no significant relationship was observed between fibrinogen and AIx75 after adjusting for confounders. CONCLUSION: The plasma fibrinogen level is independently associated with aortic stiffening. This finding underlines the important role of fibrinogen as a marker of arterial damage, and implies a possible contribution of this compound to the pathophysiology of cardiovascular disease.

An integrated assessment of family history on the risk of developing acute coronary syndromes (CARDIO2000 study).

OBJECTIVE: In this work we assessed a risk score for developing a first event of acute coronary syndrome (ACS) based on the family history of the cardiovascular risk factors. METHODS AND RESULTS: The studied population consisted of 848 randomly selected middle-aged patients with first event of ACS and 1078 sex-age-region matched controls admitted to the same hospitals for minor operations and without any clinical suspicion of cardiovascular disease in their life. A Family History Score (FHS) was developed based on the presence of coronary heart disease, hypertension, hypercholesterolaemia and diabetes mellitus, among first-degree relatives of the participants after adjusting for the family size. The evaluation of FHS was based on conditional logistic regression analysis, after controlling for demographic variables as well as for the mutual confounding effects of other risk factors. Family history of CHD, hypercholesterolaemia and diabetes was highly associated with the development of the disease. The introduced FHS was also highly associated with the development of ACS among participants who had no family history of CHD (odds ratio = 10.9, p < 0.001), whereas it was not associated with the development of the disease among participants who had a family history of CHD (odds ratio = 1.41, p = 0.543). CONCLUSIONS: The suggested FHS could be a useful tool in the primary prevention of ACS, as well as in detecting and understanding associations between genetic vulnerability and cardiovascular risk factors.