N-Terminal Pro-Brain Natriuretic Peptide Correlates with Ghrelin and Acyl-Ghrelin in Pre-Dialysis Chronic Kidney Disease.

Pro-B amino-terminal natriuretic peptide (NT-proBNP) is a diagnostic marker for heart failure (HF), a severe complication of chronic kidney disease (CKD). However, its significance in CKD is not clear, as other factors, such as renal function, may also have an impact. Recent studies have shown that ghrelin treatment is effective in HF in the general population, but the impact of ghrelin on cardiac function in CKD patients is still unknown. Our study aimed to investigate the factors associated with NT-proBNP in pre-dialysis CKD patients and to evaluate the correlation between NT-proBNP and ghrelin and acyl-ghrelin, molecules determined using ELISA methods. In a cross-sectional observational study, we included 80 patients with pre-dialysis CKD, with a mean age of 68 years and 50% men. The median values for NT-proBNP were 351.8 pg/mL, for acyl ghrelin 16.39 pg/mL, and for ghrelin 543.32 pg/mL. NT-proBNP was correlated with ghrelin (p = 0.034, r = 0.24), acyl-ghrelin (p = 0.033, r = -0.24), estimated glomerular filtration rate (p = 0.027, r = -0.25), serum urea (p = 0.006, r = 0.31), and ferritin (p = 0.041, r = 0.28). In multivariate analysis, ghrelin (p = 0.040) and blood urea (p = 0.040) remained significant predictors for NT-proBNP levels. NT-proBNP was a significant predictor for acyl-ghrelin (p = 0.036). In conclusion, in pre-dialysis CKD patients, a high value of NT-proBNP was associated with a high value of total ghrelin and a low value of acyl-ghrelin.

Triiodothyronine and Protein Malnutrition Could Influence Pulse Wave Velocity in Pre-Dialysis Chronic Kidney Disease Patients.

Cardiovascular diseases (CVD) are the first cause of chronic kidney disease (CKD) mortality. For personalized improved medicine, detecting correctable markers of CVD can be considered a priority. The aim of this study was the evaluation of the impact of nutritional, hormonal and inflammatory markers on brachial-ankle Pulse Wave Velocity (PWV) in pre-dialysis CKD patients. A cross-sectional observational study was conducted on 68 pre-dialysis CKD patients (median age of 69 years, 41.2% with diabetes mellitus, 52.9% male). Laboratory data were collected, including levels of prolactin, triiodothyronine, TGF α, IL-6, and IL-1ß. The high values of brachial-ankle PWV were associated with reduced muscle mass (p = 0.001, r = -0.44), low levels of total cholesterol (p = 0.04, r = -0.26), triglycerides (p = 0.03, r = -0.31), triiodothyronine (p = 0.04, r = -0.24), and prolactin (p = 0.02, r = -0.27). High PWV was associated with advanced age (p < 0.001, r = 0.19). In the multivariate analysis, reduced muscle mass (p = 0.018), low levels of triiodothyronine (p = 0.002), and triglycerides (p = 0.049) were significant predictors of PWV, but age (p < 0.001) remained an important factor. In conclusion, reduced triiodothyronine together with markers of malnutrition and age were associated with PWV in pre-dialysis CKD patients.

ACE2 and Apelin-13: Biomarkers with a Prognostic Value in Congestive Heart Failure.

The progression of heart failure is the result of the interaction of several pathogenetic processes that involve the activation of biomarkers belonging to the renin angiotensin aldosterone system (RAAS), to its counterregulatory mechanisms, to the sympathetic nervous system and inflammation, and to oxidative stress. This study is aimed at determining the prognostic role of biomarkers in the evolution of patients with heart failure. These biomarkers are representative of different pathogenetic pathways involved in the progression of heart failure and the possible interrelationships between them and heart remodelling. Method. This is a progressive observational study on 53 hospitalized patients with low ejection fraction heart failure, who were followed up for 12 months. The aetiology of heart failure was ischemic heart disease and dilated cardiomyopathy. The patients were clinically and biochemically evaluated by EKG (echocardiography) on admission and at 6 and 12 months. The biomarkers included in the present study were angiotensin-converting enzyme type 2 (ACE2), apelin-13, NT-proBNP (biomarkers involved in the counterregulation of RAAS), interleukin 17 (IL-17), hsCRP (inflammatory biomarkers), and urinary 8-iso-PGF2α (oxidative stress biomarker). The evolution was considered unfavourable if the patients presented complications during hospitalization, were readmitted for decompensated heart failure, or died. Results. From the study group, 14 patients (24.52%) presented an unfavourable clinical evolution. The biomarkers that were associated with the evolution of patients during hospitalization were ACE2, apelin-13, NT-proBNP, and hsCRP. Multivariate logistic regression analysis identified ACE2 and apelin-13 as independent, predictive biomarkers for the unfavourable evolution of patients over the study period. Values of ACE2 above 4000.75 pg/mL and of apelin-13 less than 402.5 pg/mL were associated with an unfavourable evolution (poor clinical outcomes). Conclusion. The serum values of ACE2 and apelin-13 correlate with the unfavourable evolution of patients with reduced ejection fraction heart failure.

Monitoring Anticoagulation with Unfractionated Heparin on Renal Replacement Therapy. Which is the Best aPTT Sampling Site?

BACKGROUND: Controlled anticoagulation is key to maintaining continuous blood filtration therapies. Objective: The study aimed to compare different blood sampling sites for activated partial thromboplastin time (aPTT) to evaluate anticoagulation with unfractionated heparin (UFH) in continuous renal replacement therapy (CRRT) and identify the most appropriate sampling site for safe patient anticoagulation and increased filter life span. METHOD: The study was a prospective observational single-centre investigation targeting intensive care unit (ICU) patients on CRRT using an anticoagulation protocol based on patient characteristics and a weight-based modified nomogram. Eighty-four patients were included in the study. Four sampling sites were assessed: heparin free central venous nondialysis catheter (CVC), an arterial line with heparinised flush (Artery), a circuit access line (Access), and a circuit return line (Postfilter). Blood was sampled from each of four different sites on every patient, four hours after the first heparin bolus. aPTT was determined using a rapid clot detector, point of care device. RESULTS: A high positive correlation was obtained for aPTT values between CVC and Access sampling sites (r (84) =0.72; p <0 .05) and a low positive correlation between CVC and Arterial sampling site (r (84) =0.46, p < 0.05). When correlated by artery age, the young Artery (1-3 day old) correlates with CVC, Access and Postfilter (r (45) = 0.74, p >0.05). The aPTT values were significantly higher at Postfilter and Arterial sampling site, older than three days, compared to the CVC sampling site (p<0.05). CONCLUSION: Considering patient bleeding risks and filter life span, the optimal sampling sites for safe assessment of unfractionated heparin anticoagulation on CRRT during CVVHDF were the central venous catheter using heparin free lavage saline solution, a heparinised flushed arterial catheter not older than three days, and a circuit access line.

Short-Term Prognosis Value of sST2 for an Unfavorable Outcome in Hypertensive Patients.

BACKGROUND: sST2 represents a useful biomarker for the diagnosis and prognosis of patients with heart failure, but limited data is available on its role in patients with hypertension. The aim of this study is to evaluate the short-term prognosis value of sST2 for an unfavorable outcome in hypertensive patients. METHODS: This was a prospective observational study which enrolled 80 patients with hypertension, who were followed for one year. All patients underwent clinical, laboratory (including sST2), and echocardiographic assessment at baseline. The patients were grouped according to the cardiovascular (CV) events reported during the follow-up: group A (with CV events) and group B (without CV events). RESULTS: Overall, 59 CV events were reported during the follow-up period. Compared to group B, the patients in group A had significantly higher sST2 levels, a higher number of CV risk factors, and a higher left ventricle mass. Except for the diastolic dysfunction parameters, the echocardiographic findings were similar in the two groups. Patients in group A had a lower E/A ratio, larger deceleration time, and increased telediastolic pressure as quantified by the E/E/p = 0.006, Kaplan-Meier analysis). CONCLUSIONS: sST2 levels were correlated with the risk of adverse CV outcomes in hypertensive patients and may represent a useful prognostic marker in these patients.

Oral Anticoagulant Therapy-When Art Meets Science.

Anticoagulant treatment is extremely important and frequently encountered in the therapy of various cardiovascular diseases. Vitamin K antagonists (VKA) are in use for the prevention and treatment of arterial and venous thromboembolism, despite the introduction of new direct-acting oral anticoagulants (NOAC). The VKA still have the clear recommendation in patients with a mechanical prosthetic heart valve replacement or moderate to severe mitral stenosis of the rheumatic origin, in deep vein thrombosis associated with congenital thrombophilia, and in cases where NOAC are prohibited by social condition (financial reason) or by comorbidities (extreme weight, severe renal or liver disease). VKA dosing required to reach the targeted therapeutic range varies largely between patients (inter-individual variability). This inter-individual variability depends on multiple environmental factors such as age, mass, diet, etc. but it is also influenced by genetic determinism. About 30 genes implicated in the metabolism coumarins derivatives were identified, the most important being CYP2C9 and VKORC, each with several polymorphisms. Herein, we review the data regarding genetic alterations in general and specific populations, highlight the diagnosis options in particular cases presenting with genetic alteration causing higher sensitivity and/or resistance to VKA therapy and underline the utility of NOAC in solving such rare and difficult problems.

Isolated very low QRS voltage predicts response to tilt-table testing in patients with neurally mediated syncope.

BACKGROUND: A number of patients with neurally mediated syncope (NMS) have isolated QRS complexes of very low voltage (≤0.3 mV) in the frontal plane leads on the 12-lead electrocardiogram (ECG). HYPOTHESIS: The aim of this study was to assess the importance of QRS voltage in predicting response to tilt-table testing (TTT) in patients with suspected NMS. METHODS: We included 216 patients (age: 49 ± 20 years, 103 men) with suspected NMS who had either a positive or negative response to TTT (n = 91 TTT+, and n = 125 TTT-). The QRS voltage was measured in mV on 12-lead ECGs performed within 3 days of the TTT. The lowest QRS voltage (QRSmin), as well as the voltage in each of the 12 leads was also determined. RESULTS: Very low voltage (QRSmin  ≤ 0.3 mV) in the frontal leads was significantly more prevalent in the TTT+ group than in the TTT- group (74 vs 22%, respectively; P  < .001). Patients in the TTT+ group had significantly lower QRSmin when compared to patients in the TTT- group. QRSmin predicted a positive tilt-table test in a multivariate model that also included patient gender, height, history of presyncope, QRS duration, and left ventricular end-diastolic diameter indexed to height. ROC analysis showed that QRSmin of ≥0.3 mV discriminated between TTT+ and TTT- patients with a sensitivity of 78% and specificity of 68%. CONCLUSION: Isolated very low QRS voltage in the frontal leads predicts a positive response to TTT in patients with suspected NMS.

Biomarkers of Inflammation in Left Ventricular Diastolic Dysfunction.

Left ventricular diastolic dysfunction (LVDD) is an important precursor to many different cardiovascular diseases. Diastolic abnormalities have been studied extensively in the past decade, and it has been confirmed that one of the mechanisms leading to heart failure is a chronic, low-grade inflammatory reaction. The triggers are classical cardiovascular risk factors, grouped under the name of metabolic syndrome (MetS), or other systemic diseases that have an inflammatory substrate such as chronic obstructive pulmonary disease. The triggers could induce myocardial apoptosis and reduce ventricular wall compliance through the release of cytokines by multiple pathways such as (1) immune reaction, (2) prolonged cell hypoxemia, or (3) excessive activation of neuroendocrine and autonomic nerve function disorder. The systemic proinflammatory state causes coronary microvascular endothelial inflammation which reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes favoring hypertrophy development and increases resting tension. So far, it has been found that inflammatory cytokines associated with the heart failure mechanism include TNF-α, IL-6, IL-8, IL-10, IL-1α, IL-1ß, IL-2, TGF-ß, and IFN-γ. Some of them could be used as diagnosis biomarkers. The present review aims at discussing the inflammatory mechanisms behind diastolic dysfunction and their triggering conditions, cytokines, and possible future inflammatory biomarkers useful for diagnosis.

Hemodynamic monitoring using thoracic bioimpedance - an optimal solution for the treatment of hypertension.

Hypertension is a major issue of public health because of its increasing prevalence and multiple complications caused by failing to achieve an efficient blood pressure control. Considering hypertension as a hemodynamic disorder allows to prescribe a tailored therapy guided by individual hemodynamic parameters, therefore leading to an increased rate of control. We present the case of a 59 years old diabetic, dyslipidemic and obese male who, although treated with 5 classes of antihypertensive drugs had uncontrolled hypertension that caused left ventricular failure. Using the HOTMAN system of hemodynamic monitoring using thoracic electrical bioimpedance allowed a quick identification of the cause and guided the therapy, achieving blood pressure control after 5 days of treatment. Treating hypertension by identifying the underlying hemodynamic imbalance allows prescribing a tailored therapy and shortens the initiation and stabilization phases of treatment.

Multimarker Assessment of Diastolic Dysfunction in Metabolic Syndrome Patients.

BACKGROUND: Metabolic syndrome (MetS) has been associated with left ventricular diastolic dysfunction (LVDD) with preserved systolic function. This study aims at identifying the predictive factors for LVDD in MetS patients. METHODS: The studied group comprised 72 consecutive hospitalized patients (2010-2011) diagnosed with MetS based on AHA/NHLBI/IDF 2009 definition, free of cardiovascular disease (36.11% males, age 59.19 ± 5.26 years), who underwent echocardiographic examination. Laboratory measurements of high-sensitivity C-reactive protein (hs-CRP), fibrinogen (Fbg) and interleukin-6 (IL-6), 8-isoprostaglandin-F2alpa (8-isoPGF2α), uric acid, glutathione peroxidases, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured. RESULTS: LVDD was identified in 47 (65.27%) of the MetS patients. The diastolic blood pressure (DBP) was the strongest prediction factor for LVDD (areas under the receiver operating curve [AUC]: 0.73, odds ratios [OR]: 1.065). The number of MetS criteria was also significantly predictive for LVDD (AUC: 0.65, OR: 2.029, P < 0.04). IL-6, hs-CRP, Fbg, and NT-proBNP were predictive for LVDD when receiver operating curve (ROC) analyses were used. The multimarker model comprising age, sex, SBP and DBP, waist, circumference, triglycerides along with hs-CRP, IL-6, and NT-proBNP had the best predictive capacity (AUC: 0.88, P = 0.0001). In multivariate analysis, IL-6 remained an independent predictive biomarker for LVDD (OR: 2.045). CONCLUSION: Both MetS components and biomarkers of inflammation (IF) are predictive factors for LVDD. The best predictive multimarker model for LVDD in MetS patients is composed of waist, triglycerides (TGL), SBP, DBP, fasting glucose, IL-6, hs-CRP, and NT-proBNP. IL-6 remains an independent predictive biomarker for LVDD in MetS patients, underlining the importance of IF in the evolution of MetS to subclinical cardiac damage.

Serum Soluble ST2 and Diastolic Dysfunction in Hypertensive Patients.

BACKGROUND: Echocardiographic evaluation of left ventricular (LV) structural and functional alterations in hypertension has some limitations, potentially overcome by using biomarkers. ST2, a prognostic biomarker for heart failure and myocardial infarction patients, was less studied in hypertension. AIM: To analyze the relationship between serum ST2 levels and diastolic dysfunction (DD) in hypertension. METHOD: We enrolled 88 hypertensive outpatients (average age 65 years, 69.3% females) in a prospective study, stratified for presence of LV hypertrophy (LVH). For each patient clinical examination, lab workup (routine and serum ST2 levels) and echocardiography were performed. RESULTS: Hypertensive patients with LVH had higher age, pulse pressure, mean arterial pressure, and serum ST2, while having lower serum albumin than those without LVH. Serum ST2 levels correlate with parameters of LV remodeling and DD. We found that 5.3% of ST2 level variability was caused by a 1-unit variation of cardiovascular risk. We identified cut-off values for discriminating hypertension with LVH versus that without LVH and grade 2 DD versus normal diastolic performance. CONCLUSION: ST2 could be used as diagnostic biomarker for cardiac remodeling and altered diastolic performance in hypertension, providing additional data to echocardiography. It could represent a milestone in early detection of cardiac performance alteration.

Nitroglycerin mediated dilation evaluated by ultrasound is associated with sTWEAK in hemodialysis patients.

AIMS: The main cause of death in hemodialysis (HD) patients is cardiovascular disease. Ultrasound assessment of the brachial artery dysfunction is easily achievable and can non-invasively detect atherosclerosis in various stages. In HD patients the cardiovascular risk profile is different and the determinants of brachial arterial function can be distinct comparing with general population. The aim of the study is to assess the determinants of arterial brachial function (flow-mediated and nitroglycerin-mediated dilation) evaluated by ultrasound in HD patients and their relation with tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) described as atherosclerotic marker in chronic kidney disease patients. MATERIAL AND METHODS: We conducted a cross-sectional observational study on 54 hemodialysis patients. We recorded clinical and biological data and we measured sTWEAK serum levels by ELISA. We evaluated the arterial brachial function by measurement of flow-mediated and nitroglycerin-mediated dilation, using B mode ultrasound. RESULTS: The determinants of flow-mediated dilation were: Kt/V (r=0.47, p<0.001), LDL-cholesterol (r=0.29, p=0.04), and total cholesterol (r=0.31, p=0.02). Flow-mediated dilation correlated with nitroglycerin-mediated dilation (r=0.70, p<0.001). In multivariate analysis kt/V was the only significant predictor for flow-mediated dilation (p=0.04). Nitroglycerin-mediated dilation correlates with sTWEAK (r=-0.30, p=0.03), systolic blood pressure (r=-0.28, p=0.04) and pulse pressure (r=-0.31, p=0.02). In multivariate analysis sTWEAK was the only significant predictor for nitroglycerin-mediated dilation (p=0.04). CONCLUSIONS: The main determinant of nitroglycerin-mediated dilation was sTWEAK. In addition, decreased nitroglycerin-mediated dilation was associated with higher systolic blood pressure and pulse pressure. The main determinant of FMD was Kt/V. Increased flow-mediated dilation was associated with better dialysis efficiency and high total cholesterol and LDL-cholesterol.

Better prognosis in overweight/obese coronary heart disease patients with high plasma levels of leptin.

BACKGROUND AND AIM: The involvement of leptin in atherosclerosis is very complex, including inflammation, the oxidative stress and thrombosis. Leptin has atherogenic and also antiatherogenic actions. In obesity elevated leptin levels are not sufficient to prevent disturbances of energy balance, suggesting that obese people are leptin resistant. The aim of the study was to investigate the relationship between baseline plasma levels of leptin and the incidence of new ischemic events in patients with CHD. METHODS: Plasma levels of leptin in fifty nine consecutive patients (29 men and 30 women) with CHD hospitalized in the County Emergency Clinical Hospital of Cluj-Napoca were measured using commercially available ELISA at admission. Patients with active infectious disease, neoplasia, acute coronary syndrome, stroke, hepatic or renal failure and severe heart failure were excluded The relationship between leptin levels and incident cardiovascular events (angina, nonfatal myocardial infarction or heart failure) over two years follow-up was studied using MEDCALC version 9.6. RESULTS: 73.6% patients with CHD were overweight or suffered of obesity. There were no significant differences between women and men regarding the plasma levels of leptin, the body mass index (BMI), the number of rehospitalizations, rehospitalizations/patient, diabetes mellitus, hypertension or dyslipidemia. Only in women plasma levels of leptin are correlated with BMI. As compared with men with overweight and obesity (BMI≥25kg/m(2)), plasma levels of leptin were significantly higher in women with overweight and obesity (3905.97±463.91 pg/ml vs 1835.17±533.9 pg/ml) (p<0.002). Patient gender could not be demonstrated to influence prognosis. During the two years we recorded one or more readmissions in 26 patients (44%). The analysis of time till readmission using Kaplan-Meier curves, showed that leptin level (cut-off 2000 pg/ml, HR 0.38, 95% CI 0.17-0.83; p=0.01) and BMI (cut-off 28 kg/m(2), HR 0.3164, 95% CI 0.145-0.0689; p<0.01) were significantly associated with prognosis. CONCLUSION: Patients with plasma levels of leptin >2000 pg/ml and BMI >28kg/m(2) had a better prognosis, suggesting a protective role of leptin in overweight/mild obesity.