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Background: Inflammatory processes can trigger acute coronary syndromes (ACS) which may increase core body temperature (BT), a widely available low-cost marker of systemic inflammation. Herein, we aimed to delineate baseline characteristics of ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation ACS (NSTE-ACS) patients stratified by initial BT and to assess its predictive utility towards major adverse cardiovascular events (MACE) after the index ACS., Methods: From 2012 until 2017, a total of 1044 ACS patients, 517 with STEMI and 527 with NSTE-ACS, were prospectively recruited at the University Hospital Zurich. BT was measured by digital tympanic thermometer along with high-sensitivity C-reactive protein (hs-CRP) and cardiac troponin-T (hs-cTnT) levels prior to coronary angiography. Patients were stratified according to initial BT and uni- and multivariable regression models were fit to assess associations of BT with future MACE risk., Results: Among patients with STEMI, BT was not predictive of 1-year MACE, but a U-shaped relationship between BT and MACE risk was noted in those with NSTE-ACS (p = .029), translating into a 2.4-fold (HR, 2.44, 95% CI, 1.16-5.16) increased 1-year MACE risk in those with BT >36.8°C (reference: 36.6-36.8°C). Results remained robust in multivariable-adjusted analyses accounting for sex, age, diabetes, renal function and hs-cTnT. However, when introducing hs-CRP, the BT-MACE association did not prevail., Conclusions: In prospectively recruited patients with ACS, initial BT shows a U-shaped relationship with 1-year MACE risk among those with NSTE-ACS, but not in those with STEMI. BT is a broadly available low-cost marker to identify ACS patients with high inflammatory burden, at high risk for recurrent ischaemic events, and thus potentially suitable for an anti-inflammatory intervention., Registration: ClinicalTrials.gov Identifier: NCT01000701., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Lipoprotein(a) [Lp(a)] is an LDL-like molecule that is likely causal for cardiovascular events and Lp(a) variability has been shown to be mostly of genetic origin. Exogenous hormones (hormone replacement therapy) seem to influence Lp(a) levels, but the impact of endogenous hormone levels on Lp(a) is still unknown. The aim of the study was to assess the effect of endogenous steroid hormone metabolites on Lp(a)., Methods: Lipoprotein(a) levels were measured in 1,021 participants from the Swiss Kidney Project on Genes in Hypertension, a family-based, multicentre, population-based prospective cohort study. Endogenous levels of 28 steroid hormone precursors were measured in 24-h urine collections from 883 individuals. Of the participants with Lp(a) data, 1,011 participants had also genotypes available., Results: The participants had an average age of 51 years and 53% were female. Median Lp(a) levels were 62 mg/L, and the 90 th percentile was 616 mg/L. The prevalence of a Lp(a) elevation ≥700 mg/L was 3.2%. Forty-three per cent of Lp(a) variability was explained respectively by: age (2%, p < .001), LDL-C (1%, p = .001), and two SNPs (39%, p value<2⋅10 -16 ). Of the 28 endogenous steroid hormones assessed, androstenetriol, androsterone, 16α-OH-DHEA and estriol were nominatively associated with serum Lp(a) levels in univariable analyses and explained 0.4%-1% of Lp(a) variability, but none of them reached significance in multivariable models., Conclusions: In this contemporary population-based study, the prevalence of a Lp(a) elevation ≥700 mg/L was 3.2%. The effect of endogenous steroid hormone levels of Lp(a) variability was small at best, suggesting a negligible impact on the wide range of Lp(a) variability., (© 2021 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Minimal lipoprotein(a) [Lp(a)] target values are advocated for high-risk cardiovascular patients. We investigated the prognostic value of Lp(a) in the acute setting of patients with acute coronary syndromes (ACS)., Materials and Methods: Plasma levels of Lp(a) were collected at time of angiography from 1711 patients hospitalized for ACS in a multicentre Swiss prospective cohort. Associations between elevated Lp(a) ≥30 mg/dL (cut-off corresponding to the 75th percentile of the assay) or Lp(a) tertiles at baseline, and major adverse cardiovascular events (MACE) at 1 year, defined as a composite of cardiac death, myocardial infarction or stroke, were assessed using hazard ratios (HR) and 95% confidence intervals (CI) adjusting for traditional cardiovascular risk factors (age, sex, smoking, diabetes, hypertension, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C] and triglycerides., Results: Lp(a) levels range between 2.5 and 132 mg/dL with a median value of 6 mg/dL and a mean value of 14.2 mg/dL. A total of 276 patients (23.0%) had Lp(a) plasma levels ≥30 mg/dL. Patients with elevated Lp(a) were more likely to be of female gender and to have higher levels of total cholesterol, LDL-C, HDL-C and triglycerides. Higher Lp(a) was associated with failure to reach the LDL-C target <1.8 mmol/L at 1 year (HR 1.71, 95% CI 1.13-2.58, P = 0.01). No association was found between elevated Lp(a) and MACE at 1 year (HR 1.05, 95% CI 0.64-1.73), nor for Lp(a) tertiles (HR 0.82, 95% CI 0.52-1.28, P > 0.20) or standardized continuous variables (0.98, 95% CI 0.82-1.19 for each increase of standard deviation)., Conclusions: Our real-world data suggest high Lp(a) levels at time of angiography are not predictive for cardiovascular outcomes in patients otherwise medically well controlled, but might be useful to identify patients who would not be on LDL-C targets 1 year after ACS., (© 2019 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Childhood obesity is associated with premature cardiovascular complications. However, little is known about the effect of a family-based behavioural intervention on the relationship between arterial function, blood pressure and biomarkers in pre-pubertal children with obesity., Design: This was a single centre randomized controlled trial (RCT) including 74 children randomized to a 6-month behavioural intervention to treat obesity. In 48 children (13 controls and 35 interventions), we assessed: serum level of cytokine (CCL2), adiponectin, and neutrophil product (MMP-8), as well as carotid intima-media thickness, flow-mediated dilation (FMD), nitroglycerin-mediated dilation; arterial stiffness (incremental elastic modulus, Einc), pulse wave velocity (PWV), resting and 24-hour blood pressure (BP)., Results: At baseline, resting systolic BP was positively associated with MMP-8 levels which was significantly higher in children with hypertension (P = 0.033). Biochemical markers were not related to endothelial function at baseline, but they globally increased after 6 months in the intervention group. The significant increase of CCL2 levels in the intervention group was associated with a decrease in diastolic BP. Furthermore, adiponectin change was positively related to a change in FMD and negatively to change in Einc and PWV., Conclusions: The usefulness of serum biomarkers for the detection of cardiovascular diseases is not well established in children. In our population, MMP-8 concentration was higher in hypertensive children. Furthermore, behavioural interventions resulted in a paradoxical increase in some biomarkers in children, with potentially beneficial effects detected with CCL2 changes. Caution should be taken when using nonspecific serum biomarkers for the clinical monitoring of children with obesity., (© 2018 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Apelin is an endogenous peptidergic system which modulates cardiovascular function. Recent studies pointed out a fundamental contribution of apelin on atherosclerosis development; however, such reports revealed contradictory data, and to date, it is difficult to accurately define a beneficial or deleterious role. To better understand apelin function on atherosclerosis, we aimed to investigate apelin-13 treatment effects on atherosclerotic plaques composition., Design: Apolipoprotein E gene-deleted mice were fed on Western-type diet for 11 weeks. Atherosclerotic plaque formation was induced in the carotid artery by a shear stress modifier device, which exposes the same vessel to distinct patterns of shear stress enabling the formation of plaques with different composition. Mice were treated with apelin-13 (2 mg kg -1 day -1 ) or vehicle for the last 3 weeks., Results: Apelin-13 treatment did not alter the lipid content of low shear stress- and oscillatory shear stress-induced plaques in the carotid. However, apelin-13 greatly ameliorated plaque stability by increasing intraplaque collagen content and reducing MMP-9 expression. Furthermore, apelin-13 decreased the infiltration of inflammatory cells (neutrophil and macrophage) and intraplaque reactive oxygen species content. Interestingly, apelin-13 treatment reduced total cholesterol, LDL levels and free fatty acid serum levels, while HDL, triglycerides serum levels were not significantly changed., Conclusions: Apelin-13 treatment for 3 weeks did not alter the lesion size, but it significantly enhanced the stable phenotype of atherosclerotic plaques and improved serum lipid profile. These results indicate that activation of apelin system decreases plaque vulnerability., (© 2018 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Different cut-off values of serum lipoprotein (a) [Lp (a)] were recently identified to better stratify cardiovascular risk categories. Both pathophysiological and prognostic values of Lp (a) remain unclear., Materials and Methods: Here, the prognostic value of Lp (a) and its correlation with intraplaque features were assessed in patients with severe carotid artery stenosis undergoing endarterectomy (n = 180). The cut-off value of 10 mg/dL for serum Lp (a) was selected to predict 24-month follow-up acute coronary syndrome (ACS). In addition, the association between serum Lp (a) and intraplaque lipids, collagen, inflammatory and vascular cells was assessed. Serum Lp (a) levels were measured by nephelometric assay., Results: Patients with high Lp (a) had similar comorbidities, medications and laboratory parameters as compared to low Lp (a) levels. At 24-month follow-up, patients with high Lp (a) had more ACS as compared to low levels. Histological parameters within plaques were comparable in the study groups. No significant correlation between Lp (a) serum levels and intraplaque parameters was found, except for a weak positive association with smooth muscle cells in upstream plaque portions. When adjusted for gender, the presence of dyslipidaemia and chronic coronary artery disease, Lp (a) ≥10 mg/dL remained predictive for ACS., Conclusions: Lp (a) determination could be a useful tool to predict ACS in patients with severe carotid stenosis., (© 2018 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Neutrophil-mediated inflammation was recently identified as an active contributor to athero-progression. Therapeutic strategies inhibiting neutrophil degranulation or recruitment were hypothesized to positively impact on plaque vulnerability. In this study, we investigated whether treatment with the recently discovered agonist of the Mas-related G-coupled receptor type D (MrgD) alamandine would impact on neutrophil degranulation in vivo and in vitro., Materials and Methods: Fifteen-week-old ApoE -/- mice were fed with a Western-type diet for an additional 11 weeks. After the first 2 weeks of diet, mice were surgically implanted with a carotid 'cast' device that alters the blood shear stress and induces different carotid plaque phenotypes. During the last 4 weeks before euthanasia, mice were randomly assigned to subcutaneously receive vehicle (NaCl 0·15 M) or alamandine (24 μg/kg/h) by micropump. For in vitro experiments, neutrophils were obtained after thioglycollate intraperitoneal injection in ApoE -/- mice., Results: Treatment with alamandine was well-tolerated, but failed to affect lipid, macrophage, neutrophil or collagen content within carotid and aortic root plaques. Also, treatment with alamandine did not affect Th-cell polarization in lymphoid organs. Conversely, alamandine administration was associated with a reduction in serum levels of neutrophil granule enzymes, such as MMP-9 and MPO as well as MMP-9 content within aortic root plaques. In vitro, preincubation with alamandine dose-dependently abrogated PMA-induced neutrophil degranulation of MMP-9 and MPO., Conclusion: These results suggest that treatment with the MrgD agonist alamandine led to a reduced release of neutrophil granule products, potentially interfering with pro-atherosclerotic neutrophil activation., (© 2016 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Soluble mediators have been investigated to predict the prognosis of acute ischaemic stroke (AIS). Among them, proprotein convertase subtilisin/kexin type 9 (PCSK9) might have both clinical and pathophysiological relevance., Materials and Methods: All available serum samples from a cohort of patients with first AIS (n = 72) were tested for PCSK9 and included in this substudy analysis. The primary endpoint investigated the predictive value of early PCSK9 level variations (ΔPCSK9) from AIS onset to day 7 or from day 1 to day 7, towards a 90-day outcome by modified Rankin Scale (mRS). The secondary endpoint explored the association between ΔPCSK9 and the risk of major adverse cardiovascular events (MACEs)., Results: Decreased serum PCSK9 levels at days 1 and 7 were associated with poor clinical outcomes at day 90. At the cut-off point identified by ROC curve analysis (-61·28 ng/mL), ΔPCSK9 day 7-day 1 predicted a poor mRS at day 90 after AIS. ΔPCSK9 day 7-day 1 ≤ -61·28 ng/mL was associated with an increased rate of MACEs., Conclusion: A decrease in PCSK9 levels was a predictor for poor outcome and increased MACEs after AIS. Additional studies targeting post-AIS PCSK9 levels and activity are required to clarify the prognostic and pathophysiological relevance of PCSK9 after AIS., (© 2016 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Autoantibodies to apolipoprotein A-1 (anti-ApoA-1 IgG) were shown to predict major adverse cardiovascular events and promote atherogenesis. However, their potential relationship with clinical disability and ischaemic lesion volume after acute ischaemic stroke (AIS) remains unexplored., Materials and Methods: We included n = 76 patients admitted for AIS and we investigated whether baseline serum anti-ApoA-1 IgG levels could predict (i) AIS-induced clinical disability [assessed by the modified Rankin Scale (mRS)], and (ii) AIS-related ischaemic lesion volume [assessed by Computed Tomography (CT)]. We also evaluated the possible pro-apoptotic and pro-necrotic effects of anti-ApoA-1 IgG on human astrocytoma cell line (U251) using flow cytometry., Results: High levels of anti-ApoA-1 IgG were retrieved in 15·8% (12/76) of patients. Increased baseline levels of anti-ApoA-1 IgG were independently correlated with worse mRS [β = 0·364; P = 0·002; adjusted odds ratio (OR): 1·05 (95% CI 1·01-1·09); P = 0·017] and CT-assessed ischaemic lesion volume [β = 0·333; P < 0·001; adjusted OR: 1·06 (95% CI 1·01-1·12); P = 0·048] at 3 months. No difference in baseline clinical, biochemical and radiological characteristics was observed between patients with high vs. low levels of anti-ApoA-1 IgG. Incubating human astrocytoma cells with anti-ApoA-1 IgG dose dependently induced necrosis and apoptosis of U251 cells in vitro., Conclusion: Anti-ApoA-1 IgG serum levels at AIS onset are associated with poorer clinical recovery and worse brain lesion volume 3 months after AIS. These observations could be partly explained by the deleterious effect of anti-ApoA-1 IgG on human brain cell survival in vitro and may have clinical implication in the prediction of poor outcome in AIS., (© 2016 Stichting European Society for Clinical Investigation Journal Foundation.)

Background and Aims: Different adipokines have been associated with atherosclerotic plaque rupture and cardiovascular events, such as acute ischaemic stroke (AIS). However, the potential role of these molecules in postischaemic brain injury remains largely unknown., Methods and Methods: We performed a substudy analysis on nonobese patients with first atherothrombotic stroke (n = 35) from a recently published prospective cohort. Primary endpoint was to investigate the predictive value of serum leptin/adiponectin ratio on neurological recovery at 90 days after AIS. The secondary endpoint was the predictive value of serum adipokine levels of clinical and radiological outcomes at a shorter follow-up (at days 1 and 7 after AIS). The radiological evaluation included ischaemic lesion volume and haemorrhagic transformation (HT). The clinical examination was based on National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS)., Results: At day 1 after AIS, serum leptin and leptin/adiponectin ratio were increased and inversely correlated with both radiological and clinical parameters at all follow-up time points. Once identified the best cut-off points by receiver operating characteristic (ROC) analysis, risk analysis showed that higher circulating leptin improved neurological recovery at day 90. In addition, leptin/adiponectin ratio maintained statistical significance after adjustment for age, gender and thrombolysis, also predicting the occurrence of HT in the first 7 days after AIS (adjusted OR 0·15 [95% CI 0·03-0·83); P = 0·030])., Conclusions: Higher leptin/adiponectin ratio at day 1 predicted better neurological outcomes in patients with atherothrombotic AIS and might be potentially useful as a prognostic biomarker of the disease., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)

Backgound: Regular physical activity is recommended to lower low-density lipoprotein cholesterol (LDL-C) in a healthy population. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) was shown to reduce (LDL-C) levels; however, the impact of physical exercise on PCSK9 levels remains unclear., Materials and Methods: We used data from 67 healthy hospital employees who participated in a 6-month intervention promoting active use of stairs instead of elevators during 3 months, followed by 3 months without recommendation. We confirmed the degree of physical activity with estimated aerobic capacity (VO2 max ) and measured serum PCSK9 levels at baseline, 3 and 6 month. Using a multilevel regression model, we analysed changes of PCSK9 levels over time adjusting for age, gender, aerobic capacity, baseline LDL-C, and LDL-C and body mass index (BMI) changes., Results: At baseline, PCSK9 levels were associated with higher aerobic capacity (P-value = 0·024). At 3 months, we observed a significant decrease in mean PCSK9 levels from 403·6 to 324·3 ng/mL (P-value = 0·001), as well a significant decrease in mean LDL-C levels from 3·5 to 3·3 mM (P-value = 0·01). During this period, mean aerobic capacity (VO2 max ) increased from 37·0 to 40·4 mL/kg/min (P-value < 0·001). Physical activity was independently associated with a decrease in PCSK9 levels after adjustment for age, gender, baseline aerobic capacity, and LDL-C and BMI changes., Conclusion: Daily physical activity at the work place is independently associated with a decrease in PCSK9 levels over time., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: After an acute ischaemic stroke (AIS), several inflammatory biomarkers have been investigated, but their predictive role on functional recovery remains to be validated. Here, we investigated the prognostic relevance of biomarkers related to atherosclerotic plaque calcification, such as osteopontin (OPN), osteoprotegerin (OPG) and the receptor activator of nuclear factor kappa-B ligand (RANKL) in a cohort of patients with AIS (n = 90) during 90-day follow-up., Materials and Methods: Radiological and clinical examinations as well as blood sampling were performed at admission and at days 1, 7 and 90 from the event. Validated scores [such as modified Rankin scale (mRS) and the National Institutes of Health Stroke Scale (NIHSS)] were used to assess poststroke outcome. Serum levels of OPN, OPG and RANKL were measured by colorimetric enzyme-linked immunosorbent assay (ELISA)., Results: When compared to the admission, OPN serum levels increased at day 7. Serum OPN levels at this time point were positively correlated with both ischaemic lesion volume and NIHSS at days 7 and 90. A cut-off of 30.53 ng/mL was identified for serum OPN by receiver operating characteristic (ROC) curve analysis. Adjusted logistic regression showed that serum OPN levels at day 7 predicted worse mRS at day 90 [OR 4.13 (95% CI 1.64-10.36); P = 0.002] and NIHSS [1.49 (95% CI 1.16-1.99); P = 0.007], independently of age, gender, hypertension and thrombolysis., Conclusions: Serum levels of OPN, but not OPG and RANKL, peaked at day 7 after AIS and predicted worse neurological scores. Therefore, OPN might have a pathophysiological and clinical relevance after AIS., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Coronary atherothrombosis due to atherosclerotic plaque rupture or erosion is frequently associated with acute coronary syndromes (ACS). Significant efforts have been made to elucidate the pathophysiological mechanisms underlying acute coronary events., Materials and Methods: This narrative review is based on the material searched for and obtained via PubMed up to August 2014. The search terms we used were as follows: 'angiotensin, acute coronary syndromes, acute myocardial infarction' in combination with 'atherosclerosis, vulnerability, clinical trial, ACE inhibitors, inflammation'., Results: Among several regulatory components, the renin-angiotensin system (RAS) was shown as a key pathway modulating coronary atherosclerotic plaque vulnerability. Indeed, these molecules are involved in all stages of atherogenesis. Classically, the RAS is composed by a series of enzymatic reactions leading to the angiotensin (Ang) II generation and activity. However, the knowledge of RAS has expanded and become more complex. The discovery of novel components and their functions has revealed additional pathways that contribute to or counterbalance the actions of Ang II. In this review, we discussed on recent findings concerning the role of different angiotensin peptides in the pathophysiology of ACS and coronary atherothrombosis, exploring the link between these molecules and atherosclerotic plaque vulnerability., Conclusions: Treatments selectively targeting angiotensins (including Mas and AT2 agonists, ACE2 recombinant, or Ang-(1-7) and almandine in oral formulations) have been tested in animal studies or in small human subgroups, expanding the perspective in the ACS prevention. These novel strategies, especially in the counter-regulatory axis ACE2/Ang-(1-7)/Mas, might be promising to reduce plaque vulnerability and inflammation., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Acute pancreatitis is characterized by inflammatory processes affecting not only the pancreas, but also the lung. Here, we investigated timing of leucocyte infiltration and chemokine expression within lung and pancreas during pancreatitis and whether treatments selectively inhibiting chemokines (using Evasins) could improve organ injury., Material and Methods: C57Bl/6 mice were submitted in vivo to 10-h intraperitoneal injections of cerulein and followed for up to 168 h. Five minutes after the first cerulein injection, a single intraperitoneal injection of 10 μg Evasin-3, 1 μg Evasin-4 or an equal volume of vehicle (PBS) was performed. Leucocytes, reactive oxygen species (ROS), necrosis and chemokine/cytokine mRNA expression were assessed in different organs by immunohistology and real-time RT-PCR, respectively., Results: In the lung, neutrophil infiltration and macrophage infiltration peaked at 12 h and were accompanied by increased CXCL2 mRNA expression. CCL2, CXCL1 and TNF-alpha significantly increased after 24 h as compared to baseline. No increase in CCL3 and CCL5 was observed. In the pancreas, neutrophil infiltration peaked at 6 h, while macrophages increased only after 72 h. Treatment with Evasin-3 decreased neutrophil infiltration, ROS production and apoptosis in the lung and reduced neutrophils, macrophages apoptosis and necrosis in the pancreas. Evasin-4 only reduced macrophage content in the lung and did not provide any benefit at the pancreas level., Conclusion: Chemokine production and leucocyte infiltration are timely regulated in lung and pancreas during pancreatitis. CXC chemokine inhibition with Evasin-3 improved neutrophil inflammation and injury, potentially interfering with damages in acute pancreatitis and related pulmonary complications., (© 2014 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: The natural history of atherosclerosis might involve coronary plaque rupture/erosion, thrombus formation and vessel lumen occlusion, clinically recognized as acute coronary syndrome (ACS). International guidelines strongly recommend early statin administration in patients admitted for ACS. In addition to lowering circulating levels of low-density lipoprotein cholesterol (LDL-c), statin treatment was shown to promote plaque stabilization or regression in several ways, including reduction in necrotic lipid core, anti-inflammatory effects and improvement in endothelial function. The aim of this review is to summarize clinical evidence on the role of statins in secondary prevention of ACS., Materials and Methods: This narrative review is based on the material found on medline and pubmed up to August 2013. We looked for the terms 'statin, acute coronary syndromes' in combination with 'atherosclerosis, acute myocardial infarction, pathophysiology'., Results: This review article emphasizes the relevance of the timing of statin administration to improve the outcomes after ACS. Early and continuous statin administration has emerged as key features to prevent adverse events, especially in patients admitted for ACS undergoing percutaneous coronary intervention. Clinical trials matching the improved clinical outcome with the imaging of atherosclerotic plaque stabilization/regression, further supporting the effectiveness of statin therapy. However, the achievement of these goals requires high dose of statins, thus increasing the risk of adverse events., Conclusions: Although clinical trials and meta-analyses have provided conflicting results, it is likely that in clinical practice, the rate of adverse events is higher, so that many concerns still remain about a statin high-dose approach in ACS patients., (© 2014 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: The clinical history of heart failure (HF) is usually characterized by frequent hospitalizations for decompensation. Therefore, several markers of subclinical hemodynamic congestion are under investigation for predicting early rehospitalization. In this field, the potential of ultrasound inferior vena cava (IVC) assessment has been recently investigated in HF but not yet assessed in the different aetiological categories., Material and Methods: Forty-eight patients admitted for decompensated HF (n = 25 with ischaemic heart disease [IHD] and n = 23 non-IHD) underwent biochemical examination (including NT-proBNP), echocardiography and IVC assessment by hand-carried ultrasound (HCU). During 60-day follow-up after discharge, the re-hospitalization rate for HF was recorded to investigate the predictive power of NT-proBNP and IVC assessment among the two study groups., Results: IHD and non-IHD patients with HF were similar except for gender distribution. During follow-up, 16·7% of patients were rehospitalized for decompensated HF, with higher prevalence in IHD group (28% vs. 4·3% P = 0·031). IVC assessment at discharge significantly predicted re-admission in the overall population and in IHD group, whereas NT-proBNP failed to predict rehospitalization in IHD group. In adjusted hazard ratio, only IVC min and the changes of IVC from admission significantly predicted re-admission. ROC analysis confirmed the change in IVC min as the best predictor of rehospitalization in patients with IHD., Conclusion: This pilot study showed a higher early re-admission rate in patients with HF due to IHD. In addition, the change in IVC min diameter from admission to discharge was the best predictor of re-admission in patients with IHD., (© 2014 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: It is well known that inappropriate or exaggerated activity of the renin-angiotensin system might contribute to the development of systemic hypertension with consequent organ injury and associated increased risk of acute cardiovascular (CV) diseases. This review will discuss evidence form basic research and clinical studies, investigating the efficacy of angiotensin II receptor blockers (ARBs) in the management of acute coronary syndromes (ACS)., Materials and Methods: This narrative review is based on the material found on MEDLINE and PubMed up to June 2013. We looked for the terms 'angiotensin, AT1 receptor, ACE inhibitors' in combination with 'acute coronary syndromes, acute myocardial infarction, pathophysiology'., Results: Preclinical studies showed relevant protective effects of ARBs to reduce adverse cardiac remodelling in animal models of acute cardiac ischaemia. However, although recommended in Consensus guidelines as a good alternative to angiotensin-converting enzyme inhibitors (ACEIs), clinical studies did not confirm a superior efficacy of the ARBs as compared to ACEIs. As a matter of fact for some authors, these drugs might potentially have deleterious effects increasing the CV risk., Conclusions: Emerging evidence from clinical trials suggests that the use of ARBs in ACS might be controversial, and caution should be used for their clinical use to replace ACEIs in ACS., (© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: Abdominal aortic aneurysm (AAA) is a complex degenerative disease, which leads to morbidity and mortality in a large portion of the elderly population. Current treatment options for AAA are quite limited as there is no proven indication for pharmacological therapy and surgery is recommended for AAA larger than 5·5 cm in luminal diameter. Thus, there is a great need to elucidate the underlying pathophysiological cellular and molecular mechanisms to develop effective therapies. In this narrative review, we will discuss recent findings concerning some potential molecular and clinical aspects of the renin-angiotensin system (RAS) in AAA pathophysiology., Materials and Methods: This narrative review is based on the material found on MEDLINE and PubMed up to April 2013. We looked for the terms 'angiotensin, AT1 receptor, ACE inhibitors' in combination with 'abdominal aortic aneurysm, pathophysiology, pathways'., Results: Several basic research and clinical studies have recently investigated the role of the RAS in AAA. In particular, the subcutaneous infusion of Angiotensin II has been shown to induce AAA in Apo56 knockout mice. On the other hand, the pharmacological treatments targeting this system have been shown as beneficial in AAA patients., Conclusions: Emerging evidence suggests that RAS may act as a molecular and therapeutic target for treating AAA. However, several issues on the role of RAS and the protective activities of angiotensin-converting enzyme (ACE) inhibitors and Angiotensin 1 receptors blockers against AAA require further clarifications., (© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: The renin-angiotensin system (RAS) has been shown to play an active role within the erectile tissues. The aim of this narrative review is to summarize the literature addressing the pathophysiological role of RAS on erectile function. Additionally, we update evidence on recent findings on the role of the Ang-(1-7) and Mas receptor on the erectile function and its therapeutic potential for treating erectile dysfunction (ED)., Materials and Methods: This narrative review is based on the material searched and obtained via MEDLINE and PubMed up to November 2012. The search terms we used are 'angiotensin, erectile dysfunction, renin, Mas receptor' in combination with 'pathophysiology, fibrosis, pathways'., Results: The levels of angiotensin (Ang) II, the main component of this system, are increased in the corpus cavernosum as compared to those found in the systemic circulation. Moreover, emerging evidence indicates that an increased activity of Ang II via AT1 receptor might contribute to the development of ED, whereas the pharmacological blockage of Ang II/AT1 actions has beneficial effects on the erection. On the other hand, the heptapeptide Ang-(1-7), known as a major endogenous counter-regulator of Ang II actions, favours penile erection via the activation of Mas receptor., Conclusions: Ang-(1-7) and Mas receptor pathway might be considered as a promising therapeutic target for the treatment of ED., (© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: Cardiovascular risk markers are related to micro-angiopathy in children with type 1 diabetes (T1DM), but there is no information about their relationship with blood pressure (BP) and endothelial function., Materials and Methods: This was a case-control study including 29 children with T1DM (mean age 10·5 ± 2·7 years, disease duration: 3·8 ± 2·2 years) and 39 healthy controls (mean age: 9·8 ± 2·7 years). We assessed 24-h ambulatory BP, vascular function and serum level of lipids, vascular cell adhesion molecule-1 (VCAM-1; ICAM) and selectins (E-selectin; P-selectin)., Results: The subject groups had similar physical characteristics and lipids level, except body mass index (BMI) which was higher in T1DM than in healthy children (18·6 ± 2·6 vs. 16·7 ± 2·5 kg/m(2), P = 0·003). Children with T1DM had increased 24 h diastolic BP z-score (0·62 ± 0·9 vs. -0·65 ± 0·8, P < 0·001), even after adjustment for BMI, as well as higher VCAM-1 concentration (492 ± 346 vs. 340 ± 225 ng/mL, P = 0·039) compared to healthy subjects. Diastolic BP z-scores were associated with disease duration, E-selectin and triglyceride levels in the T1DM group (P < 0·05). E-selectin was also related to triglycerides, otherwise there were no relationships between vascular function, markers and BP., Conclusion: E-selectin, an early atherosclerosis biomarker, is positively associated with diastolic BP values in children with T1DM, despite relatively short disease duration., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Coronary artery disease (CAD) represents the most relevant cause of death and morbidity in the adult population of developed and developing countries. During the last decades, a strong research effort has been performed to identify more selective markers and better assess the cardiovascular risk in both primary and secondary prevention., Materials and Methods: This review updates current knowledge regarding the pathophysiological relevance as possible markers of coronary calcification of the receptor activator of nuclear factor-kappa ligand (RANKL)/osteoprotegerin (OPG) system. Furthermore, the potential clinical use of both RANKL/OPG and coronary calcium score (CAC) to assess cardiovascular vulnerability has been discussed., Results: Emerging evidence indicates that atherosclerotic plaque calcification is positively correlated with vulnerability. Several inflammatory mediators have been shown to modulate arterial calcification, thus increasing the risk of plaque rupture. Among these factors, RANKL/OPG axis might be of particular interest as a promising biomarker of plaque vulnerability in subjects with diffuse coronary calcification., Conclusion: Together with clinical parameters of coronary calcification (such as CAC), circulating RANKL/OPG levels could contribute to better assess and predict cardiac events.