Katerina K. Naka

The role of vascular biomarkers for primary and secondary prevention. A position paper from the European Society of Cardiology Working Group on peripheral circulation: Endorsed by the Association for Research into Arterial Structure and Physiology (ARTERY) Society

While risk scores are invaluable tools for adapted preventive strategies, a significant gap exists between predicted and actual event rates. Additional tools to further stratify the risk of patients at an individual level are biomarkers. A surrogate endpoint is a biomarker that is intended as a substitute for a clinical endpoint. In order to be considered as a surrogate endpoint of cardiovascular events, a biomarker should satisfy several criteria, such as proof of concept, prospective validation, incremental value, clinical utility, clinical outcomes, cost-effectiveness, ease of use, methodological consensus, and reference values. We scrutinized the role of peripheral (i.e. not related to coronary circulation) noninvasive vascular biomarkers for primary and secondary cardiovascular disease prevention. Most of the biomarkers examined fit within the concept of early vascular aging. Biomarkers that fulfill most of the criteria and, therefore, are close to being considered a clinical surrogate endpoint are carotid ultrasonography, ankle-brachial index and carotid-femoral pulse wave velocity; biomarkers that fulfill some, but not all of the criteria are brachial ankle pulse wave velocity, central haemodynamics/wave reflections and C-reactive protein; biomarkers that do no not at present fulfill essential criteria are flow-mediated dilation, endothelial peripheral arterial tonometry, oxidized LDL and dysfunctional HDL. Nevertheless, it is still unclear whether a specific vascular biomarker is overly superior. A prospective study in which all vascular biomarkers are measured is still lacking. In selected cases, the combined assessment of more than one biomarker may be required.

Automated Diagnosis of Coronary Artery Disease Based on Data Mining and Fuzzy Modeling

A fuzzy rule-based decision support system (DSS) is presented for the diagnosis of coronary artery disease (CAD). The system is automatically generated from an initial annotated dataset, using a four stage methodology: 1) induction of a decision tree from the data; 2) extraction of a set of rules from the decision tree, in disjunctive normal form and formulation of a crisp model; 3) transformation of the crisp set of rules into a fuzzy model; and 4) optimization of the parameters of the fuzzy model. The dataset used for the DSS generation and evaluation consists of 199 subjects, each one characterized by 19 features, including demographic and history data, as well as laboratory examinations. Tenfold cross validation is employed, and the average sensitivity and specificity obtained is 62% and 54%, respectively, using the set of rules extracted from the decision tree (first and second stages), while the average sensitivity and specificity increase to 80% and 65%, respectively, when the fuzzification and optimization stages are used. The system offers several advantages since it is automatically generated, it provides CAD diagnosis based on easily and noninvasively acquired features, and is able to provide interpretation for the decisions made.

Endothelial function, but not carotid intima-media thickness, is affected early in menopause and is associated with severity of hot flushes.

CONTEXT The effect of early menopause on indices of vascular function has been little studied. OBJECTIVE The objective of the study was to investigate the effect of early menopause on indices of subclinical atherosclerosis and identify predictors of those indices in early menopausal women. DESIGN, SETTING, AND PARTICIPANTS This was a cross-sectional study that included 120 early menopausal women (age range 42-55 yr, <3 yr in menopause) recruited from the menopause outpatient clinic of an academic hospital and 24 age-matched premenopausal women. MAIN OUTCOME MEASURES Brachial artery flow-mediated dilation (FMD) and common carotid intima-media thickness (IMT) were studied. Estrogen receptor (ER)-alpha (rs2234693 T-->C and rs9340799 A-->G) and ERbeta (rs4986938 A-->G) polymorphisms were studied in menopausal women. RESULTS FMD was significantly lower in early menopausal women compared with controls (5.43 +/- 2.53 vs. 8.74 +/- 3.17%, P < 0.001), whereas IMT did not differ between groups (P > 0.8). Severity of hot flushes was the most important independent predictor for FMD (P < 0.001) in menopausal women. Women with moderate/severe/very severe hot flushes had impaired FMD in contrast to women with no/mild hot flushes or controls. Women with no/mild hot flushes did not differ compared with controls. Age and systolic blood pressure were the main determinants of IMT (both P = 0.004). ER polymorphisms were not associated with vascular parameters. CONCLUSIONS Impairment of endothelial function is present in the early menopausal years, whereas carotid IMT is not affected. Severity of hot flushes is the main determinant of endothelial dysfunction in early menopausal women. The studied ER polymorphisms do not offer important information on vascular health in early menopause.

The Effect of Shear Stress on Neointimal Response Following Sirolimus- and Paclitaxel-Eluting Stent Implantation Compared With Bare-Metal Stents in Humans

OBJECTIVES We aimed to explore the relationship of neointimal thickness (NT) to shear stress (SS) after implantation of sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) compared with bare-metal stents (BMS). We then tested the hypothesis that drug elution attenuates the SS effect. BACKGROUND Neointimal thickness after BMS implantation has been associated with SS; pertinent data for drug-eluting stents (DES) are limited. METHODS Three-dimensional coronary artery and stent reconstruction was performed in 30 patients at 6-month follow-up after SES (n = 10), PES (n = 10), or BMS (n = 10) implantation. Baseline SS at the stent surface was calculated using computational fluid dynamics and NT at follow-up was computed in 3-dimensional space. RESULTS Neointimal thickness was lower in DES versus BMS (0.03 ± 0.07 mm vs. 0.16 ± 0.08 mm, p < 0.001) and maximum NT was reduced in SES versus PES (0.33 ± 0.13 mm vs. 0.46 ± 0.13 mm, p = 0.025). In the total population, both SS (slope: -0.05 mm/Pa, p < 0.001) and DES (coefficient for DES vs. BMS: -0.17 mm, p = 0.003) were independent predictors of NT. Subgroup analysis demonstrated a significant negative relationship of NT to SS in PES (slope: -0.05 mm/Pa, p = 0.016) and BMS (slope: -0.05 mm/Pa, p = 0.001). Sirolimus elution significantly attenuated the effect of SS on NT (interaction coefficient for SES vs. BMS: 0.04 mm/Pa, p = 0.023), whereas the SS effect remained unchanged in PES (interaction coefficient for PES vs. BMS: 0.01 mm/Pa, p = 0.71). CONCLUSIONS Neointimal thickness is significantly correlated (inversely) to SS in PES as in BMS. Sirolimus elution abrogates the SS effect on the neointimal response following stent implantation, whereas the SS effect is unchanged in PES.

An Automated Methodology for Fetal Heart Rate Extraction From the Abdominal Electrocardiogram

This paper introduces an automated methodology for the extraction of fetal heart rate from cutaneous potential abdominal electrocardiogram (abdECG) recordings. A three-stage methodology is proposed. Having the initial recording, which consists of a small number of abdECG leads in the first stage, the maternal R-peaks and fiducial points (QRS onset and offset) are detected using time-frequency (t-f) analysis and medical knowledge. Then, the maternal QRS complexes are eliminated. In the second stage, the positions of the candidate fetal R-peaks are located using complex wavelets and matching theory techniques. In the third stage, the fetal R-peaks, which overlap with the maternal QRS complexes (eliminated in the first stage) are found using two approaches: a heuristic algorithm technique and a histogram-based technique. The fetal R-peaks detected are used to calculate the fetal heart rate. The methodology is validated using a dataset of eight short and ten long-duration recordings, obtained between the 20th and the 41st week of gestation, and the obtained accuracy is 97.47%. The proposed methodology is advantageous, since it is based on the analysis of few abdominal leads in contrast to other proposed methods, which need a large number of leads.

Determinants of vascular function in patients with type 2 diabetes

BackgroundType 2 diabetes mellitus (T2DM) is independently associated with an increased risk for cardiovascular diseases that is primarily due to the early development of advanced atherosclerotic vascular changes. The aim of our study was to investigate the predictors of vascular dysfunction in T2DM patients.MethodsWe studied 165 T2DM patients without known macrovascular or microvascular disease. Standard demographic (age, gender, cardiovascular risk factors, medications), clinical (body mass index, blood pressure) and laboratory (glucose, glycated hemoglobin, lipids, renal function) parameters were included in analyses. Brachial artery flow-mediated dilation (FMD), nitrate mediated dilation (NMD) and Carotid-Femoral Pulse Wave Velocity (PWV) were measured.ResultsMedian age was 66 years and duration since T2DM diagnosis was 10 years, 70% were females and 79% hypertensives, while only 10% had a glycated hemoglobin <7%. FMD was positively associated with NMD (r 0.391, P < 0.001), while PWV was inversely associated with FMD (r -0.218, P = 0.014) and NMD (r -0.309, P < 0.001). Time since diagnosis of diabetes was the single independent predictor of FMD (β -0.40, P = 0.003). Increased age and fasting glucose and the presence of hypertension were independent predictors of decreased NMD (P < 0.001). Increased age and systolic blood pressure were independently associated with increased PWV (P < 0.001).ConclusionsIn T2DM patients, impairment of endothelium-dependent vasodilation was independently associated only with longer diabetes duration while no association with other established risk factors was found. Vascular smooth muscle dysfunction and increased arterial stiffness were more prominent in older T2DM patients with hypertension. Worse glycemic control was associated with impaired vascular smooth muscle function.

Enoxaparin versus tinzaparin in non-ST–segment elevation acute coronary syndromes: the EVET trial

BACKGROUND Low-molecular weight heparins have different pharmacokinetic and pharmacodynamic characteristics and may vary in efficacy. We compared the efficacy of enoxaparin with that of tinzaparin in the management of non-ST-segment elevation acute coronary syndromes (NSTACS). METHODS A total of 438 patients with NSTACS were randomized to receive subcutaneous treatment with enoxaparin, 100 IU/kg twice daily (equivalent to 1 mg/kg twice daily; n = 220), or tinzaparin, 175 IU/kg once daily, (n = 218) for as long as 7 days. The primary composite end point was recurrent angina, myocardial infarction (or reinfarction), or death at day 7. Secondary end points were the primary end point at day 30 and the occurrence of individual events at days 7 and 30. RESULTS The incidence of the primary end point was 12.3% in the enoxaparin group and 21.1% in the tinzaparin group (P =.015). At day 7, the rate of recurrent angina was lower with enoxaparin than with tinzaparin (11.8% vs 19.3%). At day 30, the incidences of the composite end point, recurrent angina, and myocardial infarction were also lower with enoxaparin, 17.7% vs 28.0% (P =.012), 17.3% vs 26.1% and 0.5% vs 2.8%, respectively. The rate of revascularization was lower in the enoxaparin group, 8.6% vs 17.9% (P =.010) at day 7 and 16.4% vs 26.1% (P =.019) at day 30. Rates of bleeding complications were similar in the 2 treatment groups. CONCLUSIONS This study indicates a benefit of enoxaparin (100 IU/kg twice daily) as compared with tinzaparin (175 IU/kg once daily) in the treatment of patients with NSTACS, which is sustained for at least 30 days.

Premature ovarian failure, endothelial dysfunction and estrogen–progestogen replacement

Cardiovascular disease, including coronary artery disease, stroke and peripheral vascular disease, is the leading cause of death among women. Vascular endothelial dysfunction is an early marker of atherosclerosis. Women with premature ovarian failure (or premature menopause) present an increased risk for cardiovascular disease, which might be attributed to the early onset of vascular endothelial dysfunction, associated with sex steroid deficiency. Cyclical estrogen and progestogen therapy has been shown to restore endothelial function in these young women. Further research is required to assess primarily the long-term effects of hormone replacement therapy on cardiovascular and overall prognosis in young women with premature ovarian failure, as well as the effects of different doses, duration and routes of hormone administration in these women.

Hybrid intravascular imaging: current applications and prospective potential in the study of coronary atherosclerosis.

The miniaturization of medical devices and the progress in image processing have allowed the development of a multitude of intravascular imaging modalities that permit more meticulous examination of coronary pathology. However, these techniques have significant inherent limitations that do not allow a complete and thorough assessment of coronary anatomy. To overcome these drawbacks, fusion of different invasive and noninvasive imaging modalities has been proposed. This integration has provided models that give a more detailed understanding of coronary artery pathology and have proved useful in the study of the atherosclerotic process. In this review, the authors describe the currently available hybrid imaging approaches, discuss the technological innovations and efficient algorithms that have been developed to integrate information provided by different invasive techniques, and stress the advantages of the obtained models and their potential in the study of coronary atherosclerosis.

Oleuropein prevents doxorubicin-induced cardiomyopathy interfering with signaling molecules and cardiomyocyte metabolism

Oleuropein, a natural phenolic compound, prevents acute doxorubicin (DXR)-induced cardiotoxicity but there is no evidence regarding its role in chronic DXR-induced cardiomyopathy (DXR-CM). In the present study, we investigated the role of oleuropein in DXR-CM by addressing cardiac geometry and function (transthoracic echocardiography), cardiac histopathology, nitro-oxidative stress (MDA, PCs, NT), inflammatory cytokines (IL-6, Big ET-1), NO homeostasis (iNOS and eNOS expressions), kinases involved in apoptosis and metabolism (Akt, AMPK) and myocardial metabonomics. Rats were randomly divided into 6 groups: Control, OLEU-1 and OLEU-2 [oleuropein at 1000 and 2000 mg/kg in total, respectively, intraperitoneally (i.p.) for 14 days], DXR (18 mg/kg, i.p. divided into 6 equal doses for 2 weeks), DXR-OLEU-1 and DXR-OLEU-2 (both oleuropein and DXR as previously described). Impaired left ventricular contractility and inflammatory and degenerative pathology lesions were encountered only in the DXR group. The DXR group also had higher MDA, PCs, NT, IL-6 and Big ET-1 levels, higher iNOS and lower eNOS, Akt and AMPK activation compared to controls and the oleuropein-treated groups. Metabonomics depicted significant metabolite alterations in the DXR group suggesting perturbed energy metabolism and protein biosynthesis. The effectiveness of DXR in inhibiting cell proliferation is not compromised when oleuropein is present. We documented an imbalance between iNOS and eNOS expressions and a disturbed protein biosynthesis and metabolism in DXR-CM; these newly recognized pathways in DXR cardiotoxicity may help identifying novel therapeutic targets. Activation of AMPK and suppression of iNOS by oleuropein seem to prevent the structural, functional and histopathological cardiac effects of chronic DXR toxicity.