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Thyroid hormone (TH) signaling is strictly regulated by iodothyronine deiodinase activity, which both preserves the circulating levels of the biologically active triiodothyronine (T3) and regulates TH homeostasis at the local level, in a cell- and time-dependent manner. Three deiodinases have been identified—namely iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3—that differ in their catalytic properties and tissue distribution. The deiodinases represent a dynamic system that changes in the different stages of life according to their functions and roles in various cell types and tissues. Deiodinase activity at the tissue level permits cell-targeted fine regulation of TH homeostasis, mediating the activation (DIO1 and DIO2) and inactivation (DIO3) of THs. Deiodinase homeostasis is the driving force that leads T3-target cells towards customized TH signaling, which takes into account both the hormonal circulating levels and the tissue-specific response. This review analyzes the complex role of deiodinases in physiological and pathological contexts, exploring new challenges and opportunities deriving from a deeper knowledge of the dynamics underlying their roles and functions.

Selenium (Se), a microelement essential for life, is critical for homeostasis of several critical functions, such as those related to immune–endocrine function and signaling transduction pathways. In particular, Se is critical for the function of the thyroid, and it is particularly abundant in this gland. Unfortunately, Se deficiency is a very common condition worldwide. Supplementation is possible, but as Se has a narrow safety level, toxic levels are close to those normally required for a correct need. Thus, whether the obtaining of optimal selenium concentration is desirable, the risk of dangerous concentrations must be equally excluded. This review addressed the contribution by environment and food intake on Se circulating levels (e.g., geographical factors, such as soil concentration and climate, and different quantities in food, such as nuts, cereals, eggs, meat and fish) and effects related to its deficiency or excess, together with the role of selenium and selenoproteins in the thyroid pathophysiology (e.g., Hashimoto’s thyroiditis and Graves’ disease).

Background and Aims: Vitamin D counteracts the reduction in the peripheral conversion of tiroxine (T4) into triiodothyronine (T3), which is the mechanism of low T3 syndrome (LT3) in acute myocardial infarction (AMI). The aim of this study was to assess the relationship between LT3 and hypovitaminosis D in AMI patients. Methods and Results: One hundred and twenty-four AMI patients were enrolled. Blood samples were taken at admission, and at 3, 12, 24, 48, and 72 h after admission. LT3 was defined as a value of fT3 ≤ 2.2 pg/mL, occurring within 3 days of hospital admission. Levels were defined as follows: sufficiency as a value of ±30 ng/mL, vitamin D insufficiency as 25-hydroxyvitamin D (25(OH)D) between 21 and 29 ng/mL, deficiency in 25(OH)D as below 20 ng/mL, and severe deficiency as values under 10 ng/mL. The percentage of subjects with severe 25(OH)D deficiency was significantly higher in the LT3 group (33% vs. 13%, p &lt, 0.01). When LT3S was evaluated as a dependent variable, severe 25(OH)D deficiency (OR 2.6: 95%CI 1–6.7, p &lt, 0.05) remained as an independent determinant after logistic multivariate adjustment together with age (&gt, 69 yrs, 50th percentile, OR 3.4, 95% CI 1.3–8.3, p &lt, 0.01), but not female gender (OR 1.7, 95% CI 0.7–4.2, p = ns). Conclusions: This pilot study shows a relationship between hypovitaminosis D and LT3 in AMI patients. This association opens potential therapeutic challenges concerning the restoration of euthyroidism through vitamin D administration, together with the normalization of hypovitaminosis.

The role of thyroid hormones (THs) in the cardiovascular (CV) system, through several direct and indirect effects is recognized. Even very small modification in TH levels (as those observed in subclinical hypothyroidism or hyperthyroidism, and low triiodothyronine syndrome) may adversely affect the CV system, whereas thyroid hormones benefit the CV system and improve the prognosis. There is also evidence of vitamin D effects on cardiometabolic disease (e.g., through modulation of endothelial and smooth muscle cell activity, renin-angiotensin-aldosterone system, nitric oxide, oxidative stress, and inflammatory response), as well as an association between vitamin D [25(OH)D] deficiency and autoimmune thyroid diseases or cancer, and a relationship between vitamin D concentration and titers of antibodies and thyroid autoimmunity replacement. Interestingly, experimental data indicate a direct effect of vitamin D on Type 2 deiodinase expression causing subsequential peripheral conversion of T4 into T3. However, the functional links among THs, vitamin D and the cardiovascular system, and clinical effects of coexisting abnormalities in this new troublesome triad, have not yet been reviewed. The main aim of this review is to discuss pathophysiology of this relationship, proposing new mechanistic insights involving vitamin D in the modulation of cardiometabolic disease and thyroid profile.

The endothelium controls vascular homeostasis through a delicate balance between secretion of vasodilators and vasoconstrictors. The loss of physiological homeostasis leads to endothelial dysfunction, for which inflammatory events represent critical determinants. In this context, therapeutic approaches targeting inflammation-related vascular injury may help for the treatment of cardiovascular disease and a multitude of other conditions related to endothelium dysfunction, including COVID-19. In recent years, within the complexity of the inflammatory scenario related to loss of vessel integrity, hydrogen sulfide (H2S) has aroused great interest due to its importance in different signaling pathways at the endothelial level. In this review, we discuss the effects of H2S, a molecule which has been reported to demonstrate anti-inflammatory activity, in addition to many other biological functions related to endothelium and sulfur-drugs as new possible therapeutic options in diseases involving vascular pathobiology, such as in SARS-CoV-2 infection.

Among the various factors that could influence health-related quality of life (HRQoL) in adolescence, body mass index (BMI) seems to play a key role as a main anthropometric parameter. The aim of this cross-sectional study was to determine, in a sample of Italian adolescents, whether HRQoL is associated with the different weight status categories (underweight, normal weight, overweight, obese), according to BMI cut-off points for children, even considering sex differences. Data were collected from 1707 adolescents (n = 828 males) in seven schools. HRQoL was analyzed using the Italian version of KIDSCREEN-52. Males were more overweight and obese than females (13% vs. 10% and 4% vs. 2%, p &lt, 0.05, respectively). In females, BMI categories are associated with physical well-being (p &lt, 0.05), emotion/mood (p &lt, 0.05), self-perception (p &lt, 0.001), financial resources (p &lt, 0.05), and bullying behavior (p &lt, 0.05). In males, weight status is linked to physical well-being dimension (p &lt, 0.001) and perception of self (p &lt, 0.05). Our results may suggest that there is an association between weight status categories and HRQoL, more pronounced in females than in males. Interestingly, the weight status correlated more with the psychological dimension mainly in females, whereas in males, a stronger association between weight and physical status was observed, suggesting that given the complex, multifaceted, and dynamic nature of relationship between health-related quality of life and weight status in adolescents, multiple factors must be considered.

The incidence and prevalence of type 2 diabetes have increased in the last decades and are expected to further grow in the coming years. Chronic hyperglycemia triggers free radical generation and causes increased oxidative stress, affecting a number of molecular mechanisms and cellular pathways, including the generation of advanced glycation end products, proinflammatory and procoagulant effects, induction of apoptosis, vascular smooth-muscle cell proliferation, endothelial and mitochondrial dysfunction, reduction of nitric oxide release, and activation of protein kinase C. Among type 2 diabetes determinants, many data have documented the adverse effects of environmental factors (e.g., air pollutants) through multiple exposure-induced mechanisms (e.g., systemic inflammation and oxidative stress, hypercoagulability, and endothelial and immune responses). Therefore, here we discuss the role of air pollution in oxidative stress-related damage to glycemic metabolism homeostasis, with a particular focus on its impact on health. In this context, the improvement of new advanced tools (e.g., omic techniques and the study of epigenetic changes) may provide a substantial contribution, helping in the evaluation of the individual in his biological totality, and offer a comprehensive assessment of the molecular, clinical, environmental, and epidemiological aspects.

Background: Prediabetes (preT2D) is considered a subtle adverse cardiovascular (CV) risk factor after acute myocardial infarction. Glycated hemoglobin (HbA1c) ranges to identify preT2D are different between ADA and WHO guidelines (5.7–6.4 vs. 6.0–6.4%, respectively). Aim: To evaluate the prognostic value of HbA1c different preT2D-ranges and their correlation with demographic, instrumental, and laboratory parameters in STEMI. Methods: A total of 1681 patients (mean age 67 ± 13 years, 1217 males) were enrolled. Admission HbA1c was used to identify patients with no-T2D (&lt, 5.7%), HbA1c 5.70–5.99%, and WHO-preT2D with HbA1c 6–6.49%, and T2D (HbA1c ≥ 6.5). Results: HbA1c 5.7–5.99, WHO-preT2D, and T2D progressively correlated with an increasing number of CV risk factors. However, only T2D, but not preT2D, was significantly associated with adverse prognosis (in-hospital and one-year death). Conclusions: PreT2D is correlated with CV risk factors, but not with adverse prognosis as compared to no-T2D. Nonetheless, routine HbA1c testing in the STEMI population and HbA1c-5.7–5.99 patient inclusion in the preT2D category may help to identify those who may benefit from intervention and lifestyle strategies to early prevent preT2D progression.

Background Glycated haemoglobin (HbA1c) test, introduced for diagnosing prediabetes and diabetes by the American Diabetes Association for some years, is currently under extensive discussion for contradictory data on the concordance between this test and the oral glucose tolerance test (OGTT). Hypothesis To assess concordance between HbA1c and OGTT to diagnose prediabetes and diabetes in subjects with overweight or obesity, focusing on possible gender-related differences. Methods A total of 949 outpatients with overweight or obesity at risk for diabetes (mean age 50 ± 15 years; 660 F) were enrolled and underwent HbA1c test and OGTT. Results In both genders, HbA1c test identified more patients with prediabetes than OGTT (42% vs 22% in males, 40% vs 18% in females, respectively): a slight concordance between HbA1c and OGTT (60% of total tests in both genders). In subjects diagnosed by OGTT, post-OGTT insulin levels and HOMA INDEX were significantly higher than those found in HbA1c(+) cases. Instead, those diagnosed with HbA1c were significantly older and showed higher uric acid than those with both tests (-). Conclusions HbA1c test and OGTT did not reach full concordance for the diagnosis of diabetes and prediabetes in both genders. The two tests likely reflect different physiopathological aspects of dysglycaemia, suggesting that the 'diagnostic thresholds' could be reconsidered in light of the discordance observed.

Coronavirus disease 2019 (COVID-19) has quickly become a worldwide health crisis.Although respiratory disease remains the main cause of morbidity and mortality in COVID patients,myocardial damage is a common finding. Many possible biological pathways may explain therelationship between COVID-19 and acute myocardial infarction (AMI). Increased immune andinflammatory responses, and procoagulant profile have characterized COVID patients. All theseresponses may induce endothelial dysfunction, myocardial injury, plaque instability, and AMI.Disease severity and mortality are increased by cardiovascular comorbidities. Moreover, COVID-19has been associated with air pollution, which may also represent an AMI risk factor. Nonetheless,a significant reduction in patient admissions following containment initiatives has been observed,including for AMI. The reasons for this phenomenon are largely unknown, although a real decreasein the incidence of cardiac events seems highly improbable. Instead, patients likely may presentdelayed time from symptoms onset and subsequent referral to emergency departments because offear of possible in-hospital infection, and as such, may present more complications. Here, we aim todiscuss available evidence about all these factors in the complex relationship between COVID-19and AMI, with particular focus on psychological distress and the need to increase awareness ofischemic symptoms.

All the latest international guidelines recommend that cardiac troponin (cTn) I and T should be considered the preferred biomarkers for diagnosis of acute myocardial infarction. However, only in the last 5 years, a progressive improvement in analytical performance of immunometric assays has allowed the measurement of circulating levels of cTnI and cTnT in the large part of apparently healthy adult subjects. The routine use of these high-sensitivity methods for cardiac troponin (hs-cTn) assay has in a short time demonstrated that cardiac troponin concentrations frequently increase after strenuous prolonged exercise in healthy athletes. This acute response of hs-cTn assay following exercise was at first considered to be physiological and without long-term adverse consequences. More recent studies have suggested that exercise-induced increases in hs-cTn values may not be always a physiological response to exercise, but, conversely, it should sometimes be considered as an early cardiovascular risk marker. The aim of this review is to provide an overview of acute and chronic effects of strenuous physical exercise on hs-cTn circulating levels and also to discuss the potential pathophysiological and clinical implications of biomarker responses.

Ischemic heart disease is the main cause of morbidity and mortality worldwide and is becoming more widespread with population aging. Cardioprotection is a dynamic process characterized by mechanisms related to myocardial damage and activation of protective factors. Targeting these processes could be attractive as a new therapeutic strategy in the evolution of post-ischemic heart failure (HF). In this context, the role of thyroid hormone (TH)-mediated cardioprotection is supported by a number of findings regarding the modulation of neuroendocrine systems, inflammatory and oxidative stress status, pro-survival intracellular pathways, and epigenetic factors, its effects on cardiac angiogenesis, structure, and function and on the preservation of mitochondrial function and morphology, and its beneficial effects on cell growth and redifferentiation. Moreover, the numerous effects of TH on the heart involve genomic mechanisms, which include cardiac differentiation during the perinatal period and non-genomic action, directed toward the maintenance of cardiovascular homeostasis. This evidence suggests that there is an opportunity to treat HF patients with TH. This review is mainly focused on the clinical evidence of the role of the thyroid system in the complex setting of HF.

Increased or reduced action of thyroid hormones (THs), both hyper- and hypothyroidism, may have relevant cardiovascular effects, which include regulation of cardiac contractility and heart rate, diastolic function, and systemic vascular resistance, thus affecting the onset and development of heart failure (HF). Many of these actions are determined by thyroid-induced oxidative stress modulation, for example, through the direct production of hydrogen peroxide (H2O2) during the synthesis of THs. Oxidative stress alteration, as both increased oxidative stress and reduced availability of antioxidants, exacerbated oxidation of low density lipoproteins, modulated nitric oxide bioavailability, and increased inflammation. These events have been clearly involved in any phase of HF development and extent. The present review aims to discuss oxidative stress status under altered thyroid states in HF pathology.

Aim: to evaluate the relationship between uric acid (UA), hepatic and cardiac iron overload (T2*-MRI), ferritin, endocrinological diseases and cardiac complications in a large thalassemia major (TM) cohort. Methods: A total of 369 TM patients (187 men; 33 ± 6 years) were retrospectively studied, from the myocardial iron overload in thalassemia (MIOT) electronic databank. Results: Multiple regression model identified male sex (p 3 mg/g/dw), heart failure, endocrinopathies, ferritin (>2000 ng/l), alanine transaminase (>40 UI/l) and/or aspartate transaminase (>35 UI/l) and/or glutamyl transferase (>64 UI/l). Discussion: UA appears directly associated to T2* and inversely with derivatives of reactive oxygen species, and as such reduced according to increased oxidative stress and cardiac iron overload in TM patients.

Aim: Evaluation of gender-related differences in uric acid (UA), homocysteine and inflammatory biomarkers as metabolic syndrome (MetS) determinants. Patients & methods: Anthropometric and routine data were obtained from 825 obese subjects (591 F, mean age 54 ± 14 years). Results: Hyperuricemia was 24% in both genders. Waist circumference, creatinine, triglycerides, C-reactive protein and γ-glutamyltransferase were identified as UA-independent determinants in females and creatinine and insulin in males. Hyperuricemia increased MetS risk in both genders (2.8-fold and 1.5-fold in males and females). Conclusion: UA and γ-glutamyltransferase positively relate to MetS in both genders, although inflammatory abnormalities are closer related to UA and MetS in females. These differences in gender physiology may account for epidemiologic gender disparities and help to develop gender-targeted clinical strategies.

Background Sarcopenia is the progressive loss of muscle mass and strength that occurs with advancing age and plays a pivotal role in the causal pathway leading to frailty, disability and, eventually, to death among older persons. As oxidative damage of muscle proteins has been shown to be a relevant contributory factor, in this study we hypothesized that uric acid (UA), a powerful endogenous antioxidant, might exert a protective effect on muscle function in the oldest old and we tested our hypothesis in a group of nonagenarians who participated in the Mugello Study. Methods 239 subjects, 73 men and 166 women, mean age 92.8 years ± SD 3.1, underwent the assessment of UA serum level and isometric handgrip strength, a widely used clinical measure of sarcopenia. Results Mean UA serum level was 5.69 mg/dL ± SD 1.70 and mean handgrip strength was 15.0 kg ± SD 6.9. After adjusting for relevant confounders, higher UA serum levels remained independent positive predictors of isometric handgrip strength (β 1.24 ± SE(β) 0.43, p = 0.005). Conclusion Our results show that higher UA serum levels are associated with better muscle function in the oldest old and, accordingly, might slow down the progression of sarcopenia.

Evaluation of calcium status is important in the osteoporotic risk assessment. Although guidelines indicate total calcium (tCa) as first-line measurement, directly measured ionized calcium (m-iCa), considered as the gold standard, is more and more often required. Aim of this study is to evaluate the agreement between m-iCa, tCa and iCa calculated from a formula based on total calcium and albumin (c-iCa) in osteopenic/osteoporotic postmenopausal outpatients.A total of 140 postmenopausal outpatients, 41 osteopenic (OPN) and 99 osteoporotic (OP) were enrolled. Levels of tCa, m-iCa, c-iCa, total protein and albumin, vitamin D (25-OHD), parathyroid hormone 1-84 (PTH), bone alkaline phosphatase, osteocalcin and serum collagen type 1 cross-linked C-telopeptide (CTX) were also measured.There were no statistically significant differences between OPN and OP groups regarding values of tCa, m-iCa, and c-iCa, 25-OHD and PTH. However, OP women had lower levels of CTX (p 0.05). A significant direct correlation between m-iCa and tCa (r = 0.60, p 0.001) and c-iCa (r = 0.61, p 0.001) was found. Women with isolated hyper-m-iCa had similar DEXA parameter levels respect to the other patients. However, one patient with confirmed primary hyperparathyroidism presented hyper-m-iCa versus normal tCa and c-iCa values.The use of tCa could be sufficient to characterize the calcium status in postmenopausal outpatients, but reflexive calcium testing strategy for m-iCa test is necessary to women presenting the low or high extremes of tCa levels, or in women with suspected PHPT.

Vascular calcification (VC) represents a recognized adverse predictor for cardiovascular morbidity and mortality. Previously considered passive and degenerative, VC is now recognized as an active process that resembles bone formation, and shares a number of histopathological features, mineral composition, and initiation mechanisms with bone development and metabolism. Oxidative stress and inflammation are key factors in both VC and osteoporosis (OP). Biochemical factors known to be primarily involved in the healthy bone metabolism also regulate VC. These biomarkers include vitamin D, osteoprotegerin, osteopontin, matrix Gla protein, cathepsin K, fibroblast growth factor-23, and fetuin-A. A better understanding of this highly controlled regulatory network, with multiple, nested feedback loops and cross talk between organs, may help to decrease the growing prevalence of calcific vasculopathy as well as OP in the aging population, and to advance in common preventive and therapeutic interventions targeted at both conditions.

The aim of the study was to investigate whether TH replacement therapy is safe and impact infarct size, left ventricular (LV) volumes and function in patients with acute myocardial infarction (AMI) and low T3 syndrome (LT3S). Thirty-seven AMI/LT3S patients were randomly treated or untreated with liothyronine (T3) therapy (maximum dosage 15 mcg/m2/die) in addition to standardized treatment (T3-treated group, n = 19; untreated group, n = 18). TH and thyroxine (TSH) during hospital stay and at 1-month and 6 months were evaluated. At discharge and at 6 months LV volumes, ejection fraction, wall motion score index (WMSI) and infarct extent were measured by cardiac MR. T3-treated patients had a significant increase in fT3 (p = 0.003 and p

The heart is one of the principal targets of thyroid hormones (TH) action, affecting cardiac contractility, heart rate, and diastolic function. Oxidative damage is pivotal for onset and development of cardiovascular disease (CVD) and heart failure. Specifically, free radical generation is associated to hyper-metabolic state in hyperthyroidism, whereas hypo-metabolic state induced by hypothyroidism leads to a decrease of oxidative stress. In the present review, the role of oxidative damage in CVD and failing heart-TH interplay will be considered. The main oxidative events leading to cardiac dysfunction and TH cardiac regulation at genomic and non-genomic levels will be discussed, as well as role of TH in cardioprotection and reversion of cardiac remodeling.

Aim: To assess gender differences in uric acid (UA) as predictor for hard events (HE, mortality and nonfatal myocardial infarction) in a large cohort of patients referred for coronary angiography. Design & patients: 3020 inpatients (2177 males, age: 68 ± 9 years, mean ± SD) were retrospectively studied, collecting data from the Institute electronic databank which included demographic, clinical, instrumental and follow-up data. Results: Although the Kaplan–Meier survival estimates showed a significantly worst outcome in female patients, high UA did not remained a significant predictor for HE after adjustment. Moreover, UA correlated with antioxidant capacity in both sexes. Conclusion: Hyperuricemia was not an independent risk for HE, and being correlated with antioxidant capacity, its elevation appears more likely compensatory than causative for HE.

Aim: To explore possible inter-relationships of various biomarkers of inflammation and lifestyle and other cardiovascular risk factors (age, gender, smoking history, hypertension, Type 2 diabetes, dyslipidemia, alteration of circadian rhythms, body mass index, calf circumference, thigh circumference, abdominal circumference) in the Mugello study oldest old. Methods: In 399 noninstitutionalized nonagenarians (291 women), whole blood cells, mean platelet volume, C-reactive protein, uric acid, gamma-glutamyl transferase were assessed. Results: Aging resulted as the only independent determinant for uric acid (

We read with interest the manuscript by Lee et al. [(1)][1], which reports statin use impact on coronary plaque features. Statins increase coronary artery calcification, reducing local inflammation, changing phenotypic plaque composition, and lowering the high-risk plaques, as also observed in

Purpose/Introduction: Osteoporosis (OP) and cardiovascular (CV) disease emerge as closely related conditions, showing common risk factors and/or pathophysiological mechanisms. The aim of this study was to evaluate the association between bone health markers (BHM) and individual CV risk factors and overall CV risk (FRAMINGHAM-FRS, and PROCAM scores) in a general adult population. Methods: In 103 subjects (21 males; age: 56 ± 12 years), vitamin D (25(OH)D), osteocalcin (OC), bone alkaline phospatase (BALP), procollagen I aminoterminal propeptide (P1NP), CTx-telopeptide, as well clinical history and life style were evaluated. Results: Aging (p < 0.001) and glycemia (p < 0.05) emerged as independent 25(OH)D predictors. Aging (p < 0.001), male sex (p < 0.05), and obesity (p < 0.05) represented independent OC determinants. Aging (p < 0.05) was the only independent BALP determinant. After multivariate adjustment, low 25(OH)D (75th percentile-16.6 ng/mL) (6.7 (1.9–23.8) p < 0.01) were found to be significant FRS predictors, while subjects with elevated OC and/or BALP (>75th percentile-9.8 μg/L) showed a higher CV risk as estimated by PROCAM (3.6 (1.2–10.7) p < 0.05). CTx and P1NP did not significantly correlate with CV risk factors or scores. Conclusion: As we go further into bone and CV physiology, it is evident that a close relationship exists between these diseases. Further studies are needed to investigate mechanisms by which bone turnover markers are related to metabolic risk and could modulate CV risk. This knowledge may help to develop possible multiple-purpose strategies for both CV disease and OP prevention and treatment.

Cardiac Troponins (cTnI, cTnT), NT-proBNP, and galectin-3 (GAL-3) mirror cardiomyocyte injury, stretch, and fibrosis. However, although these biomarkers has been thoroughly studied in marathon or ultramarathon, the effects occurring running shorter distances, as half-marathon, are less known and data are generally limited to immediately post-race evaluation. Moreover, significant variation of alpha-1 antitrypsin (AAT), an anti-protease factor with anti-inflammatory properties, has been recently observed in heart failure, but not investigated in paraphysiological settings. The aim of the study was to evaluate these biomarkers concentration and trends in trained runners before half-marathon run and during a 48-h recovery period. In 18 half-marathon runners (15 males, 46 ± 6 years), cTnI, GAL-3 (Architect, Abbott), cTnT, NT-proBNP (Cobas e411, Roche), and AAT (Abcam, Cambridge, UK) were evaluated at rest, immediately post-run, and at 24 and 48-h recovery period. cTnT, NT-proBNP, and GAL-3 transiently increased after post-race, but normalized at 24 h (GAL-3 p

Background: Oxidative stress is crucial in the pathogenesis of atherosclerosis and acute myocardial infarction (AMI). Under the generic terms &ldquo, oxidative stress&rdquo, (OS), many biomarkers belonging to different pathways have been proposed. Aim: To compare the levels of recently proposed OS-related parameters in acute coronary syndromes (ACS) and stable coronary artery disease (CAD), to evaluate their effectiveness as additive risk or illness indicators of stable and acute ischemic events, and their response over time during the course of AMI. Methods: 76 ACS, 77 CAD patients, and 63 controls were enrolled in the study. Different OS-related biomarkers, including reactive oxygen metabolites (ROM), the total antioxidant capacity (OXY), nitrite/nitrate (final nitric oxide products, NOx), and Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), were evaluated. Moreover, time response during AMI course (admission, and 6, 12, 18, 24, 36, and 48 hours after, T0-T6, respectively) and correlation with traditional cardiovascular (CV) risk factors (age, gender, hypertension, diabetes mellitus, dyslipidemia, smoking habit) were also assessed. Results: Over time, ROM progressively increased while OXY and NOx decreased. Kinetics of LOX-1 during AMI shows that this biomarker boosts early during the acute event (T1 and T2) and then progressively decreases, being significantly lower from T0 to T6. Different OS-related biomarkers were differentially associated with CV risk factors and CAD or ACS presence. Conclusion: Differences in OS-related biomarkers (between groups, according to the response over time during AMI, and to the presence of CV risk factors) confirmed OS involvement in the transition from healthy status to stable CAD and ACS, although evidencing the heterogeneous nature of redox processes. In future, a multi-marker panel including different biomarkers and pathways of oxidative stress could be evaluated as an additive tool to be used in the CV prevention, diagnosis, patient stratification, and treatment.

Aims/hypothesis: Cardiac steatosis and myocardial insulin resistance elevate the risk of cardiac complications in obesity and diabetes. We aimed to disentangle the effects of circulating glucose, insulin and NEFA on myocardial triacylglycerol (TG) content and myocardial glucose uptake. Methods: Twenty-two pigs were stratified according to four protocols: low NEFA + low insulin (nicotinic acid), high NEFA + low insulin (fasting) and high insulin + low NEFA ± high glucose (hyperinsulinaemia-hyperglycaemia or hyperinsulinaemia- euglycaemia). Positron emission tomography, [U-13C]palmitate enrichment techniques and tissue biopsies were used to assess myocardial metabolism. Heart rate and rate-pressure product (RPP) were monitored. Results: Myocardial glucose extraction was increased by NEFA suppression and was similar in the hyperinsulinaemia-hypergylcaemia, hyperinsulinaemia-euglycaemia and nicotinic acid groups. Hyperglycaemia enhanced myocardial glucose uptake due to a mass action. Myocardial TG content was greatest in the fasting group, whereas hyperinsulinaemia had a mild effect. Heart rate and RPP increased in hyperinsulinaemia-euglycaemia, in which cardiac glycogen content was reduced. Heart rate correlated with myocardial TG and glycogen content. Conclusions/interpretation: Elevated NEFA levels represent a powerful, self-sufficient promoter of cardiac TG accumulation and are a downregulator of myocardial glucose uptake, indicating that the focus of treatment should be to 'normalise' adipose tissue function to lower the risk of cardiac TG accumulation and myocardial insulin resistance. The observation that hyperinsulinaemia and nicotinic acid led to myocardial fuel deprivation provides a potential explanation for the cardiovascular outcomes reported in recent intensive glucose-lowering and NEFA-lowering clinical trials. © 2014 Springer-Verlag Berlin Heidelberg.

Background Although magnesium (Mg) has recognized cardioprotective properties and hypomagnesemia is common in patients with acute myocardial infarction (AMI), data regarding the role of Mg as prognostic factor for adverse events are scarce, as well as there are conflicting results on the use of Mg as adjuvant therapy in AMI. Aim To evaluate the role of Mg as predictor for hard events (HE, all cause death, and nonfatal myocardial infarction) in AMI patients. Design and patients We studied 406 AMI patients (306 males, age: 67 ± 12 years, mean ± SD). Patient data were collected from the Institute electronic databank which saves demographic, clinical, instrumental, therapeutical and follow-up data of all patients admitted to our Coronary Unit. Results During a mean follow-up period of 21 ± 18 months, the combined endpoint accounted for 63 HE, 44 (11%) deaths (35 cardiac deaths), 19 (5%) nonfatal MI. The multiple regression model identified glycemia as the only independent determinant of Mg in AMI pts. (T value = − 2.8, standard coefficient = − 0.15, p 67 years—50th percentile), and ejection fraction (, Graphical abstract Image 1, Highlights • It has been hypothesized that Mg may play a key role in ischemic heart disease. • Mg role as predictor for HE-death, nonfatal myocardial infarction-in AMI was studied. • Our results do not give support for a role of hypomagnesia as HE predictor in AMI.

The present review aim to describe the most commonly used serum bone formation and resorption biochemical markers, discuss their advantages and disadvantages and give practical information on their use and result interpretation in the laboratory and clinical settings according to current recommendations from International Scientific Societies.

Cardiovascular disease (CVD) is the leading determinant of mortality and morbidity in women. However, a full understanding of the basic and clinical aspects of CVD in women is far from being accomplished. Sexual dimorphism in CVD has been reported both in humans and experimental animals. Menopause is a risk factor for CVD due to the reduction of endogenous estrogen, although the mechanisms underlying are poorly understood. Estrogens act through binding to vascular estrogen receptors and by non-genomic mechanisms. Advances in this field are essential to improve CVD diagnostic and clinical strategies in women, and to develop sex-specific prevention plans as much as female-oriented treatment algorithms. This paper reviews pathophysiology of CVD in women and its potential clinical implications. Particular emphasis is given to biochemical markers and to indicators of cardiovascular dysfunction and damage. Estimation of these parameters, central to cardiovascular pathophysiology, could represent a particularly relevant tool in female patients. More research is needed to identify women who will profit most of early intervention.

Latent autoimmune diabetes in adults (LADA) is a subtype of autoimmune diabetes, which shares characteristics of both Type 1 and 2 diabetes (T1D and T2D), and for this reason, it is often confused with other types of diabetes, misdiagnosed, and inappropriately treated. Two cases were presented (41-year-old and 50-year-old females), one occasionally diagnosed during routine health checkup, the other one identified as having T2D, and as far as misclassified and not optimally treated. Now, after approximately 9 months of LADA diagnosis, the first patient has an optimal metabolic control while maintaining the values of glycated hemoglobin to around 7% with small doses of analogue insulin (lispro 4-6 UI) before meals and long acting insulin (glargine 4-6 UI) at bedtime. The second patient, after approximately 2 years from the LADA diagnosis, has an optimal metabolic control, with maintenance of glycated hemoglobin to around 6.5%, and stable C-peptide level (around 1.5 ng/mL), only with dietary and exercise habits. To avoid misclassification, any patient who does not fit the typical T2D profile, or with poor glycemic control, and who does not follow the expected clinical course, as become insulin dependent sooner than expected, should be investigated to exclude LADA. To define the best therapeutic approach, each patient must be evaluated and therapy tailored on his/her specific profile, considering as very low insulin doses may be effective to maintain a successful metabolic control and the only dietary approach may be sufficient until the insulin-secretory capacity remains good.

Background: The natriuretic peptide hormone family includes various proteins characterized by similar chemical structure and shared biological functions, with important effects on the cardiovascular system. Accordingly, these molecules are widely recognized as key clinical biomarkers in the diagnosis and monitoring of heart failure, hypertension, and coronary heart disease.Content: Several single-nucleotide polymorphisms have been recently identified in genes associated with the natriuretic system. This review provides an overview of new insights into the functional role of these genetic variants, as well as their impact on cardiovascular physiopathology and drug response.Conclusions: Noteworthy relationships between some specific polymorphisms and clinical correlates of cardiovascular disease have emerged. Nevertheless, future confirming studies are needed to substantiate the clinical relevance of such variants.

Cardiovascular disease is the leading cause of death in women in Western countries. Despite preventive strategies, in the past decades the incidence of cardiovascular events has shown a decline in men but a rise in women, matching the growth of the population of postmenopausal women. Several epidemiological findings suggest the causative pathophysiological role of ovarian hormone deficiency in the development of cardiovascular disease in women. Observational and randomized studies have suggested that hormone replacement therapy in early postmenopause could be beneficial from a cardiovascular point of view. Conversely, aging, time since menopause and presence of cardiovascular risk factors or cardiovascular disease may decrease its efficacy and increase the risk of cardiovascular events. It is plausible that the unfavorable effects of the estrogen/progestin combination used in the randomized studies are not related to the hormone preparation per se but rather to the use of hormones in the less receptive group of women, older and with cardiovascular risk factors. Clinical judgment, choice of the right dose and estrogen/progestin combination are of pivotal importance to maximize the beneficial effect of estrogen replacement therapy/hormone replacement therapy, especially if given within a reasonable time after the menopause to women who need the therapy for the relief of menopausal symptoms.

Background: Genetic variants related to the natriuretic peptide (NP) system [ScaI mutated allele (A1) of the atrial NP (ANP) gene and the C variant of the natriuretic peptide clearance receptor (NPRC) gene] have been identified as independent risk factors for cardiovascular morbidity and mortality. Despite the importance of NPs in heart failure (HF), the role of these polymorphisms in HF has not been evaluated.Methods: We screened 124 HF patients [mean (SD), age 66 (12) years, 100 men, ejection fraction 32% (10%), New York Heart Association (NYHA) class I–II 65, III–IV 59] for NP concentrations [ANP, brain NP (BNP) and amino-terminal pro-BNP (NT-proBNP)] and for the ScaI and NPRC variants.Results: ScaI polymorphism had no effect on NP concentration in the NYHA I–II subgroup. Conversely, in severe HF, A1 carriers had higher ANP (P ≤0.05), BNP (P Conclusions: The ScaI polymorphism of the ANP gene might be an important additive genetic factor influencing neurohormonal activation and disease progression in severe HF. The NPRC polymorphism is not an independent determinant of NP concentration in HF.

International audience; AIMS:Refractory hyperaldosteronism is frequently observed in heart failure patients on up-to-date treatment, and holds prognostic value. Our aim was to identify which factors, either genetic or nongenetic, are associated with refractory hyperaldosteronism.METHODS:We enrolled 109 consecutive patients with left ventricular systolic dysfunction [left ventricular ejection fraction (LVEF) 32 ± 10%; 86% males; age 65 ± 13 years (mean ± standard deviation)] on optimized adrenergic and renin-angiotensin-aldosterone system (RAAS) antagonism, undergoing clinical and neuroendocrine characterization, and genotyping for six polymorphisms in key RAAS-regulating genes [angiotensinogen (AGT M235T), angiotensin-converting enzyme (ACE-240A>T and I/D), angiotensin II type I receptor (AGTR1 1166A>C), aldosterone synthase (CYP11B2-344C>T) and renin (REN rs7539596)].RESULTS:Patients with refractory hyperaldosteronism (n = 41, 38%, with plasma concentration >180 ng/l, URL, median 283 ng/l, interquartile range 218-433), when compared with those without (106 ng/l, 74-144; P

To evaluate whether the route of estrogen therapy (ET) may affect the levels of different vasoactive factors in healthy recent post-menopausal women.We conducted a cross-over study in 20 healthy nonsmoking women in recent postmenopause (1.8+/-0.1 years). Women received either 1-month oral-ET (O-ET, 2 mg oral micronized 17beta estradiol daily) or transdermal-ET regimen (T-ET, 17beta estradiol 1.5 mg gel daily) with a 1-month wash-out interval. Blood pressure, plasma levels of endothelin-1 (ET), 6-ketoPGF1a (6-ketoPG, prostacyclin metabolite), nitrite/nitrate (NOx), epinephrine (E) and norepinephrine (NE) and lipid profile were measured at baseline and after each treatment.Both regimens significantly reduced E (p0.01) and NE levels (p0.05). O-ET reduced low-density lipoproteins (LDL) levels (p0.05) and increased NOx values (p0.01). Neither regimen caused significant changes of ET or 6-ketoPG.Our results, obtained in healthy women in recent menopause, indicate that the ratio between vasodilator (NOx and prostacyclin) and vasoconstrictor (ET) bioavailability shifted towards the previous ones after O-ET, while it remained unchanged after T-ET; moreover, catecholamines levels were reduced by both treatments already from 1 month of therapy. These changes might represent very early beneficial effects evoked by ET on the cardiovascular system.

The risk of cardiovascular disease significantly increases after menopause. Accordingly, many evidences suggest that estrogens may positively affect the production of different vasoactive factors, such as nitric oxide, prostacyclin, endothelin-1 and catecholamines and induce favourable changes in lipid profile. However, although observational data indicate that hormone replacement therapy (HRT) reduces significantly the cardiovascular risk, recent results have added controversial data to the institution of HRT in postmenopausal women. These last studies present numerous bias, related to inclusion of a single combination HRT regimen, recruitment women of older age groups who began treatment years after menopause and generally with pre-existing coronary artery disease. In fact, it is known that aging and atherosclerotic injury may induce estrogen receptors depletion, endothelial dysfunction and thrombosis, thus potentially decreasing HRT efficacy. Therefore, particular attention must be paid to the age of the woman and the complexity of atheroscleriotic lesions as determinants of the response to HRT for each patient. Moreover, the maintenance of an healthy and normal functioning endothelium after menopause emerges as a major target to retain maximal cardiovascular benefit from this treatment.

Somatic DNA damage has been suggested to contribute to the pathogenesis of atherosclerosis. However, little is known about the role of oxidative DNA damage in patients with coronary artery disease (CAD).In this study, we used the comet assay to measure oxidative DNA damage (DNA strand breaks and enzyme-sensitive sites) in peripheral blood lymphocytes from 13 patients with angiographically documented CAD and 11 age- and sex-matched control participants.Mean values of DNA strand breaks, oxidized pyrimidines and altered purines were significantly higher in CAD patients than in the control group (11.9 +/- 1.4, 18.0 +/- 2.7 and 18.1 +/- 3.1 compared with 3.3 +/- 0.2, 2.7 +/- 0.5 and 4.5 +/- 1.1; P0.0001, P0.0001 and P = 0.0009, respectively). Moreover, oxidized purines (for example, 8-oxo-guanine) increased with the number of affected vessels and positively correlated with the extent of CAD measured by means of the number of the coronary lesions (P = 0.76, P = 0.003) and the Duke scoring system (P = 0.66, P = 0.01). Diabetic patients showed higher levels of oxidized pyrimidines (31.3 +/- 5.5 compared with 14.1 +/- 2.7; P = 0.013), while patients with dyslipidemia had elevated altered purines compared with normal patients (20.4 +/- 2.6 compared with 4.9 +/- 3.1; P = 0.03).These data indicate an overall elevation of oxidative DNA damage in CAD patients correlated with the severity of the disease and some atherogenic risk factors, suggesting a possible role of oxidative genetic damage in the pathogenesis of atherosclerosis.

Nitrates act as donors of nitric oxide (NO), a molecule with a recognized potential for genotoxicity. In order to assess whether chronic long-term nitrate therapy may increase genotoxicity, we evaluated chromosomal damage in peripheral lymphocytes of 27 ischaemic patients undergoing chronic nitrate treatment for vertical line4 years (7.9 +/- 3.1, mean +/- SD) and 18 age- and sex-matched subjects without any previous nitrate treatment. At the same time, after treatment in vitro with 0-20 microM sodium nitroprusside as NO donor, micronucleus induction and cell proliferation were also evaluated using blood from six different healthy donors. The results showed that the frequency of structural chromosomal aberrations was not significantly higher in the drug-treated group than the control [2.1 +/- 1.4 versus 1.6 +/- 1.2 (mean +/- SD); P = 0.23]. The frequency of micronucleated lymphocytes was higher in the nitrate group than in the control group (6.5 +/- 4.6 versus 3.5 +/- 2.9, P=0.01). In vitro treatment indicated a dose-dependent increase in the frequency of micronucleated lymphocytes with increasing SNP concentrations. Cytotoxicity and cell cycle delay, with a statistically significant difference with respect to control culture, were also observed. Our results suggest a possible genotoxic activity of nitrate therapy. Further studies focusing on the possible link between nitrate therapy and genotoxicity are warranted at this point.

Objective To evaluate whether obesity and smoking habit may accelerate the age-related increase of oxidative stress. Methods The Oxidative-INDEX, a score reflecting both oxidative and antioxidant counterparts, was estimated in 179 subjects (50 males, aged 16–79 years). Results Oxidative stress results were elevated in obese and smoker subjects. Adjusted logistic regression analysis indicated obesity and smoking as independent variables for elevated Oxidative-INDEX (odds ratio = 4.8 and 3.1, respectively). Oxidative-INDEX steadily rises at a mean rate of 5.3% (0.017 AU) per year in the overall population, showing twice and three times higher annual rate increase in smokers and obese subjects. Conclusion Our results suggest the pro-ageing effects of cigarette smoking and obesity by a more rapid and sharp elevation of the oxidative stress status.

Background: Oxidative stress has been postulated as an additive factor linking obesity to cardiovascular disease. Materials & methods: Derivatives of reactive oxygen species metabolites (d-ROMs) were measured in 136 obese (42 males, 94 females; mean age: 47 ± 12 years; BMI: 36 ± 5 kg/m2) and in 306 over- and normal-weight subjects (112 males, 194 females; age: 47 ± 12 years; BMI: 24 ± 3 kg/m2). Results: d-ROMs levels were higher in obese than in over- and normal-weight subjects (395 ± 104 vs 362 ± 102 and 351 ± 84 arbitrary units (AU); p < 0.001), in women than males (390 ± 104 vs 327 ± 68 AU; p < 0.001), in subjects with than those without hypertension (390 ± 103 vs 360 ± 95 AU; p < 0.01) and in smokers than former and nonsmokers (380 ± 97 vs 358 ± 97 AU; p < 0.05). A positive correlation was found between d-ROMs and BMI (r = 0.25; p < 0.001) and age (r = 0.13; p < 0.01). Levels of d-ROM (>75th percentile: 420 AU) remained as an independent obesity predictor (odds ratio: 2.5; p < 0.001) in women. Continuous variables are reported as mean ± standard deviation. Conclusion: d-ROMs are a powerful obesity predictor, and could represent a reliable tool in obesity and cardiovascular risk evaluation, especially in women.

Objectives. This study sought to assess the value of dipyridamole echocardiography in predicting reinfarction in patients evaluated early after uncomplicated acute myocardial infarction. Background. The identification of future nonfatal reinfarction seems an elusive target for physiologic testing. However, a large sample population is needed to detect minor differences in phenomena with a low event rate. Methods. We assessed the value of dipyridamole echocardiography in predicting reinfarction in 1,080 patients (mean [±SD] age 56 ± 9 years; 926 men, 154 women) evaluated early (10 ± 5 days) after uncomplicated acute myocardial infarction and followed up for 14 ± 10 months. Results. Submaximal studies due to limiting side effects occurred in 14 patients (1.3%); these test results were included in the analysis. Results of dipyridamole echocardiography were positive in 475 patients (44%). During follow-up, there were 50 reinfarctions: 45 nonfatal, 5 fatal (followed by cardiac death ≤4 days after reinfarction). Reinfarction (either nonfatal or fatal) occurred in 30 patients with positive and 20 with negative results (6.3% vs. 3.3%, p Conclusions. Dipyridamole echocardiographic positivity identifies patients evaluated early after uncomplicated acute myocardial infarction at higher risk of reinfarction, especially fatal reinfarction.

Uric acid (UA) is a potent endogenous antioxidant. However, high concentrations of this molecule have been associated with cardiovascular disease (CVD) and renal dysfunction, involving mechanisms that include oxidative stress, inflammatory processes, and endothelial injury. Experimental and in vitro results suggest that this biomarker behaves like other antioxidants, which can shift from the physiological antioxidant action to a pro-oxidizing effect according to their level and to microenvironment conditions. However, data on patients (general population or CAD cohorts) are controversial, so the debate on the role of hyperuricemia as a causative factor for CVD is still ongoing. Increasing evidence indicates UA as more meaningful to assess CVD in women, even though this aspect needs deeper investigation. It will be important to identify thresholds responsible for UA “biological shift” from protective to harmful effects in different pathological conditions, and according to possible gender-related differences. In any case, UA is a low-tech and inexpensive biomarker, generally performed at patient’s hospitalization and, therefore, easily accessible information for clinicians. For these reasons, UA might represent a useful additive tool as much as a CV risk marker. Thus, in view of available evidence, progressive UA elevation with levels higher than 6 mg/dL could be considered an “alarm” for increased CV risk.

AIMS To evaluate the prognostic significance of oxidative stress on the rate of major adverse cardiovascular events (MACEs: cardiac and all-cause death, nonfatal myocardial infarction, coronary revascularization-PTCA/CABG) in CAD. METHODS We studied 97 angiographically proven CAD patients (78 males, age: 67±11 years, mean± SD). Reactive oxygen metabolites and total antioxidant status, assessed by commercially assays (d-ROMs and OXY-Adsorbent Test; Diacron, Grosseto, GR, Italy), were used to calculate the oxidant/antioxidant balance. Patient data were collected from the Institute's electronic databank, which saves demographic, clinical, instrumental and follow-up data of all patients admitted to our department. RESULTS Kaplan-Meier survival estimates showed a significantly worst outcome in patients presenting with elevated oxidative stress levels (>75th percentile, p

Background: Enhanced oxidative stress has been associated with atherosclerosis and coronary artery disease (CAD). However, the predictive value of circulating oxidative stress biomarkers for cardiovascular events (CE) in patients with CAD has remained poorly understood. Aim: To assess the prognostic signifi cance of reactive oxygen metabolites, estimated as index of oxidative stress in serum samples by means of a commercial kit (ROMs, Diacron, Italy) on the rate of mortality and major adverse CE (MACE) in CAD. Methods: A study of 93 consecutive patients with angiographically documented CAD (75 males, age: 68 ± 10 years, mean ± SD) was made during a mean follow-up of 66 months until the occurrence of one of the following CE: cardiac and all cause death, non-fatal myocardial infarction and coronary revascularization [percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG)]. Patient data were retrospectively collected from the Institute ’ s electronic databank that saves demographic, clinical, instrumental and follow-up data of all patients admitted to our department. Results: The Kaplan-Meier survival estimates showed a signifi cantly worst outcome in patients presenting elevated ROM level ( > 75th percentile, corresponding to 481 AU) (log rank = 11, 7.5, 5.1; p < 0.001, p < 0.01, p < 0.05 for cardiac and all cause death and MACEs, respectively). In a multivariate Cox regression model, elevated oxidative stress remained a signifi cant predictor of cardiac and all cause death [hazard ratio (HR) 3.9, 95 % confi dence interval, 95 % (CI) 1.4 ‐ 11.1, p = 0.01; HR = 2.6, 95 % CI 1.1 ‐ 6.2, p = 0.02) and MACE (HR = 1.8, 95 % CI 1.1 ‐ 3.1, p = 0.03)]. Conclusions: The estimation of ROMs may represent an additional prognostic tool in the assessment of CE in CAD patients.