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The influences of physical and mental activity on cognitive functioning were examined in a sample of Italian healthy elderly males. The aim of the present study was to suggest aerobic training as well as cognitively stimulating activity and provide recommendations for an overall healthy lifestyle. Seventy-five healthy adult males, aged 65-81, were assigned to four groups, two groups of active subjects practicing different levels of regular aerobic exercise, and two groups of sedentary subjects, one without any relevant mental stimulating activity and the other one regularly carrying out substantial mental activity. Each group was further divided into three subgroups based on their level of education. Cognitive functioning was assessed by the Italian version of MoCA. Data was analysed in a non-parametric two-factor model by Aligned Rank Transformation, and then compared with the normative data for the Italian population. Physically active subjects showed better cognitive performance than the other groups in all the cognitive domains, except for memory and orientation. Among the sedentary subjects, the mentally active ones showed better performance in some cognitive domains, specifically in attention and memory. The influence of education was highlighted in some scores, but significant interactions with activity levels were never highlighted. Moreover, the influence of life habits (i.e. physical and mental activity) on the MoCa scores always showed a higher effect size than education. Our findings showed that both physical and mental activity improve cognitive functions in the elderly, and that they affect specific cognitive domains.

Although many studies highlight how long-term moderate dose of Recombinant Human Erythropoietin (rHuEPO) treatments result in beneficial and antioxidants effects, few studies take into account the effects that short-term high doses of rHuEPO (mimicking abuse conditions) might have on the oxidative stress processes. Thus, the aim of this study was to investigate the in vivo antioxidant activity of rHuEPO, administered for a short time and at high doses to mimic its sports abuse as doping. Male Wistar healthy rats (n=36) were recruited for the study and were treated with three different concentrations of rHuEPO: 7.5, 15, 30μg/kg. Plasma concentrations of erythropoietin, 8-epi Prostaglandin F2α, plasma and urinary concentrations of NOx were evaluated with specific assay kit, while hematocrit levels were analyzed with an automated cell counter. Antioxidant activity of rHuEPO was assessed analyzing the possible variation of the plasma scavenger capacity against hydroxylic and peroxylic radicals by TOSC (Total Oxyradical Scavenging Capacity) assay. Statistical analyses showed higher hematocrit values, confirmed by a statistically significant increase of plasmatic EPO concentration. An increase in plasma scavenging capacity against peroxyl and hydroxyl radicals, in 8-isoprostane plasmatic concentrations and in plasmatic and urinary levels of NOX were also found in all the treated animals, though not always statistically significant. Our results confirm the literature data regarding the antioxidant action of erythropoietin administered at low doses and for short times, whereas they showed an opposite incremental oxidative stress action when erythropoietin is administered at high doses.

The introduction of three-dimensional echography (3D echo) in vascular field is not recent, but it still remains a seldom-used technique because of the costs of ultrasound probe and the need of dedicated laboratories. Therefore, despite significant prognostic implications, the high diagnostic accuracy in plaque definition, and the relative ease of use, 3D echo in vascular field is a niche technique. The purpose of this review is mainly clinical and intends to demonstrate the potential strength of a 3D approach, including technical aspects, in order to present to clinicians and imagers the appealing aspects of a noninvasive and radiation-free methodology with relevant diagnostic and prognostic correlates in the assessment of carotid atherosclerosis. A comprehensive literature search (since 1990s to date) using the PubMed, MEDLINE, and Cochrane libraries databases has been conducted. Articles written in English have been assessed, including reviews, clinical trials, meta-analyses, and interventional/observational studies. Manual cross-referencing was also performed, and relevant references from selected articles were reviewed. The search was limited to studies conducted in humans. Search terms, retrieved also with PubMed Advanced search and AND/OR Boolean operators (mainly in title and abstract), included three-dimensional, echo, stroke/transient ischemic attack, predictors, carotid, imaging, and biomarkers.

Immune checkpoint inhibitors are drugs that inhibit the "checkpoint molecules". Different types of cancer immune checkpoint inhibitors have been approved recently: CTLA-4 monoclonal antibodies (as ipilimumab); anti-PD-1 monoclonal antibodies (as pembrolizumab and nivolumab); and anti-PD-L1 monoclonal antibodies (as atezolizumab, avelumab, and durmalumab). The increased immune response induced by these agents leads to immune-related adverse events (irAEs), that can vary from mild to fatal, according to the organ system and severity. Immune-related endocrine toxicities are thyroid dysfunctions, hypophysitis, adrenal insufficiency, and type 1 diabetes mellitus, and are usually irreversible in 50%. In particular, hypophysitis is the most frequent anti-CTLA-4-antibodies-related irAE, while thyroid abnormalities (as hypothyroidism, thyrotoxicosis, painless thyroiditis, or even "thyroid storm") are more frequently associated with anti-PD-1-antibodies. The combination of anti-CTLA-4-antibodies, with anti-PD-1-antibodies, is associated with about 30% of irAEs. Clinical signs and symptoms vary according to the influenced target organ. Endocrinopathies can often be managed by the treating oncologist. However in more severe cases (i.e. in the presence of insulin-dependent diabetes, adrenal insufficiency, or disorders of gonadal hormones, or severe hyperthyroidism, or hypothyroidism, or long-lasting management of hypophysitis) an endocrinological evaluation, and a prompt therapy, are needed.

Oxidative stress arises from an imbalance between the production of free radicals and antioxidant defences. Several studies have suggested that dietary antioxidants (such as polyphenols and berberine) may counteract oxidative stress through the involvement of the Sirtuin 1/Adenosine Monophosphate-Activated Protein Kinase (SIRT1/AMPK) pathway. The aim of this study was to evaluate the direct and specific antioxidant activity of some natural compounds, as well as their ability to modulate the expression of SIRT1 and the activation of AMPK. Quercetin, tyrosol, ferulic acid, catechin, berberine and curcumin were evaluated for their specific and direct antioxidant activity with TOSC assay. Their ability to modulate SIRT1 and AMPK was assessed by immunoblotting assay, while their cytotoxicity by CellTiter-Blue Cell Viability Assay. No statistically significant decrease (p > 0.05) in the number of viable cells was found upon challenging with the natural compounds. Quercetin exhibited the highest antioxidant activity against peroxyl radical and peroxinitrate derivates, while curcumin showed the best anti-hydroxyl activity with respect to the other compounds and, most importantly, respect to the reference antioxidants. Finally, all the tested compounds significantly increased the SIRT1 expression and the activation of AMPK. Our results clearly disclose the specific antioxidant activity of these natural compounds and their ability to increase SIRT1 expression and AMPK activation.

The loss of protein homeostasis that has been associated with aging leads to altered levels and conformational instability of proteins, which tend to form toxic aggregates. In particular, brain aging presents characteristic patterns of misfolded oligomers, primarily constituted of β-amyloid (Aβ), tau, and α-synuclein (α-syn), which can accumulate in neuronal membranes or extracellular compartments. Such aging-related proteins can also reach peripheral compartments, thus suggesting the possibility to monitor their accumulation in more accessible fluids. In this respect, we have demonstrated that α-syn forms detectable hetero-aggregates with Aβ or tau in red blood cells (RBCs) of healthy subjects. In particular, α-syn levels and its heteromeric interactions are modulated by plasma antioxidant capability (AOC), which increases in turn with physical activity. In order to understand if a specific distribution of misfolded proteins can occur in other blood cells, a cohort of human subjects was enrolled to establish a correlation among AOC, the level of physical exercise and the concentrations of aging-related proteins in platelets. The healthy subjects were divided depending on their level of physical exercise (i.e., athletes and sedentary subjects) and their age (young and older subjects). Herein, aging-related proteins (i.e., α-syn, tau and Aβ) were confirmed to be present in human platelets. Among such proteins, platelet tau concentration was demonstrated to decrease in athletes, while α-syn and Aβ did not correlate with physical exercise. For the first time, α-syn was shown to directly interact with Aβ and tau in platelets, forming detectable hetero-complexes. Interestingly, α-syn interaction with tau was inversely related to plasma AOC and to the level of physical activity. These results suggested that α-syn heterocomplexes, particularly with tau, could represent novel indicators to monitor aging-related proteins in platelets.

Over the past decades, the prevalence of the metabolic syndrome (MetS), a health condition identified by a cluster of risk factors linked to the development of cardiovascular disease, type 2 diabetes mellitus and some types of cancer, has dramatically increased in the world. The rising of MetS incidence and progression appear related to Westernization of dietary habits in the world, with a corresponding increase in the consumption of meat or meat products, snacks, baked desserts and sugar-sweetened beverages not only in the Western countries, but also in the Mediterranean region and among the Eastern populations. Otherwise epidemiological evidence suggests that a high dietary intake of fruits, vegetables, fish and whole grains can improve all the risk factors related to MetS. Particularly adherence to the Mediterranean diet seems to have positive effects on the prevalence and progression of the MetS. In this article we reviewed cohort studies, cross-sectional studies and clinical trials, showing new evidence supporting the beneficial role of adherence to the Mediterranean dietary pattern on the MetS progression. Analysis of the literature suggests that Mediterranean diet should be considered as a healthy and sustainable lifestyle playing a key role in primary and secondary prevention of MetS and its components.

Obesity-related glomerulopathy (ORG) is morphologically defined as focal segmental glomerulosclerosis and glomerulomegaly. Podocyte hypertrophy and reduced density are related to proteinuria which in a portion of patients is in the nephrotic range and evolvs towards renal failure. This article reviews the pathogenetic mechanisms of podocyte injury or dysfunction and lists new possible antiproteinuric strategies based on pharmaceutical targeting of the reported pathogenetic mechanisms. The pathogenetic mechnisms discussed include: renin angiotensin system, plasminogen activation inhibitor-1 (PAI-1), lipid metabolism, adiponectin, macrophages and proinflammatory cytokines, oxidative stress. The proposed antiproteinuric strategies include: AT2 receptor blockers; adipokine complement C19 TNF-related protein-1 blocker; selective PAI-1 inhibitor; farnesoid x receptor activation; increase of circulating adiponectin; selective antiinflammatory drugs; more potent antioxidants (Heme oxigenase, NOX4 inhibitors). However, because ORG is a rare disease, the need for a long term pharmaceutical approach in obese proteinuric patients should be carefully evaluated and limited to the cases with progressive loss of renal function.

Neurodegenerative disorders (NDs) are characterized by abnormal accumulation/misfolding of specific proteins, primarily α-synuclein (α-syn), β-amyloid1-42 (Aβ), and tau, in both brain and peripheral tissue. In addition to homo-oligomers, the role of α-syn interactions with Aβ or tau has gradually emerged. The altered protein accumulation has been related to both oxidative stress and physical activity; nevertheless, no correlation among the presence of peripheral α-syn hetero-aggregates, antioxidant capacity, and physical exercise has been discovered as of yet. Herein, the content of α-syn, Aβ, tau, and of their heterocomplexes was determined in red blood cells (RBCs) of healthy subjects (sedentary and athletes). Such parameters were related to the extent of the antioxidant capability (AOC), a key marker of oxidative stress in aging-related pathologies, and to physical exercise, which is known to play an important preventive role in NDs and to modulate oxidative stress. Tau content and plasma AOC toward hydroxyl radicals were both reduced in older or sedentary subjects; in contrast, α-syn and Aβ accumulated in elderly subjects and showed an inverse correlation with both hydroxyl AOC and the level of physical activity. For the first time, α-syn heterocomplexes with Aβ or tau were quantified and demonstrated to be inversely related to hydroxyl AOC. Furthermore, α-syn/Aβ aggregates were significantly reduced in athletes and inversely correlated with physical activity level, independent of age. The positive correlation between antioxidant capability/physical activity and reduced protein accumulation was confirmed by these data and suggested that peripheral α-syn heterocomplexes may represent new indicators of ND-related protein misfolding.

A common pathological feature of neurodegenerative disorders (NDs), such as Alzheimer's (AD) and Parkinson's (PD) diseases, is the abnormal accumulation and misfolding of specific proteins, primarily α-synuclein (α-syn), β-amyloid1-42 (Aβ) and tau, in brain and in peripheral tissues too. Oxidative stress has been proved to be involved in NDs at various levels and, in particular, in such protein alterations, on the contrary physical activity is emerging as a counteracting factor in NDs. In the present work, the content of Aβ, α-syn and tau in red blood cells (RBCs) derived from ten endurance athletes (ATHL) and ten sedentary volunteers (SED) were compared before and after in vitrooxidative stress treatment. Total Aβ, α-syn and tau were quantified in RBCs (isolated from the subjects) by immunoenzymatic assays. Oxidative stress was induced by in vitro H₂O₂ administration to RBCs. H₂O₂ treatment was confirmed to significantly enhance ROS accumulation in RBCs. Total Aβ content in RBCs was lower in the ATHL subgroup with respect to the SED one. In the SED subgroup, but not in the ATHL one, total Aβ levels were increased by oxidative stress. Total α-syn content was lower in the ATHL subgroup with respect to the SED one and α-syn levels were increased by oxidative stress in both subgroups, with the percentage of increase higher in SED. Total tau content was comparable in both ATHL and SED and it was not affected by oxidative stress. Our data confirm previous findings evidencing that both oxidative stress and sedentary style contribute to aberrant folding and accumulation of NDs-related proteins, pointing to the importance of both anti-oxidant therapies and exercising in the prevention and treating of such diseases.

Congenital abnormalities of the coronary arteries here described are an uncommon form of structural heart disease. Nevertheless, they deserve attention because may cause chest pain and, in some cases, sudden cardiac death even during exercise. Traditional angiography has limitations due to its projectional and invasive nature. The recent development of the 320-slide multi-detector computer tomography with low radiation exposure has the potential to modify the current diagnostic work-up, as it allows even in young people a timely identification of clinical significant coronary anomalies minimizing the risks related to radiation exposure.

Vascular oscillation (vasomotion) occurs in the microcirculation and is thought to be a significant contributor to tissue perfusion. Our aim was to assess skin vasomotion (SV) of type 1 diabetic patients (T1D-pts) and its relationship with clinical or laboratory variables of the studied T1D-pts. Forearm endothelial-, sympathetic- and myogenic-dependent SV were assessed basally and after 3 min of forearm ischemia in 40 T1D-pts and 50 healthy controls, by spectral analysis of laser-Doppler (LD) signal at the frequency ranges of 0.009-0.02 Hz, 0.021-0.06 Hz and 0.061-0.2 Hz, respectively. Post-ischemic per cent increase (PI%-increase) in power spectral density (PSD) of skin endothelial- and sympathetic-dependent VS was significantly reduced in T1D-pts compared to controls (p < 0.0005, p < 0.0001, respectively). Linear regression analysis showed a significant positive relationship between PI%-increase of endothelial-dependent SV and heart rate variation during laying-standing test (R = 0.65, p = 0.00001), and a negative relationship between PI%-increase in PSD of skin LD signal 0.009-1.6 Hz spectrum and glycated haemoglobin serum levels (R = 0.44, p = 0.0036) in T1D-pts. These results are consistent with reduced skin endothelial- and sympathetic-dependent stimulated SV and with relationships between some clinical or laboratory variables and SV parameters in the T1D-pts studied.

Objective.No study has evaluated circulating chemokine C-X-C motif ligand (CXCL)11 in patients with “mixed cryoglobulinemia and chronic hepatitis C infection” (MC+HCV). We measured CXCL11, and correlated this measurement to the clinical phenotype.Methods.Serum CXCL11, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were assayed in 97 MC+HCV patients and in 97 sex- and age-matched controls.Results.MC+HCV patients showed significantly higher mean CXCL11 serum levels than controls (254 ± 295, 68 ± 16 pg/ml, respectively; p = 0.0002; ANOVA). CXCL11 was significantly increased in 36 cryoglobulinemic patients with compared to those without active vasculitis (303 ± 208 vs 179 ± 62 pg/ml, respectively; p < 0.001; ANOVA). IFN-γ levels were significantly higher in MC+HCV than in controls [6.1 (range 0.8–114.5), 1.4 (range 0.7–2.4) pg/ml, respectively; p < 0.05; Mann-Whitney U test]. Serum TNF-α mean levels were significantly higher in MC+HCV than in controls [13.4 (range 1.8–369), 1.1 (range 0.7–3.2) pg/ml, respectively; p < 0.0001; Mann-Whitney U test]. A multiple regression analysis considering CXCL11 as a dependent variable, and age, alanine aminotransferase, IFN-γ, and TNF-α as independent variables, showed in MC+HCV patients a significant association only with IFN-γ (p < 0.0001).Conclusion.Our study demonstrates markedly high serum levels of CXCL11 in patients with MC+HCV compared to healthy controls overall in the presence of active vasculitis. A strong relationship between circulating IFN-γ and CXCL11 was shown, strongly supporting the role of a T helper 1 immune response in the pathogenesis of MC+HCV.

The aim of the study was to examine the effect of the antihypertensive AT1 receptors antagonist telmisartan on cardiovascular autonomic function and QT dispersion in hypertensive patients with LVH.Twenty-five patients (18 males and seven women, mean age 49.8±5.2 years) with mild essential arterial hypertension and LVH were compared with 25 age-matched healthy controls. All the participants underwent a complete clinical examination, including electrocardiogram for QT interval measurements and 24h ambulatory ECG monitoring for measurement of heart rate variability. The ECG, 24h ambulatory ECG, and echocardiogram were repeated after eight weeks of treatment.At baseline, hypertensive patients showed QT dispersion (p0.001) and QTc dispersion (p0.001) significantly higher than control subjects. An eight-week telmisartan treatment significantly reduced blood pressure (p0.0001), without significant change in left ventricular mass. Telmisartan-based treatment induced an increased vagal activity without significant change of sympathetic activity and a reduction of QT dispersion (p0.001) and QTc dispersion (p0.001).These data suggest that therapy with telmisartan significantly improves the sympathovagal balance increasing parasympathetic activity, and cardiac electrical stability reducing the heterogeneity of ventricular repolarization in hypertensive subjects. These effects could contribute to reduce arrhythmias as well as sudden cardiac death in at-risk hypertensive patients.

Phaeochromocytomas are rare neuroendocrine tumours secreting high levels of catecholamines, able to exert serious metabolic and cardiovascular effects. The serious and potentially lethal cardiovascular complications of these tumours are due to the potent effects of secreted catecholamines, especially noradrenaline, the main transmitter released from sympathetic nerve terminals. Hypertension, tachycardia, pallor, headache and anxiety, usually dominate the clinical presentation. Occasionally, patients with predominantly epinephrine-secreting tumours present hypotension or even shock. Other cardiovascular complications of pheochromocytoma include ischaemic heart disease, acute myocardial infarction, cardiac arrhythmias, heart failure due to toxic cardiomyopathy, or pulmonary edema. Catecholamines have been shown to influence the extracellular matrix with collagen deposition and subsequent fibrosis in the arterial wall and in the myocardium. These morphofunctional changes of the myocardium and of arterial wall can be emphasized by ultrasound imaging. Indeed, ultrasound imaging of the myocardium and arterial wall not only identifies wall thickness but also contains information on texture that may be revealed by acoustic tissue characterization. The latter can be quantified through videodensitometric analysis of echographic images or through ultrasonic integrated backscatter signal analysis. This paper reviews cardiovascular complications in patients with pheochromocytoma and utility of the new ultrasound technique as backscatter signal. It is useful for evaluating preclinical pathological morphofunctional changes of the myocardium and arterial wall, characterized by increased collagen content in pheochromocytoma patients. The recognition of early catecholamine-induced alterations in patients with pheochromocytoma, is important to prevent at least morbidity and mortality, before surgical treatment.

The iron chelator dexrazoxane has been shown to significantly reduce anthracycline-induced cardiac toxicity in several randomized controlled studies. Aim of the present study was to assess the in vitro and in vivo antioxidant effects of dexrazoxane.The in vitro antioxidant activity of dexrazoxane as its total oxyradical scavenging capacity (TOSC) was assessed and compared to that of some classic antioxidants such as reduced glutathione (GSH), uric acid and trolox. The plasma antioxidant activity of 20 newly-diagnosed non-Hodgkin lymphoma (NHL) patients scheduled to receive anthracycline-containing chemotherapy (ProMECE-CytaBOM) was also evaluated. Results were expressed as TOSC units.Dexrazoxane exhibited an in vitro scavenging capacity towards hydroxyl radicals 320% higher than that of GSH (p0.00001), 20% higher than that of uric acid (p0.001), and 100% higher than that of trolox (p0.001). In the clinical study, ProMECE-CytaBOM infusion significantly reduced plasma TOSC in NHL patients (p=0.0001). Dexrazoxane supplementation was able to restore plasma antioxidant activity in two hours from the end of the ProMECE-CytaBOM infusion.Dexrazoxane has in vitro antioxidant capacity. In vivo, it is able to reduce the epirubicin-induced free radical production. The intrinsic antioxidant effect of this compound could explain the reduction of the anthracyclines-induced toxicity in those patients treated with dexrazoxane supplementation.

The aim of our study was to evaluate the feasibility of laser Doppler flowmetry (LDF) coupled with iontophoresis in exploring the skin vasodilator activity of exogenous calcitonin gene-related peptide (CGRP) in healthy subjects and to investigate the mechanisms involved in the skin vasodilator activity of this peptide. Forearm skin blood perfusion was measured in conventional perfusion unit (PU; 1 PU=10 mV), using a LDF apparatus (Periflux PF4001, Perimed, Sweden), before and following exogenous CGRP dissolved in distilled water (0.02%) or pure saline iontophoresis. Different iontophoresis protocols were used in a preliminary dose finding study in six subjects. Two pulses (0.1 mA for 30 s each) of anodal CGRP or saline iontophoresis were used in the definitive study in 20 subjects. Power spectral density (PSD) of skin blood flowmotion frequency intervals (FI), related to endothelial (0.009-0.02 Hz), sympathetic (0.02-0.06 Hz), myogenic (0.06-0.2 Hz), respiratory (0.2-0.6 Hz) and heart (0.6-1.6 Hz) activities, was also measured in PU(2)/Hz, by means of spectral analysis of the skin LDF signal registered before and following iontophoresis of CGRP or saline in the definitive study. A significantly higher per cent increase in skin perfusion compared to baseline was observed following CGRP than saline iontophoresis (548+/-369% vs. 326+/-192%, p0.05), with higher hyperaemic response to pure saline than CGRP iontophoresis in only five subjects. A significant increase (p0.05) in PSD mean value of the five FI considered, was also observed following CGRP iontophoresis, while saline iontophoresis elicited a significant increase (p0.05) only in PSD of the FI related to endothelial, respiratory and heart activity. These findings demonstrated that LDF coupled with iontophoresis is a feasible method in evaluating the vasodilator effect of exogenous CGRP in human skin and suggest that this peptide directly or indirectly induces a smooth muscle vascular cells and sympathetic fibres stimulation.

In the hypertensive heart, epicardial arteries are not enlarged, despite increased total coronary flow related to augmented cardiac workload, wall stress, and left ventricular (LV) mass. The aims of this study were to assess the impact of different hemodynamic factors and LV mass on baseline left main coronary artery (LMA) size in hypertensive LV hypertrophy (LVH) and physiologic LVH, used as a pressure-independent model of hypertrophy.In 104 subjects without coronary disease (26 normotensive subjects without LVH, 15 athletes with physiologic LVH, and 63 untreated hypertensive subjects [28 without and 35 with LVH]), LMA size and coronary flow reserve (CFR) were measured by transesophageal echocardiography, and LV mass, volumes, stroke work, and wall stress were measured by transthoracic echocardiography.The LMA area in normotensive control subjects, athletes, and hypertensive subjects without and with LVH was 13.2 +/- 4.2, 17.5 +/- 2.9, 10.1 +/- 3.2 and 13.1 +/- 3.9 mm(2). In normotensive control subjects, LMA size increased with body surface area, rate-pressure product, stroke work, and LV mass or wall thickness (r = 0.39, 0.39, 0.47 and 0.67 or 0.62, P.05-0.01). In athletes with physiologic LVH, LMA area increased with CFR (0.65, P.01). In the whole hypertensive population, LMA lumen increased with LV mass (r = 0.40, P.01), and decreased with office systolic blood pressure (r = -0.48, P.01).In the hypertensive LVH, baseline LMA area is not increased and is inversely related to office systolic blood pressure. In the physiologic LVH, increase in baseline LMA size seems to reflect effect of high-flow stimuli.

Aim of this study was to investigate the effects of thyroxine treatment on myocardial regional left ventricular (LV) systolic and diastolic function in patients with subclinical hypothyroidism (SH) by tissue Doppler imaging (TDI). Forty-two patients (29 women and 13 men; mean age 52.2+/-15.1 years) with SH, as judged by elevated serum thyroid-stimulating hormone (TSH) levels (3.6 mIU/l; range, 3.8-12.0) and free thyroid hormones (FT4 and FT3) within the normal range, and 30 euthyroid volunteers (21 women and nine men; mean age 50.4+/-17.1 years) underwent standard echocardiography and TDI-derived early (Em) and late (Am) diastolic velocities, systolic (Sm) velocity, and isovolumetric relaxation time (IVRTm). Patients were randomly assigned to receive or not L-thyroxine replacement therapy. All patients returned after 6 months to repeat thyroid function tests and the evaluation of all parameters. No significant differences were seen in the Sm peak between SH and control groups. Respect to controls, SH patients exhibited a lower Em, a higher Am, and, subsequently, a reduced Em/Am ratio of both lateral wall (LW) and interventricular septum (IVS) (P0.001 for both). The IVRTm was distinctly longer in SH patients, as compared to controls (P0.001). At 6 months, L-thyroxine-treated patients showed a significant increase of Em (P0.01) and a subsequent increase of the Em/Am ratio (P0.01), whereas IVRTm significantly reduced (P0.05). No significant change in any of these parameters was observed in the untreated group. Our data suggest that SH is associated with a subtle, reversible impairment of myocardial function. TDI analysis detects and extends these functional defects by displaying alterations in regional myocardial function. L-T4 replacement therapy should be advised for these patients with the aim to correct preclinical cardiac dysfunction and prevent the development of clinically significant myocardial dysfunction.

Regular exercise is a key component of cardiovascular risk prevention strategies, because it is associated with a variety of beneficial metabolic and vascular effects that reduce mortality and the incidence of cardiovascular adverse events. Endothelium plays an important role in the local regulation of vascular tone and structure, mainly by nitric oxide (NO) synthesis and action. Aim of the present study was to evaluate in elderly athletes the effect of regular aerobic exercise on arterial blood pressure (BP) and on endothelium-dependent flow-mediated dilation (FMD) of the brachial artery.The study population included 30 male subjects (mean age 65.6+/-5.6 years), who had practiced endurance running at a competitive level for at least 40 years, and 28 age- and sex-matched subjects (mean age 64.5+/-4.5 years) with sedentary lifestyle and free of cardiovascular disease. Athletes and control subjects underwent standard 12-lead ECG, clinic BP, 24-h ambulatory BP monitoring and endothelium-dependent FMD and endothelium-independent response to glyceryl trinitrate (GTN), 400 microg, in the brachial artery by high-resolution ultrasonography.Systolic clinic and ambulatory 24-h BP were significantly lower in the athletes, than in the controls (P0.001, respectively). Systolic and diastolic 24-h BP variability, when assessed either by the standard deviation (S.D.), or by the coefficient of variation (CV), were also significantly lower in the athletes (P0.01). The athletes also had a lower 24-h, day-time and night-time heart rate (HR) (P0.01), as well as a lower HR variability (P0.01). As regards circadian BP change, the %Delta was statistically significant greater in athletes (P0.05). Elderly athletes showed higher FMD than elderly sedentary subjects (P0.001), whereas no differences were shown in the response to GTN.Our results, suggest that long-term physical activity can counteract the age-related endothelial dysfunction that characterizes sedentary aging, preserving the capacity of the endothelium-dependent vasodilation and reduces BP values improving arterial pressure control.

Objectives We assessed the role of cytochrome P450 2C9 (CYP 2C9)-derived endothelium-derived hyperpolarizing factor (EDHF) in the forearm microcirculation of essential hypertensive patients (EH) by utilizing sulfaphenazole (SUL), a selective CYP 2C9 inhibitor. Background In EH patients, EDHF acts as a compensatory pathway when nitric oxide (NO) availability is reduced. Cytochrome P450 2C9 is a possible source of EDHF. Methods In 36 healthy subjects (normotensive [NT]) and 32 hypertensive patients (HT), we studied forearm blood flow (strain-gauge plethysmography) changes induced by intraarterial acetylcholine (ACH) and bradykinin (BDK), repeated during NG-monomethyl-L-arginine (L-NMMA) (100 μg/100 ml/min) or SUL (0.03 mg/100 ml/min). In HT, the effect of SUL on ACH and BDK was repeated during vitamin C (8 mg/100 ml/min). Sodium nitroprusside (SNP) was utilized as control. Results In NT, vasodilation to ACH and BDK was blunted by L-NMMA and not changed by SUL. In contrast, in HT responses to ACH and BDK, reduced compared with NT, were resistant to L-NMMA. In these patients, SUL blunted vasodilation to ACH and to a greater extent the response to BDK. When retested with vitamin C, SUL was no longer effective on both endothelial agonists. In 2 final groups of normotensive control subjects, vasodilation to ACH or BDK residual to cyclooxygenase and L-NMMA blockade was further inhibited by simultaneous SUL infusion. Response to SNP, similar between NT and HT, was unaffected by SUL. Conclusions Cytochrome P450 epoxygenase-derived EDHF acts as a partial compensatory mechanism to sustain endothelium-dependent vasodilation in HT, particularly the BDK-mediated response, when NO activity is impaired because of oxidative stress.

The influence of catecholamines on vascular remodeling in humans was investigated.The objective was to study the carotid vascular wall in patients with pheochromocytoma (PHEO).An observational study was conducted in a university referral center for blood pressure diseases.Fourteen patients with PHEO, 15 matched high-normal essential hypertensives, 15 mild essential hypertensives, and 15 controls underwent two-dimensional conventional ultrasonography and ultrasonic tissue characterization of the carotid wall.Intimal media thickness (IMT), diameter, and corrected ultrasonic integrated backscatter signal (C-IBS) of carotid arteries were evaluated.IMT in PHEOs (0.844 +/- 0.18 mm, mean +/- sd) was greater than not only controls (0.596 +/- 0.09 mm, P0.0002) but also high-normal (0.710 +/- 0.17 mm, P0.03), and even mild (0.727 +/- 0.20 mm, P = 0.06) hypertensives. IMT in the latter was higher than in controls (P0.03), without difference in comparison with high-normal hypertensives. C-IBS values in PHEOs (-21.71 +/- 2.0 dB, mean +/- sd) were greater than in controls (-26.20 +/- 1.73 dB, P0.0001) but also than in high-normal (-23.84 +/- 1.16 dB, P0.002) and mild (-23.37 +/- 1.99 dB, P0.01) hypertensives. C-IBS values in controls were lower than in high-normal (P0.0005) and mild (P0.0001) hypertensives. Carotid diameter was not significantly different in the four groups. In PHEOs, C-IBS was associated with urinary noradrenaline (r = 0.640, P0.01) and normethanephrine (r = 0.737, P0.009).Carotid IMT of PHEOs is higher than in controls and matched groups of hypertensives with comparable or even higher blood pressure. This vascular rearrangement is characterized by increased IBS values due to collagen deposition and vascular fibrosis. Therefore, our data show that abnormal catecholamine levels take part per se in carotid wall remodeling of patients with PHEO.

Myocardial involvement is a common finding in certain myopathies, while it has not been extensively investigated in facioscapulohumeral muscular dystrophy (FSHD1A). Aim of this study was to assess in FSHD1A patients the electrical and functional properties of the myocardium. Twenty-four patients with FSHD1A (mean age 41.2±14.5 years) and 24 matched healthy subjects were studied. Standard- and signal-averaged electrocardiography were recorded to determine QT dispersion and the presence of ventricular late potentials (VLPs). Standard echocardiography with systo-diastolic variations of integrated backscatter signal (CV-IBS) were performed to assess functional properties of the myocardium. Compared with control subjects, patients with FSHD1A had significantly lower CV-IBS and higher QT dispersion. Nine patients had positive VLPs. QT and QTc dispersion were inversely related to CV-IBS at both septum and posterior wall levels. Moreover, septal CV-IBS was inversely related to the Kpnl-BinI4q fragment size. These results suggest a subclinical cardiac involvement in FSHD1A patients, which can represent a substrate for ventricular arrhythmias and heart failure.

Cardiac damage is a major complication of chronic starvation. The aim of this study was to evaluate the changes of left ventricular function in patients with anorexia nervosa by means of pulsed tissue Doppler imaging.A total of 20 females (age 22.4+/-4.3 years) with overt anorexia nervosa, 20 matched healthy thin females with body mass index19 kg/m2 and 20 matched healthy normal-weight females underwent both standard echocardiography and tissue Doppler imaging. Myocardial systolic wave (Sm) and early (Em) and atrial (Am) diastolic waves were measured on the basal lateral segment and the basal interventricular septum from the apical four-chamber view.When compared with control groups, the anorexia nervosa group showed lower left ventricular mass (p0.0001), lower Sm peak of both lateral wall (6.5+/-0.9 vs. 9.4+/-2.1 and vs. 9.5+/-1.9 cm/sec, p0.001) and septum (5.6+/-1.5 vs. 8.6+/-1.6 and vs. 8.8+/-1.5 cm/sec, p0.001), and comparable Em, Am and Em/Am ratio. The ratio between transmitral peak E and Em was significantly greater in anorexic patients than in controls (lateral wall: 8.1+/-0.1 vs. 6.8+/-0.2 and vs. 6.9+/-0.2, p0.001; septum: 10.8+/-0.4 vs. 8.8+/-0.5 and vs. 8.8+/-0.3, p0.001). No differences were observed between thin and normal-weight females. In the anorexia nervosa group, S(m) peak was significantly related to left ventricular mass indexed, at both septum (r = 0.55, p0.02) and lateral wall (r = 0.49, p0.03) levels.These results show that anorexia nervosa is associated with left ventricular systolic dysfunction, which is related with the reduction of cardiac mass. Tissue Doppler imaging can give useful information in the identification of regional left ventricular dysfunction, in addition to traditional parameters.

Previous studies showed that potassium chloride (48-120 mmol/day) supplementation reduced arterial blood pressure (BP) in hypertensive patients.Our aim was to evaluate the effect of a lower dose of potassium aspartate salt on BP in individuals with essential arterial hypertension.One hundred and four patients (65 males, age 53 +/- 12 years) with mild to moderate essential hypertension (systolic/diastolic BP 154.2/96.2 +/- 10.8/5.4 mmHg) were allocated in two comparable groups of 52 to receive or not 30 mmol/day per os of potassium aspartate supplementation for four weeks. Office and 24-h BP, as well as serum and urinary electrolytes, were measured at baseline and at the follow-up visit after four weeks.Office and 24-h BP did not change in the control group, while these values were significantly reduced in the potassium supplementation group. Changes in office (systolic BP: 154.4 +/- 8.2 vs. 142.2 +/- 7.6 mmHg; diastolic BP: 95.0 +/- 5.6 vs. 87.2 +/- 4.3 mmHg, P0.001 for both) and 24-h BP (systolic BP: 142.7 +/- 8.2 vs. 134.8 +/- 6.3 mmHg; diastolic BP: 90.8 +/- 4.4 vs. 84.6 +/- 3.8 mmHg, P0.001 for both) following potassium supplementation were highly significant. The changes in day time and night time BP were similar. The treated group showed significantly increased potassium serum level and 24-h urinary excretion of potassium (P0.01 in both cases) after four weeks, while the untreated group showed no significant changes of the same parameters. Urinary Na/K ratio decreased significantly with potassium supplementation (P0.001). In the treated group changes in office (r = 0.58, P0.001) and 24-h SBP (r = 0.51, P0.001), but not in DBP (r = 0.29 and r = 0.25, n.s.), correlated positively with the urinary Na/K ratio at baseline.A relatively low supplementation of 30 mmol/day of potassium as aspartate lowered office and 24-h ambulatory BP in subjects with mild to moderate essential hypertension. The antihypertensive effect was sustained throughout the day, and was greater in the patients with high basal urinary Na/K ratio.

Hypertensive patients with left ventricular hypertrophy (LVH) have increased QT dispersion, which is considered an early indicator of end-organ damage and a non-invasive marker of risk for clinically important ventricular arrhythmias and cardiac mortality. The purpose of this study was to examine the effect of nebivolol antihypertensive therapy on QT dispersion in hypertensive subjects. Twenty-five subjects (15 men and 10 women, mean age 53.6 +/- 4.5 years) with essential arterial hypertension and mild-to-moderate LVH (blood pressure: 147.2 +/- 6.2/90.6 +/- 3.8 mmHg; left ventricular mass indexed: 149.1 +/- 10.7 g/m(2)) were compared with 25 age-matched healthy control subjects. All the participants underwent a complete clinical examination, including electrocardiogram for QT interval measurements. The QT dispersion was defined as the difference between the longest and the shortest QT interval occurring in the 12-lead electrocardiogram. The QT dispersion was corrected (QTc) with Bazett's formula. Hypertensive subjects were treated with 5 mg daily of nebivolol. The ECG and echocardiogram were repeated after four weeks of treatment. At baseline, hypertensive patients showed QT dispersion (56.9 +/- 6.4 vs. 31.7 +/- 8.4 ms, P0.001) and QTc dispersion (58.3 +/- 6.2 vs. 33.2 +/- 7.8 ms, P0.001) significantly higher than control subjects. Four-week nebivolol treatment reduced blood pressure from 147.2 +/- 6.2/90.6 +/- 3.6 mmHg to 136.3 +/- 3.1/83.3 +/- 2.5 mmHg (P0.0001), and resting heart rate from 75.3 +/- 4.7 to 64.2 +/- 3.0 bpm (P0.001), without significant change in left ventricular mass (LVMi: 149.1 +/- 10.7 vs. 151.4 +/- 9.8 g/m(2), ns). Nebivolol-based treatment improved QT dispersion (56.9 +/- 6.4 vs. 40.5 +/- 5.8 ms, P0.001) and QTc dispersion (58.3 +/- 6.2 vs. 42.2 +/- 5.6 ms, P0.001), which remained higher than in control subjects (P0.001 in both cases). The reduction of QT dispersion did not correlate with arterial BP reduction. In conclusion, nebivolol reduced increased QT dispersion in hypertensive subjects after four weeks. This effect, occurred without any change in LVM, did not seem to be related to the blood pressure lowering and could contribute to reduce arrhythmias as well as sudden cardiac death in at-risk hypertensive patients.

The aim of the present study was to assess the cardiovascular autonomic function and responses to tilt test in young and elderly patients with syncope of unknown origin. We evaluated two groups of patients with previous unexplained syncope: 192 older subjects (112 males, 80 females, mean age 67.2 ± 6.8 years) and 188 young subjects (102 males, 86 females, mean age 25 ± 9 years). All patients underwent ambulatory electrocardiogram (ECG) monitoring, to evaluate time domain indices of heart rate variability (HRV), and head-up tilt test in the morning after an overnight fast. The responses of positive tilt test were classified using the VAsovagal Syncope International Study (VASIS) criteria: mixed (VASIS-1), cardioinhibition (VASIS-2A), severe cardioinhibition/asystole (VASIS-2B), pure vasodepression (VASIS-3). All the time-domain HRV indexes were lower in the older than in young subjects. The rate of positive responses was not different in the two groups. In elderly group the positive head-up tilt test responses showed: a pure vasodepressive response (VASIS 3) in 126 patients (65%), a mixed (VASIS-1) response in 25 patients (13%), a cardioinhibitory (VASIS-2A) response in 13 patients (7%). Only 28 (14.6%) of elderly group patients had negative head-up tilt test response. In contrast, in young group the positive head-up tilt test responses showed: 114 patients (61.2%) a mixed (VASIS-1) vasovagal response, 40 patients (22.3%) a cardioinhibitory (VASIS-2A) response, four (2.1%) patients a severe cardioinhibitory (VASIS-2B) and four (2.1%) patients a pure vasodepression (VASIS-3) response, respectively. The tilt test was negative in response in 26 young patients (12.2%). Our results confirm that the head-up tilt test may be useful in assessing unexplained syncope, since it is seen to be positive in 85% of elderly patients and 86% in young patients. In our subjects, vasodepressive response was the most frequent cause of syncope in older subjects, while vasovagal response is the commonest cause of syncope of young patients. This different behaviour in the elderly may be is explained with physiological aging, which is associated with a reduction of sympathetic-parasympathetic control on the cardiac rhythm, demonstrated by reduction in all the time domain HRV indices.

Aging is associated with endothelial dysfunction in both conduit arteries and peripheral microcirculation. Furthermore, aging is associated with an increased susceptibility to free radical mediated tissue damage. The aim of this study was to assess the relationship between age, regular aerobic-endurance training, plasma antioxidant activity and microcirculatory skin blood flow in healthy individuals. Thirty-six male athletes (range: 22-74 years; VO2max 54.3 +/- 5.2 ml/kg/min) and 36 age-sex-matched sedentary controls (range: 20-75 years; VO2max 34.2 +/- 3.4 ml/kg/min) were studied. Each group was divided into a younger (30 years) and an older (60 years) subgroup. Hand and foot baseline and stimulated skin blood flow (SBF) was measured by laser-Doppler flowmetry. Plasma free radicals antioxidant capacity against both peroxyl and hydroxyl radicals was also evaluated as Total Oxyradical Scavenging Capacity (TOSC) units. Baseline SBFs were not significantly different between athletes and sedentary groups, while plasma TOSC values against peroxyl radicals (18.4 +/- 3.1 vs. 13.8.0 +/- 3.4 units/ml, P0.001) and hydroxyl radicals (8.7 +/- 2.5 vs 4.9 +/- 2.3 units/ml, P0.001) was higher in athletes. Hand SBF after heating and ischemia and foot SBF after heating were higher in athletes (P0.0001) than in the sedentary group. In the sedentary groups, the lowest tertile of age had higher plasma TOSC values than the highest tertile of age (ROO- 18.2 +/- 2.2 vs 8.8 +/- 1.4 units/ml; HO- 9.2 +/- 1.3 vs 3.7 +/- 0.5 units/ml, P0.001). Among athletes, the lowest and the highest tertile of age did not show significantly different plasma TOSC (young: ROO- 20.3 +/- 1.5 and HO-: 9.7 +/- 1.4 units/ml; older: ROO-: 17.1 +/- 1.3 and HO-: 9.0 +/- 0.8 units/ml, n.s.). Resting SBF was similar in all the subgroups; stimulated SBFs were lower in both subgroups of untrained respect to trained individuals (P0.001). In the sedentary subjects, SBF was inversely related to age (r = -0.63; P0.0001) and directly related to TOSC against peroxyl (r = 0.59, P0.001) and hydroxyl radicals (r = 0.47, P0.01). In athletes SBF was related only to VO2max (r = 0.36; P0.05) and TOSC vs ROO. (r = 0.41, P0.01). In conclusion, these results suggest that regular physical activity is associated with a better microvascular endothelial function in older athletes probably due to increased antioxidant defenses.

Advancing age is characterized by structural and functional change of left ventricle (LV) and large elastic arteries. Recent advances in tissue Doppler imaging (TDI) and integrated backscatter (IBS), new ultrasound tools, have allowed non-invasive assessment of structural and functional characterization of myocardium and artery wall. Our aim was to compare LV diastolic function and carotid artery remodeling in elderly athletes and sedentary controls. Twenty-five elderly athletes (males, aged 68.6 +/- 4.2 years) were compared to 25 age-sex-matched sedentary controls. All the subjects underwent either conventional Doppler echocardiography with pulsed TDI to evaluate LV diastolic function, and conventional ultrasonography and integrated backscatter (IBS) analysis to evaluate the carotid wall. Corrected IBS values (C-IBS) were obtained by subtracting the IBS value of the adventitia. Body mass index and blood pressure were not different in the two groups; athletes showed lower heart rate (P0.0001) and, as expected, higher LV mass than sedentary subjects (P0.0001). Transmitral Doppler analysis showed in trained subjects a significantly lower peak A and a higher E/A ratio (P0.001). On regards to TDI measurements, athletes exhibited a higher Em, a lower Am, and, subsequently, an increased Em/Am ratio of both lateral wall and septum (P0.0001). The IVRTm was shorter in trained subjects (P0.001). Athletes showed a lower C-IBS (-26.8 +/- 2.9 vs. -23.4 +/- 3.8 dB, P0.001) and a smaller intima-media thickness (IMT: 0.66 +/- 0.14 vs. 0.80 +/- 0.18 mm, P0.001) respect to sedentary controls. Moreover, a significant direct correlation was found between Em/Am of LV septal and lateral wall and C-IBS values (respectively, r = 0.62 and r = 0.56, P0.001). Thus the aging heart manifests structural and functional changes in response to physical activity. The expected pattern of cardiac and arterial alterations normally seen in response to age is modified in the older athletes, suggesting the exercise training is an effective stimulus in shaping arterial structure and left ventricular function in older heart. It would appear that pulsed TDI and IBS analysis may play an important role in detecting training-induced LV and carotid artery structural and functional modifications.

To characterize the complex picture of neurohormonal abnormalities in heart failure (HF), a comprehensive characterization was prospectively performed in 105 patients with cardiomyopathy at different clinical stages and compared to 47 sex/age-matched control healthy subjects. To assess the relationship between the diagnosis of HF and clinical and neurohumoral variables, multiple logistic regression with forward stepwise selection (Wald) was used. The diseased condition was predicted by creatinine level, gamma-glutamyl transpeptidase (GGT) activity, TNF-alpha, and plasma levels of several neurohormonal indices: (a) plasma renin activity; angiotensin II; aldosterone; (b) cortisol as a stress marker; (c) norepinephrine levels; (d) triiodothyronine; (e) ANP and BNP. Thus, renal and hepatic dysfunction, overexpression of cardiac natriuretic hormones, of adrenergic and renin–angiotensin–aldosterone system significantly augment the probability of HF, which was decreased by increasing values of thyroid hormone. In conclusion, a complex neurohormonal derangement associated with an overall predominance of vasoconstrictor systems is characteristic of HF syndrome.

The purpose of this study was to examine the QT dispersion in elderly endurance athletes with left ventricular (LV) hypertrophy. Sixteen athletes (males, mean age 67.6 +/- 4.5 years) with mild to moderate LV hypertrophy, were compared with 16 age-matched hypertensive patients with similar degree of LV hypertrophy and 16 age-matched healthy sedentary controls. All the participants underwent echocardiogram and 12-lead electrocardiogram. QT dispersion was defined as the difference between maximum and minimum QT intervals in the different leads. QT dispersion was corrected (QTc) for heart rate according to Bazett's formula. The results showed in athletes and hypertensive patients comparable LV mass (258.2 +/- 14.2 vs. 262.4 +/- 16.8 g, ns), which was significantly higher than that of controls (p < 0.001). Trained subjects had QT dispersion (38.6 +/- 10.2 ms) and QTc dispersion (39.4 +/- 11.3 ms) significantly lower than hypertensive patients (QT dispersion: 68.4 +/- 11.4 ms; QTc dispersion: 72.2 +/- 8.4, p < 0.001) and comparable with controls (QT dispersion: 44.3 +/- 8.4 ms; QTc dispersion: 46.2 +/- 6.2 ms, ns). In conclusion, in elderly athletes training-induced myocardial hypertrophy was characterized by a QT dispersion significantly lower than hypertensive myocardial hypertrophy. This could provide a simple and inexpensive screening method for differentiating physiologic from pathologic myocardial hypertrophy in elderly subjects.

Background/Aims: The cardiorenal syndrome is a complication in patients hospitalized with chronic heart failure (CHF). The β2-microglobulin (b2M) level is an index of decreased glomerular filtration rate (GFR), tissue turnover and inflammation. It is an emerging new predictive marker of cardiovascular events and mortality, but its role as a biomarker of cardiorenal remodeling and failure is still unknown. TIMP1, an endogenous tissue inhibitor of activated matrix metalloproteinases, is a biomarker of heart remodeling and failure. We aimed to evaluate the circulating profile of b2M and TIMP1 in CHF patients, in sedentary controls with no tissue remodeling and in veteran athletes with physiological cardiorenal remodeling and athlete's heart (AH). Methods: We investigated the plasma levels of b2M and TIMP1 in 24 subjects with CHF without primitive renal disease, in 25 sedentary controls and in 30 veteran marathoners with AH over 50 years. Results: The b2M and TIMP1 levels were higher in CHF patients, and there was a correlation between them (r = 0.5287, p < 0.0095). The b2M level correlated with the severity of cardiorenal impairment: with proBNP (r = 0.66, p > 0.0007), percent ejection fraction (r = -0.56, p = 0.0162) and GFR (r = 0.83, p < 0.0001). b2M was also correlated with TIMP1 in AH subjects (r = 0.7548, p < 0.0001) but not in controls. This correlation was independent from GFR in both CHF patients and sedentary controls. Conclusions: In CHF patients, the plasma levels of b2M and TIMP1 were linked together and correlated with the severity of cardiorenal failure. Moreover, a strong correlation between b2M and TIMP1 characterized cardiovascular remodeling not only in CHF patients but also in AH subjects. These findings suggest that clinicians should use b2M and TIMP1 as associated biomarkers of cardiorenal remodeling and failure. © 2014 S. Karger AG, Basel

During obesity and overweight is present in adipose tissue an imbalance in macrophage activation polarization with prevalence of M1 phenotype. This functional phenotype promotes a proinflammatory state characterized by Th1 type response sustained with a mechanism of cross-talk between macrophages and adipocytes. Obesity-related dysregulation in adipokines secretion and derangement in sex steroid hormone metabolism such as insulin may concur also. These changes may contribute to the development of atherosclerosis and cancer.

Background —Aging is associated with increased cardiovascular risk and endothelial dysfunction. Since exercise can improve endothelium-dependent vasodilation, in the present study we tested whether long-term physical activity could prevent aging-related endothelial dysfunction. Methods and Results —In 12 young and elderly (age 26.9±2.3 and 62.9±5.8 years, respectively) healthy sedentary subjects and 11 young and 14 elderly matched athletes (age 27.5±1.9 and 66.4±6.1 years, respectively), we studied (with strain-gauge plethysmography) forearm blood flow modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg/100 mL per minute), an endothelium-dependent vasodilator, at baseline, during infusion of N G -monomethyl- l -arginine (L-NMMA) (100 μg/100 mL forearm tissue per minute), a nitric oxide–synthase inhibitor, vitamin C (8 mg/100 mL forearm tissue per minute), an antioxidant, and finally under simultaneous infusion of L-NMMA and vitamin C. The response to sodium nitroprusside (1, 2, and 4 μg/100 mL forearm tissue per minute) was also evaluated. In young athletes and sedentary subgroups, vasodilation to acetylcholine was inhibited by L-NMMA and was not changed by vitamin C. In elderly subjects, vasodilation to acetylcholine was blunted as compared with young subjects in both control subjects and athletes, whereas the response to sodium nitroprusside was similar. Moreover, in elderly athletes, vitamin C did not change the vasodilation to acetylcholine. In contrast, in elderly sedentary subjects, the response to acetylcholine was resistant to L-NMMA. In this subgroup, vitamin C increased the vasodilation to acetylcholine and restored the inhibiting effect of L-NMMA. Conclusions —These results suggest that regular physical activity can at least in part prevent the age-induced endothelial dysfunction, probably the restoration of nitric oxide availability consequent to prevention of production of oxidative stress.

The objective of this study was to determine the degree of vascular atherosclerotic damage at the carotid and femoral levels in a group of subjects over sixty years old prac ticing endurance sports. Using high-resolution Doppler-color flow ultrasonography the authors carried out a vascular screening, comparing two distinct groups of subjects, the first consisting of 20 elderly male subjects (age 65.6 ±5.6 years) practicing endurance sports (runners) and the second of 20 subjects of the same gender and age (63.5 ±4.5 years), clinically healthy, but leading a sedentary life. All subjects were nonsmokers, nondiabetics, with normal lipid values and normal blood pressure. The authors examined the internal, external, and common carotid arteries, bilaterally, as well as the common femoral, deep femoral, and superficial femoral arteries of both legs. For each vessel they documented: (1) presence of plaques, (2) position and quantity of the plaques, (3) stenosis percentage produced by the plaques, (4) echographic structure of the plaques. In the group of sportsmen they calculated a global score of atherosclerotic damage of 5.58 ± 2.21. This is statistically significant (P

In 1988, the U.S. Food and Drug Administration proposed guidelines for the clinical evaluation of new antihypertensive drugs. According to these guidelines, the drug effect at trough (measured as the difference in blood pressure values from placebo) should be no less than one half to two thirds of the peak effect. Unfortunately, calculation of the trough/peak ratio suffers the consequences of many methodological, interpretative, practical, and epidemiological problems. When taking readings at short time intervals, noninvasive ambulatory blood pressure monitoring allows evaluation of blood pressure variability by means of several statistical parameters. Blood pressure variability, measured as the standard deviation of the overall 24-hour blood pressure measurements, has been demonstrated to be significantly correlated with target-organ damage in hypertensive patients. Blood pressure variability may not change with long-acting antihypertensive agents, but it may increase with short-acting ones. Therefore, assessment of the trough/peak ratio may be overcome by the evaluation of drug-induced changes in the standard deviation of the mean 24-hour blood pressure.

Myocardial involvement has not been extensively investigated in mitochondrial myopathies. The aim of the study was to assess the myocardial morpho-functional changes in patients with chronic progressive external ophthalmoplegia (PEO). Twenty patients with PEO and 20 controls underwent standard echocardiography with tissue Doppler imaging (TDI) and integrated backscatter (IBS) analyses. These techniques are capable of providing non-invasively the early, subtle structural and functional changes of the myocardium. TDI myocardial systolic (Sm) and early (Em) and late (Am) diastolic velocities of left ventricular walls were determined. The systo-diastolic variation of IBS was also determined. Patients with PEO exhibited lower Sm, lower Em, and higher Am, and a reduced Em/Am ratio than controls (p0.001 for all) at interventricular septum and lateral wall levels. In PEO patients, septal and posterior wall cyclic variations of IBS were significantly lower than those in controls (p0.001). Patients with PEO showed myocardial wall remodeling characterized by increased fibrosis and early left ventricular systo-diastolic function abnormalities. Although cardiac involvement in PEO is generally considered to be limited to the cardiac conduction system, left ventricular dysfunction may be present and should receive more attention in the management of these patients.

Subclinical hyperthyroidism (SH) has been reported associated with atrial fibrillation (AF), heart failure (HF) and coronary heart disease events, including mortality. An expert opinion indicates that AF is the possible link between SH and the other important cardiovascular (CV) manifestations. We analyzed the data of three recent studies including 60,883 subjects of whom 2,284 SH patients. In these subjects, the ratio between the AF events and each of the other above reported CV events varied from 0.14 to 0.4 in SH and from 0.2 to 2.4 in euthyroidism (ET). The general pattern of this ratio in 6 comparisons performed was not significantly higher for SH than ET. This data suggest that AF is not the major link between SH and the related CV manifestations. We suggest that a further link to be considered is the higher frequency of the early atherosclerosis manifestations such as carotid intima media thickness or carotid integrated back scatter, observed in SH. This atherogenic effect of SH can affect the occurrence of all the above clinical CV manifestations.

The authors briefly review the biological effects of vitamin D on the heart and discuss the experimental and clinical studies related to the potential protective effect of vitamin D on the cardiovascular system. Experimental and observational studies in man strongly suggest that vitamin D supplementation can benefit heart failure patients and improve cardiovascular health in the population. However, presently there are limited randomized controlled studies. The authors highlight the hypothesis that vitamin D-induced mechanisms activating calcium channels may represent a novel target for therapy in patients with heart failure.

We investigated the effect of physical activity on heart rate variability (HRV) and carotid intima-media thickness (IMT) in elderly subjects and the relationship between HRV and IMT. Thirty-two elderly sedentary subjects and 32 age-matched endurance athletes underwent ultrasonography of the carotid wall for measuring IMT, and 24-h ECG monitoring for measuring HRV. Elderly athletes had evidence of increased vagal activity in the time (SDANN, rMSSD, and pNN50; p

Pharmacological treatment of hyperlipidemia may be associated with deterioration of glucose tolerance. We randomized 20 nonobese patients with primary familial hypercholesterolemia (serum total cholesterol 7.8 +/- 0.4 mM, triglycerides 1.4 +/- 0.2 mM) to an isocaloric, reduced fat (< 30%) low-cholesterol (200 mg/day) diet with placebo or pravastatin (40 mg/day). Oral glucose tolerance, endogenous insulin response to glucose, insulin sensitivity (determined by the euglycemic insulin clamp technique), hepatic glucose production (by the tritiated glucose technique), and substrate utilization (by indirect calorimetry) were measured at baseline and after 8 weeks of treatment. Ten normocholesterolemic healthy subjects, matched to the patients by age, sex, and body weight, served as the control group. Diet alone (with no change in body weight) was associated with a significant 15% decrease in both serum low density lipoprotein (LDL)-cholesterol and triglycerides (p < 0.001 for both), and a slight decrease in high density lipoprotein (HDL)-cholesterol concentrations, paralleled by reductions in Apo B, C2, C3, and E levels (p < 0.05 or less). The addition of pravastatin led to a significantly larger reduction in LDL-cholesterol (30%, p < 0.05) and an 8% increase (p < 0.02) in total HDL-cholesterol concentrations. Accordingly, the ratio of LDL:HDL cholesterol (which was 60% higher than in controls at baseline) remained unchanged in the placebo-diet group whereas it was restored to normal in the pravastatin-diet group. Glucose tolerance, insulin response, insulin-induced inhibition of hepatic glucose production and lipolysis, and insulin-mediated glucose uptake and oxidation were all slightly but not significantly improved after treatment, with no significant differences between pravastatin and placebo. In nonobese patients with primary hypercholesterolemia, pravastatin treatment in combination with an isocaloric, reduced-fat diet leads to a marked reduction in LDL-cholesterol and triglycerides levels and a normalization of the LDL:HDL ratio without affecting glucose tolerance or insulin sensitivity.

The efficacy of simvastatin in reducing plasma cholesterol is well documented. Other molecules within the apo lipoprotein family, particularly lipoprotein (a) Lp(a), have recently been found to have a predictive and/or causative role in atherosclerosis. Based on these considerations, we studied 15 patients affected by primary hypercholesterolemia to evaluate the effect of simvastatin in Lp(a) and apoprotein plasma levels (A1, B, C2, C3, E), in addition to the classic lipid parameters. Clinical and laboratory parameters were evaluated before therapy, after 12 weeks of therapy, and after 5 weeks of drug withdrawal. Simvastatin therapy produced a significant reduction in total cholesterol (CH) and LDL-CH (p < 0.0001), and a significant increase in HDL-CH (p < 0.01); no variation was observed in triglyceride (TG) levels. Simvastatin therapy further showed a significant decrease in apoC2 (p < 0.05), the apo C2/C3 ratio (p < 0.01), and apoE (p < 0.01), as well as a significant increase in Lp(a) plasma levels (p < 0.05). All of the parameters studied returned to pretreatment values 5 weeks after drug withdrawal; only HDL-CH persisted above the values reached during therapy. Our data agree with those documenting the beneficial effect of simvastatin in greatly decreasing CH and LDL-CH, but point out the need for further studies on the long-term effect of simvastatin on apoprotein molecules, such as on Lp(a), in order to fully establish its role in the secondary prevention of atherosclerosis.

We review podocyte molecular structure and function, consider the underlying mechanisms related to podocyte dysfunction and propose that podocyte dysfunction be considered in the evaluation and management of age-associated glomerulosclerosis. With aging, progressive sympathetic activation, increased intrarenal renin-angiotensin system (RAS) activity, endothelin system and oxidative stress and reduced nitric oxide (NO)-availability can damage podocytes. Apoptosis and proliferation are the principal podocyte changes following injury with the latter leading to sclerosis and loss of nephrons. Podocyte loss can be evaluated by either determining their average number in biopsed glomeruli or by estimating podocyte number or their associated molecules in urine sediment. Podocyturia may be considered a marker of active glomerular disease. Preliminary data suggest that antiadrenergic drugs, angiotensin converting enzyme (ACE) inhibitors, RAS blocking drugs, endothelin system inhibitors and reduced oxidative stress can protect podocytes. Thus podocytes appear to play an important role in the pathogenesis, evaluation and therapy of age related glomerulosclerosis.