Interaction between polyphenols intake and PON1 gene variants on markers of cardiovascular disease: a nutrigenetic observational study.

BACKGROUND: Paraoxonase 1 (PON1) gene polymorphisms and polyphenols intake have been reported independently associated to lipid profile and susceptibility to atherosclerosis and cardiovascular disease. However, the interaction between these factors remains to be investigated. We performed an observational nutrigenetic study to examine whether the interaction between polyphenols and anthocyanins intake and PON1 genetic variants can modulate biomarkers of cardiovascular health in an Italian healthy population. METHODS: We recruited 443 healthy volunteers who participated in the EC funded ATHENA project (AnThocyanin and polyphenols bioactive for Health Enhancement through Nutritional Advancement). Data collection included detailed demographic, clinical, dietary, lifestyle, biochemical and genetic data. Polyphenols and anthocyanins intake was measured by 24 h dietary recall repeated three times a year in order to get seasonal variations. We tested the interaction between 18 independent tagging SNPs in PON1 gene and polyphenols intake on HDL, LDL, cholesterol, triglycerides and atherogenic index of plasma. RESULTS: Without considering the genetic background, we could not observe significant differences in the lipid profile between high and low polyphenols and anthocyanins intake. Using a nutrigenetic approach, we identified protective genotypes in four independent polymorphisms that, at Bonferroni level (p ≤ 0.0028), present a significant association with increased HDL level under high polyphenols and anthocyanins intake, compared to risk genotypes (rs854549, Beta = 4.7 per C allele; rs854552, Beta = 5.6 per C allele; rs854571, Beta = 3.92 per T allele; rs854572, Beta = 3.94 per C allele). CONCLUSIONS: We highlight the protective role of genetic variants in PON1 towards cardiovascular risk under high polyphenols and anthocyanins consumption. PON1 variants could represent novel biomarkers to stratify individuals who might benefit from targeted dietary recommendation for health promotion and strategies of preventive medicine.

Is atherosclerosis an autoimmune disease?

Immunologic research into pathogenic mechanisms operating in autoimmune-mediated atherosclerosis initially focused on adaptive immunity. Current interest is directed to more basic inflammatory mechanisms. Chronic inflammation (innate immunity-associated) may trigger initial events that can lead to atherosclerotic cardiovascular disease. This chronic inflammation may start early in life and be perpetuated by classic atherosclerosis risk factors. Lipid peroxidation of low-density lipoprotein seems to be a key event in the initiation and progression of atherosclerosis. Oxidized low-density lipoprotein triggers inflammatory and immunogenic events that promote endothelial dysfunction and the synthesis and secretion of pro-inflammatory cytokines, leading to an autoimmune response capable of accelerating the intracellular accumulation of lipids within atherosclerotic plaques. Oxidized low-density lipoprotein binds ß2-glycoprotein I to form circulating complexes found in both autoimmune and non-autoimmune atherosclerosis. It is likely that ß2-glycoprotein I and/or these complexes contribute to early atherogenesis by stimulating pro-inflammatory innate immunity through endogenous sensors and inflammasome/interleukin-1 pathways. We discuss the chronic inflammatory (innate) and autoimmune (adaptive) responses operating in atherosclerosis to discern the role of autoimmunity in atherosclerotic cardiovascular disease.

Healthy Promotion for Fighting Metabolic Syndrome: Insights from Multi-Center HeRO-FiT Cohort.

We know that metabolic syndrome (MS) is a modern cardiovascular (CV) "epidemic", especially in western populations. MS is indeed strictly related to the risk of developing CV diseases (CVD) and/or diabetes. Therefore, the aim of our multi-center study was to promote a "healthy style" for fighting MS. Each participating center analyzed its own database of outpatients and globally we have pulled out 100 volunteers to participate in the study. Before starting, we collected their written consent. Enrolled subjects have not any history of overt CVD and/or diabetes, but they matched National Cholesterol Education Program/Adult Treatment Panel (NCEP/ATP) criteria for MS. After enrolment (t0), subjects were randomly divided into two homogeneous groups: a) only diet suggestions; b) both diet and exercise prescription. Later, we measured for each subject: blood pressure (BP), heart rate (HR), height, weight, body mass index (BMI), waist circumference (WC), waist hip ratio (WHR), six-minute walking test (WT6M), distance and common blood tests such as fasting plasma glucose, high-density lipoproteins (HDL) and triglycerides (T1 assessments). At six months (T2), the same parameters were measured and then statistical comparisons were performed. Attention to diet caused significant changes only in WC and WHR, whilst a coupling of exercise and diet revealed a statistically significant improvement in HR, BP, BMI, blood samplings and WT6M too. In conclusion, a healthy lifestyle should be more encouraged by physicians and/or collaborators (such as dieticians) operating in preventive settings. Diet and physical activity may be early useful strategies in the "battle" against MS even before any medication choices. Further studies will be necessary in order to better address the topic.

SARS-CoV-2 Aiming for the Heart: A Multicenter Italian Perspective About Cardiovascular Issues in COVID-19.

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the high fatality rate of coronavirus disease 2019 (COVID-19) have been putting a strain on the world since December 2019. Infected individuals exhibit unpredictable symptoms that tend to worsen if age is advanced, a state of malnutrition persists, or if cardiovascular comorbidities are present. Once transmitted, the virus affects the lungs and in predisposed individuals can elicit a sequela of fatal cardiovascular consequences. We aim to present the pathophysiology of COVID-19, emphasizing the major cellular and clinical manifestations from a cardiological perspective. As a roaming viral particle or more likely via the Trojan horse route, SARS-CoV-2 can access different parts of the body. Cardiovascular features of COVID-19 can count myocardial injuries, vasculitis-like syndromes, and atherothrombotic manifestations. Deviations in the normal electrocardiogram pattern could hide pericardial effusion or cardiac inflammation, and dispersed microthrombi can cause ischemic damages, stroke, or even medullary reflex dysfunctions. Tailored treatment for reduced ejection fraction, arrhythmias, coronary syndromes, macrothrombosis and microthrombosis, and autonomic dysfunctions is mandatory. Confidently, evidence-based therapies for this multifaceted nevertheless purely cardiological COVID-19 will emerge after the global assessment of different approaches.

Non-invasive assessment of coronary flow reserve and ADMA levels: a case-control study of early rheumatoid arthritis patients.

OBJECTIVE: Plasma concentration of asymmetric dimethylarginine (ADMA), a major endogenous inhibitor of nitric oxide synthase, is considered a novel risk factor for endothelial dysfunction associated with enhanced atherosclerosis. Coronary microcirculation abnormalities have been demonstrated in patients with early rheumatoid arthritis (ERA) without any signs or symptoms of coronary artery disease (CAD). The aim of the study was to compare the ERA and control groups with ADMA, intima-media thickness (IMT) and coronary flow reserve (CFR) levels. It assessed whether ERA patients have more cardiovascular risk (endothelial dysfunction and coronary microvascular abnormalities), and evaluated whether any difference in IMT/CFR between ERA and controls can be explained by any difference in ADMA levels between the groups. METHODS: The study involved 25 ERA patients (female/male 21/4; mean age 52.04 +/- 14.05 years; disease duration

Asymmetric dimethylarginine (ADMA): an endogenous inhibitor of nitric oxide synthase and a novel cardiovascular risk molecule.

Asymmetric dimethylarginine (ADMA), a methyl derivate of the amino acid arginine, is produced by the physiological degradation of methylated proteins. ADMA is the major endogenous inhibitor of nitric oxide synthase (NOS), the enzyme which synthesizes nitric oxide (NO), a molecule endowed with important anti-atherosclerotic properties. Increased plasma ADMA concentrations cause impaired NO synthesis leading to endothelial dysfunction and atherosclerotic vascular disease. Increased plasma ADMA levels mainly occur following inhibition of the enzyme responsible for ADMA catabolism, dimethylarginine dimethylaminohydrolase (DDAH), by oxidative stress triggered by several cardiovascular risk factors. This paper reviews the effects on cardiovascular function produced by ADMA administration to experimental animals and humans. In addition, a number of clinical conditions associated with increased plasma ADMA concentrations are considered. Then the growing body of literature indicating that plasma ADMA levels have a predictive value for major cardiovascular events in prospective studies is discussed. Finally, an analysis is provided of the published data concerning the possibility to modulate plasma ADMA levels using drugs belonging to different pharmacological classes.

Noninvasive imaging methods for evaluating cardiovascular involvement in patients with rheumatoid arthritis before and after anti-TNF drug treatment.

AIM: To use 2D speckle-tracking echocardiography, and conventional and tissue Doppler echocardiography to detect subclinical left ventricular myocardial dysfunction in patients with rheumatoid arthritis (RA). METHODS: Thirty RA outpatients were assessed before and after 18 months of treatment with anti-TNF drugs, along with 30 healthy controls. Cardiovascular risk was assessed by means of ultrasound carotid assessment and comprehensive echocardiographic evaluation (conventional and speckle-tracking calculation). RESULTS: The speckle-tracking analyses were significantly different between the two groups, with global longitudinal strain deformation in the apical four-chamber view being significantly lower in the RA patients (median: 18.78%, interquartile range [IQR]: 15.80-20.82% vs 20.16%, IQR: 19.03-21.89%; [p < 0.05]). After 18 months of biological treatment, global longitudinal strain showed a significant improvement (18.78%, IQR: 15.80-20.82 vs 19.24%, IQR: 18.23-19.98; [p < 0.01]), such as for DAS28 (4.80, IQR: 4.65-5.22 vs 2.78; IQR: 2.52-2.99; [p < 0.01]). CONCLUSION: Speckle-tracking echocardiography showed that left ventricular myocardial longitudinal strain was impaired in the RA patients.

Cardiovascular Imaging Techniques in Systemic Rheumatic Diseases.

The risk of cardiovascular (CV) events and mortality is significantly higher in patients with systemic rheumatic diseases than in the general population. Although CV involvement in such patients is highly heterogeneous and may affect various structures of the heart, it can now be diagnosed earlier and promptly treated. Various types of assessments are employed for the evaluation of CV risk such as transthoracic or transesophageal echocardiography, magnetic resonance imaging (MRI), and computed tomography (CT) to investigate valve abnormalities, pericardial disease, and ventricular wall motion defects. The diameter of coronary arteries can be assessed using invasive quantitative coronarography or intravascular ultrasound, and coronary flow reserve can be assessed using non-invasive transesophageal or transthoracic ultrasonography (US), MRI, CT, or positron emission tomography (PET) after endothelium-dependent vasodilation. Finally, peripheral circulation can be measured invasively using strain-gauge plethysmography in an arm after the arterial infusion of an endothelium-dependent vasodilator or non-invasively by means of US or MRI measurements of flow-mediated vasodilation of the brachial artery. All of the above are reliable methods of investigating CV involvement, but more recently, introduced use of speckle tracking echocardiography and 3-dimensional US are diagnostically more accurate.

Correction of hypovitaminosis D improved global longitudinal strain earlier than left ventricular ejection fraction in cardiovascular older adults after orthopaedic surgery.

BACKGROUND: Cardiovascular diseases and insufficient levels of vitamin D are risk factors for adverse surgical outcomes, and they are both commonly present among older adults undergoing orthopaedic surgery. Giving the cardiovascular effects of vitamin D, pre-operative diagnosis of hypovitaminosis D would be a valuable step for the implementation of supplementation protocols. We investigated if the normalization of serum 25 [OH] D could ameliorate cardiac performance of older adults suffering from cardiovascular diseases. METHODS: We enrolled 47 older adults scheduled for major orthopaedic surgery and suffering from hypovitaminosis D. Patients underwent 6-months calcifediol supplementation with a starting dose at first post-operative day of 50 µg/die in liquid preparation. Down-titration to 20 µg/die at 3-months assessment was planned. Cardiac performance was evaluated by measuring left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) during pre-operative assessments and at 1-month, 3-months, 6-months follow-ups. RESULTS: Six months of calcifediol supplementation were associated with a significant improvement of both LVEF (+ 3.94%; 95% CI: -4.0789 to -0.8232; P < 0.01) and GLS (+ 18.56%; Z = -5.895; P < 0.0001). CONCLUSIONS: Calcifediol supplementation normalized serum 25 [OH] D concentration after 1-month treatment. GLS offered better insights into myocardial contractile amelioration than LVEF, thus being useful for detecting earlier subclinical changes that may anticipate hemodynamic modifications.

Foot and Soccer Referees': A Pilot Study Searching "Performance" Throughout Prevention.

Soccer refereeing is a "not-conventional" sport in which aerobic workload is prevalent. Along the years, several studies have attempted to define best markers of referees' performance. Many studies focused their attention on field tests and their relationship with aerobic power. Instead, in this study, starting by a medical assessment satisfying the FIFA 11+ criteria for injuries prevention, we have investigated the foot of soccer referees and we have also wanted to find possible and/or unexpected improvements in performance. As performance marker, we have used the referral field test for soccer referees that is internationally validated and known as Yo-Yo test (YYiR1). While standardized foot posture index (FPI) questionnaire was used for screening foot referees conditions (40 young, all men by sex, with mean age 23.47 ± 4.36). Analyzing collected data, we have demonstrated by means of Read-Cressie Chi square test that neutral FPI is an important favor item affecting YYiR1 results. Further studies will be necessary in order to confirm our pilot investigation.

Potential target of infliximab in autoimmune and inflammatory diseases.

Tumour necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine produced by many cell types (blood monocytes, macrophages, mast cells and endothelial cells), that play a key role in the pathogenesis of multiple autoimmune and nonautoimmune disorders. A number of large placebo-controlled trials have shown that infliximab, a chimeric monoclonal antibody against TNF-alpha, is effective and well tolerated in patients with Crohn's disease, rheumatoid arthritis and spondiloarthritides and has become a widely used treatment for these diseases. Preliminary data suggest that several forms of vasculitis appear responsive to TNF antagonists: Behçet's disease, Churg-Strauss vasculitis, polyarteritis nodosa, and giant cell arteritis, among others. Wegener's granulomatosis and sarcoidosis have been shown to improve with infliximab. Polymyositis/dermatomyositis may also be responsive to TNF blockade. TNF likely plays little role in Sjögren's syndrome as evidenced by the lack of efficacy of TNF antagonists. There is a rationale for using TNF blockade even in systemic lupus erythematosus, a prototype of autoantibody-mediated disease, and a pilot study seems to confirm this potential effective approach. A number of other more rare disorders also may be responsive to TNF blockade. We here review the current and prospective roles of infliximab in the treatment of autoimmune diseases and other conditions.

What is the role of rituximab in the treatment of rheumatoid arthritis?

Rituximab is a monoclonal antibody against CD20 that was developed for the treatment of relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). Recent controlled trials have shown that B cell-targeted therapy with rituximab is effective in RA (which suggest that B lymphocytes may be critical in its pathogenesis of RA) and early exposure data suggest that the tolerability and safety profile of rituximab may be even better in RA than in NHL patients. Rituximab is generally well tolerated, with a low incidence of serious adverse events, including serious infections. Available evidence suggests that its clinical benefits depend on effective B cell depletion, and the fact that its novel mode of action leads to the depletion of B cells makes it distinct from other biological therapies for RA that target T cells and their related cytokines. Although complete peripheral B cell depletion is regularly seen in RA and other autoimmune diseases, especially systemic lupus erythematosus (SLE), incomplete depletion has been reported in a subset of patients, even after full dosing with rituximab.

Preclinical impairment of coronary flow reserve in patients with rheumatoid arthritis.

Cardiovascular involvement in rheumatoid arthritis (RA) is common, although the true prevalence of cardiac abnormalities is difficult to measure, as much disease remains clinically silent. The pathogenesis of cardiac lesions in RA is related to the primary disorder of microcirculation with diffuse arteriolar and capillary lesions. Previous studies demonstrated that coronary flow reserve (CFR) is impaired in patients with connective tissue diseases (CTD). This review focuses on transthoracic Doppler echocardiography as a noninvasive method used to assess CFR in RA patients. CFR is early reduced in RA patients without clinical evidence of heart disease as a result of impaired microcirculation. CFR seems a useful technique able to follow-up and to assess effects of new drugs on RA patients.

Left ventricular longitudinal strain in soccer referees.

Along the years, the analysis of soccer referees perfomance has interested the experts and we can find several types of studies in literature using in particular cardiac imaging. The aim of this retrospective study was to observe relationship between VO2max uptake and some conventional and not-conventional echocardiographic parameters. In order to perform this evaluation, we have enrolled 20 referees, belonging to Italian Soccer Referees' Association and we have investigated cardiovascular profile of them. We found a strong direct relationship between VO2max and global longitudinal strain of left ventricle assessed by means of speckle tracking echocardiographic analysis (R2=0.8464). The most common classic echocardiographic indexes have showed mild relations (respectively, VO2max vs EF: R2=0.4444; VO2max vs LV indexed mass: R2=0.2268). Therefore, our study suggests that longitudinal strain could be proposed as a specific echocardiographic parameter to evaluate the soccer referees performance.

Thrombotic risk factors in primary antiphospholipid syndrome: a 5-year prospective study.

BACKGROUND AND PURPOSE: Because thromboembolic events are frequently observed in primary antiphospholipid syndrome (PAPS), we assessed the risk factors for new thrombotic episodes. METHODS: Fifty-six PAPS patients (mean age, 37+/-10 years) were prospectively studied for 5 years. The preliminary Sapporo classification criteria for antiphospholipid syndrome (APS; a medium-high anticardiolipin antibody [aCL] titer and/or a positive lupus anticoagulant [LA] test in the presence of vascular thrombosis and/or pregnancy morbidity) were used to confirm the diagnosis. Thrombotic episodes or pregnancy losses before a diagnosis of PAPS were considered events, and any new disease manifestation other than thrombocytopenia was considered a recurrent event. Only patients with objectively verified thrombotic events were included in the study. RESULTS: Twenty-one new thrombotic events were observed in 15 subjects (26.8%), including 3 (5.4%) who died during the follow-up. The patients with IgG aCL levels of >40 IgG phospholipid unit (GPL-U) showed a higher incidence of new thrombotic events (43.3%) than those with levels of < or =40 GPL-U (7.7%). Univariate analysis identified a history of recurrent clinical events (P=0.004), a highly positive aCL titer (P=0.007), and the presence of cardiac abnormalities (P=0.036) as significant risk factors for new thrombotic events. A multivariate regression model confirmed that an IgG aCL titer of >40 GPL-U was an independent risk factor for thrombosis (odds ratio, 9.17; 95% confidence interval, 1.83 to 46.05). CONCLUSIONS: A high IgG aCL titer is the strongest predictor of new thrombotic events in PAPS patients.

The role of echocardiographic techniques in connective tissue diseases.

Connective tissue diseases (CTD) lead to a high prevalence of common cardiac manifestations (pericarditis and myocarditis) and of ischemic coronary events with a considerable increase in cardiac mortality related to premature atherosclerosis. Although there are several techniques able to detect cardiac involvement in CTD patients, the most useful and non-invasive technique is echocardiographic exam which is able to detect not only valvular abnormalities, pericardial diseases and pulmonary hypertension but also left ventricular (LV) systolic or diastolic (regional or global) wall motion dysfunction. It is also well known that transesophageal echocardiography (TEE) can better identify cardiac abnormalities, vegetations and embolic sources. Symptomatic patients with positive stress echocardiographic exam or dipyridamole thallium imaging test should be referred for possible cardiac catheterization, especially if a large ischemic territory is involved. Until now, the echocardiographic evaluation of coronary artery tree consisted of assessing regional and global left ventricular systolic and diastolic function at rest and during pharmacological stress test. Recently, a new echocardiographic noninvasive method that allows direct assessment of coronary flow velocity in the mid-distal portion of left anterior descending artery (LAD) has been developed and validated. Advanced ultrasound technology (high-frequency broadband transducer with second harmonic capability) has now made possible a direct arterial visualization and measurement of coronary artery flow in left anterior descending in CTD patients with the assessment of coronary flow reserve (CFR).

Five-year follow-up by transesophageal echocardiographic studies in primary antiphospholipid syndrome.

This prospective study describes valvular abnormalities assessed by transesophageal echocardiography (TEE) in patients with primary antiphospholipid syndrome (APLS) over a 5-year follow-up. Of the 56 patients with APLS evaluated at baseline, 47 (84%) had repeat TEE examinations, including 3 patients who died before the end of the follow-up. The first TEE study showed cardiac involvement (thickening or vegetations and embolic sources) in 34 subjects (61%), with mitral valve thickening, the most common abnormality, present in 30 patients (54%). Embolic sources were found in 14 patients (25%; 9 severe spontaneous echocardiographic contrast, 5 Libman-Sacks endocarditis), associated with mitral valve thickening or stenosis in 10 patients. Over the 5-year follow-up, cardiac involvement was unchanged in 30 subjects (64%). New cardiac abnormalities were observed in 17 patients (36%), 15 (88%) with high immunoglobulin-G (IgG) anticardiolipin antibody (aCL) titers and 2 (12%) with low IgG aCL titers. In conclusion, this study showed that mitral valve thickening and embolic sources are frequently observed in patients with APLS. Anticoagulant and/or antiplatelet treatment was ineffective in terms of valvular lesion regression. New appearances of cardiac involvement are significantly related to high IgG aCL titers.

Autoimmunity and anti-TNF-alpha agents.

Treatment of rheumatoid arthritis (RA) patients with anti-tumor necrosis factor-alpha (anti-TNF-alpha) biologic agents has been associated with a reduction in the levels of specific autoantibodies, such as rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP), and the induction of non- organ-specific autoantibodies (antinuclear antibodies [ANAs], anti-dsDNA, and antiphospholipid antibodies [aPLs]). The mechanisms by which the blockade of anti-TNF-alpha decreases the generation of specific autoantibodies, such as anti-CCP and RF, are not yet known. However, it has been shown that these agents can downregulate the production of several inflammatory cytokines and mediators and that these anti-inflammatory effects may account for reduced autoantibody generation, particularly in the synovial compartment. Infliximab treatment leads to the induction of ANAs in 63.8% of RA patients and 49.1% of Crohn's disease (CD) patients, and anti-dsDNA antibodies in 13% of RA patients and 21.5% of CD patients, respectively. The development of ANAs and anti-dsDNA antibodies has also been described after etanercept therapy in 11% and 15% of RA patients, respectively. In the controlled trials, increases in ANA and anti-dsDNA titers were observed in 5.3% and in 12.9% of adalimumab-treated RA patients. Only limited data on the induction of aPL antibodies during TNF-alpha blocking treatment are available.