Cognitive phenotypes and factors associated with cognitive decline in a cohort of older patients with atrial fibrillation: The Strat-AF study.

BACKGROUND AND PURPOSE: The multifactorial relationship between atrial fibrillation (AF) and cognitive impairment needs to be elucidated. The aim of this study was to assess, in AF patients on oral anticoagulants (OACs), the prevalence of cognitive impairment, defined according to clinical criteria or data-driven phenotypes, the prevalence of cognitive worsening, and factors associated with cognitive outcomes. METHODS: The observational prospective Strat-AF study enrolled AF patients aged ≥ 65 years who were receiving OACs. The baseline and 18-month protocol included clinical, functional, and cognitive assessment, and brain magnetic resonance imaging. Cognitive outcomes were: empirically derived cognitive phenotypes; clinical diagnosis of cognitive impairment; and longitudinal cognitive worsening. RESULTS: Out of 182 patients (mean age 77.7 ± 6.7 years, 63% males), 82 (45%) received a cognitive impairment diagnosis, which was associated with lower education level and functional status, and higher level of atrophy. Cluster analysis identified three cognitive profiles: dysexecutive (17%); amnestic (25%); and normal (58%). Compared to the normal group, the dysexecutive group was older, and had higher CHA2 DS2 -VASc scores, while the amnestic group had worse cognitive and functional abilities, and medial temporal lobe atrophy (MTA). Out of 128 followed-up patients, 35 (27%) had cognitive worsening that was associated with lower education level, worse cognitive efficiency, CHA2 DS2 -VASc score, timing of OAC intake, history of stroke, diabetes, non-lacunar infarcts, white matter hyperintensities and MTA. In multivariate models, belonging to the dysexecutive or amnestic group was a main predictor of cognitive worsening. CONCLUSIONS: In our cohort of older AF patients, CHA2 DS2 -VASc score, timing of OAC intake, and history of stroke influenced presence, type and progression of cognitive impairment. Empirically derived cognitive classification identified three groups with different clinical profiles and better predictive ability for cognitive worsening compared to conventional clinical diagnosis.

Effects of vegetarian versus Mediterranean diet on kidney function: Findings from the CARDIVEG study.

BACKGROUND: The aim of the present study was to assess the effects of a lacto-ovo-vegetarian diet (VD), compared to a Mediterranean diet (MD), on kidney function in a group of subjects with medium-to-low cardiovascular risk profile. METHODS: We analysed 107 subjects (82 women, 25 men; median age 52) who followed a VD (n = 54) and a MD (n = 53) for 3 months in the CARDIVEG study, a randomized, open, crossover trial that compared the effects of these 2 diets on cardiovascular disease risk. RESULTS: The effect of the two diets on kidney function markers was evaluated by conducting a general linear model for repeated measurements adjusted for possible confounding factors such as age, sex, physical activity, alcohol, smoking, hypertension, LDL cholesterol, glucose and body weight change. A significant reduction in creatinine (-5.3%; P < .001), urea nitrogen levels (-9%; P = .001), blood urea nitrogen (BUN) (-8.7%; P = .001) and BUN/creatinine ratio (-5.8%; P < .001), and an increase in estimated glomerular filtration rate (eGFR) (+3.5%; P = .001) was observed during the VD period. On the contrary, no significant changes were noted in the MD group. Variations obtained in the two dietary interventions were significantly different (P < .0001) for creatinine levels, BUN/creatinine and eGFR, for which opposite trends were observed in the VD and MD groups. CONCLUSIONS: In a selected group of subjects with medium-to-low cardiovascular risk profile, a 3 month VD period determined significant improvements in kidney function markers. Further trials are needed to confirm these results.

Effects of a dietary intervention with Mediterranean and vegetarian diets on hormones that influence energy balance: results from the CARDIVEG study.

A randomised, open, crossover trial with two intervention periods was used to compare the effects of a 3-month dietary intervention with Mediterranean diet (MD) and vegetarian diet (VD) on hormones that influence energy balance, and to investigate the relationship with changes in body composition. After 3 months, no significant differences between the two diets were observed. Both MD and VD resulted in a significant (p < .05) reduction in leptin-to-adiponectin ratio and anthropometric parameters, MD resulted in a significant decrease in leptin levels (-7.4%), while VD determined a significant increase in adiponectin (+6.8%) and a significant decrease in visfatin (-12.7%) levels. In both groups, changes in leptin, insulin and HOMA-IR were significantly and positively correlated with changes in anthropometric parameters. In conclusion, both MD and VD have led to a slight but significant improvement in hormones that influence energy balance. The effect was more evident in participants who lost weight and fat mass.

Low-Calorie Vegetarian Versus Mediterranean Diets for Reducing Body Weight and Improving Cardiovascular Risk Profile: CARDIVEG Study (Cardiovascular Prevention With Vegetarian Diet).

BACKGROUND: Only a few randomized dietary intervention studies that investigated the effects of lacto-ovo vegetarian diet (Vd) in clinically healthy omnivorous subjects are available. METHODS: We randomly assigned to overweight omnivores with a low-to-moderate cardiovascular risk profile a low-calorie Vd compared with a low-calorie Mediterranean diet (MD), each lasting 3 months, with a crossover design. The primary outcome was the difference in body weight, body mass index, and fat mass changes between the 2 groups. Secondary outcomes were differences in circulating cardiovascular disease risk parameters changes between the 2 groups. RESULTS: One hundred eighteen subjects (mean age: 51.1 years, females: 78%) were enrolled. The total participation rate at the end of the study was 84.7%. No differences between the 2 diets in body weight were observed, as reported by similar and significant reductions obtained by both Vd (-1.88 kg) and MD (-1.77 kg). Similar results were observed for body mass index and fat mass. In contrast, significant differences between the 2 interventions were obtained for low-density lipoprotein cholesterol, triglycerides, and vitamin B12 levels. The difference between the Vd and MD groups, in terms of end-of-diet values, was recorded at 9.10 mg/dL for low-density lipoprotein cholesterol (P=0.01), 12.70 mg/dL for triglycerides (P<0.01), and 32.32 pg/mL for vitamin B12 (P<0.01). Finally, no significant difference was found between Vd and MD interventions in oxidative stress markers and inflammatory cytokines, except for interleukin-17, which improved only in the MD group. Forty-six participants during the Vd period and 35 during the MD period reached the target values for ≥1 cardiovascular risk factor. CONCLUSIONS: Both Vd and MD were effective in reducing body weight, body mass index, and fat mass, with no significant differences between them. However, Vd was more effective in reducing low-density lipoprotein cholesterol levels, whereas MD led to a greater reduction in triglyceride levels. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02641834.

Role of Biological Markers for Cerebral Bleeding Risk STRATification in Patients with Atrial Fibrillation on Oral Anticoagulants for Primary or Secondary Prevention of Ischemic Stroke (Strat-AF Study): Study Design and Methodology.

Background and Objectives: In anticoagulated atrial fibrillation (AF) patients, the validity of models recommended for the stratification of the risk ratio between benefits and hemorrhage risk is limited. Cerebral small vessel disease (SVD) represents the pathologic substrate for primary intracerebral hemorrhage and ischemic stroke. We hypothesize that biological markers-both circulating and imaging-based-and their possible interaction, might improve the prediction of bleeding risk in AF patients under treatment with any type of oral anticoagulant. Materials and Methods: The Strat-AF study is an observational, prospective, single-center hospital-based study enrolling patients with AF, aged 65 years or older, and with no contraindications to magnetic resonance imaging (MRI), referring to Center of Thrombosis outpatient clinic of our University Hospital for the management of oral anticoagulation therapy. Recruited patients are evaluated by means of a comprehensive protocol, with clinical, cerebral MRI, and circulating biomarkers assessment at baseline and after 18 months. The main outcome is SVD progression-particularly microbleeds-as a selective surrogate marker of hemorrhagic complication. Stroke occurrence (ischemic or hemorrhagic) and the progression of functional, cognitive, and motor status will be evaluated as secondary outcomes. Circulating biomarkers may further improve predictive potentials. Results: Starting from September 2017, 194 patients (mean age 78.1 ± 6.7, range 65-97; 61% males) were enrolled. The type of AF was paroxysmal in 93 patients (48%), and persistent or permanent in the remaining patients. Concerning the type of oral anticoagulant, 57 patients (29%) were on vitamin K antagonists, and 137 (71%) were on direct oral anticoagulants. Follow-up clinical evaluation and brain MRI are ongoing. Conclusions: The Strat-AF study may be an essential step towards the exploration of the role of a combined clinical biomarker or multiple biomarker models in predicting stroke risk in AF, and might sustain the incorporation of such new markers in the existing stroke prediction schemes by the demonstration of a greater incremental value in predicting stroke risk and improvement in clinical outcomes in a cost-effective fashion.

A khorasan wheat-based replacement diet improves risk profile of patients with type 2 diabetes mellitus (T2DM): a randomized crossover trial.

PURPOSES: The aim of the present study was to examine whether a replacement diet with products made with organic ancient khorasan wheat could provide additive protective effects in reducing glucose, insulin, lipid and inflammatory risk factors, and in restoring blood redox balance in type 2 diabetes mellitus (T2DM) patients compared to diet with product made with modern organic wheat. METHODS: We conducted a randomized, double-blinded crossover trial with two intervention phases on 21 T2DM patients (14 females, 7 males). The participants were assigned to consume products (bread, pasta, crackers and biscuits) made using semi-whole flour from organic wheat that was either from ancient khorasan wheat or modern control wheat for 8 weeks in a random order. An 8-week washout period was implemented between the interventions. Laboratory analyses were performed both at the beginning and at the end of each intervention phase. RESULTS: The metabolic risk profile improved only after the khorasan intervention period, as measured by a reduction in total and LDL cholesterol (mean reduction: -3.7 and -3.4 %, respectively), insulin (-16.3 %) and blood glucose (-9.1 %). Similarly, there was a significant reduction in circulating levels of reactive oxygen species (ROS), vascular endothelial growth factor (VEGF) and interleukin-1ra, and a significant increase of total antioxidant capacity (+6.3 %). No significant differences from baseline were noted after the modern control wheat intervention phase. The change (from pre- to post-intervention) between the two intervention arms was significantly different (p < 0.05) for total and LDL-c, insulin and HOMA index. CONCLUSIONS: A replacement diet with ancient khorasan wheat consumption provided additive protection in reducing total and LDL cholesterol, insulin, blood glucose, ROS production, and some inflammatory risk factors, which are all key factors warranting of control in secondary prevention of T2DM compared to a diet with products made with modern wheat.

Cardiovascular benefits from ancient grain bread consumption: findings from a double-blinded randomized crossover intervention trial.

Ancient grain varieties have been shown to have some beneficial effects on health. Forty-five clinically healthy subjects were included in a randomized, double-blinded crossover trial aimed at evaluating the effect of a replacement diet with bread derived from ancient grain varieties versus modern grain variety on cardiovascular risk profile. After 8 weeks of intervention, consumption of bread obtained by the ancient varieties showed a significant amelioration of various cardiovascular parameters. Indeed, the ancient varieties were shown to result in a significant reduction of total cholesterol, low-density lipoprotein (LDL)-cholesterol and blood glucose, whereas no significant differences during the phase with the modern variety were reported. Moreover, a significant increase in circulating endothelial progenitor cells were reported after the consumption of products made from the ancient "Verna" variety. The present results suggest that a dietary consumption of bread obtained from ancient grain varieties was effective in reducing cardiovascular risk factors.

Circulating Biomarkers in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Patients.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microangiopathy presenting with variable features, including migraine, psychiatric disorders, stroke, and cognitive decline and variable disability. On neuroimaging, CADASIL is characterized by leukoencephalopathy, multiple lacunar infarcts, and microbleeds. Previous studies suggest a possible role of endothelial impairment in the pathogenesis of the disease. METHODS: We assessed plasma levels of von Willebrand factor (vWF) and thrombomodulin (TM) and the blood levels of endothelial progenitor cells (EPCs) and circulating progenitor cells (CPCs) in 49 CADASIL patients and 49 age-matched controls and their association with clinical/functional and neuroimaging features. RESULTS: In multivariate analysis, CADASIL patients had significantly higher vWF and lower EPC levels. TM levels were similar in the 2 groups. CADASIL patients with a more severe clinical phenotype (history of stroke or dementia) presented lower CPC levels in comparison with patients with a milder phenotype. On correlation analysis, lower CPC levels were associated with worse performances on neuropsychological, motor and functional tests, and with higher lesion load on brain magnetic resonance imaging (degree of leukoencephalopathy and number of lacunar infarcts). CONCLUSIONS: This is the first CADASIL series in which multiple circulating biomarkers have been studied. Our findings support previous studies on the presence and the possible modulating effect of endothelial impairment in the disease. Furthermore, our research data suggest that blood CPCs may be markers of disease severity.

Effect of Triticum turgidum subsp. turanicum wheat on irritable bowel syndrome: a double-blinded randomised dietary intervention trial.

The aim of the present study was to examine the effect of a replacement diet with organic, semi-whole-grain products derived from Triticum turgidum subsp. turanicum (ancient) wheat on irritable bowel syndrome (IBS) symptoms and inflammatory/biochemical parameters. A double-blinded randomised cross-over trial was performed using twenty participants (thirteen females and seven males, aged 18-59 years) classified as having moderate IBS. Participants received products (bread, pasta, biscuits and crackers) made either from ancient or modern wheat for 6 weeks in a random order. Symptoms due to IBS were evaluated using two questionnaires, which were compiled both at baseline and on a weekly basis during the intervention period. Blood analyses were carried out at the beginning and end of each respective intervention period. During the intervention period with ancient wheat products, patients experienced a significant decrease in the severity of IBS symptoms, such as abdominal pain (P< 0·0001), bloating (P= 0·004), satisfaction with stool consistency (P< 0·001) and tiredness (P< 0·0001). No significant difference was observed after the intervention period with modern wheat products. Similarly, patients reported significant amelioration in the severity of gastrointestinal symptoms only after the ancient wheat intervention period, as measured by the intensity of pain (P= 0·001), the frequency of pain (P< 0·0001), bloating (P< 0·0001), abdominal distension (P< 0·001) and the quality of life (P< 0·0001). Interestingly, the inflammatory profile showed a significant reduction in the circulating levels of pro-inflammatory cytokines, including IL-6, IL-17, interferon-γ, monocyte chemotactic protein-1 and vascular endothelial growth factor after the intervention period with ancient wheat products, but not after the control period. In conclusion, significant improvements in both IBS symptoms and the inflammatory profile were reported after the ingestion of ancient wheat products.

Chromatin dynamics during epigenetic reprogramming in the mouse germ line.

A unique feature of the germ cell lineage is the generation of totipotency. A critical event in this context is DNA demethylation and the erasure of parental imprints in mouse primordial germ cells (PGCs) on embryonic day 11.5 (E11.5) after they enter into the developing gonads. Little is yet known about the mechanism involved, except that it is apparently an active process. We have examined the associated changes in the chromatin to gain further insights into this reprogramming event. Here we show that the chromatin changes occur in two steps. The first changes in nascent PGCs at E8.5 establish a distinctive chromatin signature that is reminiscent of pluripotency. Next, when PGCs are residing in the gonads, major changes occur in nuclear architecture accompanied by an extensive erasure of several histone modifications and exchange of histone variants. Furthermore, the histone chaperones HIRA and NAP-1 (NAP111), which are implicated in histone exchange, accumulate in PGC nuclei undergoing reprogramming. We therefore suggest that the mechanism of histone replacement is critical for these chromatin rearrangements to occur. The marked chromatin changes are intimately linked with genome-wide DNA demethylation. On the basis of the timing of the observed events, we propose that if DNA demethylation entails a DNA repair-based mechanism, the evident histone replacement would represent a repair-induced response event rather than being a prerequisite.

Effects of a dietary intervention with lacto-ovo-vegetarian and Mediterranean diets on apolipoproteins and inflammatory cytokines: results from the CARDIVEG study.

BACKGROUND: Apolipoproteins have been recently proposed as novel markers of cardiovascular disease (CVD) risk. However, evidence regarding effects of diet on apolipoproteins is limited. AIM: To compare the effects of Mediterranean diet (MD) and lacto-ovo vegetarian diet (VD) on apolipoproteins and traditional CVD risk factors in participants with low-to-moderate CVD risk. METHODS: Fifty-two participants (39 women; 49.1 ± 12.4 years), followed MD and VD for 3 months each. Medical and dietary information was collected at the baseline. Anthropometric parameters and blood samples were obtained at the beginning and the end of interventions. RESULTS: MD and VD resulted in significant improvement in anthropometric and lipid profiles. Both diets led to a reduction in most of the inflammatory parameters. As for apolipoproteins, a significant change was observed for ApoC-I after VD (+ 24.4%; p = 0.020). MD led to a negative correlation between ApoC-III and carbohydrates (R = - 0.29; p = 0.039) whereas VD between ApoD and saturated fats (R = - 0.38; p = 0.006). A positive correlation emerged after VD between HDL and ApoD (R = 0.33; p = 0.017) and after MD between plasma triglycerides and ApoC-I (R = 0.32; p = 0.020) and ApoD (R = 0.30; p = 0.031). IL-17 resulted to be positively correlated with ApoB after MD (R = 0.31; p = 0.028) and with ApoC-III after VD (R = 0.32; p = 0.019). Subgroup analysis revealed positive effects on apolipoproteins from both diets, especially in women, individuals older than 50 years-old or with < 3 CVD risk factors. CONCLUSIONS: Both diets seem to improve CVD risk, however, MD showed a greater positive effect on apolipoproteins in some subgroups, thus suggesting how diet may influence new potential markers of CVD risk. TRIAL REGISTRATION: registered at clinicaltrials.gov (identifier: NCT02641834) on December 2015.

The serum metabolomic profiles of atrial fibrillation patients treated with direct oral anticoagulants or vitamin K antagonists.

AIMS: Long-term oral anticoagulation is the primary therapy for preventing ischemic stroke in patients with atrial fibrillation (AF). Different types of oral anticoagulant drugs can have specific effects on the metabolism of patients. Here we characterize, for the first time, the serum metabolomic and lipoproteomic profiles of AF patients treated with anticoagulants: vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). MATERIALS AND METHODS: Serum samples of 167 AF patients (median age 78 years, 62 % males, 70 % on DOACs treatment) were analyzed via high resolution 1H nuclear magnetic resonance (NMR) spectroscopy. Data on 25 metabolites and 112 lipoprotein-related fractions were quantified and analyzed with multivariate and univariate statistical approaches. KEY FINDINGS: Our data provide evidence that patients treated with VKAs and DOACs present significant differences in their profiles: lower levels of alanine and lactate (odds ratio: 1.72 and 1.84), free cholesterol VLDL-4 subfraction (OR: 1.75), triglycerides LDL-1 subfraction (OR: 1.80) and 4 IDL cholesterol fractions (ORs âˆ¼ 1.80), as well as higher levels of HDL cholesterol (OR: 0.48), apolipoprotein A1 (OR: 0.42) and 7 HDL cholesterol fractions/subfractions (ORs: 0.40-0.51) are characteristic of serum profile of patients on DOACs' therapy. SIGNIFICANCE: Our results support the usefulness of NMR-based metabolomics for the description of the effects of oral anticoagulants on AF patient circulating metabolites and lipoproteins. The higher serum levels of HDL cholesterol observed in patients on DOACs could contribute to explaining their reduced cardiovascular risk, suggesting the need of further studies in this direction to fully understand possible clinical implications.