Search

Context Vitamin D (Vit-D), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23) are the major calciotropic hormones involved in the regulation of blood calcium levels from the intestine, kidney, and bone through a tight endocrine feedback loop system. Altered levels of calcium itself or through the effect of its regulatory hormones could affect blood pressure (BP), but the exact mechanisms remain unclear. Objective To evaluate whether a causal relationship exists between serum calcium level and/or the regulatory hormones involved in its homeostasis with BP, we performed a two-sample Mendelian randomization (MR) study. Methods From 4 large genome-wide association studies (GWAS) we obtained independent (r2 < 0.001) single nucleotide polymorphisms (SNPs) associated with serum calcium (119 SNPs), Vit-D (78 SNPs), PTH (5 SNPs), and FGF23 (5 SNPs), to investigate through MR their association with systolic BP (SBP) and diastolic BP (DBP) in a Swedish urban-based study, the Malmö Diet and Cancer study (n = 29 298). Causality was evaluated by the inverse variance weighted method (IVW) and weighted median, while MR Egger and MR-PRESSO were used as sensitivity analyses. Results Genetically predicted serum calcium level was found to be associated with DBP (IVW: beta = 0.10, SE = 0.04, P = 0.007) and SBP (IVW: beta = 0.07, SE = 0.04, P = 0.04). Genetically predicted Vit-D and PTH showed no association with the traits, while FGF23 was inversely associated with SBP (IVW: beta = −0.11, SE = 0.04, P = 0.01), although this association lost statistical significance in sensitivity analysis. Conclusion Our study shows a direct association between genetically predicted calcium level and DBP, and a weaker association with SBP. No such clear association was found for genetically predicted calciotropic hormone levels. It is of interest to detect which target genes involved in calcium homeostasis mediate the effect of calcium on BP, particularly for improving personalized intervention strategies.

Type 1 diabetes mellitus (T1D) is a chronic disease leading to cardiovascular complications that can be diagnosed early as subclinical vascular damage. To prevent such damage, it is important to increase knowledge of the effects of the different cardiovascular risk factors in patients with T1D. The aim of our study was to assess possible associations between markers of subclinical arterial damage and traditional cardiovascular risk factors, with a special focus on peripheral blood pressure and central blood pressure (cBP), in a sample of young adults with T1D.The study included 172 T1D patients (mean age 24.7 ± 8.7 years, duration of T1D 13.5 ± 9.6 years). Pulse wave velocity (PWV), pulse wave analysis and cBP were assessed by tonometry (SphygmoCor Xcel). Carotid intima-media thickness (cIMT) and carotid distensibility coefficient (cDC) were assessed by high-resolution echo-Doppler analysis and further examined with dedicated hardware.Seventeen patients (10.1%) were classified as hypertensive by office peripheral blood pressure, and 48 patients (27.9%) were classified as hypertensive by cBP. One hundred sixteen patients (68.8%) had cDC under the range of normality, one patient had a PWV (0.6%) above 10 m/s, and no patients had a cIMT above 0.9 mm. In multivariable analysis, central SBP, but not metabolic parameters, remained associated with all the markers of subclinical arterial damage [cIMT ( β = 0.288 ± 0.001; P 0.001), PWV ( β = 0.374 ± 0.007; P 0.001), cDC ( β = -0.149 ± 0.055; P = 0.029)].The independent association between cBP and markers of subclinical vascular damage underlines the importance of haemodynamic factors in the development of early signs of macrovascular disease in T1D patients. Further studies are warranted to better define the role of cBP to stratify cardiovascular risk, to individualize the need for follow-up and to tailor preventive strategies in T1D patients.

International audience; No abstract available

Thyroid function has a widespread effect on the cardiometabolic system. However, the causal association between either subclinical hyper- or hypothyroidism and the thyroid hormones with blood pressure (BP) and cardiovascular diseases (CVD) is not clear. We aim to investigate this in a two-sample Mendelian randomization (MR) study. Single nucleotide polymorphisms (SNPs) associated with thyroid-stimulating hormone (TSH), free tetraiodothyronine (FT4), hyper- and hypothyroidism, and anti-thyroid peroxidase antibodies (TPOAb), from genome-wide association studies (GWAS), were selected as MR instrumental variables. SNPs–outcome (BP, CVD) associations were evaluated in a large-scale cohort, the Malmö Diet and Cancer Study (n = 29,298). Causal estimates were computed by inverse-variance weighted (IVW), weighted median, and MR-Egger approaches. Genetically increased levels of TSH were associated with decreased systolic BP and with a lower risk of atrial fibrillation. Hyperthyroidism and TPOAb were associated with a lower risk of atrial fibrillation. Our data support a causal association between genetically decreased levels of TSH and both atrial fibrillation and systolic BP. The lack of significance after Bonferroni correction and the sensitivity analyses suggesting pleiotropy, should prompt us to be cautious in their interpretation. Nevertheless, these findings offer mechanistic insight into the etiology of CVD. Further work into the genes involved in thyroid functions and their relation to cardiovascular outcomes may highlight pathways for targeted intervention.

The CYP4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at individual patients' level to capture the possible effect of ethnicity, gene-gene interaction or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95%CI 7-10%), with a higher effect in females, in patients taking acenocoumarol and in Whites. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived. This article is protected by copyright. All rights reserved.

Ion channels are transmembrane proteins that play important roles in cell function regulation modulating ionic cell permeability. In megakaryocytes and platelets, regulated ion flows have been demonstrated to modulate platelet production and function. However, a relatively limited characterization of ion channel expression and function is available in the human megakaryocyte-platelet lineage.We analyzed the expression and function of the large-conductance calcium and voltage-activated potassium channel KTo investigate the functionality of KIn megakaryocytes, KThe present study reveals new mechanisms in platelet formation and activation, suggesting that targeting K

Background Ion channels are transmembrane proteins that play important roles in cell function regulation modulating ionic cell permeability. In megakaryocytes and platelets, regulated ion flows have been demonstrated to modulate platelet production and function. However, a relatively limited characterization of ion channel expression and function is available in the human megakaryocyte-platelet lineage. Objective We analyzed the expression and function of the large-conductance calcium and voltage-activated potassium channel Kca 1.1 (also known as Maxi-K, BK, slo1) in human megakaryocytes and platelets. Methods To investigate the functionality of Kca 1.1, we exploited different agonists (BMS-191011, NS1619, NS11021, epoxyeicosatrienoic acid isoforms) and inhibitors (iberiotoxin, penitrem A) of the channel. Results In megakaryocytes, Kca 1.1 agonists determined a decreased proplatelet formation and altered interaction with the extracellular matrix. Analysis of the actin cytoskeleton demonstrated a significant decrease in megakaryocyte spreading and adhesion to collagen. In platelets, the opening of the channel Kca 1.1 led to a reduced sensitivity to agonists with blunted aggregation in response to ADP, with an inhibitory capacity additive to that of aspirin. The Kca 1.1 agonists, but not the inhibitors, determined a reduction of platelet adhesion and aggregation onto immobilized collagen underflow to an extent similar to that of aspirin and ticagrelor. The opening of the Kca 1.1 resulted in cell hyperpolarization impairing free intracellular calcium in ADP-stimulated platelets and megakaryocytes. Conclusions The present study reveals new mechanisms in platelet formation and activation, suggesting that targeting Kca 1.1 channels might be of potential pharmacological interest in hemostasis and thrombosis.

Background: Several studies identified genetic variants in FADS and ELOVL2 genes associated with obesity-related conditions, such as alterations in blood lipid parameters and insulin homeostasis. The aim of this cross-sectional study was to determine whether FADS and ELOVL2 genetic variants were associated with obesity and adiposity, besides dyslipidaemia and insulin resistance, in a large sample of obese children and adolescents. Materials and methods: One thousand six hundred and forty-nine obese children underwent physical examination, anthropometry, fasting blood tests measuring plasma glucose, lipid and liver profile. Two genetic variants were genotyped: rs2236212 in ELOVL2 gene and rs1535 in FADS2, for the gene cluster FADS. In a subgroup of obese children (n = 105), erythrocyte fatty acid composition was measured. Generalized linear models were used to assess association between genotypes and variables. Results: A positive association between zBMI and the minor allele of rs2236212 (p = 0.028), the major allele of rs1535 (p = 0.046) and the genetic score (p = 0.008), created by summing up both risk alleles, were found. The estimation of enzymatic activity revealed that minor alleles were associated significantly with a reduction of the enzymatic activity of elongase and desaturase (p = 0.048 and p = 0.0001, respectively). Discussion and conclusions: Common variants in the FADS2 and ELOVL2 genes were associated with BMI in a large population of obese Italian children. These SNPs were associated with alterations in LC-PUFAs homeostasis, not accompanied by modifications of plasma lipids or HOMA-IR. These findings provide additional support to the genetics accounting for BMI interindividual variability and the molecular basis of obesity.

Background. Childhood obesity is becoming a major health issue and contributes to increasing the risk of cardiovascular disease in adulthood. Since dysregulated metabolism of bile acids (BAs) plays a role in progression of obesity-related disorders, including steatosis and hypertension, this study aimed to investigate BAs profiles in obese children with and without steatosis and hypertension, as well as exploring the interplay between BAs profile and vascular function. Methods. BAs concentrations were quantified with liquid chromatography-tandem mass spectrometry in 69 overweight/obese children and adolescents (mean age, 11.6 &plusmn, 2.5 years, 30 females). Liver steatosis was defined with abdomen ultrasonography, whilst hypertension was defined according to the current European guidelines. Vascular function was assessed with ultrasound technique, by measuring carotid intima media thickness (cIMT) and common carotid artery distensibility (cDC). Results. Total and individual glycine-conjugated BAs concentrations were found to be significantly higher in males compared to females, as well as in pre-pubertal compared to pubertal stage (p &lt, 0.05 for both). No difference in BAs concentration was observed between hypertensive and normotensive subjects. Total BAs and glycine conjugated BAs were significantly higher in participants with steatosis compared to those without (p = 0.004 for both). The values of total glycine-conjugate acids were positively correlated with cDC and this association remained significant in linear regression after adjusting for sex, age, pubertal stage, body mass index and aspartate aminotransferase. Conclusion. The results suggest a possible role of BAs in the pathogenesis of liver and/or vascular damage in children and adolescent. Further studies are hence needed to validate these preliminary findings.

The treatment for obstructive sleep apnoea (OSA) with continuous positive airway pressure (CPAP) or mandibular advancement devices (MADs) is associated with blood pressure (BP) reduction; however, the overall effect is modest. The aim of this systematic review and meta-analysis of randomised controlled trials (RCTs) comparing the effect of such treatments on BP was to identify subgroups of patients who respond best to treatment.The article search was performed in three different databases with specific search terms and selection criteria. From 2289 articles, we included 68 RCTs that compared CPAP or MADs with either passive or active treatment. When all the studies were pooled together, CPAP and MADs were associated with a mean BP reduction of −2.09 (95% CI −2.78– −1.40) mmHg for systolic BP and −1.92 (95% CI −2.40– −1.43) mmHg for diastolic BP and −1.27 (95% CI −2.34– −0.20) mmHg for systolic BP and −1.11 (95% CI −1.82– −0.41) mmHg for diastolic BP, respectively. The subgroups of patients who showed a greater response were those aged Although this meta-analysis shows that the expected reduction of BP by CPAP/MADs is modest, it identifies specific characteristics that may predict a pronounced benefit from CPAP in terms of BP control. These findings should be interpreted with caution; however, they are particularly important in identifying potential phenotypes associated with BP reduction in patients treated for OSA.

Obesity leads to the clustering of cardiovascular (CV) risk factors and the metabolic syndrome (MetS) also in children and is often accompanied by non-alcoholic fatty liver disease. Quality of dietary fat, beyond the quantity, can influence CV risk profile and, in particular, omega-3 fatty acids (FA) have been proposed as beneficial in this setting. The aim of the study was to evaluate the associations of individual CV risk factors, characterizing the MetS, with erythrocyte membrane FA, markers of average intake, in a group of 70 overweight/obese children. We conducted an observational study. Erythrocyte membrane FA were measured by gas chromatography. Spearman correlation coefficients (rS) were calculated to evaluate associations between FA and features of the MetS. Mean content of Omega-3 FA was low (Omega-3 Index = 4.7 ± 0.8%). Not omega-3 FA but some omega-6 FA, especially arachidonic acid (AA), were inversely associated with several features of the MetS: AA resulted inversely correlated with waist circumference (rS = − 0.352), triglycerides (rS = − 0.379), fasting insulin (rS = − 0.337) and 24-h SBP (rS = − 0.313). Total amount of saturated FA (SFA) and specifically palmitic acid, correlated positively with waist circumference (rS = 0.354), triglycerides (rS = 0.400) and fasting insulin (rS = 0.287). Fatty Liver Index (FLI), a predictive score of steatosis based on GGT, triglycerides and anthropometric indexes, was positively correlated to palmitic acid (rS = 0.515) and inversely to AA (rS = − 0.472). Our data suggest that omega-6 FA, and especially AA, could be protective toward CV risk factors featuring the MetS and also to indexes of hepatic steatosis in obese children, whereas SFA seems to exert opposite effects.

Treatment of obstructive sleep apnoea (OSA) has been shown to reduce blood pressure (BP). However, the effect size is modest and treatment of OSA is not recommended as the only treatment target when treating hypertension. The aim of this systematic review and meta-analysis was to identify potential predictors for BP response in patients with OSA undergoing CPAP treatment. A systematic search was conducted in three databases (MEDLINE, Embase and Web of Science) between January 1st 1960 to December 31st 2017 using terms exploring three domains (obstructive sleep apnoea, CPAP, clinical trial) Out of 2445 articles, 59 RCTs were included (n=7,329 subjects) comparing CPAP with control groups. CPAP was associated with a net reduction in systolic BP of -2.12 (95% CI -2.82 to -1.42) mmHg and in diastolic BP of -1.97 (95% CI -2.46 to -1.48) mmHg, favouring treatment of OSA using CPAP (both p-values Younger patients (

The aim of this school-based study was to identify the possible association between diet and physical activity, as well as the anthropometric, vascular, and gluco-lipid parameters. We administered two validated questionnaires for diet and physical activity (Food Frequency questionnaire (FFQ), Children-Physical Activity Questionnaire (PAQ-C)) to children at four primary schools in Verona South (Verona, Italy). Specific food intake, dietary pattern, and physical activity level expressed in Metabolic Equivalent of Task (MET) and PAQ-C score were inserted in multivariate linear regression models to assess the association with anthropometric, hemodynamic, and gluco-lipid measures. Out of 309 children included in the study, 300 (age: 8.6 &plusmn, 0.7 years, male: 50%, Obese (OB): 13.6%, High blood pressure (HBP): 21.6%) compiled to the FFQ. From this, two dietary patterns were identified: &ldquo, healthy&rdquo, and &ldquo, unhealthy&rdquo, Direct associations were found between (i) &ldquo, fast food&rdquo, intake, Pulse Wave Velocity (PWV), and (ii) animal-derived fat and capillary cholesterol, while inverse associations were found between vegetable, fruit, and nut intake and capillary glucose. The high prevalence of OB and HBP and the significant correlations between some categories of food and metabolic and vascular parameters suggest the importance of life-style modification politics at an early age to prevent the onset of overt cardiovascular risk factors in childhood.

In previous studies, dietary and circulating fatty acids (FA) and desaturases activity (delta-5 desaturase [D5D], delta-6 desaturase [D6D], and stearoyl-CoA desaturase [SCD-16]) involved in their metabolism were associated with metabolic and cardiovascular disorders. The aim of the study was to assess the association between different FAs and desaturases activity (estimated as product:precursor ratios) with individual cardiovascular risk factors (in particular, anthropometric measurements and blood pressure [BP]) in children. The FA profile was determined on a whole-blood drop in 243 children (age: 8.6 &plusmn, 0.72 years) participating in a school-based cross-sectional study. Docosahexaenoic acid (DHA) inversely correlated with indices of adiposity, glucose, and triglycerides. Palmitoleic acid and SCD-16 were directly associated with markers of adiposity and BP, even after adjustment for main confounders. D6D correlated directly with the waist/height ratio. Children with excess weight (&gt, 85th percentile, that is overweight plus obese ones) showed higher palmitic acid, palmitoleic acid, and higher SCD-16 activity as compared to normal-weight children. Most of the associations were confirmed in the excess-weight group. Omega-3 FAs, particularly DHA, but not omega-6 FA, showed a potentially beneficial association with metabolic parameters, whereas palmitoleic acid and SCD-16 showed a potentially harmful association with indices of adiposity and BP, especially in obese children.

Obesity is often accompanied by metabolic and haemodynamic disorders such as hypertension, even during childhood. Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP450) enzymes to epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE), vasoactive and natriuretic metabolites that contribute to blood pressure (BP) regulation. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) omega-3 polyunsaturated fatty acids may compete with AA for CYP450-dependent bioactive lipid mediator formation. We aimed at investigating the role of AA, EPA and DHA and their CYP450-dependent metabolites in BP control and vascular function in 66 overweight/obese children. Fatty acid profile moderately correlated with the corresponding CYP450-derived metabolites but their levels did not differ between children with normal BP (NBP) and high BP (HBP), except for higher EPA-derived epoxyeicosatetraenoic acids (EEQs) and their diols in HBP group, in which also the estimated CYP450-epoxygenase activity was higher. In the HBP group, EPA inversely correlated with BP, EEQs inversely correlated both with systolic BP and carotid Intima-Media Thickness (cIMT). The DHA-derived epoxydocosapentaenoic acids (EDPs) were inversely correlated with diastolic BP. Omega-3 derived epoxymetabolites appeared beneficially associated with BP and vascular structure/function only in obese children with HBP. Further investigations are needed to clarify the role of omega-3/omega-6 epoxymetabolites in children&rsquo, s hemodynamics.

Objective:Physical activity plays an important role in preventing obesity and related cardiometabolic risk factors. The six-minute walk test (6MWT) is a clinical sub-maximal, easy and-cost effective test to asses functional capacity utilized also in epidemiological studies as predictor of cardiovasc

Since the publication of this paper, it has been noted that the author Denise Marcon had been missed out of the author list. The correct author list is shown above.

Objective: To investigate the influence of weight excess and blood pressure (BP) on vascular structure and function in a sample of obese children. Methods: We measured office and ambulatory BP (ABPM), carotid intima-media thickness (cIMT), endothelial function by the Flow Mediated Dilation (FMD) technique, carotid distensibility (cDC) (ultrasonograph: LogiQ P5 Pro; software: Multimedia Video Engine II, DSP Lab, Pisa CNR, Italy) (1) and stiffness index (SI) by photopletismography (Pulce Trace PT1000, MicroMedical Ltd, UK) (2) in overweight and obese children (BMI > 90th percentile for sex and age). Results: Seventy children with weight excess were enrolled (age 11.5±2.4 years; female n: 30). cDC showed inverse correlation with BMI and waist circumference (rSpearman = −0.403 and rs = −0.346, respectively), 24h-SBP (rs = −0.449) and nighttime-SBP (rs = −0.490). SI inversely correlated with BMI (rs = −0.359) and waist/height ratio (rs = −0.303). When comparing normotensive and hypertensive children, as defined on the basis of the ABPM, no significant differences in vascular tests were found, although cDC tended to be lower in hypertensive. In normotensive subjects (n: 53) cIMT directly correlated with nighttime-SBP and DBP. Most of the correlations remained significant after adjustment for age, sex, BMI and BP. Conclusions: These data suggest that arterial elasticity is negatively affected by weight excess and 24h-BP levels even in childhood. In the normotensive subgroup it is detectable an effect of BP also on arterial structure.

The clinical value of the polygenetic component of blood pressure (BP) is commonly questioned. We evaluated a genetic risk score for BP (BP-GRS 858 ), based on the most recently published genome-wide association studies variants that were significantly associated with either systolic BP or diastolic BP, for prediction of hypertension and cardiovascular end points. The genotyping was performed in 2 urban-based prospective cohorts: the Malmö Diet and Cancer (n=29 295) and the Malmö Preventive Project (n=9367) and a weighted BP-GRS 858 based on 858 SNPs was calculated. At baseline, we found a difference of 9.0 mm Hg (systolic BP) and 4.8 mm Hg (diastolic BP) between the top and the bottom quartile of BP-GRS 858 . In Malmö Preventive Project, the top versus bottom quartile of BP-GRS 858 was associated with a doubled risk of incident hypertension (odds ratio, 2.05 [95% CI, 1.75–2.39], P =1.4×10 −21 ), a risk higher than that of body mass index, as evaluated in quartiles. In Malmö Diet and Cancer, significant association was found between the age and sex-adjusted BP-GRS 858 and the incidence of total cardiovascular events, stroke, coronary artery disease, heart failure, atrial fibrillation, and total mortality. Most of these associations remained significant after adjusting for traditional risk factors, including hypertension. BP-GRS 858 could contribute predictive information regarding future hypertension, with an effect size comparable to other well-known risk factors such as obesity, and predicts cardiovascular events. Given that the exposure to high polygenetic risk starts at birth, we suggest that the BP-GRS 858 might be useful to identify children or adolescents who would benefit from early hypertension screening and treatment.

Background Different adiposity traits may be causally related to hypertension in different ways. By using genetic variants as randomly allocated proxies for studying the effect of modifying adiposity traits, the Mendelian randomization approach can be used to investigate this. Methods and Results In this study, we used 4 different genetic risk scores (GRS; GRS‐BMI 565 , GRS‐WHR 324 , GRS‐VAT 208 , GRS‐BF 81 ) including hundreds of single nucleotide polymorphisms associated with body mass index, waist‐to‐hip ratio, visceral adipose tissue, and body fat, respectively. These were applied as instrumental variables in Mendelian randomization analyses. Two Swedish urban‐based cohort studies, the Malmö Diet and Cancer, and the Malmö Preventive 795Projects were used to obtain genetic association estimates with blood pressure (BP). In both the Malmö Preventive Projects and Malmö Diet and Cancer studies, except for that for body fat, all of the genetic risk scores were significantly associated with systolic BP and diastolic BP, but with different magnitudes. In particular, in both cohorts, each standard deviation increase in the genetic risk score made up by the 324 single nucleotide polymorphisms associated with waist‐to‐hip ratio was associated with doubling of the likelihood of hypertension prevalence at baseline. However, only the genetic risk score made up by the 565 SNPs associated with body mass index was significantly associated with hypertension incidence during 23.6±4.3 years of follow‐up in the Malmö Preventive Project. Conclusions We support a causal link between genetically mediated adiposity, especially waist‐to‐hip ratio and body mass index, and BP traits including hypertension prevalence and, for the first time to our knowledge, hypertension incidence. The differences in magnitude between these associations might suggest different mechanisms by which different adiposity affects BP/hypertension and consequently may indicate that tailored interventions are needed to reduce cardiovascular risk.