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Effective high density lipoprotein cholesterol (HDL-C) is a measure of HDL functionality. We evaluated if HDL-C is associated with carotid intima-media thickness (cIMT) and incident major adverse cardiovascular events (MACE) in patients with acute ischemic stroke from two prospective cohort studies.In the MARK-STROKE cohort, 299 patients with acute ischemic stroke or TIA were included. Outcome was available in 219 patients during a median follow-up of 294 days. In CIRCULAS, 382 acute ischemic stroke patients were included and a 90-day follow-up was available in 213 patients. HDL-C was calculated based on symmetric dimethylarginine (SDMA) and HDL cholesterol concentrations. Main outcome was incident MACE (death, stroke, and myocardial infarction) and the main measure was cIMT.In both studies, HDL-C was inversely associated with cIMT in linear regression analysis adjusted for age, sex and creatinine. In MARK-STROKE, the adjusted hazard for MACE was significantly reduced for patients with one unit increase (mg/dL) of HDL-C (hazard ratio 0.95 [95% confidence interval (CI): 0.92, 0.99]). In the CIRCULAS cohort, stroke patients with higher HDL-C had less incident MACE during 90 days of follow-up (odds ratio: 0.97 [95% CI: 0.94, 0.99] for one unit increase). Neither SDMA nor HDL cholesterol predicted outcome.Our findings imply a protective role of biologically effective HDL after acute cerebral ischemia for secondary events and emphasize the relevance of lipoprotein functionality in these patients.

The evidence for an association between obesity and increased carotid intima-media thickness (CIMT) and carotid stiffness (CS) in the young has been limited by methodological challenges related to study populations, measurements, methods of percentile derivation and comprehensiveness of obesity markers investigated. This nationwide general population study developed new CS and CIMT centiles in the young and used them to study associations with body mass index, waist circumference, waist-to-height-ratio, bioimpedance-derived absolute and relative fat mass, fat-free mass, subscapular skinfold thickness and blood pressure.In its 11-year follow-up, the KiGGS cohort, which is based on a nationally representative sample, included semi-automated state-of-the-art sonographic CIMT and CS measurements in 4,709 participants aged 14 to 28. Distensibility coefficient (DC), stiffness index β, Young's elastic modulus (YEM) and Peterson's elastic modulus (Ep) centiles were modelled by sex, age and height simultaneously.CS increased with age in both sexes, and young men had stiffer arteries than young women at all ages. All obesity measures at baseline and at follow-up, except for subscapular skinfold thickness, were positively associated with several CS parameters with moderate relative risks (RR), e.g. cross-sectional RR 2.23 (95% CI 1.26-3.93) for DC ≥ 90th percentile when waist circumference ≥90th percentile; RR 5.98 (3.38-10.56) for elevated DC associated with simultaneously elevated waist circumference and BP.These new state-of-the-art CS percentiles show consistent associations of obesity with CS in the young and support primary prevention efforts starting at a young age.

Assessment of comprehensive lipoprotein subclass profiles in adolescents and their relation to vascular disease may enhance our understanding of the development of dyslipidemia in early life and inform early vascular prevention.Nuclear magnetic resonance was used to measure lipoprotein profiles, including lipids (cholesterol, free cholesterol, triglycerides, phospholipids) and apolipoproteins (apoB-100, apoA1, apoA2) of 17 lipoprotein subclasses (from least dense to densest: VLDL-1 to -6, IDL, LDL-1 to -6, HDL-1 to -4) in n = 1776 14- to 19-year olds (56.6% female) and n = 3027 25- to 85-year olds (51.5% female), all community-dwelling. Lipoprotein profiles were related to carotid intima-media thickness (cIMT) as ascertained by sonography.Adolescents compared to adults had lower triglycerides, total, LDL, and non-HDL cholesterol, and apoB, and higher HDL cholesterol. They showed 26.6-59.8% lower triglyceride content of all lipoprotein subclasses and 21.9-51.4% lower VLDL lipid content. Concentrations of dense LDL-4 to LDL-6 were 36.7-40.2% lower, with also markedly lower levels of LDL-1 to LDL-3, but 24.2% higher HDL-1 ApoA1. In adolescents, only LDL-3 to LDL-5 subclasses were associated with cIMT (range of differences in cIMT for a 1-SD higher concentration, 4.8-5.9 μm). The same associations emerged in adults, with on average 97 ± 42% (mean ± SD) larger effect sizes, in addition to LDL-1 and LDL-6 (range, 6.9-11.3 μm) and HDL-2 to HDL-4, ApoA1, and ApoA2 (range, -7.0 to -17.7 μm).Adolescents showed a markedly different and more favorable lipoprotein profile compared to adults. Dense LDL subclasses were the only subclasses associated with cIMT in adolescents, implicating them as the potential preferred therapeutic target for primary prevention of cardiovascular disease at this age. In adults, associations with cIMT were approximately twice as large as in adolescents, and HDL-related measures were additionally associated with cIMT.

Background and aims: Reduced maternal placental growth factor (PlGF) and higher soluble fms-like tyrosine kinase (sFlt-1) concentrations in pregnancy may have persistent effects on offspring vasculature. We hypothesized that suboptimal maternal angiogenic factors in pregnancy may adversely affect fetal vascular development, leading to an increased risk of adverse atheriosclerotic adaptations and higher blood pressure in offspring. Methods: In a population-based prospective cohort among 4565 women and their offspring, we examined the associations of maternal serum PlGF and sFlt-1 concentrations in the first half of pregnancy with offspring vascular development. We measured childhood blood pressure and obtained childhood carotid intima media thickness and carotid distensibility through ultrasonography at 9 years. Results: After adjustment for maternal sociodemographic and lifestyle characteristics, no associations were present of maternal first and second trimester angiogenic factors with childhood blood pressure, carotid intima media thickness (IMT) or distensibility in the total population. In preterm born children only, higher maternal second trimester PlGF concentrations, but not sFlt-1 concentrations, were associated with a lower childhood diastolic blood pressure (difference: -0.16 SDS (95% CI -0.30, −0.03) per SDS increase in maternal second trimester PlGF concentration). No associations among children born small-for-gestational age were present. Conclusions: In a low-risk population, maternal angiogenic factors in the first half of pregnancy are not associated with childhood blood pressure, carotid IMT or carotid distensibility after considering maternal socio-demographic and lifestyle factors. Only in children born preterm, lower maternal second trimester PlGF concentrations are associated with higher childhood diastolic blood pressure, but not with other vascular outcomes.

Nuclear magnetic resonance (NMR)-based metabolomics analyses have defined the lipoprotein profile of carotid artery intima-media thickness (IMT) in detail. In this study, the aim was to use multi-modal mass spectroscopy (MS) to relate multiple metabolites from different chemical classes to IMT and also to the echogenicity of the intima-media complex (IM-GSM).Multi-modal MS with 791 annotated non-xenobiotic metabolites was measured in two different population-based samples (PIVUS at age 80, n = 586 and POEM at age 50, n = 495) in which also carotid IMT and IM-GSM have been assessed by ultrasound.Four metabolites were significantly (false discovery rate, FDR0.05) related to IMT in a meta-analysis of POEM and PIVUS. The top finding was adenosine 3',5'-cyclic monophosphate (cAMP), being inversely related to IMT. Fifty metabolites were significantly related to IM-GSM in a meta-analysis of POEM and PIVUS. The top findings were branched-chained amino acids (BCAA), fructosyllysine, metabolonic lactone sulfate, a ceramide together with some sphingomyelins and phosphatidylcholines. All these top findings represented inverse relationships. Two metabolites identified by lasso regression in PIVUS increased discrimination of an echolucent IM-GSM by 3.3% in POEM compared to traditional cardiovascular risk factors (p = 0.020).IMT, especially IM-GSM, was related to multiple metabolites from different chemical classes. Although such metabolites improved the discrimination of an echolucent IM-GSM, it remains to be investigated if any of those metabolites are involved in the pathogenesis of carotid arteriopathy.

Background and aims: Both carotid intima-media thickness (IMT) and arterial plaques have been shown to predict future CV events. Since there are no previous studies on the subject, our objective was to compare carotid IMT and the length of plaques in abdominal-pelvic main arteries in CV risk assessment in a prospective study setting with a follow-up of over 20 years. Methods: A total of 1007 patients (50% men), aged 51 ± 6.0 years, participated in the current study. Carotid IMT and the summarized plaque length (SUM) from abdominal aorta to common femoral arteries were ultrasonographically assessed. Patients were followed-up a median (1st-3rd quartile) of 22.5 (17.5–23.2) years for CV events. Results: SUM significantly predicted CV events (HR per every 10 mm increase: 1.035, 95% CI: 1.027–1.044, p < 0.001). Those in the highest SUM tertile had over 3-fold risk for CV event (HR: 3.392, 95% CI: 2.427–4.741, p < 0.001) when compared to those in the lowest tertile. SUM significantly predicted CV events even after adjusting for age, sex, hypertension, diabetes, smoking (pack-years), LDL cholesterol and IMT. Adding SUM to the established model improved C-index (95% CI) from 0.706 (0.674–0.738) to 0.718 (0.688–0.747) as well as both discrimination (p < 0.001) and reclassification (p < 0.001) of the patients. In contrast, IMT predicted cardiovascular events only in univariate analysis and it did not improve discrimination or reclassification of the patients. Conclusions: In light of our findings, SUM is a superior indicator and clinical tool for evaluating the overall CV risk compared to carotid IMT.

Patients with congenital adrenal hyperplasia (CAH) are at increased risk of cardiometabolic abnormalities. We aimed to evaluate vascular endothelial dysfunction and its association with serum neopterin (NP) levels in CAH patients.The study included 40 patients, with a mean age of 14.8 ± 2.6 years; 28 (70%) subjects were females. They were compared with 40 healthy controls matched in anthropometric evaluation and measurement of fasting lipids, glucose, insulin, homeostasis model assessment for insulin resistance [HOMA-IR], and serum NP levels (nmol/L). Vascular ultrasound was used to measure brachial artery flow-mediated dilation (FMD%) and carotid intima-media thickness (CA-IMT). According to the degree of control on medical treatment, patients were classified into poor (n = 12) and good (n = 28) control groups.Compared to controls, CAH patients had lower brachial FMD% (4.60 ± 2.13 versus 9.31 ± 2.29, p = 0.001), similar CA-IMT (0.44 ± 0.08 versus 0.44 ± 0.06, p = nonsignificant) and higher NP (42.6 ± 11.6 versus 9.2 ± 3.8, p = 0.001). However, differences between poor and good control CAH patients were significant regarding FMD%, CA-IMT, and NP measurements. FMD% correlated significantly with NP (r = -0.54, p = 0.001), high-sensitivity CRP (r = -0.53, p = 0.001), HOMA-IR (r = -0.31, p = 0.01), CA-IMT (r = -0.22, p 0.05), diastolic blood pressure (r = 0.32, p = 0.01) and systolic blood pressure (r = -0.022, p 0.05). NP was the most significant independent predictor of FMD%, as determined by linear regression analysis (p = 0.001).Our study showed that CAH patients had endothelial dysfunction, which is an early process of vascular affection. This was significantly associated with NP levels, suggesting a crucial role of inflammation in the pathogenesis of vascular damage. Further studies are needed to confirm our findings and to investigate the exact role of NP, as either protective or proatherothrombotic.

Recent studies suggest that long-term endurance training may be damaging to the heart, thus increasing cardiovascular disease (CVD) risk. However, studies utilizing cardiac imaging are conflicting and lack measures of central and peripheral vascular structure and function, which are also independently predictive of CVD events.We performed a comprehensive assessment of cardiovascular structure and function in long-term (≥ 10 years) ultra-endurance athletes (ATH, 14 M/11 F, 50 ± 1 y) and physically active controls (CON, 9 M/9 F, 49 ± 2 y).As expected, left ventricular mass and end-diastolic volume (echocardiography) were greater in ATH vs CON, whereas there was no difference in cardiac function at rest. Coronary artery calcium scores (computed tomography) were not statistically different between groups. There was no evidence of myocardial fibrosis (contrast magnetic resonance imaging) in any subject. Aortic stiffness (carotid-femoral pulse wave velocity) was lower in ATH vs CON (6.2 ± 0.2 vs 6.9 ± 0.2 m/s, p 0.05), whereas carotid intima-media thickness (ultrasound) was not different between groups. Peripheral vascular endothelial function (flow-mediated vasodilation of the brachial artery) and microvascular function (peak blood velocity) in response to 5 min of forearm ischemia were not different between groups. Furthermore, there was no difference in 10-year coronary heart disease risk (ATH; 2.3 ± 0.5 vs CON; 1.6 ± 0.2%, p 0.05).Our data indicate that middle-aged ultra-endurance ATH do not have marked signs of widespread cardiovascular dysfunction or elevated CHD risk compared to CON meeting physical activity guidelines.

Cardiovascular health scores have emerged as a simple way to assess the risk to suffer from a cardiovascular disease. The American Heart Association's Life's Simple 7 constitutes of modifiable lifestyle factors to reduce cardiovascular risk. Its association with carotid properties is yet inconclusive. The aim of this study is to determine the association between the adherence to Life's Simple 7 and carotid properties in middle-aged to elderly Finns.A representative sample of Finnish men and women aged 55-74 years was included in the present study. Carotid intima-media thickness (cIMT), lumen diameter (cLD), and carotid distensibility were measured by transcutaneous ultrasound using state-of-the-art wall contour detection techniques. The Life's Simple 7 cardiovascular health score was calculated using seven categories (body mass index, cholesterol, systolic blood pressure, fasting plasma glucose, smoking status, physical activity, and diet). In accordance to the American Heart Association, for each category, an ideal score was given 2 points, intermediate scores 1 point, and poor scores 0 points.In total, 1400 (49.4% male) subjects were included in the analyses. After adjusting for age and sex, we found that subjects with a an ideal cardiovascular health score had lower cLD than those with an intermediate score (-0.21 mm, 95% CI: 0.37 to -0.05 mm, p=0.005) and a poor score (-0.39 mm, 95% CI: 0.65 to -0.12 mm, p=0.001). Similarly, subjects with an ideal health score had higher carotid distensibility than those with an intermediate score (0.0032 1/kPa, 95% CI: 0.009-0.0055 1/kPa, p=0.002) and a poor score (0.0018 1/kPa, 95% CI: 0.0005-0.0032 1/kPa, p=0.004). We found no differences regarding cIMT.In middle-aged to elderly Finns, higher adherence to the Life's Simple 7 is associated with lower cLD and higher distensibility, but not with cIMT. Adherence to healthy lifestyle habits is therefore associated with better carotid structure and carotid function in middle-aged to elderly Finns.

Cardiovascular disease (CVD) is the leading cause of mortality and disability in developed countries. According to WHO, an estimated 17.9 million people died from CVDs in 2019, representing 32% of all global deaths. Of these deaths, 85% were due to major adverse cardiac and cerebral events. Early detection and care for individuals at high risk could save lives, alleviate suffering, and diminish economic burden associated with these diseases. Carotid artery disease is not only a well-established risk factor for ischemic stroke, contributing to 10%-20% of strokes or transient ischemic attacks (TIAs), but it is also a surrogate marker of generalized atherosclerosis and a predictor of cardiovascular events. In addition to diligent history, physical examination, and laboratory detection of metabolic abnormalities leading to vascular changes, imaging of carotid arteries adds very important information in assessing stroke and overall cardiovascular risk. Spanning from carotid intima-media thickness (IMT) measurements in arteriopathy to plaque burden, morphology and biology in more advanced disease, imaging of carotid arteries could help not only in stroke prevention but also in ameliorating cardiovascular events in other territories (e.g. in the coronary arteries). While ultrasound is the most widely available and affordable imaging methods, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), their combination and other more sophisticated methods have introduced novel concepts in detection of carotid plaque characteristics and risk assessment of stroke and other cardiovascular events. However, in addition to robust progress in usage of these methods, all of them have limitations which should be taken into account. The main purpose of this consensus document is to discuss pros but also cons in clinical, epidemiological and research use of all these techniques.

Background Although carotid intima-media thickness (IMT) is an established marker of atherosclerosis and carries independent risk for cardiovascular disease, its possible association with subclinical cardiac dysfunction has not been extensively evaluated. Left ventricular global longitudinal strain (LVGLS) and peak left atrial longitudinal systolic strain (PALS) can detect subclinical left heart dysfunction. Purpose This study aimed to investigate the association between carotid IMT and subclinical left heart dysfunction in a large sample of the general population without overt cardiac disease. Methods We examined 1,161 participants who underwent extensive cardiovascular examination. Ultrasonography of common carotid artery was performed for the measurement of maximal carotid IMT. LVGLS and PALS were assessed by 2-dimensional speckle-tracking echocardiography. Results Mean age was 62±12 years, and 56% were male. The prevalence of abnormal LVGLS (>−18.6%) and PALS ( Conclusion Participants with increased IMT had significantly impaired LV and LA function in an unselected community-based cohort. This association may be involved in the higher incidence of cardiovascular disease in individuals with increased carotid IMT. Funding Acknowledgement Type of funding source: None

The relationship of polyunsaturated fatty acids (PUFAs) with cardiovascular risk is still controversial. We aimed to determine whether erythrocyte n-3 and n-6 PUFAs are related to the risk of carotid atherosclerosis.From 2008 to 2019, baseline erythrocyte n-3 and n-6 PUFAs were determined in a cohort of 4040 Chinese adults (40-75 ys). The intima-media thickness (IMT) at the common carotid artery (CCA) and bifurcation of the carotid artery (BIF) and carotid plaque were assessed using ultrasonography at baseline and every 3 years.During a median follow-up of 8.8 years, we identified the following newly diagnosed cases: 535 cases of CCAIMT thickening, 654 cases of BIFIMT thickening, and 850 cases of carotid plaque. Higher erythrocyte docosahexaenoic acid (DHA) and arachidonic acid (ARA) and lower gamma-linolenic acid (GLA) were associated with decreased risks of BIFIMT thickening. N-3 eicosatrienoic acid (ETrA), docosapentaenoic acid (DPA), and n-6 dodecylthioacetic acid (DTA) presented a significant beneficial association with carotid IMT thickening in the short-term (2.8 y) follow-up (all p trend0.02), although the association was attenuated in the relatively long-term (8.8 y) follow-up. In addition, carotid plaque risk was found to be inversely associated with ETrA and DHA but positively associated with alpha-linolenic acid (ALA). N-6 linolenic acid (LA) and eicosadienoic acid (EDA) were not significantly associated with carotid atherosclerosis risk.Higher erythrocyte very-long-chain n-3 and n-6 PUFAs (especially DHA and ARA) and lower erythrocyte GLA are associated with lower carotid atherosclerosis risk, suggesting potential cardioprotective roles of very-long-chain PUFAs.

Cardiovascular disease (CVD) is the leading cause of death in western countries. One risk factor unique to women is the menopausal status. The aim of this study was to analyse the influence of the onset of menopause (MP) on the extent and progression of atherosclerotic plaque volume (PV).Postmenopausal women with at least one cardiovascular risk factor (CVRF) but without established CVD were included. Quantification of PV was performed in peripheral arteries using a three - dimensional (3D) ultrasound (US) technique. Follow-up examination to assess PV progression was performed after 19 (±8) months.110 consecutive postmenopausal women (mean age 65.5) were included. Females with an earlier onset of MP (45 years) had a significantly higher PV than those with an intermediate (45-52 years) or later onset of menopause (52 years), irrespective of other CVRF (244 mm³ vs. 193 mm³ vs. 73 mm³, respectively, p = 0.023). In addition, women with an earlier onset of MP had a higher PV progression compared to women with an intermediate or late onset (40 mm³ vs. 35 mm³ vs. 8.5 mm³; p = 0.002, respectively). Moreover, these results were confirmed in multivariate regression, where only onset of MP (OR 0.88; 95%CI 0.81-0.96; p = 0.004) and age (OR 1.06; 95%CI 1.08-1.13; p = 0.025) were significant predictors for a higher atherosclerotic progression.An earlier onset of MP was associated with an increase in atherosclerotic PV and accelerated progression, independent of other CVRF.

Genetic loci associated with CHD show different relationships with intima-media thickness in the common carotid artery (IMT-CCA) and in the bulb (IMT-bulb). We evaluated if IMT-CCA and IMT-bulb differ also with respect to circulating protein profiles and risk of incident atherosclerotic disease.In three Swedish cohorts (MDC, IMPROVE, PIVUS, total n 7000), IMT-CCA and IMT-bulb were assessed by ultrasound at baseline, and 86 cardiovascular-related proteins were analyzed. In the PIVUS study only, IMT-CCA and IMT-bulb were investigated in relation to incident atherosclerotic disease over 10 years of follow-up.In a meta-analysis of the analysis performed separately in the cohorts, three proteins, matrix metalloproteinase-12 (MMP-12), hepatocyte growth factor (HGF) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), were associated with IMT-CCA when adjusted for traditional cardiovascular risk factors. Five proteins were associated with IMT-bulb (MMP-12, growth/differentiation factor 15 (GDF-15), osteoprotegerin, growth hormone and renin). Following adjustment for cardiovascular risk factors, IMT-bulb was significantly more closely related to incident stroke or myocardial infarction (total number of cases, 111) than IMT-CCA in the PIVUS study (HR 1.51 for 1 SD, 95%CI 1.21-1.87, p 0.001 vs HR 1.17, 95%CI 0.93-1.47, p = 0.16). MMP-12 levels were related to this combined end-point (HR 1.30, 95%CI 1.08-1.56, p = 0.0061).Elevated levels of MMP-12 were associated with both IMT-CCA and IMT-bulb, but other proteins were significantly related to IMT in only one of these locations. The finding that IMT-bulb was more closely related to incident atherosclerotic disease than IMT-CCA emphasizes a difference between these measurements of IMT.

Background and aims Osteoporosis and coronary heart disease (CHD) are very common conditions among elderly people, and both represent a public health concern due to their prognostic consequences. Osteoporosis and CHD share many risk factors and pathophysiological mechanisms, such as calcification pathways. Clinical evidence associates lower bone mass with cardiovascular diseases and endothelial dysfunction. Hence, this study aims to investigate whether bone mass density is associated with subclinical atherosclerosis and/or endothelial dysfunction in the very elderly. Methods We performed a cross-sectional study of cohort enrolled individuals, ages 80 years or older (n = 208), who had never manifested cardiovascular diseases. Medical evaluation, blood tests, flow-mediated dilation (FMD), carotid intimal-media thickness (IMT), Dual Energy X-ray Absorptiometry (DEXA) and Coronary Calcium Score (CCS) were obtained. Odds Ratio (OR) was calculated by multivariate logistic regression models using CCS, FMD and IMT categories. Adjustments for covariates were done. Results Overall bone mass was independently and inversely associated with CCS categories [OR:1.68(1.16–8.85); p = 0.024] and IMT categories [OR:2.97(1.11–7.90); p = 0.030]. Conversely, overall bone mass was independent and directly associated with FMD categories [OR:2.73(1.36–70.39); p = 0.023]. Conclusions This study indicates that overall bone mass is independently and inversely associated with subclinical atherosclerosis, endothelial dysfunction and thickness of carotid in the very elderly.

Background and aims Carotid plaque is a specific sign of atherosclerosis and adults with carotid plaque are at increased risk for cardiovascular outcomes. Atherosclerosis has roots in childhood and pediatric guidelines provide cut-off values for cardiovascular risk factors. However, it is unknown whether these cut-offs predict adulthood advanced atherosclerosis. Methods The Cardiovascular Risk in Young Finns Study is a follow-up of children that begun in 1980 when 2653 participants with data for the present analyses were aged 3–18 years. In 2001 and 2007 follow-ups, in addition to adulthood cardiovascular risk factors, carotid ultrasound data was collected. Long-term burden, as the area under the curve, was evaluated for childhood (6–18 years) risk factors. To study the associations of guideline-based cut-offs with carotid plaque, both childhood and adult risk factors were classified according to clinical practice guidelines. Results Carotid plaque, defined as a focal structure of the arterial wall protruding into lumen >50% compared to adjacent intima-media thickness, was present in 88 (3.3%) participants. Relative risk for carotid plaque, when adjusted for age and sex, was 3.03 (95% CI, 1.76–5.21) for childhood dyslipidemia, 1.51 (95% CI, 0.99–2.32) for childhood elevated systolic blood pressure, and 1.93 (95% CI, 1.26–2.94) for childhood smoking. Childhood dyslipidemia and smoking remained independent predictors of carotid plaque in models additionally adjusted for adult risk factors and family history of coronary heart disease. Carotid plaque was present in less than 1% of adults with no childhood risk factors. Conclusions Findings reinforce childhood prevention efforts and demonstrate the utility of guideline-based cut-offs in identifying children at increased risk for adulthood atherosclerosis.

Background and aims Observational studies have reported an association between periodontitis and cardiovascular disease but whether this association is causal is uncertain. We therefore used Mendelian randomization to test whether periodontitis is causally associated with stroke, coronary artery disease, or subclinical atherosclerosis. Methods A two-sample Mendelian randomization analysis was carried out using five single nucleotide polymorphisms previously associated with periodontitis in genome-wide association studies. Summary data were drawn from MEGASTROKE and combined with de novo analyses of UK Biobank for stroke and its major subtypes (up to 44,221 cases, 739,957 controls) and CARDIoGRAMplusC4D and UK Biobank for coronary artery disease (122,733 cases, 424,528 controls). We used existing data on carotid intima-media thickness in UK Biobank as a marker of subclinical atherosclerosis (N = 22,179). Causal estimates were obtained using inverse-variance weighted Mendelian randomization. Sensitivity analyses were performed using weighted median and MR-Egger approaches. Results No association was found between periodontitis and any stroke (odds ratio [OR] per doubling in the odds of periodontitis 0.99, 95% confidence interval [CI] 0.97 to 1.02), ischaemic stroke (OR 1.00, 95% CI 0.97 to 1.03) or its major subtypes (p > 0.4), or coronary artery disease (OR 1.01, 95% CI 0.99 to 1.03). Similarly, we found no association for periodontitis and subclinical atherosclerosis (β −0.002, 95% CI -0.004 to 0.001). These results were consistent across a series of sensitivity analyses. Conclusions These findings provide no robust evidence for a causal relationship between periodontitis and stroke or coronary artery disease. This suggests that associations reported in observational studies may represent confounding., Graphical abstract Image 1, Highlights • Periodontitis and cardiovascular disease correlate in observational studies. • Mendelian randomization does not support a causal association. • Results do not support treatment of periodontitis to reduce atherosclerotic disease.

Severe preeclampsia increases lifetime-risk for cardiovascular disease (CVD). It remains unclear when this risk translates to subclinical atherosclerosis and whether this is related to cardiovascular health (CVH) after pregnancy. Our aims were (1) to determine CVH after severe preeclampsia, (2) to relate CVH to carotid intima-media thickness (CIMT), as a marker of subclinical atherosclerosis and (3) to relate CVH to chronological and vascular age.A prospective cohort study was performed in women with previous severe pre-eclampsia. CVH, proposed by the American Heart Association, was assessed one year after pregnancy. The CVH score (range 0-14) includes seven metrics (blood pressure, total-cholesterol, glucose, smoking, physical activity, diet and body mass index [BMI]), each weighted as poor (0), intermediate (1) or ideal (2). Vascular age was determined by CIMT. We related CVH to delta age (chronological age - vascular age).In 244 women, the median CVH score was 10 (90% range 7.0, 13.0). Low CVH (10) was associated with a larger CIMT than high CVH (≥12) (median 626.3 μm vs. 567.0 μm, respectively). Higher CVH was also associated with a lower vascular age (-2.0 years, 95%CI -3.3, -0.60). Women with low CVH had a larger delta age (22.5 years [90% range -3.9, 49.6) than women with high CVH (16.5 years [90% range -11.9, 43.3).CVH is inversely related to subclinical atherosclerosis and to vascular age one year after severe preeclampsia. Especially low CVH is associated with a large difference between chronological age and vascular age. CVH counseling might provide the opportunity for timely cardiovascular prevention.

BACKGROUND AND AIMS: Perinatal HIV infection (PHIV) and prolonged use of antiretroviral therapy (ART) may increase the likelihood of developing subclinical vascular dysfunction at an early age. We conducted a systematic review to assess the effect of PHIV and ART on intima-media thickness (IMT), arterial stiffness and endothelial function in individuals aged 6-25 years. METHODS: Medline, Embase and Web of Science were searched, and studies screened by two independent reviewers. We performed a meta-analysis on selected studies reporting on IMT. RESULTS: A total of 680 studies were retrieved from the databases, with 21 studies deemed eligible for qualitative analysis. There were few studies assessing IMT, arterial stiffness and endothelial function. More than half of the studies found either increased IMT, stiffer arteries or impaired endothelial function in PHIV compared to uninfected controls. A minority of the studies reported that the two groups had similar vascular parameters, a conflicting finding. There was a lack of standardisation for IMT assessment and reporting in numerous studies. In a meta-analysis of seven studies with matching methodologies, IMT was higher in PHIV compared to uninfected controls, (mean difference, 0.05 (0.01-0.09; p = 0.01) but heterogeneity between the studies was substantial (I2, 96.7%; p

Diabetes is a major risk factor for cardiovascular (CV) disease. In contrast to the clear benefits from treatments which reduce blood pressure and lipids, clinical trials targeting blood glucose have not shown clear CV benefits. Interventions to intensify glycemic control early in the course of diabetes may have benefits in long term observational studies (DCCT-EDIC/UKPDS), but may not be helpful if introduced late in the course of type 2 diabetes (ACCORD, ADVANCE, VA-DT). More recent CVOT in high risk subjects suggest that the benefits of SGLT2 and GLP1-RA are glucose-independent. Type 1 diabetes provides a "cleaner" model to study the links between glucose and cardiovascular disease. Abnormalities of glucose regulation in type 1 diabetes is not restricted to hyperglycemia, but includes glycemic variability and hypoglycemia. Increasingly the mechanisms linking glycemic variability and hypoglycemia as key mediators of cardiovascular complications are being understood. Furthermore, data from pancreas and islet transplantation showing reduced cardiovascular mortality and regression of intima-media thickness supports a causal role for glucose in the pathogenesis of atherosclerosis, but suggests that restoration of normal glucose regulation may be required to demonstrate substantial impact on CV risk accrued over decades of type 1 diabetes. Considering the limited organ supply and risks of immunosuppression, advances in biology (stem cell derived beta cells) or technology (automated insulin delivery systems) will be required to provide a scalable solution to deliver optimal glucose control and reduce CV risk for people with type 1 diabetes.

Background and aims Reproductive factors are associated with later life CVD in women (e.g., age at first birth, preeclampsia, gestational diabetes), but studies have focused largely on premenopausal women. We examined the relationship of reproductive factors with subclinical CVD burden in late midlife women. Methods We included 964 parous women from the Study of Women's Health Across the Nation (SWAN), who completed a reproductive history questionnaire at the 13th SWAN visit (2011–2012), and a carotid ultrasound and brachial-ankle pulse wave velocity (baPWV) assessment. The primary outcomes were carotid intima-media thickness, plaque, and baPWV; our secondary outcome was a composite subclinical CVD index created using these measures. Linear and logistic regression was performed to examine associations with individual subclinical CVD measures, and multinomial logistic regression was used in analyses of the composite index. Models adjusted for socio-demographics and cardiovascular risk factors. Results Mean age at subclinical CVD assessment was 60.2 years (SD ± 2.7). History of gestational hypertension/preeclampsia was associated with greater carotid IMT (β: 0.038, p = 0.004). Earlier age at first birth was associated with subclinical CVD, but not when accounting for CVD risk factors. History of gestational diabetes was associated with greater baPWV, but not related to our composite index. Conclusions Pregnancy history is an important marker of subclinical CVD in late midlife and may impact the vasculature through distinct pathways. Future studies are necessary to evaluate racial/ethnic differences in the observed associations and to assess the benefit of a composite subclinical CVD index for earlier CVD risk modification in midlife women.

Fibroblast growth factor 21 (FGF21) has been suggested as a novel biomarker for cardiovascular disease (CVD), especially in people with high CVD risk. However, it is not known whether FGF21 is a CVD biomarker in an initially healthy cohort. We therefore investigated the relationship of plasma FGF21 levels with measures of subclinical atherosclerosis and cardiovascular events in Multi-Ethnic Study of Atherosclerosis participants without known CVD at baseline.A total of 5788 participants had plasma FGF21 levels measured at the baseline exam (2000-2002). Carotid intima-media thickness (IMT), ankle-brachial index (ABI) and coronary artery calcification (CAC) were measured at baseline. Participants were followed up for incident CVD events over a median period of 14 years.In cross-sectional analyses adjusting for socio-demographic variables, participants with higher FGF21 levels had higher carotid IMT, lower ABI, and higher prevalence of CAC (p 0.001). However, these associations were not significant after simultaneously adjusting for demographic, socioeconomic and lifestyle factors, traditional CVD risk factors, and biomarkers of inflammation and hemostasis. Among 5768 patients with follow-up data, 820 developed incident CVD endpoints. Higher baseline FGF21 levels were not associated with the risk for incident CVD endpoints after adjusting for multiple confounding factors (odds ratio 1.03; 95% confidence interval, 0.94-1.12, per SD increase in ln-transformed FGF21 levels).Although FGF21 has been suggested as a CVD biomarker for people with high CVD risk, our findings do not support a role of FGF21 as a CVD biomarker in those without a history of CVD.

Background and aims: Gestational diabetes (GDM) and maternal obesity are linked to weight gain in childhood and an increased risk of cardiovascular disease later in life. We assessed the effects of GDM and maternal obesity on arterial function and morphology in relation to body anthropometrics and composition in early childhood. Methods: We assessed body size and composition, blood pressure (BP), arterial morphology and stiffness in 201 pairs of obese mothers (pre-pregnancy BMI 30.7 +/- 5.6 kg/m(2), 96 with GDM) and their children at 6.1 years (SD 0.5). Results: Child BMI (z-score 0.45 +/- 0.92; p

Background and aims Endothelial injury is well-known as a process that can lead to chronic kidney disease (CKD) and atherosclerosis. Hematopoietic activity is known to be associated inversely with CKD and positively with atherosclerosis. Since bone-derived progenitor cells (CD34-positive cells) contribute to endothelial repair (including the progression of atherosclerosis), understanding the association between CKD and carotid intima-media thickness (CIMT), in relation to circulating CD34-positive cell count, may be an efficient means of clarifying the mechanisms underlying endothelial activity. Methods We conducted a cross-sectional study of 570 elderly Japanese men aged 60–69 years, who underwent a general health check-up. Participants were stratified as per a median circulating CD34-positive cell count (1.01 cells/μL). Results Independent of the known cardiovascular risk factors, CIMT was found to be positively associated with CKD in the participants with high circulating CD34-positive cell counts but not in participants with low counts. Odds ratios were 1.40 (1.04, 1.89) for participants with high and 1.01 (0.72, 1.43) for participants with low circulating CD34-positive cell counts after adjustment for known cardiovascular risk factors at 95% confidence intervals for CKD with one standard deviation increment of CIMT. Conclusions A positive association between CIMT and CKD was observed among participants with high circulating CD34-positive cell counts but not among participants with low counts. Endothelial repair activity might determine the association between CKD and CIMT.

The extent and relation of multisite atherosclerosis to cardiovascular disease (CVD) in metabolic syndrome (MetS) and diabetes (DM) are not well documented. We examined the extent of multisite atherosclerosis and its prognostic value for CVD events in MetS and DM.In CVD-free subjects from the Multi-Ethnic Study of Atherosclerosis, multisite atherosclerosis was measured as: (1) the number of arterial beds involved (coronary calcium0, abdominal aortic calcium0, carotid intima-media thickness ≥1 mm and ankle brachial index1 or ≥1.4); (2) a composite score summing the quartile rank for each atherosclerosis measure. Hazard ratios (HRs) and c-statistics were calculated for incident CVD and coronary heart disease (CHD) over 10.6 years.Of 1675 individuals (mean age 64 years, 51% male), 33.4% had MetS and 15.9% had DM. The number of atherosclerotic sites was higher in those with DM (mean ± SD = 1.67 ± 1.15) and MetS (1.49 ± 1.12) versus neither MetS/DM (1.09 ± 1.09) (p 0.0001). CVD rates per 1000 person-years ranged from 3.5, 8.2, and 10.0 in those with 0 sites positive to 35.1, 79.6 and 103.4 in those with 4 sites positive among neither DM/MetS, MetS and DM groups, respectively. HRs (95% CI) for CVD comparing those with 4 vs. 0 atherosclerotic sites were 4.0 (0.8-19.1), 4.9 (2.0-12.0), and 14.4 (3.6-57.6), respectively. C-statistics adding multisite atherosclerosis measures increased over models without the measures and with CIMT or ABI but not CAC.Multisite atherosclerosis is greater with MetS or DM, and predicts CVD and CHD events. Risk prediction is improved over CIMT and ABI but not CAC.

BACKGROUND AND AIMS: In this analysis, we estimated population-level trajectory groups of life course cardiovascular risk to explore their impact on mid-life atherosclerotic and metabolic outcomes. METHODS: This prospective study followed n=1,269 Bogalusa Heart participants, each with at least 4 study visits from childhood in 1973 through adulthood in 2016. We used discrete mixture modeling to determine trajectories of cardiovascular risk percentiles from childhood to adulthood. Outcomes included mid-life subclinical atherosclerotic measures [(carotid intima-media thickness (cIMT), pulse wave velocity (PWV)], metabolic indicators [(diabetes and body mass index (BMI)], and short physical performance battery (SPPB). RESULTS: Between the mean ages of 9.6–48.3 years, we estimated five distinct trajectory groups of life course cardiovascular risk (High-Low, High-High, Mid-Low, Low-Low, and Low-High). Adult metabolic and vascular outcomes were significantly determined by life course cardiovascular risk trajectory groups (all p

Inflammation is a pathophysiological mechanism of atherosclerosis, and several mediators have been proposed as biomarkers. Acute-phase serum glycoproteins are upregulated in the liver during systemic inflammation. Because of their unique biochemical characteristics, they can be measured byWe recruited 295 FH patients (75.6% with FH-associated genetic variants). At baseline, a full glycoprotein profile, glycoprotein A and B (GlycA and B) concentrations and their height and width ratios (H/W) were analysed byAt baseline, the GlycA and GlycB concentrations and their H/W ratios were correlated with lipid profile and adiposity parameters, with the correlation between the GlycA and triglyceride concentrations (r = 0.780; p 0001) being the strongest. Glycoprotein concentrations were also correlated with inflammation markers, mainly hsCRP. Higher glycoprotein concentrations were observed in patients with higher intima media thickness, arterial rigidity and presence of arteriosclerotic plaques. In the multivariate and random forest analyses, the baseline GlycB concentration showed a significant contribution to the detection of FH individuals prone to develop carotid plaques.The concentrations of serum glycoproteins as assessed by

BACKGROUND AND AIMS After aortic coarctation (CoA) repair, patients still suffer from cardiovascular complications. The aim of this study was to measure cardiovascular markers, intima-media thickness (IMT) and plaques in controls and patients with CoA. METHODS Sixty-four patients with CoA (66% male, mean age 48 ± 15 years) and controls (54% men, mean age 47 ± 16 years) underwent ultrasound of their arteries. A multiplex platform to analyze circulating blood levels biomarkers reflecting inflammation, tissue remodeling and repair was used. RESULTS In men following CoA repair, a significantly increased carotid bulb IMT was observed in comparison to the control group (1.05 [0.72-1.24] vs. 0.67 [0.59-0.95] mm; p = 0.003). Median common carotid artery (CCA) IMT was increased in men compared to controls (0.82 [0.61-0.97] mm vs. 0.58 [0.53-0.76] mm, p

There is a lack of studies simultaneously evaluating the impact of structural and functional atherosclerosis on cognition. We investigated the long-term predictive and interaction effects of structural and functional carotid atherosclerosis markers on future cognitive decline.Five hundred and twenty-eight middle-aged participants enrolled in the carotid atherosclerosis examination in Kaohsiung Atherosclerosis Longitudinal Study (KALS) between 2006 and 2009 were tested for cognition between 2016 and 2019. The Montreal Cognitive Assessment (MoCA) was used for the cognitive test. Baseline structural atherosclerosis was assessed by carotid intima-media thickness (cIMT) and plaque, whereas functional atherosclerosis was evaluated by carotid stiffness (β, Ep, and pulse wave velocity). Participants in the top quartile of cIMT and those with plaques were considered to have advanced structural atherosclerosis, whereas participants with all three stiffness parameters in the top quartile were defined to have advanced functional atherosclerosis.The mean participant age at baseline was 53.88 ± 8.37 years. Each case of advanced structural atherosclerosis and advanced functional atherosclerosis was associated with low 10-year MoCA scores with p 0.001 and p = 0.03, respectively. An interaction effect was observed between structural and functional atherosclerosis on the MoCA score 10 years later (p = 0.02). Participants with both advanced structural and functional markers showed a marked impact on future cognitive function, especially executive and language domains.Carotid atherosclerosis in middle-aged individuals can predict their cognitive function in 10 years. Integrated information regarding both arterial wall and stiffness could help improve the predictive power for cognitive decline.

Background and aims: Randomized clinical trials (RCT) have shown statin treatment to slow down the increase in carotid artery intima-media thickness (IMT) seen with ageing. However, those RCTs usually have a limited follow-up (1-3 years). Here an observational study was used to investigate the real-life effect of new statin treatment over a 10-year follow-up. Methods: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, 954 individuals all aged 70 years at baseline were investigated regarding carotid artery IMT three times during 10 years (n = 771 at age 75, and n = 591 at age 80). Results: At age 70, 503 subjects were statin-naive and did not receive statin during the 10-year follow-up period (the never-statin group), while 197 subjects were statin-naive but received statins during the follow-up period (the received-statin group). Low-density lipoprotein (LDL)-cholesterol increased over time in the never-statin group (+0.1 mmol/l, p = 0.0012), but decreased in the group receiving statin treatment (-1.1 mmol/l, p < 0.0001). The never-statin group increased significantly in IMT over the 10 years (+0.07 mm, p < 0.0001), while the numerical increase seen in the received-statin group was not significant (+0.02 mm, p = 0.22) A significant difference in the change in IMT over time was seen between the received-statin group and the never-statin group (p < 0.0001 for interaction between time and group, adjusted for a propensity score). Conclusions: This real-life observational study showed that new statin treatment reduced the increase in IMT seen over 10 years compared to subjects not treated with statins.