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Background: Migraine with aura is associated with an increased risk of cardiovascular disease, yet the pathophysiology is unknown. Suggested underlying mechanisms of aura formation point into the direction of an abnormal vasoreactivity that also extends to the extracranial vasculature., Methods: In the Early Vascular Ageing Tyrol study, a community-based non-randomized controlled trial conducted in 45 schools and companies in Tyrol (Austria) and South-Tyrol (Italy) between May 2015 and September 2018 aiming to increase cardiovascular health in adolescents, headache syndromes were classified according to the International Classification of Headache Disorders in a face-to-face interview. Carotid-femoral pulse-wave-velocity was measured by applanation tonometry and carotid intima-media-thickness by high-resolution ultrasound of the distal common carotid arteries. Differences in pulse-wave-velocity and carotid intima-media-thickness in youngsters with migraine with aura were compared respectively to those without headache and with other headaches by multivariable linear regression analysis., Results: Of the 2102 study participants 1589 were aged 14 to 19 (mean 16.8) years and had complete data. 43 (2.7%) reported migraine with aura and 737 (46.4%) other headaches. Mean pulse-wave-velocity was 6.17 m/s (± 0.85) for migraine with aura, 6.06 m/s (± 0.82) for all other headaches and 6.15 (0.95) m/s for participants without headaches. Carotid intima-media-thickness was 411.3 µm (± 43.5) for migraine with aura, 410.9 µm (± 46.0) for all other headaches and 421.6 µm (± 48.4) for participants without headaches. In multivariable linear regression analysis, we found no differences in carotid-femoral pulse-wave-velocity or carotid intima-media-thickness in young subjects with migraine with aura, all other headaches, or no headaches., Conclusions: In line with previous large-scale studies in adults, we could not demonstrate relevant associations of migraine with aura with markers of arterial stiffness or subclinical atherosclerosis making early vascular ageing an unlikely pathophysiological link between migraine with aura and cardiovascular diseases., Trial Registration: First registered on ClinicalTrials.gov 29/04/2019 (NCT03929692)., (© 2023. The Author(s).)

Background and Aims: Atherosclerosis starts early in life. We aimed to assess the dimension and progression of the intima-media thickness, a surrogate marker for early vascular aging, and its association with a broad palette of cardiovascular risk and lifestyle factors in a large cohort of healthy adolescents., Methods: The EVA-Tyrol cohort study enrolled 1573 adolescents with a mean age of 16.0 years (SD 0.9). 1000 participants had a prospective follow-up after 22.1 months on average (SD 3.4). Cardiovascular risk and lifestyle factors were evaluated by standardized interviews, physical examination, and fasting blood analyses. Carotid intima-media thickness (cIMT) was measured at baseline and follow-up by high-resolution ultrasound. Aortic intima-media thickness (aIMT) was assessed during follow-up only., Results: Several vascular risk factors like elevated blood pressure (4.7% > 95th percentile), overweight (9.2% > 95th percentile) and smoking (29.7%) were already prevalent at this age. Maximum cIMT progressed by 2.78 μm (95% CI, 0.39-5.17) per year. In multivariable linear regression analysis, sex, body weight, systolic blood pressure, LDL-cholesterol and physical activity were independent predictors of cIMT both at baseline and follow-up. In addition, alanine-aminotransferase, a laboratory surrogate of non-alcoholic fatty liver disease, was independently associated with cIMT at follow-up and pack-years of smoking with aIMT., Conclusions: Unfavourable lifestyle and vascular risk factors were prevalent in adolescents and several of them were associated with vessel wall thickness, even though effect sizes were modest and cIMT variability was limited. These data suggest adolescence as a prime age range for early vascular prevention., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Pentraxins like C-reactive protein are key components of the innate immune system. Recently, pentraxin-3 (PTX3) has been proposed to be a specific marker of vascular inflammation, yet its association with atherosclerosis is still unclear., Methods and Results: PTX3 serum levels were measured in three independent studies of 132 young men (ARMY Study), 205 young women (ARFY Study) and 562 individuals 55 to 94 years old (Bruneck Study). In contrast to C-reactive protein, PTX3 showed little relationships with classic vascular risk factors and pro-inflammatory conditions. In the population based Bruneck Study, PTX3 level was independently associated with prevalent cardiovascular diseases (multivariable odds ratio [95%CI] 3.09 [1.65-5.79]; P<0.001). Moreover, PTX3 level correlated with the severity of carotid and femoral atherosclerosis and was highest in individuals with multiple vascular territories affected. In contrast, there was no association with elevated intima-media thickness, a precursor lesion of atherosclerosis, in any of the three populations investigated., Conclusions: Level of PTX3 is independently associated with atherosclerosis and manifest cardiovascular disease but not early vessel pathology. Unlike C-reactive protein, PTX3 is not a component of the classic acute phase response (systemic inflammation) but appears to be more specific for vascular inflammation.

Background: Cadmium is a potential new risk factor for early atherosclerosis and cardiovascular diseases in humans, yet pathogenetic mechanisms are still a matter of debate., Methods and Results: In-depth histological analysis of 18 sections taken from 6 cadmium-fed ApoE-/- mice and 12 sections from 5 litter-mates not exposed to cadmium by light and scanning electron microscopy was performed. Cadmium-fed mice showed a marked increase in lesion load (plaque area) and severity as classified according to the American Heart Association vascular lesion grading. All inflammatory markers studied (CD68, CD3, CD25, vascular cell adhesion molecule 1 (VCAM-1), and heat shock protein 60 (Hsp60)) yielded a higher expression in cadmium-fed mice. Statistical difference was achieved for VCAM-1 and Hsp60 (P=0.03 and P=0.02). The shoulder region of atherosclerotic plaques in cadmium-fed mice showed a prominent retraction of endothelial cells on electron microscopy., Conclusions: Our data indicate that cadmium exposure amplifies the development of vessel pathology in atherosclerosis susceptible ApoE-/- mice and suggests upregulation of VCAM-1 and Hsp60 and endothelial leakage as potential pathomechanisms.

Objective: Although cadmium (Cd) is an important and common environmental pollutant and has been linked to cardiovascular diseases, little is known about its effects in initial stages of atherosclerosis., Methods and Results: In the 195 young healthy women of the Atherosclerosis Risk Factors in Female Youngsters (ARFY) study, cadmium (Cd) level was independently associated with early atherosclerotic vessel wall thickening (intima-media thickness exceeding the 90th percentile of the distribution; multivariable OR 1.6[1.1.-2.3], P=0.016). In line, Cd-fed ApoE knockout mice yielded a significantly increased aortic plaque surface compared to controls (9.5 versus 26.0 mm(2), P<0.004). In vitro results indicate that physiological doses of Cd increase vascular endothelial permeability up to 6-fold by (1) inhibition of endothelial cell proliferation, and (2) induction of a caspase-independent but Bcl-xL-inhibitable form of cell death more than 72 hours after Cd addition. Both phenomena are preceded by Cd-induced DNA strand breaks and a cellular DNA damage response. Zinc showed a potent protective effect against deleterious effects of Cd both in the in vitro and human studies., Conclusions: Our research suggests Cd has promoting effects on early human and murine atherosclerosis, which were partly offset by high Zn concentrations.

Background: Previous studies have yielded evidence of an enhanced risk of cardiovascular disease, especially stroke, among patients with migraine. Our understanding of the underlying mechanisms is far from complete. The aims of the present study were to investigate the potential association between migraine and atherosclerosis and to assess the risk of venous thromboembolism as a clinical surrogate for a procoagulant state in patients with migraine., Methods: The examination was part of the population-based Bruneck Study. During the 2005 evaluation, 574 participants aged 55-94 years underwent neurologic and laboratory examinations involving a standardized headache interview and scanning of the carotid and femoral arteries to evaluate presence, severity, and progression (2000-2005) of atherosclerosis., Results: A large number of well-founded and putative cardiovascular risk factors have emerged as being unrelated to migraine status. Prevalence, severity, and 5-year progression of carotid and femoral atherosclerosis did not differ significantly between migraineurs with and without aura and nonmigraineurs. In fact, there was even a tendency for atherosclerosis to be less pronounced among patients with migraine, and for the intima-media thickness to be lower (p = 0.029). As a novel finding migraineurs faced a significantly enhanced risk of venous thromboembolism (18.9% vs 7.6% in nonmigraineurs, age/sex-adjusted p = 0.031)., Conclusion: This study is the first to compare the burden of atherosclerosis as quantified by high-resolution duplex ultrasound between migraineurs and nonmigraineurs in the general community, and provides solid evidence against the view that migraine predisposes to atherosclerosis. The higher risk for venous thromboembolism among migraineurs (prothrombotic state) awaits confirmation and elaboration in future research.

Background: Anti-heat-shock protein 60 (HSP60) antibody-levels have been linked to carotid atherosclerosis and cardiovascular risk in a variety of studies. The potential role of cellular immune reactions against HSP60 has so far attracted little attention in epidemiological research., Methods and Results: In vitro T-cell reactivity to various HSP60s and tuberculin was assessed in blood samples from a elderly subpopulation of the Bruneck study (100 men, 50-69 years) and the young participants of the ARMY study (141 men, 17-18 years), and analyzed for a potential association with common carotoid artery intima-media thickness (IMT). In vivo skin reaction against tuberculin was recorded in subjects of the Bruneck study and correlated with the in vitro proliferative response to tuberculin (P=0.004). T-cells isolated from peripheral blood of all individuals proliferated upon stimulation with HSP60s. In multivariate linear regression analysis adjusted for standard risk factors, T-cell stimulation was significantly related to IMT in the ARMY (P=0.005 for human HSP60 and P=0.064 for mycobacterial HSP60) but not in the Bruneck study., Conclusions: T-cell reactivity against HSP60s correlated with IMT in male youngsters but not in men aged 50 and over, indicating a more prominent role of specific cellular immunity to HSP60s in the young and very early stages of atherosclerosis.

Background: Several diseases characterized by chronic inflammation and immune activation have been linked to enhanced risk for atherosclerosis. The potential association between allergies and atherosclerosis, however, remains to be defined., Methods: The association between common allergic diseases (allergic rhinitis and asthma) and 5-year development and progression of carotid atherosclerosis (Bruneck Study) and high intima-media thickness in carotid and femoral arteries (Atherosclerosis Risk Factors in Male Youngsters [ARMY] study) was investigated. The Bruneck Study is a prospective population-based survey of 826 men and women aged 40 to 70 years; the ARMY study is a cross-sectional evaluation of 141 men aged 17 or 18 years., Results: Subjects with allergic disorders were at a significantly increased risk for high intima-media thickness in the ARMY study (odds ratio, 2.5; 95% confidence interval, 1.1-5.5; P=.03) and for atherosclerosis development and progression in the Bruneck Study (odds ratio, 3.8; 95% confidence interval, 1.4-10.2; P=.007). The associations remained significant after multivariate adjustment for a broad array of established and potential vascular risk factors. When IgE levels were substituted for the clinical allergy variable, findings were confirmed in the Bruneck Study (adjusted odds ratio, 1.7; 95% confidence interval, 1.1-8.0), for a 1-SD increase in IgE level (P=.02)., Conclusions: This study documents enhanced atherosclerosis among subjects with common allergic diseases. Our findings fit well with the emerging concept that key components of allergies, such as leukotrienes or mast cells, are active in human atherogenesis and further extend the growing list of immune system-mediated and chronic inflammatory disorders that have been linked with enhanced risk for atherosclerosis.

In this review, we first briefly introduce the reader to our autoimmune hypothesis for the development of atherosclerosis based on experimental and clinical data. This hypothesis postulates that humoral and cellular immunity against heat-shock protein 60 (HSP60), a phylogenetically highly conserved stress protein, is the mechanism that initiates atherogenesis. We then turn to our investigations of arterial specimens from children and young adults. These clearly show that mononuclear cell infiltrations of the intimal layer already occur before the emergence of clear-cut atherosclerotic lesions, a phenomenon we have termed vascular-associated lymphoid tissue (VALT). In early lesions analyzed within the framework of the Pathological Determinants of Atherosclerosis in Youth (PDAY) study, T lymphocytes proved to be a major cellular constituent. In the Bruneck Study, a large, prospective atherosclerosis-prevention study in adults aged 40 years and older, we found a highly significant correlation between serum anti-HSP60 antibody titers and the occurrence and extent of sonographically demonstrable atherosclerotic lesions. However, no such correlation emerged with respect to HSP60-reactive T cells in the peripheral blood. In contrast, the similar Atherosclerosis Risk-Factors in Male Youngsters (ARMY) study, performed on 17- to 18-year-old volunteers, showed a highly statistically significant correlation between arterial intima-media thickening and HSP60 reactivity among peripheral T cells and (less pronounced) anti-HSP60 antibodies, even at this young age. We take this as indirect evidence that both T cell and B cell immunity against HSP60 plays a major role in the earliest stages of the disease. Because VALT can already be observed in healthy children and young adults, we hypothesize that T cells initiate the disease and that humoral antibodies play a facilitating, accelerating role. Finally, we provide initial evidence that smoking, as the most important risk factor for atherogenesis, also exerts its disease-inducing and disease-promoting effects by inducing HSP60 expression by vascular endothelial cells.