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Background The clinical use of carotid intima media thickness (cIMT) requires normal values, which may be subject to variation of geographical factors, ethnicity or measurement details. The influence of these factors has rarely been studied. The aim of this study was to determine whether normative cIMT values and their association with event risk are generalizable across populations.Design Meta-analysis of individual participant data.Method From 22 general population cohorts from Europe, North America and Asia we selected subjects free of cardiovascular disease. Percentiles of cIMT and cIMT progression were assessed separately for every cohort. Cox proportional hazards models for vascular events were used to estimate hazard ratios for cIMT in each cohort. The estimates were pooled across Europe, North America and Asia, with random effects meta-analysis. The influence of geography, ethnicity and ultrasound protocols on cIMT values and on the hazard ratios was examined by meta-regression.Results Geographical factors, ethnicity and the ultrasound protocol had influence neither on the percentiles of cIMT and its progression, nor on the hazard ratios of cIMT for vascular events. Heterogeneity for percentiles of cIMT and cIMT progression was too large to create meaningful normative values.Conclusions The distribution of cIMT values is too heterogeneous to define universal or regional population reference values. CIMT values vary widely between different studies regardless of ethnicity, geographic location and ultrasound protocol. Prediction of vascular events with cIMT values was more consistent across all cohorts, ethnicities and regions.

Background Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population.Methods Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses.Results Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p< 0.001); 0.0072 mm for fibrinogen (p< 0.001); and 0.0025 mm for leucocyte count (p= 0.033). ‘Inflammatory load’, defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p< 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest ‘inflammatory load’ had a greater CCA-IMT progression (p= 0.015).Conclusion Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for ‘inflammatory load’ suggest important combined effects of the three inflammatory markers on early atherosclerosis.

Background Heat therapy has been suggested to improve cardiovascular function. However, the effects of hot sauna exposure on arterial compliance and the dynamics of blood flow and pressure have not been well documented. Thus, we investigated the short-term effects of sauna bathing on arterial stiffness and haemodynamics.Design The design was an experimental non-randomised study.Methods There were 102 asymptomatic participants (mean age, 51.9 years) who had at least one cardiovascular risk factor. Participants were exposed to a single sauna session (duration: 30 min; temperature: 73℃; humidity: 10–20%). Pulse wave velocity, augmentation index, heart rate, blood pressure, mean arterial pressure, pulse pressure, augmented pressure and left ventricular ejection time were assessed before, immediately after, and 30 min after a single sauna session.Results Sauna bathing led to reductions in pulse wave velocity, blood pressure, mean arterial pressure and left ventricular ejection time. Mean pulse wave velocity value before sauna was 9.8 m/s and decreased to 8.6 m/s immediately after sauna bathing (p< 0.001 for difference), and was 9.0 m/s after the 30-minute recovery period (p< 0.001 for analysis of variance). Systolic blood pressure was 137 mm Hg before sauna bathing, decreasing to 130 mm Hg after sauna (p< 0.001), which remained sustained during the 30-minute recovery phase (p< 0.001 for analysis of variance). After a single sauna session, diastolic blood pressure decreased from 82 to 75 mm Hg, mean arterial pressure from 99.4 to 93.6 mm Hg and left ventricular ejection time from 307 to 278 m/s (p< 0.001 for all differences). Pulse pressure was 42.7 mm Hg before the sauna, 44.9 mm Hg immediately after the sauna, and reduced to 39.3 mm Hg after 30-minutes recovery (p< 0.001 for analysis of variance). Heart rate increased from 65 to 81 beats/min post-sauna (p< 0.001); there were no significant changes for augmented pressure and pulse pressure amplification.Conclusion This study shows that pulse wave velocity, systolic blood pressure, diastolic blood pressure, mean arterial pressure, left ventricular ejection time and diastolic time decreased immediately after a 30-minute sauna session. Decreases in systolic blood pressure and left ventricular ejection time were sustained during the 30-minute recovery phase.

Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A2(Lp-PLA2), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA2enzyme activity is causally relevant to coronary heart disease.Methods In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7,the gene encoding Lp-PLA2. We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA2activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA2-lowering alleles.Results Lp-PLA2activity was decreased by 64% (p= 2.4 × 10–25) with carriage of any of the four loss-of-function variants, by 45% (p< 10–300) for every allele inherited at Val279Phe, and by 2.7% (p= 1.9 × 10–12) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA2activity by 65% (p< 10–300). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA2activity were: 0.95 (0.88–1.03) with Val279Phe; 0.92 (0.74–1.16) with carriage of any loss-of-function variant; 1.01 (0.68–1.51) with Val379Ala; and 0.95 (0.89–1.02) with darapladib treatment.Conclusions In a large-scale human genetic study, none of a series of Lp-PLA2-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA2is unlikely to be a causal risk factor.

BackgroundWhether systemic inflammation is an epiphenomenon of atherosclerosis or whether it is part of the atherosclerosis causal pathway requires further study.DesignAs part of a prospective population survey on the course and aetiology of atherosclerosis, we investigated the effects of plasma on the endothelial monolayers inducing activation for leukocyte transmigration.MethodsAn age- and sex-stratified random sample of inhabitants of Bruneck (Italy) with and without atherosclerotic disease aged 50–69 years was selected. Carotid arteries were evaluated by duplex sonography at baseline (1990). Carotid arteries were re-evaluated for the development of new plaques 5 years later (1995). Frozen plasma samples from baseline were available for a random sample of 152 men. Monolayers of endothelial cells cultured in micropore filter insets were pre-treated with plasma, then normal human neutrophils were added to the endothelial cells and subsequent transmigration through the monolayers and micropore filters was measured.ResultsThe endothelial monolayers were activated for transmigration of leukocytes more potently by plasma from participants with carotid artery plaques than participants without it. Increased endothelial activation with plasma at baseline was associated with the development of new atherosclerotic lesions during a period of 5 years.ConclusionsPlasma from individuals with prevalent atherosclerosis of the carotid arteries activates the endothelium for leukocyte transmigration, suggesting the presence of systemic pro-inflammatory mediators. In an epidemiological survey, follow-up data on new lesion formation after 5 years indicated that plasma-mediated endothelium activation for interaction with leukocytes precedes the development of atherosclerotic lesions.