Cyclic variation of the common carotid artery structure in relation to prior atherosclerotic burden and physical activity

Background and aims: Cardiovascular disease (CVD) accounts for the most deaths of non-communicable diseases worldwide. It begins with structural and functional changes of the arterial system commonly known as the atherosclerotic process, starting asymptomatically in early childhood, adapting arterial structure and function with advancing age depending on genetic and environmental exposures and finally resulting in CVD events such as myocardial infarction or stroke. CVD
risk prediction today is generally based on risk scores, but substantial disadvantages occur since they account only for specific risk factors at one time point. Carotid structure and function (also called carotid stiffness) parameters measured by ultrasound may overcome this disadvantage, since they can provide information on structural and elastic carotid properties and reflect therefore vascular damage accumulated over time.
Thus, the aims of this thesis were to summarize the state of the art of ultrasound measurements, to validate the new developed ultrasound analysis system, to assess the variability and reproducibility within the study sample and to investigate the long- and short-term associations of cardiovascular risk factors and carotid stiffness with main focus on physical activity in elderly participants of the SAPALDIA cohort.
Methods: The SAPALDIA cohort study is an ongoing multicenter study with a population-based random sample of adults from eight rural and urban areas started in 1991 (SAPALDIA 1), with a first follow-up in 2001-2003 (SAPALDIA 2) and a second follow-up in 2010-2011 (SAPALDIA 3). In SAPALDIA 3, sequential B-mode ultrasound images of the common carotid artery were examined in 3489 participants (51% women) aged between 50-81 years at the time of examination. Expert readers analyzed these ultrasound images with a new analysis system called DYARA (DYnamic ARtery Analysis) according to the state of the art assessed in the review. Thereof, carotid structure parameters were measured and carotid stiffness indices were derived considering blood pressure at time of ultrasound assessment. Validation of the ultrasound analysis program DYARA and reproducibility of carotid parameters were performed in subgroup within the SAPALDIA 3 survey. The presented studies within this thesis comprise cardiovascular risk factor data from the first and second follow-up and therefore, long- and short-term associations with carotid stiffness could be investigated.
Results: The intra- and inter-reader results of the validation study were highly consistent with slightly higher bias for analyses with manual interactions compared to the automatic detection. Among the carotid structure parameters, average values across heart cycle showed lower variability than single images in diastole and systole, whereby the relative difference was smaller in lumen diameter values compared to the carotid intima media thickness (CIMT). Based on different statistical approaches, reproducibility values within SAPALDIA 3 were consistently good to excellent for carotid structure and function indices. Findings additionally revealed that subjects itself were the greatest source of variability between two measurements.
Multivariate regression analyses suggested that most single cardiovascular risk factors in SAPALDIA 2 were long-termly associated with increased carotid stiffness in SAPALDIA 3 except physical activity and high-density lipoprotein cholesterol (HDL-C). HDL-C was the only protective vascular determinant and no relation was observed for physical activity. Most carotid stiffness parameters were similar strong associated within each cardiovascular risk factor (except compliance showed main deviances among several risk factors). Estimating sex-specific associations of atherosclerotic risk factors and carotid stiffness indicated that increased heart rate was more strongly associated with stiffer arteries across all carotid stiffness parameters in men than in women. Low-density lipoprotein cholesterol (LDL-C) was significantly associated with carotid stiffness only in men and triglyceride only in women.
Multifactorial pathway analyses of cardiovascular risk factors in SAPALDIA 3 showed that age was the strongest predictor of carotid stiffness, followed by mean arterial blood pressure and heart rate. Age strongly confounded the association of physical activity and carotid stiffness in multiple regression analyses and therefore, only an univariate association of physical activity and carotid stiffness could be observed.
Conclusion: DYARA tackles the challenge of being able to analyze varying ultrasound image qualities with high precision. The high reproducibility and the feasible application in a large sample size suggest that this program can be recommended for epidemiological research, diagnostics and clinical practice. Long- and short-term cardiovascular exposures have added important information to the overall vascular damage assessed by carotid stiffness for both sexes. Although age was the strongest predictor, sex-differences in long-term associations may indicate a certain differentiated susceptibility to cardiovascular risk factors among men and women, which should be investigated in more detail.
The presented studies within this thesis provide an important basis towards future investigations targeting the early and late consequences of atherosclerosis, its progression and possible implementations of preventive and/or personalized interventions.