Long-term follow-up studies of young stroke patients have shown high mortality and vascular morbidity compared to healthy controls [6–10, 40]. Hence, a prospective cohort follow-up based on thorough investigation of clinical and sub-clinical vascular disease and risk factors is necessary in order to achieve a better long-term outcome.
Ultrasound imaging has been proved to be a sensitive and cost-effective method for the detection of arterial vessel disease in major arteries , as well as for the evaluation of adipose tissue [35, 41]. For this reason, ultrasound was chosen as the predominating tool for the investigations in the NOR-SYS protocol. IMT increases are dependent on age, sex and cardiovascular risk . However, the increase and prevalence of atherosclerotic lesions vary among different anatomical segments. Moreover, increased IMT has repeatedly been associated with cardiovascular risk factors and the incidence of cardiovascular events [19, 43], and has been validated as a surrogate marker of atherosclerosis [44, 45]. Atherosclerotic lesions are not distributed circumferentially, but develop asymmetrically , and their prevalence varies in the different artery segments . In our study, Meijer’s Carotid Arc® is used for standardized imaging at defined angles [47, 48], and cIMT and plaque measurements are aquired bilaterally in three carotid segments: the distal CCA, the bifurcation and the proximal ICA . We suppose that this approach will improve the individual risk classification, as recently suggested . It has also been suggested that the presence of carotid artery plaques may be even more representative for CVD prediction than increased cIMT itself . Hence, plaque measurements are performed in addition to the standardized IMT measurements at all three carotid sites, if present.
Atherosclerosis is a systemic disease, and lesions are often to be found in several locations of the vasculature, such as in the peripheral arteries. Intermittent claudication is a frequent condition in western European populations [51, 52] and associated with symptomatic CAD and cerebrovascular events [53, 54]. Acute death due to PAD has been shown in 9% , compared to 45% and 42% due to cerebrovascular and coronary death, respectively . The CFA has been reported as the segment most prone to IMT increase and plaque formation  compared to the SFA and the carotids. CFA IMT has beyond that been related to coronary angiographic  and echocardiographic parameters . It is considered suitable for long-term observations concerning the natural development of atherosclerosis in healthy participants, and for the observation of treatment effects in a participant group requiring intervention . For these reasons, IMT measurements are additionally performed bilaterally in the distal CFA and the proximal SFA segment, and included in study analyses. Atherosclerosis in the abdominal aorta is leading to aortic stenoses and PAD. Abdominal aortic aneurysms are also considered to be a manifestation of advanced atherosclerosis , and are frequently observed in patients with carotid stenoses, cardiovascular events and PAD . Therefore, in NOR-SYS the abdominal aorta is evaluated with respect to atherosclerotic lesions, stenoses, and aneurysms. The ABI is performed in all participants as it is a well-established tool in investigation for peripheral artery disease and adds valuable information to vascular risk prediction [60, 61].
Standard screening for a cardiac embolic source, including 24 hour heart rhythm registration and echocardiography is carried out in order to diagnose left ventricular hypertrophy, abnormal left ventricular geometry, and dilated left atrium as they are well-known predictors of stroke, both in the general as well as in the hypertensive population . Blood pressure is measured after hospital discharge as an ambulatory 24-hour measurement as it has been proven to be closer associated with cardiovascular target organ damage and incident cardiovascular events than clinic pressure . Ambulatory blood pressure measurements identify hypertension more accurately than clinic blood pressure measured during an acute stroke.
Measurement of arterial stiffness by carotid-femoral pulse wave velocity by aplanation tonometry may be useful in identifying arterial disease which is not captured by routine carotid ultrasound visualization .
NOR-SYS includes CCTA and CT of the thoracic aorta because of the well-known association between peripheral and coronary disease . In addition, aortic arch atheroma or other wall disease of the ascending aorta or the aortic arch might cause the index-stroke or recurrent stroke .
Obesity is an increasingly prevalent disorder  which is associated with atherosclerosis and cardiovascular disease. Particularily abdominal obesity has been associated with metabolic syndrome , pre-clinical atherosclerosis , cardiovascular events  and mortality .
Epicardial adipose tissue (EAT) has its embryologic origin in common with mesenteric and omental fat, and all these are accordingly classified as visceral adipose tissue (VAT) [71, 72]. Associations between VAT and cIMT , metabolic syndrome [74, 75] and cardiovascular disease [76, 77] have been reported in several studies. Release of free fatty acids due to the proximity to the portal circulation leading to direct lipotoxicity [78, 79], and release of pro-inflammatory and pro-atherogenic cytokines and hormones with impact on endothelial function [80, 81] are related issues. The accumulation of VAT has therefore been found to be an independent vascular risk factor, even within the normal range of BMI . Accordingly, the anatomical relationship of EAT to the heart is providing local interaction with modulation of the coronary arteries and the myocardium, which may subsequently affect cardiac function and morphology [83–85]. On the other hand, subcutaneous adipose tissue, which is a non-portal fat type with less metabolic activity , has previously shown only a weak relationship to increased cIMT . Its evaluation related to the amount of VAT and anthropometric parameters is assumed to be relevant for risk prediction and for that reason included in NOR-SYS. Anthropometric parameters such as BMI and WHR are simply applicable clinical tools and widely used in obesity evaluation. They are as well associated with ultrasonographic visceral adipose tissue measurements [41, 87], and applied in NOR-SYS.
In conclusion, the major objective of NOR-SYS is the standardized gathering of anamnestic, clinical, and biological data concerning life styles, medical history, and clinical and subclinical vascular disease at several sites of the vasculature including body fat composition and anthropometric measurements in young ischemic stroke patients and their families. Standardized questionnaires and standardized ultrasound examinations combined with detailed clinical data are assumed to increase the precision in diagnostics and risk estimation, and generate a solid basis of decision-making concerning secondary prophylaxis after acute ischemic stroke.
Further investigation and evaluation of vascular risk factors and sub-clinical artery wall disease in young ischemic stroke patients’ family members provide a platform for primary prophylaxis and early intervention.
NOR-SYS aims to reduce co-morbidity, disability, recurrent stroke, cognitive impairment and mortality in young patients with acute ischemic stroke. We expect that a comprehensive work-up and long-term observation, combined with biological, genetical and clinical information gathered from three family generations, will give the opportunity to improve our basic knowledge concerning preclinical atherosclerosis in families with a vascular disease burden.
NOR-SYS is reviewed and approved by the Regional Committee for Medical and Health Research Ethics, Western-Norway (REK-Vest 2010/74), and registered in ClinicalTrials.gov: NCT01597453.