In this study, we designed and tested a novel extended family history definition (Asklepios eFH) which: (1) better correlates with metabolic risk factor burden and; (2) independently predicts the presence of subclinical atherosclerosis beyond conventional risk factor burden, unlike cFH assessments. The eFH definition also shows significant improvement in reclassification for the prediction of prevalent atherosclerosis. The new definition differs from the conventional cFH definition in two aspects. First, it includes key additional elements (identified from literature review) so that the new eFH definition also takes into account later occurrence of disease, disease in second-degree relatives (grandparents) and number of affected relatives. Second, the eFH definition divides participants into 3 rather than 2 categories (): a high-risk group, which is almost identical to the guidelines-defined cFH positive group, and a moderate-risk and novel low-risk group, that has a manifestly lower prevalence of subclinical atherosclerosis.
The new Asklepios eFH definition is superior in detecting adverse CVD risk profiles in the general population. It exposes a significantly greater differential in risk profile than cFH. The eFH definition (but not the cFH definition) was additionally associated with unfavourable glycemic and lipid profiles, more components of the metabolic syndrome and more atherosclerosis. Furthermore, an important novel finding is that most relations with eFH were not graded but showed clear informational breakpoints with the eFH low-risk group being particularly interesting. Much of the additional information extracted by the novel eFH definition can be attributed to the presence of this newly defined low-risk category. The cFH positive group, the eFH high-risk and large eFH moderate-risk groups have quite similar risk factor profiles and preclinical atherosclerotic burdens. Separating out the low-risk category in many cases abolished a large part of the step-up in adverse risk profiles found in the cFH positive group, suggesting that the differences between the guidelines positive and negative groups are (in part) due to the admixture of the eFH low-risk group to the latter (i.e. some differences are due to a significantly better risk profile in the eFH low-risk group).
Most importantly, the new eFH definition (but not the conventional definition) was able to identify presence of atherosclerosis beyond conventional risk factor burden, indicating that FH conveys additional information, not completely characterized by simply measuring a risk factor profile.
A few studies already showed the value of extending FH beyond a simple yes/no question about presence of disease in a first-degree relative 
. Scheuner et al. investigated various binary definitions of FH and found significant associations between a personal history of CHD and an additional FH that goes beyond having first-degree relatives with early-onset CHD 
. In line with their work we took into account key additional elements in our new eFH definition, and we elaborated on their dichotomous definitions by defining a three-tier definition encompassing both the classic high-risk group, as well as a novel and highly interesting low-risk group.
That presence of a positive FH is associated with an adverse risk profile is largely in agreement with published reports 
. This familial aggregation of cardiovascular risk factors reflects the genetic and environmental influence on the causal pathways of familial CVD. In line with published data we found an association with fibrinogen (a thrombotic risk factor), but not with hs-CRP, for which literature is inconsistent 
Regarding the presence of atherosclerosis (a prognostically well-validated non-invasive surrogate endpoint to assess cardiovascular risk), the eFH low-risk group had significantly less atherosclerosis compared to the eFH moderate- and high-risk groups. Although other studies already demonstrated significantly more atherosclerosis in patients with a FH of CVD 
. Our study shows, for the first time, that this is in large part due to significantly less atherosclerosis in a “low-risk” group that can be readily identified by eFH (but not by cFH), separating it from an intermediate group (which would conventionally be classified as having a negative FH). The eFH moderate risk group demonstrates almost identical prevalence of atherosclerosis as the cFH positive group (corresponding to the eFH high-risk group). This large eFH moderate-risk group with a substantial atherosclerotic burden would be overlooked when using the conventional FH definition.
Although FH is an important risk factor for CVD and plays an important role in medical practice, it is underused in CVD prevention efforts 
. Recent data from a randomized controlled trial looking at the added value and feasibility of systematically collecting FH, found that it increases the proportion of persons identified as having high cardiovascular risk for further targeted prevention (many risk factors are amenable to intervention, by lifestyle or pharmacologically) 
. FH also received increased visibility as a risk qualifier in the new European guidelines on CVD prevention, where a positive cFH is considered to increase the 10-year risk of a fatal CV by 1.7-fold in women and by 2.0-fold in men 
. Conversely, it is suggested that 10-year CVD risk (SCORE) may be lower in those with a FH of longevity. Whilst knowledge of FH may not affect clinical decision making in those at very high or very low predicted risk, it may aid in discriminating risk among the very large group of subjects at intermediate levels of predicted risk 
. Since low-risk populations for CVD are gaining interest, our eFH low-risk group with a more favourable risk profile and significantly less atherosclerosis, could be an interesting phenotype for further study 
. Yeboah et al. recently studied novel risk markers, comprising (premature and non-premature) FH of CHD in a first-degree relative, for improvement in cardiovascular risk assessment in intermediate-risk individuals. The authors found that FH was an independent predictor of CHD/CVD in intermediate-risk individuals. Furthermore, besides coronary calcium score, FH performed the best for CHD risk reclassification (NRI
0.160). Interestingly, most of the correct reclassification was based on subjects reclassified into a lower risk category 
Intuitively, it seems likely that shared lifestyle risk factors (smoking, diet, physical inactivity) represent (non-genetic) pathways through which FH influences risk of CVD. The literature is inconsistent 
; we found no clear associations between FH and lifestyle parameters. It is possible that increased perception of familial risk does not automatically lead to changed behaviour; some people may even adopt a fatalistic outlook and make no efforts at all to decrease their risk 
Study Strengths and Limitations
The major limitation of the present study is the absence of outcome data. We used a surrogate measure that is well validated as a prognostic marker: presence of atherosclerosis. Furthermore, it remains to be tested if our findings can be extrapolated to the much younger (where relatives might not have aged sufficiently to have suffered CV events) or older populations. One of the major problems of defining and studying FH is that it is a “moving target”. A 52-year old man today that is eFH low-risk could end-up tomorrow in the eFH high-risk category after his brother had a myocardial infarction. Reassuringly, sensitivity analyses in our cohort looking at the older and younger subjects (with correspondingly older/younger family members) showed similar results. A major strength is the population-based nature of the study, combining a well-balanced, representative sample with stringent methodology, and a broad and detailed array of carefully assessed cardiovascular intermediate phenotypes.
Self-reported FH of CVD was not validated through medical records, which is another potential limitation. Many, though not all, previous studies showed that questionnaires considering FH of CVD can be considered as accurate and people can correctly report their FH for CVD 
. Moreover, our assessment of FH through self-report is similar to general practice, thus the present findings can be generalized to the usual clinical setting. We used a categorical definition rather than a (theoretically attractive) continuous FH score, where entry is restricted to more informative (i.e. larger) families and a single affected family member is ruled out 
. Considering the characteristics of our study population families (average European family size), we followed the recommendations from Silberberg et al., who previously recommended that the use of categorical definitions are more likely to be adequate in smaller families and few affected relatives 
. Finally, 13.6% of subjects could not be correctly classified because of insufficiently accurate knowledge of their FH.
In this study, we designed and tested a novel extended family history definition (Asklepios eFH) which: (1) better correlates with metabolic risk factor burden and (2) independently predicts the presence of subclinical atherosclerosis beyond conventional risk factor burden, unlike cFH assessments and (3) shows significant improvement in reclassification for the prediction of prevalent atherosclerosis. Adding information on non-first degree relatives, late occurrence of disease and number of affected relatives to the FH construct improves the discrimination for cardiovascular risk factors and atherosclerotic burden in order to better target individuals for CVD prevention efforts. The new eFH definition separates the cFH negative group into two categories: a large eFH moderate-risk group, and a smaller eFH low-risk group. The latter is a particularly interesting phenotype for further study, having a more favourable risk profile and significantly less atherosclerosis (odds ratio 0.74). There remain clear opportunities to refine and increase the performance and informational content of this readily available, simple, inexpensive tool.