INTRODUCTION
The heritability of stroke assessed by genome-wide association studies is estimated to be 38% [1]. Contributing factors include: monogenic diseases predisposing a person to stroke (such as Fabry disease), single-nucleotide gene polymorphisms (SNPs) (such as the blood type gene ABO or forkhead transcription factor [FOXF2]) [2], and polygenic risk factors (such as hypertension), as well as environmental and lifestyle factors, which are often shared by family members. Due to the complex interactions between genetic traits and shared familial environments, it might be difficult to rely on specific gene identification to predict an individual’s risk of stroke. Instead, the guidelines of the American Heart Academy/American Stroke Association suggest obtaining “family history of stroke (FHS)” as a way of identifying individuals at increased risk (Class IIa; Level of evidence A) [3]. The association of FHS with stroke risk is well established and has been studied systematically [4-6]; however, to our knowledge its link to risk factors and stroke outcomes has not been updated systematically since 2004.
The purpose of this paper is to review the available data regarding family history of stroke. We will focus separately on information that is useful in primary and secondary stroke prevention. This review will not encompass monogenic disorders and SNPs predisposing to stroke, which have been broadly covered elsewhere [1, 2].
METHODS
We conducted this systematic review according to the PRISMA guidelines [7]. We searched the Scopus database up to 31st October 2022 for the phrase TITLE-ABS-KEY (“family history” AND “stroke”). Titles and abstracts were screened by one of the authors using the following criteria: observational studies or systematic reviews/meta- analyses, manuscript in English, definition of FHS as any first-degree relative who suffered from ischemic or hemorrhagic stroke at any age, clear report of association of FHS with the risk of stroke, stroke risk factors, and outcomes after stroke treatment. We excluded case reports, narrative reviews and studies relating to carotid artery dissection, subarachnoid hemorrhage or specific genetic stroke etiologies such as moyamoya disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), or mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). Details on article selection are presented in Figure I.
RESULTS
A total of 140 articles met the pre-specified criteria and were included in the review. The most important associations are shown in Tables 1 and 2.
Table 1
Associations of family history of stroke (FHS) in primary prevention
Table 2
Associations of family history of stroke (FHS) in secondary prevention
Family history of stroke in primary stroke prevention
The prevalence of family history of stroke in the stroke- free population reported in the literature ranged from 16% to 37% [8-13]. In 15-30% of the cases the relative who suffered from stroke was a sibling, otherwise one of the parents [8, 9, 14]. Information about the geographical distribution of FHS was available for Europe and it was found to be more prevalent in southern than central and northern parts of the continent [13].
The risk of stroke
According to the seminal systematic review from 2004 [4], the family history of stroke at any age increased a proband’s stroke risk by 30% in prospective studies and 70% in case-control studies. However, when only high-quality case-control studies were included, the risk of stroke was similar to prospective cohorts (28%). Authors of studies not included or published after the completion of this systematic review also consistently reported increased risk of stroke in probands with FHS [15-43], except one [44]. Another large systematic review conducted in 2019 found that all types of FHS increase the risk of stroke – paternal by 40%, maternal by 36%, and sibling by 44% [5]. The risk increased with the number of relatives who had suffered strokes [10]. Other inferences regarding the association of FHS and the risk of stroke can be drawn from single studies. Some authors argued that FHS predisposes an individual to stroke at a younger age [31, 45-49], even in children [50], whereas others found the opposite [51]. Among patients with AF, having a sibling who has had an ischemic stroke increased the risk of stroke and all-cause mortality [52]. Family history of stroke was also associated with a higher calculated risk of stroke as determined by the ASA Risk Score [53], but not with the LS7 score [9].
Interaction with stroke risk factors
Generally, subjects with FHS were shown to accumulate risk factors over time [54]. The most frequently reported of these in subjects with FHS was hypertension [8, 9, 15, 45, 55-58]. This association was supported by evidence of aggregation of stroke and hypertension in families [12]. The second most consistently reported risk factor associated with FHS was hypercholesterolemia [9, 59-63]. In conjunction with a lack of physical exercise, it was shown to display additive interactions with FHS on stroke [64]. One study found a greater prevalence of FHS among women with atrial fibrillation [8]. Data on diabetes mellitus [8, 61, 65] and obesity [8, 59-61, 66] were conflicting. Similarly, in several studies FHS was associated with smoking [26, 65, 67], though other authors did not confirm this [9, 61, 68]. Apparently, subjects with positive FHS more often experienced transient ischemic attack (TIA) [8, 69]; however, in a prospective study the presence of FHS did not predict stroke after TIA [70]. In stroke- and TIA-free individuals FHS was linked to a greater prevalence of self-reported stroke symptoms in anamnesis [8] and increased anxiety [71]. Subjects with FHS were found to have higher blood levels of factor VII:C [72], homocysteine [73], C-reactive protein, insulin and diagnosed insulin resistance [63], as well as higher brachial-ankle pulse wave velocity, indicating arterial stiffness [74]. According to one study, stroke-free subjects with FHS more often had significant carotid artery stenosis [75], which however was not confirmed by other authors [76].
Family history of stroke in secondary stroke prevention
The prevalence of family history of stroke among patients with ischemic stroke ranged from 12 to 52% [4, 77-86]. It was more common in younger stroke probands [82] and in females, probably due to a more common maternal history of stroke [6]. Compared to the stroke-free group, a greater contribution of family history of stroke in siblings was noted (up to 45%) [79].
The risk of second stroke or death
Several papers postulated that FHS increases the overall risk of second stroke [41, 87-90], three authors did not confirm this [77, 91, 92], and others suggested it might hold true for younger patients and those with siblings who had suffered strokes [78]. The latter subgroup was also found to experience more severe stroke symptoms [93]. One meta-analysis found a greater risk of stroke mortality in all patients with FHS [94]; three studies confirmed this in subgroups: younger age [77, 95] and with parental FHS [11, 77]; three studies did not show any association of FHS with mortality [91, 96, 97].
Type of stroke, etiology, and interaction with risk factors
Most studies investigated the family history of stroke in survivors of ischemic stroke (or both ischemic and hemorrhagic stroke). Four papers specifically showed a higher prevalence of FHS in patients with hemorrhagic stroke [98-101] and one study did not find this association [102]. Notably, in a head-to-head comparison, FHS was more common among survivors of ischemic stroke than hemorrhagic [103].
With regards to stroke etiology, authors consistently reported an association of FHS with small vessel disease [80, 82, 104-108], subclinical lacunes [109, 110], intracranial artery stenosis [111-115] and large vessel disease [80, 98, 105-108], but not with cardioembolic stroke [45, 116, 117]. One paper found that FHS was related to lacunar stroke in older subjects and cryptogenic etiology in the younger [118]. Only one did not find any association of FHS with stroke subtype [119]. Similarly to primary prevention cohorts, it has been found that family history of stroke is associated with an increased prevalence of risk factors such as hypertension, diabetes mellitus and smoking [120-124].
Secondary prevention
FHS was related to increased intima-media thickening in young stroke victims [125], left ventricular hypertrophy [126], serum triglyceride [127] and lipoprotein (a) levels [128, 129], vitamin D deficiency [130], but not with inflammatory markers [131], homocysteinemia [132] or uricemia [133]. Subjects with FHS had negative screening results for thrombophilia [134, 135]. Importantly, the presence of FHS was associated with increased risk of a cardiovascular event after carotid artery stenting in patients > 70 years of age [136] and restenosis [137] or ischemic events [138] after carotid endarterectomy.
Rehabilitation outcomes
Data regarding the association of FHS with rehabilitation outcomes are conflicting. Some authors demonstrated improved short-term outcomes based on crude indices, such as modified Rankin scale and “discharge to home” [80, 139], whereas others found the opposite [81]. Using more complex functional measures in stroke patients at discharge from a rehabilitation unit, no difference was found between patients with positive and negative FHS [140, 141]. However, FHS was a risk factor for post-stroke depression [142] and vascular dementia [143].
Future perspectives
Recently, Hammerle et al. [144] introduced a “family risk score”, which is based on information about family history of stroke weighted for disease onset and number of relatives. They demonstrated that it outperformed simple measures and was associated with increased risk of stroke independently from other risk factors or risk scores based on single-nucleotide polymorphisms (so-called “polygenic risk scores” [145, 146]). It seems that developing easy-to-administer scores combining information about family history of stroke and genetic investigations might increase predictive power in identifying individuals at increased risk of stroke.
Limitations of the studies analyzed
Among the studies analyzed there were only four systematic reviews with meta-analyses; otherwise they were single observational studies, among which there was substantial heterogeneity [4]. Most of the studies defined FHS as family history of total stroke, without separating the ischemic from the hemorrhagic type. Additionally, FHS was most often self-reported; however, this has been shown to be a reliable measure of the incidence of stroke [147].
CONCLUSIONS
A positive family history of stroke is associated with a greater prevalence of risk factors for stroke and increased risk of first-time TIA and stroke. In ischemic stroke patients this might indicate a non-cardioembolic etiology and increased risk of revascularization procedures. An association of FHS with the risk of second stroke, mortality or rehabilitation outcomes are debated. As such, information about family history of stroke may prove useful both for primary care physicians and stroke neurologists in everyday clinical practice.
