Background and rationale for the study

Burden of stroke at younger ages is increasing worldwide

Worldwide, approximately 1.3 million annual ischemic strokes (ISs) occur prematurely in adults aged 18 to 49 years. Incidence in this age range is ≈10 per 100 000 person-years in people of European origin (Putaala et al. Stroke 2009a), but 2-fold higher for example in African-American people (Kittner et al. Stroke 1993). The incidence of early-onset stroke has strikingly increased in both American and European populations due to yet unknown reasons (Kissela et al. Neurology 2012; Rosengren et al. Stroke 2013). Furthermore, there is a largely unexplained gender discrepancy in IS at the very young ages, since the incidence remains higher among women at their 20-30s as compared with men (Putaala et al. Stroke 2012).

Survival and vascular and cognitive outcomes are poor after early-onset IS

Young stroke patients exhibit a four- to ten-fold long-term mortality rates compared with background populations of same age (Rutten-Jacobs et al. JAMA 2013; Waje-Andreassen et al. Eur J Neurol 2013). Potentially preventable cardiovascular events represent the largest group of causes of death in these patients (Putaala et al. Stroke 2009b). Furthermore, studies from Finland, the Netherlands, and Norway show high rates of recurrent stroke in the young, suggesting an active underlying pathology (Putaala et al. Ann Neurol 2010; Rutten-Jacobs et al. Ann Neurol 2013; Waje-Andreassen et al. Eur J Neurol 2013). Young stroke survivors may not only have physical disability, but include also negative effects on cognition, education, working ability, productivity, family- and other social relations, leading to a long-standing decrement in quality of life and loss of disability-adjusted life-years (Leys et al. Neurology 2002, Naess et al. Stroke 2006, Feigin et al. Lancet 2014). Therefore, early-onset stroke potentially leads to long-standing burden of not only cardiovascular and neurovascular comorbidity, but also severe neuropsychological comorbidity and social sequalae (Maaijwee et al. Nat Rev Neurol 2014).

Pathogenetic mechanisms leading to young-onset IS are generally poorly understood

The known key differences that separate the young-onset strokes from older stroke cases are the distributions of stroke subtypes and pre-existing co-morbidities, and the larger proportion of unknown etiology (i.e. cryptogenic) in younger patients (Maaijwee et al. Nat Rev Neurol 2014; Ferro et al. Lancet Neurol 2010). A recent European study based on hospital-based registries of first-ever early-onset IS (n=3331) showed that cryptogenic IS (CIS) is more common the younger the patient, with an average proportion of ≈50% (Figure) (Yesilot Barlas et al. Eur J Neurol 2013). Since the cause remains unknown in such a large proportion, the evidence base to guide prevention and treatment of early-onset stroke remains very unsatisfactory. Furthermore, young adults are usually underrepresented in randomized clinical trials on secondary prevention, and due to differences in risk factor and etiologic profiles as compared with elderly, data from trials cannot be generalized to directly apply young individuals.

Stroke etiology in the 15 Cities Young Stroke Study
Proportion of etiologic subtypes according to age group (figure adapted from Yesilot Barlas et al. Eur J Neurol 2013).

Vascular and cardiac imaging findings in young patients frequently are non-explanatory

Neuroimaging often suggests an embolic origin for the ischemic lesions in a young patient despite apparently normal cardiac and vascular workup. There is an ongoing debate, whether certain common cardiac findings in the general population, in particular patent foramen ovale (PFO), are or are not causally related to IS in young adult (Wessler et al. Circ Cardiovasc Imaging 2014). On the one hand, this illustrates the need of properly designed studies, utilizing more advanced and standardized echocardiography imaging to evaluate PFO and other uncertain cardiac findings and assess conditions when these findings might be causally relevant. On the other hand, the debate suggesting that other currently poorly known factors may play a role in the etiology of early-onset CIS. Recent findings also suggest a larger role for atherosclerosis in young-onset IS than previously thought (von Sarnowsky et al. Neurology 2013). Furthermore, even subclinical atherosclerosis, as measured by increased intima media thickness (IMT), has been linked with increased vascular morbidity and higher risk for recurrent stroke in young adults after IS (Waje-Andreassen et al. Eur J Neurol 2008).

Abnormalities of thrombosis and hemostasis may play a key role in early-onset IS

There is evidence that prothrombotic mutations, such as factor V Leiden or prothrombin gene mutations, have impact on childhood stroke (Kenet et al. Circulation 2010), but controversy remains on their role in IS risk in young adults (Morris Stroke 2010), although more careful selection of patients in case-control studies may reveal significant associations between such mutations and stroke (Hamedani et al. Stroke 2010). Importantly, coexistent PFO and prothrombotic mutations have been linked to higher IS risk in case-control studies (Karttunen et al. Blood Coagul Fibrinolysis. 2003; Pezzini et al. Thromb Haemost 2009).

Antiphospholipid antibodies have been shown to be risk factors for arterial thrombotic events in young women (Brey et al. Stroke 2002; Urbanus et al. Lancet Neurol 2009). Regarding more recently found prothrombotic conditions, a group from the Netherlands revealed that activation of intrinsic coagulation proteins (factor XII, factor XI, and prekallikrein)—factors traditionally thought to have only minor role in thrombosis formation— increased the risk for ischemic stroke in women at young age (Siegerink et al. Circulation 2010). Furthermore, determinants of platelet adhesion factors (von Willenbrand Factor [vWF] and its regulator ADAMTS13) are examples of components of blood coagulation that increased the risk of both ischemic stroke and myocardial infarction in these women (Andersson et al. Blood 2012). These associations strikingly augmented in the presence of cardiovascular risk factors or oral contraceptive use. Examples of other yet not thoroughly investigated early-onset stroke susceptibility factors are genes regulating thrombosis and inflammation (Cole et al. BMC Neurol 2004) and polymorphism of platelet glycoprotein receptor proteins (Stoll et al. Blood 2008).

Understudied transient triggers

IS may be triggered by several transient factors, such as acute alcohol abuse (Hillbom et al. Stroke 1995) and infection (Guiraud et al. Stroke 2010). Infection, inflammation, and genetic modulation of inflammation and thrombosis—in conjunction with environmental risk exposure such as cigarette smoking—may promote cerebral thrombosis especially in younger individuals (Grau et al. Stroke 2010; Cole et al. Thrombosis Journal 2008; Voetsch et al. Stroke 2007). Furthermore, less studied other triggers, such as acute stress, heavy physical activity with or without Valsalva maneuver, or sleep deprivation may be important precipitants for stroke in the active young adult population. Given the relatively high frequency of chronic risk factors in young adults (von Sarnowsky et al. Stroke 2013), the triggering factors likely interact with the traditional or less-well established chronic risk factors.

Early-onset IS forms an attractive window for finding genetic variants predisposing to IS at all ages

There is a significant genetic susceptibility particularly to early-onset stroke (Cheng et al. Circ Cardiovasc Genet 2014), suggesting a larger genetic contribution, possibly from rarer and more highly penetrant genetic variants. Although several rare single-gene disorders are known to include stroke at young age as their clinical manifestations, stroke is a complex disorder and mostly affected by common genetic variants with relatively small effect. For general stroke patients, the first common variants have been recently identified as genotyping technologies and analytical methods have advanced and reasonable sample sizes for genome-wide association studies (GWAS) have become available (Falcone et al. Lancet Neurol 2014). The larger genetic contribution in young-onset stroke makes the young patient population a particularly attractive target for discovering novel genetic loci; yet, highly accurate phenotyping is mandatory for success. Apart from GWAS, exome and whole genome sequencing have become affordable and offer the potential to identify rare, high penetrance variants. By combining the next-generation sequencing with traditional genetic family study methods, even a single informative family may reveal such rare variants. Although not accounting for very large number of patients, rare genetic variants in early-onset cases provide an important window into novel mechanisms common to several cardiovascular endpoints at all ages and new opportunities for their prevention (Cheng et al. Circ Cardiovasc Genet 2014).

Rationale to establish a large consortium to investigate early-onset CIS

There is an urgent need to better understand precipitants, mechanisms, and prognosis of early-onset CIS. INTERHEART and INTERSTROKE studies showed that large multinational standardized case-control studies are feasible and valuable in establishing risk factors for myocardial infarction and stroke in the general population (O’Donnel Lancet 2010; Yusuf Lancet 2004).

SECRETO is a multicenter, international, prospective observational study designed to collect a comprehensive data on transient triggers, subclinical and clinical risk factors, family history, genetic profile, imaging features, medication, and long-term prognosis in young adults aged 18 to 49 with first-ever IS due to unknown cause after standardized and timely investigations. Control subjects without history of stroke matched by age and gender will be recruited at study sites in a 1:1 fashion to allow case-control investigation of risk factors. Due to the stroke incidence of ca 10/100.000 per year in this age group, a large international consortium is the only way to recruit a proper number of patients in reasonable time. Patients will be followed-up for 10 years.

Key areas of interest

The key aims of this project can be summarized in 5 areas of interest:

  1. Transient triggers and chronic risk factors
  2. Advanced cardiac imaging
  3. Thrombosis and hemostasis and other biomarkers
  4. Genetics
  5. Prognosis

Substudies

The study infrastructure provides a possibility of running various substudies. At present, three optional subsidies will be conducted in parallel with the main study. They may involve patients from defined stroke subtypes screened for the main study, patients’ family members, or the subtudies may require specific devices or infrastructure.

  1. Genetic family study
  2. Extended cardiovascular evaluation
  3. Oral health

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