PFO, Risk Factors Both Exert Influence in Younger Cryptogenic Stroke Patients

Both traditional and less conventional risk factors contribute strongly to the risk of cryptogenic ischemic stroke in adults younger than 50 years, but their relative importance varies by the presence of a clinically relevant patent foramen ovale (PFO), a European study shows.

While traditional risk factors like hypertension, smoking, abdominal obesity, and psychosocial stress drove risk in patients without a PFO, nontraditional factors like venous thrombosis, cancer, chronic multisystem disorders, and illicit drug use play a greater role in patients with that characteristic.

In addition, irrespective of the presence of PFO, migraine with aura contributed to a large part of the risk of cryptogenic ischemic stroke in this younger cohort, especially in women.

The findings were published online last week in Stroke.

“The most important clinical implication is that we have to be aware of all the nontraditional risk factors and how they increase the risk of stroke in individuals,” lead author Jukka Putaala, MD, PhD (Helsinki University Hospital and University of Helsinki, Finland), told TCTMD, noting that this information is not systematically assessed in patients or included with sufficient detail in their medical records.

Additional research is needed, however, to understand the mechanisms of the interplay between migraine with aura, PFO, and cryptogenic ischemic stroke, Putaala said.

A Focus on Younger Patients

The incidence of ischemic stroke has been on the rise in younger adults in recent decades, and although this is partly explained by increases in known vascular risk factors, there is evidence that the trend is being fueled by nontraditional risk factors as well, the researchers say.

There is a lack of studies exploring the combined influence of traditional, nontraditional, and female sex-specific risk factors in younger adults with cryptogenic ischemic stroke, and Putaala et al addressed this gap while also incorporating information on PFO. “It is known that young patients with cryptogenic ischemic stroke and PFO are less likely to have traditional risk factors and more likely to have nontraditional risk factors, especially migraine,” they note.

In the SECRETO study, conducted at 19 European sites, the investigators included 523 patients ages 18 to 49 who had a recent ischemic stroke classified as cryptogenic after a clinical workup and 523 stroke-free controls of similar age and sex. Median patient age was 41, and 47.2% of participants were women.

More than one-third (37.5%) had a clinically relevant PFO, defined as one accompanied by high-risk features (atrial septal aneurysm or large right-to-left shunt).

The researchers assessed the impact of 12 traditional risk factors, 10 nontraditional risk factors, and five female sex-specific risk factors (including gestational diabetes, gestational hypertension, various pregnancy complications, current pregnancy or puerperium, and current estrogen use), stratified by the presence of a PFO.

Overall, patients without PFO had a higher number of traditional risk factors.

In patients without a PFO, the risk of cryptogenic ischemic stroke increased with each additional traditional risk factor (OR 1.42; 95% CI 1.28-1.57), nontraditional risk factor (OR 1.70; 95% CI 1.34-2.16), and female sex-specific risk factor (OR 1.70; 95% CI 1.11-2.61).

In patients with a PFO, on the other hand, the relationship between each traditional risk factor and risk of cryptogenic stroke fell shy of statistical significance in fully adjusted models. There were, however, strong associations between stroke risk and each additional nontraditional risk factor (OR 2.66; 95% CI 2.04-3.46) and female sex-specific risk factor (OR 1.94; 95% CI 1.24-3.04).

An assessment of population-attributable risks for cryptogenic ischemic stroke showed that in patients without a PFO, traditional factors contributed to 64.7% of cases, nontraditional factors to 26.5% of cases, and female sex-specific factors to 18.9% of cases. Corresponding figures in patients with a PFO were 33.8%, 49.4%, and 21.8%, indicating a greater influence of nontraditional factors.

Migraine with aura was the individual risk factor with the highest population-attributable risk, both for patients with a PFO (45.8%) and those without a PFO (22.7%), which is consistent with prior research linking migraine to cryptogenic stroke.

“Our findings underscore the need to systematically screen not only traditional risk factors with sufficient detail but also nontraditional and female-specific factors, which often receive too little attention,” Putaala et al write. “This comprehensive approach is crucial for planning preventive strategies for young individuals, even those who appear to have low stroke risk.”

Mechanisms Unclear

Commenting for TCTMD via email, American Heart Association spokesperson Daniel Lackland, DrPH (Medical University of South Carolina, Charleston), said most of the findings “were expected and consistent with new studies.”

What is novel, he added, is that traditional risk factors were more predictive of cryptogenic ischemic stroke in patients without a PFO while nontraditional factors were more important for patients with a PFO. “This needs further research,” said Lackland, “but could be of great value for young-onset cryptogenic ischemic stroke.”

Additional studies also are needed to fully understand the relationship between migraine with aura and cryptogenic stroke, Lackland indicated.

“This is clinically important as migraine with aura symptoms can sometimes mimic a stroke or transient ischemic attack,” he noted. “However, the association between migraine with aura and cryptogenic stroke is mechanistically complex, with some studies suggesting a potential causal relationship, and others indicating a shared etiology. Thus, while PFO is a potential factor, future research needs to consider other mechanisms such as altered blood flow in the brain and increased susceptibility to blood clots.”

Because symptoms can overlap, patients with migraine with aura should be aware of the signs of stroke and “seek medical attention promptly if they experience any sudden neurological changes,” Lackland stressed, adding that they also “should work with their healthcare providers to identify and manage any other stroke risk factors, such as high blood pressure, high cholesterol, and smoking.”