The spontaneous closure of foramen ovale usually occurs within the first year of life but only in three-fourths of the population, leaving approximately 25% [26,27] of the adult population with a PFO, which translates to about 1.9 billion people globally [28]. The prevalence of PFO differs according to patients’ age, from 34.3% during the first three decades of life to 20.2% during the 9th and 10th decades [26]. Additionally, in autopsy studies of healthy hearts, the PFO size is larger in the 10th decade of life compared to the 1st decade of life [26], which is clinically relevant since large-size PFOs have a stronger causal relationship with a PFO-related stroke [3].

In young patients (<55 years) diagnosed with cryptogenic stroke, multiple studies have shown an increased prevalence of PFO compared to their stroke of known origin counterparts [29,30], as much as four times higher than patients with stroke of known causes [30] among all diagnostic modalities [27].

Although the initial effort in the search for an association between a PFO and cryptogenic stroke among the elderly population failed (vaguely defined as having a stroke without a predetermined cause) [31], more recent studies have shown an increasing association within this population. Alsheikh-Ali et al. [29] performed a systematic review identifying 23 case-control studies, showing an OR of 2 (>1 to 3.7) for PFO in patients older than 55 years diagnosed of cryptogenic stroke. However, one important limitation of that study was the diagnostic method of PFO since in 74% of the studies was transesophageal echocardiogram (TEE), but in 26% was transcranial Doppler. More recently, Handke et al. [12] reported a TEE prevalence of PFO in 28.3% of older patients with cryptogenic stroke, compared to 11.9% in patients of the same age with a known cause of stroke. In the multivariable analysis, PFO was independently associated with cryptogenic stroke in the younger and older groups. Likewise, in a population-based study nested in the Oxford Vascular (OXVASC) study, compared to patients with transient ischemic attack (TIA) or stroke of known cause, patients with cryptogenic events had a higher prevalence of right-to-left shunt in the overall population (odds ratio [OR] 1.93, 95% CI: 1.32-2.82; P=0.001), but remarkably, this was even higher among patients >60 years (OR 2.06, 95% CI: 1.32-3.23; P=0.001) [13]. One important limitation was that the PFO prevalence was evaluated by contrast-enhanced transcranial Doppler. The authors extrapolated their results amongst the British population, estimating that every year 8,477 cryptogenic cerebral ischemic events could be attributed to significant right-to-left shunting, with 70% of them occurring in patients older than 60 years.

Two main potential mechanisms can explain the role of PFO in a systemic arterial embolism. Firstly, paradoxical embolism, meaning the passage of a right-sided venous thrombus to the systemic circulation through the PFO, especially during the transient or persistent elevation of right-heart pressures [32]. This mechanism will only need a PFO gap as small as 1-3 mm to cause either severe impairment or a large infarct since 1 mm is the average size of any major cerebral cortical branch and 3 mm is the size of the middle cerebral artery stem [33]. The second mechanism would be in situ PFO thrombus formation, which can lead to an embolization into the arterial circulation [34].

Although a PFO can only be a bystander in the settings of an otherwise cryptogenic stroke, several morphologic characteristics have been described as being more prone to a higher risk for paradoxical embolization or in situ thrombus formation, thus, with a higher likelihood of causal relationship. These morphologic characteristics include a large PFO (maximum separation of the septum primum from the secundum >2-3 mm) [35-37], long tunnel (>10 mm) [38], atrial septal aneurysm (ASA) (usually defined as hypermobility of the septum with >10 mm excursion) [14,31,36,39], shunt size [14,37,39,40], and prominent Eustachian valve [41]. Identifying these high-risk PFO features is crucial since there is potentially a higher benefit from PFO closure among patients with high-risk anatomical PFO features [42].

Moreover, score systems based on these high-risk anatomical characteristics have been developed to help proper patient selection for closure therapies [38,43]. Identifying these high-risk PFO features is important, as a recent meta-analysis from randomized trials showed that there is potentially a higher benefit from PFO closure among patients with high-risk anatomical PFO features [44], which according to observational studies on PFO closure in younger versus older patients, these high-risk features are more prevalent among the elderly population undergoing PFO closure due to a PFO-related cerebrovascular event [17,18,21].

The risk of paradoxical embolism (RoPE) score allows an evaluation of the potential causal role of a PFO in any given patient with a stroke of unknown cause [45]. It mainly uses the patient’s age, with younger patients having an increased risk of causality, the absence of atherosclerotic risk factors, and infarct topography, to determine the likelihood that a PFO is causally related to stroke in individual patients [45]. This score has been validated and is used in clinical practice and PFO research [46].

According to the RoPE score, the higher the score, particularly above 6 points, the stronger the link of causality between a PFO and a cryptogenic stroke. Also, as per RoPE score, younger patients and patients without traditional cardiovascular risk factors have the highest PFO-attributable fraction [45]. For example, a 29-year-old non-smoker patient with a PFO and a cryptogenic cortical stroke, without hypertension, diabetes, and no history of stroke/TIA, has a RoPE score of 10 points (maximum score) and a PFO-attributable fraction of 88%. However, any patient ≥50 years with a history of hypertension, diabetes, stroke, and smoking, even in the presence of an embolic-like stroke on imaging, has a RoPE score of 3 points, meaning a PFO-attributable fraction of 0%, basically discarding any possible association between a stroke and a PFO [45], an estimation that can be misleading in the elderly population. Moreover, in this scoring system, for every 10-year increase in patients’ age, there is a decrease in the total RoPE score, and in patients with ≥70 years, the age factor adds 0 points; thus, the possible association between a PFO and an index ischemic stroke is even less likely just by the age. Additionally, based on the RoPE original dataset, Thaler et al. [14] showed that older age was a significant predictor of recurrent stroke among patients with a low (<6) RoPE score (hazard ratio [HR] 1.47, 95% CI: 1.18-1.83).

Trying to overcome some RoPE score limitations, the PFO-Associated Stroke Causal Likelihood (PASCAL) Classification System emerged to further assess the potential causal role [25] by combining the RoPE score with the most consistent high-risk PFO anatomical features to provide a more precise causal correlation. Compared to the conventional RoPE score mainly focused on patient age and other vascular risk factors, PASCAL classification with the addition of the anatomical features of PFO (namely ASA and shunt severity) showed a better performance in distinguishing subgroups who may benefit from PFO closure from those unlikely to benefit from it; thus, selection of patients with ESUS and high-risk PFO features seems to be the first step to expect a significant reduction of recurrent events. However, although the PASCAL classification system is already validated [47], it is still limited among older patients since it is based on the RoPE score, which includes age as one of the main variables.

According to meta-analyses, patients with a PFO-related stroke, the annual recurrence rate on medical therapy ranges from 0% to 5.8% for stroke and from 0% to 14% for stroke or TIA [48,49]. Several factors have been associated with a higher risk of recurrent events, such as older age, presence of ASA, use of acetylsalicylic acid (compared to oral anticoagulation), thrombophilia, stroke as index event, and PFO size [7].

Remarkably, compared to younger patients, elderly patients are at higher risk of recurrent cryptogenic stroke after an index PFO-related event. According to the latest European guidelines on the management of patients with PFO, based on four studies with a total of 2,171 patients [12,14-16], older patients are at an increased risk of recurrent cerebrovascular events after an index PFO-related cryptogenic stroke; among other factors, older age has an HR of 1.47 (95% CI 1.2-1.8) for cryptogenic stroke recurrence in the presence of PFO [7]. In an analysis of the CLOSE (Patent Foramen Ovale Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence) and DEFENSE-PFO (Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk Patent Foramen Ovale) trials, one of the variables associated with time to recurrent stroke was age, with a crude HR of 1.52 (95% CI 1.17-1.97, P=0.001) per 10-year increase [39]. Interestingly, another study in patients with ESUS showed that older patients had twice recurrent embolic strokes after a median follow-up of 3 years, and, when analyzed by potential embolic sources, this difference was mainly driven by PFO-related strokes among the older population (recurrent embolic stroke 12.5% vs. 5.6% in young patients with PFO-related stroke) [50].

The most recent evidence on recurrent events was reported by Mazzucco et al. [51]. The authors showed that the absolute risk of recurrent ischemic stroke in the overall population was 2.0 per 100 patient-years (95% CI, 1.57-2.55), based on 268 recurrent events during 15,058 patient-years. After analyzing by age groups, the pooled ischemic stroke risk in patients of 60 years or older was 3.27 per 100 patient-years (95% CI, 2.59-4.13). Remarkably, the authors performed another pooled analysis of four studies reporting ischemic stroke risk stratified by age in patients with cryptogenic TIA/stroke with PFO versus patients without PFO, finding that the association between PFO and stroke risk also increased with age (<65 years: OR, 0.8; 95% CI, 0.4-1.5; ≥65 years: OR, 2.5; 95% CI, 1.4-4.2; P=0.001).

The cause behind the recurrent strokes in older patients with PFO left under medical treatment remain unclear since the data on this subject is very limited. In the DEFENSE PFO trial, all recurrent strokes were considered as PFO-related [52]. Additionally, observational data shows recurrent strokes being cryptogenic even with negative AF after prolonged cardiac monitoring [20]. In observational PFO closure studies, recurrent stroke rates are lower and importantly, the main causes are atherothrombotic, AF-related, vertebral dissection and small vessel disease, among others, with the most strongly associated factors being diabetes and chronic renal disease [18,21]. Ongoing trials will provide further details on the cause of recurrent stroke in these patients.

The causal relationship between a PFO and a stroke among elderly patients was once thought to be lower as the incidence of stroke due to other causes increased. Nevertheless, this causal association may be higher than expected. Autopsy studies including healthy hearts showed that PFO size is larger in the last decades of life [26] with an increase in mean PFO size from 3.4 mm in the first decade to 5.8 mm in the 10th decade of life [26], and the larger the PFO, the higher the risk of having a PFO-related stroke [38].

Another special consideration is the increased risk of venous thromboembolism. The risk of deep venous thrombosis (DVT) is strongly associated with age [53], and its overall incidence has been increasing over time, particularly among elderly patients [54], also including those cases with silent thrombus formation [55]. When a DVT develops, it can serve as the nidus for a barrage of thromboemboli directed at the right atria, with 300 to 50,000 emboli per hour [56]. Both DVT and pulmonary embolism are essential considerations since, in these patients, the presence of PFO is associated with ischemic brain lesions, both at baseline and at follow-up [57].

It is known that right ventricular systolic and diastolic function, as evaluated by transthoracic echocardiogram, decreases gradually among the healthy elderly population [58], data that has been recently refined by cardiac magnetic resonance imaging [59]. Although not directly proven, having increased filling pressures in the right ventricle could increase the risk of a right-sided thrombus migrating to the systemic circulation through an interatrial shunt, especially during transitory pressure elevation in the right side of the heart observed in the Valsalva maneuver.

The DEFENSE PFO trial is the only randomized clinical trial in the PFO closure field which included a small proportion of patients older than 60 years. This trial included 120 patients between 18 to 80 years (mean age of 50 years) [3]. In a recent subanalysis comparing younger (<60 years) versus older (≥60 years) patients, the 2-year event rate difference between medical treatment versus PFO closure was 24.6% (HR, 7.36; 95% CI, 0.28-195.81; log-rank P=0.07) in patients >60 years after a median follow-up of 3 years, and it was even higher (80%) in patients ≥70 years (HR, 11.64; 95% CI, 0.43-318.81; log-rank P=0.03) [52].

Besides the aforementioned sub-analysis, all the evidence available on PFO closure among older patients with PFO-related thromboembolic events comes from observational studies.

Not surprisingly, all studies showed that older patients had a higher prevalence of traditional age-related cardiovascular risk factors [17,18,20,21]. Most importantly, most studies showed a higher prevalence of high-risk anatomical PFO features among older patients [17,18,21] compared to younger patients. Transcatheter PFO closure was safe in all studies, with a very low complication rate between groups, except for one study that reported a higher incidence of vascular complications in the elderly population [17].

Overall, the mean incidence of recurrent stroke events following PFO closure in older patients (excluding ancient studies with discontinued PFO closure devices) has been about 1.38 per 100 patients-years (from 0.55 to 2.67 per 100 patients-years) [17-21], which appears to be lower than 3.27 per 100 patient-years, which is the reported incidence of recurrent cerebrovascular events in studies of older patients with PFO treated medically [51].

One important confounder in studies involving older patients with ischemic cerebrovascular events is the role of AF (frequently silent episodes) as the primary source of thromboembolism and the risk of PFO closure procedure-related AF. As a consequence, the workup of any cryptogenic ischemic cerebrovascular event includes prolonged cardiac monitoring for the detection of episodes of symptomatic or silent AF [8]; however, the optimal duration of post-stroke cardiac monitoring remains unknown [61]. A recent meta-analysis [61] including 8 studies (5 randomized clinical trials) showed that prolonged post-stroke cardiac rhythm monitoring after an ischemic stroke or TIA could lead to higher rates of AF detection and anticoagulant initiation. Nevertheless, the authors concluded that there was no solid evidence from randomized trials supporting prolonged cardiac rhythm monitoring for the prevention of recurrent stroke events.

The next clinically challenging question is how often occult AF is causally related to cryptogenic ischemic stroke. Chaisinanunkul et al. [62] identified, in a systematic review, all case-control and cohort studies on patients with identical long-term monitoring techniques in patients with cryptogenic and know-source strokes. After performing a random-effects meta-analysis applying Bayes’ theorem to determine the probability of silent AF being causal or incidental, they concluded that in patients with cryptogenic stroke, when occult AF is found, it is causal in about 38.2% of patients. Remarkably, after age stratification, occult AF detected in patients with cryptogenic stroke was considered causal in 62.3% (95 CI, 0%-87.1%) of patients under the age of 65 years and only in 28.5% (95 CI, 0%-63.7%) of patients aged 65 years and older.

In a recent meta-analysis in the younger population undergoing PFO closure, the incidence of AF after PFO closure was 3.7 per 100 patient-years (95% CI: 2.6-4.9), which was higher than the incidence of 0.1 per 100 patient-years (95% CI: 0.0-0.4) observed in patients treated medically (HR: 5.3, 95% CI: 2.5-11.41), P<0.001) [60]. Interestingly, the increased risk of AF development occurred mainly in the first 45 days post-procedure, and according to a meta-regression analysis, a higher risk was observed in older patients (P=0.001).

Observational studies on PFO closure in the elderly population have reported a rate of de novo symptomatic AF ranging from 2% to 9.2% versus 0.7% to 8.4% among their younger counterparts [17-21]. While seven studies reported no impact of age in the incidence of AF after PFO closure, two studies showed a higher rate of post-procedural AF among older patients [21,63]. Overall, before PFO closure, only one study excluded patients with prior evidence of AF [17], while the others did not exclude or mention the rate of patients with a history of AF before the procedure. Several limitations on detection methods of AF before and after the procedure and the unknown rates of asymptomatic AF would preclude drawing definite conclusions from these studies in terms of AF before and after PFO closure in older patients with a PFO-related stroke.

A potential approach for PFO closure candidates older than 55-65 years with no history of AF could be an implantable loop recorder 6 months before the procedure and systematic midterm monitoring for arrhythmia detection and its corresponding treatment. Ongoing clinical trials addressing the recurrence of AF among older patients undergoing PFO closure will provide definitive insights on this important confounder among the elderly population with PFO and a cryptogenic stroke (Figure 1).