Patent Foramen Ovale Risk Research Articles

Abstract WP248: PFO Shunting is Associated With Increased Long-Term Risk of Dementia

Background: Right-to-left interatrial shunting through a patent foramen ovale (PFO) has been associated with white matter lesions in literature and in our data. Since white matter lesions, particularly those in the periventricular and subcortical regions, increase the risk of cognitive impairment, we investigate the relationship between PFO shunting and dementia. Method: 1078 consecutive PFO stroke patients were prospectively recruited in accordance with IRB protocol. No patient had diagnosis of dementia prior to initial stroke. PFO shunt size was evaluated by echocardiography with saline contrast. Cognitive status and recurrent events were followed for up to 11 years. Result: 27 patients (2.50%) developed vascular cognitive impairment and dementia over 11 years. As expected, dementia patients were older (p<0.001) and were more likely to have hypertension (p<0.001) and hyperlipidemia (p=0.001) (Table 1). Notably, the dementia patients were also more likely to have a large PFO shunt (22.2% vs 8.3%, p=0.023). The association of PFO shunt and dementia remained robust (Odds ratio: 3.07; 95% CI: 1.11~8.55; p=0.031) after adjusting for important traditional risk factors (age, hypertension, hyperlipidemia, diabetes). But PFO risk factors (hypermobile septum, atrial septal aneurysm) that enhance PFO shunting remain significant (Table 2). Conclusion: Our study provides support for the hypothesis that the presence of large PFO right-to-left shunting is associated with increased risk of later dementia. We previously reported that PFO shunting enables vasoactive factors to stay elevated in circulation and to contribute to cerebrovascular dysfunction. We hypothesize here that prolonged exposure to PFO shunting may lead to cognitive decline. Further studies assessing PFO shunt size, dementia severity, and other confounders in a non-stroke PFO cohort are ongoing to validate these findings.

Identification of High-Risk Patent Foramen Ovale Associated With Cryptogenic Stroke: Development of a Scoring System

Transcatheter closure of patent foramen ovale (PFO) has become an effective therapeutic strategy for cryptogenic stroke (CS). The identification of high-risk PFO is essential, but the data are limited. This study aimed to clarify the factors related to CS and to develop a score for high-risk PFO. We retrospectively analyzed 57 patients with prior CS and 50 without CS who were scheduled for transcatheter closure. PFO characteristics were evaluated by transesophageal echocardiography. Based on factors related to CS, we estimated the risk score. Patients with CS had a greater frequency of large-size PFO (≥2mm in height), long-tunnel PFO (≥10mm in length), atrial septal aneurysm, hypermobile interatrial septum, prominent Eustachian valve or Chiari's network, the large right-to-left shunt at rest and during Valsalva maneuver, and low-angle PFO (≤10° of PFO angle from inferior vena cava), compared with patients without CS. Multivariate analysis showed that long-tunnel PFO, the presence of hypermobile interatrial septum, the presence of prominent Eustachian valve or Chiari's network, the large right-to-left shunt during Valsalva maneuver, and low-angle PFO were independently related to CS. When the score was estimated based on 1 point for each factor, the proportion of CS was markedly elevated with a score of ≥2 points. The probability of CS was markedly different between scores of ≤1 or ≥2 points. PFO risk can be assessed with a score based on high-risk features. The presence of two or more high-risk PFO features is associated with CS.

Abstract WP260: Evaluation of Transcranial Doppler as a Screening Tool for High Embolic Risk Patent Foramen Ovale in Cryptogenic Stroke

Background: Identifying high embolic risk patent foramen ovale (PFO) from the innocent bystanders has become important in the evaluation of patients with cryptogenic stroke (CS) since the recent clinical trials showed the benefits of the closure of PFO on the prevention of recurrent stroke. Transesophageal echocardiography (TEE) is a gold standard to diagnose and evaluate the risk of PFO, but the tolerability and cooperation of handicapped stroke patients limit clinical applications. In this study, we aimed to evaluate the predictability of transcranial Doppler (TCD), a test deemed more feasible to stroke patients than TEE, in diagnosing high-risk PFO on TEE. Methods: We reviewed the data of 485 patients with CS who underwent TEE and TCD to evaluate PFO. To classify the shunts, we applied a 5-level visual classification for TCD either at rest or during Valsalva maneuver (VM): no occurrence of micro-embolic signals; grade I, 1-10 signals; grade II, 11-30 signals; grade III, 31-100; grade IV, 101-300; grade V, >300. High-risk PFO on TEE is defined as PFO with atrial septal aneurysm, hypermobility (phasic septal excursion into either atrium ≥10 mm), or PFO size (maximum separation of the septum primum from the secundum) ≥2 mm. Receiver operating characteristic (ROC) curve was used to determine the threshold value of TCD shunt grade for high-risk PFO which was demonstrated by TEE. Results: Concordant results between TCD and TEE appeared at 344 patients; present of shunt in 235 patients, and no-shunts in 109 patients. Patients with high risk PFO on TEE were detected in 133 among the 238 patients that were PFO positive on TEE. The proportion of high-risk PFO dramatically increased in accordance to the increase in TCD grade with VM. The best cut-off point of TCD grade with VM for detecting high risk shunt was grade III with an area under the curve (AUC) of 0.79, sensitivity of 73.1%, and specificity of 75.6% TCD with VM missed only 2 patients as having PFO among the 133 patients with high-risk PFO on TEE. Conclusions: This study showed that the findings of TCD on the diagnosis and evaluation of the risk of PFO were well correlated with those of TEE. Negative of shunt on TCD can exclude the possibility of high risk PFO; grade III or more on TCD suggests the presence of high risk PFO in patients with CS.

Cardioembolic stroke

Cardiac sources of emboli account for over one quarter of all ischemic strokes. Strokes due to cardioembolism are in general severe and prone to early and long-term recurrence. Nonvalvular atrial fibrillation remains the most common cause of cardioembolic stroke. Despite the proven efficacy of oral anticoagulation, it is prescribed for less than half of the patients with risk factors for embolism and no contraindications for anticoagulation. The embolic risk of patent foramen ovale is low except when combined with an atrial septal aneurysm. Aortic arch atheroma as an independent risk factor for ischemic stroke is the subject of ongoing debate. As the risk of embolism is heterogeneous for the various potential cardioembolic conditions, accurate definition of stroke mechanism is very important to guide the most effective therapy.

Quantitative Trait Loci Modifying Cardiac Atrial Septal Morphology and Risk of Patent Foramen Ovale in the Mouse

Atrial septal defect (ASD) is a common congenital heart disease (CHD) occurring in 5 to 7 per 10,000 live births. Mutations in 5 human genes (NKX2.5, TBX5, GATA4, MYHC, ACTC) are known to cause dominant ASD, but these account for a minority of cases. Human and mouse data suggest that ASD exists in an anatomical continuum with milder septal variants patent foramen ovale (PFO) and atrial septal aneurysm, strongly associated with ischemic stroke and migraine. We have previously shown in inbred mice that the incidence of PFO strongly correlates with length of the interatrial septum primum, defining a quantitative trait underlying PFO risk. To better understand genetic causation of atrial septal abnormalities, we mapped quantitative trait loci (QTL) influencing septal morphology using mouse strains (QSi5 and 129T2/SvEms) maximally informative for PFO incidence and 3 quantitative septal anatomical traits including septum primum length. [QSi5x129T2/SvEms]F2 intercross animals (n=1437) were phenotyped and a whole genome scan performed at an average 17-cM interval. Statistical methodology scoring PFO as a binary phenotype was developed as a confirmatory mapping technique. We mapped 7 significant and 6 suggestive QTL modifying quantitative phenotypes, with 4 supported by binary analysis. Quantitative traits, although strongly associated with PFO (P<0.001), correlated poorly with each other and in all but 1 case QTL for different traits were nonoverlapping. Thus, multiple anatomical processes under separate genetic control contribute to risk of PFO. Our findings demonstrate the feasibility of modeling the genetic basis of common CHD using animal genetic and genomic technologies.

Brain embolism - Answers to practical questions.

Embolism of cardiac origin accounts for about 1/4 of ischemic strokes. Strokes due to cardioembolism are in general severe and prone to early and long-term recurrence. Cardioembolism can be reliably suspected in clinical grounds but is often difficult to document. Magnetic resonance imaging, transcranial Doppler, echocardiogram, Holter and electrophysiological studies can help to demonstrate the source of cardioembolism. Aortic arch atheroma is an emerging embolic source, but non-valvular atrial fibrillation remains the commonest cause of cardioembolic stroke. Despite its preventive potential, continuous oral anticoagulation is prescribed for less than half of the patients with atrial fibrillation with risk factors for embolism and no contraindications for anticoagulation. The embolic risk of patent foramen ovale is low except when combined with an atrial septal aneurysm. Available evidence does not support routine immediate anticoagulation of acute cardioembolic stroke.

Risk of patent foramen ovale for thromboembolic events in all age groups

The association between a patent foramen ovale (PFO) and thromboembolic events in young patients has been reported. Autopsy data suggest that a PFO may be present in 20 to 35% of the population. To further assess the role of a PFO in patients with possible thromboembolic events, precordial and transesophageal contrast echocardiography was performed in 104 consecutive patients (age range 16 to 84 years) presenting with a stroke, transient ischemic attack or peripheral artery embolus (group I). These patients were compared with 94 consecutive patients (age range 23 to 82 years) undergoing transesophageal echocardiography for other reasons (group II). A PFO was found in 22 patients; 9 of 35 (26%) with an event but no risk factor (group Ia), 10 of 69 (14%) with an event but a recognized risk factor (group Ib), and 3 of 94 control patients (3.2%) (group II) (group Ia vs II: relative odds 10:1, p < 0.001; group Ib vs II: relative odds 5:1, p < 0.01; and group Ia vs Ib: p = not significant). The detection of a PFO was not related to age. The relatively low prevalence of a PFO in this study may reflect patient selection, but other explanations include: (1) Transesophageal contrast echocardiography may be relatively insensitive for its detection; (2) the prevalence in the general population may have been overestimated; and (3) most PFOs are very small, clinically insignificant and undetectable with this technique. Our data suggest an association between a PFO and thromboembolic event regardless of age, but many patients with a PFO have other risk factors for such events, and this anatomic variant is probably implicated in only a minority.