Ischemic Stroke and Pulmonary Arteriovenous Malformations: A Review

Abstract

The potential of covert pulmonary arteriovenous malformations (PAVMs) to cause early onset, preventable ischemic strokes is not well known to neurologists. This is evident by their lack of mention in serial American Heart Association/American Stroke Association (AHA/ASA) Guidelines and the single case report biased literature of recent years. We performed PubMed and Cochrane database searches for major studies on ischemic stroke and PAVMs published from January 1, 1974, through April 3, 2021. This identified 24 major observational studies, 3 societal guidelines, 1 nationwide analysis, 3 systematic reviews, 21 other review/opinion articles, and 18 recent (2017-2021) case reports/series that were synthesized. Key points are that patients with PAVMs have ischemic stroke a decade earlier than routine stroke, losing 9 extra healthy life-years per patient in the recent US nationwide analysis (2005-2014). Large-scale thoracic CT screens of the general population in Japan estimate PAVM prevalence to be 38/100,000 (95% confidence interval 18-76), with ischemic stroke rates exceeding 10% across PAVM series dating back to the 1950s, with most PAVMs remaining undiagnosed until the time of clinical stroke. Notably, the rate of PAVM diagnoses doubled in US ischemic stroke hospitalizations between 2005 and 2014. The burden of silent cerebral infarction approximates to twice that of clinical stroke. More than 80% of patients have underlying hereditary hemorrhagic telangiectasia. The predominant stroke mechanism is paradoxical embolization of platelet-rich emboli, with iron deficiency emerging as a modifiable risk factor. PAVM-related ischemic strokes may be cortical or subcortical, but very rarely cause proximal large vessel occlusions. Single antiplatelet therapy may be effective for secondary stroke prophylaxis, with dual antiplatelet or anticoagulation therapy requiring nuanced risk-benefit analysis given their risk of aggravating iron deficiency. This review summarizes the ischemic stroke burden from PAVMs, the implicative pathophysiology, and relevant diagnostic and treatment overviews to facilitate future incorporation into AHA/ASA guidelines.

Figure 1. Pulmonary Arteriovenous Malformations and Right to Left Shunts

(A) Thoracic CT scan of a pulmonary arteriovenous malformation (PAVM) in a patient admitted with acute ischemic stroke. (B) Diagnosis and quantification of pathologic right-to-left shunt (RLS) on right lateral head projections following injection of ^99mTc-labeled albumin macroaggregates in a patient pre and post PAVM embolization, resulting in a visible reduction of shunt size and corresponding improvement in oxygen saturation (SaO₂) levels.^, Note the intense activity in the lung apices is as expected, but that in the postembolization image, although the gain has been turned up, trivial cerebral activity is still visible. (C) PubMed-indexed English language literature (1 January 2017–April 3, 2021) on “pulmonary arteriovenous malformation” and “stroke” depicting a publication bias favoring case reports, especially those describing rare associations; for example, Fontan circulation and hepatopulmonary syndrome (HPS), rather than hereditary hemorrhagic telangiectasia (HHT), which is responsible for PAVMs in >70% of cases.

Figure 2. Prevalence and Risk Markers of Pulmonary Arteriovenous Malformation in Patients Hospitalized With Ischemic Stroke

(A) 2021 nationwide analysis of pulmonary arteriovenous malformations (PAVMs) across a non-selected US population of 4,271,910 patients hospitalized with acute ischemic stroke (2005–2014), observing a significant increase in the prevalence of PAVMs in a combined cohort of patients with and without a concomitant ICD-9-CM diagnosis of hereditary hemorrhagic telangiectasia (HHT). (B) Clinical variables found to be independently associated with ischemic stroke on multivariable logistic regression analysis included hypoxemia as the strongest independent stroke risk marker (odds ratio [OR] 8.4, 95% confidence interval [CI] 6.3–11.2); iron deficiency anemia (OR 2.03, 95% CI 1.5–2.7) and epistaxis (OR 3.7, 95% CI 2.0–6.7), a common cause of iron deficiency anemia in patients with HHT, were the major modifiable risk markers. *Patients with PAVMs were 2.3-fold more likely to be on long-term anticoagulation even after adjusting for age, atrial fibrillation, primary hypercoagulable states, venous thrombosis, and pulmonary embolism.

Figure 3. Schematic Model of the Implicative Pathophysiology of Pulmonary Arteriovenous Malformation–Related Ischemic Stroke

Iron deficiency, which in patients with hereditary hemorrhagic telangiectasia (HHT) is most likely to be a result of underreplacement of hemorrhagic losses, has been shown to mediate a complex serotonergic proaggregatory platelet response facilitated by a dysfunctional platelet monoamine oxidase. Patients with ischemic stroke with pulmonary arteriovenous malformations (PAVMs) have also been found to have elevated plasma fibrinogen levels, a protein that normally serves to crosslink the glycoprotein (Gp) IIb-IIIa platelet receptors (inset), further accentuating the role of platelet aggregation. While iron deficiency has also been associated with elevated serum factor VIII levels and venous thromboembolism (VTE), clinical and epidemiologic studies have not found conventional VTE to be commonly associated with PAVM-related ischemic stroke. Recurrent endothelial injury (e.g., from dysplastic vasculature) or other molecular mechanisms of hypercoagulability implicated in different right-to-left shunts (e.g., elevated homocysteine levels in patent foramen ovale) may further constitute additional thromboembolic or clot-independent mechanisms of cerebrovascular injury. APPT = activated partial thromboplastin time; FAD = feeding artery diameter; FVII = factor VIII; Hb = hemoglobin; RBC = red blood cell.

Figure 4. Diagnostic and Management Algorithm for Embolic Stroke Related to Pulmonary Arteriovenous Malformations

Proposed diagnostic algorithm incorporating thoracic CT scans in the workup of embolic stroke of undetermined source (ESUS). ^aTransesophageal echocardiography (TEE) is considered when the transthoracic echocardiography (TTE) is technically limited or patient age is ≤60 years and there is high suspicion for atrial cardiopathy or aortic pathology. ^bPermanent or paroxysmal atrial fibrillation, sustained atrial flutter, intracardiac thrombus, prosthetic cardiac valve, atrial myxoma or other cardiac tumors, mitral valvulopathy, recent (<4 weeks) myocardial infarction, left ventricular ejection fraction less than 30%, or infective/other endocarditis. ^cCT chest may be performed as a part of a screening CT chest/abdomen/pelvis on a case-by-case basis, which may help identify a potentially occult solid organ malignancy. ^dPAVMs do not grow by any measurable extent in adult life (exceptions may include postpregnancy), and thus there is little value is repeating PAVM screening, even if the patient presents with subsequent ischemic stroke. ^eIf the risk-benefit analysis after considering surgical risk stratification, baseline functional status, concomitant vascular risk factor profile, and age (>60 years with a life expectancy <5 years considered a relative contraindication) is favorable, then endovascular embolization is performed. Rarely is surgical resection indicated when PAVMs are too diffuse to realistically achieve endovascular cure. ^fThe majority of treated patients will have residual right-to-left shunt (RLS), as demonstrated in Figure 1B. ^gLeft heart contrast opacification from an intrapulmonary RLS occurs within seconds, is not affected by cardiac cycles or respirations, and becomes certain if the bubble density is greater within left-heart than right (requires >30 seconds of recording). HHT = hereditary hemorrhagic telangiectasia; PFO = patent foramen ovale.