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Simultaneous cardiac and cerebral infarcts in a patient with hip fracture and previously unknown patent foramen ovale: management between Scylla and Charybdis

Alexander Fisher 1,2, Emily Walsh 1*

1Department of Geriatric Medicine. The Canberra Hospital, Canberra, Australian Capital Territory, Australia.
2Australian National University Medical School, Canberra, Australian Capital Territory, Australia

*Corresponding author

*Dr Emily Walsh, Department of Geriatric Medicine, The Canberra Hospital, Yamba Drive, Garran ACT, m 2605, Australia.

Abstract

We report a rare case of an 84-year-old man with left femoral neck fracture who presented with three interrelated life-threatening pathologies–systemic hypoxaemia, simultaneous cardiac and watershed brain infarctions due to previously unknown patent foramen ovale (PFO) and septal defects with a right-to-left shunt. Computed tomography scans, magnetic resonance imaging and echocardiography (with bubble study) confirmed the diagnosis.

The report describes diagnostic and treatment challenges, which required a multidisciplinary approach, provides possible explanations for these conditions, and discusses the therapeutic management (appropriateness of thrombolysis, use of antithrombotic, antiplatelet and antifibrinolytic drugs). The patient did not receive thrombolysis, was treated with heparin, aspirin, and tranexamic acid (during hip fracture surgery). Previous literature reports on simultaneous cardiac and brain infarctions and/or PFO are reviewed. We emphasise the necessity of close monitoring and intensive workup for all perioperative symptoms and signs, to maintain a high index of suspicion for PFO and multimodality evaluation to reduce misdiagnosis, timely identify paradoxical embolic events and the possible underlying cause(s).

Keywords: Patent foramen ovale; Simultaneous cardiac and cerebral infarcts; Hip fracture.

Introduction

Cardiovascular and cerebrovascular diseases, the leading causes of morbidity and mortality worldwide, are frequently interconnected due to common risk factors and underlying pathology involving atherosclerosis and thromboembolism. Although patients with acute myocardial infarction (AMI) have a subsequent risk of acute ischaemic cerebrovascular stroke and vice versa, occurrence of simultaneous AMI and acute cerebral stroke is a rare clinical entity. These concomitant life-threatening conditions require extensive preoperative diagnostic investigation, appropriate management, and timely intervention. Such combination of pathologies has never been reported in patients undergoing orthopaedic surgery, including hip fracture (HF) repair. Here we present a unique case of concurrent AMI, paradoxical embolic multiple cerebral infarcts due to interatrial right-to-left shunt in the setting of previously unknown patent foramen ovale (PFO) and atrial septal defect/aneurism in a patient with HF. We discuss the diagnostic difficulties and highlight therapeutic challenges that occurred in the course of the disease.

Case Presentation

An 84-year-old right-handed man presented to the emergency department with a left impacted subcapital femoral neck fracture (Figure 1) and head strike after an unwitnessed mechanical fall. His past medical history was notable for transient ischemic attack (TIA, right arm weakness spontaneously resolved in less than two hours) 5 years ago (since then he was using aspirin 100 mg daily, ezetimibe 10 mg daily, and esomeprazole 20 mg daily), follicular non-Hodgkin lymphoma (2010, relapse in 2014, treated with six cycles of rituximab, cyclophosphamide, oncovin and prednisolone [R-COP], maintenance rituximab for two years, complete remission since), hypothyroidism (on thyroxine, 50 mcg daily), invasive nodular basal cell carcinomas (right cheek, 2012, and left nasal tip, 2013, complete excisions of both), benign paroxysmal positional vertigo (BPPV, since 2012 using betahistine 16 mg up to three times a day) and benign prostatic hyperplasia (on tamsulosin 400 mcg daily). No history of smoking, alcohol overuse, drug addiction as well as no family history of thrombophilia or thromboembolism. He and his wife lived in a permanent residential care facility; they had two sons and a daughter.

Figure 1. CT scan (a) and Xray (b) showing left basicervical neck of femur fracture.

On arrival to his home, the ambulance paramedic team noted that the patient was conscious, alert, well perfused with Glasgow Coma Scale (GCS) of 15, but had blue tinged lips, respiratory rate of 30/minute and required 5 L/min of supplemental oxygen (via nasal prong) to keep oxygen saturation (O2 sat) ≥92%. On the patient’s arrival at the hospital, although he denied any shortness of breath or chest pain, marked hypoxaemia was documented (pO2 of 51 mmHg on FiO2 of 44%, pH 7.45, PaCO2 36 mmHg, and O2 sat 84%); he was put on oxygen via high flow nasal prongs (HFNP) FiO2 30% at 30 L/min to maintain saturation ≥ 92% (pO2 increased to only 69 mmHg). On examination, he was calm, showing no signs of respiratory distress. The blood pressure (BP) was 145/95 mmHg, heart rate 95 beats per minute (bpm), respiratory rate 16/minute, temperature 36.9oC, GCS 15 (E4V5M6), body mass index (BMI) 27.3 kg/m2. Pulmonary auscultation revealed crepitations bilaterally up to the middle zones, and the jugular venous pressure (JVP) was elevated (9 cm). Otherwise, his cardiovascular and abdominal examination was unremarkable. Neurological examination did not reveal focal motor or sensory deficit, facial droop, signs of meningeal irritation, tremor of extremities; the flexor plantar responses and deep tendon reflexes were normal. No skin rashes, petechia and no significant lymphadenopathy was noted. On admission, a twelve-lead electrocardiogram (ECG) showed sinus tachycardia (100 bpm) without specific ST-T segment changes but with Q waves in leads III and aVF (Figure 2a). Computed tomography (CT) of the brain without contrast was performed within 90 minutes of arrival, it demonstrated chronic white matter ischaemic changes (microangiopathy), mild focal gliosis in the inferior aspect of the right frontal lobe (consistent with old infarct), global cortical atrophy with corresponding sulcul widening and no features of acute intracranial pathology (Figure 3a). The chest X-ray showed pulmonary venous congestion (Figure 4). The clinical and radiological signs of acute pulmonary oedema (due to possible fluid overload) were interpreted as the main explanation of hypoxia and requirement of high oxygen supplementation (periodically up to HFNF FiO2 40% at 40L/minute). Blood tests results including full blood count (haemoglobin 155 g/L, red blood cells 4.84 x1012/L, haematocrit 0.46), liver enzyme levels, urea, creatinine, electrolytes, thyroid function, parathyroid hormone, vitamin D, vitamin B12, folic acid, indices of iron metabolism were all within reference ranges; urinalysis and urine culture ruled out urinary tract infection and coronavirus nucleic acid testing (PCR) was negative. However, four immuno-inflammatory markers were abnormal: the neutrophil lymphocyte ratio (NLR) was 21.8 (normal value <3), lymphocyte monocyte ratio (LMR) was 0.93 (normal value >1.1), the systemic immune inflammation index (SII = platelet × NLR) was 3248.2 (normal value <1000.0) and CRP was 96.9 mg/L (normal value <6 mg/L) indicating presence of an inflammatory process.

Figure 2. ECGs: (a) on admission (sinus tachycardia at a rate of 100 bpm, old Q waves in leads III and aVF, and poor R wave progression); and (b) on the next day when cardiac troponin I level was 1093 ng/L (NSTEMI).

Figure 3. CT brain: (a) on admission (did not show any acute ischemia or haemorrhage); (b) CT angiogram and perfusion (did not show acute ischemia, haemorrhage, or vessel occlusion); and (c) on day eight of admission (did not show any acute ischemia or haemorrhage).

Figure 4. Anteroposterior chest X-ray on admission showing pulmonary venous congestion.

On the second admission day (25 hours post arrival to the hospital) he reported inability to move his arms. His physical examination was positive for bilateral proximal arm weakness, worse on the left (grade 1-2/5); he was sleepy, confused, at times not fully oriented to place, and uncooperative, GCS was 13 (E3V4M6) and his BP was 200/105 mmHg. Although he denied chest pain, the high sensitivity cardiac troponin I (hs-cTrI) level was 1093 ng/L (normal value <26 ng/L) and 852 ng/L 4 hours later consistent with a non-ST elevation myocardial infarction (NSTEMI) (Figure 2b). He maintained an O2 sat of 85-89%, despite high-flow oxygen nasal cannula. The second CT of the brain and cervical spine did not show any acute intracranial ischemic or haemorrhagic changes, cervical spine abnormality or mass lesion (Figure 3b). The cardiology, neurology and stroke teams were consulted. Following cardiologist’s advice, he was treated with frusemide (20 mg iv, then 40 mg daily), glyceryl trinitrate patch (5 mg/hour, removed when systolic BP ≤160 mmHg), heparin infusion (for 48 hours), aspirin (300 mg stat, followed by aspirin 100 mg daily); coronary angiogram was not performed due to patient’s comorbid status, and clopidogrel was not commenced as he required urgent surgery for the HF.

On the third admission day, the left sided arm weakness persisted, GCS dropped to 8 (E1V2M5), the National Institutes of Health Stroke Scale (NIHSS) score was 23, temperature 38°C, the C-reactive protein (CRP) level raised to 103.1 mg/L, neutrophil count to 10.2 x109/L (normal range: 1.8-7.5 x109/L) without leucocytosis 11.6 x109/L (normal range: 4.0-11.0 x109/L), and the NLR was 17.9, LMR was 0.78 and SII was 9554. The CT pulmonary angiogram showed no acute pulmonary embolism (PE), consolidation or pneumothorax, no aortic dissection, but dependent ground-glass opacities and intra-lobular septal thickening within both lungs, most predominantly within the right lung (Figure 5). Further septic workup revealed Streptococcus agalactiae (Group B) in the urine (the patient had an indwelling urinary catheter since admission). The hypoactive delirium and fluctuating GCS were thought to be secondary to evolving infection and NSTEMI. The patient was commenced on ceftriaxone (1 g iv daily) and azithromycin (500 mg daily) to treat the urinary tract infection and possible aspiration-related lung injury.

Figure 5. CT pulmonary angiogram (no acute pulmonary embolism, dependent ground glass opacities and intralobular septal thickening, most marked within right lung base, in keeping with pulmonary oedema).

On the fourth admission day, the patient had an episode of left facial droop, intermittent left arm twitch and GCS of 8 (E4V3M1) which improved spontaneously within 20 minutes to 14 (E4V4M6); a subtle left facial droop remained and focal myoclonic activity on the left side of the face were noted. A repeated CT scan (fourth) of the brain did show no acute cerebral ischemia or intracranial haemorrhage. Contrast enhanced CT angiogram from aortic arch to circle of Willis revealed no large vessel occlusion involving the circle of Willis with good contrast opacification of the carotid and vertebral arteries bilaterally; there were calcified atheromas at both carotid bulbs and proximal internal carotid arteries associated with 30% stenosis on the right and 35% stenosis on the left. However, on the next day (5th day of admission) his brain magnetic resonance imaging (MRI) disclosed widespread infarcts in multiple vascular territories (Figure 6)—frontal lobes, including the centrum semiovale, parietal and occipital lobes, involving the grey matter and grey-white matter junction, and similar foci in the right cerebellar hemisphere; a small focus of microhaemorrhage was present in grey matter of the right parietal zone; there were also periventricular T2/FLAIR hyperintensities indicating chronic small vessel ischaemic changes.

Figure 6. Axial diffusion-weighted magnetic resonance imaging showing acute multi-territorial infarcts (in an internal boarder zone distribution) involving the frontal, parietal, occipital lobes, and the right cerebellum (a), with corresponding apparent diffusion coefficient hypointensity in frontal lobe subcortical white matter (b).

Extensive watershed infarcts, which were not visible on previous CT scans, and the patient’s persisted hypoxaemia (disproportionate to the APO, atelectasis, AMI, and infection) in the absence of a pulmonary embolism, prompted further investigation; an anatomic shunt was considered. Cardiac and lower extremities ultrasound and Holter monitoring were performed. No signs of deep vein thrombosis of the lower extremities were detected. Holter monitoring that recorded about 25 hours showed dominant sinus rhythm, infrequent isolated supraventricular ectopic beats with 7 couplets and 9 non-sustained supraventricular tachycardia events (longest 14 beats at 129 bpm and fastest 4 beats at 145 bpm) and infrequent isolated ventricular ectopic beats with 2 triplets and 1 non-sustained wide complex tachycardia lasting 29 beats at 182 bpm; there was no evidence of atrial fibrillation (AF), flutter or symptomatic arrhythmia. Transthoracic echocardiography discovered a dilated left atrium, normal right atrial size, aneurysmal and mobile inter-atrial septum with evidence of right-to-left shunt across the interatrial septum (on colour Doppler) consistent with PFO and atrial septal defect; left and right ventricular cavity sizes and systolic function were normal, ejection fraction (EF) 59%, and no obvious regional wall motion abnormalities; there was a mildly dilated aortic root (42 mm), moderately dilated proximal ascending aorta (46 mm), mild aortic, tricuspid and pulmonary regurgitation; no thrombi or other sources of emboli were detected (Figure 7a). The echocardiography examination with saline contrast bubble infusion showed an aneurysmal and mobile interatrial septum and confirmed the PFO with a large right-to-left shunt (Figure 7b).

Figure 7. Transthoracic echocardiograms, (a) with colour duplex showing the PFO; and (b) showing a positive “bubble” study confirming a right-to-left shunt across a PFO, agitated saline is injected intravenously and bubbled are seen opacifying the right atrium.

The patient underwent left hip hemiarthroplasty on the fifth admission day (6 hours after he completed 48 hours of heparin infusion) under general anaesthesia. A left suprainguinal fascia iliaca block (prior to induction) was followed by intravenous propofol (2 mg/kg), fentanyl (200 mcg) and rocuronium (0.8 mg/kg); tranexamic acid (1g iv) was given for surgical haemostasis. Throughout the procedure general anaesthesia was maintained with sevoflurane (1.8% to 2.2%) in O2. Intraoperatively his BP readings ranged between 90/50 mmHg and 170/90 mmHg; to maintain mean arterial pressure (MAP) of ≥ 80mmHg metaraminol was administered. At the end of the procedure, tranexamic acid (6 g) and vancomycin (2g) were flushed into the surgical wound. The patient was extubated and returned to the ward; he tolerated oxygen supplementation using nasal cannula. Postoperative haemoglobin and haematocrit were 125 g/L and 0.37, respectively (dropped from preoperative 151 g/L and 0.40, respectively). Preoperatively hs-cTrI was 140 ng/L, it dropped to 81 ng/L two days later.

Thrombolytic therapy for myocardial infarction was considered to be of high risk for developing haemorrhage (both intracranial and from the surgical wound). Following the advice by the neurologist and cardiologist, prophylactic anticoagulation with low molecular weight heparin (LMWH, enoxaparin 40 mg subcutaneously) was started while aspirin, low density lipoprotein cholesterol lowering therapy with ezetimibe, esomeprazole and antibiotics were continued. Plans were made for percutaneous closure of the PFO a week later.

On the second postoperative day he developed a drop of GCS to 3 (E1V1M1) for about 30 minutes, was unresponsive but no tonic or clonic features were observed; the GCS subsequently improved to 13 (E4M5V4). The fifth CT brain scan did not show any acute ischemic or haemorrhagic changes (Figure 3c). With ongoing neurological presentation due to cerebral infarcts an absence seizure was suspected, the patient was commenced on levetiracetam (1 g twice daily). Over the next two weeks the patient remained stable, and an overall improvement was observed, consciousness restored, he had better verbal responses, but maintained the left-sided upper and lower extremity weakness with inability to resist gravity (3/5) and moderate-severe unsteadiness. On the fifth postoperative day, the levels of hs-cTrI and inflammatory markers were in the normal range. Unfortunately, on the third postoperative week his dysarthria and dysphasia increased, he developed dysphagia (mild-moderate) and aspiration-related lung injury associated with elevated inflammatory markers (CRP raised from 38.2 mg/L on the sixth postoperative day to 201.0 mg/L on the 21st day); he required feeding via a nasogastric tube.

A week later he was diagnosed with hospital acquired COVID-19 infection (treated with remdesivir and prednisolone) and two days later developed upper gastrointestinal bleeding, anaemia (haemoglobin 102g/L, haematocrit 0.31) and severe hypotension (70/45 mmHg) requiring ICU admission. Despite aggressive medical management including red blood cell transfusion, proton pump inhibitor pantoprazole (40 mg iv every 8 hours), discontinuation of all anti-thrombotic and antiplatelet agents he continued to decline; the status was discussed with the family, which decided on comfort care, and he died the next day.

The discharge diagnosis was simultaneous acute myocardial infarction and acute cerebral infarctions due to PFO and atrial septal defect in a patient with left hip fracture and perioperative urinary tract infection, postoperatively complicated with aspiration-related lung injury, COVID-19 infection, and fatal upper gastrointestinal bleeding.

Discussion

In this report, we described a patient with a HF who presented (preoperatively) with severe hypoxaemia, simultaneous AMI (clinically asymptomatic) and multiple cerebral embolic infarcts (not visible on numerous CT brain scans)–three interrelated life-threatening conditions linked to previously undiagnosed PFO and atrial septal defect. At arrival, the patient posed diagnostic challenges–cause(s) of hypoxaemia, very high hs-cTrI levels, neurological signs indicative a stroke, right-to-left shunting (due to PFO) and its pathophysiological impact/relevance. The management difficulties included minimizing the delay of HF repair and balancing anti-thrombotic therapy for both heart and brain infarcts (appropriateness of administration of thrombolytics, anticoagulants and/or antiplatelet drugs) with the risk of bleeding (haemorrhagic transformation of intracerebral infarcts and from the surgical wound).

Because of the unusual clinical presentation at arrival—no chest pain/discomfort, no signs of haemodynamic instability /decompensation or acute ECG changes and unremarkable CT brain scan (no intracranial and extracranial abnormalities)—the establishment of a correct diagnosis (recognition of AMI, watershed infarctions and PFO with a right-to-left shunt) was delayed. Initially the main cause of hypoxeamia was not detected; the first assumption was fluid overload causing acute pulmonary oedema. On the second admission day, however, extremely high hs-cTrI uncovered the AMI concomitant with neurological deficit suggestive of acute stroke (which was not confirmed by repeated CT scans). Given persistent clinical abnormalities, the patient underwent MRI and was found to have severe brain damage (multiple watershed infarctions). Subsequently, a reasonable explanation of the clinical features/syndromes was provided by transthoracic echocardiogram showing a PFO, septal defect (aneurysmal and mobile interatrial septum) with a large right-to-left shunt. Due to the delayed diagnosis (outside time window), risks of haemorrhagic transformation of cerebral infarcts and bleeding from the surgical wound, the patient did not receive acute reperfusion therapy (intravenous thrombolysis). The uniqueness of this case emphasises the importance of a through preoperative evaluation, especially when clinical signs persist and/or could not be fully explained by laboratory findings. In a surgical patient, a comprehensive diagnostic work-up approach is justifiable and should be arranged even it may delay an urgent (not emergent) operation. Indeed, in patients undergoing non-cardiac surgery, including HF repair, perioperative troponin rise is often observed (approximately in 40%) and usually asymptomatic (appears as a clinically silent event in about 90% of patients) indicating that assessment based only on the patient’s complaint is insufficient and in the vast majority would be missed in the absence of systematic screening [1-6]. Among HF patients before surgery, about 2% have significantly elevated hs-cTrI levels with a NSTEMI in three out of four such subjects [7]. The decrease of myocardial oxygen supply is considered the main pathophysiological mechanism of perioperative myocardial injury [6]. In our patient, hypoxaemia could not be explained by toxicity (i.e., carboxyhaemoglobinaemia, methaemoglobinaemia), he did not have a prior history of coronary artery disease, hypertension, AF, heart valve disease, heart failure, diabetes, obesity, or lifestyle risk factors (smoking, alcohol overuse, limited mobility), he was receiving antiplatelet and cholesterol lowering treatment (after TIA), and no intracardiac thrombus and/or left ventricular systolic dysfunction was found on transthoracic echocardiography. Apart from age and history of TIA he had no additional risk factors for AMI or ischaemic stroke; the inflammatory state (urinary tract infection with significantly elevated immuneinflammatory markers) possibly affected the homeostatic mechanisms responsible for the coagulation balance, causing hypercoagulability and increasing the risk of thrombosis formation.

Although cardiac catheterization was not performed (initially postponed given the risk of haemorrhagic complications with high doses of anticoagulation and dual antiplatelet therapy) and therefore the coronary artery status was not documented, it appears that the AMI in our patient was caused predominantly by the persistent hypoxaemia due to right-to-left shunt (PFO), fracture-related stress, increases of inflammatory cytokines and reactive oxygen species (ROS) imbalance. Extensive evaluation at the time of arrival did not reveal other potential mechanisms for acute myocardial injury. Possible causes of hypoxia other than right-to-left shunting in this patient have been ruled out: no history of parenchymal lung or pleural diseases, severe asthma, obstructive sleep apnoea (OSA), hepatopulmonary syndrome, kyphoscoliosis, severe anaemia, haemoglobinopathy, muscular weakness, impaired breathing regulation by dysfunction of central nervous system, opioid use; no pulmonary artery thromboses were detected.

Hypoxaemia driven by intracardiac right-to-left shunt is an uncommon and underdiagnosed phenomenon. The intracardiac shunt may be transient depending on the interatrial pressure gradient and direction of blood flow. Anatomical (size of PFO, atrial septal defect characteristics, persistent Eustachian valve, Chiari's network), different medical (i.e., pulmonary thromboembolism, right ventricular myocardial infarction, cardiac tamponade, pneumothorax, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), OSA, obesity hypoventilation syndrome, thoracic spine kyphoscoliosis, hemidiaphragmatic paralysis, post pneumonectomy), specific perioperative [8,9] and/or functional (transient or chronic) conditions (e.g., coughing, Valsalva manoeuvre, squatting, defecation) that raise right atrial pressure and reverse the physiological pressure gradient between the left and right atrium (normally in the adult, the left atrium pressure is slightly–about 5-8 mmHg–higher than the right atrium pressure) promote deoxygenated venous blood across the PFO with resultant significant venous admixture, hypoxaemia and/or paradoxical embolism into the systemic circulation [10-18]. Profound hypoxemia has also been observed in the presence of normal right-sided pressures [15,18,19] without pulmonary hypertension [13,20-22], without right-to-left gradient after pneumonectomy [23], thoracotomy [24], in the setting of stroke [25], kyphoscoliosis [20], pleural effusion [26], diaphragm paralysis, elevation of the right hemidiaphragm [27], dilation/aneurysm of the ascending aorta [12,20] and OSA [15,21,28]. In our patient, the PFO-related hypoxaemia was possibly accentuated and worsened by tricuspid regurgitation and interstitial APO. Preoperative haemodynamic stability despite persistent hypoxaemia (as in our case) was also observed and reported previously [29]; the flow of blood from right-to-left atrium may counteract hypotension (no decrease in left heart filling) and, consequently, help to maintain adequate systemic perfusion [9]. To our knowledge, only one earlier report [22] has described development of refractory hypoxaemia due to right-to-left shunt via a PFO after orthopaedic surgery (elective left hip replacement).

Unfortunately, our patient’s persistent hypoxaemia and high supplemental oxygen requirements despite the absence of pulmonary parenchymal and vascular diseases, pneumothorax, pleural effusion(s), and relatively moderate APO at arrival, did not trigger appropriate differential diagnostic tests. An anatomic shunt was not initially considered, only a CT scan for PE, but not an echocardiogram, was performed. This case illustrates that in patients with unexplained/not fully explained acute and persistent hypoxaemia (out of proportion to clinical and radiological findings, not corrected by high inspired oxygen concentration) the differential diagnosis should/must include right-to-left shunting and an echocardiogram performed as a diagnostic investigation of choice. This is especially important in the presence of medical conditions that may precipitate/increase the right atrial pressure (therefore exacerbating the right to left blood flow facilitating desaturated blood flow redirection through the PFO) and/or when new localising signs arise.

PFO, an embryonic remnant of the foetal circulation and the most common congenital cardiac abnormality, is present in 9.2% [30] - 27.3% [31,32] of the general population and is responsible for up to 95% of intracardiac right-to-left shunts [33-36]. Though in most individuals PFO is completely asymptomatic throughout life (usually an incidental finding), it is also as a possible cause of serious clinical syndromes including paradoxical (venoarterial) systemic embolism (cerebral, myocardial, splenic, bowel, renal infarctions, extremity ischemia), platypnea-orthodeoxia, migraines, complications of pulmonary embolism, Alzheimer's dementia, high-altitude pulmonary oedema and decompression sickness in divers [29,37-44].

Paradoxical embolus (PDE), the most common complication of PFO [17], more often occurs in the fourth to sixth decade without gender preferences [45]. The main factors reported to be involved in the development of an arterial embolism in patients with PFO include younger age, PFO size, right-to-left shunt degree and venous thrombosis [42], atrial septal aneurysm [36,37,46-51] and/or increased interatrial septal mobility, especially in combination with PFO (as seen in our patient), increase the risk of stroke [42,52-54]. Other specific morphologic features, which may also act synergistically or independently, include co-existence of PFO with prominent Eustachian valve [53,55], Chiari network [54,56], left atrial dysfunction [40,57-59] and an intrinsic imbalance in the coagulation-anticoagulation system. The role of genetic factors in the pathophysiology of PFO is uncertain [44,60], most PFO cases are sporadic, but a Mendelian inheritance pattern has also been reported [61].

On the other hand, it should be noted that the presence of PFO in a patient with acute ischemic stroke does not necessarily imply causality, as it may simply be an innocent bystander. A ten point risk of paradoxical embolism (RoPE) score has been proposed to determine a high risk PFO [62] which takes into account the absence of other potential risk factors for stroke (e.g., history of hypertension, diabetes mellitus, previous stroke or TIA, smoking, presence of cortical infarction on imaging, younger age <70 years). A RoPE score of 0-3 estimates 0% probability of pathogenic PFO, whereas a score of ≥6 represents a high probability of paradoxical embolus secondary to PFO [21,62]. This approach appears to be a convenient and useful clinical tool; however, a high probability index cannot confirm with certainty the causative role of PFO, and low RoPE scores do not exclude the possibility of PFO attributable stroke. In our patient the RoPE score was four.

The patient’s history of TIA and benign paroxysmal positional vertigo raises concern that PFO may have been present earlier but not detected and may be a source of paradoxical emboli. Sensations of vertigo and dizziness, common conditions among older adults, may reflect multiple aetiologies (dysfunction in the vestibular, somatosensory, or visual systems or in their central integration [63-64]) including platypnea (positional dyspnoea: shortness of breath that is relieved when lying down and worsens when sitting or standing)-orthodeoxia (arterial desaturation: a fall in arterial oxygen saturation upon assuming an upright position) syndrome (POS) [11,18,21,65-71]. A right-to-left shunt through interatrial communications is the most frequent cause of POS [18,70,71]. Emerging evidence suggests that in patients with PFO, microemboli and vasoactive substances bypass the pulmonary circulation, enter the brain, act on the vestibular system, and impair cerebral autoregulation causing dizziness [71] and migraine [37,43,44,72-74]. This uncommon and often misdiagnosed condition occurs predominantly in the elderly, insidiously (and progresses for months to years) or acutely as a life-threatening unexplained hypoxemia [75], in most cases without elevated right atrial pressures (i.e., in the absence of a continuous pressure gradient) [70]. As a physiological response to chronic hypoxia, patients may develop cyanosis and erythrocytosis with increased haematocrit [76]. Our patient’s fall resulting in HF, unexplained hypoxaemia, cyanosis and trend to erythrocytosis at presentation were possibly caused by POS (due to PFO). However, this has not been documented (thorough blood gas analysis in different body positions was not performed). Our case indicates that in a patient with a history of ischaemic stroke/TIA who has minimal risk factors and vertigo-like symptoms an echocardiogram is important for early detection of PFO and to prevent complications (paradoxical embolic events causing ischaemic stroke and systemic embolism). Only echocardiographic evaluation may reveal the presence and severity of PFO.

Regarding the delay and difficulties in radiological documentation of brain infarcts (missed by repeated CT of the brain as in our case), it should be acknowledged that some cerebrovascular infarctions may be beyond the resolution capacity of the CT scan [77-85]. CT, which is very sensitive and specific for haemorrhage, has only 10-25% sensitivity for acute infarction [86,87], whereas MRI with the combination of diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) achieves >90% sensitivity in detecting parenchymal lesions within 30 minutes after infarction [84,88-91], but up to 7% (6.8%) of patients with acute ischaemic stroke (AIS), particularly caused by posterior circulation ischaemia, have a negative DWI scan [89,92]. The importance of clinically oriented interpretation of imaging findings, prioritising clinical signs, and paying attention to the possibility of false negative imaging results in the diagnostic evaluation of a patient with acute neurological deficit is another lesson offered by this case. Cardioembolic cerebral infarctions (tissue damage due to occlusion of the brain blood vessels by unwanted materials pumped from the heart) account for 14-30% of all ischaemic strokes [40,93,94]. Embolic strokes of undetermined source (cryptogenic, CS) comprise 9-40% (on average 17%) [38,95-101] and demonstrate a high (about 50%) prevalence of PFO [102,103]. Each year, 345,000 patients worldwide, aged 18 to 60 years old, present with a PFO and an embolic stroke [104]. A meta-analysis of case-control studies on ischaemic stroke reported odds ratios (OR) of 3.16 for PFO, 3.65 for atrial septal aneurysm (ASA), and 23.26 for PFO combined with ASA [46]. Other studies found that the prevalence of PFO among patients with CS was 2.9 times [105], 4.4 times [106] and 4.7 times [48] higher compared to individuals with stroke of known cause. In patients with acute PE, the risk of stroke is four times higher (21.4% vs. 5.5%) in the presence of PFO [107]. An observational study on 144,563 patients showed that the risk of stroke after surgery in subjects with PFO is 4.4 and 4.1 times higher within 1 (4.7% vs.1.1%) and 2 (6.6% vs.1.6%) years, respectively [108].

Whilst in young CS patients PFO is strongly considered as an aetiological factor [46], in the elderly PFO-attributable strokes are also not rare and should not be overlooked [48,109]; with each decade of life the prevalence of PFO is decreasing but its size/diameter (an independent risk factor for stroke occurrence) tends to grow [42,110].

The reported incidence of stroke following AMI ranges between 0.25-0.52% [111,112], 0.7-2.2% [113-123], 6% [118,124] and 12.7% [125,126]. AMI in the acute phase of ischaemic stroke occurs in approximately 1% of the population [127], but troponin positivity status was reported in 10-20% of patients with acute ischemic stroke [128-132]. Although there is a considerable risk of acute stroke following AMI and vice versa, simultaneous cardio-cerebral infarction (CCI, as termed by Omar et al. [133]) has been rarely reported [111,124,134,135], with an incidence 0.009-0.52% [124,136-138]. However, in a recent prospective observational study of patients with acute embolic stroke (n=1150) related to newly diagnosed atrial fibrillation, the frequency of simultaneous cardiac and cerebral ischemia (double coronary and cerebral arteries embolization) was found to be present in 35% (in 12 of 34 patients who underwent cardiac magnetic resonance assessment) [139]. CCIs and cardiocerebral embolizations are probably underestimated [131]. There are two types of CCI [133]: simultaneous or synchronous (both AMI and stroke occur at the same time possibly due to the same pathology) and metachronous (infarction in one organ precedes the infarction in the other within 24-72 hours); about two thirds of CCIs are metachronous [120]. The mean age of patients with CCI is about 59 years and most (up to 90%) are men [112,120], while the incidence of perioperative stroke is higher among older patients and females [140].

The major pathophysiologic mechanisms of CCI include [122,141]: (1) sudden haemodynamic compromise (severe hypotension, cardiogenic shock) causing reduction of cerebral blood flow to watershed areas of the brain and subsequent infarction [124,133]; (2) left ventricle thrombus (cardio-ventriculo-cerebral infarction, as termed by Bhandari et al. [122]) typically associated with atrial fibrillation [135,139,142-145] and/or heart failure (systolic dysfunction of the anterior wall and apex, especially, are associated with and promote formation of left ventricular mural thrombus [146,147], and may simultaneously embolize both the cerebral and coronary arteries [131,139,142,148]; nearly 60 such cases have been reported [39]; (3) polyvascular arterial atherothrombotic disease with multiple embolisms, particularly often in the brain [94,148-150]; (4) paradoxical embolization via PFO in patients with deep vein thrombosis or right ventricular thrombus [133,141]; (5) adrenergic surge from acute ischaemic injury to the left insular lobe of the brain which impairs the sympathetic/parasympathetic balance, causes blood pressure dysregulation, arrhythmias, abnormal wall movement (neurogenic stunned myocardium) and formation of intracardiac thrombus [133,137,151-155]; stress cardiomyopathy with normal coronary arteries (Takotsubo syndrome) appears soon after stroke involving the insular cortex, nine such CCI cases have been reported [124,147,156-159]; (6) type A aortic dissection (with extension to the coronary ostia, carotid, vertebral, or basilar arteries) [160-163]. Of note, haemodynamic impairment and mechanisms causing embolization may act independently or synergistically promoting watershed infarcts [164].

Understandably, CCI requires a broad differential diagnosis [39,40,70,112,165]. In cases of paradoxical embolism through a PFO the following should also be considered as risk factors (predisposing to embolic and hypercoagulation events) and/or accompanying pathological conditions: atrial septal aneurysm, abnormally lying Eustachian valve or Chiari’s network in dextral atrium, AF (permanent or paroxysmal), sustained atrial flutter, pulmonary hypertension, pulmonary embolism, cardiomyopathies (ischaemic and non-ischaemic), cardiac valve diseases (mitral stenosis, mitral valve prolapse, aortic valve stenosis or calcification), endocarditis (bacterial and non-bacterial), pulmonary arteriovenous fistula, intracardiac thrombus, vegetations, right atrium myxoma, aortic arch atherosclerotic plaques, vasculitis, systemic lupus erythematous, disseminated intravascular coagulation, malignant (paraneoplastic syndrome) [166] and haematologic [167] disorders, hypercoagulable state due to antiphospholipid syndrome and inherited thrombophilias (deficiencies in protein C, protein S, and antithrombin, factor V Leiden mutation G1691A, prothrombin G20210A, elevated factor VIII,) [10,42,103,168-169], hyperhomocysteinaemia, COVID-19 infection [170], concurrent coronary and cerebral artery vasospasm [171] and hypereosinophilic syndrome [172]. The differential diagnosis should also include non-PFO/atrial defect related sources of paradoxical embolism (i.e., arteriovenous malformations, ventricular septal defects, patent ductus arteriosus, tetralogy of Fallot). In a hip fracture patient, an embolic phenomenon in addition to vascular factors may be caused (especially during operative manipulation) by fat/lipid micro-emboli [173-178], air [179] or cement [174,180-181]; altered mental status in such a scenario should raise the question of a possible paradoxical cerebral embolization (PFO presence). PFO and paradoxical embolization has been described in four out of 110 patients during invasive intramedullary procedures for fresh fracture of the femur and tibia [182], and in a morbidly obese patient undergoing orthopaedic surgery following motor vehicle accident [183].

In our patient, preoperative AMI was not associated with hypotension and haemodynamic compromise, conditions which by decreasing cerebral blood perfusion may contribute to stroke [112,133,184-186]. Some studies have suggested that in patients with acute ischaemic stroke normotension at presentation (as in our case) is strongly associated with cardioembolic aetiology [185]. A clinicopathological analysis of CCIs (30 autopsies) found that the major aetiological factors were AF, non-bacterial thrombotic endocarditis or disseminated intravascular coagulation (DIC) [187]; none of these factors have been observed in our patient. He had not used any medications known to be associated with ischaemic stroke (i.e., antipsychotic, antineoplastic or immunomodulating agents, NSAIDs, etc. [188]). The diagnostic work-up as mentioned did not reveal pulmonary embolism, AF, intracardiac thrombus, valvular heart disease, extracranial or intracranial atherosclerosis causing luminal artery stenosis (> 50%), brain-heart axis dysregulation as well as any other of the abovementioned causes except the right-to-left shunt (due to PFO, atrial septal aneurysm and increased interatrial septal mobility) that could explain the preoperative hypoxaemia and concurrent acute cardiac and brain infarcts. Therefore, we assume that in our case, the most likely explanation to the aetiology of these events can be attributed to PFO-related paradoxical embolism (as other major causes of CCI were excluded). The clinical features of our patient (no elevation of blood pressure, maximal neurologic deficit/hemiplegia at onset of stroke, decreased level of consciousness at onset, progressive course of worsening of conscious level, dysphasia, syncope and seizure-like symptoms) in combination with an absence of cerebral atherosclerosis and traditional risk factors for ischaemic stroke (hypertension, hypercholesterolaemia, hyperglycaemia, arrhythmias, smoking, etc.), characteristics which are relatively rare in patients with PFO [37,42], as well as absence of significant atherosclerotic changes in main arteries and absence of left ventricular hypertrophy (factors independently associated with PFO [100]), also imply an embolic PFO-related aetiology of the multiple cerebrovascular infarcts. However, the source of embolism (e.g., a deep venous thrombus) has not been documented, and no predisposing conditions (such as prolonged immobility, Valsalva-like activities, etc.) around the time of admission have been identified. The existing literature on cryptogenic ischaemic stroke indicates that a venous source of embolism is often not found [37,42,189-191].

The watershed (border-zone) infarctions (WSI) occur at the junction between two major cerebral arteries [164,192] and account for 10% - 12.7% of all infarcts [193-195]. Usually, two types of WSI are distinguished: subcortical (internal, in the white matter) and cortical (external). The internal WSI are traditionally attributed to haemodynamic dysregulation (systemic hypotension and/or hypovolemia) due to cardiac arrest, bleeding, anaemia, severe stenosis, or occlusion of proximal cranio-cervical arteries (in particular carotid stenosis), rising from a supine position, exercise, Valsalva's manoeuvre, use of antihypertensive drugs, etc., whereas cortical WSI are mostly due to a microembolic mechanism and may occur in the absence of severe haemodynamic impairment [196]. However, both mechanisms are believed to act synergistically [164,192,194,197-203] and underlie combined cortical and internal WSIs.

Our patient demonstrated widespread mixed (both internal and cortical) WSI involving the frontal, parietal and occipital lobes, and right cerebellum hemisphere (with a small focus of microhaemorrhage in the parietal lobe) along with chronic small vessel ischaemic changes. There was neither history of acute blood loss nor hypotension prior to the MRI study and no occlusion or significant stenosis of cerebral, carotid, and vertebral arteries was found on contrast enhanced CT angiogram.

Considering the past history of TIA, “benign paroxysmal positional vertigo”, post-HF (preoperative) systemic hypoxaemia, simultaneous onset of the acute silent myocardial infarct and brain infarcts, in the context of definite presence of a large PFO and septal defects, we speculate that paradoxical embolism through the right-to left shunt was the most likely pathogenic mechanism of stroke (small yet unidentified emboli arising /originating from the lower extremities and/or the heart may have lodged in the brain).

The following consequence of events can be hypothesised: POS-related fall and HF stress further increased the pressure in the right atrium, leading to augmentation of the right-to-left shunt and hypoxaemia, which, in turn, together with hypercoagulability (triggered by the inflammatory state) produced acute myocardial injury and brain infarcts (due to the accelerated passage of thrombotic material in systemic circulation through the PFO and septal defect). This case underlines the importance of searching for PFO for possible sources of embolism, especially in patients with CCI. Transthoracic echocardiography and investigation for POS preoperatively to detect a PFO in selected subgroups of patients undergoing major non-cardiac surgery (history of a cerebrovascular accident, unexplained vertigo, dizziness, migraine, known intracardiac defects) seems a reasonable approach.

Preoperative diagnostic uncertainties mentioned above complicated the management in our patient. Dilemmas associated with comanagement of the HF (need to repair as soon as possible, within 24-48 hours) paralleled the puzzling diagnosis of hypoxaemia and clot burden and became highly challenging when the MRI demonstrated multiple brain infarcts (despite unremarkable findings by previous non-enhanced CT scans and CT angiography of the intracranial and extracranial vessels) and the echocardiography revealed PFO. At this point the patient was awaiting HF surgery and received prophylactic anticoagulation with enoxaparin and aspirin (started on the second admission day when the AMI was diagnosed). Although fibrinolytic therapy can be used for both AMI and acute stroke (with different dosages and timing), it was decided (after multidisciplinary discussion) not to treat the patient with intravenous thrombolysis because of the late diagnosis (outside time window: thrombolytic therapy with recombinant tissue plasminogen activator is currently recommended within 4.5 hours of onset) and the subsequent concerns of haemorrhagic transformation of stroke as well as the risk of bleeding from the surgical wound.

The management of CCI, one of the most challenging medical emergency conditions, which demands immediate attention, is still unclear, there is no evidence-based guideline. Prioritising therapy of one infarcted territory for the other may result in permanent irreversible morbidity or death. The use of antiplatelet drugs and anticoagulants (essential for AMI management) increase the risk for the haemorrhagic conversion of brain infarcts, whereas intravenous thrombolysis used in ischaemic stroke may increase the risk of cardiac wall rupture in the setting of an AMI [126]. Current recommendations for optimal reperfusion strategies emphasise the importance of an individualized (case by case basis) approach guided by the patient’s hemodynamic status [40,126,131].

Nowadays, percutaneous PFO closure is indicated only in highly selected patients with clear documentation of non-lacunar CS with moderate or large right-to-left shunt, an atrial septal defect (aneurysm, prominent Eustachian valve or Chiari's network), high risk of paradoxical embolism (RoPE) scores, no evidence of atrial fibrillation, platypnea-orthodeoxia syndrome, and shunt-induced cyanosis [16,18,21,50,66,204-212]. After percutaneous PFO closure for optimal secondary prevention of cerebral ischemia, dual antiplatelet therapy is recommended for 1–6 months, followed by single antiplatelet therapy thereafter [18,211]. The procedure significantly reduces the risk of recurrent stroke, has low procedural risks and low costs. However, recurrent neurologic events after PFO closure were more frequently observed in subjects with RoPE score ≤5 than those with >5 (14.5% vs. 4.2%) indicating the role of an alternative aetiology to paradoxical embolism [213]. The optimal management of patients aged >60 years remains unresolved [214]. Patients with CS who reject a PFO closure should receive oral anticoagulation or antiplatelet therapy; both treatments are equally effective, therefore, aspirin or clopidogrel is recommended for secondary prevention [207]. The risk of annual recurrence rate on medical therapy is low (< 2%) [212].

HF surgery is known to be associated with blood loss and need for blood transfusion, as well as increased risk of thromboembolism postoperatively. Current literature including recently published meta-analyses showed that in orthopaedic surgery, including HF repair, use of tranexamic acid (TXA, an antifibrinolytic drug that by inhibiting the conversion of plasminogen to plasmin decreases the degree of fibrinolysis) is safe and effective in  promoting haemostasis, reducing intraoperative blood loss and postoperative transfusions, although its influence on thromboembolism or postoperative mortality, especially in the elderly, is uncertain [215-224].

In our patient TXA was administrated during HF surgery (despite uncertainty regarding the risk of thromboembolism). The patient experienced a moderate drop of haemoglobin (of 26 g/L), not requiring RBC transfusion, and no new thromboembolic events occurred. This observation is consistent with numerous studies showing that TXA is effective in reducing postoperative transfusions and haemoglobin decline, and possibly does not increase the risk of thromboembolic complications (even in subjects with such conditions as in our patient). Use of TXA has previously been reported in a patient with ischaemic stroke and PFO [225] and in a 65-year-old male with a previously undiagnosed PFO who suffered cerebrovascular infarction and pulmonary emboli after bilateral total knee replacement [226].

The lesson to be learned is that CCI in a patient with a HF and previously unknown PFO with a right-to-left shunt precipitating brain infarcts is challenging concerning diagnosis and treatment decisions, the latter are not yet fully determined and should be personalised based on a multidisciplinary consensus and stepwise approach.

Conclusion

This unusual and complicated case comprised three interrelated life-threatening pathologies—hypoxaemia, simultaneous cardiac and brain infarctions—due to previously unknown PFO in a patient with HF. The report describes diagnostic and therapeutic challenges, which required a multidisciplinary approach, provides possible explanations for these conditions, and highlights the necessity to maintain a high index of suspicion for PFO to reduce misdiagnosis, timely identification of paradoxical embolic events and possible underlying cause(s).

Author Contributions: A.F.; case description and writing original draft preparation. E.W.; review and editing. Both authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Written informed consent has been obtained from the patient’s family to publish this paper.

Conflicts of Interest: The authors declare no conflict of interest.

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