LIST OF CONTENTS
LIST OF ABBREVIATIONS AND ACRONYMS ... 3
LIST OF FIGURES ... 4
LIST OF TABLES ... 5
ABSTRACT ... 8
I. INTRODUCTION ... 10
The concept of futility in interventional cardiology... 10
II. OBJECTIVE OF THE RESEARCH ... 12
III. BACKGROUND ... 13
III.1. Embryology of the atrial septum ... 13
III.2. Patent Foramen Ovale ... 14
III.2.1. Anatomy ... 14
III.2.2. Physiology of right-to-left shunt through a PFO ... 16
III.2.3. Pathological conditions associated with PFO ... 17
III.2.4. PFO diagnosis ... 19
III.2.4. PFO and cryptogenic stroke- treatment ... 22
III.3. Atrial septal defects ... 24
III.3.1.Anatomy ... 24
III.3.2. ASD pathophysiology... 25
III.3.3. ASD clinical presentation ... 25
III.3.4. ASD detection... 26
III.3.5. ASD indications for closure ... 26
III.4. Percutaneous closure of the interatrial communications ... 27
III.4.1.Percutaneous device options ... 27
III.4.2.Pharmacological prevention of complications of percutaneous therapy ... 29
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V. MATERIALS AND METHODS ... 31
V.1. Study population... 31
V.2. Pre-procedural evaluation... 32
Ultrasound assessment ... 32
V.3. Procedure of percutaneous closure of the interatrial shunts ... 35
V.4. Follow-up evaluation ... 36
V.5. Statistical analysis ... 36
VI. RESULTS ... 37
VI.1. Clinical characteristics ... 38
VI.2. Procedural data and in-hospital outcome ... 39
VI.3. Follow-up data ... 42
VII. DISCUSSION ... 43
VII.1. Major findings ... 43
VII.2. Comparison with previous studies ... 43
VII.3. Study strenghts and limitations ... 45
VIII. CONCLUSIONS... 45
IX. FUTURE PERSPECTIVES ... 46
3
LIST OF ABBREVIATIONS AND ACRONYMS
ASA= atrial septal aneurysm
ASD= atrial septal defect
CS= cryptogenic stroke
GA= general anaesthesia
IAS= interatrial septum
ICE= intracardiac echocardiography
LA= left atrium
LAA= left atrial appendage
LtR shunt= left to right shunt
PFO= patent foramen ovale
RA= right atrium
RtL shunt= right to left shunt
TCD= transcranial Doppler
TEE= transesophageal echocardiography
TIA= transient ischemic attack
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LIST OF FIGURES
Figure 1: Development of the atrial septum in utero. ... 14
Figure 2: Schematic representation of the atrial septal anatomy from an en-face view of the right atrium... 15
Figure 3: Anatomical variants of PFOs seen on two-dimensional TEE. ... 16
Figure 4: The list of the main ultrasound techniques for PFO diagnosis... 20
Figure 5: Bubble contrast echocardiography ... 21
Figure 6: Scheme of the recommendations for treatment of cryptogenic stroke/TIA with PFO and summary of the considered anatomical and clinical risk factors.. ... 23
Figure 7: Types of ASDs. An illustration of the anatomy of atrial septal defects.. ... 24
Figure 8: Amplatzer Septal Occluder (ASO)(LEFT), Gore Helex Septal Occluder (RIGHT). . 28
Figure 9: General description of devices most often used for PFO closure.. ... 29
Figure 10: Proposed pharmacological protocol before, during and after percutaneous closure of PFO (expert consensus opinion).. ... 30
Figure 11: PFO size and tunnel length... ... 33
Figure 12: Eustachian valve.. ... 33
Figure 13: ASD with a short aortic rim assessed by TEE in short axis view. ... 34
Figure 14: Contrast TCD during the Valsalva maneuver.. ... 34
Figure 15: Temporal distribution of the percutaneous closure of the interatrial communications.. ... 37
Figure 16: Types of devices used for percutaneous closure of the interatrial shunts. ... 39
Figure 17: The total procedure time in the 3 different groups of patients.. ... 40
Figure 18: The radiation exposure dose in the 3 different groups of patients.. ... 40
Figure 19: The contrast agent doses used during the 3 types of procedures... 41
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LIST OF TABLES
Table 1: Baseline characteristics of the study population. ... 52
Table 2: Pre-procedural imaging data. ... 53
Table 3: Coagulation screening. ... 54
Table 4: Indications to percutaneous closure of the interatrial shunts. ... 55
Table 5: Procedural data. ... 56
Table 6: Procedural data for Group C. ... 57
Table 7: Periprocedural complications. ... 58
Table 8: Ultrasound follow-up. ... 59
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Acknowledgements
I dedicate this work to my folks. Thanks for the unconditional support and encouragement you have always given me.
Many thanks to Dr. Andrea Pieroni, Prof. Anna Sonia Petronio and Prof. Mario Marzilli in their roles as tutors throughout the course of my residency program.
I would also like to thank my colleagues, all the doctors and nurses, and all the paramedic stuff I worked with for being my big family in the last 5 years.
A special word to the entire Cath Lab team for “adopting” me, they really made me feel at home.
7
Primum Non Nocere
8
ABSTRACT
Background. The interatrial communications that could be treated by percutaneous approach are represented by the patent foramen ovale (PFO) and secundum type of atrial septum defect (ASD). The indications to ASD closure are well defined by the international guidelines for the management of the congenital heart diseases. The management of PFO related to thromboembolic events is still controversial, despite an increase in interventional closure procedures with newer devices.
Aim. The aim of this study was to identify an alternative approach to the standard percutaneous closure procedure of the interatrial shunts, in order to reduce the intraprocedural risk.
Methods: Between 2005 and 2015, a total of 176 patients underwent percutaneous PFO and ASDs closure in our institution. A contemporary and retrospective review of the interventional reports identified 3 groups of patients: Group A, represented by the patients treated under general anaesthesia with transesophageal echocardiographic (TEE) guidance; Group B, represented by the patients treated with intracardiac echocardiography (ICE); Group C, represented by the patients who were treated without general anaesthesia, and under TEE guidance. Data on the pre-procedural evaluation (clinical, imaging), on percutaneous procedure and the ultrasound controls during the first 6 months after the procedure were collected.
Results: A total of 176 pts were enrolled (mean age 49±12.2 yrs, 68 females) and distributed in 3 groups: Group A, 53 pts; Group B, 55 pts; Group C, 68 pts. The main indications to perform the interatrial shunt closure was represented by TIA in 91 pts (51.7%), stroke in 64 pts (36.3%), migraine in 15 (8.5%), increased right heart chambers in 11 pts (6.2%). Successful device deployment was obtained in 172 pts (97.7%).
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There was a statistically significant difference of total procedure time between the groups: 82.5±16.6 min for Group A, 65.8±22.7 min for Group B, and 59.9±25.4 min for Group C (p= .05 Group B vs. Group A; p< .001 Group C vs. Group A; p= n.s. Group B vs. Group C). The total radiation exposure was higher in Group A (3995.6±4486 cGy/cm2) compared to Group B (2223.4±2540 cGy/cm2, p= .02) and Group C (1452.6±1158 cGy/cm2, p< .0001). The dose of contrast agent was significantly lower in Group C (15.8±18 ml) than in the other groups (Group A: 39.6±35 ml, p< .0001, Group B: 25.4±18.4, p= .01).
One major intraprocedural complication was observed in Group B (device embolization). At the 6 months follow-up assessed by transcranial Doppler, a minimal shunt with the appearance of late micromebolic signals was observed in 5 cases (1 in Group A and 2 in each of the other groups), with no clinical impact.
Conclusions: To our knowledge this is the first study that demonstrates that the percutaneous closure of interatrial shunts is feasible and safe in conscious patients under transesophageal echocardiographic guidance. This “alternative approach” helps to reduce the intraprocedural risk of complications and the complexity of the procedure, reducing the total procedure time, the contrast agent dose and total radiation exposure.
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I. INTRODUCTION
The concept of futility in interventional cardiology
In ancient Greece and Rome, as expressed particularly through the Hippocratic writings, the physician’s duties were described as assisting nature to restore health and alleviate suffering. Life and death were viewed as natural cycles. Indeed, the Hippocratic physician shunned claims of supernatural powers in order to avoid the taint of charlatanism. It was not until many centuries later in the late Middle Ages, when religion began to play a dominant role in Western Europe, and later in the seventeenth century, when scientists began to view science as a power to be exerted against nature, that the goal of prolonging life was introduced (1).
The concept of medical futility emerged in the 1980s in response to concerns about families who demanded life-prolonging treatments for their loved ones that caregivers deemed to be inappropriate (2). It probably should not be surprising, in this time of soaring medical costs and proliferating technology, that an intense debate has arisen over the concept of medical futility, and several alternative definitions of futility were made.
One proposed definition holds that medical futility should depend upon the likelihood of achieving the patient’s goals. In other words, the patient is entitled to receive any treatment and seek any outcome he or she wishes from the physician. This view has arisen out of the patient autonomy movement in reaction to abuses that took place in the previous era of strong physician paternalism. And although in many respects it is an admirable view, it is clearly flawed. Physicians are not obligated to yield, for example, to a patient’s desire for mutilating or useless surgery (1).
Another definition of medical futility has to do with the unacceptable likelihood of prolonging life. Physicians, according to this notion, cannot declare a treatment futile as long as it can prolong life, even permanently unconscious life.
Another proposal is that the definition of medical futility should be limited to the unacceptable likelihood of achieving any physiological effect on the body. According to this proposal, the physician cannot regard a treatment as futile as long as it can maintain the function of any part of the body, such as pumping blood by means of cardiac compression, moving air by means of mechanical ventilation, or eliminating wastes via dialysis, even if the patient is permanently
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unconscious or in the last moments of a terminal condition. In short, the instruments of technology are the focus of attention rather than the patient (3). The focus on physiologic measures is also proving to be dangerous. For example, many diabetes specialists promoted strict control of blood glucose on the assumption that producing a physiological effect (lowering blood glucose) was equivalent to achieving a benefit for the patient (preventing complications and prolonging life). Well designed randomized control trials examining patient outcomes showed that strict control failed to reduce adverse cardiovascular outcomes and either increased or had no effect on mortality; moreover, it increased the risk for severe hypoglycemia in type 2 diabetes (4).
The physicians tend to seek specific and descriptive definitions of futile, inappropriate, or burdensome treatments. By contrast, lawyers and judges were more concerned about putting in place detailed procedures that protect vulnerable patients.
Therapeutic futility has been defined as a lack of medical efficacy, particularly when the therapy is unlikely to produce its intended clinical result, as judged by the physician; or lack of a meaningful survival, as judged by the personal values of the patient (5). Ascertaining benefit versus futility in individual patients is therefore a multifaceted exercise that must integrate information to facilitate a collective judgment. Considering the importance of doing no harm and the reality of limited resources, in each case, tough questions about whether we should perform a certain intervention even if we can perform it must be asked.
In interventional cardiology the concept of futility became very important in the last decades, due to technology progress, especially for those interventions which are performed in peculiar categories of patients, such as transcatheter aortic valve replacement (6), percutaneous MitraClip repair (7), renal sympathetic denervation (8), and percutaneous patent foramen ovale closure (9).
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II. OBJECTIVE OF THE RESEARCH
The interatrial communications that could be treated by percutaneous approach are represented by the patent foramen ovale (PFO) and secundum type of atrial septum defect (ASD). The indications to ASD closure are well defined by the international guidelines for the management of the congenital heart diseases. The management of PFO related to thromboembolic events is still controversial and sometimes considered futile, despite an increase in interventional closure procedures with newer devices, and reducing the risk for intraprocedural complications as much as possible should be one of the goals of the interventional cardiologists.
The percutaneous closures of interatrial shunts are performed in a standard catheterization laboratory under physiological monitoring, fluoroscopic and/or echocardiographic guidance (transesophageal echocardiography-TEE, including real-time three dimensional imaging- RT 3D, or ICE). General anesthesia or deep sedation is usually required for TEE-guided procedures, whereas ICE-guided procedures can be performed without sedation.
The aim of this research was to identify an alternative approach to the standard percutaneous closure procedure of the interatrial shunts in order to reduce the intraprocedural risk. We evaluated the feasibility, safety and short-term efficacy of percutaneous interatrial shunts closure in conscious patients, without general anaesthesia or deep sedation under uninterrupted transesophageal echocardiographic guidance.
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III. BACKGROUND
III.1. Embryology of the atrial septum
The cardiac septa form between day 27 and day 37 post-conception (Figure 1). Initially, the septum primum grows from the roof of the atria towards the endocardial cushion, which develops in the atrioventricular canal. The gap between the septum primum and the endocardial cushion is the ostium primum. Before closure of the ostium primum, fenestrations develop within the superior portion of the septum primum, which coalesce to form the ostium secundum. This structure replaces the ostium primum as the conduit for right-to-left (RtL) shunting of oxygenated blood from the umbilical arteries, thus bypassing the fetal pulmonary circulation.
The septum secundum then develops by an infolding of the atrial walls. As such, the septum secundum is a “false” septum and any transseptal puncture through this structure in later life will, in theory, exit the heart and potentially cause pericardial tamponade. The septum secundum grows downwards around the right atrial aspect of the septum primum, forming a thick arc over the ostium secundum. A hole remains inferiorly in the septum secundum where the septum primum is exposed on the right atrial side. This region is called the fossa ovalis and is composed only of the septum primum. The two septa eventually fuse together in the areas where they overlap, including around the edges of the fossa ovalis. However, at the anterosuperior edge of the fossa ovalis (adjacent to the aortic root) they remain unfused. This tunnel, or “flap valve”, permits the RtL shunting of blood that is necessary for normal fetal circulation. At birth, the increase in pulmonary blood flow causes the left atrial pressure to exceed the right atrial pressure, leading to closure of the PFO. The primum and secundum septa lining the PFO tunnel usually fuse shortly after birth (10).
Modified from Calvert P.A.. et al., Nat. Rev.Cardiol, 2011 Figure 1. Development of the atrial septum
Fenestrations develop within the septum primum. c) The septum secundum develops by an walls. The ostium secundum acts as a conduit for right
anterosuperior edge of the fossa ovalis, the primum and secundum septa remain unfused, which constitutes a PFO. Arrow denotes blood flowing through the PFO from the embryonic righ
EC, endocardial cushion; FO, fos
patent foramen ovale; SP, septum primum; RA, right atrium; SS, septum secundum.
III.2. Patent Foramen Oval
Patent foramen ovale (PFO) is a failure of the primum and secundum atrial septa to fuse postpartum, and it persists in a large minority of the population. A postmortem series of 965 patients showed that the prevalence of PFO decreased with age, from 34.3
0–30 years, to 20.2% in the group aged 80
III.2.1. Anatomy
Failure of the primum and secundum septa to fuse usually occurs at the superior (aortic) border of the fossa ovalis (Figure 2).
Modified from Calvert P.A.. et al., Nat. Rev.Cardiol, 2011
atrial septum in utero. a) The septum primum grows from the roof of the atria. b) Fenestrations develop within the septum primum. c) The septum secundum develops by an
acts as a conduit for right-to-left shunting of oxygenated blood. d) At the anterosuperior edge of the fossa ovalis, the primum and secundum septa remain unfused, which constitutes a PFO. Arrow denotes blood flowing through the PFO from the embryonic right atrium to the left atrium. Abbreviations: EC, endocardial cushion; FO, fossa ovalis; LA, left atrium; OP, ostium primum; OS, ostium secundum; PFO, patent foramen ovale; SP, septum primum; RA, right atrium; SS, septum secundum.
Patent Foramen Ovale
Patent foramen ovale (PFO) is a failure of the primum and secundum atrial septa to fuse postpartum, and it persists in a large minority of the population. A postmortem series of 965 patients showed that the prevalence of PFO decreased with age, from 34.3
30 years, to 20.2% in the group aged 80–99 years (11).
Failure of the primum and secundum septa to fuse usually occurs at the superior (aortic) border Figure 2).
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a) The septum primum grows from the roof of the atria. b) Fenestrations develop within the septum primum. c) The septum secundum develops by an infolding of the atrial left shunting of oxygenated blood. d) At the anterosuperior edge of the fossa ovalis, the primum and secundum septa remain unfused, which constitutes a PFO. t atrium to the left atrium. Abbreviations: ostium primum; OS, ostium secundum; PFO,
Patent foramen ovale (PFO) is a failure of the primum and secundum atrial septa to fuse postpartum, and it persists in a large minority of the population. A postmortem series of 965 patients showed that the prevalence of PFO decreased with age, from 34.3% in the group aged
15
Modified from Calvert P.A. et al., Nat. Rev.Cardiol, 2011
Figure 2: Schematic representation of the atrial septal anatomy from an en-face view of the right atrium. The septum primum is dark green and the septum secundum is light green. The PFO usually lies at the anterosuperior border next to the aortic root. The arrows denote the passage of blood through the PFO from the right to left atrium. Abbreviations: AO, aorta; CS, coronary sinus; FO, fossa ovalis; IVC, inferior vena cava; PFO, patent foramen ovale; PV, pulmonary valve; RV, right ventricle; SVC, superior vena cava; TV, tricuspid valve.
The anatomy of PFOs is highly variable, which has important implications when considering an appropriate closure device. The dimensions and position of the tunnel can vary, and must be carefully defined before PFO closure. Examples of anatomical variants are shown in Figure 3. Some PFOs consist of a tunnel that is long, with the septa tightly opposed (Figure 3a) whereas others open widely (Figure 3c). In some PFO tunnels, the septum primum is held away from the septum secundum by a fold of tissue on the left atrial side, a so-called “PFO with fixed opening”, or “held open PFO” (Figure 3d). These ridges can result in a continuous left-to-right shunt, and could prevent a closure device from correctly apposing the tissues of the primum and secundum septa, thus preventing an adequate seal.
The presence of an atrial septal aneurysm (ASA) is an important feature sometimes associated with a PFO (Figure 3b). An ASA has been defined as a total movement of the septum primum from the left to the right atria of >10 mm, although some groups propose stricter criteria, including a base width of the aneurysm of at least 15 mm (12). The mobile aneursymal segment lies within the septum primum and can cause this structure to retract, resulting in a potentially large RtL shunt. Retraction of the septum primum can also undermine the stability of a closure device, and some operators will intentionally oversize the device in anticipation of this problem, or even choose a closure for an atrial septal defect rather than using a PFO occluder.
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Figure 3: Anatomical variants of PFOs seen on two-dimensional TEE. a) Long tunnel PFO (arrow). b) PFO associated with atrial septal aneurysm (arrow). c) Spontaneous retraction of primum septum resulting in widely opening PFO (arrow). d) “Held open” PFO with permanent separation of the primum and secundum septa (arrow). Abbreviations: EV, Eustachian valve; LA, left atrium; PFO, patent foramen ovale; RA, right atrium; TEE, transesophageal echocardiography.
An Eustachian valve (valve of the inferior vena cava) or Chiari network are both embryological remnants of the right valve of the sinus venosus and are reported in 55.5–82% and 1.3–4% of patients, respectively, depending on the population selected. Both of these structures direct blood flow from the inferior vena cava towards the right atrial opening of the PFO and can interfere with deployment of the right atrial disc of an occlude or with the retrieval of a closure device (13).
III.2.2. Physiology of right-to-left shunt through a PFO
In the basal state, the left atrial (LA) pressure is higher than right atrial (RA) pressure, so the septum primum flap of the PFO is pressed against the septum secundum, which keeps the foramen ovale closed. However, if the RA pressure exceeds the LA pressure, blood can then flow from the RA to the LA. This occurs frequently when a person coughs, laughs, sneezes, takes a deep breath, or upon release of the Valsalva maneuver, which increases the return of venous blood to the RA. Approximately 5% of patients with stroke or migraine have a history of vigorous straining or exercising immediately before their event.
17 III.2.3. Pathological conditions associated with PFO
Under certain hemodynamic conditions, where there is a transient pressure gradient from the right to left atria, a PFO can open and enable blood or any bloodborne substances to pass from the venous to the arterial circulation, known as the paradoxical embolism (14), (15), the first paradoxical embolism through a PFO being described in 1877 by Julius Cohnheim during an autopsy of a young woman with fatal occlusion of a cerebral artery.
A number of conditions have been linked to PFO, the most important being the cryptogenic stroke, and it represents by far the most common reason for the closure. The others are represented by migraine with aura, decompression syndrome, platypnea-orthodeoxia syndrome, myocardial infarction with normal coronaries, obstructive sleep apnea exacerbation.
Cryptogenic stroke
Up to 61% of patients younger than 55 years of age who had a cryptogenic stroke (CS) have reportedly a PFO, and evidence from observational studies suggests an association between cryptogenic stroke and PFO (16), (17). Furthermore, the presence of PFO is associated with a 3-fold increased risk of recurrent stroke (18). The recurrence rate in patients with a PFO who have already suffered a stroke is approximately 2% annually. Higher stroke rates (15%) have been associated with the presence of an atrial septal aneurysm (ASA). The mechanism for the increased risk of paradoxical embolism in patients with an ASA and PFO was initially thought to be due to thrombus formation on the redundant interatrial tissue, but this has not been documented, despite intensive investigation with TEE. The current theory is that an ASA permits greater flow and therefore increases the chance of a thrombus passing from the venous to the arterial circulation (19).
Although it is logical to assume that larger PFOs would be associated with an increased frequency of cryptogenic stroke or a larger stroke burden, the data have been conflicting. There is a loose correlation between stroke volume on magnetic resonance imaging and PFO size on echocardiography, but there is wide overlap, and it is possible for a large stroke to occur with a small PFO (20). Thus, PFO size and anatomy should not be the criteria to determine whether a PFO should be closed. Venous thrombosis is believed to be the source of paradoxical embolism in cryptogenic strokes associated with PFOs. However, the incidence of detectable veno-occlusive disease in the lower extremities and pelvis is low.
18 Migraine with aura
Migraines affect approximately 13% of the population aged 20-64 years, with 36% migraines preceded by aura. Many studies have reported an association between PFO and migraine with aura (21), (22). Patients who have undergone PFO closure for non migraine indications have reported an improvement in migraine-related symptoms (23), (24). It is hypothesized that a bloodborne substance, which would ordinarily be filtered out by the lungs, is delivered to the cerebral circulation via the shunt. However, the mechanisms that trigger migraines are unknown, and this theory remains unproven. A randomized, controlled trial showed no benefit of PFO closure for migraines (25), but this trial had an ambitious end point-complete headache cessation in a complex group of patients who were resistant to multiple drug therapies and, therefore, its results do not rule out a possible effect of PFO closure to improve the migraine symptoms.
Decompression syndrome
Decompression illness is caused by nitrogen microbubbles formed in the vasculature as a result of a reduction in environmental pressure. Symptoms are usually constitutional and nonspecific. The rate of occurrence has decreased due to improved decompression procedures but still affects approximately 1,000 divers/year. The risk of developing decompression illness is 5- to 13-fold higher in individuals with a PFO (26). No specific guidelines exist for PFO closure in people who have decompression illness, but the options are to stop diving, decrease the depth or time of dives, or undergo percutaneous PFO closure.
Platypnea-Orthodeoxia syndrome
Platypnea- Orthodeoxia is a rare syndrome consisting of hypoxemia and shortness of breath upon assuming an upright position. It is believed that anatomic changes with age, such as uncoiling of the aorta, diaphragmatic paralysis, stretch of the atrial septum, and increase shunting through a PFO, produce significant desaturation of arterial blood when the patient stands up or bends over. A recent French registry of 78 patients reported a significant increase in oxygen saturation and dyspnoea improvement immediately after percutaneous PFO closure (27).
19 III.2.4. PFO diagnosis
The most common reason for PFO closure is the cryptogenic stroke, which is carried out after a careful investigation that includes brain, carotid and heart imaging, a screen for thrombophilia, and a neurologic and cardiologic assessment. Considering the complexity of all these evaluations, it is mandatory the creation of a local HEART-BRAIN TEAM. It is recommended that a heart/brain team should perform case-by-case evaluation and be composed of a neurologist, a clinical cardiologist, a cardiac-imaging expert, an interventional cardiologist and possibly of an hematologist, and a neuroradiologist (28).
The first aim of any diagnostic workflow in this context is to identify the probability of a link between the index cryptogenic cerebral ischemic event and any given PFO. An initial neurologic examination is performed in all patients. The mechanism for a stroke cannot be determined from clinical evaluation alone; a thorough diagnostic evaluation, with proper timing, must be performed, and the results must be unequivocal for a stroke to be classified as cryptogenic. Silent cryptogenic strokes located in the grey matter should be considered, but also the possibility that silent white matter infarcts have a cardioembolic origin should be addressed.
It is recommended to give a special attention to an accurate diagnostic workout for arrhythmias including a 12-lead electrocardiogram (ECG) and a 24-72 hr dynamic Holter ECG monitoring, or continuous monitoring in patients admitted to a stroke unit or intensive care unit. If there is a strong clinical suspicion for atrial arrhythmias, a loop recorder may be implanted.
Before any invasive testing, an accurate clinical history is taken, focusing on symptoms potentially related to cardiac embolism and symptoms suggestive of arrhythmias. Blood tests for thrombophilia may be considered in selected patients.
The detection of PFO is performed using the ultrasound techniques, the transthoracic echocardiography (TTE), the transesophageal echocardiography (TEE) and transcranial Doppler (TCD). The advantages and disadvantages of these diagnostic studies are listed in Figure 4.
20
Modified from Pristipino C. et al, Catheter Cardiovasc Interv. 2013
Figure 4: The list of the main ultrasound techniques for PFO diagnosis. Echocardiography
For a PFO to be implicated in cryptogenic stroke, it must be capable of right-to-left shunting, which can be demonstrated by bubble contrast ecography. RtL shunting will only occur if the right atrial pressure transiently exceeds the left atrial pressure, which is best achieved by certain maneuvers, such as the Valsalva maneuver, sniffing, or coughing. Unless the septum primum is seen to deviate suddenly to the left atrial side, at the time when the right atrium is completely opacified by contrast, then the existence of a PFO cannot be confidently excluded.
The bubble contrast studies are initially performed during transthoracic echocardiography (TTE), in which no sedation is necessary. Bubble contrast echocardiography requires an experienced operator who is aware of the potential pitfalls of misdiagnosis, which include the difficulty in distinguishing a pulmonary-level shunt from a cardiac-level shunt. Contrast from a cardiac shunt usually appears within three cardiac cycles (29), (Figure 5).
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Figure 5: Bubble contrast echocardiography. a) Two-dimensional TEE image demonstrating the septal bounce to the LA (arrow) created by release of the Valsalva maneuver. b) Bubble contrast seen exiting a PFO into the left atrium (arrow). c) TTE images demonstrating a right-to-left shunt upon release of the Valsalva maneuver. Note the atrial septum bowing to the left (arrow). Abbreviations: LA, left atrium; LV, left ventricle; PFO, patent foramen ovale; RA, right atrium; RV, right ventricle; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.
If analysis with TTE bubble contrast shows a RtL shunt, transesophageal echocardiograpy (TEE) is necessary to confirm the presence and define the anatomy of the PFO, as well as to exclude the presence of other potential shunts. The most common shunts in adults are secundum atrial septal defects, which can appear anywhere in the fossa ovalis, even within the roof of the PFO tunnel. A potential limitation of TEE may be inadequate image quality of the inferior atrial septum. This region is imaged particular well by intracardiac echocardiography (ICE) that is used prevalently during the procedure.
Other shunts to be excluded in PFO diagnosis include anomalous pulmonary venous drainage, sinus venosus defects, unroofed coronary sinus, and ventricular septal defect. Pulmonary arteriovenous malformations can be diagnosed with TEE by observing bubble contrast entering the left atrium first via the pulmonary veins.
The position and size of the PFO must be determined before a closure procedure is undertaken, in particular, the dimension of the right and left atrial openings of the tunnel must be assessed, as well as the presence of single or multiple openings. The length of the tunnel is also important, as is the potential of the septum primum to retract, which is a feature often associated with ASAs and large PFOs. The echocardiologist needs a good knowledge of the various devices for PFO closure and should be able to predict which device might be the most
22
appropriate for the anatomy of each individual PFO. The distance of the PFO from surrounding structures is also important when estimating the behavior of the device, such as the presence and extent of Eustachian valve and ridge, Chiari network, aortic root, and superior left atrial free wall. More distant structures, such as the mitral valve and the coronary sinus, are only usually a concern in closure of large atrial septal defects.
Transcranial Doppler ultrasonography
Contrast transcranial Doppler ultrasonography (TCD) is a highly sensitive and noninvasive method to screen for right-to-left shunting, and shows close agreement with contrast echocardiography in shunt detection. This technique uses ultrasound to quantify the number of bubbles that reach the cerebral circulation (30). Patients with microemboli detected with contrast transcranial Doppler ultrasonography are more likely to have a history of cerebral ischemia. However, TCD does not provide the anatomical information that can be derived from echocardiography and, therefore, cannot be used in isolation.
III.2.4. PFO and cryptogenic stroke- treatment
The HEART-BRAIN TEAM should jointly take all the decisions regarding the treatment of patients. Primary prevention of stroke, either with drugs or device-based therapies, is not indicated in patients with an incidental PFO. In patients with cryptogenic ischemic stroke, transient ischemic attack (TIA), or systemic embolism, the therapeutic strategy is based on the evaluation of the probability that any given PFO is causally related to the clinical event and of the risk of recurrence. Given the invasive procedure-related adverse events, the indications for a progressively more aggressive or invasive therapy should be limited to patients with higher likelihood of a causative event and with a higher risk of recurrence (28), (Figure 6).
23
Modified from Pristipino C. et al, Catheter Cardiovasc Interv. 2013
Figure 6: Scheme of the recommendations for treatment of cryptogenic stroke/TIA with PFO and summary of the considered anatomical and clinical risk factors. Abbreviations: PFO, patent foramen ovale; R-L, right-to-left; AP, antiplatelet; OA, oral anticoagulants; CT, computer tomography scan; MR, magnetic resonance imaging; DVT, deep vein thrombosis; PE, pulmonary embolism; OSAS, obstructive sleep apnea syndrome.
The optimal pharmacologic strategy (anticoagulant vs. antiplatelet therapy) of medically treated patients with PFO and previous CS remains unclear (31). Percutaneous closure of PFO is a valid treatment for selected patients with paradoxical embolism (32), (33). Although three randomized trials have established poor benefits of percutaneous closure of PFO over medical therapy in prevention of recurrent CS (34), (35), (36), PFO closure is deemed useful in case of significant RtL shunt and recurrence of embolism (37). A recent large study-level meta-analysis (3311 patients from 21 clinical studies) showed that anticoagulant therapy was more effective that antiplatelet therapy in preventing recurrent stroke and/or transient ischemic attack, and that PFO closure was associated over the long term with significant net clinical benefit versus both medical therapy (38).
24 III.3. Atrial septal defects
The atrial septal defects (ASDs) represent one of the most common forms of congenital heart disease. The incidence of ASD is estimated to be 1 in 1500 live births and accounts for 30% to 40% of congenital defects presenting in adulthood. Females are affected twice as often as males.
III.3.1.Anatomy
A deficiency of the inter-atrial septal structure can present in several different forms (Figure 7). Ostium secundum ASDs account for approximately 75% of septal defects. The majority of secundum ASDs result from excessive resorption of the atrial septum primum, resulting in a deficient or absent fossa ovalis area. Absence or underdevelopment of the superior limbus of the septum secundum accounts for a minority of ostium secundum ASDs, and is likely the result of a distinctive morphogenetic process. Although the size and shape of secundum ASDs vary greatly, the vast majority of these defects are amenable to transcatheter closure. Other types of interatrial defects such as ostium primum, sinus venosus, or coronary sinus defects are usually not amenable to catheter-based closure.
Modified from Tobis J. et al., J Am Coll Cardiol, 2012
Figure 7: Types of ASDs. An illustration of the anatomy of atrial septal defects. Abbreviations: ASD, atrial septal defect; VSD, ventricular septal defect.
25 III.3.2. ASD pathophysiology
The degree of interatrial shunting is dependent upon the compliance of the right and left ventricles, the systemic and pulmonary circulation resistance, and the size of the defect. Larger ASDs lead to nearly equal right atrium (RA) and left atrium (LA) pressures, and therefore left-to-right shunting depends on the higher right ventricular compliance compared with the left ventricle. Volume overload of the right-sided structures leads to dilation of the RA, right ventricle (RV), and pulmonary system. Chronic left-to-right shunting in adults might lead to mild-to-moderate pulmonary hypertension, the single most influential factor in the clinical course of ASD (39). However, ASDs are not likely to produce the classic Eisenmenger’s syndrome seen with ventricular septal defect. Cases of severe pulmonary hypertension in ASD patients are possibly due to simultaneous primary pulmonary hypertension. In addition, atrial arrhythmias, most commonly atrial flutter/fibrillation, occur due to chronic right-sided heart volume and pressure overload.
III.3.3. ASD clinical presentation
Approximately 75% of adult patients with ASD are symptomatic by the fifth decade of life, with dyspnea on exertion and fatigue being the most common presenting symptoms. Small ASDs (10 mm) may close spontaneously by the age of 10 years. However, small ASDs might present later in life due to decreased left ventricular compliance associated with aging. Adults might also present with atrial tachyarrhythmias, paradoxical embolism, RV failure, platypnea, orthodeoxia, or recurrent pulmonary infections.
Atrial flutter and fibrillation are commonly seen in unrepaired ASD patients. The prevalence of these atrial arrhythmias increases with age and is seen in up to 22% of ASD patients over the age of 50 years. The likely mechanism for these arrhythmias is stretching of the atrium from chronic volume overload. Similar to a PFO, an ASD has an increased risk of paradoxical embolism, leading to cryptogenic stroke. Although the predominant inter-atrial shunt in ASD is left-to-right, transient elevations in RA pressure can produce reversal of flow and facilitate paradoxical embolism. The incidence of paradoxical embolism is reported as 11% to 14% in ASD patients referred for percutaneous closure (40).
Atrial septal defect is one of the most common congenital heart defects found during pregnancy. Pregnant patients with an unrepaired ASD suffer a higher risk of preeclampsia and fetal mortality when compared with the general population. The pregnant woman with an ASD
26
is predisposed to paradoxical embolism due to a hypercoagulable state and enhanced RtL shunting from increased plasma volume and decreased peripheral vascular resistance. Although percutaneous closure of an ASD during pregnancy can be accomplished, it is preferable to close large ASDs before pregnancy.
III.3.4. ASD detection
Transthoracic echocardiography remains the primary diagnostic modality for the detection of ASD, especially in children. In adults, a TTE can identify the margins of the deficient atrial septum and also assess the bordering structures (i.e., aorta, superior vena cava/inferior vena cava, pulmonary veins, atrioventricular valves, and coronary sinus). Patients with inadequate imaging, questionable ASD diagnosis, or unexplained RV volume overload, warrant further assessment with TEE. Contrast echocardiography with agitated saline has a limited role in the detection of ASDs but plays more of a role in the evaluation of residual shunts after transcatheter closure. A TEE with 3-dimensional imaging is a newer technique, which improves the visualization of ASDs, their surrounding atrial rims and structures, and can assist during percutaneous closure.
III.3.5. ASD indications for closure
The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommend ASD closure for patients with RA and RV enlargement, regardless of symptoms (Class I) (41). Long-term complications occur in up to 10% of patients with unrepaired ASDs. The age at which an ASD is repaired is the single most important predictor of long-term outcomes. In patients undergoing ASD repair before age 24, long-term survival is similar to age- and sex-matched control subjects. Patients with ASD surgical repairs between ages 25 and 41 had a reduced survival after 27-year follow-up, compared with an age- and sex-matched control group (42).
The ACC/AHA guidelines state that smaller ASDs (a diameter of < 5 mm) with no evidence of right ventricular enlargement or pulmonary hypertension do not require closure, because they are not considered significant enough to affect the clinical course of these individuals. Smaller ASDs that are associated with paradoxical embolism or orthodeoxia-platypnea can be closed according to guideline recommendations (Class IIA).
The only absolute contraindication for ASD closure pertains to patients with irreversible pulmonary hypertension (pulmonary vascular resistance > 8 Woods units) and no evidence of
27
left-to-right shunting (Class III). Therefore, in patients with known pulmonary hypertension, a complete assessment of reversibility should be performed. Patients with a pulmonary artery pressure less than thirds systemic pressure, a pulmonary vascular resistance less than two-thirds of systemic resistance, or a positive response to pulmonary vasodilator therapy can be considered for ASD closure.
Percutaneous closure of an ASD was pioneered by King and Mills in 1976 (43), but technology has evolved such that most adult secundum ASD closures can be performed as an outpatient procedure. Percutaneous ASD closure has largely replaced surgical treatment of secundum ASD, except for large defects (38 mm diameter), insufficient septal rims, or insufficient LA size to accommodate a device.
III.4. Percutaneous closure of the interatrial communications
Percutaneous closure of ASDs preceded percutaneous coronary intervention (PCI) by a couple of years (1976), and PFO only caught modest attention when it was described as a derivate of ASD closure in 1992 (44). The procedures are performed in a standard catheterization laboratory under physiological monitoring, fluoroscopic and/or echocardiographic guidance (TEE, including real-time three dimensional imaging or ICE). General anesthesia or deep sedation is usually required for TEE-guided procedures, whereas ICE-guided procedures can be performed without sedation. The intraprocedural imaging is mandatory to achieve the best results, being extremely valuable in defining the anatomy of the interatrial communication, and its interaction with the device during closure procedure and in assessment of the eventual complications.
III.4.1.Percutaneous device options
Although there are 15 devices internationally available for percutaneous secundum ASD closure, there are only 3 FDA-approved devices in the United States. The AMPLATZER Septal Occluder (ASO) was the first device approved by the FDA for transcatheter closure of ASD (Figure 8). The ASO device is composed of a braided nitinol wire mesh. It is a self-centering, self expandable device that is shaped into 2 flat discs with a connecting waist. Polyester fabric inserts are sewn into the nitinol wire mesh to promote tissue growth and defect closure. The ASO device is delivered via a 60- to 80-cm length sheath that is 6- to 12-F in diameter, depending on the device size. The device size is determined by the waist diameter, which ranges from 4 to 40 mm and corresponds to the atrial defect diameter. Once the device has been
28
placed, it can be easily recaptured into the delivery sheath for re-positioning, as long as the delivery cable has not been released. The ASO has been the most-used percutaneous device for structural heart disease with high success rates and low complication rates.
The Amplatzer Multi-Fenestrated Septal Occluder or “cribriform occluder” is similar to the ASO device with the exception of a narrow waist and equal sized atrial discs. This device is designed for use in ASDs with multiple contiguous defects.
The Gore HELEX Septal Occluder (HSO) was approved by the FDA in 2007 for percutaneous ASD closure. The HSO is composed of an expanded polytetrafluoroethylene membrane connected by a single nitinol wire (Figure 8). Once deployed, the HSO device has a double disc shape that straddles the septal defect. The nitinol wire frame forms a locking loop that secures the LA and RA disks to each other, thus sealing the atrial defect. The HSO device is available in diameters ranging from 15 to 35 mm, in 5-mm increments, and requires a 10-F delivery sheath catheter. The HSO device can be repositioned if the locking loop has not been deployed. Once the locking loop has been set, a retrieval cord is available for device removal if necessary. The HSO is soft and flexible and is well-tolerated but not self-centering and is preferable for use in smaller ASDs.
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The devices used for the PFO closure are very similar to those used for ASD closure; a general description of them is illustrated in Figure 9 (45).
Modified from Freixa X. et al., Can J Cardiol, 2014
Figure 9: General description of devices most often used for PFO closure. Abbreviations: ePTFE, polytetrafluoroethylene; GSO, Gore Septal Occluder; HSO, Helex Septal Occluder; PET, polyethylene; PFO, patent foramen ovale.
These procedures are relatively safe, with a major complication rate between 0.2% and 1.5% for procedural-related death, hemorrhage requiring transfusion, cardiac tamponade, fatal pulmonary emboli, device embolization, endocarditis, and thrombosis for PFO (46), and 1.2% to 2.5% for ASD, respectively (47). Minor complications including peri-procedural atrial arrhythmias, inflammatory reactions (perhaps due to nickel allergy), and femoral access site complications range from 3.4% to 11.5% (46), (48). Newer percutaneous devices and smaller catheters have led to a decrease in reported major and minor complications (35).
III.4.2.Pharmacological prevention of complications of percutaneous therapy
The position paper on the management of patients with PFO and cryptogenic stroke published in 2013 recommend a double antiplatelet therapy that should be started at least 12 hr before the procedure (28). In patients on oral anticoagulants, the anticoagulants are stopped, and when international normalized ratio (INR) is less than 2, the patient is started on intravenous, unfractionated heparin. Anticoagulants are stopped before the procedure to allow a proper and controlled heparin regimen during the procedure. Patients are maintained on heparin throughout the procedure, maintaining an activated clotting time greater than 200 sec.
30
After the procedure, they suggest to treat patients with aspirin and clopidogrel for 3–6 months, and aspirin alone for an additional 6 months. The decision to continue therapy beyond 6 months is at the discretion of the HEART-BRAIN TEAM, based on the evaluation of the residual shunt resulting from incomplete device endothelialization and on the relative weight of probability that further single factors (needing antiplatelet therapy) others than PFO may have come into play in the genesis of the index cerebral ischemic event(s).
Patients are also prescribed antibiotic prophylaxis against endocarditis in case of invasive procedures or surgical interventions during the first 6 months after the procedure. Patients who require oral anticoagulation for another condition resume warfarin as indicated for that condition, and do not take antiplatelet therapy while on anticoagulation unless otherwise indicated (e.g., some patients who have implantation of drug eluting stents may need ‘‘triple therapy’’ with oral anticoagulation, aspirin, and clopidogrel). The same pharmacological protocol could be extended also to the patients who underwent the transcutaneous closure of ASD (Figure 10).
Modified from Pristipino C. et al, Catheter Cardiovasc Interv. 2013
Figure 10: Proposed pharmacological protocol before, during and after percutaneous closure of PFO (expert consensus opinion). a) See specific companies instructions. b) > 6 months in case of residual shunt; indefinitely in older pts with atherovascular disease. c) > 6 months at physician discretion. Abbreviations : PFO, patent forame ovale; ASA, atrial septal aneurysm; Rx, therapy; UFH, unfractioned heparin; LMWH, low-molecular weight heparin; AB, antibiotics; IE infective endocarditis; tid, ter in die.
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IV. AIM OF THE STUDY
The aim of this study was to evaluate the feasibility, safety and short-term efficacy of percutaneous interatrial shunts closure in conscious patients, without general anaesthesia or deep sedation under transesophageal echocardiographic guidance.
V. MATERIALS AND METHODS
V.1. Study populationBetween 2005 and 2015, a total of 176 patients underwent percutaneous PFO and ASDs closure in our institution. A contemporary and retrospective review of the interventional reports identified 3 groups of patients: Group A, represented by the patients treated under general anaesthesia with TEE guidance; Group B, represented by the patients treated with intracardiac echocardiography (ICE); Group C, represented by the patients who were treated without general anaesthesia, and under TEE guidance.
The indications to PFO closure were one or more cerebral and/or peripheral suspect paradoxical embolism and neuro-imaging (CT or MR) evidence of single or multiple brain lesions. Paradoxical embolism was defined by the following features: 1) clinically and radiologically confirmed TIA, ischemic stroke or peripheral embolic event; 2) absence of other cardio-embolic sources or predisposing conditions; 3) migraine with aura not responsive to pharmacological therapy; 4) concomitant presence of a PFO with a spontaneous or Valsalva- induced RtL shunt at the contrast TEE.
The indications to ostium secundum ASD closure were represented by the evidence of at least one thromboembolic event or by the enlargement of right heart chambers, regardless of symptoms, following the American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines (41).
The exclusion criteria were neurodegenerative, inflammatory, or infective diseases, contraindication to antiplatelet therapy, irreversible pulmonary hypertension (pulmonary vascular resistance >8 Woods Units) and no evidence of left-to-right shunt, the presence of large defects (>38 mm diameter). All patients were carefully informed about all the steps of the procedure, and its possible complications; a particular attention was given to the issues
32
connected to a probabilistic approach to their cardioembolic event. All patients gave their written informed consent to perform the procedure.
V.2. Pre-procedural evaluation
The patients with PFO and indication to percutaneous closure underwent case-by-case evaluation by the HEART-BRAIN TEAM, with an initial neurological evaluation followed by the cardiologic and interventional one; the first aim of the diagnostic workflow was to identify the probability of a link between the thrombembolic event and the interatrial shunt. Screening for protein C, protein S and antithrombin III deficiency, factor V Leiden mutation, hyperhomocysteinemia and methylenetetrahydrofolate reductase mutations were performed in young patients with a history of deep venous thrombosis.
Ultrasound assessment
Transthoracic echocardiography (TTE)
In all patients an initial complete transthoracic echocardiography was performed, with the quantification of the dimensions and function of the heart chambers, as well as of the valves. In case of ASD and normal right heart, the pre-procedural evaluation consisted in repeated TTE to access volume overload and enlargement of right sided chambers in order to determinate the appropriate time for closure.
Transesophageal echocardiography (TEE)
Pre-procedural TEE was routinely performed in all patients by use of a commercially available system (Acuson Sequoia; Philips iE33), in order to examine the presence of the interatrial communication and its morphology, and to exclude additional abnormalities, such as an anomalous pulmonary venous drainage. During TEE the presence of other embolic sources, such as left atrial appendage thrombus, or atherosclerotic aortic plaques were assessed.
In PFO closure, tunnel length, associated aneurysms (ASA) of the interatrial septum (IAS) and septal pouch are important factors (Figure 11). A PFO was categorized as “complex” if any of the following findings is present: tunnel length beyond 7 mm, multiple openings into the LA, ASA or septal pouch, IAS thickness of 10 mm or more, presence of a Chiari network or a Eustachian valve (Figure 12), and hybrid defects (IAS with multiple fenestrations).
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Figure 11: PFO size and tunnel length. Overview of PFO anatomy in a longitudinal-axis view on 2-dimensional TEE. The arrow separating the septum primum from the septum secundum measures the PFO size. The arrow showing the overlap between the septum primum and the septum secundum indicates the tunnel length. Abbreviations: LA, left atrium; RA, right atrium.
Figure 12: Eustachian valve. Longitudinal view on TEE demonstrating a prominent Eustachian valve at the junction of the right atrium (RA) and the inferior vena cava (IVC). Abbreviations: LA, left atrium; SVC, superior vena cava.
It is particularly important to characterize the ASD rims defined as the IAS tissue surrounding the ASD (Figure 13). The rims are named after the respective adjacent structures: superior vena cava rim (superior), aortic rim (anterosuperior), coronary sinus rim (anteroinferior), inferior vena cava rim (inferior), and posterior rim (posterior). If the inferior rim was less than 5 mm wide, device closure was not an option. Absence of an aortic rim is no contraindication for device closure but may require a certain degree of over-sizing of the ASD-occluder encompassing the aortic bulb.
34
Figure 13: ASD with a short aortic rim assessed by TEE in short axis view. Abbreviations: ASD, atrial septal defect; IAS, interatrial septum; Ao, aorta; RA, right atrium.
Improved spatial orientation and a substantial information gain regarding the characteristics of an ASD, “complex” PFO, or an IAS with multiple fenestrations was obtained using the RealTime-3D TEE.
Transcranial Doppler ultrasonography
In all patients with suspected RtL intracardiac shunt the TCD was performed by monitoring middle cerebral artery flow through the temporal bone window. The middle cerebral artery was identified with color Doppler in its proximal portion, and the effectiveness of the Valsalva manoeuvre was verified by the reduction of the arterial flow velocity, in comparison with the basal spectrum. The TCD was considered positive if at least 10 microembolic signals were recorded (Figure 14).
Figure 14: Contrast TCD during the Valsalva maneuver. The “curtain” effect of numerous microembolic signs in the middle cerebral artery which was identified with color Doppler.
35 V.3. Procedure of percutaneous closure of the interatrial shunts
All the procedures of percuteneous closure of the interatrial shunts were performed in the catheterization laboratory with a right femoral venous access approach, under fluoroscopy and echocardiographic (TEE or ICE) guidance.
In patients from Group A the procedure was performed in general anaesthesia under TEE guidance. For Group B the echocardiographic images of the IAS were assessed by ICE in local anaesthesia using 8 or 10 Fr. introducers from left or right femoral vein. The patients from Group C underwent the procedure in local anaesthesia, under uninterrupted TEE guidance, and a mild sedation obtained with small bolus of morphine intravenously; 0.5 mg of atropine were administered intramuscularly 30 minutes before the start in order to reduce salivary secretion.
All patients received an intravenous antibiotic prophylaxis before the procedure; a 300 mg loading dose of clopidogrel or 250 mg of ticlopidine and 100 mg of acetylsalicylic acid were administered to all the patients without any antiplatelet therapy. They received also intravenous heparin in order to keep an activated clotting time > 250 sec during the procedure.
In the PFO procedures the IAS was crossed with a 5/6 Fr. diagnostic catheter (multipurpose or pigtail catheter). The pigtail catheter was preferred to the multipurpose one when it was possible, in order to cross the biggest defect in case of multiple defects. After catheter exchange, the delivery sheath was then placed in the left atrium. After positioning of the left and right atrial part of the occluder, the correct positioning of the device and the absence of a RtL shunt was verified under echocardiographic and fluoroscopic guidance. The firmness of the device was consequently tested through the Minnesota wiggle; after verification of correct placement, the device was released and the transseptal sheath was removed.
Balloon sizing of the ASD defect was performed in all cases in order to choose the appropriate device size. Device size was selected depending on the ASD diameter as assessed during balloon sizing of the defect. In cases where the balloon was firmly stabilized in the ASD on a regular 0.035˝ guidewire, the device was selected about 30% larger than the ASD diameter as assessed by determination of the diameter of the waist of the sizing balloon. In other cases, oversizing was 50% or more. After the confirmation of a secure position (the push-and-pull maneuver, like for PFO) the device was released from delivery system.
36
The devices used were those commercially available for the PFO and ASD closure at the time of implantation. A TTE was performed in all patients before discharging in order to confirm unchanged device position.
V.4. Follow-up evaluation
At discharge, dual antiplatelet therapy with acetylsalicylic acid 100 mg once daily for 3-6 months and clopidogrel 75 mg once daily for 1-3 months was prescribed for antithrombotic protection until full device coverage by endothelium. All patients were scheduled for TTE at 1 month to assess the right positioning of the device, and to exclude its migration, erosion and thrombosis, and for TCD at 6 months to evaluate the presence of residual shunting. The patients from Group C underwent a telephonic interview in order to identify the recurrence of symptoms.
V.5. Statistical analysis
The statistical analyses were performed using SPSS 17.0 (SPSS Inc., Chicago, IL, USA). Parametric data are expressed as mean ± SD and non-parametric data were given as frequency and percentage. Groups were compared for categorical data or frequency of events using the 2 test and for continuous variables using unpaired Student’s t-test. All tests were 2-sided, and p< .05 was considered statistically significant.
37
VI. RESULTS
A total of 176 patients (mean age 49±12.2 yrs, 68 females) who underwent percutaneous PFO and ASDs closure in our institution were enrolled in our study. From 2005 to 2007 the procedures were performed in general anaesthesia (GA) under TEE guidance (32 pts.) (Figure 15). In 2008, the intracardiac echocardiography had began to be used, so the number of the procedures under GA were progressively reduced (8/25 in 2008, 4/21 in 2009), and they completely stopped in 2009. In 2010 almost all the procedures were carried out using ICE for intraprocedural imaging (10/11pts.), 1 being performed without GA and under TEE guidance. The number of procedures without GA and with TEE started to increase in 2011 (14/21 with ICE, 7/21 with TEE), and 2012 (6/21 with ICE, 15/21 with TEE) and they represented all the procedures from 2013 to 2015 (45 pts.).
According to the methodology used to perform the intervention, the study population was divided in 3 groups: Group A (TEE+GA)= 53 patients, Group B (ICE, no GA)= 55 patients, and Group C (TEE, no GA)= 68 patients.
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 0 5 10 15 20 25 30 TEE ICE General anesthesia Total n° of procedures
Figure 15: Temporal distribution of the percutaneous closure of the interatrial communications. Abbreviations: TEE, transesophageal echocardiography; ICE, intracardiac echocardiography; n°, number.
38 VI.1. Clinical characteristics
The baseline characteristics of all consecutive 176 patients are presented in Table 1. In Group B there were more women than in group A (p= .02 Group B vs. Group A), with no significant difference between B and C. No significant difference in BMI, blood pressure and cardiovascular risk factors between the 3 groups was observed.
158 pts. had a PFO, and an ASD was present in 19 pts, one patient having a dual communication (Table 2). In 31.9% of the population the ASA was present, with no difference between groups. The TCD was performed in 93 pts (52.8%), with evidence of the RtL shunt in 92/93. All patients had normal systolic left ventricular function (62.4±3.7%), and dilated right heart chambers were found in 11 pts, with 10 belonging to the Group C. Data on positive neuroimaging for the presence of ischemic brain lesions were available in 135 pts (76.7%).
A hypercoagulable state was present in 17 pts, 11 with hyperhomocysteinemia, 4 with MTHFR polymorphism, and the rest of 2 pts with antiphospholipid syndrome (Table 3).
The indications to percutaneous closure of the interatrial shunts (Table 4) were represented by: TIA in 91 pts. (51.7%); stroke in 64 pts. (36.3%); migraine in 15 pts. (8.5%); dilated right heart chambers in 11 pts (6.2%), decompression disease in 1 pts (0.5%), and temporary closure in 1 pts (0.5%). The last one was performed during dual chamber PM lead extraction for endocarditis; a large vegetation was present in the right atrium near the right appendage, and the diagnosis of PFO was made before the procedure, so the decision to perform the temporary closure of PFO was taken to minimize the risk of embolization. No embolic complications were observed during the transvenous extraction of the leads; the TEE performed one month later, showed no signs of endocarditis, and a small RtL shunt at the level of PFO during Valsalva manoeuvre, with no clinical indication till that moment, to the permanent closure, so the patient continues his periodical clinical and ecographic follow-up.
39 VI.2. Procedural data and in-hospital outcome
Procedural data are shown in Table 5. The implantation procedure with the correct release of the device was successful in all, but 4 patients (172/176, 97.7%). In 3 pts. the procedure was aborted due to impossibility to cross in the left atrium with the diagnostic catheter and the lack of evidence of passage of bubbles with echocardiography. The forth patient underwent surgical closure of the ASD for anatomical reasons (the disappearance of the posterior rim during the balloon inflation).
The devices used were those commercially available at the time of the implantation (Figure 16); the majority were AMPLATZER, with a total of 139 devices (80.8%), most of them in Group B and C (26 in Group A, 49 in Group B, and 62 in Group C respectively). The AMPLATZER Cribriform Occluder, designed for the closure of multifenestrated defects, was implanted in 25 pts. The STARFLEX device was used exclusively in the Group A (14/53 pts, 26.4%), and the BIOSTAR one in 18 pts (13 pts. from Group A, and 5 from Group B). The mean diameter of all the devices used was 24.8±5 mm (range 8-40 mm).
Figure 16: Types of devices used for percutaneous closure of the interatrial shunts.
The mean of the total procedure time was 72.9±24.7 min., with significant differences between groups (Figure 17). The longest were the procedures performed under general anaesthesia and TEE guidance (Group A): 82.5±16.6 min. The total time was reduced after the introduction of ICE (65.8±22.7 min, p=.05). The shortest total time procedure was found for the procedures performed in conscious patients, under TEE guidance (59.9±25.4 min., p=.001 vs. Group A).
40
Figure 17: The total procedure time in the 3 different groups of patients. * p= .05 Group B vs. Group A; ** p= .001 Group C vs. Group A; p= n.s. Group B vs. Group C.
The mean radiation exposure was of 2493±3160.7 cGy/cm2. There was a significant decreasing in radiation exposure dose in Group B (2223.4±2540 cGy/cm2) and Group C (1452.6±1158 cGy/cm2) when compared to Group A (3995.6±4486 cGy/cm2) (Figure 18).
Figure 18: The radiation exposure dose in the 3 different groups of patients. * p= .02 Group B vs. Group A; ** p< .0001 Group C vs. Group A; p= .05 Group C vs. Group B.
41
A mild decrease in the total contrast agent dose was also observed when ICE was introduced for the procedure monitoring (25.4±18.4 ml). The decrease was significantly lower in group C (15.8±18 ml), when compared with 39.6±35 ml in Group A (p<.0001) (Figure 19).
Figure 19: The contrast agent doses used during the 3 types of procedures. * p= .01 Group B vs. Group C; ** p< .0001 Group C vs. Group A; p= n.s. Group B vs. Group A.
54 patients from Group C had a PFO and 15 an ASD, one patient having a dual defect; in this particular patient the device was successfully deployed at the level of ASD, the PFO remained uncovered. The total time procedure, the radiation exposure and dose of contrast agent were significantly higher in the patients with ASD than in the patients with PFO. No significant difference was observed in the dose of morphine used for the mild sedation (Table 6).
There were registered one major intraprocedural complication in Group B (device embolization), and a total of 12 minor complications (6.8%) distributed in all three groups (Table 7). During the procedure 5 episodes of new onset atrial fibrillation were recorded, 4 of them being treated in cath lab with amiodarone i.v., and one with electrical cardioversion the next day following the intervention. The vascular complications (1.7%) consisted in 2 femoral superficial hematomas and one femoral pseudoaneurysm, resolved with local compression. At the end of procedure an erythematous skin reaction likely to allergic reaction to contrast agent was found in 3 patients, treated with i.v. cortisone.
A patient from Group B underwent psychomotor agitation during the initial phase of femoral vascular access, with successive development of sustained ventricular tachycardia with
