Indications for AFR implantation

In spite of the significant heterogeneity and complexity of baseline anatomies, commonly shaped by a history of multiple surgical and percutaneous treatments, the atrial flow regulator device was implanted according to five primary clinical indications.

Its use spans a wide age range, with clinical indication rather than patient age serving as the main determinant. In paediatric patients, it has been employed in cases of left heart failure—particularly in those with congenital left ventricular inflow or outflow tract obstruction—as a bridge to further interventions. It has also been used in children with dilated or restrictive cardiomyopathy as a venting strategy during extracorporeal membrane oxygenation support.

In both children and adults, the atrial flow regulator has shown utility in managing pulmonary hypertension unresponsive to maximal pharmacological therapy, as well as in patients with a failing Fontan circulation, regardless of age. These varied applications underscore its versatility and indication-driven use across the lifespan.

Heart failure

Structural or functional impairment of ventricular filling or ejection of blood is a defining characteristic of heart failure. ^{Reference Heidenreich, Bozkurt, Aguilar, Larry Allen, Joni Byun and Monica Colvin8}

The burden of heart failure is increasing, especially in the CHD population and in many cardiomyopathies affecting children; a common finding in these conditions is left ventricular diastolic and/or systolic dysfunction, elevated left ventricular filling pressures, and consequently, an increase in left atrial pressure and often postcapillary pulmonary hypertension.

This is frequently the cause of dyspnoea at rest or during exercise in these categories of patients. ^{Reference Fukuta and Little9} After failure of medical therapy, reducing increased left atrial pressure with a percutaneously delivered device to create an interatrial left–right shunt to decompress the left atrium is an appealing, non-pharmacological strategy to alleviate symptoms in patients with heart failure. ^{Reference Feldman, Komtebedde and Burkhoff10}

Recently, several novel devices to treat heart failure symptoms have been tested successfully in adults. ^{Reference Malek, Neuzil and Gustafsson11} They include the V-Wave® Ventura®Interatrial Shunt system (V-Wave Ltd., Or Akiva, Israel), the Corvia IASD (Corvia Medical, Tewksbury, MA, USA), the AFR (Occlutech, Schaffhausen, Switzerland), and the Edwards Transcatheter Atrial Shunt System (a left atrium-to-coronary sinus shunt device by Edwards Lifesciences, Irvine, California).

These appropriately sized devices create passive left atrial decompression with controlled decrease in left ventricular output and potential reduction in pulmonary artery wedge pressure, without significantly increasing the right atrial and pulmonary artery pressures. ^{Reference Søndergaard, Reddy, Kaye, Malek, Walton and Mates12,13}

In this setting, the implantation of the atrial flow regulator device in paediatric patients with CHD—such as left ventricular inflow or outflow tract obstruction, often requiring multiple surgeries—or in children with dilated or restrictive cardiomyopathy on extracorporeal membrane oxygenation support, facilitates left heart decompression by creating a left-to-right shunt. This intervention helps relieve pulmonary congestion, improves subendocardial perfusion, and reduces myocardial oxygen consumption. ^{Reference Malek, Neuzil and Gustafsson11,Reference Bakhshaliyev and Ozdemir14}

In the largest multicentre case series of 40 patients with CHD or children with cardiomyopathies or pulmonary hypertension, most patients were affected by left heart lesions, varying from critical aortic stenosis with fibroelastosis to Shone-like complex to hypoplastic left heart syndrome after multiple surgeries.

At median FU of 330 days, the NYHA functional class evaluated before and after the implantation of the atrial flow regulator device improved in 20 patients, and in 12 patients, it did not change. In only one patient, his NYHA functional class worsened. ^{Reference Butera, Piccinelli, Kolesnik, Averin, Seaman and Castaldi15}

Similar data have been reported in another case series of 8 children with heart failure and high filling pressure due to dilated or restrictive cardiomyopathy requiring an atrial flow regulator device implantation. The authors reported two patients with dilated cardiomyopathy on extracorporeal membrane oxygenation run who died from sepsis and multiple organ failure, and one patient with pulmonary hypertension secondary to restrictive cardiomyopathy who died 8 months after device implantation for disease progression. In the remaining patients, a reduction of left atrial dilation, postcapillary pulmonary hypertension, and heart failure symptoms were observed. ^{Reference Castaldi, Cuppini, Sirico, Cattapan, Fumanelli and Pozza16}

A special population is represented by patients with restrictive cardiomyopathy, which is a condition characterised by a normal or decreased volume of both ventricles associated with biatrial enlargement, impaired ventricular filling with restrictive physiology, and normal (or near normal) systolic function. ^{Reference Maron, Towbin and Thiene17}

In the paediatric population, several single-centre studies have shown poor outcomes for this condition, with approximately 50% of patients dying within 2 years of diagnosis, usually of sudden death. ^{Reference Lewis18–Reference Rivenes, Kearney, Smith O’Brian, Towbin and Denfield21}

The causes of restrictive cardiomyopathy are several and include infiltrative conditions, storage diseases, and endomyocardial processes; this leads to a decrease in the relaxation capacity of the ventricle with consequent increase in ventricular filling pressures and postcapillary pulmonary hypertension. Isolated postcapillary pulmonary hypertension in heart failure with preserved ejection fraction can progress to combined pre- and postcapillary pulmonary hypertension, and ultimately to right ventricular pressure overload and failure. ^{Reference Webber, Lipshultz and Sleeper22}

Medical treatment options are limited, and other device-based solutions in the adult population, such as atrial shunts, electrical and neurostimulators, and mechanical circulatory support, have been proposed to reduce the left atrial volume overload, postcapillary pulmonary hypertension, ameliorate the symptomatology of heart failure, and the clinical history of these patients.

Several of these devices are currently under investigation and have shown promising results in a variety of preclinical and clinical studies. ^{Reference Burlacu, Simion, Nistor, Covic and Tinica23,Reference Rosalia, Ozturk, Shoar, Fan, Malone and Cheema24}

Hansmann et al. reported the first use of an atrial flow regulator in the paediatric population with restrictive cardiomyopathy. The authors described clinical and haemodynamic improvement in 3 children with restrictive cardiomyopathy. One patient died 25 months after the device implantation for disease progression.

They conclude proposing atrial flow regulator implantation as a bridge to heart transplant or destination therapy in restrictive cardiomyopathies due to the haemodynamic and clinical benefit of unloading the left atrium, reducing the postcapillary pulmonary hypertension. ^{Reference Hansmann, Sabiniewicz and Sabiniewicz25}

These outcomes have been independently validated by other case series of the paediatric population, including young patients with restrictive cardiomyopathy, confirming its role as a bridge to heart transplant or a destination therapy in those patients who are not heart transplant candidates. ^{Reference Butera, Piccinelli, Kolesnik, Averin, Seaman and Castaldi15–Reference Maron, Towbin and Thiene17,Reference Castaldi, Padalino, Sirico, Guariento, Vida and Di Salvo26}

Pulmonary hypertension

Pulmonary hypertension is defined as the elevation of pulmonary arterial pressure and is commonly diagnosed by echocardiography or cardiac catheterisation after it becomes clinically apparent. ^{Reference Abman, Hansmann, Archer, Ivy, Adatia and Chung27}

Pulmonary hypertension associated with CHD is an important cause of long-term pulmonary hypertension in children.

It is increasingly being recognised that paediatric pulmonary hypertension is different from adult pulmonary hypertension in aetiology, clinical presentation, and outcomes. ^{Reference Mukherjee and Konduri28}

Children with pulmonary hypertension suffer more frequently from syncope than adults. The aetiology for syncope in children with pulmonary hypertension is more related to haemodynamic changes than to arrhythmia.

This is due to an acute and severe increase in pulmonary vascular resistance resulting in an insufficient transpulmonary blood flow with massive dilation of the right ventricle and subsequent compression of the left ventricle, low stroke volume, and low blood pressure. ^{Reference Rosenzweig, Abman, Adatia, Beghetti, Bonnet and Haworth29–Reference Sanz, García-Alvarez and Fernández-Friera33}

According to the clinical practice guidelines, the creation of a pre-tricuspid restrictive defect with atrial septostomy may be considered for patients in WHO/Ross III-IV functional class with syncope and/or severe right ventricular failure who remain unresponsive to maximal pharmacological treatment or as a bridging therapy to lung transplant. ^{Reference Marc, Gabor and Marius Hoeper31}

The creation of an interatrial right-to-left shunt with the implantation of device such as atrial flow regulator in patients with pulmonary arterial hypertension may reduce the clinical signs of acute or chronic right heart failure and congestive dilatation of the right atrium, maintaining systemic output during pulmonary hypertension crisis and preventing syncope, at the expense of systemic desaturation.

Besides enlarged and distended right heart structures, a reduced filling of the left side due to significantly reduced transpulmonary blood flow may be additionally present in patients with pulmonary arterial hypertension. ^{Reference Takatsuki, Yanai, Ikehara, Nakayama and Matsuura34–Reference Kerstein, Levy, Hsu, Hordof, Gersony and Barst37}

The effectiveness of the atrial flow regulator in adult patients with pulmonary arterial hypertension is under evaluation in the PROPHET trial (Pilot Study to Assess Safety and Efficacy of a Novel Atrial Flow Regulator in Patients with Pulmonary Hypertension), but results are still unavailable. ⁷

Some case reports and case series described the benefits of creating an interatrial shunt in children and adult patients with severe pulmonary hypertension not responsive to medical treatments.

The atrial flow regulator offers the advantage of a predictable shunt size with restricted flow, instead of septostomy with unrestricted right-to-left shunt, potentially reducing the risk of acute severe desaturation. Device sizing in this context depends on multiple factors, including the patient’s weight and haemodynamics, to maintain stroke volume during an acute pulmonary hypertension crisis and controlled desaturation.

Implantation of the atrial flow regulator device has been reported in 12 patients with severe pulmonary arterial hypertension presenting with syncope and right heart failure. All procedures were successful without major complications. All patients had relief of syncope with improvement of the 6-min walk distance test at a median follow-up of 189 days; the device was patent in all patients. ^{Reference Rajeshkumar, Pavithran, Sivakumar and Vettukattil38}

Other series included patients with idiopathic pulmonary hypertension, pulmonary hypertension associated with CHD or lung disease, presenting with syncope and/or right heart failure, and unresponsive to standard drug treatment. ^{Reference Butera, Piccinelli, Kolesnik, Averin, Seaman and Castaldi15,Reference Youssef, Averin, Richards, Sheppard, Seaman and Pietrosanu39}

Fontan circulation

The Fontan operation has improved the survival of children born with CHD, resulting in a functional single ventricle physiology, such as hypoplastic left heart syndrome or tricuspid atresia; the Fontan procedure is the final stage of three operations; however, it cannot recreate a physiological circulation. ^{Reference Gewillig and Brown40}

In this operation, the systemic venous blood is diverted from the systemic veins to the pulmonary arteries in the absence of a subpulmonic ventricle, resulting in a passive flow of blood through the pulmonary vasculature.

The absence of the right ventricle to pulmonary arterial coupling has a profound influence on the systemic venous return and the pulmonary circulation. ^{Reference Gewillig and Brown40}

Differently from the normal cardiovascular system, where the pulmonary and systemic circuits are connected in series and driven by two synchronised pumps, in the Fontan circulation, the loss of the sub pulmonary pump is associated with an elevated pressure in the caval system, a non-pulsatile blood flow in the pulmonary circuit and at least a mild reduction of the systemic output. ^{Reference Rychik, Fogel, Donofrio, Goldmuntz, Cohen and Spray41}

The natural history of Fontan patients is characterised by a progressive increase in pulmonary vascular resistance, associated with chronic preload deprivation. This pathophysiological state may lead to the development of both systolic and diastolic dysfunction, ultimately resulting in a reduction of cardiac output.

This, together with other poorly known mechanisms, leads to Fontan circulation failure with chronic venous hypertension, peripheral stasis, congestion in the lymphatic system, and clinical symptoms of Fontan-associated liver disease, plastic bronchitis, and protein-losing enteropathy. ^{Reference Laine, Katz, Gabel and Drake42,Reference Itkin, Piccoli, Nadolski, Rychik, DeWitt and Pinto43}

Creating a conduit fenestration, establishing a right-to-left shunt, is traditionally employed to relieve venous pressure in the Fontan conduit and improve early postoperative haemodynamics, decreasing systemic venous pressure and congestion, and improving cardiac output; furthermore, it may decrease postoperative morbidity and mortality in selected cases, not only in high-risk patients. ^{Reference Hraška44}

However, the haemodynamic improvements are obtained at the cost of reduced oxygen saturation due to right-to-left shunting, which may be excessive in the case of large fenestration. ^{Reference Albal, Menon, Kowalski, Undar, Turkoz and Pekkan45}

An occluded surgical fenestration can be recanalised and stented, or a new fenestration can be created using a baffle puncture and stent placement. Thrombotic occlusion and/or systemic embolisation are frequent complications, particularly if the fenestration diameter is less than 5 mm. ^{Reference Albal, Menon, Kowalski, Undar, Turkoz and Pekkan45}

In the context of a Fontan circulation, the atrial flow regulator device implantation has a dual potential function:

1. 1. In a patient with failing Fontan circulation, an atrial flow regulator device can be implanted to create a calibrated shunt between the conduit and the common atrium to relieve elevated systemic venous pressures at the expense of controlled systemic desaturation. ^{Reference Manuri, Calaciura, de Zorzi, Oreto and Raponi46}

2. 2. Severely cyanosed patients with large Fontan fenestration may benefit from the use of the atrial flow regulator device, which can be used to downsize the fenestration, and consequently, the right-to-left shunt, thus leading to an increase in systemic oxygen saturation. ^{Reference Pascall, Jones, Savis, Rosenthal and Qureshi47}

From a technical point of view, the atrial flow regulator implantation is possible both in extracardiac conduit and in a lateral tunnel.

In most cases, the device is implanted through a preexisting conduit fenestration or by creating a new one using a transeptal needle or radiofrequency via femoral vein access.

The presence of a stent in the conduit does not represent a contraindication to the procedure.

In such cases, a Brockenbrough needle, with the help of the hard tip of a 0.014″ coronary wire connected to a surgical electrocautery system set to “cutting” mode, can be used to successfully perforate the previously stented conduit. ^{Reference Butera, Piccinelli, Kolesnik, Averin, Seaman and Castaldi15}

Alternative approaches, such as the transjugular or transhepatic approach, have been described to create a fenestration between native tissues and the atrium. ^{Reference Rafał, Anna, Joanna, Paweł and Tomasz48–Reference Kenny, McMahon and Walsh50} . In case of transhepatic approach, a short sheath 3–4 Fr larger than the required Occlutech delivery system should be used to avoid friction in the hepatic vein and liver parenchyma. ^{Reference Butera, Piccinelli, Kolesnik, Averin, Seaman and Castaldi15}

Generally, smaller devices (ie, 4–6 mm) have been used for patients with desaturating Fontan to reduce the fenestration, improving oxygen saturation without a significant increase in pressure in the Fontan circulation.

Deciding to implant an atrial flow regulator device seems to be a valid option over surgical approaches due to the poor pre-procedural status of many of these patients and because the use of other devices, such as stents or custom-made fenestrated atrial septal devices, has a potential higher risk of thrombotic occlusion and/or systemic embolisation. ^{Reference Vyas, Driscoll, Cabalka, Cetta and Hagler51}

Interestingly, only 4-mm devices have shown early thrombosis in patients with failing Fontan and Fontan desaturation; the devices were removed and successfully replaced with 6-mm devices.

This can be mainly explained by the increased thrombotic risk associated with the Fontan population, which is inherently predisposed to thromboembolic complications. ^{Reference Butera, Piccinelli, Kolesnik, Averin, Seaman and Castaldi15,Reference Youssef, Averin, Richards, Sheppard, Seaman and Pietrosanu39}

Extracorporeal membrane oxygenation

The atrial flow regulator device might be used to unload the left cavities in patients with end-stage heart failure or cardiomyopathies and high filling pressure during extracorporeal membrane oxygenation support by creating a calibrated interatrial shunt. This procedure has been demonstrated to have some benefits in terms of shorter support duration.

Several case series have shown effectiveness in this setting, with the aim to unload the left cavities, improving the myocardial perfusion, reducing oxygen consumption and the risk of arrhythmias, showing some potential in patients with low weight. ^{Reference Piccinelli, Castro-Verdes, Fraisse and Carles52–Reference Bautista-Rodriguez, Hascoët and Fraisse54}

The mortality and the risk of adverse events appear to be higher in the subpopulation of patients on extracorporeal membrane oxygenation run when compared to patients with different indications for device implantation; the reasons seem to be the poor underlying clinical conditions and the higher thromboembolic risk of these patients. ^{Reference Butera, Piccinelli, Kolesnik, Averin, Seaman and Castaldi15,Reference Castaldi, Cuppini, Sirico, Cattapan, Fumanelli and Pozza16}

Although the device was used as a rescue therapy in this patient subpopulation, it has proven effective in improving left ventricular function, reducing left atrial hypertension and pulmonary oedema, and decreasing the need for inotropic support.

These effects, in turn, can lead to clinical improvement, serving as a bridge to ventricular assist device implantation or heart transplantation. ^{Reference Piccinelli, Castro-Verdes, Fraisse and Carles52–Reference Bautista-Rodriguez, Hascoët and Fraisse54}

The use of the stent in the atrial septum has the same application principle, although the use of the atrial flow regulator device is potentially simpler, faster, and safer than atrial septum stent implantation or balloon atrial septal angioplasty, even in terms of thromboembolic risk. ^{Reference Veeram Reddy, Guleserian and Nugent55}

Description of the procedure

The atrial flow regulator is made of self-expandable Nitinol wire mesh preshaped into two discs for the right atrium and left atrium, with a smaller waist between them (5- and 10-mm height) and a central fenestration of size 4-, 6-, 8-, and 10-mm diameters (only 8- and 10-mm devices are CE Mark).

The diameters of the discs are 16 mm, 18 mm, 21 mm, and 23 mm, respectively. They are delivered through 8, 10, 12, and 14 Fr sheaths. ^{Reference Paitazoglou and Bergmann56}

In most cases, transcatheter interventions are performed in the cardiac catheterisation laboratory under general anaesthesia or in selected patients under conscious sedation, guided by transesophageal echocardiography.

Femoral venous access is usually preferred, although transhepatic, jugular, or subclavian vein access is also possible. Heparin with a dose of 100 IU/Kg and prophylactic intravenous antibiotics are usually given. Haemodynamics assessment is mandatory.

In the absence of preexisting atrial or conduit fenestration, transeptal puncture with the transeptal needle to access the atrium is necessary, especially in patients with Fontan circulation.

Sometimes it is useful to predilate the created/ existent fenestration with a balloon, to create a better landing zone for device implantation and to reduce the risk of thrombosis.

In most cases reported, the authors used intermediate pressure and high pressure with a size chosen from 2 to 8 mm larger than the final device size selected.

In some cases, a cutting balloon is used both at the level of the atrial septum and the Fontan conduit. When the fenestration is already present, it is generally not predilated with a balloon before atrial flow regulator implantation. ^{Reference Butera, Piccinelli, Kolesnik, Averin, Seaman and Castaldi15}

After creating an atrial defect, a long delivery sheath is introduced over a stiff guide wire positioned in a pulmonary vein.

Device implantation technique is similar to the percutaneous closure of atrial septal defects, with a procedural success rate approaching 100% and a low risk of procedural and periprocedural complications.

After confirming the proper positioning and efficacy of the prosthesis using a transesophageal echocardiogram, the device is released by removing the delivery cable.

Antithrombotic therapy and device size

Establishing a specific antithrombotic or anticoagulant therapy for these patients seems to be challenging due to the heterogeneity of this patient subgroup in terms of anatomy, indication, and pro-coagulant states. ^{Reference Andreas and Harald Kühl57}

In most cases, maintaining device patency is achieved through single antiplatelet therapy.

The use of oral anticoagulation is often recommended for patients with Fontan to reduce the risk of thromboembolism caused by chronically congested systemic veins in the presence of a right-to-left shunt. ^{Reference Seipelt, Franke, Vazquez-Jimenez, Hanrath, von Bernuth and Messmer58}

The use of unfractionated heparin continuous infusion in patients with end-stage cardiomyopathy or advanced heart failure on extracorporeal membrane oxygenation appears to be the most commonly used therapy to prevent both circuit and patient thrombosis. ^{Reference Rebecca, Vera and Paul59}

Device size

Choosing the most appropriate size of the fenestration to achieve the expected haemodynamic effects is challenging, and it is, in most cases, based on the patient’s weight, anatomy, and clinical indication for implantation.

Clear guidance on atrial flow regulator size for children is not available. Patient-tailored evaluation is essential to determine the optimal fenestration size for each patient.

A 4-mm fenestration is usually aimed for failing Fontan patients, and then the 6– 8 mm devices are usually preferred with some degree of under-expansion by extrinsic conduit compression.

The 4-mm and 6-mm atrial flow regulator devices are more frequently used to reduce the size of a Fontan fenestration.

In patients on extracorporeal membrane oxygenation, 6 mm and 8 mm fenestration devices have been used to help maintain adequate cardiac output.

The relatively low delivery profile of the atrial flow regulator allows its implantation even in small children, including those weighing less than 10 kg. This is particularly advantageous as the device can be safely delivered through sheaths that are 1–2 Fr smaller than those officially recommended by the manufacturer. ^{Reference Butera, Piccinelli, Kolesnik, Averin, Seaman and Castaldi15,Reference Bautista-Rodriguez, Hascoët and Fraisse54}

Possible adverse events

Conclusion and limitation

In conclusion, the atrial flow regulator device has great potential in different paediatric and adult congenital settings, being effective and safe in establishing a calibrated shunt.

Literature data support the use of the atrial flow regulator in adult patients with non-congenital heart failure and pulmonary hypertension.

The wide range of indications for atrial flow regulator implantation in the congenital population, combined with the limited scientific evidence available, makes evaluating outcomes in this context particularly challenging.

Device selection is based on clinical indication, anatomy, haemodynamic data, patient weight, and device availability.

Future multicentre prospective studies are necessary to clarify the role of the atrial flow regulator in CHD patients, specifically to define optimal indication and timing for device implantation.