Aortic regurgitation (AR) has long been an underdiagnosed and underestimated valvular heart disease. Nevertheless, large cohort studies demonstrated that the prevalence of clinically relevant AR ranges from 1.6% to 4.5% in individuals aged ≥65 years. Despite a markedly increased mortality risk, AR was often treated conservatively, especially in patients considered unsuitable for surgery. Early attempts to treat AR patients with conventional transcatheter devices led to unsatisfactory results, mainly due to elevated rates of valve migration or embolization, and relevant paravalvular regurgitation. Recently, dedicated transcatheter heart valves, such as the JenaValve Trilogy System and the J-Valve, have been introduced and indicated high procedural success rates and improved clinical outcomes. However, both interventional and surgical treatment of AR are associated with increased need for pacemaker implantation, follow-up data is scarce, and referring physicians are often unaware of novel dedicated devices. Awareness needs to be spread to provide optimal treatment for AR patients with increased surgical risk.
The Clinical Problem—Epidemiology and Pathophysiology
The first case of aortic regurgitation (AR) was described back in 1705 by William Cooper, an English surgeon, who described a relationship between insufficient aortic valves and severely dilated human hearts. In the 20th century, rheumatic heart disease was the predominant cause of clinically relevant AR worldwide. Although its incidence has markedly declined in industrialized countries due to improved hygiene standards and socioeconomic progress, it remains a leading etiology of AR in low- and middle-income countries with vulnerable health care systems. Conversely, the predominant causes of AR in industrialized countries are degenerative valve alterations, bicuspid aortic valves, and conditions leading to dilatation of the aortic root. Calcification and degenerative changes of the aortic valve most commonly result in aortic stenosis (AS) but may also lead to regurgitation or a combined lesion, particularly due to structural alterations of the valve leaflets. Bicuspid aortic valves are present in approximately 1% to 2% of the population and are more likely than tricuspid valves to develop stenosis or regurgitation. At initial evaluation, nearly one-third of patients present with at least moderate concomitant AR. In addition, bicuspid valve morphology is strongly associated with aneurysmal dilatation of the ascending aorta, largely attributed to altered transvalvular flow patterns and abnormal aortic wall stress. Evidence from large cohort studies indicates that clinically relevant AR is at least as common as AS. The Framingham Heart Study reported a prevalence of significant AR of 2.2% among individuals aged ≥70 years, while in the more recent Heart of New Ulm cohort, clinically relevant regurgitation (≥moderate) was observed in 4.5% participants aged 65 years or older. , In the OxValve study moderate or severe AR was identified in 1.6% of 2,500 individuals aged ≥65 years, even exceeding the prevalence of calcific AS (0.7%). With respect to prognosis, patients with severe AR have a 10-year mortality of approximately 34%. However, once symptoms occur, prognosis worsens substantially, with an annual mortality approaching 25% in those presenting with New York Heart Association functional class III or IV. Another study on severe AR reported 5-year survival rates of 55% and 70%, with better survival observed in the patient group receiving beta-clocker therapy.
AR pathophysiology can be categorized into 3 distinct types, according to the anatomical characteristics of the aortic annulus and the dynamic motion of the valve leaflets. , Type I AR is characterized by normal cusp motion in the presence of dilatation of 1 or more components of the aortic root. In contrast, types II and III are defined by abnormal cusp motion. Type II results from excessive cusp mobility, such as prolapse or flail, whereas type III is defined by restricted cusp motion. , On a more detailed level, type I AR can be further classified into types Ia-Id. Type Ia is defined by dilatation of the sinotubular junction and the ascending aorta. In type Ib, both the sinus of Valsalva and the sinotubular junction are dilated, whereas type Ic is characterized by isolated dilatation of the aortic annulus. , Moreover, destruction and perforation of the cusps, which may occur in infective endocarditis or as an iatrogenic complication, results in AR classified as type Id. It is important to note that these subtypes often coexist, may overlap, and cannot always be distinctly classified. ,
Current management of AR—Diagnostic Imaging and Guideline Indications
Imaging modalities
Transthoracic echocardiography (TTE) represents the foundation of diagnostic evaluation for all valvular heart diseases, including AR. It is widely available, noninvasive, and routinely employed by referring and community-based cardiologists. TTE allows for comprehensive assessment of both the mechanism and severity of AR. Initial evaluation includes morphological assessment of the ascending aorta and valve cusps. Color Doppler imaging provides visualization of the regurgitant jet and its course, while quantitative parameters such as vena contracta width, the ratio of jet width to left ventricular outflow tract (LVOT) diameter, and two-dimensional (2D) proximal isovelocity surface area (PISA) enable an initial estimation of severity. , In addition, continuous-wave and pulsed-wave Doppler can be applied to determine pressure half-time and to evaluate the presence of holodiastolic flow reversal in the descending aorta. In addition, TTE is essential for accurate assessment of left ventricular (LV) ejection fraction (LVEF) and LV dimensions, both of which play a pivotal role in determining the timing of intervention. , Despite the fundamental value of TTE, it is important to recognize its limitations. Image acquisition may not always be optimal, and acoustic windows can be markedly impaired by thoracic deformities, severe cachexia, chronic lung disease, or obesity, rendering adequate evaluation challenging or even impossible. Moreover, in case of eccentric AR jets, quantitative parameters such as vena contracta, PISA as well as visual assessment of the regurgitant jet is demanding and critically influenced by the physician’s experience.
Therefore, even moderate AR detected in TTE, borderline LV dimensions, and particularly the presence of holodiastolic flow reversal should warrant further evaluation.
Transesophageal echocardiography (TEE) is recommended for further evaluation of individuals with suspected relevant AR. This modality usually provides elevated resolution and better image quality, as the transducer is positioned closer to the aortic valve. TEE allows for explicit assessment of aortic valve leaflets and pathologies such as prolapse, flail, perforation or aortic root dilatation and therefore providing a better understanding of underlying mechanisms. In addition, vena contracta and PISA can be evaluated with greater precision, prompting a more reliable quantification of AR. In summary, TEE is indispensable for preoperative or preinterventional planning of valve procedures due to its superior ability to outline leaflet and aortic root morphology. However, TEE has some limitations: it requires conscious sedation and is semi-invasive, which may lead to complications such as bleeding or injury to the pharynx or esophagus in rare cases. Furthermore, in a small subset of patients, adequate evaluation of AR remains a demanding task because of markedly limited acoustic windows, event with TEE.
Cardiovascular magnet resonance (CMR) represents another key imaging modality for the diagnostic evaluation of AR by both the European Society of Cardiology/European Association for Cardiothoracic Surgery (ESC/EACTS) and the American College of Cardiology/American Heart Association (ACC/AHA) Guidelines. , The main advantages of CMR over other imaging modalities are its high reproducibility, independence of acoustic windows, and the absence of radiation exposure. , CMR is primarily recommended in situations where echocardiography is not feasible or yields inconclusive results and provides precise assessment of regurgitant volumetric analysis and the regurgitant fraction (RF). , Moreover, the LV outflow tract (LVOT), the aortic root and the thoracic aorta can be evaluated accurately. Performing a 2D phase contract CMR analysis perpendicular to the sinotubular junction, a direct quantification of the RF and the regurgitant volume (RV) can be conducted.
Current ESC/EACTS and the ACC/AHA guidelines recommend an RF of 40% to 50% as the threshold for severe AR. , While an RF of 40% to 50% is highly specific for severe AR, it seems plausible that this threshold may lack sensitivity leading to delayed identification of relevant AR when LV remodeling is already present and adverse outcomes become inevitable. Recent studies suggest that using an RF of approximately 32% to 35% as a cut-off value may be more appropriate for AR evaluation. Myerson et al demonstrated that 85% of patients with an RF >33% progressed to surgery within 3 years of follow-up, while surgery was performed in only 8% of patients with an RF ≤33%. A similar study reported that a threshold of >35% has shown high sensitivity (86%) and specificity (88%) for predicting the need for aortic valve replacement. Recently, another study found that an RF of 32% correlated with the need for aortic valve surgery, while Hashimoto et al have shown an association with mortality and symptom progression. Furthermore, holodiastolic retrograde flow can be assessed easily and correlates with adverse outcomes. Indeed, its presence in CMR is associated with a nearly 3-fold elevated risk for death or heart failure hospitalization.
Even though the accessibility of CMR is steadily growing, examination can be completed in half an hour, and cardiac implantable electronic devices (CIED) no longer constitute an absolute contraindication, several challenges remain. Cardiac implantable electronic devices (CIED) may cause image artefacts, and patients with claustrophobia cannot be examined. Moreover, concomitant AS can lead to underestimation of forward flow.
Although electrocardiogram-synchronized cardiac computed tomography (CT) is not routinely performed for the assessment of AR, it can provide useful complementary information in borderline cases, owing to the precise visualization of aortic valve structures and root anatomy. Nevertheless, direct flow measurements are not feasible, and cardiac CT is dependent on geometric measurement of the regurgitant orifice area (ROA). ROA measurement is recommended in patients in whom sufficient echocardiographic image acquisition is not achievable or when CMR is desired but not available. Data regarding the correlation between ROA and the severity of AR are scarce, but 1 study revealed that ROA assessment correlates well with CMR evaluation of AR. Furthermore, the authors found that cut-off ROAs of 15 mm 2 and 23 mm 2 can be used to distinguish between mild, moderate and severe regurgitation. However, eccentric jet flow does not necessarily correlate with the ROA and may be underestimated. Moreover, ROA assessment is impaired in patients with valve prolapse or flail, and severe calcification of the valvular structures may cause artefacts. Despite its secondary role in quantification of AR severity, CT is often essential for preoperative or preinterventional procedural planning due to its high spatial resolution allowing for exact display and measurements of cardiac structures, the aorta and access routes.
Current guideline indications
Current ESC/EACTS and ACC/AHA guidelines state clear indications for aortic valve surgery in case of severe AR. There is broad consensus that severe symptomatic AR is strongly associated with mortality and adverse outcomes. Accordingly, both the ESC/EACTS and the ACC/AHA guidelines recommend surgery (Class I, Level B) once patients develop typical symptoms. , In asymptomatic patients, aortic valve surgery is recommended when severe AR and a left ventricular end-systolic diameter (LVESD) >50 mm, LVESD of >25 mm/m 2 when indexed to the body surface area, or a LVEF <50% are present (Class I, Level B). Moreover, the 2025 ESC/EACTS guidelines state, that patients who undergo surgery for coronary artery bypass grafting or for the ascending aorta should receive aortic valve surgery in case of concomitant asymptomatic severe AR (Class I, Level C). For asymptomatic patients with severe AR and an indexed LVESD >22 mm/m 2, an indexed left ventricular end-systolic volume (LVESV) >45 mL/m 2, or a resting LVEF <55% surgery should still be considered if the surgical risk is deemed low. However, clinicians should bear in mind that in this scenario the class for recommendation and underlying evidence is markedly lower (Class IIb, Level C). Moreover, the ESC/EACTS guidelines for the first time consider transcatheter aortic valve replacement (TAVR) as a possible treatment approach for patients deemed unsuitable for surgery by the interdisciplinary Heart Team, provided that the patient’s anatomy is favorable (Class IIb, Level B). The ACC/AHA guidelines are in line with the ESC/EACTS recommendations regarding thresholds of LV-dimensions (LVESD >50 mm, indexed LVESD >25 mm/m 2) for surgery in asymptomatic patients with severe AR. However, the ACC/AHA guidelines apply a different threshold regarding LVEF and recommend surgery as soon as it reaches values <55% (Class IIa, Level B). Further, the ACC/AHA guidelines state that patients with severe AR who do not meet the above-mentioned criteria, but show progressive decline in LVEF on at least 3 serial studies to the low-normal range (LVEF 55%–60%) or a progressive LV dilatation to an left ventricular end-diastolic diameter (LVEDD) >65 mm should also be considered for surgery as well (Class IIb, Level B).
Interventional Therapies for AR—From Off-Label Use to Dedicated Devices
Off-label use of TAVR in AR
Only a few years after the first TAVR procedure in 2002, and driven by the continuous advancement and clinical progression of both ballon-expandable and self-expandable prostheses for treatment of AS, efforts were made to amplify the TAVR approach to patients with AR. The first case illustrating the potential of TAVR for pure AR was published in 2008 and performed in France. The first data from a multicenter registry regarding the off-label use of a self-expanding prosthesis for severe AR was reported 5 years later. The authors demonstrated feasibility, but underlined that 18.6% required a second valve during the index procedure and residual AR ≥moderate was present in one fifth of patients. In the recent PURPOSE study, a multicenter registry comparing a dedicated transcatheter heart valve (THV) with off-label THVs for AR technical challenges persisted: the device success rate was significantly lower in the off-label group (73% vs 95%, p <0.001), primarily driven by higher incidences of THV embolization (15% vs 1.1%; p <0.001), the need for a second valve, and ≥moderate residual AR. These findings were in line with data from the PANTHEON registry, which reported similar rates of THV embolization or migration (12.4%) with off-label THVs and underscored the adverse impact of these complications on mortality and rehospitalization. In summary, these findings highlight technical limitations of current generation THVs designed for AS and the challenging anatomy of AR patients. Indeed, AR is often associated with concomitant dilatation of the annulus and the aortic root and usually lacks significant leaflet or annular calcification which is essential for anchoring conventional TAVR protheses. Procedurally, this translates into insufficient fluoroscopic visualization of the native aortic valve. These hostile features, in combination with a relevant regurgitant jet, frequently lead to THV embolization or migration, and relevant residual AR.
Dedicated THVs
In order to address the limitations of conventional TAVR platforms in pure AR, dedicated THVs have been engineered to warrant safe and reliable procedural outcomes and low complication rates. The first and most developed of these THVs is the JenaValve Trilogy System (JenaValve Inc., Irvine, California, USA) ( Figure 1 ). The JenaValve Trilogy System comprises a porcine pericardial valve attached to a nitinol frame. Moreover, the self-expanding device features a unique fixation mechanism with 3 dedicated locators that engage the native aortic cusps and get positioned at the base of each cusps securing commissural alignment. Upon release of the prosthesis, the locators clip onto the native valve leaflet, rendering reliable fixation even in the absence of annular calcification. First prospective data of the ALIGN-AR trial showed excellent rates of technical success (95.0%), low-mortality (2.0%), and only 1 patient with residual AR ≥ moderate (0.6%) at 30 days. A European real-world registry reported even better outcomes with a 100% technical success rate and zero residual AR at 30-day follow-up ( Figure 2 ). In spite of these promising results, both studies report a high rate of conduction disturbances and subsequent permanent pacemaker implantation (PPI). The rate for PPI in the ALIGN-AR trial was 24%, while a rate of 19.6% was reported in real-world settings. , In consideration of the PANTHEON registry, it is remarkable that PPI rates were increased in both the JenaValve Trilogy and the off-label THV group, insinuating that the high incidence of conduction disturbances is mainly attributable to the noncalcific and vulnerable anatomy of patients with pure AR. The JenaValve Trilogy platform has reached Conformité Européenne Mark approval for the treatment of AR in 2021 and is available in 3 sizes (23, 25, and 27 mm) covering annulus diameters from 23 mm up to 27 mm. Nevertheless, FDA-approval for the JenaValve Trilogy platform is still pending, but is anticipated for late 2025 based on the above-mentioned promising results.
The JenaValve Trilogy system for the treatment of pure aortic regurgitation. Specific valve design features render the device ideal for the treatment of noncalcific aortic regurgitation (A). The device is placed above the valve (B), then the dedicated locators “clipping” the device onto the leaflets are placed in the sinuses (C), and then the self-expanding device is released for final implantation (D).
Current Evidence of the JenaValve system from Real-World Experience and from the ALIGN-AR Study. Abbreviations: AR = aortic regurgitation, NYHA = New York Heart Association.
Analogous to the composition of the JenaValve Trilogy, the J-Valve consists of a self-expanding nitinol frame and bovine pericardial leaflets ( Figure 3 ). The valve-fixation feature is composed of 3 nitinol anchor rings built to align with the native aortic valve sinuses. During valve deployment, these U-shaped anchor rings grasp onto the native cusps and secure axial and radial fixation. The first implantation of the J-Valve system was conducted via transapical access in 2014 and yielded excellent hemodynamic results. Subsequently, a multicenter registry from China comprising 43 patients reported high procedural success rates (97.7%), absence of ≥moderate residual AR and few cases of PPI (4.7%) for the transapical J-Valve platform. In 2023 the first and, to date, only multicenter registry regarding the transfemoral J-Valve reported a procedural success rate of 81% in 27 patients. Interestingly, the authors state that procedural success reached 100% in the last 15 cases, after technical refinements of the J-Valve were conducted. In addition, PPI (13%) was observed less frequently than in cohort treated with the JenaValve Trilogy System. However, these promising findings need to be confirmed in larger cohorts. A pivotal trial is currently underway and will continue to evaluate safety and efficacy of the transfemoral J-Valve platform. The device is available in 5 sizes that can cover a wide range of aortic anatomies allowing treatment for annulus perimeters from 54 to 104 mm, which marks a critical advantage over the JenaValve Trilogy platform, which can only be used for a maximal annulus perimeter of 85 mm. , The J-Valve has reached groundbreaking FDA-approval, but clearance for the European market is still pending.
Overview of current dedicated transcatheter heart valve systems for treatment of pure aortic regurgitation. Abbreviations: BE = balloon-expandable, mort. = mortality, proc. = procedural, pt. = patients, PPM = permanent pacemaker, SE = self-expandable, techn. = technical, TF = transfemoral.
The Hanchor Valve is a novel device specifically designed for the treatment of pure native AR. In contrast to the JenaValve Trilogy and the J-Valve, it represents the first ballon-expandable THV for AR and features a cobalt-chromium alloy frame, a Nitinol anchor element semifixed to the frame, and bovine pericardial leaflets. The steerable delivery system comprises an 18 Fr sheath and allows for a maximum bending angle of 240°. , The Hanchor Valve is available in 4 sizes (20, 23, 26, and 29 mm) covering for area-derived annulus diameters from 16 to 28 mm. A recent multicenter trial from China reports high rates of procedural success (96.1%) in 128 high risk patients. Hemodynamics were favorable, as transvalvular gradients were low and residual AR > mild was absent. The 30-day PPI rate was lower than in cohorts treated with the JenaValve Trilogy (12.0% vs 24.0%), suggesting that valve designs and the deployment mechanism may impact conduction disturbances in pure AR patients. ,
Remaining Challenges—Need for Further Data and Technical Refinements
ESC/EACTS and ACC/AHA practice guidelines have formulated clear thresholds regarding LVEF and LVESD or indexed LVESD for intervention of severe AR in asymptomatic patients. , However, recent evidence suggests that earlier treatment of asymptomatic patients may be beneficial while delayed intervention based on contemporary guideline recommendations may lead to preventable adverse events. A cohort study of 356 individuals undergoing surgery for severe AR demonstrated that 10-year survival was improved in patients without operative indication or with class II indication compared to patients with class I recommendation (89.0% vs 85.0% vs 71.0%, respectively, p = 0.10). The authors conclude that class I triggers for AR intervention carry major risk for long-term outcomes and emphasize that patients should be undergoing treatment before their onset. Indeed, several studies demonstrated that the risk of adverse outcomes rises once the LVEF decreases to 55% or the indexed LVESD reaches a range of 20 to 25 mm/m 2. ,,
In addition, LV remodeling in the presence of severe AR is exclusively evaluated through 2-dimensional echocardiographic parameters. However, the dependency on linear dimensions entails important limitations as these are susceptible to measurement errors and heavily influenced by the physician´s experience and accessible acoustic windows. Consequently, crucial thresholds of LV-dimension and LV-function may be underestimated or overseen. Conversely, emerging imaging modalities like 3-dimensional echocardiography or cardiac magnetic resonance imaging (MRI) allow for a more precise evaluation of the left ventricle. A recent MRI study found that indexed LVESV ≥43 mL/m 2 was independently associated with serious adverse events like mortality and LV-dilatation.
Furthermore, quantification of severe AR remains controversial and is a matter of ongoing debate. Established cut-off-values are based on early echocardiographic studies in which the reference standard was angiography. Additionally, cohorts were small and included young male patients with bicuspid aortic valves or aortic root dilatation, thereby further challenging the generalizability of these thresholds across different demographic groups. Recently, a cardiac MRI study revealed that an RF ≥35% or and RV ≥45 mL/m 2 was already predictive for adverse outcomes, representing markedly lower thresholds than the current criteria for AR.
Apart from an analysis based on volumes and performed by state-of-the-art multimodality imaging, entirely novel parameters should be taken into consideration as detecting early-stage LV-remodeling in AR patients remains challenging.
One of the emerging metrics is global longitudinal strain (GLS). Two studies illustrated that echocardiographically derived GLS correlated with an elevated risk for all-cause mortality in patients with grad III+ AR and preserved LVEF. Notably, the authors found that a GLS below −19.0% was already indicative for an increased probability of mortality. , Data analyzing the correlation between cardiac MRI derived GLS and mortality in presence of severe AR remain scarce, but 1 study comprising 55 patients with AR was able to depict an association between impaired global circumferential and global radial strain and a composite endpoint including all-cause mortality, cardiovascular mortality, aortic valve surgery, or cardiovascular hospital admission due to heart failure. Moreover, a correlation between progressive decline of GLS values and increasing AR severity was observed.
Additionally, early evidence indicates a link between myocardial fibrosis and adverse outcomes among patients with severe AR. Malahfji et al found that, in patients with ≥moderate AR, the presence of myocardial scar pictured by late gadolinium enhancement (LGE) was independently associated with a 2.5-fold increasing risk in mortality. Interestingly, both infarction-related and noninfarction related scars correlated with mortality, and aortic valve replacement was associated with higher survival rates. Another parameter reflecting myocardial fibrosis is indexed extracellular volume (iECV), which has shown to significantly increase with AR severity and is associated with a composite event of death and aortic valve replacement.
Lastly, few studies suggest that circulation biomarkers may have prognostic impact in patients with severe AR. Pizarro et al demonstrated that an B-type natriuretic peptide (BNP) of ≥130 pg/mL was predictive for the occurrence of congestive heart failure, LV dysfunction, and mortality in patients with severe AR and preserved LVEF. Another study confirmed the correlation between biomarkers and adverse outcomes and illustrated the predictive accuracy of BNP for aortic valve replacement. However, further prospective studies are needed to allow for the integration of biomarkers in the decision-making process regarding asymptomatic patients with severe AR and preserved LV function.
The development and clinical implementation of dedicated THVs for treatment of AR have paved the way to markedly improved technical success, primarily attributable to their calcium-independent anchoring mechanisms, which have drastically reduced the rates of THV embolization and migration as well as residual AR. ,, Nonetheless, the heightened incidence of PPI after TAVR for AR patients continues to represent a relevant complication. Current studies report PPI rates of up to 24% in AR patients treated with either dedicated or off-label THVs, while in AS patients latest generation THVs of the Evolut and the Sapien family show PPI rates of 11.9% and 5.6%, respectively. ,, These observations suggest that inherent pathophysiological features such as lack of calcification, annular dilatation and altered valve dynamics render patients vulnerable to conduction disturbances. Moreover, a retrospective multicenter registry demonstrated that pre-existing first degree atrioventricular-block or right bundle branch block were associated with PPI but found no modifiable risk factors. A lower PPI-rate of 13% in the first experience with the J-Valve sparks the idea that different radial forces between the THVs may also play a role. In general, interventionalists should consider both the anatomic and procedural aspects to evaluate the risk of conduction disturbances in AR patients. Further research is required to fully decode the influence of these different factors and enhance strategies to minimize pacemaker dependency in AR patients.
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