Aortic regurgitation (AR) is the third most common valvular heart disease, with a higher relative incidence in men (19.7 per 100,000 person-years) than women (10.8 per 100,000 person-years).1,2 The prevalence and severity of AR increase with age, so the AR burden is expected to increase due to demographic ageing.1–4 Notably, AR can remain asymptomatic or misinterpreted, leading to underestimation of the actual frequency. Undiagnosed mild and moderate AR has been observed in 8–14% of elderly patients with no known valvular heart disease in the UK.4,5 Severe AR was present in <2%. A recent report from the Society of Thoracic Surgeons database shows that AR accounts for 7% of all surgical aortic valve replacement (SAVR) procedures, which implies that aortic stenosis (AS) remains the principal indication for surgery.6 This is partly explained by AS being two to three times more prevalent in the general population.1,4 However, it may also reflect AR underdiagnosis and misinterpretation. Delayed or missed diagnoses of AR lead to progressive left ventricular (LV) dilatation and decline in ejection fraction, which are common reasons to defer SAVR. This underscores a need for good diagnostic tools and clinical awareness to ensure timely diagnosis of AR.
Echocardiography is the primary imaging modality for diagnosing and guiding treatment in AR. Current guidelines recommend intervention based on AR severity, LV ejection fraction (LVEF) and LV dimensions.7,8 However, assessing AR severity with echocardiography can be challenging, particularly with eccentric jets or complex anatomy, and the evidence for current dimensional and ejection fraction cut-offs remains disputed.9,10 Emerging evidence suggests that additional or complementary imaging tools and biomarkers may offer a more accurate assessment of disease progression. LV volumes may be preferable to dimensional measures, while global longitudinal strain and interstitial fibrosis on cardiac MRI have shown predictive value in chronic AR and could complement LVEF as indicators of significant, maladaptive LV remodelling due to AR.9,11
The aetiology of AR may be diverse, encompassing degenerative (degeneration of aortic root and/or aortic leaflet), congenital, inflammatory and infectious factors (Table 1). The AR mechanism can be primary with aortic valve leaflet abnormality, secondary with preserved aortic leaflets such as aortic root or annular dilatation, or a combination.8,12
Primary Aortic Regurgitation
Aortic valve leaflet degeneration is the dominant cause of primary AR.12. Primary AR consists of calcific degenerative leaflet disease, commonly associated with AS. Up to 18% of individuals with AR exhibit some degree of AS.1 However, calcification in AR varies and can be mild to non-existent. The amount of calcification will affect contemporary transcatheter treatment options.
Other causes of primary AR feature intrinsic leaflet disorders such as leaflet perforation, prolapse, or restriction. Rheumatic fever primarily impacts the mitral valve but can also cause fibrous infiltrations and restriction of the aortic valve. In developing countries, rheumatic heart disease remains the dominant cause of AR, affecting a younger population compared to developed countries.13,14
Infective endocarditis is the most common cause of acute aortic regurgitation.15 The vegetation can cause perforation, restriction, or malcoaptation of the aortic leaflets and may require urgent surgical intervention. Rarely, acute AR develops because of traumatic injury to the aortic valves. Furthermore, acute AR can result from complications caused by balloon valvuloplasty or transcatheter aortic valve implantation (TAVI). Structural surgical or transcatheter bioprosthetic valve degeneration may result in acquired primary AR.
Secondary and Mixed Forms of Aortic Regurgitation
In secondary AR, the aortic valve leaflets appear structurally normal.
Aortic root pathology with dilatation can create secondary AR through aortic valve leaflet malcoaptation, retraction and prolapse. Overall, degenerative aortopathy is thought to contribute more to the development of AR than calcific degenerative leaflet disease.16 The bicuspid aortic valve phenotype is the most common congenital heart defect, and associated with AR in 20–70% of cases.17,18 Primary AR can develop due to abnormal shear stress leading to degenerative leaflet thickening, restriction, or prolapse.15,17,18 Altered flow dynamics surrounding the bicuspid valve, concomitant aortopathy, and aortic dilatation may result in secondary AR.17 At least a quarter of AR cases in bicuspid aortic valve undergoing aortic valve surgery are deemed secondary AR.12,18
Connective tissue disorders such as Marfan, Loeys-Dietz and vascular Ehlers-Danlos syndromes commonly result in secondary AR due to aortopathy.19 These patients are also at an elevated risk for aortic dissection and need to be monitored on a regular basis. In Marfan syndrome, mutations in the FBN1 gene result in defective fibrillin-1, the main component of microfibrils which together with elastin forms elastic fibres that give support to the extracellular matrix in connective tissue, including the aortic wall.20
Additionally, fibrillin-1 regulates transforming growth factor-β (TGF-β) signalling. When defective, it leads to increased TGF-β activity, promoting the degeneration of medial smooth muscle cells and further contributing to the weakening of the aortic wall.21 Likewise, patients with Loeys-Dietz syndrome have mutations in the TGF-β receptors (TGFBR1 and TGFBR2), which leads to increased TGF-β signalling and aortopathy at an early age compared to Marfan syndrome.22,23 In vascular Ehlers-Danlos syndrome, mutations in the COL3A1 gene result in insufficient production of type III procollagen, leading to reduced tensile strength and integrity of the connective tissue in the aortic wall.24
Vasculitis such as granulomatosis with polyangiitis, Takayasu’s arteritis and eosinophilic granulomatosis with polyangiitis may cause inflammation and dilatation of the aortic wall leading to secondary AR. Primary AR has also been described in vasculitis, due to the inflammatory cell infiltration and fibrotic thickening of the aortic leaflets, although it is less common.19 Autoimmune rheumatoid diseases such as systemic lupus erythematosus, antiphospholipid syndrome and rheumatoid arthritis may cause AR through systemic inflammation, autoantibody production and immune complex deposition.19
The main cause of acute secondary AR is aortic dissection, which may be iatrogenic or due to the above-mentioned aortopathies.
Non-structural surgical or transcatheter bioprosthetic valve degeneration is characterised by its paravalvular location and is typically detected immediately after the bioprosthetic valve replacement. Transcatheter valve migration may be a rare cause of delayed secondary paravalvular AR. Clinically relevant paravalvular leak (PVL) affects 2–10% of SAVR.25 TAVI is associated with higher rates of predominantly trace or mild PVL. Moderate to severe PVL is linked to increased mortality and rates of such cases have fallen below 5% with newer TAVI devices.26–28 Factors affecting PVL include annular characteristics (e.g. root calcifications, irregular shapes), valve positioning and under-sizing, and, for surgery, tissue quality and procedural technique (e.g. continuous suture use).25 Additionally, endocarditis can result in paravalvular AR.
Pathophysiology of Acute and Chronic Aortic Regurgitation
In acute AR, the sudden onset of severe diastolic regurgitation results in a rapid increase in LV end diastolic volume and pressure, which may spiral towards pulmonary congestion and cardiogenic shock (Figure 1A). In chronic AR, the left ventricle has the time to adapt to the volume overload and the LV end diastolic pressure volume relationship flattens, which postpones the occurrence of symptoms (Figure 1B). Remodelling includes LV dilatation, eccentric hypertrophy and increased stroke volume to compensate for the regurgitation volume. However, over time the incessant volume overload will overrule the ventricular compensatory remodelling capacity. Eventually, this cascade will progress to LV dilatation, myocardial fibrosis and systolic failure with depressed LVEF.
Conclusion
AR is the third most common valvular heart disease, and its burden is expected to rise due to demographic ageing. Managing AR remains challenging due to complexities in patient selection, diagnosis and evolving treatment strategies. A thorough understanding of the diverse aetiologies, from primary leaflet disease to secondary aortopathy, along with the distinct pathophysiological mechanisms of acute and chronic AR, is essential for optimising current management and guiding future therapeutic advancements.