Chronic aortic regurgitation (AR) is a common valvular disease characterized by an overload of left ventricular (LV) volume and pressure [1, 2]. The prevalence of AR is 5% among people aged 50 years and can reach 16% in the elderly population (aged $\ge$70 years) [1]. Although AR progresses slowly, it reaches an annual mortality rate of 10%–20% once symptoms appear [3]. Despite the clear benefit of timely surgery, many patients undergo operations late in the disease course, when they show advanced symptoms and high rates of heart failure and ventricular dysfunction [4].

As an important cardiovascular imaging technique, cardiac magnetic resonance (CMR) imaging provides accurate data on LV function, size, and volume, as well as valve morphology, aortic regurgitant volume (ARV), and aortic regurgitant fraction (ARF) in AR patients [5, 6]. The new guidelines for the management of valvular heart disease suggest that CMR should be used when the echocardiographic images are poor, and the measured value or AR grade is inconsistent with the clinical status of the patients [7, 8]. In the past decade, most studies have focused on the consistency between CMR and echocardiography in evaluating AR, and many studies on AR prognosis have used only echocardiography [9, 10, 11]. With the advances in CMR technology, new imaging markers, such as global longitudinal strain (GLS), late gadolinium enhancement (LGE), and extracellular volume (ECV), have been gradually applied to AR [12, 13]. Therefore, the role of CMR in the management of AR patients and the prognostic values of CMR-related parameters should be clarified. Accordingly, this study aimed to assess the prognostic value of CMR in chronic AR through a systematic review and meta-analysis.

This study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [14] and the published recommendations [15]. The detailed protocol is accessible at PROSPERO (CRD42022311827) [16, 17].

This study is the first systematic review focusing on the prognostic values of CMR parameters in isolated chronic AR. By reviewing the existing clinical studies, we summarized the CMR methods and aprameters that can provide effective information for the prognostic evaluation of AR patients and sorted out the existing research directions. Although transthoracic echocardiography is the most commonly used imaging modality in AR, CMR has unique advantages due to its accuracy and repeatability in assessing cardiac volume and function [31, 32, 33]. Recent guidelines [7, 8] consider CMR complementary to echocardiography, but the role of CMR cannot be replaced. Since improving the prognosis in AR is the ultimate goal of optimization of the clinical management, it is essential to assess the prognostic values of CMR parameters.

Recently, studies have shown that CMR is superior to echocardiography for evaluating chronic AR severity [34]. CMR directly measures aortic blood flow, thereby enabling accurate quantification of AR volume and regurgitation fraction and consequently offers unique advantages [34]. It is crucial to fully recognize the importance of accurately quantifying ARV and ARF in clinical practice. The majority of the studies we included focused on ARV and ARF. The meta-pooled results of our study suggest that ARF is a significant parameter in predicting the outcome of aortic valve surgical intervention (HR: 4.31, p = 0.034). Although the combined results of ARV showed no statistical significance (HR: 3.88, p = 0.116), this observation does not negate the value of ARV in the prognosis of AR. Many scholars have noted that following the guideline-recommended criteria (ARF $>$50% and ARV $>$60 mL) may cause delayed intervention in AR. In our included studies, the ARF threshold ranged from 32% to 37%, and the ARV threshold ranged from 38 mL to 50 mL, which were lower than the guideline levels. The earliest one among the included studies [30] proposed that ARF $>$33% can be considered as an indicator of aortic valve surgery, and the latest multicenter study [20] proposed that the optimal ARF and ARV thresholds are 35% and 38 mL, respectively. These findings not only reaffirm the significance of CMR-derived ARF and ARV for prognosticating AR patients but also indicate the necessity of redefining the corresponding thresholds.

The current guidelines [7, 8] emphasize the importance of monitoring LV size and function in AR patients and suggest critical thresholds for intervention, which are based on echocardiographic measurements of linear dimensions and LVEF in asymptomatic patients. Multiple scholars have stated that guideline-based indications might cause poor prognosis in patients with severe AR and that the threshold should be modified [11, 35, 36]. Despite the higher reproducibility and accuracy of cardiac volume data in tracking changes in patients with AR, the existing guidelines do not include cardiac volume parameters as factors for initiating clinical intervention, whether through echocardiography or CMR. Our study results also demonstrated that LVEDV (HR: 2.20, p = 0.039) and LVESV (HR: 3.14, p = 0.018) have meaningful prognostic value in guiding surgical intervention for AR patients. Theoretically, indexing cardiac volume parameters by using body surface area may be more accurate than using LVEDV and LVESV. However, due to the limited number of studies currently available, clinical prognostic value of LVEDV index (LVEDVi) and LVESV index (LVESVi) in the management of AR has not been fully confirmed. According to the study by Kočková et al. [28], to more accurately predict the timing of surgical intervention for asymptomatic patients with severe AR, the threshold values for LVEDV, LVEDVi, LVESV, and LVESVi should be 281 mL, 124 mL/m${}^2$, 121 mL, and 56 mL/m${}^2$, respectively. Furthermore, the authors have also demonstrated that combining volume parameters with quantitative regurgitant parameters can increase the prognostic value (90–95% sensitivity with 78–89% specificity). The research of Harris et al. [29] has shown that an LVESVi threshold of 65 mL/m${}^2$, based on CMR, can better predict the development of cardiac symptoms or the necessity of AVS. The latest European guidelines [8] recommend LV end-systolic parameters to be used as important references in the evaluation of surgical indications for AR. The study conducted by Hashimoto et al. [37] in 2022 revealed that among patients with chronic, moderate, or severe AR, those with heart-failure symptoms had a higher LVESVi, measured using CMR, than the asymptomatic or mildly symptomatic patients. Additionally, in the asymptomatic patients or in those under pharmaceutical treatment for mild symptoms, CMR-based LVESVi was found to be independently associated with adverse clinical events, including death and heart failure.

The clinical application of LVEF in the context of AR is limited primarily because it assesses changes in ventricular size rather than myocardial contractility. Due to the powerful compensatory ability of the ventricle, AR patients before stage D may not display a significant decline in LVEF. To date, several CMR techniques have been proposed for early detection of myocardial dysfunction, including strain, LGE, and ECV. Strain imaging allows dynamic assessment of LV function, reflecting the contractility of the myocardial wall. CMR-FT is a technique similar to speckle tracking echocardiography (STE) but with different imaging methods, and can be obtained from SSFP cine sequences and has a better image quality and repeatability than STE [38]. The study by Fernández-Golfín et al. [23] showed that LV deformation parameters are superior to the severity of AR, LVEF, and LV volume in predicting the prognosis of patients with AR. The same study also suggested that GLS worsens in the early stage of the disease course and is a very sensitive marker of severe AR; however, global circumferential strain (GCS) and global radial strain (GRS) are responsible for maintaining normal LVEF until advanced stages and can better predict the outcome of aortic valve surgery than GLS. LV strain parameters evaluated via CMR-FT can provide prognostic information for AR patients without prolonging the scanning time. Additionally, this technology is easy to implement in daily clinical practice and thus should be popularized and further studied in patients. LV-pressure and LV-volume overload in AR patients induce myocardial fibrosis (MF), characterized by increased fibronectin and glucosamine deposition and collagen tissue changes [39]. MF is a common feature of many heart diseases and has been linked to increased mortality and other adverse outcomes [40, 41, 42]. MF has been demonstrated in AR patients via myocardial biopsies obtained during active valve surgery [43, 44]. Contrast-enhanced CMR is well established for directly imaging myocardial replacement fibrosis by using LGE. Among the studies we analyzed, the study by Malahfji et al. [26] reported that myocardial scar was present in one-third of 392 AR patients they evaluated and was associated with mortality in their multivariable analysis. In another study [21], of the 166 AR patients analyzed, 84 (50.6%) had MF, determined via LGE. In addition, multivariate analysis showed that MF is independently associated with poor medium-term survival and can be used as a prognostic predictor in AR. The latest CMR-T1 mapping technique has proven useful in quantifying extracellular matrix expansion, and interstitial fibrosis assessed using this technique has a good histological correlation with valvular heart disease [45]. The following three T1-mapping-derived metrics have been proposed as markers of increased MF: native T1 time, post-contrast T1 time and myocardial ECV. Myocardial ECV fraction is considered a reliable indicator of MF and is related to the early stage of the disease [46]. To date, the study by Senapati et al. [22] is the largest study to evaluate the ventricular cavity and myocardial tissue remodeling in patients with isolated chronic AR by using CMR. Their study found that the incidence of replacement fibrosis in AR is low and not correlated with AR severity. Furthemore, compared with replacement MF and ECV, ECV index (ECVi), which was calculated from ECV multiply by LVEDVi has a stronger correlation with AR severity and adverse clinical outcomes. This is because ECVi represents the absolute total load of LV fibrosis and can better characterize the remodeling changes in cardiomyocyte and extracellular matrix expansion in progressive AR. However, ECV only provides the ratio of extracellular space to total myocardium, concealing the increase in extracellular space under the condition of balanced cellular hypertrophy. Several studies have shown that cellular hypertrophy with interstitial fibrosis occurs before the symptoms in chronic AR, and LV remodeling starts as early as 14 days after the onset of AR, accompanied by MF and extracellular matrix expansion [47, 48, 49]. Therefore, imaging markers derived from LGE and T1-mapping can detect subclinical diseases and myocardial dysfunction before symptoms appear, and can play an important role in the management and risk stratification of chronic AR patients.

Future research on the prognosis of AR should pay extra attention to two aspects. The first is the gender difference in the prognosis of AR patients. Although the research on this issue is limited, related studies have increasingly gained attention. As early as 2002, the existence of this problem was confirmed via animal experiments [50]. Kammerlander et al. [51] have demonstrated a clear linear relationship between ARF severity and LV size in men and a relatively less pronounced relationship in women. Moreover, LV remodeling was not obvious in women, implying that women are subjected to surgical intervention later than men and have a relatively worse prognosis. The latest study [52] combining CMR and echocardiography confirmed once again the significant gender difference in LV remodeling in AR patients, revealed that LV-indexed volume is always smaller and LV-indexed inner diameter is significantly larger in women than in men, and pointed out that the error range of echocardiography measurement is more significant in women with larger LV diameter index. Standardized parameters of body surface area may help address the issue, but establishing female-specific standards for ARF and ARV warrants careful consideration. Further research will be needed to determine the pathophysiological mechanisms of passivated LV remodeling in women with chronic AR and to optimize the therapeutic management of female AR patients. Another issue in studies evaluating the prognosis of AR is the BAV. BAV is a congenital heart malformation, with an incidence of 1%–2% in the general population and a male/female ratio of 3:1 [53]. BAV is a common cause of AR and affects LV function and aortic hemodynamics early during the disease course [54]. BAV leads to uneven opening of the aortic valve and eccentric regurgitant jets. In the evaluation of such patients, CMR offers unique advantages, including precise quantification of ARV and ARF, visualization of changes in myocardial morphology and function, as well as assessment of aortic dilation [55]. It has been shown that the BAV group has significantly increased LV volume, aortic diameter, and AR severity than the tricuspid-aortic-valve group. In addition, BAV has been identified to be an independent risk factor for MF, and BAV patients with LGE have a worse prognosis than those without [21]. Therefore, CMR is more valuable than echocardiography for diagnostic, prognostic, and therapeutic assessment in AR patients with BAV.

Although CMR provides additional significant values to AR evaluation, its widespread application still faces several challenges. Firstly, the cost of CMR is relatively high, which increases the economic burden of patients. Furthermore, it is challenging to minimize scan time while obtaining a high spatiotemporal resolution in large volumes of interest. Cardiac arrhythmias pose a challenge, and caution is advised when quantifying the flow in these patients. The CMR technology should be improved for highly accurate imaging and measurement under an irregular rhythm [55]. Additionally, post-processing is time-consuming and affected by user experience, thus delaying the implementation of these techniques into general clinical practice [56]. Finally, although CMR can also be used in assessing cardiac structure and function and monitoring postoperative cardiac remodeling and myocardial changes in postoperative AR patients, related research data are limited and thus cannot provide evidence for the prognostic value of CMR in postoperative AR patients. With the advances in scanning technologies and post-processing software, advanced sequences and methods as well as efficient data collection and analysis strategies will emerge. Meanwhile, the reduction in cost of CMR and its wider application will provide more favorable conditions for clinical practice and research.

The present study has several limitations. Firstly, most of the included studies were single-center observational studies, with limited sample sizes and from tertiary referral centers, and therefore it is difficult to avoid the bias of study subjects. Secondly, the CMR methods, thresholds, and endpoints in the included studies were different, and there were relatively few clinical events. Consequently, statistical limitations hinder further meta-analysis. In addition, advanced technical parameters such as LGE, ECV, and strain were studied individually, causing a lack of robust evidence for the prognostic value of CMR. Finally, there have been very few studies on the use of CMR to follow up postoperative AR patients. Despite the limitations mentioned above, it is important to note that our study still provides valuable insights into the prognostic value of CMR in AR.

CMR can inform clinicians about multiple parameters, including cardiac size, regurgitant severity, myocardial morphology, and function in the context of AR. CMR-based ARF, LVEDV, and LVESV have significant values in predicting the prognosis of AR patients with AVS as an endpoint. It is recommended to consider using multi-parameter CMR in the clinical management of AR patients for timely interventions and prognostic evaluation. Additional high-quality studies in the future can be used to confirm the prognostic value of CMR-related parameters for AR and to lay a foundation for defining the thresholds of these parameters.

AR, aortic regurgitation; CMR, cardiac magnetic resonance; ARF, aortic regurgitation fraction; ARV, aortic regurgitation volume; LVEF, left ventricular ejection fraction; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; HR, hazard ratio; LGE, late gadolinium enhancement; ECV, extracellular volume; GLS, global longitudinal strain; GRS, global radial strain; GCS, global circumferential strain.

The corresponding author JQL is responsible for the design and implementation of the study. JKL conducted quality control on the links between literature inclusion and data extraction. SDL provided guidance on literature retrieval and data processing methodology and was responsible for the quality evaluation part. JRN, WLX, YH and ZHW have undertaken a systematic review of the literature and extracted data. All authors contributed to revising the manuscript. All authors read and approved the final manuscript. The corresponding authors JQL and JRN take responsibility for the integrity of the analyses. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

We would like to acknowledge all individuals who provided suggestions and help with the data analysis and writing of this study.

This study has received funding by Hospital Fund Project of the First Hospital of Lanzhou University (No. LDYYYN-2020-063).

The authors declare no conflict of interest.