International review board approval was not required for this systematic review, as it did not involve any patient interaction and was conducted solely using publicly available published data. To ensure project integrity, the review was registered with PROSPERO (CRD42024579540) on August 24, 2024. PROSPERO is an international database with which systematic reviews on a variety of topics, including health care, can register to prevent duplication and reduce reporting bias by comparing the protocol with the final review.

Guided by the population, exposure, control or comparison, outcome, and study design framework [23], we aim to answer the following question: “What is the prognostic value of BNP and/or GLS in asymptomatic severe AR cases with preserved ejection fraction?”

The systematic review used the population, exposure, control or comparison, outcome, and study design method as detailed in (Table 1).

The systematic review included case studies, randomized controlled trials (RCTs), and single-arm studies. The meta-analysis focused exclusively on RCTs and relevant follow-up studies. Only English-language papers published before November 28, 2024, were included. Case reports, abstract-only papers, animal studies, commentaries, position papers, opinions, and editorials were excluded. Rival meta-analyses and systematic reviews were also excluded.

The study population consisted of patients aged >18 years with asymptomatic severe AR of the native heart valves who had preserved LV EF and normal LV diastolic and systolic diameters as defined by the European Society of Cardiology. Patients who did not meet these criteria, including those aged <18 years, with mild to moderate AR, reduced LV EF, previous transcatheter or surgical aortic valve replacement, or symptomatic AR, were excluded from the systematic review. Studies meeting the population inclusion criteria that used GLS and/or BNP as markers of progression were included in the study. Studies that did not include these measurements or the outcomes of interest were excluded.

Bibliographic databases, including PubMed, Cochrane, and Embase, were used from database inception to November 28, 2024. The search strategy was developed by a librarian with expertise in medical sciences and was designed in accordance with the Peer Review of Electronic Search Strategies guidelines. The search strategy was initially created for PubMed and used key search criteria specific to that database. It was then modified to suit subsequent searches across other databases. The detailed search strategy is provided in Tables 2 and 3.

Every study identified using the aforementioned search strategy was reviewed by ≥4 independent researchers to ensure that every study met the inclusion criteria. This was done in a systematic manner, including reviews of the title, abstract, and full text. A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram (Figure 1 [24]) will be included in the final review to further detail the screening process.

Four research team members individually extracted data from studies deemed eligible through the screening process to ensure that a thorough and accurate review was performed. Differences in findings following data extraction were discussed with the first author and another independent team member to determine the appropriate use. In addition to the outcomes listed below, the following data will be extracted from each eligible study: (1) study characteristics, including first author, publication year, study design, sample size, and follow-up duration; (2) patient characteristics, including mean age, sex distribution, and relevant comorbidities; and (3) biomarker data, including mean or median BNP or N-terminal pro-B-type natriuretic peptide values, predefined thresholds used, and method of BNP measurement; and, for GLS, the echocardiography vendor and speckle-tracking software used.

The outcomes of the meta-analysis or systematic review included: (1) symptom development (frequency, timing, and severity); (2) changes in LV morphology and function (LV EF; LV systolic and diastolic diameters); (3) all-cause mortality; (4) hospitalizations (initial hospitalizations, rehospitalizations, and length of hospital stay); (5) the need for intervention based on disease progression, including transcatheter or surgical aortic valve replacement (with interventions for other indications excluded; eg, multivessel coronary artery disease requiring coronary artery bypass grafting with concomitant aortic valve replacement); and (6) MACEs.

All studies that met the inclusion criteria and were included in the final publications were assessed using the National Heart, Lung, and Blood Institute quality assessment tool [25]. Evaluation was performed using the National Heart, Lung, and Blood Institute criteria detailed in (Textbox 1). In the event that any RCTs are identified and included, the Cochrane Risk of Bias 2 tool will be applied to assess their methodological quality, as this instrument is specifically designed for evaluating randomized study designs.

The statistical analysis for this meta-analysis will include several key steps to assess the prognostic value of BNP and GLS in patients with severe asymptomatic AR and preserved EF. First, data will be pooled using a random-effects model, as this model accounts for potential variability between studies [26]. For continuous outcomes, such as changes in LV morphology and function (eg, LV EF, systolic and diastolic diameters), mean differences or standardized mean differences will be calculated. For dichotomous outcomes, such as symptom development, hospitalization rates, and the occurrence of MACEs, risk ratios or odds ratios with 95% CIs will be computed. The outcomes of interest include symptom development (frequency, timing, and severity), changes in LV function, all-cause mortality, hospitalizations (initial hospitalizations, rehospitalizations, and length of stay), the need for intervention based on disease progression (eg, transcatheter or surgical aortic valve replacement), and MACEs. Subgroup analyses will be conducted to explore potential differences based on factors such as BNP and GLS thresholds, age, sex, and study design (RCTs vs observational studies). Sensitivity analyses will be performed by excluding studies with a high risk of bias or small sample sizes to evaluate the robustness of the results. The heterogeneity of the results will be assessed using the I² statistic, and if significant heterogeneity is detected, meta-regression and subgroup analyses will be used to explore its sources. Publication bias will be assessed using funnel plots and the Egger test [27]. Statistical significance will be defined as a 2-sided P value of <.05. The Comprehensive Meta-Analysis package (version 4.0; Biostat Inc) will be used to analyze the data.

Assuming sufficient data are extracted, the data will be displayed as a final table, accompanied by a summary detailing the final analysis performed. A data extraction form will be created and reviewed by all investigators prior to analysis. The articles that are part of the final publication will constitute the horizontal rows within the table, and the multiple variables identified by the team will serve as the columns. Quantitative analysis will be performed on all variables extracted from the available data.

The purpose of this meta-analysis is to determine the prognostic value of GLS and BNP in patients with asymptomatic severe AR and preserved EF. We will analyze the correlation of these 2 biomarkers with disease progression by examining symptom development and changes in LV function, and by identifying any additional indications requiring surgical intervention. We will also assess MACEs, including myocardial infarction, coronary revascularization, stroke, hospitalization due to heart failure, and all-cause mortality, to estimate the association of these 2 biomarkers with clinical outcomes. The results of our meta-analysis will be valuable in assessing these 2 biomarkers as independent variables for risk stratification and the need for early surgical intervention in these patient populations. This will improve prognosis and ultimately enhance the quality of life in this patient group.

By analyzing all the existing clinical trials conducted to date, our study will solidify the current evidence regarding the prognostic value of BNP and GLS in patients with asymptomatic severe AR and preserved EF. There is no prior meta-analysis or systematic review analyzing BNP as a prognostic marker in these patient populations, indicating the need for novel analysis. GLS has been researched before; however, the most recent meta-analysis published in 2024 combined both AR and aortic stenosis. The meta-analysis published in 2020 focused only on AR; however, given new research, it is now out of date. Our meta-analysis will include primary RCTs and secondary, or follow-up, RCTs derived from the original studies. This will extend the end points available for subgroup analysis and broaden our understanding of these 2 biomarkers in this population.

Additionally, this study will guide future research by improving the knowledge regarding the potential of BNP and GLS in patients with asymptomatic severe AR and preserved EF. If enough sample studies are available for pooling, our review will be the largest meta-analysis with quantitative analysis on this topic.

Our meta-analysis will have several limitations. Heterogeneity will exist due to the individually selected studies, as each study has its own methodologies, settings, primary and secondary end points, time periods, and length of follow-up used to track the biomarkers. Additionally, there is an inherent risk of reviewer bias while filtering articles during the literature search. This will be mitigated by using individualized searching processes with 2 or 3 independent reviewers for each biomarker, resulting in a total of 5 independent reviewers for the 2 biomarkers, and subject matter experts will monitor every step of this meta-analysis. We will assess the risk of bias in the selected studies with standardized tools. Finally, there is a risk of missing literature applicable to our research topic.

The findings from this meta-analysis will be disseminated through a manuscript submitted to a peer-reviewed journal by August 2026, and the abstract originating from the manuscript will be submitted and presented at academic conferences.

This study is a comprehensive review of GLS and BNP as prognostic markers in patients with asymptomatic severe AR and preserved EF. The primary end point will be symptom development, changes in LV function, or the emergence of additional indications requiring surgical intervention. The secondary end points will include hospitalizations (initial hospitalizations, rehospitalizations, and length of hospital stay), MACEs, and all-cause mortality. Overall, by aggregating all the available literature relevant to our topic, we anticipate that our analysis will evaluate the reliability of these 2 biomarkers for predicting the prognosis in this patient population, and we hope that this study may provide insights into future directions for improving health outcomes in this population.