Prognostic role of myocardial fibrosis markers in aortic stenosis: implications for clinical decision-making

Abstract

Aortic stenosis (AS) causes chronic pressure overload in the left ventricle (LV) that ultimately results in myocardial fibrosis. This fibrosis is associated with advanced symptoms, LV decompensation, and poor prognosis. Cardiovascular magnetic resonance (CMR) offers a non-invasive method to assess myocardial fibrosis, correlating well with histology and predicting adverse events in AS patients. Histologic studies have confirmed the prevalence of myocardial fibrosis in AS and its association with symptoms and LV dysfunction. CMR techniques, including late gadolinium enhancement (LGE) and T1-mapping, effectively demonstrate and quantify fibrosis, with LGE identifying focal replacement fibrosis and T1-mapping assessing diffuse interstitial fibrosis. Both techniques complement each other in capturing the extent of myocardial fibrosis. The reversibility of fibrosis post-aortic valve replacement (AVR) varies, with diffuse fibrosis showing potential for regression while replacement fibrosis remains irreversible. Importantly, recent studies have highlighted the powerful prognostic value of LGE and T1-mapping markers. There are ongoing trials that aim to establish the clinical role of CMR-guided early intervention in improving AS outcomes. Identifying novel indicators for myocardial fibrosis, such as serum biomarkers or strain imaging, could further enhance the prediction of fibrosis and patient selection for CMR. Ultimately, the integration of myocardial fibrosis markers into clinical practice may optimize the timing of intervention and improve prognosis for AS patients. This review summarizes the current evidence from CMR studies investigating myocardial fibrosis in AS, focusing on its prognostic value and potential role in guiding intervention timing.

Keywords

aortic valve stenosis myocardial fibrosis cardiovascular magnetic resonance imaging

Introduction

Aortic stenosis (AS) contributes to significant mortality globally.¹ Progressive restriction of the aortic valve (AV) opening causes chronic pressure overload in the left ventricle (LV), leading to hypertrophic remodeling of the LV. Through mechanical shear stress, cardiomyocyte apoptosis, and increased oxygen demand, myocardial fibrosis develops as AS progresses.^2–4 Although cardiac function is preserved over a substantial period, without intervention, these changes ultimately result in symptoms and heart failure.^3,4 Histologically, myocardial fibrosis is prevalent in AS and is associated with more advanced symptoms, LV decompensation, and ultimately, a worse prognosis.⁵

Cardiovascular magnetic resonance (CMR) provides non-invasive methods to assess and quantify the degree of myocardial fibrosis. Multiple studies have demonstrated a strong correlation between CMR-assessed myocardial fibrosis and histology.^6–8 Importantly, CMR-assessed myocardial fibrosis predicts adverse events in patients with AS.^9,10 There is considerable interest in using these markers to optimize the timing of intervention in AS, serving as an early indicator of LV decompensation that may trigger earlier intervention even in asymptomatic patients. This strategy is supported by accumulating evidence from CMR studies demonstrating the natural course of fibrosis with or without intervention,^11,12 as well as evidence that supports its important prognostic role. An ongoing randomized control trial will provide valuable information on the benefits of CMR-guided early intervention in severe AS.¹³

This review summarizes the current evidence from CMR studies investigating myocardial fibrosis in AS, highlighting its potential role in guiding the timing of intervention for severe AS. Additionally, we discuss the gaps in the current literature that may serve as future directions for research on the role of CMR in AS patients.

Myocardial fibrosis in AS: histologic data

Studies using myocardial biopsy specimens obtained during surgery have confirmed that myocardial fibrosis, identified through histology, is prevalent in patients with significant AS and is closely associated with symptoms and LV decompensation.^5,6,14 Myocardial fibrosis, along with myocyte degeneration and cell death, has been recognized as a main driver leading to the transition to heart failure in AS.² A previous study involving patients with severe AS undergoing aortic valve replacement (AVR) found that myocardial fibrosis was observed among 62% of patients with severe AS.⁵ The degree of fibrosis was closely related to a higher New York Heart Association functional class and lower systolic function, as well as subsequent mortality following AVR.⁵

There are two main types of myocardial fibrosis in AS: diffuse interstitial fibrosis and focal replacement fibrosis, also known as scar. Diffuse fibrosis is characterized by the deposition of excessive collagen fibers in the interstitium and perivascular space in response to cardiac injury, while replacement fibrosis is focal and occurs following cardiomyocyte apoptosis or necrosis.^3,15 Treibel et al reported that in 133 patients with symptomatic severe AS, myocardial fibrosis exhibited complex morphology and topology, which could be characterized by patterns related to diffuse interstitial fibrosis and microscars.¹⁶

Diffuse fibrosis develops in the earlier phase of AS and may be reversible with timely AVR. In contrast, replacement fibrosis/scar develops later, accumulates as AS becomes more severe, and is considered irreversible even after AVR.⁴ The scheme of change in myocardial fibrosis in the natural course of AS evolution and after AVR is shown in Figure 1. These progression characteristics of myocardial fibrosis provide the rationale for early intervention in AS, which aims to halt the progression of replacement fibrosis and possible ongoing LV decompensation.

Figure 1.

Schematic illustration of the natural course of diffuse and replacement myocardial fibrosis and their reversibility post-AVR.

CMR imaging for myocardial fibrosis

CMR provides excellent soft tissue characterization and enables non-invasive assessment and quantification of myocardial fibrosis in AS. Multiple studies have demonstrated a strong correlation between the biopsy-driven extent of fibrosis and CMR-quantified fibrosis, either by late gadolinium enhancement (LGE) or T1-mapping technique.^6,7,16–19 Several blood biomarkers, including soluble suppression of tumorigenicity 2 (sST2), matrix metalloproteinases (MMPs), and growth differentiation factor-15 (GDF-15), may reflect the degree of myocardial fibrosis in AS.²⁰ Although these biomarkers may improve diagnostic and prognostic accuracy in AS, CMR is ultimately required to evaluate detailed characteristics of fibrosis, such as its location, whether it is diffuse or focal replacement fibrosis, and whether it is infarct-related.

LGE imaging, obtained 10-15 min after gadolinium contrast injection, distinguishes between the normal myocardium and myocardial fibrosis based on the differential accumulation and retention of gadolinium contrast in fibrotic tissue. The fibrotic area has a significant expansion of the extracellular space and exhibits prolonged retention of the gadolinium contrast compared to the normal myocardium.^21,22 Phase-sensitive inversion recovery sequence is considered the reference standard technique to evaluate LGE, provided that a patient can cooperate with sufficient breath-holding.²³ In AS, the mid-wall pattern of LGE is a distinctive and unique pattern of scarring, different from that observed in other conditions such as myocardial infarction, and provides significant prognostic information (Figure 2).²⁴ The percentage of LGE divided by the entire myocardial mass (LGE%) also serves as a marker of the extent of replacement fibrosis.⁹ However, LGE is limited in evaluating diffuse interstitial fibrosis, as imaging the myocardial scar with LGE requires nulling the myocardium that does not have scar tissue but does have diffuse fibrosis, which itself is not entirely ‘normal’ myocardium.

Figure 2.

Illustration and examples of infarct-related and non-infarct LGE on CMR.

Diffuse myocardial fibrosis can be quantified using the T1-mapping technique. T1 relaxation time, which represents the recovery of longitudinal magnetization or spin-lattice relaxation after excitation by a radiofrequency pulse, varies according to the underlying pathologies of the myocardium and allows us to evaluate diffuse interstitial fibrosis.²⁵ In T1-mapping, the T1 relaxation time of the myocardium is quantified within each voxel, generating a parametric T1 map.^26,27 Modified Look-Locker Inversion recovery (MOLLI) pulse sequence is the most widely used sequence for T1-mapping, and its variant, the shortened MOLLI (ShMOLLI), requires a shorter breath-hold.²⁶ Other pulse sequences using saturation recovery (ie, SASHA) or combined saturation/inversion recovery (ie, SAPPHIRE) are also used in practice.^25,26

Native or pre-contrast T1 values reflect the space comprising both intracellular and extracellular compartments. By additionally using contrast agents, extracellular volume fraction (ECV%) can be calculated to evaluate the degree of the extracellular component of the myocardium, using T1 values of the myocardium and the ventricular blood pool obtained pre- and post-contrast (Figures 3).²⁶ Conventionally, the calculation of ECV% requires information on the hematocrit level on the same day as the CMR exam, although synthetic ECV% has been proposed as a method to avoid blood sampling.²⁸ Indexed ECV% (iECV%) also has been suggested as a marker that modifies the ECV% to act as a measure of the total volume of the extracellular compartment in the LV, using the following formula: ECV% × LV end-diastolic myocardial volume normalized to the body surface area.²⁹ Native T1 value, ECV% and iECV% are strongly correlated with the histologic extent of diffuse fibrosis in AS.^{17,18,29–31}

Figure 3.

T1-mapping and calculation of ECV% for diffuse myocardial fibrosis in AS.

Figure 4.

Myocardial fibrosis assessment and risk stratification in AS.

Both LGE and T1-mapping techniques are complementary to each other, and neither is sufficient on its own to capture the heterogeneity and extent of fibrosis in the myocardium.¹⁶ Accumulating data suggest that a multiparametric approach, utilizing the assessment of both types of fibrosis markers, is essential to accurately evaluate fibrosis and LV remodeling in AS.

Late gadolinium enhancement: Replacement fibrosis in the myocardium

The subtypes of LGE can be categorized into infarct-related and non-infarct LGE according to their location and pattern. LGE is considered infarct-related when observed aligning with the coronary territories and when it is either subendocardial or transmural. In contrast, non-infarct LGE does not correlate with the coronary artery territories and is predominantly located in the mid-wall of the LV, usually presenting as a focal, patchy, or diffuse pattern (Figure 2).^4,32 Although infarct-related LGE is prevalent and predicts mortality in AS, mid-wall non-infarct LGE reflects fibrosis related to chronic pressure overload by AS and is of interest for its prognostic role.^9,24 CMR reports of LGE analysis include information on the presence of LGE, characterization of the LGE type, the location of LGE, and quantification of LGE% relative to the entire myocardium.³³

Multiple studies have shown a significant association between LGE and LV decompensation, including higher LV end-diastolic volume, higher LV mass index, elevated cardiac serum biomarkers, electrocardiography strain, and worse systolic and diastolic function.^34–38 One of the first studies investigating LGE in AS, reported in 2006, found that among 22 patients with AS, LGE was present in 27% and was associated with higher severity of AS.³⁹ A more recent study by Chin et al, involving 166 patients with AS, demonstrated an increase in LV hypertrophy, myocardial injury, diastolic dysfunction, and longitudinal systolic dysfunction in the following order: patients with normal myocardium, myocardium with diffuse fibrosis without LGE, and mid-wall LGE.²⁹ These data on LGE suggest that the formation of myocardial scarring is accompanied by the progression of AS and the decompensation of the myocardium over the course of the disease. This highlights that AS is not only a disease of the valve but also has significant implications for myocardial health.³

The prognostic role of LGE, including mid-wall fibrosis related to AS, is well established. One of the largest studies investigating this was conducted by Musa et al, which reported a strong association of LGE with mortality in 674 patients with severe AS.⁹ LGE was present in approximately half of the study population (18% infarct LGE, 33% non-infarct LGE), and its presence was associated with a two- to threefold higher risk of all-cause and cardiovascular mortality. The presence of LGE confers worse survival irrespective of surgical or transcatheter AVR. Notably, patients with non-infarct LGE also exhibited poor survival, equivalent to those with infarct-related LGE, highlighting the prognostic role of AS-related replacement fibrosis. Long-term follow-up results of this population have been recently reported, and during a median 11.3 years follow-up, the presence of LGE, including non-infarct LGE, remained associated with mortality even in the long-term.⁴⁰

T1-mapping and ECV%: Diffuse fibrosis

In contrast to LGE, the T1-mapping technique allows us to evaluate diffuse interstitial myocardial fibrosis; however, the clinical implications of T1-mapping are still relatively under-investigated. The native T1 value, without the use of gadolinium contrast, reflects both the intracellular and extracellular compartments of the myocardium. Studies have shown that native T1 values are correlated with LV hypertrophy and systolic dysfunction in AS.^18,41–43 Lee et al demonstrated that, in 80 asymptomatic patients with moderate or severe AS, native T1 values significantly correlated with diffuse myocardial fibrosis from biopsy (R=0.777, P<.001), and were associated with LV volumes, global longitudinal strain, e’ velocity, and indexed left atrial volume.¹⁸ However, one limitation of this method is the variability of T1 values, which can depend on CMR scanners, pulse sequence, cardiac phase (systole vs diastole), and magnetic field strength. For instance, native T1 values are higher at 3T compared to 1.5T.^10,26 Additionally, age, sex, and possibly menopause in females may contribute to variability in T1 values.⁴⁴ Given that T1-mapping is currently the only clinically available imaging modality for capturing diffuse myocardial fibrosis, standardizing pulse sequences and protocols across cardiovascular centers worldwide is essential. This effort could facilitate the early detection of myocardial fibrosis and enable timely intervention for AS.

In contrast to the native T1 value, ECV% represents solely the extracellular components of the myocardium.¹¹ Similar to native T1 value, both ECV% and iECV% are associated with LV decompensation in AS,^30,45 including worse diastolic dysfunction and advanced symptoms related to AS.^29,46,47 Diffuse fibrosis increases as AS progresses¹² and is thought to precede the formation of myocardial scarring. ECV% represents an earlier fibrotic change in the entire myocardium, following the sequence from normal myocardium to extracellular expansion and eventually replacement fibrosis.²⁹ This progression suggests that ECV% could serve as an early marker of LV damage. However, longitudinal data to verify this hypothetical sequence of events following chronic pressure overload on the LV in AS is limited. Additionally, combining ECV% and LGE% may provide more valuable information for identifying histologic alterations, adverse LV remodeling, evidence of heart failure, and functional capacity impairment than using each parameter alone.¹⁶

Evidence supporting the prognostic association of T1-mapping fibrosis markers with hard clinical outcomes has emerged recently,^{10,29,30,46,48–55} though it remains relatively limited compared to that with LGE, necessitating further research in the near future. The related outcome studies are summarized in Table 1. One of the first outcome studies, reported in 2016, included 94 AS patients clinically indicated for transcatheter AVR. This study showed that ECV% was associated with a trend toward post-AVR heart failure incidence, though this did not reach statistical significance.⁴⁸ However, a recent international multicenter study by Everett et al investigated 440 patients with severe AS undergoing AVR, all of whom underwent CMR with T1-mapping shortly before AVR, and demonstrated a strong association between ECV% and mortality.¹⁰ The mean ECV% was 27.7%, and it did not vary by the field strength of the scanner (1.5T or 3T) and showed minimal variation across the participating centers, supporting the generalizability of this marker. The adjusted hazard ratio for all-cause mortality per 1% increase in ECV% was 1.10 (95% confidence interval 1.02 to 1.19, P=.013). The prognostic power and potential utility of this marker could be strengthened with additional data, including among those with less severe AS. These data could help establish the role of diffuse fibrosis assessed by ECV% in risk stratification and clinical decision-making in AS, determining the optimal timing of intervention in significant AS.

Table 1.

T1-mapping studies investigating hard clinical outcomes in aortic stenosis.

Study	Year of publication	Number of AS patients	Population	CMR	Outcomes	Findings
Nadjiri J et al⁴⁸	2016	94	Patients undergoing clinically indicated TAVR	1.5T MOLLI	HF and TAVR-associated conduction abnormalities	Elevated myocardial ECV was a predictor of HF by trend
Chin et al²⁹	2017	166	At least mild AS (peak velocity ≥2 m/s)	3T MOLLI	All-cause mortality AS-related mortality	Stepwise increase in all-cause and AS-related mortality: normal myocardium < extracellular expansion (iECV ≥22.5 mL/m²) < replacement fibrosis (mid-wall LGE)
Lee et al⁴⁹	2018	127	Moderate or severe AS	3T MOLLI	Composite of all-cause mortality and HF admission	Native T1 value was an independent predictor of composite events (adjusted HR for every 20-ms increase in native T1: 1.28, P=.003)
Park et al³⁰	2019	71	Severe AS with preserved ejection fraction undergoing SAVR	1.5T MOLLI	Composite of all-cause mortality, HF admission, and development of HF symptoms	Composite events occurred more frequently in patients with a higher ECV%
Everett et al¹⁰	2020	440	Severe AS undergoing AVR (SAVR with or without CABG, TAVR)	1.5T/3T MOLLI/ ShMOLLI	Post-AVR all-cause mortality and CV mortality	ECV% was independently associated with all-cause mortality (adjusted HR: 1.10 per 1% increase in ECV%, P=.013) and CV mortality
Hwang et al⁵⁰	2020	43	Severe AS scheduled for isolated AVR	3T MOLLI	Composite of CV death, hospitalization for CV causes, stroke, and symptoms aggravation	A reduction in native T1 value 1 year post-AVR was associated with improvements in prognosis
Lee et al⁴⁶	2020	191	Moderate or severe AS	1.5T/3T MOLLI	Composite of all-cause mortality and HF admission	Increased ECV% was associated with diastolic dysfunction and was an independent predictor of composite events
Kwak et al⁵¹	2021	799	Severe AS undergoing AVR (SAVR with or without CABG, TAVR)	1.5T/3T MOLLI/ ShMOLLI	All-cause mortality	Prognostic cutoffs for mortality were identified as ECV% >27% and LGE% >2%
Zhang et al⁵²	2022	2430	Patients with AS from 13 studies (meta-analysis)	1.5T/3T -	All-cause mortality Cardiac mortality MACE CV events	Native T1 was significantly associated with MACEs, and higher ECV was associated with an increased risk of CV events
Ramchand et al⁵³	2022	117	Severe AS with CKD stage 3 to 5	1.5T MOLLI	Composite of all-cause mortality and HF admission	A longer native T1 was associated with the occurrence of composite events
Fukui et al⁵⁴	2022	147	Low-gradient moderate to severe AS	1.5T/3T MOLLI	All-cause mortality and a composite of all-cause mortality and HF admission	Increasing ECV% and a higher number of CMR risk markers (GLS, LGE, and ECV%) were associated with adverse events
Tessari et al⁵⁵	2023	41	Classical low-flow, low-gradient AS	1.5T MOLLI	All-cause mortality	ECV% and iECV% were not significant predictors of mortality

Studies were ordered by publication date.

AS, aortic stenosis; AVR, aortic valve replacement; CABG, coronary artery bypass grafting; CKD, chronic kidney disease; CMR, cardiovascular magnetic resonance; CV, cardiovascular; ECV, extracellular volume fraction; GLS, global longitudinal strain; HF, heart failure; HR, hazard ratio; iECV, indexed extracellular volume fraction; LGE, late gadolinium enhancement; MACE, major adverse cardiovascular events; MOLLI, Modified Look-Locker Inversion recovery; SAVR, surgical aortic valve replacement; ShMOLLI, shortened Modified Look-Locker Inversion recovery; TAVR, transcatheter aortic valve replacement.

Reversibility of myocardial fibrosis post-AVR

Non-invasive CMR assessments enable us to characterize the natural course of myocardial fibrosis in AS and its potential reversibility through intervention. Myocardial fibrosis progresses as AS becomes more severe (Figure 1). Although some medical treatments, including renin-angiotensin-aldosterone system inhibitors, may help attenuate LV hypertrophy,^56–58 no studies have yet demonstrated their efficacy in reversing myocardial fibrosis.

After AVR, LV reverse remodeling occurs, including regression in LV volume and mass, along with improvements in systolic and diastolic function.^11,59 Regarding myocardial fibrosis, the reversibility after AVR varies depending on its type. Replacement myocardial fibrosis progresses without AVR,¹² even in an asymptomatic state,⁶⁰ and remains constant and irreversible post-AVR.^5,11,12 However, diffuse fibrosis is reversible and regresses after AVR.^11,12,61 One study reported that the amount of mid-wall LGE rapidly increased before valve intervention, particularly among those with existing LGE (78% increase in LGE mass per year), and did not decrease even up to 2 years post-AVR, but iECV% was significantly reduced following AVR.¹² Another study also reported that focal fibrosis assessed by LGE did not significantly change 1 year post-AVR, but matrix volume decreased along with the reduction of cell volume.¹¹ Studies have shown that regression of diffuse myocardial fibrosis assessed by CMR is accompanied by improvements in myocardial function and symptoms, suggesting that this marker could be a potential therapeutic target.^11,50,62 However, studies investigating longitudinal changes in diffuse fibrosis in the early stages of AS are scarce. Such studies could help establish the benefits of early intervention for AS in reversing diffuse fibrosis and improving outcomes.

Clinical trials investigating CMR-guided early AVR

Considering the following facts: (1) LGE progresses without intervention once established,¹² (2) a higher extent of LGE confers a worse prognosis even after AVR,^9,63 and (3) LGE does not regress but only ceases to progress after AVR,^11,12 it is reasonable to speculate that early intervention may improve the outcome of AS patients when the extent of LGE remains low. This is important as symptoms related to AS are often subjective, especially considering the frailty of elderly patients with significant AS, and mortality during medical management in asymptomatic patients is not negligible.⁶⁴ Additionally, the excellent long-term outcomes of surgical AVR have been established despite increasing patient complexity,⁶⁵ and the periprocedural complications and mortality rates of transcatheter AVR have decreased over the past couple of decades.⁶⁶

The EVOLVED trial (NCT03094143) is the first multicenter randomized controlled trial to compare early AVR, including both surgical and transcatheter AVR, to conservative care in asymptomatic patients with severe AS and mid-wall LGE.¹³ This trial allows for the evaluation of the effectiveness of a decision-making strategy regarding whether the CMR-guided intervention is clinically beneficial. Approximately 400 patients with mid-wall LGE will be randomized 1:1 to either early AVR or conservative care. Those without LGE will be assigned to the conservative care group or have no further follow-up. The primary endpoint is a composite of all-cause mortality and unplanned AS-related hospitalization. A few studies have shown the efficacy of early AVR in asymptomatic patients with severe AS,^67,68 and additional ongoing randomized trials are investigating this patient group (DANAVR, NCT03972644; EARLY TAVR, NCT03042104; EASY-AS, NCT04204915; ESTIMATE, NCT02627391). However, none of these trials have used markers of myocardial fibrosis to guide early intervention. The EVOLVED trial will further explore whether a more targeted intervention strategy based on fibrosis assessment by CMR is beneficial in asymptomatic patients with severe AS.

In addition, the utility of diffuse myocardial fibrosis detected by T1-mapping, including ECV%, may be of interest in identifying potential high-risk populations and determining the type of AVR in patients with AS. These possibilities should be tested in future studies.

Specific considerations: Prognostic thresholds for decision-making and sex-related differences

To improve clinical interpretability and guide decision-making regarding valve intervention, it is essential to define thresholds for identifying high-risk patients. Kwak et al investigated the non-linear relationship between fibrosis markers and mortality, determining optimal cutoffs for ECV% and LGE% using machine learning algorithms.⁵¹ The study found that mortality steeply increased once ECV% exceeded 27%, while the elevated risk associated with increasing LGE began at low levels and plateaued beyond 2%. These findings were validated in an independent external cohort. The study also highlighted that a higher number of myocardial damage indicators (including ECV%, LGE%, LV end-diastolic volume index, and right ventricular ejection fraction) predicts mortality post-AVR. This research suggests that mortality thresholds of myocardial fibrosis may be useful in guiding AVR and underscores that CMR assessment of myocardial damage is predictive of subsequent mortality in patients with AS undergoing AVR.

Another important issue is the sex differences in myocardial fibrosis in AS. It is relatively well known that outcome following AVR differs by sex,^69,70 which raises the suspicion that the degree and prognostic impact of myocardial fibrosis in AS may also vary between males and females. Significant differences exist in how the LV adapts to chronic pressure overload caused by severe AS between males and females. Female individuals tend to have smaller hearts, lower wall thickness and mass index, and higher ejection fractions.^71,72 However, regarding myocardial fibrosis, previous studies have shown inconsistent results on whether females develop more or less fibrosis, both in terms of LGE and ECV%, compared to males.^73–75 Some studies have reported higher overall LGE in males,^73,75 which could be attributed to a greater burden of ischemic heart disease and the resulting higher infarct-related LGE in this group. The largest of these studies included only 76 female patients, highlighting the need for a larger cohort with a greater number of female participants, ensuring that AS severity and comorbidities are well-balanced between sexes. Moreover, whether this fibrosis assessment has a differential impact on hard clinical outcomes between sexes remains unclear. Considering the significant sex differences in LV remodeling patterns, prognosis, and surgical outcomes,⁷⁶ it is now essential to establish sex-specific data, particularly focusing on female patients, who have been underrepresented in most CMR studies in AS.

Future directions

Although accumulating data has demonstrated the significant prognostic value of myocardial fibrosis markers in AS, and their utility in triggering early AVR is being tested in a randomized clinical trial (Figure 4), there are remaining questions that require further research. First, it remains to be determined whether these fibrosis markers, particularly ECV%, which represents early diffuse interstitial fibrosis, have any prognostic value in the earlier stages of AS. If they do, it would be important to explore whether different monitoring and surveillance strategies could be clinically beneficial for patients with less severe AS and fibrosis. Investigating these questions may provide additional insights into the potential benefits of earlier intervention in a population with less severe AS, particularly when myocardial damage remains low. This is crucial, as surgical techniques and outcomes have significantly improved over the last decades, alongside novel developments in less invasive interventional strategies.

Second, despite the independent prognostic role of myocardial fibrosis, how can we determine whether this is the major determinant of symptoms, heart failure, and subsequent adverse events in patients with multiple comorbidities?⁷⁷ This question also relates to how and when to intervene in multi-morbid patients with severe AS.⁷⁸ Incorporating information on myocardial fibrosis and comorbidities could lead to better stratification of high-risk populations, helping to determine the most appropriate type of AVR (surgical vs transcatheter) for multi-morbid patients, and even considering deferral of intervention when the overall risk is very high.

Third, are there any simpler imaging modalities or markers for detecting myocardial fibrosis? Computed tomography (CT)-derived ECV has been studied for the evaluation of myocardial fibrosis in several cardiac disorders,⁷⁹ including AS.^80–82 Recently, one study has shown that ECV assessed by CT, along with global longitudinal strain by CT, provides important prognostic information after transcatheter AVR among a low-risk AS population.⁸³ This method may offer additional value given the widespread use of CT in routine practice, particularly in the preoperative or pre-interventional evaluation for significant AS, and considering several limitations associated with CMR (ie, higher costs, claustrophobia). It is also important to identify surrogate markers that predict myocardial fibrosis, which could help in selecting candidates for CMR. For example, a previous study has shown that electrocardiographic strain was predictive of the presence of mid-wall LGE in patients with AS.³⁶ Serum biomarkers, such as N-terminal pro-B-type natriuretic peptide or troponin levels, as well as strain imaging, have been suggested as potential indicators of fibrosis.^{16,20,35,37,41} With upcoming trials or large-scale registries investigating CMR-guided early intervention expected to be reported soon, efforts to identify novel indicators for myocardial fibrosis in AS are becoming increasingly important.

Multiple non-invasive prognosticators are now available to assess the structural remodeling and function of the LV, including echocardiography, strain imaging, blood biomarkers, and CMR techniques. It is now essential to integrate these parameters to better predict risk and implement a more tailored management and intervention strategy.⁵⁴ A comprehensive assessment of these markers, including CMR, combined with data-driven analysis, may help achieve optimal outcomes for each individual with AS.

Conclusion

This review summarizes the current clinical data related to myocardial fibrosis assessed by CMR in AS. Recently accumulating evidence suggests that myocardial fibrosis in AS provides important, independent information on LV decompensation and serves as a powerful predictor of adverse clinical events. These markers hold the potential to guide decision-making in AS and optimize the timing of intervention; however, large-scale studies are warranted in the future.

Footnotes

Abbreviations

Acknowledgements

None

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This research was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea grant number (HI22C0154) and a grant from the National Research Foundation of Korea, Ministry of Science and ICT, Republic of Korea (grant number RS-202300208947).

Supplemental Material

There is no supplemental material for this manuscript.

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