Imaging and Impact of Myocardial Fibrosis in Aortic Stenosis

Aortic stenosis is characterized both by progressive valve narrowing and the left ventricular remodeling response that ensues. The only effective treatment is aortic valve replacement, which is usually recommended in patients with severe stenosis and evidence of left ventricular decompensation. At present, left ventricular decompensation is most frequently identified by the development of typical symptoms or a marked reduction in left ventricular ejection fraction <50%. However, there is growing interest in using the assessment of myocardial fibrosis as an earlier and more objective marker of left ventricular decompensation, particularly in asymptomatic patients, where guidelines currently rely on nonrandomized data and expert consensus. Myocardial fibrosis has major functional consequences, is the key pathological process driving left ventricular decompensation, and can be divided into 2 categories. Replacement fibrosis is irreversible and identified using late gadolinium enhancement on cardiac magnetic resonance, while diffuse fibrosis occurs earlier, is potentially reversible, and can be quantified with cardiac magnetic resonance T1 mapping techniques. There is a substantial body of observational data in this field, but there is now a need for randomized clinical trials of myocardial imaging in aortic stenosis to optimize patient management. This review will discuss the role that myocardial fibrosis plays in aortic stenosis, how it can be imaged, and how these approaches might be used to track myocardial health and improve the timing of aortic valve replacement.

Decisions about if, when, and how to intervene have therefore become increasingly complex, requiring careful assessment of individual patients within a multidisciplinary heart team.
Current guidelines recommend intervention in patients with severe aortic stenosis and evidence of left ventricular decompensation. Most commonly this is in the form of development of typical symptoms, but other markers include a reduction in ejection fraction <50%, an abnormal exercise tolerance test, or a rise in brain natriuretic peptide levels (14,15). B, for intervention in the most common scenariosymptomatic, severe aortic stenosis. However, intervention in asymptomatic patients with a reduction in ejection fraction <50% or an abnormal exercise test is only Level of Evidence: C (i.e., expert opinion) (15).

The American College of Cardiology and American
Heart Association guidelines are largely in alignment (14). This highlights the need for more robust data to better risk-stratify patients and optimize management strategies before the onset of symptoms and heart failure.  17). Attention has focused on myocardial fibrosis in particular, given its structurefunction correlation with heart failure and the fact that it can now be identified reliably and noninvasively with modern imaging techniques. This review will discuss the pathophysiology of myocardial fibrosis and left ventricular decompensation in aortic stenosis, the imaging techniques that can be used to detect it, and how these might be employed to track myocardial health and optimize the timing of AVR.

PATHOLOGY
It is useful to consider aortic stenosis as a disease of both the valve and the myocardium (4). In addition, the importance of arterial stiffness and systemic pulsatile arterial load cannot be underestimated in this elderly population (18,19). A detailed discussion of events within the valve is beyond the scope of this review (20); however, an understanding of the pathological factors driving the hypertrophic remodeling response and its subsequent decompensation are critical to understanding the rationale for myocardial fibrosis imaging (Central Illustration).
Progressive valve narrowing causes pressure overload of the left ventricle and triggers a hypertrophic response that maintains wall stress and left ventricular performance for many years. Over time, this process decompensates and patients transition from hypertrophy to heart failure, leading to adverse clinical outcomes. This evolution is complex but is closely related to the development of myocardial fibrosis, myocyte injury, and cell death. Furthermore, there is adverse remodeling of the extracellular matrix, with degradation and disruption of the matrix structure (21). These changes are regulated by several factors, including the renin-angiotensin-aldosterone system, transforming growth factor beta, apoptosis signal-regulating kinase 1, and tissue inhibitor of metalloproteinase (22)(23)(24): all potential targets for novel therapeutic interventions.
Two distinct myocardial fibrosis patterns have been described. Reactive interstitial fibrosis is diffuse and follows increased myofibroblast activity and collagen deposition that begins even in the early stages of aortic stenosis. Importantly, this diffuse fibrosis is reversible and has been demonstrated to regress following AVR (16). In contrast, replacement fibrosis appears to occur later and is irreversible (25). Treibel et al. (26) recently demonstrated that patients with advanced disease undergoing AVR manifest a complex combined pattern of both replacement and diffuse fibrosis. Moreover, they observed a fibrosis gradient from the subendocardium to the midmyocardium, perhaps suggesting supply-demand ischemia as a contributing factor.
The degree of myocardial remodeling and fibrosis is closely related to hemodynamic markers of myocardial performance, such as end-diastolic pressure and ejection fraction (4). Moreover, multiple Imaging and Impact of Myocardial Fibrosis in Aortic Stenosis F E B R U A R Y 2 0 1 9 : 2 8 3 -9 6 histological studies have now demonstrated an association between myocardial fibrosis at the time of AVR and both impaired recovery of left ventricular systolic function and poor long-term outcomes following valve replacement (17,(27)(28)(29). Although it is certainly plausible that myocardial fibrosis might directly contribute to such outcomes, a causal relationship is yet to be demonstrated.

IMAGING MODALITIES FOR THE ASSESSMENT OF MYOCARDIAL FIBROSIS
Although myocardial biopsy and histological analysis are still considered the gold standard assessments of myocardial fibrosis, they have several important limitations precluding their routine clinical application. Myocardial biopsy is an invasive procedure that carries an attendant risk of complications (30).
Additionally, as only small areas of the myocardium can be sampled, biopsy is prone to sampling error. By contrast, modern imaging techniques, in particular those provided by cardiovascular magnetic resonance (CMR), allow comprehensive, noninvasive assessments of fibrosis across the entire myocardium as well as quantification of its functional consequences ( Schematic of the left ventricular remodeling response in aortic stenosis, describing the transition from hypertrophy to fibrosis, heart failure, and cardiac death. LGE is now well established and widely used as a method for detecting replacement myocardial fibrosis in a broad range of cardiovascular conditions such as ischemic cardiomyopathy, nonischemic dilated cardiomyopathy, cardiac sarcoidosis, cardiac amyloidosis, myocarditis, and hypertrophic cardiomyopathy (31)(32)(33)(34)(35)(36)(37)(38). In each condition, replacement fibrosis    Imaging and Impact of Myocardial Fibrosis in Aortic Stenosis F E B R U A R Y 2 0 1 9 : 2 8 3 -9 6 incremental value to valve assessments, comorbidity, and left ventricular ejection fraction (28,41,(44)(45)(46) ( Table 2).
The poor prognosis associated with non-infarct LGE appears to persist long after AVR is performed, in keeping with the irreversible nature of replacement Noninfarct LGE was also demonstrated to be an independent predictor of both all-cause and cardiovascular mortality.
LGE is reliable, well-validated, and easily inte-    LGE appeared to be concordant with histology (88% with severe fibrosis had $2 positive segments; 89% with no fibrosis had no positive segments) and did not regress at 9 months post-AVR.
LGE was an independent predictor of all-cause mortality
LGE progressed from baseline and was most rapid in patients with more severe stenosis. In patients undergoing AVR, iECV reduced by 11% (4%-16%) but there was no change in LGE.

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LGE was present in 32.3%. Native T 1 was increased compared with control patients, with overlap. Native T 1 and LGE were independent predictors of poor prognosis.  regress, but cellular mass regresses more rapidly, thereby resulting in an apparently paradoxical increase in ECV% as the ratio of matrix to total mass is increased (25,42). iECV, however, decreases as it represents the extracellular matrix as a total volume, LGE is the best validated of these approaches, is relatively simple to perform and analyze, and is
CT ¼ computed tomography; DCM ¼ dilated cardiomyopathy; HF ¼ heart failure; HFpEF ¼ heart failure with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction; other abbreviations as in Table 2.
research expands, this approach may offer clear advantages over LGE. For example, future investigation of antifibrotic therapies will require biomarkers to monitor myocardial health and treatment effects; T 1 mapping will be indispensable in this regard.
Further work to investigate the role of emerging CT techniques is also warranted, particularly as they may be more easily integrated into current clinical care pathways and workflows than CMR. There has also been early investigation of collagen-and elastin-specific CMR contrast agents, which may provide greater contrast to noise ratio compared with current GBCAs, but further advances in this field are awaited (73,74