The Role of Imaging in Measuring Disease Progression and Assessing Novel Therapies in Aortic Stenosis

Aortic stenosis represents a growing health care burden in high-income countries. Currently, the only definitive treatment is surgical or transcatheter valve intervention at the end stages of disease. As the understanding of the underlying pathophysiology evolves, many promising therapies are being investigated. These seek to both slow disease progression in the valve and delay the transition from hypertrophy to heart failure in the myocardium, with the ultimate aim of avoiding the need for valve replacement in the elderly patients afflicted by this condition. Noninvasive imaging has played a pivotal role in enhancing our understanding of the complex pathophysiology underlying aortic stenosis, as well as disease progression in both the valve and myocardium. In this review, the authors discuss the means by which contemporary imaging may be used to assess disease progression and how these approaches may be utilized, both in clinical practice and research trials exploring the clinical efficacy of novel therapies.

ASSESSING THE VALVE ECHOCARDIOGRAPHY. While there may not be a true reference standard for AS severity, echocardiography is considered the gold standard for clinical assessment. Early work in the 1970s found that Doppler ultrasound could be used to examine the jets of stenotic and regurgitant lesions (17). This laid the groundwork for Hatle et al. (18,19)   Noninvasive imaging provides the ability to directly image the aortic valve and consequent pathophysiological effects on the myocardium. Imaging the valve may be performed by computed tomography (CT) to quantify aortic valve calcification (AVC) load (CT-AVC), positron emission tomography (PET) to measure calcification activity and/or echocardiography to assess hemodynamic severity. The response of the left ventricle (LV) may be assessed by echocardiographic measures of mass, ejection fraction and/or strain, whereas cardiac magnetic resonance (CMR) offers additional quantification of fibrosis. The ability of these techniques to detect therapeutic efficacy depends on the scan-rescan repeatability of the test and the rate of change of the parameter being measured. These attributes are being exploited in a number of ongoing studies to investigate novel therapies for aortic stenosis. AS ¼ aortic stenosis; ECV ¼ extracellular volume; iECV ¼ indexed extracellular volume; LGE ¼ late gadolinium enhancement; PDE5 ¼ phosphodiesterase type 5.

POSITRON EMISSION TOMOGRAPHY
Positron emission tomography (PET) is another novel technique, the use of which is being explored in AS.
By monitoring biological processes within the body, this modality has the potential to offer important mechanistic insights into pathophysiology. Furthermore, as a marker of disease activity and very early calcium formation, there is growing interest in using PET to detect early therapeutic effects in AS at a stage in the process when calcium is more likely to be reversible ( Figure 2).
Radiolabeled sodium fluoride ( 18 F-NaF) is a widely available PET tracer that can be used to measure calcification activity in the vasculature, with an affinity for developing microcalcification (42)(43)(44)(45). 18 F-NaF activity is increased in patients with aortic valve disease compared with the healthy population, with a progressive rise in PET uptake with increasing severity of AS (jet velocity and calcium score) (39).
Furthermore, early studies have suggested that 18 F-NaF activity predicts the rate of future disease progression as measured by CT-AVC and Measuring Disease Progression and Assessing Novel Therapies in AS echocardiography (45,46). Indeed, new areas of macrocalcification appear to subsequently develop at sites of increased baseline 18 F-NaF uptake, consistent with this tracer identifying developing calcification before it is visible on CT ( Figure 3). As a marker of disease activity, 18 F-NaF therefore holds potential in detecting therapeutic effects more rapidly than conventional anatomical imaging approaches do (47 (49).

ASSESSING THE MYOCARDIUM
In addition to monitoring progressive valve narrowing, noninvasive imaging may also provide detailed assessments of the LV remodeling response: from    Regardless of the stage of disease, it appears probable that calcification is more likely to be reversible in its earlier stages of development, meaning that imaging techniques that can identify early developing calcification, such as 18 F-NaF PET, are likely to be of value (Table 1).