Aortic stenosis and bioprosthetic valve degeneration

Introduction

Aortic stenosis is the most common valvular heart disease in the developed world with an incidence set to treble by 2050. The prevalence of aortic sclerosis in the general population is estimated to be 25% at the age of 65, increasing to almost 50% by the age of 80. The rate of progression to hemodynamically significant aortic stenosis is projected to be almost 2% per year, which translates to a relatively low prevalence (<1%) at age 60 and younger ^, but a rapid growth to greater than 10% for patients over the age of 75. The natural history is characterized by a long asymptomatic period, in which there is generally a good prognosis. By the time symptoms develop, mortality rates increase dramatically for patients who do not undergo valve replacement, up to 50% after 2 years.

Once thought merely to be related to age-associated wear and tear, aortic stenosis is now known to be an active process, displaying pathophysiologic similarities to atherosclerosis and bone formation. Initially, injury to the endothelium leads to lipid and inflammatory cell infiltration followed by the development of progressive valvular fibrosis and calcification. A progressive vicious cycle of increased mechanical stress, leaflet injury, and further calcification leads to progressive valve stiffening and stenosis, triggering a hypertrophic remodeling response in the myocardium.

Histopathologic studies have demonstrated that early valve lesions, or those in the initiation phase of the disease, are characterized by endothelial damage, lipid deposition, chronic inflammatory infiltrates, and microcalcification. Risk factors for the incidence of aortic stenosis are similar to atherosclerosis, and like atherosclerosis, the starting event is believed to be injury to the valvular endothelium because of mechanical stress or other risk factors, which permit infiltration of lipoproteins and recruitment of inflammatory cells. The importance of mechanical stress is best exemplified by individuals with bicuspid aortic valves (1% to 2% in the general population), in whom the altered valve structure results in abnormal hemodynamics and increased mechanical stresses. Patients with bicuspid aortic valves almost invariably develop aortic stenosis and, in general, require valve replacement one to two decades earlier than patients with tricuspid valves.

The initiation phase is followed by a propagation phase, during which valve interstitial cells (VICs) assume an osteoblast-like phenotype and drive a vicious cycle of valve fibrosis and calcification, the latter demonstrating similarities with skeletal bone formation. In contrast to the initiation phase, atherosclerotic risk factors do not predict disease progression. Rather, it is the burden of calcification that is the strongest independent predictor or disease progression. The Multi-Ethnic Study of Atherosclerosis (MESA), a longitudinal population study, used repeat computed tomography (CT) scans to quantify aortic valve calcium. It showed that the presence of valvular calcification at baseline was a strong and independent predictor of progression of aortic valve calcium, whereas traditional cardiovascular risk factors did not predict disease progression when adjusted for baseline calcium.

Computed tomography

Imaging of the valve is critical in determining the diagnosis of aortic stenosis, grading severity, and informing the timing of valvular intervention. Current guidelines focus on echocardiography, which remains the gold standard method for assessing patients with aortic stenosis. ^, Recently, however, multidetector computed tomography calcium scoring of the valve has emerged as an alternative assessment of aortic stenosis severity to complement echocardiography. CT aortic valve calcium (CT-AVC) scoring provides a quantitative and accurate measurement of the aortic valve calcium burden, with high intraobserver, interobserver, and scan-rescan reproducibility. ^, Sex-specific thresholds demonstrate high diagnostic accuracy for severe aortic stenosis and provide a powerful prediction of future disease progression and clinical events. ^, CT-AVC was included in the most recent European Society of Cardiology guidelines as an arbitrator of aortic stenosis severity in patients with discordant echocardiographic measurements. Contrast-enhanced computed angiography is now used as the standard in the work-up of patients who are being considered for transcutaneous aortic valve implantation (TAVR), providing accurate valve sizing, quantifying the proximity to the coronary arteries, and assessing the optimal access route. Semiquantitative assessment of the aortic valve calcium burden is feasible but not well validated.

Positron emission tomography

Combined with CT, recent advances in positron emission tomography (PET) now allow for the assessment of disease activity in the aortic valve. So far, the literature has focused on two tracers: ¹⁸ F-fluorodeoxyglucose ( ¹⁸ F-FDG) to measure valve inflammation and ¹⁸ F-fluoride for calcification activity, with both discussed in the following sections ( Fig. 28.1 ).

¹⁸ F-Fluoride positron emission tomography

¹⁸ F-Fluoride has been used for over 50 years as a bone tracer and has recently emerged as a marker of vascular calcification activity in multiple different disease states. Fluoride ions exchange with hydroxyl ions in areas of exposed hydroxyapatite crystal (a key component of both bone and vascular calcification), with binding highest in areas of developing microcalcification because of surface area effects. In preferentially targeting developing microcalcification, ¹⁸ F-fluoride PET therefore acts as a marker of calcification activity and provides different information to the macroscopic deposits of calcium identified by CT.

In a study by Dweck et al., participants underwent ¹⁸ F-fluoride PET/CT. Compared with FDG, the ¹⁸ F-fluoride uptake in the valve was much stronger and more distinct with comparatively little activity observed in the surrounding structures. Compared with control subjects, valvular ¹⁸ F-fluoride uptake was higher in patients with both aortic sclerosis (TBR _MAX : 1.55 ± 0.17 vs. 1.92 ± 0.31; p < .001) and aortic stenosis (TBR _MAX : 1.55 ± 0.17 vs. 2.87 ± 0.82; p < .001). In total, 45% of patients with aortic sclerosis and 91% of those with aortic stenosis had increased uptake. The proportion of patients with increased activity rose sharply with increasing disease severity, such that 100% of patients with severe disease had increased uptake, and patients with moderate or severe aortic stenosis demonstrated far higher ¹⁸ F-fluoride activity than FDG. Interestingly, although ¹⁸ F-fluoride uptake was higher than FDG uptake in the valve, the reverse was true in areas of aortic atheroma, highlighting the importance of the pathologic differences between these two conditions. This also underlines the central importance of calcification in aortic stenosis, particularly in the latter stages of the disease, potentially explaining the disappointing results of statin therapy in treating this condition.

A subsequent follow-up study of this cohort demonstrated that both ¹⁸ F-fluoride and FDG predicted disease progression and adverse clinical outcomes in aortic stenosis. Disease progression was assessed at 1 and 2 years using CT-AVC and transthoracic echocardiogram. On repeat CT, new valvular macroscopic calcium was visible in a similar distribution to the ¹⁸ F-fluoride activity on the baseline PET imaging ( Fig. 28.2 ). Indeed, baseline ¹⁸ F-fluoride uptake correlated strongly with the subsequent rate of progression in the AVC score (Spearman r = 0.80; p < .001) and with echocardiographic measures of hemodynamic progression (mean gradient r = 0.32; p = .001). FDG showed similar but weaker correlations (r = 0.43; p < .001 and r = 0.26; p = .01, respectively). The study also looked at clinical outcomes. The primary clinical outcome end point was a composite of cardiovascular death and AVR. Average follow-up was 1232 days, at which point 23 patients (17%) had undergone AVR and 9 had a cardiovascular death. Both ¹⁸ F-fluoride and FDG were independent predictors of all-cause mortality and AVR (hazard ratio [HR] 1.46 [1.24 to 1.71]; p < .001 and HR 1.59 [1.21 to 2.09]; p = .002, respectively).

Left ventricular remodeling and the role of positron emission tomography imaging

Aortic stenosis progression is characterized by increasing left ventricular (LV) pressure afterload. This triggers a hypertrophic response that for many years normalizes wall stress and maintains cardiac performance. With time, however, this process decompensates. The hypertrophied myocardium outgrows its blood supply, leading to relative ischemia, myocyte cell death, and myocardial fibrosis. In combination, these processes lead to the transition from hypertrophy to heart failure and the development of symptoms and adverse events.

These processes can be investigated using novel imaging techniques, including PET/cardiac magnetic resonance (CMR) imaging, which combines the excellent temporal and spatial resolution of magnetic resonance imaging (MRI) with the sensitive molecular imaging of PET. Cine imaging exposes the LV remodeling and function, and late gadolinium enhancement (LGE) and T1 mapping provide tools for myocardial tissue characterization. Replacement midwall fibrosis identified by LGE is common in aortic stenosis (29% to 62%) ^, and is irreversible even after AVR. On the other hand, diffuse fibrosis is believed to be reversible, and it can be assessed using native T1 mapping and the extracellular volume fraction (ECV) . Recently, Chin et al. showed that ECV indexed to body surface area (iECV) correlates linearly (Pearson’s correlation, r = 0.87) with diffuse fibrosis and was increased in patients with aortic stenosis. It also provides good discrimination between the different stages of aortic stenosis, where increased iECV correlated with increased all-cause mortality.

Fibrosis quantification is a major strength of CMR imaging, but it only defines the presence of established fibrosis and cannot determine fibrosis activity or, indeed, disease activity. In the future, radiotracers targeting fibrosis activity, such as ⁶⁸ Gallium (Ga)-fibrosis activating peptide inhibitor, will be crucial in determining myocardial disease and fibrosis activity. This will pave the way for the optimal PET/CMR assessment of myocardial fibrosis in aortic stenosis, defining both established and developing fibrosis activity.

The formation of fibrosis secondary to ischemia is a key potential pathophysiologic pathway and the assessment of myocardial perfusion can be linked with the detailed investigation of myocardial function and fibrosis. Steadman et al. measured myocardial perfusion reserve (MPR) and showed for the first time that MPR is independently associated with LV remodeling and the severity of aortic stenosis. More recently, Zhou et al. confirmed that myocardial flow reserve (MFR) impairment correlated directly with aortic stenosis severity using ⁸² rubidium (Rb) PET. They further showed that the presence of concentric and eccentric patterns of hypertrophy were associated with impaired MFR, as was global longitudinal strain, suggesting a possible association between subclinical myocardial ischemia and fibrosis. Nevertheless, definitive studies linking myocardial ischemia with myocardial fibrosis have yet to be undertaken and are keenly awaited.