Valve and the ventricle: advances in the assessment and management of aortic stenosis
Background Aortic stenosis is the commonest valve disease in the Western world, progresses inexorably over years and has no effective lifestyle or drug treatments. Left untreated, aortic stenosis leads to symptoms such as breathlessness and chest pain, followed by cardiac failure and death. Aortic valve replacement (AVR) is the only treatment, for which surgery has been the default technique for decades. Transcatheter aortic valve implantation (TAVI), a much less invasive strategy, has substantially expanded the population in whom we now consider AVR. Importantly, the implantation of a prosthetic valve should be considered a means of converting a patient with severe native valve disease to a patient with a well-functioning prosthesis, rather than a cure for valve disease per se. There are potential complications that can arise following successful valve replacement, including valve thrombosis and structural valve degeneration. Given the above, several controversies and questions exist. These include: 1) What is the optimal method of assessing aortic stenosis severity in low-flow states and in valves where fibrosis contributes significantly to valve obstruction? 2) Are there deleterious effects on myocardial health from aortic stenosis that occur prior to symptom onset or a fall in ejection fraction, and that provide prognostic information? 3) Are there drug therapies that can retard the progression of aortic stenosis? 4) Are there novel methods of detecting bioprosthetic valve thrombus that may provide insight into mechanisms governing valve durability? Methods In study one, we developed a unique method of assessing the anatomy of the aortic valve and the severity of aortic stenosis using contrast-enhanced computed tomography (CT). This method has several advantages over non-contrast CT aortic valve calcium scoring (CT-AVC) – the current standard flow-independent measure of aortic stenosis severity – which include spatial resolution, anatomical definition and the ability to quantify non-calcific leaflet thickening in addition to calcific volume. This technique was applied in a post-hoc analysis of a prospectively recruited population of patients with aortic stenosis enrolled in a randomised controlled trial. Patients had undergone standardised echocardiography, non-contrast CT and contrast-enhanced CT. In study two, we investigated a novel echocardiographic measurement, first-phase ejection fraction (EF1), in aortic stenosis. This parameter is the ejection fraction measured at the time of peak aortic velocity, rather than across the entire cardiac cycle, and is a measure of early left ventricular contractility which can be impaired in aortic stenosis. This technique was applied in a post-hoc analysis of a prospectively recruited population of patients with aortic stenosis enrolled in an observational study. Patients had undergone standardised echocardiography and cardiac magnetic resonance (CMR). Subsequent AVR and death were captured from medical records. In study three, we undertook a double-blind randomised controlled clinical trial of the anti-osteoporotic drugs denosumab and alendronic acid to determine whether they could slow disease progression in aortic stenosis. This hypothesis arose from a body of pre-clinical and observational data suggesting that bone turnover and osteoblastic differentiation of valvular interstitial cells are important contributory mechanisms to aortic valve calcification, and that modification of the receptor activator of nuclear kappa B (RANK) ligand/RANK/osteoprotegerin axis might ameliorate valvular calcification. Patients were randomised in a 2:1:2:1 ratio to denosumab (60 mg every 6 months), placebo injection, alendronic acid (70 mg once weekly) or placebo capsule. Participants underwent serial assessments with Doppler echocardiography, CT-AVC and 18F-sodium fluoride (18F-NaF) positron emission tomography and computed tomography (PET-CT). The primary endpoint was the calculated 24-month change in CT-AVC. In study four, we undertook the first ever cardiac study of 18F-GP1. This is a novel radiotracer that binds to the glycoprotein IIb/IIIa receptor, which are upregulated on activated platelets. We investigated whether 18F-GP1 PET-CT could detect thrombus formation on bioprosthetic aortic valves. First, ex vivo validation of 18F-GP1 binding was conducted in explanted bioprosthetic valves leaflets using histology (Movat’s pentachrome), immunohistochemistry (CD41) and autoradiography (18F-GP1). Second, patients with bioprosthetic aortic valve prostheses who were not on anticoagulation were enrolled and underwent standardised echocardiography and 18F-GP1 PET-CT. Patients with normal native aortic valves who had undergone 18F-GP1 PET-CT as part of a contemporaneous study formed a control cohort. Two patients with clinically confirmed obstructive bioprosthetic valve thrombosis, recruited as part of a proof-of-concept case series by collaborators in Germany, were also included in the analysis. Results In study one, 164 patients with aortic stenosis were included for analysis (78% male; 41 mild, 89 moderate, 34 severe). We demonstrated that non-calcific and calcific aortic valve leaflet volumes on contrast-enhanced CT correlated well with echocardiographic peak aortic jet velocity (r=0.67, p<0.001). In particular, quantification of the total non-calcific and calcific leaflet volume demonstrated better correlation with echocardiographic peak aortic velocity than non-contrast CT-AVC in women (r=0.72 and r=0.38 respectively). In study two, 149 patients with aortic stenosis were included for analysis (70% male; 34 mild, 40 moderate, 75 severe). We demonstrated that EF1 can be impaired despite a normal overall ejection fraction, that a low EF1 is associated with increased global left ventricular afterload and more myocardial fibrosis, and that there is a potential for EF1 to improve following AVR. Importantly, a low EF1 was associated with future AVR or death, independent of mean aortic valve gradient (hazard ratio 5.6, 95% confidence interval 3.4-9.1). In study three, we enrolled and randomised 150 patients (mean age 72±8 years, 21% female, peak aortic jet velocity 3.36 [interquartile range 2.93 to 3.82] m/s) to denosumab (n=49), alendronic acid (n=51) or placebo tablet or injection (total n=50). Despite an unequivocal pharmacodynamic effect of the active drugs, as confirmed by a halving of the serum C-terminal telopeptide concentration at 6 months in the denosumab and alendronic acid arms, we found no differences in 24-month change in CT-AVC between denosumab and placebo (343 [198 to 804] Agatston Units (AU) versus 354 [76 to 675] AU, p=0.41), or alendronic acid and placebo (326 [138 to 813] AU versus 354 [76 to 675] AU, p=0.49). Similarly, there were no differences in change in peak aortic jet velocity or 18F-NaF aortic valve uptake. In study four, we undertook 18F-GP1 PET-CT in 75 participants (53 with bioprosthetic valves, median time from implantation 37 [12 to 80] months; 22 with normal native valves). All bioprosthetic valves, but no native aortic valves, demonstrated focal 18F-GP1 uptake in the valve leaflets. On multivariable analysis, higher 18F-GP1 uptake was independently associated with duration of valve implantation (p=0.002) and hypoattenuated leaflet thickening (p=0.004) but not with valve type. One patient had suspected clinical valve thrombosis, confirmed on 18F-GP1 PET-CT, in addition to the two patients with known obstructive valve thrombosis. All 3 were anticoagulated for 3 months, leading to resolution of symptoms, improvement in mean valve gradients and a reduction in 18F-GP1 uptake. Extra-valvular 18F-GP1 uptake was evident across a range of extra-valvular prosthetic material such as aortic interposition grafts and pacemaker leads. Conclusions We have demonstrated that contrast-enhanced CT assessments of non-calcific and calcific aortic valve leaflet volumes correlated well with echocardiographic assessments of aortic stenosis severity. This technique has clear benefits over non-contrast CT-AVC. We envisage the potential for standard integration of contrast-enhanced leaflet volume assessments into routine TAVI workflows, where a large proportion of patients have discordant echocardiographic findings, and in patients where the contribution of fibrosis, rather than purely calcium, may lead to underestimation of stenosis severity as assessed by CT-AVC. We went on to show that EF1 is a potentially useful echocardiographic measure of early left ventricular systolic dysfunction that may help risk stratification in patients with asymptomatic severe aortic stenosis. This is pertinent in the current era where early AVR is being tested in several randomised controlled trials. Additionally, we conclusively demonstrate in a randomised controlled trial that neither denosumab nor alendronic acid substantially affect the progression of aortic stenosis. This was a disappointing result but an important finding that also highlights the importance of randomised controlled trials when investigating causal relationships. Finally, 18F-GP1 PET-CT may have utility in identifying focal areas of thrombus and distinguishing them from other causes of hypoattenuation on CT as well as providing a novel approach to explore factors that may influence valve thrombogenicity and durability. Taken together, these four studies have provided incremental advances in the diagnosis, assessment and follow-up of patients with aortic stenosis as well as generated major impetus for future clinical studies in this important and topical field.