What can we do to improve the diagnosis and treatment of aortic stenosis?

Calcific aortic valve stenosis (aortic stenosis [AS] characterised by progressive fibrocalcific leaflet remodelling) leading to blood flow restriction is the most frequent structural heart disease, with mortality rates increasing across Europe since 2000. Symptoms are insidious at onset and development of any of the three cardinal symptoms of angina, syncope, or heart failure portend a poor prognosis, with aortic valve replacement (AVR) showing a consistent improvement for both symptom-free and overall survival.

Current guidelines recommend AVR in symptomatic severe AS but the role of AVR in patients with asymptomatic severe or moderate stenosis is evolving. In the last decade the rapid adoption of transcatheter AVR (TAVR) has raised new treatment paradigms for AVR across the spectrum of risk. Opportunities to improve outcomes include earlier diagnosis and a reconsideration of intervention timing in the asymptomatic severe and moderate categories of AS, along with a reconsideration of the patient lifelong aortic valve care plan.

International guidelines recommend multi-disciplinary ‘Heart Teams’ as the preferred clinical method in decision-making¹ for multi-dimensional, pre-procedural work-up: surgical risk evaluation; clinical assessment; multi-modality valve imaging; and coronary disease management. Heart Teams have evolved central to the process, and bear responsibility for offering each patient a tailored approach.² With approximately 5,000 AS patients having not received treatment, over eight months in 2020, following the COVID-19 outbreak (UK TAVR Registry and the National Adult Cardiac Surgery Audit),³ there is a need to meet increasing demands and reverse the drop in SAVR/TAVR activity. The authors have reviewed what the future holds for AS management.

Discussion

Biomarkers have not been used routinely in clinical AS management, but recent advances look set to change this. The PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study identified that a higher ratio of apolipoprotein B/apolipoprotein A-I was associated with a 3.4-fold increase in haemodynamic progression in the younger (<70 years) AS cohort. The balance of atherogenic and anti-atherogenic lipid factors appears to play a crucial role in pathogenesis in younger patients,⁴ presenting a screening target. Regardless of symptom status, biomarkers have application in risk stratification. Systematic review and meta-analysis of 83 blood biomarker studies demonstrated all-cause AS mortality to be associated with elevated baseline levels of brain natriuretic peptide (BNP), N-terminal pro B-type natriuretic peptide (NT-proBNP), troponin and galectin-3.⁵ Observing changes in these biomarker levels could prove helpful in optimal timing of intervention. Most recently, pre-clinical models of AS have heralded the emergence of microRNAs as innovative biomarkers.⁶ The utilisation of this novel technique may add to the management armamentarium.

Imaging is central to the assessment, diagnosis, follow-up, selection of intervention type and optimal timing. The British Society of Echocardiography regularly updates its guidelines.⁷ Clinical dilemmas related to discordant haemodynamic data, asymptomatic haemodynamically severe AS and normal/low-flow low-gradient AS have been tackled with the help of novel echocardiographic approaches to better evaluate disease severity, enhance risk stratification and provide prognostic information.⁸ This is not to suggest echocardiography is without limitations. Compared with magnetic resonance imaging (MRI), echocardiography has been shown to underestimate left ventricular outflow tract area, stroke volume and, consequently, aortic valve area (AVA).⁹ Low cost, portability and reproducibility of echocardiographic imaging has made it the current best choice, but with more widely available MRI scanners this may change. Novel multi-modality imaging techniques, such as combined positron emission tomography (PET)/computed tomography (CT) and PET/MRI, are being explored. Both approaches provide unique insight with respect to valve disease activity, alongside more conventional anatomic assessments of valve and myocardium.¹⁰ Techniques such as the use of 4D-flow MRI for measuring valve effective orifice area using the jet shear layer detection method¹¹ have yielded promising results for the future.

Registry data from 10 centres across Europe and Canada have shown improvement in quality of life at three months following intervention, with either SAVR or TAVR, using the Toronto Aortic Stenosis Quality of Life Questionnaire.¹² A smaller study, using the 36-item Short Form Health Survey at three months, has confirmed greater increase in quality of life parameters in the older (>70 years) cohort with TAVR.¹³

TAVR is a valid alternative to SAVR in inoperable patients or patients with intermediate and high operative risk with severe AS.¹⁴ The choice of transcatheter approach versus open-heart surgery in the low surgical risk group remains a matter of debate. Meta-analysis of randomised-controlled trials (RCTs) of 13 reports has shown no difference in short-term (30-day) mortality in adults, and low surgical risk undergoing either approach. Similarly, no difference in risk of stroke, myocardial infarction (MI), and cardiac death between either approach exists. TAVR does reduce risk of atrial fibrillation, acute kidney injury, and bleeding, but this benefit is offset by increased permanent pacemaker implantation rates.¹⁵ Further analyses of RCTs have corroborated that TAVR can provide similar mortality outcome to SAVR in low- to intermediate-surgical-risk patients with critical AS.¹⁶ Finnish registry data, over a 10-year period, confirm TAVR achieves similar short- (30-day) and mid-term (three-year) survival in low-risk patients.¹⁷ Long-term follow-up data are needed to further assess and validate these outcomes, especially durability, before extending the use of TAVR to the low-risk cohort. Consideration must now be given to the lifelong plan of aortic valve disease management for younger patients electing to have bioprosthetic valves. Repetitive relining of valve-in-valve has physical limitations, and the combined role of SAVR and TAVR in patients with the appropriate sequence of procedures will be important in optimising the lifespan of AS patients.

Whether intervention should be performed in patients with asymptomatic severe AS remains debated. Patients with asymptomatic severe AS and AVA <0.6 cm² have displayed increased adverse events risk, including all-cause mortality, during short-term follow-up.¹⁸ Meta-analysis of 29 studies suggests that many patients with asymptomatic severe AS develop an indication for aortic valve intervention, and deaths are mostly cardiac. Early intervention reduces long-term mortality. Factors associated with worse prognosis included: severity of AS; low-flow AS; left ventricular damage; and atherosclerotic risk factors.¹⁹

Historically, moderate AS has been considered benign, for which the potential benefits of AVR are outweighed by the procedural risks. Emerging data demonstrating the mortality risk in untreated moderate AS, and improvements in peri-procedural and peri-operative mortality with AVR, have challenged the traditional risk/benefit paradigm.²⁰ Patients with less than severe AS have been known to suffer symptomatically, making decisions more challenging.

The most important clinical management task has been to differentiate true-severe AS, benefiting from AVR, from pseudo-severe AS, requiring conservative management. Low-dose dobutamine stress echocardiography has proved useful in those with classical low-flow, low-gradient AS, whereas aortic valve calcium scoring by multi-detector CT is the preferred modality for paradoxical low-flow, low-gradient or normal-flow, low-gradient AS.²¹

Normal-flow, low-gradient severe AS is the most prevalent form of low-gradient AS. However, the true severity of AS, and the management of normal-flow, low-gradient severe AS, are controversial. Analysis of patients with normal-flow, low-gradient severe AS, moderate AS, and high-gradient severe AS has shown the former to have comparable outcome following AVR to those with moderate AS, mostly at the stage of high-gradient severe AS.²²

With increasing AS mortality, a growing elderly population, widening of indications for AVR and a fall in activity following the COVID-19 outbreak, it is incumbent on Heart Teams to provide expeditious care to meet demands. Future care will integrate biomarkers and higher-quality imaging to deliver optimally timed bespoke care. Early signs are that TAVR will supersede SAVR in the low-risk cohort.

Funding Statement

Funding None.