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Optimal management of asymptomatic patients with aortic stenosis (AS) remains one of the challenges of modern cardiology. Attention has focused on improving risk stratification in these patients, with the aim of identifying important biomarkers of disease progression and outcome, so that early intervention can be targeted to those who would potentially benefit the most, without additional risk.
Low flow, or a reduced stroke volume index (SVI, stroke volume/body surface area), has been identified as one of the markers of poor prognosis in patients with both symptomatic1 2 and asymptomatic severe AS.3 A study published in this issue of Heart aimed to investigate the effect of SVI on outcome in asymptomatic patients with mild to moderate AS from the SEAS study cohort. The SEAS study was a multicentre, prospective, double-blind placebo-controlled study in asymptomatic patients with peak transvalvular jet velocity of 2.5–4.0 m/s, randomised to treatment with simvastatin and ezetimibe or placebo.4 Lonnebakken et al 5 have looked at the association of SVI with major cardiovascular events and all-cause mortality during a median follow-up period of 4.3 years in 1671 of the total 1873 of the SEAS patients, who had adequate quality images for analysis. The primary endpoint was a composite of major cardiovascular events (AS-related events and ischaemic cardiovascular events). Low SVI (<35 mL/m2) was identified in 23% of the patients, who were older, with higher body mass index (BMI) and heart rate, and lower mean gradient, ejection fraction, left ventricular mass, annular diameter and aortic valve area (AVA) than those with normal SVI. Although there were more females in the low SVI group (43% vs 38%), this did not reach statistical significance (p=0.098). Low SVI was found to be both a univariate and multivariate associate of the primary endpoint and all-cause mortality, after adjusting for age, sex, atrial fibrillation, mean aortic gradient, ejection fraction, mass, BMI and study treatment. The authors also conducted Cox regression analysis of categorical low SVI against normal SVI and found SVI <35 mL/m2 to be associated with major CV events but was not associated with all-cause mortality.
The current study has demonstrated a link between SVI at baseline and outcome in a large cohort of minimally symptomatic patients with ‘mild to moderate’ AS. However, there are some limitations that need to be acknowledged. First, the inclusion criteria in the SEAS study incorporated only a single measure of AS severity (peak transvalvular flow of 2.5–4.0 m/s) and did not differentiate those with an AVA <1 cm2, as a result of which some patients would now be classified as low flow/low gradient ‘severe’ AS. Indeed, the mean AVA was significantly lower, as well as being in the severe range (0.91±0.28 cm2), in the low SVI group (Table 2). Perhaps those with AVA in the severe range should have been excluded from the current analysis. Second, as acknowledged by the authors, there are major limitations to the accurate assessment of left ventricular outflow tract (LVOT) diameter on echocardiography (annular calcification, assumptions about LVOT shape shown to be elliptical rather than circular on CT6 and MRI studies), which has a major impact on the calculated SVI (figure 1), as can be seen by the significantly lower annular diameter in the low SVI group. Lastly, as is well known, females (both normal and with AS) have lower SVI, and some of the differences between the groups may be due to gender differences, although the authors did correct for gender in the multivariate analysis. Perhaps a gender-specific analysis of these data may provide further insight into the pathophysiology of disease progression and outcome in AS.
Low SVI has been shown to be a poor prognostic marker in severe AS, and this study extends these findings to milder forms of the disease. The authors have demonstrated a weak but significant association with outcome in this large cohort of patients with ‘pure’ AS and recommend implementing SVI assessment in routine clinical practice when assessing AS severity. However, SVI is dependent on multiple factors, including LV volume, contractility, filling pressures and afterload, and not just valvular obstruction, and therefore will be influenced by other common comorbidities such as coronary artery disease and hypertension. Indeed, SVI was not associated with outcome in our cohort of asymptomatic patients with moderate to severe AS in the recently published PRIMID-AS study.7 Symptom status remains the most important indication for intervention at present, and while low flow may help guide intervention in those with borderline severe AS, its role in those with asymptomatic mild to moderate disease remains questionable in routine clinical practice, especially given the limitations in its measurement on echocardiography.
Numerous markers have now been identified that are associated with adverse outcome in asymptomatic AS8 including echocardiographic markers, ECG left ventricular hypertrophy/strain, biomarkers (brain-natriuretic peotide (BNP), N-terminal pro-BNP, high sensitiviryTroponin), exercise testing and cardiac MRI markers (late gadolinium enhancement, myocardial perfusion reserve). However, none in isolation is particularly useful and a multimodality approach with a combined score may improve risk stratification for individual patients, which should be confirmed with replication studies in the future. Ultimately, randomised clinical trials are needed to determine whether early intervention, for which transcutaneous aortic valve insertion looks increasingly attractive,9 improves clinical outcomes, and two such studies are planned (EVOLVED-AS and EARLY TAVR NCT03042104).
Contributors Both authors have written this Editorial and given final approval.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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