The importance of big databases in understanding valvular heart disease

This editorial refers to ‘Normative values of the aortic valve area and Doppler measurements using two-dimensional transthoracic echocardiography: results from the Multicentre World Alliance of Societies of Echocardiography Study’, by J.I. Cotella et al., https://doi.org/10.1093/ehjci/jeac220.

Aortic valve (AV) disease is related to high morbidity and mortality worldwide, and its prevalence is still rising with the ageing population.¹ Cotella et al.² propose normal values for AV area (AVA) and Doppler measurements using 2D transthoracic echocardiography, on the basis of a large data set from the ‘Multicenter World Alliance of Societies of Echocardiography’ study.

Currently, reference values and cut-off values [published by the European Association of Cardiovascular Imaging (EACVI) and the American Society of Echocardiography (ASE)^3,4] are based on parameters derived from several well-designed cross-sectional population-based studies. However, these data have been derived predominantly from North-American observational registries with limited sample size.⁴ Moreover, the epidemiology of AV disease varies significantly around the world, with a predominance of rheumatic heart disease in developing countries, whereas in developed countries, the greatest burden of valvular heart disease is due to calcific AV disease.¹ Therefore, these reference values may not be extrapolated to the worldwide population. Additionally, sex-related differences for several AV parameters have been reported, and significant variation is observed between racial and ethnic groups.^5,6 This underscores the need for subgroup-specific echocardiographic reference values.

With the Normal Reference Ranges for Echocardiography (NORRE) study, Lancellotti et al. already provided reference values for several echocardiographic parameters, obtained from a large cohort of healthy subjects. However, the registry included a predominantly Caucasian European population.⁷ The World Alliance of Societies of Echocardiography (WASE) has performed a worldwide multinational prospective echocardiographic study, which included a wider variety of nationalities, races, ethnicities, and ages from 19 countries all over the world.⁸

Cotella et al.² have used data from the large WASE registry, aiming to define sex-, age-, and race-specific normative values for AVA and Doppler measurements, obtained by 2D transthoracic echocardiography. The population included 1903 healthy subjects (977 men and 926 women), aged 47 ± 17 years, with 413 Asian, 94 black, and 411 white individuals.² The main findings can be summarized as follows. First, sex-, age-, and race-specific normative values of the AVA and Doppler measurements were provided. Next, the authors highlighted differences between men and women with regard to the various left ventricular outflow tract (LVOT) diameter, AVA, and Doppler parameters. Also, differences between older and younger patients were highlighted. Last, the authors showed that various LVOT and AV parameters were smaller in Asians than in whites and blacks.²

Cotella et al.² provide a clinical example, illustrating the clinical relevance of these new normative values as follows. A significant percentage of healthy women in the WASE registry with a normal echocardiogram has mild or moderate aortic stenosis on echocardiography when the criteria of the EACVI/ASE guidelines are applied. Importantly, more than 50% of these women were from Asia, and when the WASE normative values for sex, age, and race were applied, these measurements were all within the normal range, therefore labelling these echocardiograms as normal.

Besides these differences in the various populations that affect the size of the LVOT and AV parameters, it is also important to realize that small differences in the measurement of these variables, that are needed to calculate the AVA, have a major impact on the potential for error in the calculation of the AVA by the continuity equation. Particularly, a small variation in the measurement of the LVOT diameter has a major impact, because the LVOT diameter must be squared to calculate the LVOT area.⁹ This example underscores the need for an accurate assessment of the different AV parameters that affect the evaluation normality.

Moreover, all echocardiographic measurements in the assessment of AV disease need to be interpreted in the context of careful evaluation of AV calcification, left ventricular function, wall thickness, aortic pathology, and blood pressure control, because all these parameters may affect the transvalvular gradients. In clinical practice, it will be impossible to correct for all these variables, but it is important to realize their potential influence on the assessment of AV stenosis and regurgitation.

Moreover, an accurate diagnosis of the severity of AV disease is paramount in the risk stratification of patients, because severe AV disease is independently associated with increased morbidity and mortality.^10,11 Of interest, women with AV disease have higher long-term mortality rates as compared to men, because of differences in pathophysiology and left ventricular remodelling patterns as a consequence of AV disease. Women present with more paradoxical low-flow AV stenosis as compared to men, which is known to be associated with worse outcomes as compared to normal flow high-gradient AV stenosis.⁶ Furthermore, conflicting results have been published with regard to racial and ethnic differences in the risk stratification of patients with AV disease. Alkhouli et al.¹² showed in a sub-analysis of the Transcatheter Valve Therapy registry, including 70 221 patients, that 1-year adjusted mortality rates were similar in black and white patients but lower in Asian patients.

Defining uniform values of normality for AV disease will enable researchers to ‘speak the same language’ when designing randomized controlled trials and develop homogenous criteria for patient inclusions.

In summary, Cotella et al.² have to be complemented for the effort of collecting this large data set and the meticulous data analysis, providing for the first time normative AV reference values according to sex, age, and race, derived from a prospective cohort and analysed in a standardized manner. The authors report significant differences for all echocardiographic variables between men and women as well as for most of the variables according to age and race.² However, the differences for some of these variables are very small, and the clinical importance needs further study.

References

Author notes