Do we need different threshold values to define normal left atrial size in different age groups? Another piece of the puzzle of left atrial remodelling with physiological ageing

This editorial refers to ‘Sex differences and higher upper normal limits for left atrial end-systolic volume in individuals in their mid-60s: data from the ACE 1950 study’, by P.S. Rønningen et al., pp. 501--507. The left atrium (LA) is a crucial component of cardiac performance that stores pulmonary venous return during left ventricular contraction and isovolumic relaxation and modulates left ventricular filling. LA enlargement is the hallmark of the structural remodelling process, which occurs most commonly in association with atrial fibrillation, left ventricular diastolic dysfunction, left ventricular hypertrophy, and mitral valve diseases. Moreover, LA enlargement may be the cause of significant mitral regurgitation.1 Finally, LA size and function parameters are associated with increased risk of atrial fibrillation and ischaemic stroke and with adverse outcomes in multiple disease states, including acute myocardial infarction and heart failure with both reduced and preserved ejection fraction.2 Therefore, the identification of patients with enlarged and/or dysfunctioning LA is relevant in clinical practice. Among the physiological determinants of LA size, the role of body size is evident. Body size is a major determinant of LA size.3,4 Conversely, the role of sex and age is more controversial. Despite absolute LA volumes are larger in men than in women, indexation of LA volumes to body surface area has led to similar values between men and women and corrected for the effect of sex in most of the studies about the reference ranges of LV volumes. Accordingly, current guidelines have identified a single-threshold value of LA volume (34 mL/m2) for both men and women to differentiate between normal and enlarged LA.5 The effects of healthy ageing on LA volume have been more controversial, with some studies reporting an increase in LA volumes only at extremes of age,6 while others demonstrating a progressive age-related increase in LA volumes.7,8 Finally, it seems that ethnicity may also have a role in determining LA size, with Europeans and North Americans having larger LA compared with South and East Asians.9 Rønningen et al.10 add another piece to the puzzle of defining the reference values for the normal LA size and function by focusing their study on healthy subjects in their mid-60s. This age group is usually under-represented in cohorts of healthy subjects used to obtain reference values for cardiac chamber size and function. They found that, despite indexing for body surface area, in this age group there were significant sex differences in both maximal and minimal LA volume. Moreover, 13% of healthy men and 5% of healthy women had maximal LA volume larger than 34 mL/m2 (the upper limit of normality set by current guidelines5). According to their data, the upper limit of normality for maximal LA volume around 68 years of age would be 39 and 37 mL/m2 for men and women, respectively. By using the proposed cut-off values, the prevalence of enlarged LA among healthy individuals would have been reduced to 3.7% in men and 2.5% in women. The definition of the upper limits of normality for maximal LA volume remains an unsolved issue. The 2015 update of the joint American Society of Echocardiography/European Association of Cardiovascular Imaging5 increased the upper limit of normality from 28 to 34 mL/m2 compared with the upper limits reported in the 2006 version of the same guidelines.11 This revision of the normal upper limit of LA volume was based on pooled data coming from larger cohorts of healthy subjects and also on the need to align the ‘enlarged LA’ cut-off value with the one recommended in the algorithm to diagnose LV diastolic function.12 Moreover, the revised value of >34 mL/m2 used to define LA enlargement is perhaps more clinically relevant, as a LAVmax >32 mL/m2 was associated with adverse outcomes in ischaemic stroke, diabetes, and heart failure.13 Although the upper limits of normality allowed a reclassification into normal LA volume for 21% of patients previously reported as having an enlarged LA, there was no loss of the prognostic power associated with an enlarged LA.14 However, both 2D4 and 3D3 echocardiographic studies have reported larger maximal LA volumes in healthy subjects. Unfortunately, Rønningen et al.10 did not provide any follow-up data to show how the new cut-off values impact the prognostic power of LA volume in their patients. Being able to prove that, although the proposed cut-off values reduce the prevalence of enlarged LA, the prognostic power of LA volume remains unchanged or increased would have strengthened the clinical impact of their study. Another issue to consider is the way the LA volume is measured using two-dimensional echocardiography. Rønningen et al.10 used dedicated (i.e., non-foreshortened) four- and two-chamber apical views to obtain LA volumes. This method usually provides larger LA volumes than those obtained from the conventional apical views optimized for the left ventricle.5 However, the concepts that the long axes of the left ventricle and the LA are not coaxial (Figure 1) and that we need separate acquisitions and dedicated views to accurately measure left ventricular and LA volumes, is relatively new. Most of the papers which reported the LA volumes in healthy subjects in the past did not take into account this methodological problem. Notably, Kou et al. who measured the LA volume in healthy subjects using dedicated apical views reported an upper limit of normality of 37 mL/m2 which is quite similar to the values proposed by Rønningen et al.10 However, Rønningen et al.10 studied only patients in their seventh decade of life. Therefore, it is not possible to establish if the larger LA normal volumes found were the effect of the ‘physiological’ ageing process on LA size or just the effect of a different way of measuring the LA compared with previous normative papers. Apical views of the heart obtained from a 3D echocardiography data set to illustrate the fact that the long axis of the left ventricle (red-pointed line) and left atrium (yellow-pointed line) do not lie in the same plane. LA size displayed in the four-chamber view optimized for the LV (4CH) is significantly shorter than the LA size displayed in the two-chamber (2CH) and apical long-axis (LAX) views. Apical views of the heart obtained from a 3D echocardiography data set to illustrate the fact that the long axis of the left ventricle (red-pointed line) and left atrium (yellow-pointed line) do not lie in the same plane. LA size displayed in the four-chamber view optimized for the LV (4CH) is significantly shorter than the LA size displayed in the two-chamber (2CH) and apical long-axis (LAX) views. Another interesting point raised by the study of Rønningen et al.10 was the difference of the upper limit of normality for LA volume between men and women despite normalization for body surface area. Although the 2 mL/m2 difference is more statistical than a clinical problem, it raises the issue of the actual clinical value of single-threshold values for everybody: men and women, young and elderly, Caucasians, and non-Caucasian, etc. The concept of ‘one size fits all’ represents an old concept of the so-called ‘observational medicine’. Nowadays, we should move towards a more personalized approach in both diagnosis and treatment, i.e. ‘precision medicine’.15 Moreover, regarding the differentiation between normal and abnormal, the use of allometric equations that take into account body metrics (independent on the body surface area, since obesity may be a confounder), age, sex, and ethnicity would be a more physiologically and methodologically sound approach than the use of a single-threshold value. Conflict of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of EHJCI, the European Heart Rhythm Association or the European Society of Cardiology.