Left atrial (LA) enlargement is associated with poor prognosis and cardiovascular events such as cerebral infarction and heart failure (HF) and as well as adverse overall outcomes [1-3]. There are several factors that determine LA size, i.e. age, gender, body size; therefore we use LA volume indexed to body surface area (BSA) as more precise method to examine LA size [4]. In terms of pathophysiologic aspects, mitral stenosis and left ventricular (LV) dysfunction induce LA pressure overload [5]. In addition, LA volume overload resulting from mitral valve regurgitation, arteriovenous fistula, left to right shunt, or high cardiac output state can also contribute to LA enlargement (LAE) [5]. However, there are controversies that “high cardiac out HF” is misnomer or not, because some authors suggest that high out state is intrinsically normal and capable of generating a high cardiac output [6]. Others have suggested that high output HF occurs only when there is the presence of underlying heart disease [7]. Among them, chronic anemia is a major cause of high cardiac output state which we easily encounter in daily practice [8]. However, there are only few studies exist which evaluating cardiac enlargement [9] or clinical implications [10,11] in patients with chronic anemia. Most recently, Hammoudi et al. reported that LA volume is not an index of LV diastolic dysfunction in patients with sickle cell anemia [12], however, sickle cell anemia is very rare in South Korea. Uterine myoma (UM) is well known cause of anemia because of high frequency of menorrhagia [13] occurring 5 to 20% of women [14]. LAE is common in patients with anemia caused by UM even they did not have overt heart disease. However, frequency or degree of LAE and its clinical implications have not been investigated in those patients. Therefore, we aimed to study on factors associated with LAE and its clinical implications in patients with anemia caused by UM in South Korea.

Study design and participants

We conducted a retrospective observational cross sectional study. In this study, we enrolled 139 female patients who were admitted to Kangnam Sacred Heart Hospital and diagnosed anemia caused by UM from April 2012 to December 2015. Anemia was defined when hemoglobin level was lower than 12 g/dL for women [15]. LAE was defined as LA volume index (LAVI) was 35 ml/m² or more [4]. Patients with chronic kidney disease, systolic blood pressure = 160 mm Hg, decreased LV EF<50%, regional wall motion abnormalities, arrhythmia, severe valvular heart diseases, pericardial diseases, thyroid disease, moderate to severe pulmonary hypertension, sepsis, hemodynamic instability, and age = 80 years were excluded from this study. The participants underwent transthoracic echocardiography and we collected participant data on demographic, anthropometric, and laboratory parameters.

Transthoracic echocardiography (TTE)

TTE was performed using standard techniques with a 2.5-MHz transducer. The standard 2-D and Doppler echocardiography was performed using a commercially available echocardiographic machine (Vivid 7R GE Medical System, Horten, Norway). LV end-diastolic dimensions (LV EDD), end-diastolic interventricular septal thickness, and end-diastolic LV posterior wall thickness were measured at enddiastole according to the standards established by the American Society of Echocardiography [4]. LV ejection fraction (EF) was determined by the biplane Simpson’s method [16]. Maximal LA volume was calculated using the biplane Simpson method [17] and indexed to the body surface area as LAVI. LV mass was calculated using the Devereux formula [18]=1.04 [(LVEDD + IVSTd + PWTd)3 - (LVEDD)3] - 13.6. Thereafter, the LV mass index (LVMI) was calculated and indexed to body surface area (BSA). Mitral flow velocities were recorded in the apical four-chamber view. Mitral inflow measurements included the peak early (E) and peak late (A) flow velocities and the E/A ratio. The tissue Doppler of the mitral annulus movement was also obtained from the apical four-chamber view. A 1.5-mm sample volume was placed only at the septal side of the mitral annulus. The analysis was performed for early diastolic (E’) and late diastolic (A’) peak tissue velocities. As a noninvasive parameter for LV stiffness, the LV filling index (E/E’) was calculated by the ratio of transmitral flow velocity to annular velocity. Adequate mitral and tissue Doppler image (TDI) signals were recorded in all patients [19]. Right ventricular systolic pressure was evaluated by calculating right ventricle-right atrium (RV-RA) pressure gradient (PG) using the modified Bernoulli equation (4 V²). Using the peak tricuspid regurgitation jet velocity as V, the RV-RA PG can be calculated [20]. RA pressure was determined by assessing IVC size and collapsibility. There was no patient with intra-cardiac shunt in this study.

Statistical analysis

All continuous data are expressed as mean ± SD, and all categorical data are presented as percentage or absolute numbers. Continuous variables were analyzed using Student’s t-test and dichotomous variables were analyzed using the chi square test. In addition, multivariate analysis (logistic and linear regression, SPSS for Macintosh, version 23, SPSS, Inc., and Chicago, Ill., USA) was performed. All variables that had a p value of 0.05 or less were considered statistically significant.

Echocardiographic parameters of the study population

Echocardiographic measurements are showed in Table 1. Patients with LAE showed larger LV than patients without LAE. More dilated LV and more increased LVMI were noted in patients with LAE. However, most patients with anemia showed normal LV diastolic function and variables associated with LV diastolic function (E and A velocities, E/A ratio, DT, E’ velocity, E’/A’ ratio, E/E’) even though they had enlarged cardiac size. Only E/E’ was slightly but significantly elevated in patients with LAE (10.0 ± 2.6 vs. 8.4 ± 2.2, p<0.001). There was no significant difference of EF between the two groups, but S’ which related to LV systolic function, was slightly lower in patients with LAE (S’: 7.8 ± 1.3 vs. 8.3 ± 1.4 cm/s, p=0.039). In addition, right ventricular systolic pressure was slightly higher in patients with LAE (34.5 ± 8.5 vs. 29.9 ± 5.5 mm Hg, p<0.001).

Table 1: Echocardiographic parameters of the study population.

Clinical parameters of the study population

The clinical characteristics of the patients are showed in Table 2. The study population included 60 patients with LAE and 79 patients without LA). Patients with LAE were slightly older (mean age: 48.9 ± 7.3 vs. 45.0 ± 7.4 years, p=0.003) and heart rate (HR) was slower (66.7 ± 12.4 vs. 77.0 ± 15.6, p<0.001). In laboratory parameters, level of hemoglobin was more lowered in patients with LAE (6.7 ± 1.9 vs 7.4 ± 1.7 g/dl, p=0.024).

Table 2: Clinical and laboratory parameters of the study population.

Correlations of continuous variables with LAVI in patients with anemia

As shown in Table 3, age and slower HR were significantly correlated with LAVI, whereas body mass index and serum creatinine level did not. Echocardiographic findings showed enlarged LV and increased LVMI were closely correlated with increased LAVI. Of the tissue Doppler parameters, deceleration time (DT) of E velocity, E’ and S’ velocity showed negative correlation with LAVI, and E velocity and E/E’ showed were closely correlated with LAVI.

Table 3: Correlation of clinical and echocardiographic variables with left atrial volume index.

Multivariate analysis

The results of multivariate analysis using parameters had significant correlations with LAVI were shown in Table 4. Among variables found to be correlated with LAE, older age (OR: 0.192, 95% confidence interval: 1.014-1.236, p=0.026) and slower HR (OR: 0.926, 95% confidence interval: 0.878-0.977, p=0.005) were independently associated with LAE. It shows positive correlation of age and LAVI and 1-B showed negative correlation of HR and LAVI.

Table 4: Multiple logistic regression analysis to predict high left atrial volume index in patients with anemia.

We found that almost half of patients with anemia caused by UM showed LAE (60/139, 43%). Older age, slower HR, lower level of hemoglobin, dilated LV, increased LVMI, shortened DT, elevated E/E’ ratio and right ventricular systolic pressure, and decreased S’ velocity were found to be associated with LAE in patients with anemia. Among them, older age and slower HR were independently related to LAE according to our study. Furthermore, even patients with anemia showed LAE, they did not have significant clinical and/or echocardiographic problems which supposed to be associated with LAE.

Sanghvi et al. reported that 120 of 155 patients reported cardiac enlargement by chest X-ray, and enlargement disappeared rapidly in 92 patients with correction of the anemia in 1960 [9]. More recently than previous study, Naito et al. showed that chronic iron-deficiency anemia leads to LV hypertrophy and HF in molecular level among animals [10]. Metivier et al. reported that anemia-related LV hypertrophy which is mainly due to increased cardiac output - mediated by lower afterload, increased preload, and positive inotropic and chronotropic effects - are reversible, not associated with impaired diastolic dysfunction [11]. However, even in the absence of underlying cardiovascular disorders, severe anemia (hemoglobin concentration <4-5 g/dl) could leads to congestive HF. All previous studies mentioned above were mainly focused on LV hypertrophy, not LAE, and the report from Metivier et al. was on patients with end-stage renal disease [11]. Rather different from previous studies, we focused on LAE which is very common in patients with anemia without underlying heart diseases or end-stage renal disease.

It is well known that patients with established cardiovascular disease and HF, the presence of anemia is associated with disease severity and affects outcome unfavorably [21-23]. Furthermore, Klip et al. recently published that hemoglobin level affected on new onset HF as U shaped pattern [24]. In terms of low hemoglobin level, only severe anemia increased annual HF incidence, not just anemia. In addition, Kim et al. reported that the presence of anemia was significantly associated with elevated LV filling pressure and LV structural changes – increased LVMI and LAVI, like our studies – in newly diagnosed hypertensive patients over 50 years old even before development of overt HF [25]. However, it has not been studied about clinical implications or its associating factors of LAE in anemic patients without underlying heart disease or other significant systemic diseases. Patients with anemia showed LAE comparable to patients with diastolic dysfunction, and showed even more dilated LV with increased LVMI according to our study likewise previous studies. However, most patients with anemia showed normal LV diastolic function and more favorable LV diastolic indices. Interestingly, patients with LAE showed slightly but significantly decreased S’ velocity than patients with anemia even though there was no difference in EF at all. TDI allows the quantitative evaluation of myocardial function [26,27] and it is well known that TDI is more sensitive to detect subclinical abnormalities in systolic and diastolic LV function over conventional echocardiography [28,29]. Decreased S’ velocity was well represent with subtle LA or LV dysfunction in asymptomatic individuals with cardiovascular risk factors [30].

Conventionally, chronic severe anemia is known to be often associated with various degree of salt and water retention [31-33]. Study from Anand et al. in 1993 told us that patients with chronic severe anemia (hematocrit 9-16%) had edema caused by retention of salt and water, reduction of renal blood flow and glomerular filtration rate, and neurohormonal activation similar to that seen in patients with edema caused by myocardial disease [34]. However, none of anemic patients used diuretics to eliminate congestion in our study because none of patients had significant pulmonary congestion. In addition, there are only small patients (14/139, 10%) showed severe anemia (hematocrit lower than 16%) in our study.

Our findings were similar to the recent study by Hammoudi et al., which reported that LAE is common in sickle cell anemia and related to age, hemoglobin concentration and LV morphology [12], however, sickle cell anemia is very rare in South Korea. Even we did not investigate the duration of anemia, when consider their cause of anemia, which were mostly UM or iron deficiency anemia-, their duration of anemia might be not acute event, rather several months exist. That is supposed to be why older age and slower HR were independently associated with LAE in patients with anemia caused by UM in this study. The longer anemia existed, the larger LA developed and slower HR represents its chronicity and adaptation. Nevertheless, patients with anemia or even with severe anemia did not have any clinical problems even cardiac enlargement detected by echocardiography.

This study has lots of limitations. First, relatively small number of study population was one of major limitation. Second, we did not investigate longevity of anemia, because most patients were asymptomatic until they found their anemia via routine health checkup. Therefore, our results may be different from other chronic severe anemia. However, this study might be useful in treating patients with mild to moderate anemia showing LAE without other problems. Third, the most common cause of anemia was caused by UM in this study and we exclude few men patients with anemia. Therefore our results were impossible to translate all anemic patients. Fourth, some laboratory data – brain natriuretic peptide, anemia study such as ferritin, iron, total iron-binding capacity, were not examined in whole study population. Therefore, important laboratory data associated with anemia were not fully investigated in this study. At last, we did not perform follow-up echocardiography after correction of anemia (i.e. myoma operation, blood transfusion). Therefore, we could not see if there was a reversal of LA or LV enlargement. It is important to see atrial reverse remodeling after proper therapy, because of high occurrence of atrial fibrillation (AF) in patients with LAE [35]. Patients with non-ischaemic dilated cardiomyopathy performed cardiac resynchronization therapy had less occurrence of AF if they had favorable atrial and ventricular reverse remodeling [36,37]. Therefore, it would be needed to see the relation between occurrence of AF and presence of atrial reverse remodeling in patients with anemia in the future study.

In summary, patients with anemia showed LAE even absence of underlying heart diseases but had favorable LV diastolic and systolic function. Older age, lower level of hemoglobin, dilated LV, increased LVMI, shortened DT, elevated E/E’ ratio, right ventricular systolic pressure and decreased S’ velocity were associated with LAE in patients with anemia caused by UM. Among them, older age and slower HR were independently related LAE. In conclusion, LAE is common in patients with anemia caused by UM without significant clinical implications.

This research received no specific grant from any funding agency.