Evaluation of left atrial function in patients with iron-deficiency anemia by two-dimensional speckle tracking echocardiography

Background

World Health Organization (WHO) defines Anemia ashemoglobin levels < 13 g/dL (hematocrit < 39 %) inmales, < 12 g/dL (hematocrit < 36 %) in non-pregnantfemales, and < 11 g/dL (hematocrit <33 %) in pregnantfemales [1]. Iron deficiency and iron-deficiency anemia(IDA) are global health problems and common medicalconditions that can be seen in everyday clinical practice[2]. WHO estimates that 42 % of pregnant women, 30 %of non-pregnant women (aged 15 to 50 years), 47 % ofpreschool children (aged 0 to 5 years), and 12.7 % of menolder than 15 years worldwide are anemic [3]. Anemiaaffects one-fourth of world’s population, accounted for8.8 % of the total global burden of disease [4]. Irondeficiency is the predominant cause of anemia acrosscountries, with women more commonly afflicted thanmen [4]. Although the prevalence of iron-deficiencyanemia somehow has recently declined, iron deficiencycontinues to be the top-ranking cause of anemia worldwide. Iron deficiency may result from inadequate ironintake and absorption, increased iron requirements forgrowth, and excessive iron losses [5].Based on the physiological significance of oxygentransported to myocardial tissue, anemia may be a causeof more severe cardiovascular diseases or a sign of othersevere diseases that occur in the body. The physiologicresponse to anemia is a compensatory increase in cardiac output in order to maintain adequate oxygen delivery [6]. Patients are asymptomatic with mild anemia.Dyspnea and fatigue may occur when anemia is furtheraggravated. In severe cases, iron-deficiency anemia canlead to LV dysfunction and heart failure [6]. It has reported that myocardial contractility would decreasewhen hemoglobin was below 7 g/dL [7] and chronicanemia would result in increased LV end-diastolic pressure as well as decreased functional reserve [8]. Frequentresearch has been conducted on LA structural andfunctional remodeling, which is a cause of LV diastolicdysfunction, therefore the significance of LA has drawnmuch attention nowadays [9]. Increased left atrial sizehas been shown as an important predictor of targetorgan damage and multiple adverse cardiovascularevents [10, 11].2D-STE is a new technology to accurately evaluate LAfunction in normal subjects [12]. It has the advantage inaccurate quantification of myocardial deformation andbeing angle independent [13, 14]. Hence the goal of theresearch is to evaluate the LA function in patients withIDA by 2D-STE.

Methods

Study population

Between November 2014 and April 2016, we studied 65patients between the age of 22 and 65 with IDA, (male::female = 1:5.5). 38 patients with IDA were caused bygynecological disease such as uterine leiomyoma, adenomyosis and increased menstrual flow. 18 patients withIDA were caused by digestive system disease such assubtotal gastrectomy. Another 9 cases with IDA werecaused by unknown reasons. We rejected other causesof heart disease such as coronary heart disease, hypertension, congenital heart disease, diabetes mellitus, systemic lupus erythematosus, cardiopulmonary surgeryand any grade of valvular stenosis etc. According to thedegree of hemoglobin, 65 patients were classified intomild group (34 patients, 90 g/L≤Hb < 120 g/L, aged 25–65 years, mean age: 48.8 ± 14.1 years, male: female =7:27, IDA duration were all between 7 months and15 years,mean time: 6.5 ± 3.3 years) and moderate group(31 patients, 60 g/L≤Hb < 90 g/L aged 22–62 years,mean age: 47.6 ± 16.6 years, male: female = 6:25, IDAduration were all between 8 months and 14 years,meantime: 6.2 ± 3.6 years). In addition, we did not haveenough patents with severe IDA as patients withhemoglobin below 60 g/L were very rare to find, and inmost of all cases were being cured immediately, thustheir duration at severe anemia stage did not last long.The control group consisted of 30 healthy volunteers(aged 23–64 years, mean age: 47.0 ± 14.5 years, male: female = 6:24). All of them had no cardiovascular diseaseswith all examinations results shown as normal. Thisstudy was consented by the Second Affiliated Hospital’sEthics Committee of Dalian Medical University on human research and all patients were being informed andconsented to participate in this research.

Clinical and laboratory examination

All patients had completed a physical examination, Fromwhich height and weight were measured, and body massindex (BMI, kg/m2) and body surface area (BSA, m2)were calculated. Blood pressure and blood glucose weremeasured before echocardiographic examination. A 12-lead standard resting electrocardiogram (ECG) was performed among all patients.

Conventional echocardiography

An ultrasound system (Vivid E9, GE Medical Health,USA) and an M5S-D probe (1.5–4.5 MHz) were usedfor the study. Every subject had a conventional echocardiography examination in sinus rhythm. Every subjectwas connected with ECG and was in the left lateraldecubitus position, eupnea. The parameters were measured by conventional echocardiography, such as left ventricular end-diastolic dimension (LVDd), end-diastolicthickness of ventricular septum (IVSTd), end-diastolicthickness of LV posterior wall (PWTd) and left atrialchamber dimension (LAD). Early (E) and late (A) diastolicmitral inflow velocities were measured by pulsed wave Doppler, and E/A ratio was also calculated. Maximal,preatrial contraction, and minimal LA volume were acquired by the biplane modified Simpson’s rule [15]. Themaximum LA volume (LAVmax) was obtained beforestandard mitral valve opening. The precontraction LA volume (LAVp) was obtained at the precise beginning of theECG P wave, and the minimum LA volume (LAVmin)was obtained precisely at the late diastolic left ventriculus.Then left atrial active ejection fraction (LAAEF) and leftatrial passive ejection fraction (LAPEF) were calculatedusing the following formulas [16, 17]: passive emptyingindex (LAPEF) was calculated by ([LAVmax-LAVpre-a]/LAVmax), active emptying index (LAAEF) was calculatedby ([LAVpre-a-LAVmin]/LAVpre-a). Standard apical fourand two-chamber views were acquired according to theguidelines of the American Society of Echocardiography(3 consecutive heart cycles). Images were stored for offlineanalysis.

Speckle tracking

Standard images obtained in 2D mode were analyzedusing the EchoPAC software. Frame rates were controlled between 40 and 60 frames/sec. The endocardialinterfaces of left atrial were demonstrated completelyand they were traced manually by using a point-andclick method at the end of atrial contraction. Epicardialsurface tracing were then generated automatically by thesoftware and were changed manually based on the thickness of LA wall. The LA wall was then divided into 6segments automatically. If some segments were unavailable due to unsatisfactory tracking quality, these imageswould be removed. At the end, the final results were acquired in both four and two chamber views. Longitudinal strain and strain rate curves were generated forglobal LA wall. Global peak LA longitudinal strain rateof early and late diastolic LV (GLSRe, GLSRa), as well asthe global peak LA longitudinal strain and strain rate ofsystolic LV (GLSs, GLSRs) were obtained. Last but notthe least, the peak longitudinal systolic strain of LV wasobtained and their absolute values were compared.

Statistical analysis

The data were analyzed with SPSS 17.0 for Windowssystem. Numeric variables were presented as mean ±standard deviation (SD). One-way Analysis of Variance(ANOVA) was performed to test for statistically significant differences among the four groups. Continuousdata were compared between differences among individual groups using the Student-Newman-Keuls post-test.All statistical tests were two sided, andp< 0.01 was setfor statistical significance. Intra-observer analysis of global longitudinal strain and strain rate in the 4-chamberview were conducted two months after completion ofthe initial measurements (SJQ). For inter-observer

variability, a second observer (LGS) analyzed 20 % of theinitial images. Intra-observer variability and interobserver variability were assessed using the intra-classcorrelation coefficient (ICC).

Results

Demographic and clinical characteristics

Demographic and clinical characteristics of the threegroups are presented in Table 1. There were no significant differences among the three groups with respect toage, gender, duration of IDA, heart rates, body massindex, systolic arterial pressure, diastolic arterial pressureor blood glucose level (all P > 0.05).

Traditional echocardiographic parameters

There were no significant differences between groupB and group A (allP> 0.05). None of LVDd, IVSTdand PWTd were significant among the three groups.The LAD, LAVp, LAVmax, LAVmin, A and LAAEFof group C were significantly higher than those ofgroups A and B. E, E/A and LAPEF of group C weresignificantly lower than those of groups A and B (allP< 0.01) (Seen in Table 2).

Left atrial strain and strain rate

The group B was not significant compared with the control group (allP> 0.05). The GLSRa of group C were significantly higher than that of group A and B (P< 0.01).The GLSRe, GLSs, GLSRs of group C were significantlylower than those of group A and B (allP< 0.01) (Seen inTable 3). The 2D-STE strain rate curves of the threegroups were shown in Fig. 1, 2 and 3.

Left ventricular longitudinal strain

Meanwhile, the LV longitudinal strain values was manifested in the study. The strain value of the moderategroup was reduced, compared with both control groupand the mild group (all P < 0.01) (Seen in Table 4).The inter- and intra-observer results revealed goodreproducibility and small variability by using 2D-STE inevaluation of patients with IDA (Seen in Table 5).

Discussion

Anemia has been shown to be an important factor in increasing cardiac output to maintain adequate oxygensupply to the tissues [6]. The transition from a highoutput (compensated) state to a state of LV dysfunction(decompensated) begin at the hemoglobin below 7 g/dLin iron-deficient patients. The reduction of hemoglobinlevel is related to future increased morbidity and mortality [18]. So early diagnosis and treatment in irondeficiency can greatly improve quality of life and canpromptly reduce hospitalization rate, unemploymentrate and ultimately, reduce medical consumption [19].Therefore it has a significant prognosis to allow for earlyand correct diagnosis.

The LA function is an important factor influencingcardiac output [20] by regulating the filling pressure ofthe left ventricular with its reservoir, conduit and pumpfunctions. Although LA structural and functional remodeling is a barometer of LV diastolic dysfunction[21], there were no studies to reveal the changes of LAfunction in patients with IDA. Previous reports haveshown that some disease (hypertension, atrial fibrillation,

coronary artery disease, etc.) may lead to left atrialphasic dysfunction evaluated by 2D-STE [22, 23].Additionally, the longitudinal strain and strain rate,which are inversely related to LA wall fibrosis, havebeen reported to be a feasible and reproduciblemethod to assess LA myocardial function [24, 25]. Sowe try to evaluate the LA function in patients withIDA by 2D-STE.In our study, there were no significant differencesbetween group B and group A (allP> 0.05). None ofLVDd, IVSTd and PWTd were significant among thethree groups. The longitudinal strain of LV from basal toapical were decreased in the moderate group comparedto the control and mild group (allP< 0.01). The LAD,LAVp, LAVmax, LAVmin, A and LAAEF of group Cwere significantly higher than those of groups A and B(allP< 0.01). E, E/A and LAPEF of group C were significantly lower than those of group A and B (allP< 0.01).We found that the conventional echocardiographyparameters and strain and strain rate of LA, and

longitudinal strain of LV were changed with the decreasein hemoglobin concentration. When Hb > 90 g/L, therewere no obvious differences between the parameters ofgroup B and group A compared with the control group.This suggested that the structure and function did nothave obvious change in the mild group. When Hb 60–90 g/L, LAAEF and GLSRa of group C were higher thanthose of groups A and B. LAPEF, GLSs, GLSRe andGLSRs of group C were lower than group A and B. Thismeant that the LA longitudinal myocardial deformationhad impaired in this stage.

However, LA abnormalities are associated with abnormal diastolic function of the LV [26–28]. LA conduitfunction is correlated with LV early diastolic function[29], LA reservoir function is correlated with LV systolicfunction [30, 31], and LA pump function is associatedwith LV late diastolic function [32, 33]. The result of ourstudy had agreed to these above. At some degree, decreasing strain values means rising LV filling pressure.Based on the results, we found the following: the valueof GLSs and GLSRs, the reservoir function which receives blood from the pulmonary veins during ventricular systole was decreased in the moderate group. GLSReand LAPEF, the conduit function for transporting bloodfrom the pulmonary veins to the LV were also decreasedin the moderate group. They indicated that the movements of myocardial tissue had slowed down. These results were consistent with the longitudinal strain of LVand had indicated the LV diastolic dysfunction in themoderate group, which had associated with chronicmyocardial ischemia and hypoxia [6]. Both ischemia andhypoxia may lead to LA remodeling. On the other hand,the increase of LV filling pressure could result in increasing of LA afterload, which then could affect transporting blood from the pulmonary veins to the LA.

GLSRa and LAAEF, the parameters for the functionalevaluation of the pump phase that established the finalLV end-diastolic volume were increased in the moderategroup. Perhaps it was due to the strong contraction ofleft atrial, which was caused by increasing length of leftatrial myocardial fibers and rising LA pressure accordingto the Frank-Starling mechanism [34]. In addition, compared to the control and mild groups, the LV globallongitudinal strain decreased in the moderate group(Table 4). Studies have manifested that longitudinalstrain could be sensitive to subtle LV dysfunction, whichallowed investigation of earlier stages of myocardium. Inthe study, the investigation of strain values in the moderate group was decreased and it was a good illustrationof the sensitivity of 2D-STE in detecting earlier cardiacdysfunction. Therefore LA function and LV function areinteractional. Nowadays, many clinicians cognize theimportance to assess the role of left atrial function inprognosis of multiple adverse cardiovascular events, including death. After the study, most of patients in thestudy were made aware of the important effects ofanemia to their hearts. They had all actively acceptedthe clinical treatment, and the result may have effectivelyprevented further cardiac dysfunction.

Clinical implications

2D-STE is a sensitive tool for evaluating LA function inpatients with IDA. The application of 2D-STE in patients with IDA may help clinicians to identify earlierchanges of LA function. It greatly helps in early detection of abnormal LA function, even indicates clinicaltherapy. An aggressive therapeutic and preventive approach could improve the outcome of this disease.

Limitations

Our study had several limitations. First, we only analyzed a part of LA wall in apical four- and two-chamberviews, but in some studies, another three segments fromapical three-chamber view were also included [35].Secondly, lack of standardization could make our resultincomparable with others. Thirdly, the obesity, such aslung weight may impede image quality and the unclearendocardium may also affect the result. Lastly, only 65patients were selected in this study, the objects in the research were relatively small and only limited numberof patients in extremely severe group could be obtained.In these situations, we would select more samples tostudy in the future.

Conclusions

2D-STE could significantly evaluate the left atrial function in patients with IDA. And in our study, GLSs,GLSRs, GLSRe and GLSRa, the new LA function parameters, which are measured by 2D-STE, exert better potential for the accurate assessment of LA dysfunction inpatients with IDA.