Left Atrial Volume Index in Diagnosis of Heart Failure With Preserved Ejection Fraction

Objective To assess the value of left atrium volume index(cid:0)LAVI(cid:0)for diagnosing heart failure with preserved ejection fraction (HFpEF) based on the invasive determination of left ventricular end-diastolic pressure (LVEDP). Methods A total of 710 cases of patients with dyspnea (LVEF ≥ 50%) were enrolled in this retrospective study. Left ventricular end-diastolic pressure (LVEDP) was measured through selective coronary angiography. According to the value of LVEDP, cases were divided into the HFpEF group ( LVEDP ≥ 15mmHg) and the control group (LVEDP<15mmHg). LAVI was calculated based on cardiac compartment diameter, as measured by echocardiography, and body surface area (BSA). Differences of LAVI between the HFpEF group and the control group, and between subgroups in the HFpEF group were analyzed. Results The difference in LAVI between the control group and the HFpEF group was statistically signicant (41.35±2.28vs.46.78±2.63ml/m 2 , p=0.008). LVEDP was positively correlated with LAVI (Pearson: r=0.787, P(cid:0)0.001). When LAVI took the best cutoff value of 43.7 mm/m 2 , the sensitivity and specicity of diagnosis of HFpEF were 92.0% and 88.9%. When the boundary value of LAVI was from 41.7 to 45.7 mm/m 2 , the sensitivity of the diagnosis of ejection fraction retention heart failure was from 97.4% to 64.4% and the specicity was from 51.2.0% to 92.2%. Conclusion In patients with dyspnea after exclusion of heart failure with reduced ejection fraction (HFrEF), LAVI is positively correlated with LVEDP. LAVI can be used to diagnose HFpEF when HFrEF is excluded.


Introduction:
The clinical diagnosis of heart failure with preserved ejection fraction (HFpEF) is di cult [1][2] . HFpEF is diagnosed as heart failure based on typical signs and symptoms in association with a diastolic dysfunction and a relevant structural heart disease [2][3][4] . Heart failure associated symptoms and signs lack speci city due to the drawbacks of imaging and biomarkers in many clinical settings. Left atrial enlargement has been suggested by studies and guidelines as evidence for diagnosing HFpEF, but its e cacy has not been evaluated by left ventricular end-diastolic pressure (LVEDP),which is accepted as the gold standard for diagnosing HFpEF [5,6] . This study aims to evaluate the value of left atrium volume index (LAVI) in diagnosis of HFpEF based on the invasive determination of LVEDP.
Materials And Methods

1.Research population
The retrospective study included cases admitted between January 2015 and December 2018 to the emergency or cardiology department of Dongzhimen Hospital A liated to Beijing University of Chinese Medicine. This study has been reviewed by the ethics committee of Dongzhimen Hospital A liated to Beijing University of Chinese Medicine. Due to its retrospective nature, the study did not obtain informed consent forms.
Exclusion criteria: (i) incomplete medical history data, loss of related examination results or existence of uncertain values; (ii) pericardial disease or pericardial effusion; (ii) severe anemia (HGB 60g/L ); (iv) no history of selective coronary angiography; (v) presence of serious changes of illness during cardiac color Doppler examination or selective coronary angiography; (vi) presence of serious adverse events during examinations; (vii) Moderate to severe mitral regurgitation.

3.Diagnostic criteria
LVEDP is considered to be the gold standard for diagnosing HFpEF, and heart failure can be diagnosed with LVEDP ≥ 15mmHg.

4.Collection of general information
Patients' medical history, age, sex, height, weight, BMI (kg/m 2 ), heart rate, and blood pressure (mmHg) were recorded. Blood sugar, serum creatinine, blood urea nitrogen, blood lipids, peripheral blood leukocytes, hemoglobin, smoking history, drinking history, chest X-ray, echocardiography, cardiogram, 12lead electrocardiogram, and types and names of medications were also recorded.

Echocardiography
The Philips iu 22 color doppler ultrasound system (probe frequency 2.5MHZ) was used. All patients were told to remain in the left lateral position and do calm breathing for the transthoracic ultrasound examination, according to standard procedures. The following indicators were recorded: 1. left atrial diameter LAd; 2. left ventricular end diastolic diameter (Left ventricular end diastolic diameter, LVEDd); 3. interventricular septum diameter (IVSd); 4. left ventricular posterior wall diameter (LVPWd); 5. left ventricular ejection fraction (Left Ventricle Ejection Fraction, LVEF); 6. early mitral diastolic blood ow spectrum: E; 7. mitral regurgitation late anterior blood ow spectrum: A; 8. mitral regurgitation; 9.LAVI was obtained through the following steps [7] : Obtain the left heart apex four-chamber view and the left-heart two-chamber view (Fig. 1), and plot the area of the left atrium (Al, A2) at the maximum volume of the left atrium. Also, measure the distance from the midpoint of the mitral annulus to the top of the left atrium (L1, L2). left atrial volume = 8 / 3π (A1 XA2 / L) = 0.85 X A1 X A2 / L, L for the apex Lavi = atrial volume / body surface area (BSA), BSA (m2) = 0. 0061 X height (cm) + 0. 0128 X body weight (kg) )-0.1529. 6. Selective coronary angiography and left ventricular enddiastolic pressure measurement Selective coronary angiography was performed using the Judkins method. After selective coronary angiography was completed, a pigtail catheter was slowly delivered to the left ventricle along the guide wire. There was no irritative ventricular premature contraction or adjustment before the contraction disappeared. The external pressure sensor was connected and left ventricular end-diastolic pressure was printed after the pressure screen was clearly displayed on the test screen.

Statistical analysis and control
(1) Data entry and control All data were entered in an EpiData database (EpiData Association, Odense, Denmark) by the researchers using the double entry method, and cross-validation was used for control. All researchers have received professional training in reading relevant indicators.
(2) Bias control In order to avoid control bias, the people who analyze the results of the index examination did not know the grouping.

(3) Statistical analysis
The data were imported into SPSS (Version 20.0, SPSS, Inc., Chicago, IL, USA) software for data processing. The normal distribution of continuous measurement data was expressed as mean ± standard deviation. The Pearson chi-square test was used to analyze the categorical variables, and the Student t test was used to compare the two sets of measurement data (two-tailed test, p < 0.05 was considered statistically signi cant). LVEDP ≥ 15mmHg was used as the gold standard for diagnosing HFpEF. The ROC curves of LAVI and N terminal pro B-type natriuretic peptide (NTpro-BNP) in diagnosing HFpEF were drew and the diagnostic e cacy between the two was compared according to the study diagnostic gold standard. The diagnostic test method was used to explore the optimal cutoff value for LAVI in diagnosing HFpEF, and the authenticity evaluation (the degree the results obtained by the diagnostic test is consistent with the actual situation) was conducted. The sensitivity, speci city, missed diagnosis rate, misdiagnosis rate, diagnosis ratio, Youden index, likelihood ratio, and the area under the ROC curve were calculated.

2.Baseline data
Baseline data of patients with normal heart function and the HFpEF group are shown in Table 1. There were no signi cant differences between the two groups in age and sex. Both groups had normal hepatic and renal functions. But levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) were higher in the HFpEF group than in the control group. Ratios of concomitant diseases such as hyperlipidemia, hypertension, diabetes, hypertrophic cardiomyopathy (HCM), atrial brillation and coronary artery disease were higher in the HFpEF group than in the control group whereas ratios of COPD, pulmonary interstitial brosis (PIF), pulmonary infection, pleural effusion and asthma were higher in the control group than in the HFpEF group. These phenomena may re ect the intrinsic features of cardiac and non-cardiac dyspnea.

5.ROC curve of NT-proBNP for diagnosig HFpEF
The ROC curve of NT-proBNP for diagnosing HFpEF was drawn with LVEDP ≥ 15 mmHg as the standard.

6.Diagnostic test parameters of LAVI for diagnosing HFpEF
When LAVI took the best cutoff value of 43.7mm/m 2 , with reference to LVEDP ≥ 15mmHg as the standard for diagnosing HFpEF, the sensitivity and speci city for diagnosis of heart failure were 92.0% and 88.9%. The area under the curve was 0.949. When the LAVI threshold was from 41.7 to 45.7 mm/m 2 , the sensitivity for diagnosis of ejection fraction retention heart failure ranged from 97.4-64.4%, and the speci city ranged from 51.2-92.2%, as shown in Table 3.

Discussion
Heart failure with preserved ejection fraction (HFpEF) is di cult to diagnose. If LVEF is in the normal range, further identi cation of HFpEF is di cult [8] . Ultrasound assessment of diastolic function indexes such as E/A and E/E′are not easy to carry out under many clinical conditions. However, measuring the size of the left atrium as LVEF is comparatively easier. Epidemiological studies suggest that the size of the left atrium is associated with HFpEF and that left atrial volume index can be used to aid in the diagnosis of HFpEF [9] . But the e cacy of this method has not been evaluated by LVEDP, which is accepted as the gold standard for diagnosing HFpEF [10] . To further clarify the value of LAVI in the diagnosis of HFpEF, this study used LVEDP to evaluate the value of LAVI for diagnosing HFpEF.
In this study, LVEDP, LAD and LAVI were collected from cases of patients with dyspnea whose diagnoses have excluded the possibility of HFrEF. Left ventricular end-diastolic pressure (LVEDP) was measured by catheterization, the left atrial diameter was measured by cardiac color Doppler examination and LAVI was calculated thereby. Cases of patients with dyspnea were divided into an HFpEF group and a control group according to LVEDP [5] . The correlation between LAVI and LVEDP in the HFpEF group showed that LAVI was positively correlated with LVEDP (r = 0.787, P < 0.001). The value of LAVI for diagnosing HFpEF was evaluated by using LVEDP ≥ 15mmHg as the gold standard. The results show that LAVI is a valuable indicator for diagnosing HFpEF, and consistent with our hypotheses, its value is superior than that of of NT-proBNP (ROC: 0.949 vs. 0.760, p < 0.0001).
In the subgroup analysis, though the level of LAVI was higher in atrial brillation subgroup than in nonatrial brillation group (47.78 ± 3.35 ml/m 2 vs. 45.26 ± 2.71 ml/m 2 , p 0.01), all its level was higher than the best cutoff value of 43.7mm/m 2 . The e cacy of LAVI for diagnosing HFpEF were reserved in our study population.
The role of changes in left atrial structure and function in heart failure is receiving growing interest [11] . The pathophysiological mechanism of HFpEF is mainly characterized by myocardial hypertrophy, brosis, impaired dysfunction, left ventricular remodeling in patients with HFpEF, increased left ventricular mass, reduced left ventricular long axis shortening, left ventricular geometry changes, and concomitant diastolic dysfunction [12][13] . When left atrial mass begins to increase in moderate left ventricular diastolic dysfunction, it is likely that the volume of the left atrium has not increased and that left atrial enlargement is a sign of a sustained increase in left ventricular lling pressure [14][15] . Continued elevated left atrial pressure and volume load increase left atrial hypertrophy and its mass [16][17][18][19] , and thus the left atrium is considered to be closely related to HFpEF [24] .
Currently there is no invasive method to explore the relation between left atrial volume and left ventricular end-diastolic pressure in patients with HFpEF although previous studies have shown that left atrial volume is closely related to the prognosis of HFpEF [20][21] , or suggest that left atrial volume is associated with HFpEF comorbidities such as atrial brillation [22][23] or with diabetes [24] . Recently, Melenovsky and his colleagues used hemodynamics and echocardiography to study the structure and function of the left atrium in 198 cases (51% with HFpEF) with heart failure. They found that patients with HFpEF have higher left atrial peak pressure, left atrial stiffness, and pulsation index [25] . Impaired left atrial function is associated with right ventricular dysfunction and elevated pulmonary vascular resistance. Gani Bajraktari believed that, in addition to the effects of elevated left ventricular lling pressure, impaired compliance of the left atrium also leads to enlargement of the left atrium [26] . These studies suggest that the structure and function of the damaged left atrium are prevalent in HFpEF and play an important role in the pathophysiological changes of HFpEF. The structural changes of HFpEF in the left atrium (left atrial remodeling and enlargement) can be used as diagnostic indicators for HFpEF. Our study con rmed that LVEDP elevation is closely related to LAVI and can be used to diagnose HFpEF. It is an inexpensive and convenient means of diagnosis [25,27] .

Limitations
Some patients received treatment during the interval between selective coronary angiography and echocardiography, so the results may be affected and the errors were not excluded.

Conclusions
The left atrial volume index gradually increased with the increase of left ventricular end-diastolic pressure, and they were positively correlated. LAVI can be used to diagnose HFpEF. In the differential diagnosis of clinical dyspnea, if left ventricular ejection fraction is normal whereas the left atrium is enlarged, HFpEF should be considered. LAVI is superior to NTproBNP in the diagnosis of HFpEF. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
No con ict of interest exits in the submission of this manuscript.  Scatter plot of LAVI and LVEDP The gure shows that LAVI was positively correlated with LVEDP r=0.787, P<0.001). ROC curve of LAVI for diagnosing HFpEF The AUC acquired from the ROC curve of LAVI for diagnosing HFpEF is 0.949 with sensitivity of 90.8% and speci city of 90.4% P<0.001