Left atrial strain during stress echocardiography for the assessment of myocardial ischaemia

Study population and design

This study prospectively included patients referred for assessment of myocardial ischaemia with DSE at the echocardiography laboratory of the Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil. Patients who met any of the following criteria were excluded from the study: age <18 years or >80 years, acute coronary syndrome, ejection fraction (EF) < 50%, poor acoustic window, significant valvular heart disease (defined as stenosis or regurgitation graded as ⩾moderate, or the presence prosthetic valves), atrial fibrillation (confirmed by electrocardiographic findings and/or documented in medical records), allergy or abnormal reaction to dobutamine (Figure 1). All patients provided written consent before being included in the study, in accordance with the principles of the Helsinki Declaration. This study was approved by the local ethics committee (no. 5.861.661) and registered with Plataforma Brasil (Brazilian database of research involving human subjects, no. 64793422.2.0000.0096) and with ReBEC (Brazilian registry of clinical trials, no. U1111-1294-1711).

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Figure 1.

Study sample.

Clinical characteristics, including demographics, comorbidities and laboratory tests, were extracted from medical records. The pretest probability of coronary artery disease (CAD) was calculated using the model recommended in the 2019 European Society of Cardiology (ESC) guidelines on chronic coronary syndrome (2019-ESC-PTP), ⁹ which is based on age, sex and symptoms (chest pain and dyspnoea). A low probability of CAD was defined when it was estimated at ⩽5%, a moderate probability was between 5% and 15%, and a high probability was defined when it was ⩾15%. Cardiovascular risk stratification was performed using the pooled cohort equations from the American Heart Association/American College of Cardiology (AHA/ACC), ¹⁰ and patients were categorised into low cardiovascular risk (<7.5% in 10 years), intermediate cardiovascular risk (7.5%—20% in 10 years), and high cardiovascular risk (⩾20% in 10 years) groups.

The study protocol consisted of performing DSE by board-certified echocardiographers. The digital loops were stored and analysed offline. Speckle-tracking strain was measured retrospectively by an analyst blinded to the patient’s clinical data and conventional DSE results.

Dobutamine stress echocardiography

All patients underwent a complete transthoracic echocardiography prior to dobutamine stress. Images were obtained using an Affiniti 70 ultrasound machine (Philips, Netherlands) equipped with a 2–5 MHz transducer. Two-dimensional and Doppler images were obtained with continuous electrocardiographic monitoring with the patient in the left lateral decubitus position, following current guidelines. ¹

During DSE, cineloops were recorded at rest, at low doses of dobutamine (between 10 and 20 µg/kg/min), at high doses of dobutamine (between 30 and 40 µg/kg/min), and at recovery 1 minute after stress. If the patient had no contraindication to atropine use (such as glaucoma or obstructive prostatic disease), its use was permitted (at doses of 0.25 mg per minute from the high-dose stage of dobutamine, up to a total of 1.0 mg), aiming to reach 85% of the predicted maximum heart rate. Dobutamine infusion was stopped 2 minutes after the patient reached the target heart rate. The test was terminated prematurely in the presence of new WMAs, progressive chest pain, severe ischaemic electrocardiographic changes, a systolic blood pressure >230 mmHg, severe arrhythmias, or intolerable symptoms. Beta-blockers were discontinued 5 days before the exam.

WMAs were visually analysed according to the 16-segment model of the American Society of Echocardiography by two experienced and certified echocardiographers blinded to the patients’ clinical data, and the wall motion score index (WMSI) was calculated. ¹ The diagnosis of myocardial ischaemia was defined as a new or worsening WMA during stress in at least two contiguous segments.

Speckle-tracking strain analysis

For the evaluation of myocardial strain, images were acquired with the device adjusted to record two cardiac cycles with a period of 100 ms before and after the cycle. The image was in the second harmonic, greyscale, with a frame rate between 60 and 90 frames/s. Strain analysis was performed using QLab software (version 10.8; Philips, Netherlands).

LA strain analysis was performed according to the recommendations of the European Association of Cardiovascular Imaging and American Society of Echocardiography task force for deformation imaging. ¹¹ Strain was evaluated using the apical four-chamber (A4C) and apical two-chamber (A2C) views with a zero-reference set at end-diastole (i.e. R-R gating). Endocardial borders were traced with the aid of manually marked reference points, extrapolating across the pulmonary veins and/or LA appendage orifices, with a region of interest (ROI) width of 3 mm. Images were acquired at the end of each stage of DSE, and the three components of atrial strain were measured for each patient: the reservoir phase (LASr) from end-ventricular diastole until mitral valve opening, the conduit phase (LAScd) from mitral valve opening until the onset of atrial contraction, and the contractile phase (LASct) from the onset of atrial contraction until end-ventricular diastole (Figure 2).

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Figure 2.

Original recording of the LA strain obtained using speckle tracking echocardiography. In the upper panel, the area of interest surrounding the LA wall in the two-chamber view is shown. In the bottom panel, the strain curves during the cardiac cycle for the six LA segments are shown. Yellow arrows point to the average strain values for the three phases of atrial function: reservoir (LASr), conduit (LAScd) and contractile (LASct).

Images for LVGLS analysis were acquired at the end of each stage of DSE. Endocardial borders were automatically traced, with manual adjustment when necessary, and the peak LVGLS was calculated as the average of the peak systolic strain values obtained from all the LV segments contained in the A4C, A2C, and apical three-chamber views.

For each studied parameter, a random sample of 20 patients was used to test interobserver agreement.

Sample size calculation

The sample size calculation was based on the hypothetical association of LA strain with the diagnosis of ischaemia by stress echocardiography (yes = 1 or no = 0) through receiver operating characteristic (ROC) curve analysis. It was estimated that 45 patients would be needed for an area under the curve (AUC) of 0.80 to be significantly different from the null hypothesis (AUC = 0.5), with a type I error (alpha) of 0.05 and type II error (beta) of 0.2, with a proportion of negative and positive patients for myocardial ischaemia of 4:1.

Statistical analysis

Data are expressed as medians and interquartile ranges or proportions (categorical variables). We compared means between two groups using the t test or, alternatively, the Mann‒Whitney test when the variables had a non-Gaussian distribution. Fisher’s exact test and the chi-square test were used to analyse the associations between categorical variables. Multiple linear regression was used to identify independent determinants of continuous variables. Univariable logistic regression was used to assess the association between each variable and the occurrence of inducible ischaemia during DSE. ROC analysis was used to obtain optimal discriminatory values, sensitivity, specificity and AUC for each variable. Comparisons between AUCs were performed using the DeLong method. The intraclass correlation coefficient (ICC) and the coefficient of variation were used to assess interobserver agreement for strain analysis. Statistical tests were two-tailed, and p < 0.05 was considered statistically significant. All analyses were performed using MedCalc software for Windows, version 18.5 (MedCalc Software, Ostend, Belgium).

Left atrial strain as a marker of systo-diastolic dysfunction

LA strain is affected by both LV systolic and diastolic function. During the LA reservoir phase, the LV sequentially undergoes isovolumic contraction, ejection, and isovolumic relaxation. The downwards movement of the mitral annulus towards the apex promotes LA expansion, accommodating venous return from the pulmonary veins until the maximum volume of the LA is reached. Therefore, the LASr is determined by the atrial compliance, the movement of the mitral annulus and the LV end-systolic volume. ¹²

During ventricular diastole, the elastic recoil of the mitral annulus in the opposite direction combined with ventricular relaxation promotes reciprocal changes in ventricular and atrial volumes, allowing LV filling during the LA conduit phase. In the presence of ischaemia, this process may be impaired since myocardial relaxation is highly energy dependent, and its impairment could lead to diminished ventricular suction. ¹³ In terms of LA function, the LASr and LAScd components contribute mainly to early diastole, whereas the LASct component contributes to ventricular filling during late diastole. ¹⁴

Brecht et al. ¹⁵ reported a progressive decrease in LASr and LAScd values with the progression of diastolic dysfunction from mild to severe grade, whereas LASct initially increased in patients with mild diastolic dysfunction before decreasing in those with moderate to severe diastolic dysfunction, supporting the role of increased filling pressure in LA contractile dysfunction. The role of LA strain as a marker of diastolic dysfunction was also studied by Singh et al., ¹⁶ who reported that LASr is a parameter that correlates independently with the degree of diastolic dysfunction, with a progressive decline in strain values with worsening diastolic dysfunction.

Left atrial strain during ischaemia

In the ischaemic cascade, LV diastolic dysfunction precedes systolic dysfunction; furthermore, impaired ventricular relaxation promotes changes in the dynamics of the LA, whose function is to modulate ventricular diastolic filling without increasing the mean atrial pressure. ¹⁷

In a study by Liu et al., ¹⁸ the assessment of LA function by 2D speckle-tracking strain revealed reduced LASr and LAScd in patients with chronic CAD and normal LA volume, whereas in those with an enlarged LA, a reduced contractile function (LASct) was also observed, which could be explained by secondary atrial contractile dysfunction due to sustained LA afterload in subjects with impaired LV relaxation and decreased compliance. This finding suggests that the decline in LA reservoir strain (corresponding to atrial ‘diastole’) may precede the decline in LA contractile strain (corresponding to atrial ‘systole’), which would occur in a later phase after LA remodelling.

Furthermore, previous studies suggest that LASct may differ according to the compromised coronary territory in patients with CAD. In subjects with proximal circumflex coronary artery occlusion (which supplies the majority of LA perfusion, with smaller contributions from branches of the right coronary artery), a reduction in contractile function has been observed, whereas in those with anterior descending coronary artery occlusion (which does not perfuse the LA), an enhancement of LA contractile function has been reported as a mechanism to maintain LV stroke volume despite LV dysfunction.^18,19

The reduced values of LASr observed in subjects with positive DSE in our study are in line with previous studies that evaluated left atrial function in individuals with CAD. In a case‒control study that included patients with stable angina referred for invasive coronary angiography, assessment of LA strain by tissue Doppler during rest revealed lower absolute values of LASr and LA strain rates in those with obstructive CAD, and the measures correlated negatively with the severity of CAD. ²⁰ However, no study has described the LASr response to dobutamine-induced ischaemia across all phases of DSE.

In a group of patients with acute ST-segment elevation myocardial infarction who underwent coronary angiography, Durmaz et al. ²¹ investigated the role of LASr in comparison with invasive assessment for the detection of increased LV filling pressure and demonstrated a significant correlation between reduced LA reservoir strain and increased end-diastolic pressure of the LV in response to myocardial ischaemia.

In our study, both LASr and LAScd were predictors of ischaemia during DSE, indicating that ischaemic patients present baseline changes in atrial function in the initial phase of ventricular diastole. Our findings also demonstrated that in individuals with positive DSE, there is a significant reduction in LASr values during peak stress compared with baseline values (ΔLASr = -12.4%), which could therefore be used to identify patients who have exhausted atrial reserve in response to haemodynamic stress, leading to an elevation in mean atrial pressure due to systo-diastolic dysfunction secondary to myocardial ischaemia. Moreover, with the increase in stress from low to high doses of dobutamine, the LASct was also associated with the presence of ventricular ischaemia, suggesting that LA contractile dysfunction occurs with increased LV filling pressures.

Clinical utility of left atrial strain in assessment of myocardial ischaemia

The use of 2D speckle-tracking echocardiography in the assessment of inducible myocardial ischaemia has been studied primarily with the evaluation of LVGLS, which has demonstrated greater accuracy than LV circumferential or radial strain for detecting ischaemia. ²² In our study, the LVGLS values at the peak stress and recovery phases were significantly lower in the group of patients with positive DSE tests; however, the sensitivity was lower than that observed with LASr at the peak stress and recovery phases. Possible explanations for these findings are as follows:(1) Positive tests due to new WMAs in fewer than 3 segments (i.e. low WMSi), suggestive of low ischaemic burden, may not result in a significant decline in LVGLS, since the reduction in regional strain of ischaemic segments could be compensated for by a hyperkinetic response of healthy segments. (2) LASr is a parameter that reflects both the systolic and diastolic changes in the LV and thus has greater sensitivity for ischaemia detection. Furthermore, the execution of LA strain is more practical than that of LVGLS, as it requires imaging acquisition in only two views (A4C and A2C) and can even be performed using a single view. ¹¹ On the other hand, performing LVGLS may be more difficult during peak stress with a high heart rate, and adequate visualisation of all 16 segments of the LV might not be possible.

Thus, LA strain assessment provides incremental value to visual WMA analysis in conventional DSE. It is a fast and quantitative method with diagnostic value for ischaemia detection, which could reduce the subjectivity of DSE and assist in decision-making, especially regarding patients with inconclusive findings during visual evaluation.

Limitations

Some methodological aspects of this study should be acknowledged. First, it was conducted at a single centre with a relatively small sample size. Second, the interpretation of WMAs during DSE was performed visually by board-certified echocardiographers without adjudication by a core laboratory, introducing the possibility of observer-related bias. Third, neither invasive coronary angiography nor non-invasive coronary computed tomography angiography were included in the study protocol, precluding anatomical correlation between newly detected WMAs and the presence of obstructive CAD; however, the aim of this study was not to correlate the decline in LA strain with the detection of CAD but rather with the occurrence of inducible myocardial ischaemia. It is known that up to 70% of patients with angina and inducible ischaemia do not have obstructive CAD on anatomical imaging, which may be attributed to microvascular coronary disease, vasospasm, myocardial bridge, or diffuse nonobstructive atherosclerosis (without focally obstructive stenoses).^23,24