Our institutional review board approved this retrospective observational study and waived the requirement for documentation of informed consent from patients. An opt-out option on our website allowed patients to decline inclusion of their data in the study.
Patients
We identified 783 consecutive patients with AF who underwent Transesophageal echocardiography (TEE) evaluation of SEC and flow velocity in the LAA prior to percutaneous pulmonary vein isolation (PVI) at our institution between January 6, 2013 and December 16, 2019. Among these cases, we also assessed data of transthoracic echocardiography (TTE) performed within the 6 months prior to PVI and cardiac CT performed within the 3 months prior to PVI. We excluded 139 patients who did not undergo TTE and/or cardiac CT within that period and 3 patients whose CT data could not be analyzed because of image degradation caused by an artifact (one case), the absence of part of the LAA from imaging range (one case), and inability to recognize the LAA structure (one case). No patient demonstrated LAA thrombus on TEE. The final study included data of 641 patients (570 men, mean age, 59.35 ± 9.16 years, age range, 26–81 years; 71 women, mean age, 65.17 ± 6.88 years, age range, 44–79 years). When a patient underwent TEE more than once during the study period, we analyzed findings of only the initial TEE (Fig. 1). All patients who underwent PVI for AF routinely received anticoagulation therapies, either warfarin or non-vitamin K antagonist oral anticoagulants, prior to echocardiography and CT. For patients receiving warfarin, the international normalized ratio of prothrombin time (PT-INR) was controlled within the therapeutic range between 2 and 3 [8].
Transesophageal Echocardiography
Transesophageal echocardiography was performed at our institution according to standard clinical procedure using one of 4 ultrasound systems: Pro Sound Alpha 10 (multiplane 5.0 MHz transducer) (Aloka, Tokyo, Japan); Pro Sound F75cv (multiplane 5.0 MHz transducer) (Hitachi, Tokyo, Japan); iE33™ (multiplane 2.0 to 8.0 MHz transducer) (Philips Healthcare, Best, The Netherlands); or EPIQ7 (multiplane 2.0 to 8.0 MHz transducer) (Philips Healthcare). All TEE examinations were performed within 3 months before the scheduled PVI procedure (interval between TEE and PVI, 0 to 10 days [mean 2.12 days] in the group with SEC and 0 to 93 days [mean 2.77 days] in the group without SEC). Lidocaine was used for local anesthesia of the hypopharynx. All patients received intravenous midazolam for conscious sedation. Multiple planes of the LAA, including a continuous view through the LAA from 0 to 180 degrees, were examined at the appropriate level within the esophagus. Detailed observations were made of all LAA structures. Flow velocity in the left atrial appendage was assessed using pulsed-wave Doppler interrogation on TEE in the view at 0 and 90 degrees. Peak LAAFV was measured after optimally aligning the pulsed-wave Doppler signal with LAA flow using color flow imaging, with sampling done at the site where maximal flow velocities were obtained. The highest LAAFV between the two values for each patient was applied for further analysis. SEC was defined as dynamic “smoke-like” echoes characterized by a swirling motion and observed during the cardiac cycle using an optimal gain setting [9]. The observation of echo-dense material acoustically separate from the endocardium within the LAA confirmed a definite thrombus. Two echocardiographers blinded to the CT results interpreted all images.
Transthoracic Echocardiography
Transthoracic echocardiography was performed according to standard clinical protocol. All patients underwent TTE within the 6 months prior to PVI (interval between TEE and TTE, -6 to 178 days [mean 28.97 days] in the group with SEC and -92 and 181 days [mean 27.97 days] in the group without SEC). Quantitative assessment of the left ventricular ejection fraction (LVEF) was determined using the modified Simpson’s method. Conventional TTE was performed using one of 5 ultrasound systems: Pro Sound Alpha 10 (1.5 to 4.3 MHz transducer) (Aloka, Tokyo, Japan); Pro Sound F75cv (3.0 MHz transducer) (Hitachi, Tokyo, Japan); Vivid E9 (3.3 MHz transducer) (GE Healthcare, Tokyo, Japan); Vivid 7 (3.3 MHz transducer) (GE Healthcare); or Artida™ (2.5 MHz transducer) (Canon Medical Systems, Tochigi, Japan).
Computed Tomography
All patients underwent cardiac CT with either of 2 dual-source systems (SOMATOM® Definition Flash [SDFlash] or SOMATOM® Definition [SD], Siemens Medical Solutions, Forchheim, Germany) within the 3 months prior to PVI (interval between TEE and CT, 0 to 81 days [mean 20.22 days] in the group with SEC and -11 and 87 days [mean 20.29 days] in the group without SEC). The CT scan protocol did not call for the use of beta-adrenergic blocking agents prior to scanning. Patients were administered sublingual nitroglycerine a few minutes before CT scanning to allow simultaneous evaluation of the coronary artery. During scan acquisition, each patient received intravenous administration of contrast material (Iopamiron®, 370 mg I/mL; Bayer AG, Leverkusen, Germany). Early-phase scanning was controlled by bolus tracking in the ascending aorta and followed by injection of 30 mL of pure saline at the same speed when enhancement was achieved. Delayed-phase scanning began 60 seconds after the start of contrast material injection. The injection speed was computed using the formula: injection speed (mL/s) = body weight (kg) × 0.07 mL/s, and the volume of the iodine bolus was computed as: volume (mL) = injection speed × duration of CT data acquisition (seconds) + 5. Scan parameters were: slice collimation, 2 × 64 × 0.6 mm (SDFlash) or 2 × 32 × 0.6 mm (SD) with a z-flying focal spot; gantry rotation time, 280 ms (SDFlash) or 330 ms (SD); pitch, 0.2 to 0.5; tube voltage, 120 kVp; and tube current, 330 mAs (SDFlash) or 300 mAs (SD). Scanning ranged from the level of the carina to just below the dome of the diaphragm. We retrospectively applied electrocardiography (ECG) gating and ECG-dependent tube-current modulation to reconstruct images. All reconstructed image data were transferred to workstations (MultiModality Workplace, Siemens), and ECG gating of data of transaxial slices (effective slice width, 0.75 mm; increment, 0.4 mm; medium-smooth convolution kernel B 36 F) permitted reconstruction of images. Reconstructed images were obtained during the 1-96% -R interval of the cardiac phase. Heart rates ranged between 39 and 148 beats per minute (bpm) (mean 64.75 bpm).
Image Evaluation
Two radiologists with 9 and 25 years’ experience in cardiovascular radiology who were blinded to the patient's history and TEE results retrospectively reviewed the CT examinations in consensus. In the present study, we classified the morphology of the LAA into 4 types according to the shape and complexity of the appendage–chicken-wing, wind-sock, cauliflower, and cactus– using 3-dimensional volume-rendered structures based on findings of a previous study [10] (Fig. 2). The chicken-wing type displays only one lobe (length > 40 mm) and demonstrates bending of less than 100 degrees in the proximal part of the LAA; the wind-sock type shows one dominant lobe (length > 40 mm) with several secondary, or even tertiary, lobes and bending that exceeds 100 degrees; the cauliflower type is characterized by its length less than 40 mm and complex internal structures; and cactus type morphology manifests a dominant central lobe (length < 40 mm) with one or more secondary lobes.
LAA early filling defect was defined as a clear low attenuating lesion representing incomplete mixing of the contrast agent and blood that appeared only on early-phase images and demonstrated complete homogenous enhancement on late-phase images [11] (Fig. 3).
We quantified the volume of the LAA from its contours as depicted in cross-sectional images obtained using SYNAPSE VINCENT® 3-dimensional analytical volume software (Fujifilm Medical Co., Tokyo, Japan) (Fig. 4). The operator contoured and filled the LAA at each slice (Figs. 4a–c, green area), and the computer added the volumes of all of the slices to calculate the LAA volume; volumes of the slices were calculated automatically by multiplying the contoured area and slice thickness in cubic centimeters (cm3) (Fig. 4d). The ostium of the LAA was defined by the plane that connected between the base of the Coumadin ridge and the proximal left circumflex artery [12]. These procedures were evaluated against the original transverse images and multiplanar reformations that included short- and long-axis views of the heart. LAA volume was indexed for body size by dividing by body surface area calculated using the DuBois formula.
One radiologist with 9 years’ experience in cardiovascular radiology who was blinded to the patient's history and the results of TEE and TTE performed visual and quantitative measurement of the LAA, and two assessors independently measured the LAA volume of 100 randomly selected patients to allow examination of inter-rater reliability [13]. The inter-observer agreement regarding LAA morphology was also evaluated using Cohen's kappa [14, 15].
Statistical analysis
We tested normal distribution for the continuous variables to describe the frequencies and distributions of these factors and used Fisher’s exact test to compare categorical data between the groups with and without SEC and Wilcoxon rank sum test and Student's t-test to compare continuous data between the 2 groups. Categorical variables were presented as number and percentage of cases, and continuous variables were presented as mean (± standard deviation [SD]) or median (interquartile range).
We prepared multivariable logistic-regression models to estimate the incidence of SEC with potential predictors that we selected based on previous studies and clinical perspectives associated with the appearance of SEC or LAA thrombus [5–7]. Before the multivariate logistic regression analysis, we analyzed statistics using the variance inflation factor (VIF) to check for multicollinearity and selected AF type (paroxysmal/persistent), CHADS2 score, LVEF, LAAFV, indexed LAA volume, LAA morphology, and LAA early filling defect as independent variables. We assessed the odds ratios (OR) for each variable with 95% confidence intervals (CI).
A CHADS2 score ranging from 0 to 6 was calculated for each patient at the time of TEE, assigning one point each to congestive heart failure (CHF), hypertension, or age above 75 years and two points each to history of stroke, transient ischemic attack (TIA), or systemic embolism [5, 16].
We classified AF as either paroxysmal, defined as recurrent AF terminating spontaneously or with intervention within 7 days of onset, or persistent, defined as AF failing to self-terminate within 7 days and considered longstanding when it failed to resolve after more than 12 months [17].
We also computed a receiver operator characteristic (ROC) curve for the completed model, choosing a threshold value at which the likelihood of SEC could be predicted based on the indexed LAA volume and estimating the resulting sensitivity and specificity.
We used intraclass correlation coefficients (ICC) to calculate inter-rater reliability for measurements of LAA volume (ICC 2, 1), and based on the 95% confidence interval of the ICC estimate, we judged reliability to be poor (values below 0.5), moderate (between 0.5 and 0.75), good (between 0.75 and 0.9), and excellent (above 0.90) [18].
We used κ-statistics to measure inter-rater reliability regarding the assessment of LAA morphology, with values below 0.2 representing slight agreement, between 0.21 and 0.40, fair agreement, 0.41 and 0.60, moderate agreement, 0.61 and 0.80, substantial agreement, and above 0.81, almost perfect agreement [19].
A P-value below 0.05 was considered statistically significant.
We conducted all statistical analyses using R commander 2.7-0 (R 4.0.2; CRAN, freeware).