Quantification of left atrial strain and strain rate using Cardiovascular Magnetic Resonance myocardial feature tracking: a feasibility study

CMR

All CMR measurements were performed at 1.5 Tesla (Philips Intera, Philips Achieva, Siemens Sonata or Siemens Symphony TIM) in the supine position. LV dimensions and function were assessed with ECG-gated SSFP cine sequences during brief periods of breath-holding in the following planes: 12 to 14 equidistant short-axis planes covering entire ventricles as well as 2-chamber and 4-chamber views. Typical image parameters were: repetition time (TR) 3.3 ms, echo time (TE) 1.6 ms, matrix size 228 × 220, field of view (FOV) 270 × 260 mm, slice thickness 6¿8 mm (Philips Intera); TR 2.7 ms, TE 1.3, matrix size 208 × 184, FOV 260 × 230 mm, slice thickness 8 mm (Philips Achieva); TR 30.9 ms, TE 1.3 ms, matrix size 256 × 164, FOV 400 × 256 mm, slice thickness 6¿8 mm (Siemens Sonata); TR 45.9 ms, TE 1.3 ms, matrix size 192 × 192 mm, FOV 340 × 340, slice thickness 6 mm (Siemens Symphony TIM).

Feature tracking

LA myocardial feature tracking was performed using dedicated software (TomTec Imaging Systems, 2D CPA MR, Cardiac Performance Analysis, Version 1.1.2.36, Unterschleissheim, Germany). LA endocardial borders were manually traced in the 2- and 4-chamber views using a point-and-click approach when the atrium was at its minimum volume after atrial contraction. The atrial endocardial border surface was manually delineated and the automated tracking algorithm was applied. Tracking performance was visually reviewed to ensure accurate tracking of the atrial myocardium (Figure 1). In case of insufficient automated border tracking, manual adjustments were made to the initial contour and the algorithm was reapplied. The atrium was divided into six segments and averaged strain and strain rate profiles were calculated for all segments as previously described [11]. Tracking performance was visually reviewed on a segmental basis. If the tracking quality was not sufficient, e.g. due to the presence of pulmonary veins or left atrial appendage, the corresponding segment was excluded from the analysis. Tracking was repeated for three times in both the 2- and 4-chamber view. LA longitudinal strain and SR results were averaged across all three repetitions in both views. Similar to previous definitions from echocardiographic speckle tracking [11],[12] three aspects of atrial strain were analysed (Figure 2): passive strain (?_e, corresponding to atrial conduit function), active strain (?_a, corresponding to atrial contractile booster pump function) and total strain, the sum of passive and active strain (?_s, corresponding to atrial reservoir function). Accordingly, three SR parameters were evaluated (Figure 2): peak positive strain rate (SRs, corresponding to atrial reservoir function), peak early negative strain rate (SRe, corresponding to atrial conduit function) and peak late negative strain rate (SRa, corresponding to atrial contractile booster pump function) [1],[13].

Volumetric analysis

Volumetric analysis was performed with commercially available software (QMass, Medis, Leiden, The Netherland). Left and right ventricular ejection fraction, end-diastolic and end-systolic volumes were assessed from the short-axis stack. End-diastolic and end-systolic volumes were normalized to body surface area. Semi-automated tracings of the LA area and length were performed in the 2- and 4-chamber view. LA volumes were calculated using the previously validated biplane area-length method [14] according to the formula: LA volume (ml)?=?0.85*A_2C*A_4C/L, where A_2C and A_4C are the LA areas on the 2-chamber and 4-chamber views, respectively, and L is the shorter long-axis length of the LA from either the 2-chamber or the 4-chamber views. LA volumes were assessed at left ventricular end-systole (LAVmax), at left ventricular diastole just before LA contraction (LAVpre-ac) and at late left ventricular end diastole after LA contraction (LAVmin) [1],[15]. Total LA emptying fraction (LAEF Total, corresponding to atrial reservoir function), passive LA emptying fraction (LAEF passive, corresponding to atrial conduit function) and LA active emptying fraction (LAEF Booster, corresponding to atrial contractile booster pump function) were defined as fractional volume changes according to the following equations:

Statistical analysis

Statistical analysis was performed using Microsoft Excel and IBM SPSS Statistics version 22 for Macintosh. Data are expressed as mean (±standard deviation). Differences between groups in continuous variables were assessed by the Kruskal¿Wallis test. Pearson¿s correlation coefficients were calculated to investigate for potential relations between variables from CMR-FT and volumetric analyses regarding LA reservoir, conduit and contractile booster pump function. Correlation coefficients were considered weak if r???0.35, moderate if r was between 0.36-0.67 and strong if r???0.68. The intra- and inter-observer variability for strain and SR measurements were assessed by the coefficient of variation (CV), intraclass correlation coefficient (ICC) and Bland Altman analysis [16] in 10 randomly selected subjects. The CV was defined as the standard deviation of the differences divided by the mean [17]. Two independent observers analysed all cases to assess inter-observer variability (JTK & AS), while intra-observer variability was derived from the repeated analysis by the first observer (JTK) after four weeks. All statistical tests with p values?<?0.05 were considered statistically significant.

Feasibility of left atrial CMR-FT

LA CMR-FT was successfully performed in all subjects. Atrial strain profiles followed atrial physiology and allowed an evaluation of atrial total, passive and active strain. Furthermore, peak positive SR, peak early negative SR and peak late negative SR were successfully analysed in all cases. Tracking quality was sufficient in 321/360 segments (89.2%). In 14/30 subjects, averaged strain and SR profiles were calculated from all six segments in both the 2-chamber and 4-chamber view. In 16/30 subjects, 39 individual segments were excluded (15 segments in 4-chamber view, 24 segments in 2-chamber view) from the analyses resulting in a total proportion of 10.8% of excluded segments. Exclusion of segments was predominantly associated with poor tracking quality related to the insertion of the pulmonary veins.

Bivariate correlation demonstrated a strong to moderate relation between volumetric indexes and deformation parameters from CMR-FT for atrial reservoir, conduit and contractile booster pump functions (Table 2).

Left atrial function in patients and controls

LA strain and SR parameters from CMR-FT revealed significantly different values between patients with HCM or HFpEF and healthy controls (Table 3). ?_s and SRs (both corresponding to LA reservoir function) as well as ?_e and SRe (both corresponding to LA conduit function) were lower in both patient groups. Interestingly, ?_a and SRa (both corresponding to LA booster pump function) were increased in patients with HCM while decreased in patients with HFpEF. These parameters were not significantly different in patients with mitral regurgitation as compared to patient without mitral regurgitation both in the HCM and HFpEF group.

Intra- and inter-observer variability

LA strain and SR parameters were reproducible on an intra- and inter-observer level. Bland-Altman Plots for strain and SR measurements are displayed in Figures 3 and 4, respectively. Table 4 shows ICC and CV for repeated measurements within the single and between observers.

Left atrial function in patients with HCM and HFpEF

Abnormal LA function is present in patients with ventricular diastolic dysfunction. For instance, Kaminski et al. demonstrated that impaired LA contractile function was the strongest predictor of major adverse cardiac events and all-cause mortality in patients with chronic hypertension but no other prevalent cardiovascular disease [22]. Since diastolic dysfunction is present in HFpEF and HCM as well [23],[24] it is particularly interesting to investigate LA deformation in both patient groups. Looking at our data, CMR-FT revealed significantly decreased passive strain and peak early negative SR in patients with HCM and HFpEF. Both parameters correspond to atrial conduit function. LA conduit function is closely related to left ventricular compliance [1]. Therefore, decreased passive strain and decreased peak early negative SR from CMR-FT might be directly correlated with impaired ventricular relaxation. Furthermore, total strain and peak positive SR correspond to atrial reservoir function. Both parameters were decreased in HCM and HFpEF, which might refer to impaired atrial compliance. Increases in booster pump function in HCM have previously been reported [1],[25],[26]. In contrast, impaired atrial contractility has been described in HFpEF by echocardiographic speckle tracking [27]. Consistently, our results show increased active strain and peak late negative SR (both corresponding to contractile booster pump function) in HCM while decreased in HFpEF. The presence of mitral regurgitation did not seem to be associated with the increased booster pump function in the HCM group. It might be interesting to speculate whether or not the increased booster pump function with decreased reservoir and conduit function in HCM represents a form of compensated milder functional diastolic dysfunction as opposed to severe diastolic dysfunction in HFpEF with complete atrial performance impairment. Indeed Murata et al. reported initial increase in LA booster pump function at early stages of impaired left ventricular relaxation, followed by progressive decompensation of global LA performance with worsening of diastolic dysfunction at later disease stages [28]. Future studies will need to investigate whether atrial performance analysis could be a useful parameter for the identification of patients at risk for congestive heart failure with associated poor prognosis that may specifically benefit from early therapeutic interventions.

Reproducibility

The reported amount of reproducibility and repeatability of ventricular strain and SR measurements from CMR-FT varies between studies with most studies reporting reasonable reproducibility of global strain and SR levels [5],[29]-[31]. Therefore, intra- and inter-observer variability of LA deformation indexes need to be taken into special consideration. In order to further maximise reproducibility all measurements were repeated three times in both the 2-chamber and 4-chamber view. All strain and SR parameters had excellent reproducibility both on the intra-observer as well as inter-observer level. The calculation of global strain and SR parameters (average of 6 segments) might explain the excellent reproducibility as opposed to previously reported bad segmental reproducibility of some of the ventricular CMR-FT measurements [32]. Furthermore the good reproducibility might also be associated with the good image quality of the CMR images with reliable delineation of the thin LA myocardium in contrast to LA echocardiographic speckle tracking that suffer from the far-field location of the LA and reduced signal-to-noise ratio. On the other side, lower temporal resolution of CMR images might affect deformation analysis, e.g. the capacity to measure peak strain rates. However a reasonable inter-modality agreement for left ventricular longitudinal strain analysis has been demonstrated between CMR-FT and echocardiographic speckle tracking despite differences in temporal resolution [33]. Future studies will need to investigate the effect of these parameters for LA strain and SR imaging with CMR-FT.

Limitations

We have performed a feasibility study to demonstrate the use of CMR-FT for the assessment of atrial deformation. The sample size of healthy volunteers and patients was relatively small and has not been powered to detect gross differences between groups. Nevertheless we were able to detect significant differences between health and disease and future studies will need to investigate the clinical utility of CMR-FT derived LA strain and SR parameters in a larger cohort of patients with different pathologies. CMR measurements were performed on different scanner types. Importantly the reproducibility assessed in the current study was excellent for all parameters irrespective of scanner type. This is in line with previous studies demonstrating similar reproducibility of CMR-FT ventricular strain analysis at 1.5 and 3 Tesla [30],[31].

Furthermore LA CMR-FT faces several challenges as opposed to ventricular deformation tracking that may limit the performance of the LA tracking: 1. The LA myocardial wall is thinner than the ventricular myocardial wall, 2. LA anatomy is more variable than ventricular anatomy, 3. LA physiology is quite complex (reservoir function, conduit function, booster pump function), 4. The presence of pulmonary veins and left atrial appendage can compromise tracking quality. Notwithstanding these facts, CMR-FT analysis was successful in all controls and patients. Tracking quality was sufficient in the vast majority of segments (89.2%) and reproducibility was excellent.