The Prognostic Role of Global Longitudinal Strain in Severe Primary Mitral Regurgitation

Moving Past the Proof-of-Concept Era

Corresponding Author

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• global longitudinal strain
• mitral regurgitation
• mitral valve repair
• mitral valve replacement

Severe mitral regurgitation (MR) can lead to adverse outcomes, even without symptoms, demanding imaging or biomarker parameters that indicate the need for early surgery. Remarkably though, even in 2018, the guidelines confine such imaging parameters to simple left ventricular (LV) diameters and ejection fraction (EF) (1). These simple measures can be misleading, especially in the altered loading of MR, and neglect 20 years of progress in echocardiography, in particular 3-dimensional volumetric quantitation and myocardial deformation analysis. We simply must apply more sophisticated measures of LV size and function.

Speckle-tracking echocardiography (STE) offers an angle-independent assessment of myocardial deformation (2). STE-derived global longitudinal strain (GLS) can detect subclinical myocardial disease and provides incremental diagnostic and prognostic information in a wide variety of clinical settings. Prior concerns about intervendor variability have been largely dispelled by an intersocietal and industry collaboration to standardize GLS, with recent reports showing better reproducibility and reliability than EF (3). Still at issue, though, is the recent demonstration of preload dependence of GLS (with the tilt maneuver) (4), making its applicability to the volume overloaded state of severe MR challenging, requiring different cutoffs than other conditions. Nevertheless, because of the critical need for more sensitive parameters to identify patients at risk, STE-derived GLS has emerged as a promising tool to detect subclinical myocardial dysfunction in patients with severe MR.

In this issue of iJACC, Kim et al. (5) investigated the role of STE-derived GLS in predicting clinical outcomes after MR surgery (n = 506, 75%/25% repair/replacement). The cohort was followed for a median of 3.5 years for the occurrence of cardiac events (heart failure hospitalization, MV reoperation, and cardiac death) and all-cause mortality. The patients had relatively pure, organic MR without prior surgery, endocarditis, or other significant valve lesions. Cardiac events were relatively rare with heart failure hospitalization of 8.1%, 10 reoperations (2%), and 3 heart transplantations. All-cause/cardiac death was 11.1%/4.5%. Those with events were older, more likely to have atrial fibrillation and myocardial infarction, were more symptomatic, and were more likely to have coronary artery bypass grafting at surgery. Baseline GLS was significantly lower (i.e., closer to zero, a convention adopted for GLS) among those with versus without post-operative events (−16.5 ± 4.0% vs. −20.0 ± 4.1%; p < 0.001). In contrast, conventional echocardiographic parameters such as LV end-systolic diameter, LV volumes, left atrial (LA) volume index and resting pulmonary artery systolic pressure were not significantly different; LVEF was only slightly lower among those with cardiac events (57.3 ± 9.6% vs. 60.3 ± 7.9%, respectively; p = 0.024). On multivariate analysis, GLS and (barely) LA dimension (but not LA volume index) were the only echocardiographic parameters that predicted adverse cardiac events and all-cause mortality with a baseline GLS cutoff value of −18.1% predicting cardiac events with sensitivity and specificity of 71.4% and 70.7%, respectively, and an area under the receiver operating curve of 0.738. GLS also identified patients with less LVEF recovery and reverse remodeling (Figures 2 to 4 from Kim et al. [5]).

Despite study limitations of retrospective design and the inclusion of patients with a wide range of cardiovascular comorbidities, Kim et al. (5) have expanded the evidence base of the value of GLS in identifying severe MR patients at higher risk of adverse cardiac events. These findings supplement prior reports on the utility of GLS in severe MR (6–9). In 88 patients undergoing surgery for degenerative MR, Mascle et al. (6) showed that a baseline GLS <−18% predicted 6-month post-operative LVEF <50% (area under the curve of 0.76 with sensitivity and specificity of 53% and 79%, respectively), which was better than other echocardiographic parameters. Similarly, we found (7) in 233 MR patients that pre-operative GLS <−19.9% predicted 1-year post-operative EF <50% (area under the curve of 0.88). Recently, Mentias et al. (8) (n = 733) showed a pre-operative GLS below −21.7% predicted mortality with median follow-up of 8.3 years. In contrast to these studies and Kim et al. (5), Pandis et al. (9) showed that having a higher GLS (beyond −20.5%) in severe MR appeared to reflect maladaptive remodeling, resulting in LV dysfunction (decrease in EF >10%) immediately after surgery. Reconciling these conflicting findings with the other studies likely relates to the much shorter time-frame for Pandis et al. (9) (<1 week).

GLS observed in these studies is higher than normal due to volume overload and afterload reduction in severe MR patients, leading to increased LV stroke volume. Therefore, strain values that would otherwise be quite normal may actually predict adverse post-operative events, analogous to the 60% EF cutoff currently in the guidelines. The variability in GLS cutoff values in these studies (5–9) likely relates to differences in the study populations, endpoints, and follow-up period, as well as intervendor variation, mandating adherence to strain standardization (10) in localization (endocardium vs. full-wall), timing (peak-systolic vs. end-systolic), and frame rate. Critically, in the retrospective study by Kim et al. (5), we do not know how end-systole was defined or the actual frame rate analyzed (regardless of acquisition frame rate, long-term archiving is commonly at 30 Hz, which may be too low for accurate analysis). Although good reproducibility was reported for strain, it is unclear if these repeat analyses were conducted on identical loops or different ones.

In conclusion, there is convincing evidence that GLS can detect subclinical LV dysfunction in patients with severe primary MR, making it a suitable tool to guide timing of surgical intervention, particularly in asymptomatic patients. Caution is appropriate before implementing any specific GLS cutoffs clinically, but most studies (including this one) have confirmed worrisome outcomes when GLS is in a range that would otherwise be considered normal, with lower values (closer to 0) becoming more alarming. Larger prospective studies are needed to further define the role of GLS and better identify cutoff values. Finally, because GLS as a parameter is still preload dependent, newer noninvasive technologies for the assessment of LV myocardial work (pressure-strain loop) might be a more accurate parameter for the identification and quantification of myocardial function in the setting of severe MR (11). Regardless, the bulk of evidence indicates that GLS is useful in MR patients, and practitioners are encouraged to measure this parameter on a routine basis in patients with severe MR.