Author + information
- Martin S. Maron, MD∗ ( and )
- Sophie Wells, MD
- Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical Center, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Martin S. Maron, Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical Center, 800 Washington Street, #70, Boston, Massachusetts 02111.
Over the last 60 years, significant advances in evaluation and treatment strategies have transformed hypertrophic cardiomyopathy (HCM) from a disease associated with high morbidity and mortality to one now compatible with normal longevity and excellent quality of life (1). A contemporary risk stratification algorithm in accord with the 2011 American College of Cardiology/American Heart Association expert consensus management guidelines has been implemented to identify high-risk HCM patients for primary prevention implantable cardioverter-defibrillator (ICD) therapy (2,3). Additionally, in patients with obstructive HCM, severe limiting heart failure (HF) symptoms can be reversed with surgical myectomy, and in select cases alcohol septal ablation, with both procedures associated with low risk when performed in experienced HCM centers. The evolution of this complex genetic heart disease into a highly treatable condition represents a significant achievement and a source of much reassurance for HCM patients.
Nevertheless, there is opportunity for improvement, including our ability to more reliably predict which individual HCM patients will develop adverse disease complications. For example, sudden death occurs in a small subset of patients not identified with the current risk stratification strategy. In addition, it remains challenging to precisely define prospectively which obstructive HCM patients will ultimately require septal reduction therapy and which nonobstructive HCM patients will develop end-stage HF necessitating consideration of advanced HF therapies. Therefore, additional novel predictive markers would be of clinical significance and potentially lead to improved outcomes for HCM patients, particularly given the relatively young age of the HCM patient population in which the risk periods often extend over many decades.
With this in mind, we again look to advances in cardiovascular imaging to improve our understanding and management of HCM. Global longitudinal strain (GLS) using speckle tracking echocardiography has garnered increasing interest as a novel imaging technique to assess myocardial contractile performance. Conventional echocardiographic assessment of systolic function using ejection fraction (EF) has inherent limitations, dependent on image quality and loading conditions and some measurement variability. GLS has emerged as a more sensitive index of contractility, providing a direct measure of myocardial tissue deformation and a quantitative assessment of global function (4,5). In clinical studies, abnormalities in GLS have been observed to precede reduction in EF in patients receiving cardiotoxic chemotherapy, with on going trials now evaluating if outcomes can be improved by guiding early therapeutic interventions in these patients (6). Observational data also suggests that GLS may provide prognostic data independent of EF in a range of other cardiovascular disease states, with increasing interest in assessing the role of GLS in HCM.
In this issue of iJACC, Tower-Rader et al. (7) perform a systematic review of the 14 observational studies, including more than 3,000 HCM patients, evaluating the association between GLS and HCM outcomes. In the majority of studies, speckle tracking analysis of GLS was performed with 2-dimensional echocardiography using proprietary software programs. Notable was the enormous heterogeneity between studies, with wide variation in cohort size (range: 41 to 1,019 patients), inclusion criteria, methodology, clinical and demographic profile, and follow-up duration (range: 1 to 9.5 years). Outcome measures differed significantly between studies, with the majority incorporating composite clinical endpoints combining HF and arrhythmic events, as well as all-cause mortality in a minority. Intra- and interobserver variability were not consistently reported. For all these reasons, the authors were unable to perform a statistically appropriate meta-analysis.
The authors observed that mean GLS was reduced in HCM patients, ranging from -10% to -16%, and reported a statistically significant association between lower (less negative) GLS values and increased risk of adverse disease-related outcomes. However, threshold GLS value associated with adverse events varied significantly between studies. Tower-Rader et al. (7) conclude that abnormal GLS represents an emerging noninvasive marker of increased cardiovascular risk in HCM patients.
This review represents a comprehensive summary of the published data on GLS in HCM. However, if GLS is to be integrated into routine clinical practice impacting management strategies, a number of considerations that influence interpretation of these data should first be explored. First, it remains uncertain what specific adverse disease outcome GLS may be predicting. The current studies have generally considered endpoints that are a combination of numerous hard and soft HF and arrhythmic events. Without studies that are adequately powered to inform on specific clinically relevant HCM-related outcomes, the current use of composite outcome measures prevents us from drawing any definite conclusions on how to incorporate GLS into therapeutic decision-making.
Moreover, the patient cohorts that have been studied to date represent a heterogeneous group, with important clinical and imaging data regarding risk of developing HF or sudden death events not uniformly included in the analysis. For example, outflow tract obstruction is the most powerful independent determinant of progressive HF symptoms in HCM (8). Therefore, the relevance of an observed association of lower GLS with development of progressive HF would have different clinical implications depending on if the study population was comprised of obstructive versus nonobstructive patients. Additionally, the effect of profound afterload (with outflow tract obstruction) on GLS measurement has not been clearly established, and it is possible that the cutpoint for clinically relevant GLS values may in fact be different between obstructive and nonobstructive HCM populations.
Likewise, it is currently unknown whether abnormal GLS in HCM reflects myocardial contractile abnormalities related to focal areas of left ventricular (LV) hypertrophy or an abnormal myocardial substrate of fibrosis and disarray diffusely distributed throughout the LV chamber. In this regard, a limited number of small investigations have characterized LV segmental strain in HCM, demonstrating worse strain values in LV segments with greater wall thickness and extent of myocardial fibrosis by cardiac magnetic resonance (4,9). However, the clinical significance related to segmental strain with respect to outcomes in HCM remains uncertain and an area for future investigation.
While the authors show that strain is reduced in HCM patients, the range of GLS values in HCM patients as well as the cutpoints associated with adverse outcomes are highly variable between studies. This may reflect the heterogeneous patient populations studied, small study size, and/or differences between strain imaging platforms. Notably, there has been significant variation between normal ranges reported in healthy patients as well (10), and there remains no consensus guideline for what constitutes normal GLS. This is a particularly important issue if we are going to promote cutoff values that could ultimately justify changes in HCM patient management, such as recommendations for primary prevention ICD or predicting which patients are at greatest risk for developing end-stage HF. Future studies with larger cohorts are needed to further clarify the range of strain values in different HCM populations (e.g., obstructive and nonobstructive patients) and to establish robust clinically relevant cutpoints.
Measurement of GLS is also not systematically acquired in all echocardiographic laboratories due to a number of factors, including variability across different vendor software platforms. In this review, speckle tracking was performed using multiple vendor-specific proprietary software programs. Despite efforts to standardize GLS measurement (11,12), the potential for inconsistent GLS measurement between different software programs dampens enthusiasm for the clinical applicability of this technique. In addition, reproducibility of GLS values between echocardiographic laboratories and between interpreters is another potential limitation to improve moving forward.
Despite all of these important considerations, do these data support including GLS in the routine assessment of HCM patients? First, in agreement with the authors, it is far too premature to consider GLS in clinical decision-making in HCM. However, the signal demonstrated between GLS and increased risk noted in this review should provide the necessary motivation to pursue large prospective studies in well-characterized cohorts of HCM patients. In this regard, we offer the following specific areas for GLS to address with future HCM investigations: 1) Within the general HCM population, does GLS, as a potential marker of underlying abnormal myocardial substrate, strengthen the current risk stratification strategy and recognize additional at-risk patients who would benefit from primary prevention ICD placement?; 2) In asymptomatic obstructive HCM patients, does GLS identify a subset of HCM patients who will develop advanced limiting symptoms and who could potentially benefit from earlier septal reduction therapy?; and 3) In nonobstructive HCM patients with preserved EF, can GLS identify prospectively those patients at risk for developing progressive adverse LV remodeling with systolic dysfunction (i.e., end-stage) and who may therefore require closer clinical follow-up and earlier therapeutic interventions?
It is time to move beyond GLS as a marker of generalized risk or poor prognosis and toward a clinically relevant predictor of specific adverse disease-related outcomes that will expand the application of appropriate and highly effective treatment options to those at-risk HCM patients.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of iJACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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