Cardiac mechanics assessment and the risk of heart failure in the general population

This article refers to ‘Layer-specific global longitudinal strain and the risk of heart failure and cardiovascular mortality in the general population: the Copenhagen City Heart Study’ by K.G. Skaarup et al., published in this issue on pages 1819–1827. It has been more than 50 years since Folse and Braunwald1 first described a technique to measure left ventricular ejection fraction (LVEF), the cornerstone metric for evaluation of cardiac function.2 Decades later, advances in cardiovascular (CV) imaging technology are providing new tools for early identification of cardiac impairment, even subclinical impairment.3 Such approaches will become even more essential as we shift our focus from treatment of full-blown disease to prevention strategies in heart failure (HF), a shift that is reminiscent of the move from reactive to preventive approaches for treating coronary artery disease. Patients who ultimately develop HF are exposed to multiple factors over a long period of time that affect myocyte biology. Nevertheless, the effects of these influences on myocardial mechanics may not be readily identifiable using standard assessment of left ventricular (LV) function.3, 4 LVEF, as a volume-derived index, relies on geometric assumptions, is highly sensitive to loading conditions, and is a poor surrogate for LV contractile function. In the last 15 years, newly developed echocardiographic measures aimed to assess myocardial fibre deformation have been widely adopted in clinical practice and have proven to be more reliable and reproducible measures of LV function. Indeed, these techniques have been incorporated into the diagnosis and treatment in a variety of clinical settings.5-8 Tracking the acoustic scatter, or myocardial speckles, generated by the ultrasound beam throughout the cardiac cycle allows for assessment of a variety of measures of myocardial strain, including global and regional strain, and has been shown to correlate well with sonomicrometry and magnetic resonance based myocardial tagging. Moreover, these measures have now largely been standardized across vendors, providing clinical utility regardless of equipment, and can even be performed post-hoc from images collected in a standard manner. Since the first descriptions of the feasibility of two-dimensional strain, its clinical use has been widely adopted in different populations and across all the HF stages,8, 9 from prevention to treatment, and also has been extended to the evaluation of the left atrium and the right ventricle.10-12 Global longitudinal strain (GLS), a measure of systolic myocardial deformation, takes into account not just the net longitudinal displacement of the basal segments towards the apex but also the underlying twisting motion resulting from the complex helical fibre arrangement of the subendocardial and subepicardial layers, arranged respectively in a right-handed and left-handed helix, which are essential for the development of simultaneous ventricular torsion and shortening.6 Given the complex myocardial fibre architecture of the left ventricle consisting of endo- and epicardial longitudinal layers, there has been keen interest in the development of novel algorithms able to assess myocardial deformation across various layers. The extent to which discriminating the degree of deformation between the different myocardial layers might facilitate early detection of subtle myocardial changes remains unknown. In this issue of the Journal, Skaarup et al.13 assess for the first time the prognostic value of overall GLS compared with layer-specific strain measures in a large low-risk general population free of prevalent HF from the fifth Copenhagen City Heart Study (4013 participants with a mean age of 56 years). The authors found that impairment of all the three strain measures, whole GLS and both endocardial strain (GLSendo) and epicardial strain (GLSepi), significantly increases the risk for incident HF or CV mortality by 15%, 10% and 18%, respectively, regardless of clinical confounders and LVEF. Interestingly, in a sex stratified analysis, the authors found that lower values of whole GLS and GLSepi, but not GLSendo, significantly predicted worse outcomes among males but not among females. Similarly, strain measures provided incremental prognostic information to the SCORE risk chart and the Framingham risk model only in males. As whole GLS assessment derives from the net deformation of both myocardial layers, the lack of prognostic value found for GLSendo might suggest that the clinical value of standard whole GLS is driven by the primary impairment of the epicardial layer. This may occur at an early stage of the pathological processes affecting the myocardium, with preservation of LVEF and even potentially GLS. From this perspective, assessment of layer-specific strain might improve early identification of subclinical myocardial involvement affecting primarily a myocardial layer before involvement of the entire myocardium. There are several clinical implications of the current work: (i) assessment of layer-specific strain measures is feasible with good reproducibility; (ii) layer-specific strain measures may improve early identification of myocardial impairment compared to GLS, and enhance risk stratification in a low-risk general population on top of well-known CV risk factors and regardless of LVEF; and (iii) assessment of layer-specific analysis may help to understand the progression from preclinical disease to overt HF in males vs. females. Although the aforementioned effect modification should be interpreted with caution, in light of the lower incidence rate of events encountered among women, sex differences in the CV biology leading to HF should be considered. With age, men tend to have greater LV thickness and mass and larger LV wall area compared to women, potentially reflecting a higher vulnerability of the epicardial layer. Assessment of GLSepi can therefore be used as an early marker of myocardial damage, even when whole GLS is normal. Conversely, women are more susceptible to develop concentric remodelling and diastolic dysfunction, characterized by relatively normal layers deformation at the early stages, and eventually HF with preserved ejection fraction.14 Ultimately, differential vulnerability across the myocardial layers may account for the sex prognostic discrepancies. Whether layer-specific strain analysis may help in stratifying the risk of HF phenotypes needs further exploration. Although no consensus has yet been established for the proper tracking and interpretation of layer-specific GLS, it seems a promising clinical tool for early identification of subtle pathological processes affecting the myocardial wall in a non-uniform way (Figure 1). To date, limited advances have been made with regard to the development of effective strategies to prevent HF. The study by Skaarup et al. highlights the importance of identifying novel diagnostic tools to assess subtle abnormalities of ventricular function prior to the development of full-blown disease. While further efforts are needed to better standardize the use of layer-specific strain assessment, and to consider whether specific therapies might alter these measures for the better, these approaches incorporate a more comprehensive understanding of cardiac biology to better identify patients with abnormalities in ventricular function previously considered too subtle to warrant consideration. Conflict of interest: R.M.I. reports speaker and advisor honoraria from Daiichi-Sankyo. S.D.S. has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta.