Prognostic Significance of Global Longitudinal Strain in Chronic Kidney Disease: The Evidence is Building

This article refers to ‘Prevalence of left ventricular systolic dysfunction in pre-dialysis and dialysis patients with preserved left ventricular ejection fraction’ by L.C.R. Hensen et al., published in this issue on pages 560–568. Chronic kidney disease (CKD) is a major health burden affecting roughly 11% of the population with a disproportionally increased propensity to develop cardiovascular disease and events.1 CKD perpetuates systemic inflammation and oxidative stress, well-known instigators in cardiovascular disease. Proposed mechanisms by which renal dysfunction causes cardiac dysfunction include uraemic toxins, altered levels of renal endocrine factors, and haemodynamic overload. There is mounting evidence to support that CKD patients have an accelerated disease process with premature atherosclerosis, calcification, and cardiac remodelling resulting in left ventricular (LV) hypertrophy and diastolic dysfunction in early stages of the disease. LV systolic function when measured by LV ejection fraction (LVEF) is often preserved. We have a limited understanding of how to use echocardiographic parameters to risk stratify these patients. Although the relative risk of adverse events and death increases with decreasing estimated glomerular filtration rate and increasing proteinuria, patients within the same CKD classification may have very different absolute risks, while there is substantial overlap between the categories. In patients with heart failure and preserved LVEF, CKD is independently associated with increased cardiac remodelling (high LV mass, impaired diastolic relaxation), significantly worse cardiac mechanics (impaired LV longitudinal, left atrial, and right ventricular free wall strain), and worse outcome.2, 3 However, the role of CKD in patients with heart failure and preserved LVEF remains controversial as it was recently reported that although CKD is more common among these patients, it is less important with a weaker association and a less discriminatory power for mortality compared to heart failure with reduced or mildly reduced LVEF.4 Global longitudinal strain (GLS) assessed by two-dimensional speckle-tracking echocardiography is a direct echocardiographic assessment of myocardial fiber deformation that has emerged as an effective tool to detect early subtle disturbances of LV systolic function when LVEF is still normal. Reproducibility of GLS measurements is good and in many cases superior to that of LVEF. Since longitudinal myocardial fibers are located predominantly in the subendocardium, the wall layer most susceptible to ischaemia, reductions in longitudinal strain may be found prior to reduction in LVEF.5, 6 GLS reflects the quantitative measurement of myocardial longitudinal contractility and is impaired in patients with heart failure with preserved LVEF. GLS further detects myocardial interstitial changes that are compromised due to ischaemia and fibrosis.5 An increasing number of studies have suggested that GLS is more sensitive than LVEF as a marker of LV dysfunction (e.g. in patients with hypertrophic cardiomyopathy the LVEF may be normal or even supernormal at a stage when systolic function is markedly reduced)5, 6 and as a predictor of mortality and cardiovascular adverse events in various clinical settings.6-8 In CKD, GLS has been shown to have superior prognostic value compared with LVEF in predicting cardiovascular and all-cause mortality.9-16 In this issue of the Journal, Hensen et al.17 report on the prevalence, determinants, and prognostic value of GLS in 200 pre-dialysis and dialysis patients with CKD stage 3B to 5 and preserved LVEF (≥50%). First, the prevalence of LV systolic dysfunction as defined by a GLS ≤15.2% was 32%. It may be a bit surprising that so many patients classified as normal by LVEF would be abnormal by GLS, suggesting that there is a heterogeneity of intrinsic myocardial function in patients with normal LVEF. The dissociation between these two physical measures of cardiac function is expected as strain is a measure of contractile function on tissue level in a single direction, while LVEF reflects the relative change of LV volumes because of myocardial contraction. Longitudinal strain is considered the most reproducible strain measure by echocardiography and generally declines in pathologic states before there is a noticeable decline in LVEF. This may partly be due to the enhanced sensitivity of strain measuring techniques and also perhaps due to the fact that in some pathologies strain in other dimensions can compensate for a decreased GLS and thus maintain a normal LVEF. Therefore, a normal measured LVEF may not reflect the frequent subclinical cardiac dysfunction in CKD patients. Second, the authors have shown that increased heart rate and LV mass index are independently associated with reduced GLS. Underlying sympathetic overactivity, increased arterial stiffness, and arteriovenous conduits leading to hyperdynamic circulation may lead to increased heart rate, which, in turn, may have a direct adverse impact on the myocardium. Increased wall thickness is a common sequela of both uraemia and hypertension and appears early in the course of CKD. GLS is known to decrease in pathologic hypertrophy likely due to increased fibrosis and worse subendocardial perfusion among other factors. Third, the major finding of this study is that a worse longitudinal systolic deformation reflected by a low GLS (≤15.2%) is an independent and significant predictor for heart failure hospitalization and death over a median follow-up of 33 months; this association was independent of known cardiac risk factors and other established echocardiographic measures commonly used in clinical practice, such as LVEF, indexes of LV diastolic dysfunction (as defined by lower E' and higher E/E' ratio), and LV mass index. The results of the present study are entirely consistent with and build on prior literature on the predictive value of GLS in CKD patients with reduced or preserved LVEF (Table 1).9-17 Pre-dialysis: 60.4 ± 9.6 Dialysis: 51.8 ± 11.8 A number of issues merit attention. This study was a single-centre retrospective study and is subject to inherent biases. The study cohort consisted of a mix of pre-dialysis and dialysis patients including patients with coronary artery disease and significant valvular disease. Given the heterogeneous risk profile of these patients, the generalizability of results from this cohort is unclear. It is important to note that only 2% of the patients included in the study had New York Heart Association class III or IV symptoms, therefore, the results of this study may not be applicable to patients with clinically advanced heart failure but preserved LVEF. The inclusion of natriuretic peptides would have been an interesting addition to the study, given robust data on their ability to identify CKD patients at risk of future adverse events.18 Finally, the effects of loading condition on LV GLS values may not be excluded, though echocardiography was performed after dialysis and ultrafiltration rate and delta systolic blood pressure appear to be similar between patients with LV GLS ≤15.2% and LV GLS >15.2%.17 New echocardiographic modalities such as speckle-tracking echocardiography have improved our understanding of the pathophysiology of cardiac disease in CKD, especially in its subclinical state. There is currently much research devoted to the study of novel echocardiographic indexes with a goal of refining risk stratification approaches. If subtle LV myocardial dysfunction could be detected early in the course of CKD, it would be possible to identify patients at high risk and investigate treatment strategies to reverse or prevent the evolution of the disease and consequent adverse events. GLS offers such a possibility and could act as a cardiovascular biomarker of outcome in the high-risk cohort of CKD patients. As the differences among vendors and software packages are still of concern, the European Association of Cardiovascular Imaging and the American Society of Echocardiography do not give recommendations on universal normal values of LV GLS and lower limits of normal values, though they suggest that values of LV GLS in the range of –20% are expected in healthy individuals.19 Relevant studies to date have suffered from retrospective designs, variable follow-up, incomplete data, and small numbers of events. If further validated by well-designed, prospective studies in larger populations, GLS may be a useful addition to the current risk stratification tools. Conflict of interest: none declared.