Background
Global longitudinal strain (GLS) has emerged as an objective and more reproducible imaging modality to quantify subtle disturbances in left ventricular (LV) function [
1]. GLS detects subendocardial contractility and viability which often precedes an overt impairment of LV function measured by ejection fraction (EF) [
2]. It is increasingly reported to be a powerful prognostic tool over other measures of systolic function in various clinical settings including myocardial infarction, cardiomyopathy and valvular heart disease [
3‐
5]. In parallel with these observations, GLS was shown to be a superior predictor of all-cause and cardiovascular (CV) mortality in patients with CKD [
6‐
8].
The pathogenesis of CV disease in CKD is complex and uniquely different resulting in a progressive change in myocardial composition and function [
9]. Traditional ‘Framingham’ risk factors such as hypertension, diabetes mellitus, obesity and hypercholesterolemia are highly prevalent in patients with CKD [
10] and remain an important component of patient management; however, they do not completely account for the accelerated CV risk in CKD. Renal-specific disturbances known as ‘non traditional risk factors’, including vascular calcification, abnormal bone mineral metabolism (BMM), anemia, hemodynamic overload, inflammation and uremic toxins are putative contributors to cardiac remodeling [
11‐
14]. Similar hemodynamic and metabolic changes also predisposes to arterial stiffening [
15]. Whilst arterial and cardiac remodeling can occur in parallel in CKD, arterial stiffness may lead to poor ventricular compliance and hemodynamic decompensation [
16,
17].
Early evidence suggests that GLS may have a role in detecting uremic related cardiac remodeling. Kramann et al. reported that strain parameters not only detected LV contractile abnormalities but also correlated with the severity of interstitial myocardial fibrosis and hypertrophy in rat models with uremic cardiomyopathy [
8]. There is, however, a lack of information on the association of GLS with CV risk factors in the CKD cohort. Accordingly, the aim of this study was to characterize the association of GLS with traditional and CKD-related risk factors. The current study hypothesized that GLS will be associated with traditional and CKD-related CV risk factors in patients with CKD stage 3 and 4.
Discussion
This study showed in patients with established CKD stage 3 and 4, LV systolic function assessed by GLS was independently associated with aortic PWV, uremic toxins and BMI. Other traditional risk factors did not demonstrate an association with GLS. Importantly, to our knowledge this is the first study to identify the highly significant association between aortic stiffness and GLS.
There are few studies that have assessed clinical factors associated with GLS in the general population. The current study explored the associations between risk factors and GLS in CKD. In a meta-analysis, Yingchoncharoen et al. found systolic BP was an important source of variation in GLS values [
28]. Dalen et al. have also reported that among healthy individuals increasing age and male gender were associated with worse GLS [
29]. The current findings did not show significant associations between GLS and SBP, age or gender. There are several possible explanations for these differences including our study cohort consisted of CKD patients that have many distinctive characteristics compared to the general population. A history of hypertension was universal and BP was well controlled in this study cohort. In addition, historical values of BP readings were not available for comparison and the relatively small sample size could account for the lack of association between GLS and BP seen in this study.
CKD is a unique risk factor for cardiac remodeling; studies have demonstrated that this occurs early and is significantly worse in CKD patients compared to non-CKD [
30,
31]. The structural changes are characterized by cardiomyocyte cell loss and hypertrophy, increased wall stress, dilatation or thinning of ventricular wall, scar formation and myocardial fibrosis which progresses to a maladaptive response and results in functional decompensation [
32,
33]. Previous work has also demonstrated that hemodynamic and metabolic changes associated with the uremic milieu can result in endothelial dysfunction and a cascade of vascular injury in this cohort [
34‐
36]. Endothelial dysfunction is a major pathogenic mechanism for exaggerated atherosclerosis and arteriosclerosis resulting in reduced vascular and myocardial compliance, increased vascular calcification and stiffening [
37]. Arterial stiffness, assessed using PWV, has been widely described and is associated with adverse CV outcome in CKD [
38,
39]. It has been hypothesized that arterial stiffness may have deleterious effects on LV filling pressure resulting in greater LV wall stress and stiffness and subsequent injury to the subendocardium which is highly sensitive to wall stress and myocardial oxygen demand [
40]. As GLS quantifies longitudinal contraction, especially in the subendocardial fibers, it may be a more sensitive marker of systolic dysfunction occurring prior to overt clinical disease [
2,
41]. In this study, the independent association of arterial stiffness and GLS persisted following adjustment for inducible ischemia, LVMI, EF and indices of diastolic function. Whilst classically vascular stiffness is directly related to ventricular stiffness and diastolic function, our study indicates that LV systolic function can be compromised in response to ventricular- vascular stiffening in patients with moderate CKD.
The present study also demonstrated that increasing BMI was associated with worsening GLS in patients with moderate CKD. Obesity is an established risk factor for cardiomyopathy and is a growing problem in CKD. Obesity results in various metabolic and neuro-humoral alterations that can augment myocardial remodeling. Excessive free fatty acids through alteration of fatty acid β-oxidation rates has been shown to increase myocardial oxygen consumption and impair myocardial contractility [
42]. Obesity is related to activation of inflammatory cytokines, especially tumour necrosis factor (TNF), that contribute to fibrotic changes of the myocardium [
43]. Activation of the sympathetic and renin-aldosterone system is also widely demonstrated in obese persons and can further facilitate cardiac damage [
44]. Some of these factors co-exist or are attenuated in CKD patients [
45]. As a result, there are numerous maladaptive changes of the myocardium that overlap between CKD and obesity, including abnormal LV relaxation, hypertrophy and interstitial fibrosis [
46].
CKD- related risk factors are increasingly thought to amplify the multifaceted mechanisms of cardiovascular disease. Accordingly, this study showed a novel and independent association between the free circulating concentrations of uremic toxin IS and worsening GLS in this cohort with moderate CKD. Protein bound uremic toxins, such as IS and PCS, have been shown to accumulate with progression of CKD and are associated with adverse CV outcomes [
47]. IS and PCS are both by-product of bacterial protein fermentation in the large bowel and are not efficiently cleared in the presence of kidney disease. Although these toxins are primarily protein-bound, their free fraction, which is the unbound metabolically active component, increases with deterioration of kidney function [
48]. Further, these toxins have been closely linked to the synthesis of inflammatory mediators and up-regulation of inflammation among CKD patients [
49,
50].
In vitro studies demonstrate exposure to free IS and PCS results in activation of the Nuclear Factor-kappa B (NF-kB) pathway [
49] and exposure to IS in particular stimulates mitogen-activated protein kinase (MAPK) pathways, with subsequent fibrotic, oxidative and pro-inflammatory effects on the myocardium [
14].
Myocardial ischemia is a pivotal factor for cardiac remodeling in CKD and GLS was previously reported to provide prognostic information on myocardial ischemia and infarct size [
51]. This study observed a trend towards an association between GLS and myocardial ischemia (p = 0.05).
This investigation is a comprehensive analysis of CV risk factors and GLS. However, a cause-effect relationship was unable to be identified due to the cross-sectional nature of the study. In this study traditional risk factors were well controlled which may have limited our ability to detect associations between these parameters and GLS. Moreover, the study was limited to subjects with an eGFR of 25 – 60 ml/min/1.73 m2 and included only 30 patients with impaired GLS. Even though a large number of patient characteristics were adjusted for, the possibility of residual confounding cannot be excluded. Larger studies are required to further explore associations with GLS in CKD.
Competing interests
CMH has received research funding from Baxter Healthcare Pty Ltd and Fresenius Medical Care. She has received travel grants from Amgen Australia. NMI has received research funding from Baxter Healthcare Pty Ltd, Roche Pharmaceuticals and Amgen in the form of peer-reviewed grants. She has also received travel grants from Shire Australia, Alexion Pharmaceuticals and Pfizer. RK has received speaking honoraria from Shire Australia. TS has acted as a consultant to Medtronic and Novartis Pharmaceuticals. WP has received research funding from Roche Pharmaceuticals in the form of peer-reviewed grants, and travel grants from Shire Australia and Shire UK. However, the current study was not supported by those grants. The remaining authors have no competing financial interests to declare.
Authors’ contributions
NMI, CMH, JC, KLC, KST: Participated in study design and helped to draft the manuscript. RK, TS, KSB, BAH, RL, WP, MR: were involved in recruitment, carried out blood testing, cardiac and vascular imaging and helped to draft the manuscript. RK and EMP: performed statistical analysis and helped to draft the manuscript. All authors read and approved the final manuscript.