Left atrial dysfunction may precede left atrial enlargement and abnormal left ventricular longitudinal function: a cardiac MR feature tracking study

For the last decades, left atrial (LA) size has been related to increased morbidity and adverse outcomes in hypertension (HTN) and hypertrophic cardiomyopathy (HCM) patients, including atrial fibrillation (AF), heart failure (HF) and death [1, 2]. According to current guidelines, LA size is considered as one of the significant prognostic factors for sudden cardiac death in selected populations [3‐5]. However, this parameter is not only insensitive, but also often inaccurate for assessing abnormality and predicting outcome, especially in the early stages of the two diseases [4, 6, 7]. In recent years, the role of the dysfunction of left atrium in the occurrence and development of cardiovascular disease has been gradually recognized [7‐9]. Previous studies have demonstrated impaired LA function prior to LA enlargement assessed by LA deformation and LA volumetric indices and is tightly associated with left ventricular hypertrophy (LVH) and LV diastolic dysfunction [4, 10]. One of the probable mechanism is that it is not a simple adaptive hypertrophy, but a complex remodeling process impacted by the responses of the non-cardiomyocytic and cardiomyocytic components of the heart to dynamic mechanical and neurohumoral stimuli [11].

During hemodynamic stress or exertion, LA serves as the modulation of LV diastolic filling and cardiac performance by reservoir, conduit, and booster pump function [12]. Cardiovascular magnetic resonance (CMR) has emerged as a robust imaging technique to provide a detailed performance of HCM and HTN, including both identification of LV remodeling and impaired function [13, 14]. LA deformation was initially studied by volumetric and strain measurements using echocardiographic speckle tracking (STE) with the advantage of detailed evaluation of LA phasic function [15]. CMR feature tracking (CMR-FT) is a novel offline approach to assess myocardial deformation from steady-state free precession (SSFP) cine CMR by the tracking of tissue voxel motion [16]. In view of the thin anatomical LA walls, CMR-FT is superior to STE considering spatial resolution, view fields and reproducibility [14, 16]. It has been reported that impaired LA function independently predicts new-onset atrial fibrillation and LA function is associated with LV outflow gradient after septal ablation or septal myectomy in patients with HCM using CMR-FT [7, 17]. However, there is limited data comprehensively focusing on the association among LA function, abnormal LA-LV coupling and prognosis in HTN and HCM patients with normal LA size.

In the current study, we aim to compare the impact on LA function between patients with HCM and HTN without LA enlargement, as assessed through simultaneous LA and LV structural and functional analyses using CMR-FT, and explore the capability of LA function for providing clinical implication and predicting clinical adverse events in HTN and HCM patients with normal LA size.

In the current work, we explored LA function by CMR-FT in patients with HTN or HCM with normal LA size. The results provide several important insights: (1) Even without apparent LA enlargement, LA reservoir and conduit function were impaired in both HTN and HCM patients regardless of the different stage of LA booster pump dysfunction, which may suggest the different pathophysiological mechanisms of LA dysfunction in these two diseases. (2) LA strain is a promising biomarker to assess the hemodynamics dysfunction and impaired LA-LV coupling among different diseases. (3) At the early stage of cardiovascular disease, LA strain was a more sensitive and representative metric for evaluating myocardial impairments and more capable risk factor for prognosis, superior to LV strain.

Left atrial functional impairments have been previously reported in HTN and HCM using myocardial deformation imaging based on echocardiography and-more recently-using CMR-FT [26, 27]. Our data showed that LA reservoir and conduit function were impaired in HTN and HCM consistent with prior investigations concerning patients with LA enlargement [19, 26]. These abnormalities were significantly correlated with LVH and impaired LV GLS. The potential mechanisms contained increased LV wall stiffness, elevated LV filling pressure and impaired LA-LV coupling [6, 28]. We also noticed that HTN patients had lower LA active strain compared to HCM patients and the controls. In contrast to the HTN group, a trend of increased LA contractile function was present in patients with HCM, but this difference was not statistically significant. Preserved LA active function represents a compensatory mechanism to maintain stroke volume and LV filling with mild diastolic dysfunction and its deterioration reflects resultant reduction of LA compliance with LV fibrosis in a stage of “decompensation” [29, 30]. Therefore, LA dysfunctions at an earlier stage are predominantly provoked by the diastolic function abnormalities and may in turn provoke to LV fibrosis and systolic dysfunction [29]. Similarly, in this research, LA functions correlated more strictly with the severity of LV diastolic function (LV mass index, LV peak GLS during atrial contractility) in HCM. While in HTN, it correlates with the chronicity of disease (LV maximal wall thickness, LV deformation parameters reflecting systolic function). Although subjects performed preserved absolute values of LV mass index compared to the relative reference value about LVH in our study [31], we also found HCM patients had greater LV mass index and LV maximal wall thickness, reflecting LV diastolic function, compared to HTN patients. And HCM patients suffered from more serious longitudinal strain impairment, reflecting LV systolic function or fibrosis. In contrast, Dr. Lio and his colleagues described that HCM patients had more serious LA contractile dysfunction and larger LA volume than HTN patients without significant difference in LV mass index [10]. Therefore, it is important to evaluate pathophysiological mechanisms and LA-LV coupling in patients with HTN or HCM. Previous studies demonstrated that LA dysfunction could be initiated by pressure-related LV diastolic dysfunction imposed by chronic hypertension before the clinically apparent LVH in HTN [26, 32]. While HCM is the most common inheritable heart disorder [33], characterized by myocyte hypertrophy, disarray, and fibrosis [34, 35]. The pathological mechanism of HCM reported by studies in animal models has found significant and upregulation of genes involved in extracellular matrix synthesis [36]. These genetic pathways were activated to make increase in extracellular matrix, and then to give rise to LVH or myocardial fibrosis developed [37]. In this context, it is interesting to speculate that LA function derived from CMR-FT may be a promising ongoing biomarker to assess the hemodynamics dysfunction and impaired LA-LV coupling among diseases with pathologic LVH in the early stage.

Although, previous studies roughly demonstrated impaired LA function without LA enlargement, assessed by global longitudinal LA strain and LA volumetric indices, few studies have been completely focused on the association between LA function and prognostic implications in the scenario of various etiology [4, 8, 9, 26]. In our cohort, although no differences were noted in LA volumetric parameters, impaired LA reservoir and contractile strain are significantly worse in patients admitted in primary endpoints, within the normal range of parameters representing LV hypertension. This finding extends finding of prior prospective research with 257 post-MI patients who suffered different grades of diastolic dysfunction [38]. It supported the concept that LA strain, derived of both echo- and CMR, has diagnostic utility for stratifying presence and severity of diastolic dysfunction. In addition, we found patients with abnormal LA contractile strain (< 22.5%) experienced significantly higher rate of adverse clinical events. Investigation in HF subjects proposed that LA declined contractility, coinciding with adverse changes in reduced intrinsic contractility, remodeling, apoptosis, collagen matrix turnover and myosin isoform expression, may contribute to greater burden of AF in HF patients with preserved LVEF [39]. It has been suggested that LA strain could potentially identify ambulatory patients with cardiovascular events at a higher risk of overt HF performances [40]. Interestingly, there was no significantly prognostic value in LV strain in this study. In recently, there are large of studies regarding the prognostic efficacy of LA strain and LV GLS with contradictory results. Some researchers reported that LA reservoir strain and conduit strain were independent predictors of major adverse cardiac events following ST-segment elevation myocardial infarction after adjustment for established clinical and CMR markers of cardiovascular risk including GLS [41, 42]. Negishi et al. demonstrated that LA booster pump strain was an independent and incremental predicted marker of arrhythmias over GLS in 124 patients with non-ischemic dilated cardiomyopathy [43]. In contrast, in a multicenter prospective study that included 1110 patients with myocardial infarction referred for invasive coronary angiography, they found that LA reservoir strain did not add further information in regard to adverse outcome, when readily obtained GLS and maximum LA volume were known [44]. Our results suggest that underlying mechanism of LA-LV coupling is promisingly urgent issue and larger studies are necessary to explore the prognostic role of myocardial phasic function during the different stages of cardiovascular diseases. Although, further studies are needed to support our findings and validate the availability of this tool, the application of cine CMR-FT for assessment and risk stratification in these populations undergoing clinical routine examination, particularly in the early stage, may become a short-term reality [45].

There are some limitations in the present study. Firstly, in consideration of the major aim, limited cases in HCM with normal LA size who came to see the doctors, the sample size in our study was relatively small. the correlations of LA-LV measurements are weak-to-fair. Despite age-related correlation and survival analyses, difference in age between groups may confound the conclusions. More and larger scale studies are needed to confirm these findings. Secondly, due to the relatively early disease stage with a few cardiovascular events in this cohort, we acknowledge that only univariable Cox regression analyses were performed at a single time point. Thus, the power of prognostic analysis is limited, and we cannot confirm whether LA strain is an independent risk factor for primary endpoint. Thirdly, differences of strain measurements caused by various CMR-FT vendors cannot be excluded. So standardized postprocessing methods would be desirable to facilitate comparative analysis of LA deformation and may reduce inter-vendor variability.

CMR-FT-derived strain is a promising and robust tool in demonstrating impaired LA mechanics, quantifying LA dynamics and underlining the importance of LA-LV coupling in patients with HTN and HCM, whose left atrium is even in the normal size. The corresponding LA dysfunctions were strictly associated with clinical implication and provided prognostic utility at the early stage of HTN and HCM superior to GLS. Further multicenter, large scale and prospective studies are need to confirm and verify our findings.