While cardiac amyloidosis (CA) is a rare systemic disease characterized by extracellular deposition of protein-derived fibrils,1 hypertrophic cardiomyopathy (HCM) is a relatively common genetic cardiac disease histopathologically characterized by myocyte hypertrophy and disarray, interstitial fibrosis, and small intramural coronary arteriole dysplasia.2 CA and HCM are both known to be associated with left atrial (LA) dysfunction. Three-dimensional (3D) speckle-tracking echocardiography (STE) has been demonstrated to have unique potential for detailed ventricular and atrial volumetric and functional analysis.3 The specific aim of this study was to compare volumetric and functional characteristics of the left atrium between light-chain (AL) CA and HCM by 3D-STE.

A commercially available ultrasound system (Toshiba ArtidaTM, Toshiba Medical Systems, Tokyo, Japan) equipped with a broadband (1-5MHz) PST-30SBP phased-array transducer was used for standard transthoracic echocardiographic examinations. Measurements of left ventricular (LV) dimensions, volumes and ejection fraction were obtained in accordance with the recommendations of the American Society of Echocardiography.8 The degree of mitral regurgitation (MR) was graded visually by color Doppler echocardiography.

During the same echocardiographic examination, 3D datasets were acquired in apical view using a commercially available 1-4MHz PST-25SX matrix-array transducer (Toshiba Medical Systems, Tokyo, Japan).3 During end-expiratory breath-hold and six ECG-gated beats, six wedge-shaped subvolumes were acquired to create the LV full volume. Off-line analysis of the 3D datasets was performed using 3D Wall Motion Tracking software, version 2.5 (Toshiba Medical Systems, Tokyo, Japan). Apical 2-chamber (AP2CH), 4-chamber (AP4CH), and short-axis views at different levels of the left atrium (basal, mid, and superior) were automatically selected at end-diastole (Figure 1). Non-foreshortened AP2CH and AP4CH views were determined by finding the largest long-axis LA dimensions, then the mitral annulus and the LA apex were marked manually. The LA appendage and pulmonary veins were excluded from the examination. Following LA border detection at the end-diastolic reference frame, wall motion tracking was performed automatically in 3D space throughout the cardiac cycle. The shape of the LA was corrected if needed. Due to the absence of an LA-specific segmentation model, the left atrium was automatically divided into 16 segments using standard LV segmentation.9

Figure 1.

Apical 4-chamber (A) and 2-chamber views (B), and different parasternal short-axis views at basal (C3), mid (C5) and superior (C7) left atrial regions, extracted from the three-dimensional volume. A three-dimensional wireframe reconstruction of the left atrium based on three-dimensional speckle-tracking echocardiographic analysis together with volumetric data and segmental (circumferential) time-strain curves are also presented. White, dashed and yellow arrows represent segmental (systolic) peak strain, (late-diastolic) strain at atrial contraction and global time-volume curve, respectively. LA: left atrium; LV: left ventricle; RA: right atrium; RV: right ventricle.

(0.53MB).

Using the ECG-gated 3D-LA model, end-systolic maximum volume (Vmax), diastolic volume before atrial contraction (VpreA) and end-diastolic minimum volume (Vmin) were measured in each case10–16 (Figure 1). From the three volumes, the following features of different phases of LA function were also calculated:

For (systolic) reservoir function:

• Total atrial stroke volume (TASV): Vmax−Vmin

• Total atrial emptying fraction (TAEF): TASV/Vmax×100

For (early diastolic) conduit function:

• Passive atrial stroke volume (PASV): Vmax–VpreA

• Passive atrial emptying fraction (PAEF): PASV/Vmax×100

For (late diastolic) active contraction:

• Active atrial stroke volume (AASV): VpreA−Vmin

• Active atrial emptying fraction (AAEF): AASV/ VpreA×100

The following parameters of LA deformation were assessed13–18: global, mean segmental and regional (basal, mid and superior) radial (RS), longitudinal (LS), circumferential (CS), area (AS) and 3D (3DS) strain. Using LA time-strain curves, the first peak (feature of systolic LA reservoir function) and the second peak (strain at atrial contraction, a characteristic of LA booster pump function) were calculated in each patient.

Continuous variables were presented as mean ± standard deviation and tested for normality. Categorical data were expressed as percentages. A value of p<0.05 was considered statistically significant. Variables were compared using the independent samples Student's t test and the chi-square test as appropriate. Recently, data from the MAGYAR-Path Study confirmed excellent intraobserver and interobserver agreements for 3D-STE-derived LA volumetric and strain data.12,15 MedCalc software was used for statistical calculations (MedCalc, Mariakerke, Belgium).

Standard 2D echocardiographic data are summarized in Table 1. Significant (grade ≥2) MR was detected in seven HCM patients (35%) and in two AL-CA patients (13%).

Increased LA volumes were demonstrated in AL-CA and HCM patients compared to controls. None of the LA stroke volumes showed alterations in AL-CA patients, while TASV and AASV were found to be increased in HCM patients compared to controls and AL-CA patients. Only AAEF was found to be significantly reduced in AL-CA patients compared to controls. However, emptying fractions of HCM patients were between the values of AL-CA patients and those of controls.

Peak global and mean segmental CS, LS and AS showed significant reductions in AL-CA patients compared to controls (Table 2). Differences were observed in certain global and mean segmental peak strains of AL-CA and HCM patients. Only peak mean segmental LS was significantly decreased in HCM patients compared to controls. Regional peak strains of age-matched AL-CA and HCM patients and controls are presented in Table 2.

While no differences were demonstrated in global and mean segmental strain at atrial contraction between HCM patients and controls, AL-CA patients showed reductions in certain strain parameters compared to controls and HCM patients. Results of detailed regional analysis are presented in Table 3.

To the best of the authors’ knowledge, this is the first time 3D-STE-derived LA functional properties have been compared by volumetric and strain analysis between AL-CA and HCM. Several features of the three different phases of LA function were assessed by 3D-STE during the same examination: systolic reservoir phase (by TASV, TAEF and peak strains); early-diastolic conduit phase (by PASV and PAEF); and late-diastolic booster pump function (by AASV, AAEF and strains at atrial contraction). The present analysis showed different patterns of LA dysfunction: impairment of the systolic LA reservoir phase occurs in both diseases, because reduced peak strain was found both in CA and HCM, but impairment in LA active contraction phases occurred only in CA (reductions in AAEF and strain at atrial contraction).

Several imaging methodologies have been demonstrated to be useful for non-invasive assessment of LA dimensions, volumes and function. 3D-STE is based on a block-matching algorithm of myocardial speckles on the endocardial border during their frame-to-frame motion.3,19,20 It is a relatively new echocardiographic technique that aims to incorporate all the benefits of STE and 3D echocardiography, including LA volumetric10–16 and strain13–18 assessments.

LA functional remodeling in AL-CA appears to be more extensive than in HCM. This could be explained by the fact that while HCM represents a myopathic process affecting ventricular and atrial myocardium, CA results in much more diffuse and ubiquitous involvement,1,2 due to mainly interstitial, nodular and branching deposition of amyloid, which can have a major impact on LV diastolic function that directly impairs LA structure and function. Moreover, hemodynamic reasons could not be excluded; higher MR grades were detected in 13-35% of AL-CA and HCM patients, which could also have an effect on atrial remodeling.

Increased LA volumes and impaired LA myocardial deformation are well-known features in HCM.13,21 Moreover, increased LA volume is a predictor of adverse outcome and impaired LA function is presumed to be due to LV diastolic dysfunction as a result of hypertrophy and myocardial fibrosis.22 LA volumes and strains were found to be more affected in patients with obstruction.22 In a recent 3D-STE study of volumetric and strain functional properties, only TAEF differed significantly between HCM patients with vs. without grade ≥2 MR, but no differences were found between the same parameters in HCM patients with vs. without classic risk factors.13 On the other hand, LA enlargement was found to be an independent predictor of long-term mortality, aiding risk stratification and management of patients presenting with amyloidosis.23 LA dysfunction was also observed in AL amyloidosis patients without other echocardiographic features of cardiac involvement using conventional and strain echocardiography for measuring LA ejection force, LA strain and strain rate.24 All these results suggest increased LA volumes and reduced LA functional properties in both HCM and CA. In the present study, detailed analysis of LA dysfunction was performed by 3D-STE in CA and HCM patients. Different patterns of LA dysfunction demonstrate that 3D-STE theoretically has potential for differentiating these patient populations. However, further studies in larger patient populations are warranted to confirm our findings.

Despite recent improvements in 3D echocardiographic analysis, one of the main limitations of 3D-STE is its relatively low temporal and spatial resolution compared to 2D techniques.

Although 3D-STE has been validated for the assessment of LA volumes and functional properties including strain assessments against different reference techniques,10–12,15 further studies are warranted to confirm its accuracy. Since no 2D-STE or other imaging technique was used together with 3D-STE and no clinical or prognostic correlations were performed between these methodologies, the accuracy of 3D-STE could not be established in this study.

The diversity of HCM patients, including genetic background, development of dynamic obstructions and arrhythmias, may also have had an effect on the results.

It is important to emphasize the effects of age on LA parameters. In a recent study using the same methodology, LA functional properties of HCM patients were compared with those of controls, and more significant differences were found in volume-based functional parameters; the mean age of the participants was significantly lower in this previous study. In the present study, the mean age of the control group was greater than in the previous study, and differences in TAEF and PAEF disappeared due to impaired LA functional parameters of this older control group.13 These findings highlight the importance of age in influencing the results.

Only visual grading of MR was used, which could lead to misgrading; other parameters were not calculated in this study.

Moreover, dependence on the place of measurement, even in healthy subjects, should be taken into account when interpreting results.25

Different patterns of LA functional characteristics were demonstrated between AL-CA and HCM patients by 3D-STE. This may be explained by the different nature of the diseases: while HCM represents a myopathic process, AL-CA results in much more diffuse and ubiquitous involvement of the myocardial tissue with amyloid deposition.

The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008, and has been approved by the institutional committee of the University of Szeged.

Attila Nemes – study design, writing paper

Dóra Földeák – study design, writing paper

Árpád Kormányos – patient management, performing 3D-STE examinations

Péter Domsik – patient management, performing 3D-STE examinations

Anita Kalapos – patient management, performing 3D-STE examinations

Nóra Ambrus – supervision

Zénó Ajtay – supervision

Róbert Sepp – supervision, writing paper

Zita Borbényi – supervision, writing paper

Tamás Forster – supervision, writing paper

This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

The authors have no conflicts of interest to declare.