Intraventricular dyssynchrony in light chain amyloidosis: a new mechanism of systolic dysfunction assessed by 3-dimensional echocardiography

Light chain amyloidosis (AL) is a rare multiorgan disease with extracellular deposition of fibrillar amyloid proteins derived from immunoglobulin light chains [1, 2]. Amyloid deposits in the heart, kidneys, liver and nervous system cause organ failure. There is poor prognosis with median survival of 4 months with heart failure [3, 4]. It is associated with diastolic dysfunction but often preserved left ventricular (LV) ejection fraction, especially in the early stages [5‐9]. Left ventricular dyssynchrony is common in heart failure patients and may contribute to its pathophysiology [10]. Intraventricular dyssynchrony reduces ventricular efficiency and cardiac performance [11] while cardiac resynchronization therapy improves symptoms and prolongs life [12, 13]. Amyloid deposition can potentially alter regional cardiac mechanics. In a recent paper, Bellavia, et al. reported that patients with less advanced AL cardiac amyloidosis had increased segmental dyssynchrony compared to controls, but more advanced amyloidosis was associated with hypersynchronization using Doppler tissue velocity imaging [14]. Three dimensional (3D) assessment of regional dyssynchrony has potential advantage over 2-dimensional based tissue Doppler studies as the temporal relationships of all 16 segments can be related with ease. Recently, 3D echocardiography has been utilized to study the temporal pattern of the dispersion in segmental ventricular volumes during the cardiac cycle in the novel assessment of ventricular dyssynchrony [11, 15] The dispersion (expressed as standard deviation) of the duration/timing from beginning of systole to the minimal systolic volume in the 16 different regions of the left ventricle (16-SD%, normalized to cycle length) has been shown to be a marker of dyssynchrony that was associated with ventricular dysfunction [11, 15]. We hypothesize that AL subjects have left ventricular dyssynchrony compared to healthy controls. The aim of the study was to compare 16-SD% in AL subjects versus healthy controls.

Eight AL patients had New York Heart Association functional classification I, with 1 each presenting in Class III and IV heart failure. Left ventricular ejection fraction was 62.4 ± 0.6% in control subjects and 58.6 ± 2.8% for AL (p = NS) (Table 1). AL subjects had thicker anteroseptum, increased left atrial volume index and tendency towards increased left ventricular mass index. The lateral mitral annular velocity (E') was 15.4 ± 9.2 cm/s and ratio of mitral inflow velocity to E' (E/E') was 7.2 ± 3.3 in AL subjects. Although E and E/E' data were not available in control subjects, the mean values of E' and E/E' in AL subjects in addition to increased left atrial volume index are consistent with diastolic dysfunction and increased left ventricular filling pressures based on prior validation studies [27‐30]. Based on conventional evaluation of degree of diastolic dysfunction using mitral inflow and mitral annular velocity [31], 1 AL patient had normal diastolic function, 3 had mild (impaired relaxation pattern), 4 had moderate (pseudonormalization) and 2 had severe (restrictive) diastolic dysfunction.

There was higher 16-SD% in AL subjects compared to controls (Table 1, Figures 1, 2, see Additional files 1, 2). There was shorter cycle length in AL subjects compared to controls. There was no correlation between cycle length and 16-SD% (R = -0.2, p = NS). 16-SD% was weakly correlated with left ventricular mass index (R = 0.45, p = 0.04). There was no correlation between 16-SD% and left ventricular ejection fraction (R = -0.3, p = 0.14).

Intraclass correlation coefficient was 0.625 (p = 0.001) for intraobserver and 0.606 (p = 0.002) for interobserver differences in 16-SD%. The ICC together with the Bland-Altman analysis (Figure 3) show good reproducibility of 16-SD% measurements. The Bland-Altman plot further shows better agreement in the measurement at lower 16-SD% values.

Light chain amyloidosis is an often fatal disease with about 2500 new cases per year in the United States [3, 32‐35]. Patients with cardiac involvement have the worst outcomes in the presence of heart failure [3, 36]. Amyloid deposition in the heart leads to ventricular thickening and impaired relaxation, classically presenting as diastolic dysfunction often with preserved systolic function as measured by left ventricular ejection fraction [5‐8]. Indeed, left ventricular ejection fraction was found not to be an independent risk factor for mortality in this disease [4]. The elevated mitral annular velocity E' and ratio of transmitral inflow velocity to mitral annular velocity E/E' together with increased left atrial size suggest diastolic dysfunction [27] that is more prominent than conventional measures of systolic function (mean left ventricular ejection fraction 58.6 ± 2.8%) in our cohort of AL subjects.

Heart failure is an important cause of morbidity and mortality in AL amyloidosis. There is increasing recognition that timing of regional ventricular contraction or ventricular synchrony is important in the development of cardiac dysfunction and heart failure. Both interventricular and intraventricular dyssynchrony reduce ventricular efficiency and performance [11]. Treatment of dyssynchrony with cardiac resynchronization therapy has been shown to improve survival, reduce heart failure symptoms and improve quality of life [12, 13, 37‐39]. 3D echocardiography is a recent advance in the volumetric assessment of left ventricular function and software allows the quantification of the dispersion of timing to peak systole among the different ventricular regions, a measure of intraventricular dyssynchrony. Early studies demonstrate that dyssynchrony measured by the dispersion of systolic timing among the 16 segments (16-SD%) is associated with systolic dysfunction [11, 15]. In addition to quantifying the temporal relationship among segments, 3D echocardiography also allows acquisition that does not require correct acquisition axis. In the current study, significant dyssynchrony was demonstrated in AL subjects. The presence of dyssynchrony in the setting of relatively preserved LV ejection fraction in the AL group suggests that systolic dysfunction may occur earlier than previously recognized and that amyloid deposit in the heart, although diffuse in distribution [40], still result in regional contractile dysfunction. The study points to the potential of 3D echocardiography to detect early changes of left ventricular systolic dysfunction in AL amyloidosis that might not otherwise be detected by conventional measures of systolic function. The degree of dyssynchrony is correlated with left ventricular mass index suggesting that 16-SD% abnormality may be an early indication of cardiac amyloid deposition.

The current finding needs to be related to the recent study of Bellavia, et al. [14] that utilized 2-dimensional tissue Doppler imaging to assess regional dyssynchrony. In this study involving AL amyloid patients with relatively preserved left ventricular systolic function, they found that patients with less advanced cardiac involvement (ventricular thickness < 1.1–1.2 cm and without restrictive filling pattern) had significantly higher standard deviation of timing of segmental longitudinal and radial strain signifying regional dyssynchrony compared to age and sex-matched controls. However, patients with advanced cardiac involvement (ventricular thickness > 1.1–1.2 cm or restrictive filling pattern) surprisingly had reduced regional dyssynchrony. Although the thickness of the ventricle is consistent with advanced classification in most of our subjects using Bellavia's thickness criteria, most of our subjects had mild-moderate dysfunction (70%) with only 20% having restrictive filling pattern. It is possible therefore, that our patients are more closely related in degree of disease to the no-advanced group in that study. Our sample size is too small to compare more advanced versus less advanced disease. However, 3D echocardiography is theoretically superior to 2-dimensional based techniques in assessing regional dyssynchrony if data is acquired in 1 cardiac cycle as it allows simultaneous measurement of systolic timing in all 16 segments versus non-simultaneous sequential determination in different views for 2-D based methods. Differences in systolic timing of segments taken at different time points may not only be due to regional dyssynchrony but may also be affected by beat to beat variation in cycle length and systolic timing. It remains to be seen whether hypersynchronization would be also observed in advanced cardiac amyloid patients using 3-dimensional echocardiography.

The 3D echocardiographic method of assessing ventricular dyssynchrony appears to have good, although not excellent, agreement when measured by the same or different observers based on intraclass correlation coefficient and Bland-Altman analysis. The reliability of this technique for use in AL amyloidosis subjects needs to be validated in a larger number of subjects. In future studies, comparing the presence and degree of dyssynchrony between amyloid subjects and other benign conditions presenting with ventricular thickening such as hypertension may be useful in determining whether this novel measure is clinically useful in the early diagnosis of AL cardiac amyloidosis.

Intraventricular segmental dyssynchrony is demonstrated for the first time in light chain amyloidosis subjects compared to healthy controls with higher temporal pattern of dispersion of regional volume systolic change (16-SD%) on 3D echocardiography. Since left ventricular ejection fraction is relatively preserved in this cohort of AL subjects, regional intraventricular dyssynchrony by 3D echocardiography is a novel technique that may allow earlier detection of systolic dysfunction in this disease condition.