Biatrial performance in children with hypertrophic cardiomyopathy: CMR study

A standard CMR study was performed using a 1.5-Tesla scanner (Sonata and Avanto, Siemens, Erlangen, Germany). Late gadolinium enhancement (LGE) images in long-axis and short-axis imaging planes were obtained with a breath-hold, segmented inversion recovery sequence performed 10 min after contrast injection (gadobutrol, Gadovist, Bayer, Germany and gadoteridol, Prohance, Takeda, Japan). The control subjects did not receive gadolinium contrast agent.

Two-dimensional, conventional pulsed Doppler and M-mode echocardiography was performed at rest using standard methods (iE 33, Philips, Healthcare). Conventional pulsed Doppler was used to record the mitral and tricuspid inflow patterns at the leaflet tips in the apical four-chamber view. Peak velocities of E and A waves (cm/s) and their ratio (E/A) were measured.

To determine maximal degree of LVOTO, two-dimensional and Doppler echocardiography was performed during the Valsalva manoeuvre in the sitting position, and then during standing if no gradient was provoked. A maximum gradient greater than 30 mmHg was considered significant. Neither pharmacological stimuli nor exercise tests were used to determine maximal LVOT gradients. Furthermore, CMR cine images were visually assessed for the presence of LVOTO.

Steady-state free precession images were used for calculating ventricular volumes and ejection fractions with the aid of dedicated software (MASS 7.6, Medis, Leiden, Netherlands). Manual delineation of endocardial and epicardial contours was performed in end-diastolic and end-systolic phases. Left ventricular end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV mass (LVM) and LV ejection fraction (LVEF) were calculated. LVEDV, LVESV and LVM were indexed to BSA (LVEDVI, LVESVI and LVMI, respectively). Also, on the basis of two- and four-chamber views, maximal LV wall thickness was measured. Images were visually assessed for the presence of LGE areas for each LV myocardial segment using the 17-segment cardiac model. In addition, the quantitative extent of LV LGE was determined using dedicated software (MASS 7.6, Medis). Regions of elevated signal intensity had to be confirmed in two spatial orientations. A region of interest (ROI) was selected in effectively nulled myocardium. The mean signal intensity and SD of the ROI were measured. The LV myocardium was delineated by endocardial and epicardial contours, which were traced manually. Enhanced myocardium was defined as myocardium with a signal intensity exceeding 6 SDs above the mean of the ROI. The extent of LGE was expressed as a percentage of the LV mass (LGE%LV).

Left atrial and RA volumes were quantified using dedicated software (MASS 7.6, Medis). The LA volumes were calculated according to the biplane area–length method [16]. Manual tracking of the LA area and length was performed in two- and four-chamber views excluding pulmonary veins and the LA appendage. The RA volumes were calculated according to the single-plane area–length method [17]. Manual tracking of RA area and length was performed in four-chamber view. The LA volumes, indexed for BSA, were assessed at LV end-systole (LAV max), at LV diastole before LA contraction (LAV pac) and at late LV diastole after LA contraction (LAV min). The RA volumes, indexed for BSA, were assessed at RV end-systole (RAV max), at RV diastole before RA contraction (RAV pac) and at late RV diastole after RA contraction (RAV min). The LA and RA volumetric analysis was performed twice by two independent and skilled observers. Total atrial emptying fraction (LAEF total, RAEF total corresponding to LA and RA reservoir, respectively), passive atrial emptying fraction (LAEF passive, RAEF passive corresponding to LA and RA conduit function, respectively) and active atrial emptying fraction (LAEF booster, RAEF booster corresponding to LA and RA contractile booster pump function, respectively) were defined according to the following equations:

Atrial strains and strain rates were analysed using dedicated software (Cvi42, Alberta, Canada). Left atrial endocardial borders were tracked in two- and four-chamber views. Right atrial borders were tracked in four-chamber view (Fig. 1). The atrial endocardial border was manually delineated in diastolic phase and tracked automatically. Three aspects of LA and RA mechanics were analysed: passive strain (εe, corresponding to atrial conduit function), active strain (εa, corresponding to atrial contractile booster pump function) and total strain, the sum of the passive and active strains (εs, corresponding to atrial reservoir function). Accordingly, three strain rate parameters were evaluated: the peak positive strain rate (SRs, corresponding to atrial reservoir function), the peak early negative strain rate (SRe, corresponding to atrial conduit function) and the peak late negative strain rate (SRa, corresponding to atrial contractile booster pump function).

All of the continuous variables were expressed as mean ± SD or as median and interquartile range and were tested for normal distribution using the Kolmogorov–Smirnov test. Comparisons between groups were performed using the Student’s t test or the Wilcoxon–Mann–Whitney U test for continuous variables and the chi-square or Fisher’s exact test for categorical variables, as appropriate.

The comparisons of volumetric and mechanical components of biatrial function between children with HCM and healthy controls are presented in Table 3. All LA volumes were higher in HCM subjects than in the controls (p = 0.01–0.02). Furthermore, children with HCM had conduit (p = 0.04) and booster (p = 0.03) fractional volume changes significantly lower than those of the controls. There were no differences in strain or strain rate booster functions between HCM juveniles and controls (p = not significant, NS); all other LA mechanics indices were significantly compromised in the study group compared with the controls (p = 0.01–0.04).

Right atrial minimal volume (p < 0.01) and volume just before contraction (p = 0.01) were higher in HCM subjects than in the controls. All emptying fractions were decreased in patients with HCM compared with the controls (p < 0.01–0.04). Moreover, the majority of markers of atrial deformation (p < 0.01–0.03), with the exception of the strain rate reservoir component (p = NS), were reduced in children with HCM compared with the control subjects.

All LA volumes were higher in children with LVOTO compared with children without LVOTO (p < 0.01–0.03). Furthermore, the reservoir (p = 0.02) and conduit (p < 0.01) emptying fraction were decreased in children with LVOTO. It is noteworthy that the active booster contractile function (p = 0.02) as well as the reservoir (p < 0.01) and booster (p = 0.01) strain mechanical components were higher in children with vs without LVOTO. All other emptying fractions and strain rates (p < 0.01–0.04) were significantly reduced in children with LVOTO (Fig. 2).

None of the RA volumes were significantly affected by the presence of LVOTO (p = NS). Moreover, there were no differences in booster pump or total RA contractile functions between subjects with and without LVOTO (p = NS). On the other hand, all deformation indices of RA were significantly lower in patients with LVOTO than in subjects without LVOTO (p < 0.01–0.02) (Fig. 3).

The associations of indices of LA and RA dynamics with the amount of fibrosis, the extent of hypertrophy and the degree of LVOTO are summarised in Tables 4 and 5, respectively. Nearly all of the LA dynamics markers attained a significant association with the LVOT gradient (p < 0.01–0.04). On the other hand, the LA volume prior to atrial contraction (p = 0.04), total volume (p = 0.04) and booster (p = 0.03) fractional volume change were related to LV mass. Lastly, only the LA conduit emptying fraction (p = 0.03) could be linked to the amount of LV fibrosis.

None of the RA volumes and only the RA conduit (p < 0.01) fractional function exhibited an association with the degree of LVOTO (p = NS). However, all of the markers of RA deformation, with the exception of the strain booster component (p = NS), exhibited an association with LVOT gradient (p < 0.01–0.04). The maximum RA volume (p = 0.03) and volume before atrial contraction (p = 0.03) were associated with the extent of LV fibrosis. Finally, the minimum RA volume (p = 0.01) and the total (p = 0.01) and booster (p = 0.01) pump functions with strain rate booster component (p = 0.04) were linked to the LV mass.

None of the indices of RV diastolic function had detectable association with LA dynamics and vice versa—none of transmitral velocities was connected with RA dynamics (p = NS). Only maximal RA volume was linked to transtricuspid A wave velocity (β = – 0.25, p = 0.02). On the other hand, transmitral A wave velocity was associated with maximal LA volume (β = – 0.21, p = 0.02) and E wave velocity with LA volume just before contraction (β = 0.37, p = 0.01).

The indices of reproducibility of both atrial volumes and function as well as LV fibrosis were reasonably good. For all components of biatrial function the intraobserver ICCs ranged from 0.81 to 0.98 (CoV = 0.11–0.84) and interobserver ICCs ranged 0.78 to 0.94 (CoV = 0.21–1.62). The ICCs and CoVs for the intraobserver and interobserver reproducibility regarding the quantification of LV fibrosis were 0.98 (CoV = 5.42) and 0.99 (CoV = 6.02), respectively.

In this study we compared atrial performance indices in HCM children versus controls. The control group was not age matched. This was mainly due to ethical concerns, which limited the recruitment of healthy children for CMR examination. For this reason, a limited number of studies recruited entirely healthy juvenile cohorts who underwent CMR [18, 19]; but only Robbers–Visser et al.’s [19] included a paediatric population with a wide age spectrum. Consequently, the vast majority of previous paediatric CMR works did not include any control groups at all [20] or included control subjects with clinically indicated CMR scans [21]. However, in patients with clinical suspicion of HCM or arrhythmogenic right ventricular cardiomyopathy and normal CMR scan, the preclinical stages of the disease cannot be excluded. Furthermore, fibrosis has been found in adult subjects with preclinical HCM in whom no LV hypertrophy was noted [22]. Therefore, the question may arise whether the observed reduction in atrial performance is more a result of younger age rather than cardiac disease. Bhatla et al. showed that LA volume indexed for BSA remained constant throughout infancy, childhood and adolescence [23]. What is more, Kutty et al. also reported a marked rate of maturational changes in biatrial strains and strain rates during the first year of life, reaching normal adult values by adolescence [24]. This data suggests that age-matched controls would have very similar values of volumetric and mechanical indices of atrial performance as our control population of healthy young adults.

In the human heart, it appears that LV systolic function largely influences LA reservoir function while LV relaxation and compliance are key modulators of atrial conduit and contractile functions [15, 24, 25]. Previous studies of echo and FT CMR in HCM adult patients consequently presented the reduction of all indices of LA dynamics [15, 26]. Our results revealed that the majority of LA volumetric and functional indices were significantly compromised in HCM children compared with healthy controls. Previous works found that conduit function was impaired in early stages of the disease [15]. Furthermore, LA reservoir volumetric function constantly exacerbates during progressive impairment of LV compliance, an increase in LV end-diastolic pressure and an advance of heart failure [15, 27]. A reduction of conduit functional components with preserved reservoir function indices in our population suggests that the severity of the disease was rather moderate. In fact, the mean NYHA class in our population was 1.7 ± 0.5.

Previous studies have identified diastolic dysfunction as a prominent factor of LA remodelling and dysfunction in adult populations [26‐31]. In our study, the magnitude of LA dynamics impairment appeared to be similar to that found by Kowallick et al. [15] and Kim et al. [31]. However, our population had much smaller amounts of substrates for LV diastolic dysfunction than the populations of either Kowallick et al. or Kim et al. That finding may imply that the grade of LV compliance is not the primary factor responsible for LA functional abnormalities in a juvenile HCM population. Accordingly, we found that neither the amount of intestinal fibrosis nor hypertrophy but rather LVOTO severity was associated with both LA volume and function. Presumably, the small amounts of fibrosis and hypertrophy, as substrates for the development of diastolic dysfunction, were unable to result in increased LV loading conditions in juveniles with HCM. The haemodynamic effect of LVOTO (e.g. severe pressure overload or a decrease of coronary blood flow) appears to play a more important role in the development of LA malfunction in our population. Presumably, the progressive nature of hypertrophy and fibrosis during growth leads to the deterioration of diastolic function and escalates the effects of LVOTO and finally results in further impairment of LA function.

Our contemporary understanding of atrial physiology and function stems predominantly from studies of the left adult heart. It appears that RA size and performance are likely to be subject to similar regulations as its left-sided counterpart. Even so, existing reports exploring human right atrium mechanics are very sparse. To date, there have been no CMR-derived studies focused on RA dynamics in an HCM juvenile population. Willens and colleagues, in an echocardiographic study of patients with pulmonary hypertension, demonstrated a decreased RA passive function associated with increased contribution of active atrial contraction to RV filling [32]. Similar RA functional disorders have been reported in an experimental model of chronic pulmonary arterial hypertension in dogs with banded main pulmonary arteries [33]. The researchers found an analogy between the reaction of well-studied LA and RA dynamics, concluding that the decline in compliance of the respective ventricle is the presumable mechanism of deterioration of function in both atria. Therefore, it is possible that HCM-specific ultrastructural changes are not only an attribute of hypertrophied LV myocardium but instead represent a widespread process involving RV as well, despite the lack of hypertrophy. On the other hand, elevated LV end-diastolic pressure is transmitted backwards through the RV and RA, which results in further deterioration of atrial function. Consequently, we found that the causes of RA mechanics abnormalities were likely to be multifactorial; the degree of LVOTO was mostly associated with markers of RA deformation, and RA volumetric parameters were mostly related to LV mass and fibrosis. All of these findings may imply that decreased RV compliance and a backwardly transmitted pressure burden are responsible for primary stages of the disease, which includes RA dilatation and reduced emptying performance. The severe additional load generated by LVOTO leads to additional deterioration of RA mechanics.

Reports analysing diastolic function in HCM children are limited to LV only. Abnormal LV and RV relaxation, based on echocardiographic transatrioventricular valve velocities and tissue Doppler measurements, was found in the majority of adult HCM patients [34, 35]. However, in those cohorts no correlations were noted between 2D echocardiographic parameters of diastolic function and strain or strain rate parameters [36]. In our study very few atrial volumes and none of the strains were associated only with transmitral or transtricuspid velocities. These findings may confirm that diastolic dysfunction is not a major factor triggering biatrial malfunction. On the other hand, it was found that assessment of diastolic dysfunction in children using traditional Doppler techniques seems to be inadequate. Poor discriminatory performance of key echocardiographic indices and large range of normal paediatric reference values allows diagnosis of disturbed ventricular relaxation in only a small proportion of patients [37]. That may suggest that the true incidence and magnitude of diastolic dysfunction in children with HCM are not known. Further studies with novel techniques and/or modalities are needed to confirm the connection between abnormal ventricular relaxation and atrial performance in the paediatric HCM population.

The limitations of our study are mostly inherent to its design. This study recruited a relatively small sample size with no genetic testing. No myocardial T1 mapping was available during data acquisition; thus, fibrosis was quantified using classical LGE technique and was limited to LV myocardium only. Also, data on diastolic function of healthy subjects was not available; hence, the comparison of ventricular relaxation indices between HCM children and controls was not possible.