The impact of atrial mechanical function on age‐dependent presentation of neurocardiogenic syncope

Abstract Background The contribution of atrial and ventricular function in neurocardiogenic syncope (NCS) pathophysiology is elusive. Hypothesis We assessed the influence of echocardiographic properties to the age of presentation and NCS recurrences. Methods We assigned 124 patients with symptoms suggesting NCS, to those with syncope initiation at age <35 (group A, n = 56) and >35 years (group B, n = 68). Echocardiographic indices were measured before head‐up tilt test (HUTT). Results A total of 55 had positive HUTT (44%) with a trend favoring group A (p = .08). Group A exhibited lower left atrial (LA) volume index (17 ± 6 vs. 22 ± 11 ml/m2, p = .015), higher LA ejection fraction (69 ± 10 vs. 63 ± 11%, p = .008), LA peak strain (reservoir phase 41 ± 13 vs. 31 ± 14%, p = .001, contraction phase 27 ± 11 vs. 15 ± 10%, p < .001) and LA peak strain rate (reservoir phase 1.83 ± 1.04 vs. 1.36 ± 0.96 1/s, p = .012, conduit phase 2.36 ± 1.25 vs. 1.36 ± 0.78 1/s, p = .001). Group A showed smaller minimum right atrial (RA) volume, better RA systolic function, superior left ventricular diastolic indices, and lower filling pressures. Group A patients were more likely to have >3 recurrences (82.0% vs. 50.1%, p < .05). Conclusions Patients with younger age of NCS onset and more syncopal recurrences manifest smaller LA and RA dimensions with distinct patterns of systolic and diastolic function and better LA reservoir and contraction properties. These findings may indicate an increased susceptibility to preload reduction, thereby triggering the NCS mechanism.


| INTRODUCTION
Neurocardiogenic syncope (NCS), is a common condition accounting for 50-66% of unexplained syncope in both children and adults. 1,2 Despite its high prevalence, the natural history and the underlying mechanisms of NCS are not well understood. [3][4][5][6] In addition, the reason that some people start fainting early with clusters of syncopal attacks while others later with long periods of syncope quiescence is also unknown.
Head-up tilt test (HUTT) is frequently used as part of the diagnostic algorithm with a class IIa indication according to the latest European Society of Cardiology guidelines. [7][8][9] The association however of HUTT outcome with anatomical and physiological cardiac chambers characteristics has not been sufficiently investigated especially using novel echocardiographic techniques like tissue doppler imaging (TDI) and speckle tracking echocardiography (STE). [10][11][12] The systematic use of these modalities could contribute in the evaluation of the atrial and ventricular performance leading to further insights into the mechanism of NCS. [13][14][15] The aim of this study, was to study the impact of anatomical and functional properties of cardiac chambers in the clinical presentation of syncope and the outcome of HUTT, in patients with NCS based on the age of syncope onset.

| METHODS
We studied 200 consecutive patients referred to our center for the investigation of syncope, presenting with symptoms suggestive of NCS. We excluded patients with underlying structural heart disease or conduction abnormalities that could be related to the mechanism of syncope. Patients with neurological or other diseases manifested with syncope were also excluded. Figure 1 illustrates our standard stepwise patient evaluation. Following this approach, 124 patients overall were included in the study ( Figure 2).
We hypothesized that patients starting fainting at a younger age might have different clinical and echocardiographic features. We dichotomized therefore the patient population into two groups using as cut-off the age of 35 based on previously published data. 16 and contraction phase, as previously described. 18 All peak strain data were averaged and a single value for peak LA strain and peak LA strain rate were derived for each patient. Mean values (average of three measurements) for all measurements were used for the final analysis.
All measurements were performed according to current guidelines and recent documentation in the literature. 18,19 Echocardiographic studies were performed using a commercially available ultrasound system (Vivid S5, GE Healthcare, Horton, Norway). Measurements including two-dimensional (2D) STE were made offline using a commercially available ultrasound software package (EchoPAC GE, version 113, GE Healthcare, Milwaukee, WI). Two experienced blinded physicians (C. P. and M. S.) were responsible for the off-line echocardiographic analyses. Inter-and intra-observer variability for LA strain and LA strain rate measurements was performed in a group of 15 randomly selected patients and assessed using intra-class correlation coefficient (two-way mixed effects model).
HUTT was performed in a dark and quiet room by specialized personnel following a standard protocol. 4,9 A positive response was defined as the occurrence of syncope, accompanied by hypotension, bradycardia, or both and resembling the patient's original symptoms.

| RESULTS
The study population comprised of 124 patients (mean age 47 ± 21 years, 71 female) with NCS divided into two groups. Group A consisted of patients with early syncope presentation (before the age of 35 years) and Group B of patients with late syncope presentation (after the age of 35 years). Table 1 summarizes the main characteristics of the study population.  and lower LV mass index (62 ± 30 vs. 93 ± 29 g/m 2 , p < .001). LV systolic function was superior in group A compared to group B as evidenced by LVEF (67 ± 5 vs. 64 ± 7%, p = .028). LV diastolic function was more favorable in Group A, as reflected by a higher E-wave velocity, E/A ratio values, and a lower TDI E'-wave mitral annulus velocity. Furthermore, LV diastolic filling pressures as reflected by E/E' were lower in Group A (5.8 ± 2.1 vs. 7.5 ± 3.5, p < .001).
LA volume index was lower (17 ± 6 vs. 22 ± 11 ml/m 2 , p = .015) and LA ejection fraction was higher (69 ± 10 vs. 63 ± 11%, p = .008) in Group A patients. LA mechanical function evaluated by 2D STE was significantly better in Group A. LA peak strain during the reservoir phase and the contraction phase were higher in Group A (41 ± 13 vs. 31 ± 14%, p = .001 and 27 ± 11 vs. 15 ± 10%, p < .001 respectively), while LA peak strain rate during the reservoir phase and con- In terms of right heart, there were no significant differences between the two groups concerning RV dimensions and function.

| Patient consent statement
Informed consent was obtained from all subjects involved in the study.

| DISCUSSION
The main finding of this study is that patients who first experience episodes of NCS at a younger age demonstrate better LA and RA contractile function along with enhanced LV diastolic function compared to the subjects who commenced having NCS episodes at an older age.
Most people with NCS faint first in adolescence or early adulthood. 20,21 We speculated that fainters in younger ages may have different characteristics compared to older patients and this may have implications in their management. The POST study showed a different response of older vasovagal syncope patients to b-blockade therapy compared to the younger suggesting a different underlying syncope mechanism. We tested this hypothesis in two prespecified and based on age 35 groups of patients according to the results derived from the Syncope Symptom Study and the POST study. 16,17 The LA plays an essential role in the filling of the LV and overall cardiac performance through its reservoir, conduit, and contractile function. test. 15 Goel et al, also reported a paradoxical decrease of LV strain in adults with NCS and a positive HUTT. 29 The atria, which are rich The function of the right cardiac chambers in vasovagal syncope is inadequately studied. 14  iability seems to exist and steps must be taken to underscore this limitation. 31 In this specific study, we used EchoPac software for LA strain analysis and our results should not be generalized and should be evaluated with caution.
The use of age 35 as a cutoff for further categorization of the study population into two groups was somewhat arbitrary. We prespecified this because it was the dichotomous diagnostic variable for vasovagal syncope that was derived from the Syncope Symptom Study. 32 Furthermore, there was a difference in sex predominance between the two groups that might have influenced our results. Women were overrepresented in our population a finding that is frequent in syncope trials. However, this reflects the common incidence of vasovagal syncope in women, especially in high-risk populations.

| CONCLUSIONS
Conclusively, patients with early onset of NCS are more prone to syncopal recurrences. These patients exhibit better LA and RA mechanical function as well as "healthier" LV diastolic function. The above findings may indicate an increased susceptibility of this group to preload reduction, thereby triggering the mechanism of NCS. This subgroup of patients might respond favorably to more aggressive hydration management.

CONFLICT OF INTEREST
The authors declare no conflicts of interest.

ETHICS STATEMENT
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by 1.