Novel functional advanced echocardiography for the assessment of myocardial mechanics in children with neurocardiogenic syncope – a blinded prospective speckle tracking head-up tilt-table challenge study

Syncope is a sudden, brief loss of postural tone and consciousness followed by spontaneous recovery [1]. Up to 15% of children experience an episode of syncope to the end of adolescence [2, 3]. While a few underlying etiologies include potentially life-threatening cardiogenic conditions such as cardiac arrhythmia and structural heart disease, most cases of syncope are of benign origin. Vasovagal syncope - also known as situational, reflex or neurocardiogenic syncope (NS) - is the most common cause of pediatric syncope accounting for more than 50% of cases [4–6]. The development of effective therapies for NS is hindered by the vague and yet conflicting knowledge of the underlying pathophysiologic processes. Sympathetic failure/withdrawal is thought to play a role leading to decreased cardiac contractility and peripheral vascular tone [7]. The “ventricular hypothesis” on the other hand is based on an increase in left ventricular (LV) contractility – i.e. due to ventricular underfilling, sympathetic overactivity or hypovolemia. This may result in LV mechanoreceptor activation, the Bezold-Jarisch reflex, which in turn causes systemic hypotension, peripheral vasodilation and severe bradycardia [8]. However, the origin of the precipitating hemodynamic changes and the specific underlying pathomechanisms resulting in vasovagal syncope in children yet remain a subject of considerable speculation.

Advanced echocardiography techniques – including tissue-Doppler echocardiography (TDI) and speckle-tracking echocardiography (STE) – are promising modalities for the real-time quantitative evaluation of myocardial performance without the disadvantages of adverse effects or high costs. Based on TDI studies, cardiac mechanics such as left atrial and LV filling and contractility are postulated to be altered in neurocardiogenic syncope in adults [9, 10]. STE is reproducible tool for the detection of myocardial strain and strain rate [11, 12]. It has been successfully used to detect subclinical myocardial dysfunction in a variety of clinical settings such as arterial hypertension [13], systemic inflammatory disease [14], diabetes mellitus [15] and short-term alterations of glucose metabolism [16]. In 2013, the “ventricular theory” was fundamentally questioned by Goel et al. as they reported a paradoxical decrease of LV strain in adults with neurally mediated syncope and a positive head-up tilt-table (HUTT) exam utilizing STE [17]. However, echocardiographic assessment of cardiac strain was not performed at the same time as tilt-testing and LV strain rate – which, other than strain, is less dependent of cardiac loading conditions and therefore a better parameter to reflect LV contractility [18] - was not measured. This is the first study utilizing speckle-tracking imaging to shine a light on real-time cardiac mechanics in HUTT testing in children with vasovagal syncope.

This is the first study to simultaneously perform speckle-tracking echocardiography (STE) and head-up tilt-table (HUTT) testing in children with NS. Interestingly, we found LV resting longitudinal strain rate to be significantly lower in NS patients than in healthy controls with a more pronounced decrease in the HUTT+ group. During HUTT challenge we found a similar but not statistically significant tendency of lower longitudinal strain rate in patients with NS. This is in line with findings from Kojo et al., who utilized a Doppler flow meter during HUTT testing and found reduced carotid artery blood flow in pediatric patients with NS [26]. Our findings are furthermore in agreement with results from Sucu and colleagues, who detected atrial conduction delay in adolescents and young adults with NS [27]. Moreover, our data is in accordance with a HUTT echocardiography study in adults reporting that vigorous contraction is probably less responsible for vasovagal syncope release than left ventricle volume reduction [28]. Similarly, HUTT+ NS patients had reduced end-systolic stress, LV volume, and chamber function during HUTT testing in another study, which provides further evidence that if paradoxic activation of LV mechanoreceptors has a role in mediating NS, it is not triggered by increased systolic wall stress or LV hypercontractility [8].

On the other hand, our findings are counterintuitive in the light of the “ventricular theory” in that we did not measure an increase but a decrease in LV contractility in patients with NS and a positive HUTT response. This, however, apart from the fact that the ventricular hypothesis is far from being established conclusively, is in agreement with a similarly performed study by Goel et al., who report attenuated resting LV strain in HUTT+ patients and conclude that – other than previously believed – increased resting LV contractility is not a prerequisite for the development of NS [17]. Notably, even though the authors have measured a similar phenomenon as we did in this study, their study bares significant technical limitations which gives incremental value to our observations. Firstly, Goel et al. have performed STE measurements on a different day then HUTT challenge. Moreover, they utilized LV strain as a measure for LV contractility; strain rate was not assessed. Importantly, STE-derived strain rate has been shown to be more robust to dynamic ventricular unloading than strain in several well-performed animal experimental studies [29–31]. In humans, LV strain has been shown to be affected by changes in cardiac loading conditions such as hemodialysis [32] or gravitational gradients [33]. Furthermore, other than strain, strain rate has been demonstrated to be unaffected by preload and correlate well with end systolic elastance as verified by invasive catheterization [18]. In addition, utilizing a stress testing echocardiography set up, strain rate has been shown to reflect myocardial contractility demonstrating a positive force-frequency relationship in both children and young piglets [34]. In conclusion, our study closes that gap as we performed STE and HUTT on the same occasion and detected LV strain rate in addition to LV strain.

The cardiac autonomic response pattern of patients with NS during HUTT challenge has been distinguished between HUTT+ and HUTT- patients in previous studies [35]. In line with this, we measured more attenuated longitudinal strain rate in HUTT+ patients. The lack of statistical significance for circumferential strain rate and longitudinal strain rate during HUTT is most probably a result of the limited sample size as well as suboptimal image quality during HUTT testing. In the present study, we further found HUTT+ patients to have a lower LV stroke volume when compared to HUTT- and healthy control subjects. This is in accordance with the findings from Moon et al., who described decreased left atrial volumes in HUTT+ patients and concluded a limited intracardiac volume reserve to play an important role in the mechanism of NS [36]. A subset of patients with NS had increased strain rate values – corresponding to a “hyperdynamic” type of NS. Interestingly, none of those patients had a positive response during HUTT challenge. While one could speculate about the pathophysiologic significance of this observation, the small sample size underlying this finding should be taken into consideration. Hence, no definite conclusion can be drawn from this observation at this point. Future studies should further investigate the different types of LV deformation in patients with NS with a specific focus on hemodynamics and cardiomechanics.

Another unresolved issue regarding the enigmatic pathogenesis of NS is the factor age. Even though younger and older patients react differently on the HUTT, especially in the early phase [37], the role of the autonomic nervous system for the etiology of NS seems to be similarly important in adults and children [38]. In extreme cases, the cardioinhibitory effect of the adult autonomous nervous system can reach an extent that can cause death, i.e. cardiac arrest due to extensive inhibitory vagal reflex following a laryngoscopic procedure [39]. Neither has a definite origin in the pathogenesis of neurally mediated syncope been identified, nor do previous studies point toward a definite answer for the “chicken or egg” question. While the “ventricular theory” is centered on the heart as the primarily malfunctioning source, arterial distensibility was also shown to be decreased in patients with recurrent episodes of NS [40]. Similarly, Sucu and colleagues have reported increased aortic stiffness as expressed by altered aortic strain in mid-aged adults with NS and a positive HUTT response [41].

Interestingly, based on the evidence of fear and threat bradycardia in animals and the beneficial vasovagal reflex during hemorrhagic shock in humans and animals, some researchers suggest NS not to be a recently evolved human-only disease but rather the remnant of an ancient defense mechanism that has once reduced myocardial oxygen consumption and supported hemostasis before the development of larger blood losses [42–44]. Under this assumption, it is well imaginable, that this trait is now differentially passed on to subsequent generations and therefore despite being common it is variously pronounced which could explain the different response patterns during HUTT challenge. The principle mechanism during the actual faint is an impaired ability to maintain vasomotor tone in the skeletal muscle blood vessels due to sympathetic withdrawal [45]. While – due to the technical design of this study – we did not perform STE during the event of fainting (HUTT+ group), we assessed LV performance at rest and during HUTT testing before termination of the challenge. The detected lower strain rate may reflect a lower sympathetic tone and thus decreased LV performance which may be a relevant factor in the etiology of NS.

This study provides further evidence that decreased LV resting performance may be a relevant factor in the etiology of neurocardiogenic syncope in children. Further experimental animal and human studies should be designed to investigate LV contractility in children and adults with NS under different cardiac loading conditions at baseline and in the context of HUTT challenge.