Novel cardiovascular biomarkers in unexplained syncopal attacks: the SYSTEMA cohort

Abstract

Objectives. The aim of the study was to investigate the resting levels of novel cardiovascular biomarkers in common types of noncardiac syncope.Design and setting. An observational study was conducted including 255 patients (mean age 60 years, range 15-93; 45% men) with unexplained syncopal attacks. Subjects underwent an expanded head-up tilt test including carotid sinus massage, and nitroglycerin provocation if indicated. Using logistic regression, we explored the associations between specific diagnoses of syncope and resting levels of circulating biomarkers: C-terminal pro-arginine vasopressin (CT-proAVP), C-terminal endothelin-1 precursor fragment (CT-proET-1), midregional fragments of pro-atrial natriuretic peptide (MRproANP) and pro-adrenomedullin (MR-proADM).Results. A total of 142 (56%) patients were diagnosed with vasovagal syncope (VVS), 85 (33%) with orthostatic hypotension (OH) and 47 (18%) with carotid sinus hypersensitivity (CSH); in addition, 74 (29%) patients had more than one diagnosis. Thirty-five patients (14%) demonstrated a cardioinhibitory reflex. The probability of VVS was highest in the first quartile of MR-proANP [Q1 vs. Q4: odds ratio (OR) 5.57, 95% confidence interval (CI) 1.86-16.74; P < 0.001] and CT-proET-1 (OR 7.17, 95% CI 2.43-21.13; P < 0.001). By contrast, the probability of OH was highest in the fourth quartile of CT-proET-1 (Q4 vs. Q1: OR 8.66, 95% CI 2.49-30.17; P < 0.001). Furthermore, CSH was most frequently observed in the first quartile of MRproANP (Q1 vs. Q4: OR 6.57, 95% CI 1.62-26.62; P = 0.008) among those over 60 years of age, whereas the cardioinhibitory reflex was strongly associated with low CT-proET-1 levels (Q1 vs. Q4: OR 69.7, 95% CI 6.97-696.6; P < 0.001). Moreover, in patients with VVS, a high concentration of CT-proET-1 was predictive of OH (OR per 1 SD 2.4, 95% CI 1.15-5.02; P = 0.02), whereas low CTproET-1 suggested involvement of the cardioinhibitory reflex (OR per 1SD 0.42, 95% CI 0.25-0.70; P = 0.001).Conclusions. The levels of MR-proANP and CT-proET-1 are markedly changed in common forms of syncope, suggesting the involvement of novel neurohormonal mechanisms in syncopal attacks.

Endothelial function in vasovagal syncope

“…Fedorowski and colleagues reported that in patients with VVS, unlike those with orthostatic hypotonia, showed decreased ET-1 levels during orthostatic stress. Measurement of ET-1 may be useful for discriminating between classical reflex syncope and that induced by orthostatic hypotension [5].…”

“…Recent research has focused on the regulation of the peripheral circulation in patients with VVS in an attempt to identify the active or passive mechanism driving peripheral vasodilation [4][5][6].…”

Neuropeptides and peptide hormones in syncope and orthostatic intolerance

“…3). Taken together, the observations of Jardine et al [8] and Fedorowski et al [17] may be reasonably interpreted to reflect the impact of progressively diminished atrial stretch during upright posture, with NP's acting to provide a fluid conservation state particularly in syncope-prone individuals.…”

“…In this regard, changes in circulatory catecholamines have tended to be of greatest interest given the apparent association of VVS with anxiety or stress states [8][9][10][11][12][13][14]. However, the potential role of NPs has also attracted attention; specifically, BNP [8], vasopressin (VP) [8,15,16], atrial natriuretic peptide (ANP) [8,17], adrenomedullin (ADM) [17][18][19], galanin (GAL) [19,20], and endothelin-1 (ET-1) [17,[21][22][23]. A summary of the primary physiologic effects of these NPs is shown in Table 2.…”

“…Fedorowski et al [17] recently examined the relationships between certain NPs and mechanisms underlying syncope in a series of patients with unexplained transient loss of consciousness undergoing head-up tilt table testing; a cardiac etiology for symptoms was deemed excluded by the initial clinical evaluation. They studied the mid--regional fragments of pro-atrial natriuretic peptide (MRproANP); findings revealed that ANP levels tended to be lowest in patients prone to tilt-induced fainting and highest in non-fainters (Fig.…”