Mechanistic explanation of test positivity
Recent studies have indicated that TT positivity is associated with neuroendocrine activation characterized by excess epinephrine and vasopressin release21,22, whereas adrenomedullin seems to play a protective role, probably acting against intravascular volume escape.21 Further, older age and higher resting SBP have been suggested to be predictors of hemodynamic stability on TT.11,21 These findings were corroborated by Lindenberger et al. who also found upregulation of vasopressin release, reduced cardiac filling and cardiac output in women prone to reflex syncope.23 Despite these studies, there remains a tenable possibility that the documented endocrine changes are precipitated by the developing adverse hemodynamic picture.
Lower circulating blood volume and tendency to blood pooling in the capacitance vessels during orthostatic challenge may have a critical impact in abruptly reducing stroke volume during TT and compensatory HR increase, as confirmed by Buszko et al.12 The higher resting HR and DBP may signal better neuroendocrine preconditioning against orthostatic challenge, engaging the entire sympathetic system. In contrast, those with a more pronounced epinephrine and vasopressin release during tilt testing appear to be in greater need of circulatory compensation as their resting SBP and DBP are lower. This may provoke a protective response from the central nervous system, leading to reflex syncope in extreme situations.24,25 Typically, this response occurs when cerebral tissue oxygenation is strongly compromised.26
Interestingly, only younger age but not gender was independently predictive of TT positivity. The protective factors against TT intolerance were resting SBP above 128 mmHg, heart rate above 69 bpm and presence of hypertension, even while on antihypertensive treatment. These findings emphasize the crucial role of global hemodynamic reserve for reflex triggering. Higher HR might indicate more efficient chronotropic compensatory mechanisms. Higher SBP suggests greater intravascular volume, well-functioning preload- and afterload-preserving mechanisms, whereas hypertension implies chronic sympathetic activation with increased total peripheral resistance and elevated arterial tone in the precapillary vascular bed. Arterial hypertension, as a variant of cardiovascular dysautonomia, is detrimental for long-term cardiovascular integrity and promotes end-organ damage.27 On the other hand, patients with syncope affected by hypertension seem to be more resistant to orthostatic stress, either due to altered hemodynamic reserve, increased circulating blood volume, chronic neuroendocrine activation and arterial vasoconstriction or by baroreceptor resetting.