Mechanisms of sympathetic regulation in orthostatic intolerance

Abstract

Sympathetic circulatory control is key to the rapid cardiovascular adjustments that occur within seconds of standing upright (orthostasis) and which are required for bipedal stance. Indeed, patients with ineffective sympathetic adrenergic vasoconstriction rapidly develop orthostatic hypotension, prohibiting effective upright activities. One speaks of orthostatic intolerance (OI) when signs, such as hypotension, and symptoms, such as lightheadedness, occur when upright and are relieved by recumbence. The experience of transient mild OI is part of daily life. However, many people experience episodic acute OI as postural faint or chronic OI in the form of orthostatic tachycardia and orthostatic hypotension that significantly reduce the quality of life. Potential mechanisms for OI are discussed including forms of sympathetic hypofunction, forms of sympathetic hyperfunction, and OI that results from regional blood volume redistribution attributable to regional adrenergic hypofunction.

Figures

Fig. 1.

Top to bottom: heart rate, stroke volume, cardiac output, systolic and diastolic blood pressure, cerebral blood flow velocity by transcranial Doppler ultrasound, total peripheral vascular resistance (TPR), and muscle sympathetic nerve activity (MSNA) from the peroneal nerve from a representative healthy volunteer. During upright tilt heart rate progressively increases, stroke volume decreases ∼40%, whereas cardiac output only decreases ∼20% because of the increase in heart rate. Systolic and diastolic blood pressure increase slightly, diastole more than systole. Cerebral blood flow decreases by 5–10%, while both TPR and MSNA are increased.

Fig. 2.

Top: arterial pressure (AP); bottom: cerebral blood flow (CBF). Left: data from a representative vasovagal syncope patient; Right: data from a postural tachycardia syndrome (POTS) patient. AP and CBF are at first stable (Stage 1), fall slowly (Stage 2), and then abruptly decrease by >50% in the syncope patient at which time consciousness is lost. This compares with the POTS patient who has no decrease in AP but has a >20% reduction in CBF throughout tilt.

Fig. 3.

Synthetic pathway for norepinephrine (NE) and a cartoon of a sympathetic nerve ending. NE is stored in vesicles and released into neurovascular synapses in response to MSNA bursting. Postsynaptic binding results in vasoconstriction, which can be assessed by measuring local blood flow with Doppler ultrasound and other methods. Some of the released NE spills over into the plasma. However, the NE transporter (NET) takes up and conserves the large majority of released NE. A specific vesicular monoamine transporter (VMAT2) is responsible for translocating NE from the cytoplasm into the vesicles. A recent technique of venous biopsy has been successfully used to detect changes in synthetic proteins (46). [Modified with permission from (98); inset courtesy of Dr. Elisabeth Lambert of the Baker IDI Heart and Diabetes Institute.]

Fig. 4.

Representative tracings during upright tilt for a postural syncope patient (left) and for a POTS patient (right). Heart rate (HR) is shown at top and mean arterial pressure (MAP) at bottom. HR increases in syncope, and POTS and is more excessively increased in POTS. MAP is stable throughout tilt in POTS. MAP is stable at first, decreases gradually in a second stage, and falls abruptly and rapidly in the third stage as loss of consciousness supervenes.

Fig. 5.

Response to upright tilt for a representative patient with postural hyperpnea. From top to bottom: ventilatory parameters: left, expiratory minute volume (VE), tidal volume (TV), and respiratory rate (RR); middle, arterial pressure (AP), HR, and cardiac output; right, cerebral blood flow CBFv, total peripheral resistance (TPR), and muscle sympathetic nerve activity (MSNA). VE rapidly increases on tilt attributable to an increase in TV. Increase in VE is progressive and preceded by an increase MSNA and TPR and decrease in CO and CBFv. Note that HR may reach levels commensurate with POTS.