Andrew T. Del Pozzi

Reduced Cerebral Blood Flow With Orthostasis Precedes Hypocapnic Hyperpnea, Sympathetic Activation, and Postural Tachycardia Syndrome

Hyperventilation and reduced cerebral blood flow velocity can occur in postural tachycardia syndrome (POTS). We studied orthostatically intolerant patients, with suspected POTS, with a chief complaint of upright dyspnea. On the basis of our observations of an immediate reduction of cerebral blood flow velocity with orthostasis, we hypothesize that the resulting ischemic hypoxia of the carotid body causes chemoreflex activation, hypocapnic hyperpnea, sympathetic activation, and increased heart rate and blood pressure in this subset of POTS. We compared 11 dyspneic POTS subjects with 10 healthy controls during a 70° head-up tilt. In POTS subjects during initial orthostasis before blood pressure recovery; central blood volume and mean arterial pressure were reduced (P<0.025), resulting in a significant (P<0.001) decrease in cerebral blood flow velocity, which temporally preceded (17±6 s; P<0.025) a progressive increase in minute ventilation and decrease in end tidal CO2 (P<0.05) when compared with controls. Sympathoexcitation, measured by muscle sympathetic nerve activity, was increased in POTS (P<0.01) and inversely proportional to end tidal CO2 and resulted in an increase in heart rate (P<0.001), total peripheral resistance (P<0.025), and a decrease in cardiac output (P<0.025). The decrease in cerebral blood flow velocity and mean arterial pressure during initial orthostasis was greater (P<0.025) in POTS. Our data suggest that exaggerated initial central hypovolemia during initial orthostatic hypotension in POTS results in reduced cerebral blood flow velocity and postural hypocapnic hyperpnea that perpetuates cerebral ischemia. We hypothesize that sustained hypocapnia and cerebral ischemia produce sympathoexcitation, tachycardia, and a statistically significant increase in blood pressure.

Oscillatory Cerebral Blood Flow Is Associated With Impaired Neurocognition and Functional Hyperemia in Postural Tachycardia Syndrome During Graded Tilt

We hypothesize that upright cognitive impairment in patients with postural tachycardia syndrome (POTS) is caused by reduced cerebral blood flow (CBF). The CBF velocity (CBFv) measured by transcranial Doppler ultrasound decreased excessively during 70° tilt in a minority of patients with intermittent hyperpnea/hypocapnia. Incremental tilt showed no difference in mean CBFv. But N-back memory tasking indicated progressive compromised memory, reduced functional hyperemia, and reduced neurovascular coupling. Orthostasis caused slow oscillations in CBFv linked to oscillations in arterial pressure in patients with POTS. We also hypothesize that oscillatory CBFv degrades neurovascular coupling. We performed 2-back testing when subjects were in supine position and during incremental tilts to 15°, 30°, 45°, and 60° in 11 patients with POTS and 9 controls. Oscillatory arterial pressure, oscillatory CBFv, and neurovascular coupling were similar in supine position. The oscillatory arterial pressure increased by 31%, 45%, 67%, and 93% in patients with POTS during tilt and remained unchanged in the controls. Oscillatory CBFv increased by 61%, 82%, 161%, and 264% in patients with POTS during tilt and remained unchanged in the controls. Functional hyperemia decreased from 4.1% to 3.0%, 1.1%, 0.2%, and to 0.04% in patients with POTS, but it was unchanged at 4% in the controls. Percent correct N-back responses decreased from 78% to 33% in patients with POTS, whereas they remained at 89% in the controls. In patients with POTS, oscillatory CBFv was linearly correlated with functional hyperemia (r2=0.76). Increased oscillatory CBF is associated with reduced neurovascular coupling and diminished cognitive perf ormance in patients with POTS.

Altered oscillatory cerebral blood flow velocity and autoregulation in postural tachycardia syndrome

Decreased upright cerebral blood flow (CBF) with hyperpnea and hypocapnia is seen in a minority of patients with postural tachycardia syndrome (POTS). More often, CBF is not decreased despite upright neurocognitive dysfunction. This may result from time-dependent changes in CBF. We hypothesized that increased oscillations in CBF occurs in POTS (N = 12) compared to healthy controls (N = 9), and tested by measuring CBF velocity (CBFv) by transcranial Doppler ultrasound of the middle cerebral artery, mean arterial pressure (MAP) and related parameters, supine and during 70° upright tilt. Autospectra for mean CBFv and MAP, and transfer function analysis were obtained over the frequency range of 0.0078–0.4 Hz. Upright HR was increased in POTS (125 ± 8 vs. 86 ± 2 bpm), as was diastolic BP (74 ± 3 vs. 65 ± 3 mmHg) compared to control, while peripheral resistance, cardiac output, and mean CBFv increased similarly with tilt. Upright BP variability (BPV), low frequency (LF) power (0.04–0.13 Hz), and peak frequency of BPV were increased in POTS (24.3 ± 4.1, and 18.4 ± 4.1 mmHg2/Hz at 0.091 Hz vs. 11.8 ± 3.3, and 8.8 ± 2 mmHg2/Hz c at 0.071 Hz), as was upright overall CBFv variability, low frequency power and peak frequency of CBFv variability (29.3 ± 4.7, and 22.1 ± 2.7 [cm/s]2/Hz at.092 Hz vs. 14.7 ± 2.6, and 6.7 ± 1.2 [cm/s]2/Hz at 0.077Hz). Autospectra were sharply peaked in POTS. LF phase was decreased in POTS (-14 ± 4 vs. -25 ± 10 degrees) while upright. LF gain was increased (1.51 ± 0.09 vs. 0.86 ± 0.12 [cm/s]/ mmHg) while coherence was increased (0.96 ± 0.01 vs. 0.80 ± 0.04). Increased oscillatory BP in upright POTS patients is closely coupled to oscillatory CBFv over a narrow bandwidth corresponding to the Mayer wave frequency. Therefore combined increased oscillatory BP and increased LF gain markedly increases CBFv oscillations in a narrow bandwidth. This close coupling of CBF to MAP indicates impaired cerebral autoregulation that may underlie upright neurocognitive dysfunction in POTS.

Effect of sympathetic nerve blockade on low-frequency oscillations of forearm and leg skin blood flow in healthy humans

To Examine the effect of inhibiting sympathetic function on cutaneous vasomotion in the forearm and leg.

The effect of heating rate on the cutaneous vasomotion responses of forearm and leg skin in humans.

We examined skin blood flow (SkBF) and vasomotion in the forearm and leg using laser-Doppler fluxmetry (LDF) and spectral analysis to investigate endothelial, sympathetic, and myogenic activities in response to slow (0.1 °C·10 s(-1)) and fast (0.5 °C·10 s(-1)) local heating. At 33 °C (thermoneutral) endothelial activity was higher in the legs than the forearms (P ≤ 0.02). Fast-heating increased SkBF more than slow heating (P=0.037 forearm; P=0.002 leg). At onset of 42 °C, endothelial (P=0.043 forearm; P=0.48 leg) activity increased in both regions during the fast-heating protocol. Following prolonged heating (42 °C) endothelial activity was higher in both the forearm (P=0.002) and leg (P<0.001) following fast-heating. These results confirm regional differences in the response to local heating and suggest that the greater increase in SkBF in response to fast local heating is initially due to increased endothelial and sympathetic activity. Furthermore, with sustained local skin heating, greater vasodilatation was observed with fast heating compared to slow heating. These data indicate that this difference is due to greater endothelial activity following fast heating compared to slow heating, suggesting that the rate of skin heating may alter the mechanisms contributing to cutaneous vasodilatation.

The contribution of sensory nerves to the onset threshold for cutaneous vasodilatation during gradual local skin heating of the forearm and leg.

During local skin heating, the temporal onset of vasodilatation is delayed in the leg compared to the forearm, and sensory nerve blockade abolishes these differences. However, previous work using rapid skin heating did not allow for determination of sensory nerve influences on temperature thresholds for vasodilatation. Two sites were examined on both the forearm and leg, one control (CTRL), and one treated for sensory nerve blockade (EMLA). Skin blood flux was monitored using laser-Doppler probes, with heaters controlling local skin temperature (Tloc). Tloc was increased from 32-44 °C (+1 °C·10 min(-1)). Stimulus-response curves were constructed by fitting a four-parameter logistic function. EMLA significantly increased Tloc onset in the forearm (CTRL=35.3 ± 0.4 °C; EMLA=36.8 ± 0.7 °C) and leg (CTRL=36.5 ± 0.4 °C; EMLA=38.4 ± 0.5 °C; both P<0.05). At both CTRL and EMLA, Tloc onset was higher in the leg compared to the forearm (both P<0.05). In the forearm, median effective temperature to elicit 50% vasodilatation (ET50) was similar between sites (CTRL=39.7 ± 0.3 °C; EMLA=40.2 ± 0.4 °C; P=0.09); however, in the leg, EMLA significantly increased ET50 (CTRL=40.2 ± 0.3 °C; EMLA=41.0 ± 0.3 °C)(P<0.05). At CTRL sites, no limb difference was observed for ET50 (P=0.06); however, with EMLA, ET50 was significantly higher in the leg (P<0.05). EMLA significantly increased the gain of the slope at the forearm, (CTRL=0.31 ± 0.01%CVCmax·°C(-1); EMLA=0.45 ± 0.07%CVCmax·°C(-1)), and leg (CTRL=0.37 ± 0.05%CVCmax·°C(-1); EMLA=0.54 ± 0.04%CVCmax·°C(-1))(both P<0.05). At CTRL sites, the gain was significantly higher in the leg (P<0.05); however, for EMLA, no significant limb difference existed (P=0.10). These data indicate that the onset of vasodilatation occurs at a lower temperature in the forearm than the legs, and sensory nerves play an important role in both limbs.

Neuropeptide Y not involved in cutaneous vascular control in young human females taking oral contraceptive hormones

We previously reported that the cutaneous vasodilator response to local warming in males required noradrenaline (NA) and neuropeptide-Y (NPY). Animal work has shown no role for NPY in female vascular control. We investigated the contribution of NA and NPY in human female cutaneous vascular control. Nine female and nine male participants volunteered. To elucidate whether synthetic oestrogen and progesterone altered cutaneous vascular responses, females were tested in high-hormone (HH) and low-hormone (LH) phases of oral contraceptive pill (OCP). Skin blood flow was assessed by laser-Doppler flowmetry and expressed as cutaneous vascular conductance (CVC). Treatments were: control, combined yohimbine and propranolol (YP), BIBP-3226, and bretylium tosylate (BT). YP and BT increased basal CVC (p<0.05) relative to control sites in both HH and LH phases; though, BIBP-3226 had no effect in either phase (both p>0.05). Males basal CVC was increased at all treated sites compared to control sites (all p<0.05). YP and BT treated sites were higher in HH compared to LH (p<0.05). YP and BT treatment reduced the local warming-induced vasodilatation compared to control sites (p>0.05) in both HH and LH phases; whereas, BIBP-3226 treatment had no effect (p>0.05). In males, the vasodilatation achieved at all treated sites was reduced compared to the untreated control site (p<0.05). Data indicate that NA, not NPY, regulates basal skin blood flow and contributes to the vasodilator response to local warming in young females; however, both NA and NPY play a role in both basal and heat-induced cutaneous responses in males.

The contribution of sensory nerves to cutaneous vasodilatation of the forearm and leg to local skin warming

Purpose The initial cutaneous vasodilatory response to local skin heating is larger in the forearm than the leg. While the initial vasodilatation of the forearm to local heating is primarily dependent on sensory nerves, their role in the leg is unknown. We compared the contribution of sensory nerves in driving the cutaneous vasodilatory response of the forearm and leg to local heating using local anaesthetic (EMLA) cream.

REDUCED CEREBRAL BLOOD FLOW WITH ORTHOSTASIS PRECEDES HYPOCAPNIC HYPERPNEA, SYMPATHETIC ACTIVATION AND POTS

Hyperventilation and reduced cerebral blood flow velocity can occur in postural tachycardia syndrome (POTS). We studied orthostatically intolerant patients, with suspected POTS, with a chief complaint of upright dyspnea. On the basis of our observations of an immediate reduction of cerebral blood flow velocity with orthostasis, we hypothesize that the resulting ischemic hypoxia of the carotid body causes chemoreflex activation, hypocapnic hyperpnea, sympathetic activation, and increased heart rate and blood pressure in this subset of POTS. We compared 11 dyspneic POTS subjects with 10 healthy controls during a 70° head-up tilt. In POTS subjects during initial orthostasis before blood pressure recovery; central blood volume and mean arterial pressure were reduced (P<0.025), resulting in a significant (P<0.001) decrease in cerebral blood flow velocity, which temporally preceded (17±6 s; P<0.025) a progressive increase in minute ventilation and decrease in end tidal CO2 (P<0.05) when compared with controls. Sympathoexcitation, measured by muscle sympathetic nerve activity, was increased in POTS (P<0.01) and inversely proportional to end tidal CO2 and resulted in an increase in heart rate (P<0.001), total peripheral resistance (P<0.025), and a decrease in cardiac output (P<0.025). The decrease in cerebral blood flow velocity and mean arterial pressure during initial orthostasis was greater (P<0.025) in POTS. Our data suggest that exaggerated initial central hypovolemia during initial orthostatic hypotension in POTS results in reduced cerebral blood flow velocity and postural hypocapnic hyperpnea that perpetuates cerebral ischemia. We hypothesize that sustained hypocapnia and cerebral ischemia produce sympathoexcitation, tachycardia, and a statistically significant increase in blood pressure.

Reduced Cerebral Blood Flow With Orthostasis Precedes Hypocapnic Hyperpnea, Sympathetic Activation, and Postural Tachycardia SyndromeNovelty and Significance

Hyperventilation and reduced cerebral blood flow velocity can occur in postural tachycardia syndrome (POTS). We studied orthostatically intolerant patients, with suspected POTS, with a chief complaint of upright dyspnea. On the basis of our observations of an immediate reduction of cerebral blood flow velocity with orthostasis, we hypothesize that the resulting ischemic hypoxia of the carotid body causes chemoreflex activation, hypocapnic hyperpnea, sympathetic activation, and increased heart rate and blood pressure in this subset of POTS. We compared 11 dyspneic POTS subjects with 10 healthy controls during a 70° head-up tilt. In POTS subjects during initial orthostasis before blood pressure recovery; central blood volume and mean arterial pressure were reduced (P<0.025), resulting in a significant (P<0.001) decrease in cerebral blood flow velocity, which temporally preceded (17±6 s; P<0.025) a progressive increase in minute ventilation and decrease in end tidal CO2 (P<0.05) when compared with controls. Sympathoexcitation, measured by muscle sympathetic nerve activity, was increased in POTS (P<0.01) and inversely proportional to end tidal CO2 and resulted in an increase in heart rate (P<0.001), total peripheral resistance (P<0.025), and a decrease in cardiac output (P<0.025). The decrease in cerebral blood flow velocity and mean arterial pressure during initial orthostasis was greater (P<0.025) in POTS. Our data suggest that exaggerated initial central hypovolemia during initial orthostatic hypotension in POTS results in reduced cerebral blood flow velocity and postural hypocapnic hyperpnea that perpetuates cerebral ischemia. We hypothesize that sustained hypocapnia and cerebral ischemia produce sympathoexcitation, tachycardia, and a statistically significant increase in blood pressure.