Neurogenic hyperadrenergic orthostatic hypotension: a newly recognized variant of orthostatic hypotension in older adults with elevated norepinephrine (noradrenaline)

Abstract

Patients with neurogenic orthostatic hypotension (OH) typically have impaired sympathetic nervous system tone and therefore low levels of upright plasma norepinephrine. We report a subset of patients who clinically have typical neurogenic OH but who paradoxically have elevated upright levels of plasma norepinephrine. We retrospectively studied 83 OH patients evaluated at the Vanderbilt Autonomic Dysfunction Center between August 2007 and May 2013. Based upon standing norepinephrine, patients were dichotomized into a hyperadrenergic orthostatic hypotension group (hyperOH: upright NE ≥3.55 nmol/L [600 pg/mL], n=19) or a non-hyperadrenergic orthostatic hypotension group (nOH: upright NE < 3.55 nmol/L [600 pg/mL], n=64). Medical history and data from autonomic testing, including the Valsalva maneuver (VM), were analyzed. HyperOH patients had profound orthostatic falls in blood pressure, but less severe than in nOH (change in SBP: −53±31 mmHg vs. −68±33 mmHg, P=0.050; change in DBP: −18±23 mmHg vs. −30±17 mmHg, P=0.01). The expected compensatory increase in standing heart rate was similarly blunted in both hyperOH and nOH groups (84±15 bpm vs. 82±14 bpm; P=0.6). HyperOH patients had less severe sympathetic failure as evidenced by smaller falls in DBP during phase 2 of VM, and a shorter VM phase 4 blood pressure recovery time (16.5±8.9 sec vs. 31.6±16.6 sec; P<0.001) than nOH patients. Neurogenic hyperOH patients have severe neurogenic orthostatic hypotension, but have less severe adrenergic dysfunction than nOH patients. Further work is required to understand if hyperOH patients will progress to nOH or if this represents a different disorder.

Orthostatic Circulatory Disorders: From Nosology to Nuts and Bolts

“…In the hyperadrenergic form, a larger rise in plasma norepinephrine at the nadir denotes a robust sympathetic response. 78 In OI, the mean decrease in BP at the nadir is generally more modest than in neurogenic OH, and a large percent of the subjects present with VVS.…”

“…In the case of neurogenic OH, and in the asymptomatic elderly, 109 both the depth of the BP nadir in phase 2 and the pressure recovery time correlate inversely with muscle nerve sympathetic activity. 64 In hyperadrenergic OH, 78 the decrease in BP at the nadir is less than in hypoadrenergic comparators. In the hyperadrenergic form, a larger rise in plasma norepinephrine at the nadir denotes a robust sympathetic response.…”

“…In the subject with orthostatic hypotension (OH), the nadir is 60 mm Hg below baseline, and the pressure recovery time is markedly prolonged. If this were a patient with the hyperadrenergic form of OH, 78 or with orthostatic intolerance, 81 the nadir would be intermediate between the normal and the neurogenic OH pattern. Close inspection shows that the longest beat-to-beat interval in phase 4 (overshoot) is greater than the shortest beat-to-beat interval in phase 2.…”

Orthostatic hypotension for the cardiologist

“…In nOH, the normal physiologic BP and HR response is either severely dysfunctional or outright absent. In conditions such as multiple system atrophy (MSA), pure autonomic failure (PAF), dementia with Lewy bodies, or Parkinson’s disease, there is a characteristic profound deficiency in norepinephrine release during standing in over 75% of patients [11,12]. This deficiency in norepinephrine release reflects an inability of sympathetic vasoconstrictor neurons to fire adequately, which is responsible for the lack of peripheral vasoconstriction and consequent hypotension (Figure 1).…”

Hyperadrenergic Orthostatic Hypotension With Pure Peripheral Sympathetic Denervation Associated With Sjogren’s Syndrome

“…In addition to the fact of SNS denervation preferentially occurred in the lower limbs showed by Dr. David Streeten, they concluded hyper OH is a clinical expression of partial autonomic neuropathy of the peripheral sympathetic nerves innervating the lower extremities, as well as certain types of neuropathy such as diabetic neuropathy showed length-dependent polyneuropathy in its earlier stage. When the lower extremities have been affected but the upper extremities not yet, the excessive amounts of NE may be produced with compensation by the sympathetic nerves innervating upper extremities via the baroreflex [3,4]. Thus, hyper OH may be an earlier form of typical OH, but the relationship between intrinsic diseases and hyper OH remains unclear.…”