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J Neurol Neurosurg Psychiatry 82:1394-1398 doi:10.1136/jnnp-2011-300444
  • Research paper

Muscle ischaemia in patients with orthostatic hypotension assessed by velocity recovery cycles

  1. Werner Josef Z'Graggen1,3
  1. 1Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
  2. 2Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK
  3. 3Department of Neurosurgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
  1. Correspondence to Professor H Bostock, Sobell Department of Neurophysiology, Institute of Neurology, Queen Square, London WC1N 3G, UK; h.bostock{at}ion.ucl.ac.uk
  1. Contributors All authors contributed to this research paper.

  • Received 3 May 2011
  • Accepted 5 May 2011
  • Published Online First 7 June 2011

Abstract

Objective Patients with orthostatic hypotension may experience neck pain radiating to the occipital region of the skull and the shoulders while standing (so-called coat-hanger ache). This study assessed muscle membrane potential in the trapezius muscle of patients with orthostatic hypotension and healthy subjects during head-up tilt (HUT), by measuring velocity recovery cycles (VRCs) of muscle action potentials as an indicator of muscle membrane potential.

Methods Eight patients with multiple system atrophy (MSA), orthostatic hypotension and a positive history for coat-hanger pain and eight normal controls (NCs) were included in this study. Repeated VRCs were recorded from the trapezius muscle by direct muscle stimulation in the supine position and during HUT for 10 min.

Results Muscle VRC recordings did not differ between MSA patients and NCs in the supine position. During HUT, early supernormality decreased progressively and relative refractory period increased in MSA patients whereas VRC measures remained unchanged in NCs. Ten minutes after the start of HUT, early supernormality was reduced by 44% and relative refractory period was increased by 17%.

Conclusions Muscle membranes in patients with orthostatic hypotension become progressively depolarised during standing. Membrane depolarisation is most likely the result of muscle ischaemia, related to the drop in perfusion pressure caused by orthostatic hypotension. Coat-hanger ache is most likely a consequence of this muscle ischaemia.

Introduction

Cardiovascular dysautonomia resulting in orthostatic hypotension is increasingly recognised as an important non-motor feature in Parkinsonism, in atypical forms such as multiple system atrophy (MSA) and in idiopathic Parkinson's disease. Orthostatic hypotension is defined as a fall in systolic blood pressure (BP) of ≥20 mm Hg and/or a fall in diastolic BP of ≥10 mm Hg within 3 min in the upright position.1 Orthostatic hypotension may be clinically asymptomatic, but can also lead to posture-related symptoms such as dizziness, gait instability, visual or hearing disturbances, neck pain radiating to the occipital region of the skull and the shoulders (so-called coat-hanger ache) and finally loss of consciousness.2 Coat-hanger ache has been attributed to muscle hypoperfusion/ischaemia in the presence of systemic hypotension in the upright position,3–5 but so far there has been no independent evidence for muscle ischaemia in these patients.

Velocity recovery cycles (VRCs) of muscle action potentials offer a new electrophysiological approach to the investigation of muscle membrane function.6 The changes in conduction velocity of a muscle action potential as a function of the interstimulus interval after a conditioning stimulus provide an indirect measure of the afterpotential following the muscle action potential. The afterpotential and therefore the recovery cycle are strongly dependent on membrane potential, so the VRC can be used to follow the changes in membrane potential. Membrane depolarisation reduces the influx of sodium ions and increases the efflux of potassium ions during an action potential. As a consequence, depolarisation reduces the net depolarising charge left on the membrane at the end of an action potential, which is responsible for the early depolarising afterpotential. Conversely, the early depolarising afterpotential is increased if the membrane is hyperpolarised. The muscle VRC measures most sensitive to membrane potential are early supernormality (ESN), which is related to the early depolarising afterpotential, and relative refractory period (RRP). In addition, muscle VRCs exhibit a late phase of supernormality (LSN), which is probably due to potassium accumulation in the t-tubule system.6 We previously demonstrated that ischaemia progressively prolongs RRP and reduces ESN, confirming that these parameters are sensitive to membrane depolarisation.6 In addition, we found evidence that muscle membranes are depolarised in patients with chronic renal failure7 and in patients with critical illness myopathy.8

The aim of this study was to compare the changes in muscle membrane properties in patients with orthostatic hypotension with those in healthy subjects. Muscle VRCs were recorded from the trapezius muscle in the supine position and during a tilt manoeuvre that provokes coat-hanger ache. The cephalad region of the trapezius muscle was chosen because this part of the muscle is usually the site where the coat-hanger ache occurs.

Methods

Subjects and ethical approval

Eight patients with MSA (four women and four men; mean age 65.5 years, range: 55–80 years) and eight healthy subjects (five women and three men; mean age 54.8 years, range: 32–70 years) not differing significantly in age (unpaired t test: p>0.05) participated in this study. All patients had documented sympathetic and parasympathetic dysfunction with severe symptomatic orthostatic hypotension, including a positive history of coat-hanger ache. All patients reported daily occurrence of coat-hanger ache during mild to moderate physical activities, for example, standing still for a few minutes, climbing a flight of stairs or performing household tasks such as hanging the washing. Any vasoactive medication was stopped at least five half-lives prior to testing. All procedures were approved by the local ethics committee (Kantonale Ethikkommission Bern, Switzerland) and conformed to the Declaration of Helsinki. Patients and subjects gave written informed consent to participate in the study.

Tilt table testing

All studies were carried out in a dedicated autonomic laboratory. Patients and subjects had nil by mouth during 6 h before testing. Patients and subjects were comfortably placed on an electrical tilt table in the supine position. Beat-to-beat BP and heart rate (HR) were measured with the Finometer device (Finapres Medical Systems BV, Arnhem, The Netherlands) on the left arm. At the start of the assessment, intermittent brachial BP and HR values were simultaneously recorded using an automated Dinamap Pro 100 sphygmomanometer (GE Medical Systems, Tampa, Florida, USA) on the right arm for 10 min. A maximal and stable difference of ±5 mm Hg between Finometer and Dinamap readings was tolerated to obtain further measurements using the Finometer device only. Before recording the muscle VRCs, a pressure-controlled Valsalva manoeuvre (40 mm Hg for 15 s) was performed in the supine position to test for the integrity of sympathetic and parasympathetic cardiovascular functions. Valsalva ratio was calculated as the highest HR at the end of active pressing divided by the lowest HR during recovery. In addition, the beat-to-beat BP profile during the Valsalva manoeuvre was analysed qualitatively. At the end of this period, recording of the muscle VRC was started. After BP and HR settled again and stable muscle VRCs were achieved, head-up tilt (HUT) with a tilt angle of 60° was applied for a maximum of 10 min. HUT was terminated earlier if severe presyncope or syncope occurred.

Multi-fibre VRCs

Stimulation

This study was performed using a recently described protocol.6 A monopolar insulated needle electrode served as cathode (TECA, VIASYS Healthcare, Madison, Wisconsin, USA). This needle was inserted perpendicularly into the trapezius muscle along the linea nuchalis at about one-third of the distance from the acromion. A non-polarisable surface electrode served as anode (Red Dot, 3M Health Care, Borken, Germany) and was placed at about 1 cm lateral to the cathode. For stimulation, rectangular current pulses of 0.05 ms duration, generated by a computer, were converted to current with an isolated linear bipolar constant-current stimulator (DS5, Digitimer Ltd, Welwyn Garden City, Hertfordshire, UK).

Recording

For recordings, a concentric 30G EMG electrode (Medtronic, Skovlunde, Denmark) was used. The needle electrode was inserted into the trapezius muscle at about 15–20 mm further medial to the stimulating electrodes along the linea nuchalis. The needle was repositioned until a stable monophasic electric response could be recorded with stimulus intensities of less than 15 mA. The signal was amplified (gain 1000, bandwidth 1.6 Hz to 2 kHz) and digitised (National Instruments NI DAQCARD-6062E, National Instruments Europe Corp., Debrecen, Hungary) with a sampling rate of 20 kHz. Both stimulation and recording were controlled by QTRAC software (written by H. Bostock, copyright Institute of Neurology, London, UK), using the menu-driven recording protocol 1200RCM.QRP.

Multi-fibre VRCs with test stimuli alone and single conditioning stimuli were recorded repeatedly for at least 2 min in the supine position and during the whole extent of HUT. The test stimuli were delivered every 1.5 s. The interval between the conditioning and the test stimulus was varied in 15 steps between 1000 and 2 ms in an approximately geometric series.6 This protocol allowed the estimates of RRP, ESN and LSN every 30 s.

Data analysis

The haemodynamic parameters analysed were HR, systolic BP and diastolic BP. Beat-to-beat haemodynamic parameters were determined at 2 min intervals for the last 2 min of supine rest and during HUT.

Muscle VRC data were acquired and analysed with QTRAC, using the features previously described in detail.6 In brief, stimuli were presented sequentially on QTRAC channels 1 and 2, with the test stimulus at 1100 ms preceded by a conditioning stimulus on channel 2 only. Latencies of elicited responses were measured from the start of the test stimulus to the negative peak of the muscle action potential. The effect of the conditioning stimulus on the latency of the test response was calculated as the percentage change in latency, compared with the preceding trial with test stimulus alone. Latency changes as a function of interstimulus interval were converted to slowing as a function of the inter-spike interval (ISI) to take into account the changes in ISI with conduction distance. This conversion has no effect on RRP or on ESN.6 9

Repeated VRCs were analysed over intervals of 2 min using the QTRAC software. The following measures were derived from the median muscle VRC recordings: (1) RRP in milliseconds, that is, the interpolated ISI at which the velocity first reached its unconditioned value; (2) ESN, measured as the peak percentage increase in velocity at ISIs shorter than 15 ms; (3) LSN, measured as the average percentage increase in velocity at ISIs between 50 and 150 ms. Statistical analyses were performed by the QTRAC data analysis software, which was also used to generate the figures. Because the MSA patient data were expected to be more variable than the control data, and because some of the data sets were not normally distributed, group means were compared by applying the unequal variance two-tailed t test (Welch–Satterthwaite test) to the ranked data.10

Results

All patients fulfilled the criteria for orthostatic hypotension with concomitant supine hypertension, whereas supine BP and orthostatic reaction were normal in all controls (table 1). In MSA patients, Valsalva ratio was reduced to 1.1±0.04 (mean±SEM, normal range >1.2) with an abnormal BP profile. In controls, Valsalva ratio (1.6±0.1) and BP profile during Valsalva manoeuvre were normal.

Table 1

Demographic data and screening autonomic function testing in patients with multiple system atrophy (n=8) and healthy subjects (n=8)

In three patients, HUT had to be terminated after 6 min because of severe presyncope. The other five patients tolerated HUT for 10 min. All patients developed coat-hanger ache during HUT. The mean time of onset of coat-hanger ache after the start of HUT was 6.7 min (range 2.3–9.6 min). All healthy subjects tolerated HUT for 10 min without orthostatic symptoms. All healthy subjects and MSA patients tolerated the recording of muscle VRCs well and considered the procedure as not painful. Special attention had to be given to the positioning of the stimulation and recording needle electrodes in order to prevent the displacement of the electrodes during movement of the tilt table.

Multi-fibre VRCs

Figure 1 shows mean VRCs±SEM for the supine position and during HUT for MSA patients and healthy subjects. Systolic and diastolic BP in the supine position and during HUT are shown in figure 2A,B. In the supine position, VRCs of MSA patients and NCs overlapped. While VRC curves did not change during HUT in NCs, there was a progressive shift of the VRC curves to the right and upwards in MSA patients. This finding is reflected in a progressive decrease in ESN during HUT in MSA patients (figure 2C) (ESN in the supine position—MSA patients: 7.96±1.13%, NCs: 7.76±0.43%, p>0.05; ESN after 10 min HUT—MSA patients: 3.56±0.77%, NCs: 7.86±0.63%, p<0.01). In parallel, RRP increased during HUT progressively in MSA patients (figure 2D) (RRP in the supine position—MSA patients: 4.27±0.29 ms, NCs: 3.76±0.14 ms, p>0.05; RRP after 10 min HUT—MSA patients: 5.00±0.42 ms, NCs: 3.97±0.22 ms, p<0.05). Although LSN decreased during HUT in MSA patients and remained unchanged in NCs, LSN was not significantly different between MSA patients and NCs at any time point (figure 2F). The mean ESN of the MSA patients showed a significant linear decline with the time of HUT, whereas RRP and ISI for peak supernormality showed a significant increase, and the slopes of these relationships with the time of HUT differed significantly from the NCs (table 2). By contrast, there was no significant difference in slope for LSN between MSA patients and NCs.

Figure 1

Muscle velocity recovery cycles (VRCs) following single conditioning stimulus in patients with MSA, compared with those in normal subjects. VRCs are expressed as velocity slowing (so that supernormality shows a downward trend). (A) Means and SE bars for muscle VRCs in eight patients with MSA, recorded in the supine position (black filled triangles), compared with eight normal control subjects (grey open circles). (B—F) Mean and SE bars from same MSA patients (black filled triangles) and healthy subjects (grey open circles) 2 min (B), 4 min (C), 6 min (D), 8 min (E) and 10 min (F) after the start of HUT.

Figure 2

Differences in blood pressure (BP) and muscle velocity recovery cycle parameters between MSA patients and healthy subjects in the supine position and during head-up tilt of 10 min: (A) systolic BP (mm Hg), (B) diastolic BP (mm Hg), (C) early supernormality (peak % increase in velocity for interstimulus intervals up to 15 ms), (D) relative refractory period (ms), (E) time to peak in early supernormality (ms), (F) late supernormality due to one conditioning pulse (%). Error bars indicate SE of the mean. Asterisks indicate probability (p) values for two-tailed unequal variance t tests (Welch–Satterthwaite test) on the ranked data: *p<0.05, **p<0.01. NS, not significant.

Table 2

Linear changes in mean excitability properties with the time of head-up tilt

Discussion

In this study, direct muscle stimulation and multi-fibre recording were used to assess muscle VRCs from the trapezius muscle in MSA patients with orthostatic hypotension and a positive history for coat-hanger ache. We found that RRP progressively increases and ESN decreases during HUT in MSA patients compared with NCs (figure 1), resulting in a shift of the VRC curve to the right and upwards. A similar shift of the VRC curve was observed earlier in healthy subjects during limb ischaemia and was attributed to membrane depolarisation.6 Membrane depolarisation reduces the number of available sodium channels, so refractoriness increases and the depolarising afterpotential is reduced, leading to a reduction in supernormality.6 The changes in ESN and RRP observed after 10 min of orthostatic hypotension are comparable with those seen in our earlier study after about 2.5 min of absolute limb ischaemia, induced by inflating a pressure cuff above systolic BP.6 Hence, it can be concluded that the drop in perfusion pressure because of orthostatic hypotension is sufficient to cause muscle ischaemia in MSA patients.

In the current study, BP was always measured at the level of the heart and therefore the perfusion pressure of the trapezius muscle was overestimated. To calculate the true perfusion pressure in the 60° HUT position, a correction for the influence of gravity has to be taken into account. The cephalad part of the trapezius muscle is roughly 10–15 cm above the heart level. As a consequence, the true perfusion pressure in this part of the muscle is about 10 mm Hg lower than the systemic BP.

This study gives strong evidence that muscle ischaemia occurs in the presence of systemic orthostatic hypotension. The appearance of pain in the occipital region of the skull and the shoulders (coat-hanger ache) is most likely the consequence of ischaemia in a tonically active muscle, as previously suggested.3–5 The ischaemic muscle pain is probably due to the combined action on intramuscular nerve fibres of lactic acid, released during ischaemia, and ATP, released when an ischaemic muscle is activated. It has recently been shown that active ischaemic muscles release ATP, which increases the sensitivity to lactic acid of ASIC3 (acid-sensing ion channel number 3) channels on nociceptors.11

In conclusion, our data indicate that muscle fibres in patients with orthostatic hypotension have a normal membrane potential in the supine position, but become progressively depolarised in the upright position, most likely due to the drop in perfusion pressure and consequent ischaemia. Hence, coat-hanger ache is most likely the result of muscle ischemia.

Footnotes

  • Funding The study was supported by a grant from Parkinson Schweiz and from the Bern University Research Foundation, University of Bern, Bern, Switzerland.

  • Competing interests None.

  • Ethics approval This study was approved by Kantonale Ethikkommission Bern, Switzerland.

  • Provenance and peer review Not commissioned; externally peer reviewed.

References

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