According to a recent hypothesis HIV-associated adipose redistribution syndrome (HARS) may result from an imbalance between sympathetic and parasympathetic tone within subcutaneous and visceral adipose tissues, mediated by antiretroviral therapy-induced selective damage of autonomic pathways . In particular, a relative dominance of sympathetic over parasympathetic tone in subcutaneous adipose tissue could induce selective subcutaneous fat loss.
To test the hypothesis that HARS results from differential changes in sympathetic nervous system (SNS) activity to relevant tissues such as fat and muscle, we studied three groups of male subjects: seven HIV-1-infected individuals with HARS who had previously participated in a trial assessing the effect of protease inhibitor withdrawal on HARS [2–4] (HARS patients, currently treated with three nucleoside analogue reverse transcriptase inhibitors, all with HIV-1 RNA < 50 copies/ml), seven age and body mass index-matched healthy volunteers (control subjects), and seven similarly matched asymptomatic, therapy-naive, HIV-1-infected patients (HIV patients).
We measured interstitial noradrenaline levels in the periumbilical subcutaneous adipose tissue and skeletal muscle tissue (quadriceps of the right leg), using microdialysis to provide an index of selective fat and muscle sympathetic activity . Global SNS activity was assessed by muscle sympathetic nerve activity (MSNA, microneurography) and the measurement of arterial and venous plasma noradrenaline . Cardiovascular sympathetic activity was measured by power spectral analysis of the heart rate and systolic blood pressure. All measurements were performed under baseline conditions and during sympathetic stimulation (lower body negative pressure of −25 mmHg for 30 min or cold pressor test).
In HARS patients, global sympathetic activity as reflected by plasma noradrenaline levels and power spectral analysis was normal. However, sympathetic nerve traffic (MSNA) was lower (Table 1).
At the tissue level, HARS patients had a significantly higher skeletal muscle noradrenaline concentration than control subjects (1.51 ± 0.38 versus 0.74 ± 0.10, P < 0.05, Table 1). The subcutaneous adipose tissue noradrenaline concentration also tended to be higher in HARS patients (1.96 ± 0.72 versus 0.83 ± 0.23 nmol/l, P = 0.07, Table 1). The muscle/fat noradrenaline ratio (M/F NA) was significant lower in HARS patients compared with control subjects (M/F NAHARS patients 0.88 ± 0.19 versus M/F NAcontrolsubjects 1.75 ± 0.33, P < 0.05), indicating relatively high noradrenaline levels in subcutaneous fat tissue, compared with skeletal muscle.
For all indices of both global and local sympathetic activity, except for venous noradrenaline levels, HIV patients showed similar results to the control subjects.
In response to sympathetic stimulation, plasma noradrenaline concentrations increased significantly in all three groups. This increase was similar in HARS patients and control subjects. In response to sympathetic stimulation by the cold pressor test, MSNA increased in both groups, but the increase was larger in the HARS patients (Table 1).
Muscle and adipose tissue noradrenaline levels did not change significantly in response to lower body negative pressure, neither did the muscle/fat noradrenaline ratio in HARS patients.
The results of this study indicate that the SNS activity in muscle and subcutaneous adipose tissue is increased in HARS patients, but not in HIV-infected patients without HARS. The overall whole-body and cardiovascular SNS activity is normal in HARS patients.
Up to now, only a few studies have reported on SNS activity in HIV patients or HIV patients with HARS, and have reported conflicting results. Mittal et al.  recently showed a reduced heart rate variability in asymptomatic, therapy-naive HIV-1-infected individuals. In contrast, Becker et al.  found no difference in any heart rate variability parameter in HIV-infected patients. Our results obtained by combining different techniques, do not provide any evidence of an increased SNS activity at the whole-body level in this group of patients.
The MSNA of HARS patients was significantly lower compared with both groups. The decreased MSNA at the peroneal nerve may reflect a more generalized decrease in sympathetic nerve traffic activity. Another explanation is that the lower MSNA level is caused by sympatho-inhibition by the increased interstitial noradrenaline levels.
The interstitial concentration of noradrenaline in subcutaneous fat relative to that in skeletal muscle tended to be higher in HARS patients, consistent with an increased noradrenaline content in subcutaneous fat, compared with the other groups. This finding may be consistent with a relatively local sympathetic overactivity in HARS patients, particularly within subcutaneous adipose tissue. This is consistent with the hypothesis that the peripheral lipoatrophy observed in HARS may result from selective regional changes in autonomic innervation [1,9].
How can this increased interstitial noradrenaline concentration in skeletal muscle and fat tissue be explained? Once noradrenaline is released from the nerve terminal into the synaptic cleft it can undergo reuptake into the neuron, or spill over from the synaptic cleft to the interstitium and further to the intravascular compartment. Although an increased interstitial noradrenaline concentration can be caused by an increased sympathetic firing rate, this was excluded by our findings. Alternatively, an increased interstitial noradrenaline concentration can be caused by a decrease in noradrenaline reuptake, even in the presence of a decreased sympathetic nerve firing rate to the skeletal muscle (as a result of negative feedback). Finally, even if neuronal noradrenaline reuptake is normal, intraneuronal noradrenaline metabolism by monoamine oxidase, which is located within the mitochondria may be inhibited and result in increased noradrenaline release into the synaptic cleft and subsequently in an increased interstitial noradrenaline concentration. It is tempting to speculate whether antiretroviral agents may affect either noradrenaline reuptake or monoamine oxidase activity, the latter for instance by way of nucleoside reverse transcriptase inhibitor-associated mitochondrial toxicity .
In summary, in the context of an unchanged global sympathetic activity, HIV-infected patients with HARS appear to have increased noradrenaline concentrations at the level of skeletal muscle and subcutaneous fat tissue, which may be consistent with the hypothesis that regional changes in autonomic activity contribute to the selective loss of peripheral fat as observed in HARS. These findings suggest that disturbances in local SNS activity play a role in this remarkable syndrome, but this requires further investigation.
The authors would like to thank R. Simonse and A. Jansen van Rosendaal, research nurses, for their technical assistance. They are also very grateful to H.A. Ross for the development of the microdialysis recovery technique and performing the catecholamine measurements. C.J.T. is a recipient of a clinical fellowship of the Dutch Diabetes Foundation. The Dutch Diabetes Foundation had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
1. Fliers E, Sauerwein HP, Romijn JA, Reiss P, van der Valk M, Kalsbeek A, et al
. HIV-associated adipose redistribution syndrome as a selective autonomic neuropathy. Lancet 2003; 362:1758–1760.
2. van der Valk M, Gisolf EH, Reiss P, Wit FW, Japour A, Weverling GJ, Danner SA. Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV-1 infection. AIDS 2001; 15:847–855.
3. van der Valk M, Reiss P, van Leth FC, Ackermans MT, Endert E, Romijn JA, et al
. Highly active antiretroviral therapy-induced lipodystrophy has minor effects on human immunodeficiency virus-induced changes in lipolysis, but normalizes resting energy expenditure. J Clin Endocrinol Metab 2002; 87:5066–5071.
4. van der Valk M, Allick G, Weverling GJ, Romijn JA, Ackermans MT, Lange JM, et al
. Markedly diminished lipolysis and partial restoration of glucose metabolism, without changes in fat distribution after extended discontinuation of protease inhibitors in severe lipodystrophic human immunodeficient virus-1-infected patients. J Clin Endocrinol Metab 2004; 89:3554–3560.
5. Muller M. Science, medicine, and the future: microdialysis. BMJ 2002; 324:588–591.
6. Grassi G, Esler M. How to assess sympathetic activity in humans. J Hypertens 1999; 17:719–734.
7. Mittal CM, Wig N, Mishra S, Deepak KK. Heart rate variability in human immunodeficiency virus-positive individuals. Int J Cardiol 2004; 94:1–6.
8. Becker K, Gorlach I, Frieling T, Haussinger D. Characterization and natural course of cardiac autonomic nervous dysfunction in HIV-infected patients. AIDS 1997; 11:751–757.
9. Kreier F, Fliers E, Voshol PJ, Van Eden CG, Havekes LM, Kalsbeek A, et al
. Selective parasympathetic innervation of subcutaneous and intra-abdominal fat – functional implications. J Clin Invest 2002; 110:1243–1250.
10. Lewis W, Day BJ, Copeland WC. Mitochondrial toxicity of NRTI antiviral drugs: an integrated cellular perspective. Nat Rev Drug Discov 2003; 2:812–822.