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Rheumatology Advance Access originally published online on April 22, 2008
Rheumatology 2008 47(7):1012-1017; doi:10.1093/rheumatology/ken117
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Blunted increase of digital skin vasomotion following acetylcholine and sodium nitroprusside iontophoresis in systemic sclerosis patients

M. Rossi, L. Bazzichi, C. Di Maria, F. Franzoni, K. Raimo, A. Della Rossa, G. Santoro and S. Bombardieri

Department of Internal Medicine, University of Pisa, Pisa, Italy.

Correspondence to: M. Rossi, Department of Internal Medicine, University of Pisa, Via Roma 67, 56100 Pisa, Italy. E-mail: mrossi{at}int.med.unipi.it


   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
 References
 
Objectives. To test the hypothesis that finger skin vasomotion (FSV), a known factor influencing microvascular blood flow motion, is impaired in SSc patients. Possible relationships between FSV abnormalities and the severity and/or activity of SSc were also investigated.

Methods. FSV was investigated by means of spectral Fourier analysis of finger skin laser Doppler flowmetry (LDF) tracing, recorded before and following acetylcholine (ACh) or sodium nitroprusside (SNP) iontophoresis in 26 SSc patients and in 20 age-matched healthy controls. The power spectral density (PSD) of the 0.01–0.02, 0.02–0.06 and 0.06–0.2 Hz LDF oscillations (related to endothelial-, sympathetic- and myogenic-dependent FSV, respectively) was measured in PU2 (perfusion units)/Hz.

Results. Compared with controls, SSc patients exhibited a significantly lower post-ACh and/or post-SNP percentage increase in PSD of 0.01–0.02 Hz (492 ± 297% vs 283 ± 167%; P < 0.005), of 0.02–0.06 Hz (336 ± 205% vs 239 ± 170%; P < 0.05) and of 0.06–0.2 Hz (223 ± 91% vs 194 ± 227%; P < 0.01) skin LDF oscillations. The post-SNP normalized PSD value of the 0.01–0.02 Hz and of the 0.02–0.06 Hz LDF oscillations was negatively related to SSc severity index (r = –0.407, P < 0.05 and r = –459, P < 0.05, respectively).

Conclusions. This study showed a selective abnormality of the endothelial, sympathetic and myogenic-dependent FSV in SSc patients, consistent with a parallel endothelial, sympathetic and myogenic macrovascular dysfunction. This study also suggests a possible role of endothelial and sympathetic dysfunction in the progression of SSc.

KEY WORDS: Finger skin vasomotion, Flow motion, Systemic sclerosis, Laser Doppler flowmetry, Spectral Fourier analysis, Acetylcholine, Sodium nitroprusside, Iontophoresis


   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Conclusions
 References
 
A number of studies [1–6] based on laser Doppler flowmetry (LDF) investigation of skin microcirculation have been recently performed in patients affected by SSc. The aim of these studies was to evaluate skin microcirculatory abnormalities in SSc, which have been suggested to be a primary vascular disease [7, 8] and to improve the understanding of its complex pathophysiology. In particular, LDF, together with iontophoresis of the endothelial-dependent vasodilator acetylcholine (ACh) and the endothelial-independent vasodilator sodium nitroprusside (SNP), has been used in SSc patients for evaluating the skin endothelial function [1–6]. The majority of these studies showed a reduced skin vasodilator response to both ACh and SNP iontophoresis in SSc patients [1, 2, 4, 5], a finding which cannot be formally ascribed to endothelial dysfunction, but only to a reduced skin microvascular wall compliance. A selective reduction in the skin vasodilator response to ACh, consistent with endothelial dysfunction, has been demonstrated only in two studies [3, 6]. Different LDF apparatus and iontophoresis protocols used in these studies, as well as different clinical characteristics of the studied patients, may explain these discrepancies.

More recently, spectral analysis of LDF tracings has been used for examining the cyclical variation in blood flow [9–12], the so-called flow motion, which has been demonstrated to be partly related to the periodic contraction and dilation of arterioles, the so-called vasomotion [13–15]. Vasomotion and the consequent skin blood flow motion have been suggested to have an important role in increasing the mean blood flow in the microvascular network by the functional recruitment of previously inactive microvascular units [16–18].

Spectral analysis of skin LDF tracing allows different spectral frequency ranges of flow motion to be identified in the total spectrum of 0.01–1.6 Hz. Three of them have been demonstrated to be selectively related to different mechanisms that control vasomotion: the LDF oscillations in the frequency range of 0.01–0.02 Hz, related endothelial activity [9–12], the LDF oscillations in the frequency range of 0.02–0.06, related to the local sympathetic activity [19, 20] and the LDF oscillations in the frequency range of 0.06–0.2 Hz, related to the spontaneous activity of the microvessel smooth muscle cells [9, 10]. The spectral amplitude of each of these LDF frequency range oscillations has been suggested to reflect the efficiency of the corresponding vasomotion mechanism [9–12], Thus, this method has been recently proposed as a useful tool for investigating skin microvascular endothelial, sympathetic and myogenic function in clinical setting [11, 21]. A specific pattern of perturbed skin vasomotion was observed in hypertensive patients [21] and in the end-stage renal disease patients [22] during post-ischaemic reperfusion, as well as in diabetes patients under basal conditions [23, 24] in studies based on the spectral analysis of skin LDF tracing. On the contrary, a recent study based on the same method [25] showed no finger skin vasomotion (FSV) abnormalities in SSc patients under basal conditions. Nevertheless, according to dysregulated endothelial and smooth muscle control of skin microvascular tone found in SSc patients in some previous studies [1, 3, 6], we hypothesised that SSc patients could show a perturbed FSV when investigated under effect of vasomotor stimuli. To test this hypothesis, we performed spectral Fourier analysis of the finger skin LDF tracing registered either under basal conditions or following ACh or SNP iontophoresis in a cohort of SSc patients. A further aim of our study was to evaluate possible relationships between hypothetical skin vasomotion abnormalities and the severity and/or activity of SSc.


   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Conclusions
 References
 
Subjects
The present study included 26 patients (22 females, 2 males; aged 55 ± 13 yrs) affected by SSc, according to the American Rheumatism Association Subcommittee for Scleroderma Criteria [26]. In all patients, RP was present at the time of the diagnosis of SSc. The extent of skin sclerosis was limited in 16 patients and diffuse in 10 patients. All patients were positive for ANA and seven of them were positive for anti-topoisomerase I (Scl-70) antibodies. Interstitial lung fibrosis was demonstrated in 22 of the studied patients. In all patients, nail-fold capillary microscopy examination showed a typical scleroderma pattern—that is, reduced capillary number and severely enlarged loops. The studied patients had an SSc severity score index [27] of 5.6 ± 2.9 (range: 1–12) and an SSc activity score index [28] of 2.8 ± 1.7 (range: 0–6). Seven patients had digital ulcers at the time of the study and two of them had history of it. No patients had diabetes mellitus, heart failure, renal failure, arterial hypertension or any other disease possibly responsible for microangiopathy. None of the patients was a smoker. Pharmacological treatment consisted of nifedipine in 10 patients, MTX in 3 patients, methylprednisolone in 3 patients and iloprost in 6 patients. Patients treated with nifedipine, methylprednisolone or MTX were studied after a 1 day of therapy discontinuation. Patients treated with iloprost were studied after 1 week of this drug discontinuation. Twenty healthy non-smoker subjects (15 females, 5 males; aged 56 ± 13 yrs) were also recruited to form the control group. The clinical features of SSc patients and control subjects are reported in Table 1.


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  		TABLE 1. Main clinical features of SSc patients and control subjects recruited in the study

 
The study protocol was approved by the local ethics committee and conformed to the principles outlined in the Declaration of Helsinki. All enrolled subjects gave their written informed consent to participate in the study.

Measurement of digital skin blood flux
Digital skin blood flux was measured by means of an LDF apparatus (Periflux PF4001, Perimed, Järfälla, Sweden) with the following characteristics: 780 nm wavelength, 10–19 kHz bandwidth, 0.1 s time constant, 32 Hz sampling frequency. Calibration was performed using colloidal latex particles whose Brownian motion provided the standard value. The LDF outputs were recorded continuously by an interfaced computer (Acer, Travelmate 202 T, Taipei, Taiwan) equipped with Perisoft dedicated software. This software allows measurement of LDF output in conventional perfusion units (PU): 1 PU = 10 mV. Investigations were performed in a quiet room with controlled temperature (22–24°C). All subjects fasted for at least 2 h before the study and refrained from caffeine and alcohol from midnight before the study day. Each subject had 20 min of acclimatization in supine position before the test.

ACh and SNP iontophoresis
ACh and SNP were delivered to the skin by means of iontophoresis following a procedure previously described [12]. Iontophoresis was performed by means a battery-powered iontophoresis controller (Periiont 328, Perimed), equipped with a drug delivery electrode (PF 383, Perimed). An indifferent electrode (PF 384, Perimed) was also used to provide the current needed for ACh or SNP delivery.

ACh was delivered using a drug delivery electrode filled with 0.05 ml of 1% ACh solution, which was attached on the dorsal aspect of the third right finger by a double-sided adhesive disc. An indifferent electrode was attached on the dorsal aspect of the right hand. ACh was then delivered by means of nine iontophoretic pulses of 0.1 mA for 20 s with a 60-s interval between one and the other pulse. After ACh iontophoresis procedure, SNP was delivered using another drug delivery electrode filled with 0.05 ml of 1% SNP solution, which was attached to the dorsal aspect of the second right finger. An indifferent electrode was attached on the dorsal aspect of the right hand. SNP was then delivered by means of seven iontophoresis pulses of 0.2 mA for 20 s with a 180-s interval between one and the other pulse. Skin vasodilator response to each iontophoresis pulse was measured in PU as mean value during each interval from one pulse to the following pulse, as well as during 2 min following the last pulse.

Investigation of digital skin vasomotion
Digital skin vasomotion was investigated before and following ACh and SNP iontophoresis by means of the spectral Fourier analysis of the skin LDF signal, as previously reported [12, 21, 23–25]. Spectral Fourier analysis was performed on an LDF tracing segment registered during 10 min under basal conditions, immediately before ACh or SNP iontophoresis, as well as on a 10-min ‘steady state’ LDF tracing segment obtained during ACh or SNP iontophoresis.

Following previous studies [9–12], the LDF frequency range from 0.01 to 1.6 Hz was divided into five sub-ranges: the 0.01–0.02 Hz sub-range (associated with the endothelial-dependent vasomotion activity), the 0.02–0.06 Hz sub-range (associated with the sympathetic-dependent vasomotion activity), the 0.06–0.2 Hz sub-range (related to the myogenic-dependent vasomotion activity), the 0.2–0.6 Hz sub-range (related to the respiratory activity) and the 0.6–1.6 Hz sub-range (synchronous with heart activity).

For the spectral Fourier analysis of the LDF signal we used a Perisoft dedicated software [12, 21] that measures in PU2/Hz the power spectral density (PSD) of each LDF frequency range investigated. This software uses the basic fast Fourier transform algorithm, in which the beginning and end of each LDF sub-range investigated are attenuated by means of a windowing Parzen function to avoid the well-known leakage phenomenon (frequency components in the spectra leaking into other frequencies). In the windowing Parzen function, a short-time Fourier transform, with a different window length for each sub-range, was used. The highest PSD identified in each frequency range was considered as the PSD value of that frequency range. The PSD value of each frequency range was also expressed as normalized value, defined as the percentage ratio between the PSD value of that frequency range and the PSD value of the total spectrum from 0.01 to 1.6 Hz (obtained by the sum of the PSD value of each frequency range). The increase in PSD value following ACh or SNP iontophoresis for each frequency range was also calculated as percentage change from baseline.

Statistical analysis
Data are presented either as mean ± S.D. (or mean ± S.E.M. when specified) or as box plots.

The three horizontal lines at the boxes are the 25th, 50th and 75th percentiles. The two lines out of the boxes represent the highest and the lowest values, respectively. Student's t-test for non-paired data was used to compare basal LDF blood flux values obtained in SSc patients and in control subjects. Analysis of variance (ANOVA) for repeated measures (Scheffé's test for multiple comparison testing) was used to compare the skin blood flux response to ACh or SNP iontophoresis between SSc patients and control subjects. Wilcoxon's test for non-paired data was used to compare the PSD values obtained in the two studied groups both under basal conditions and following ACh or SNP iontophoresis, as well as to compare the percentage change in PSD value following each procedure between the two groups. Wilcoxon's test for paired data was used to compare PSD values obtained under basal conditions and following ACh or SNP iontophoresis in each group. When Wilcoxon's test was used, the P-value was corrected by means of the Bonferroni method. Regression analysis was performed to explore the relation between each of the skin vasomotion or skin blood flux parameters investigated and the SSc activity or severity score index of the studied SSc patients. Differences were considered as statistically significant when P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Conclusions
 References
 
Results of ACh and SNP iontophoresis
Figure 1 shows the digital skin blood flux response to ACh and SNP iontophoresis in SSc patients and in control subjects. SSc patients and control subjects did not differ in digital skin blood flux under basal conditions. SSc patients exhibited a significantly lower skin blood flux response to both ACh and SNP compared with control subjects (P < 0.001 for both procedures; ANOVA for repeated measures). No significant difference was observed between skin blood flux response to ACh and to SNP in SSc patients.


Figure 1
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  		FIG. 1. Digital skin laser Doppler blood flux values (mean ± S.E.M.) obtained under basal conditions and following each pulse of ACh iontophoresis (A) or SNP iontophoresis (B), in the 26 SSc patients and in 20 control subjects enrolled in the study. The numbers under the abscissa represent the time of iontophoresis pulses. *P < 0.001, **P < 0.05 between SSc patients and control subjects (ANOVA for repeated measures).

 
Results of skin vasomotion investigation
Table 2 and Fig. 2 show the results of vasomotion investigation performed under basal conditions and following ACh iontophoresis in SSc patients and in control subjects.


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  		TABLE 2. Absolute and normalized (in parentheses) PSD (PU2/Hz) values (median ± S.D.) of each laser Doppler signal frequency range investigated under basal conditions and during ACh iontophoresis in the SSc patients and in the control subjects recruited in the study

 

Figure 2
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  		FIG. 2. Percentage increase from baseline in PSD (mean ± S.E.M.) following ACh iontophoresis for each of the different skin laser Doppler signal frequency ranges investigated in the 26 SSc patients and in the 20 control subjects enrolled in the study. *P < 0.05, between SSc patients and control subjects. **P < 0.001, between SSc patients and control subjects.

 
No statistically significant difference was observed under basal conditions in absolute PSD mean value for all frequency ranges investigated between SSc patients and control subjects, with the only exception of the 0.06–0.2 Hz frequency range, related to the myogenic-dependent vasomotion, which showed a significantly lower absolute PSD mean value in SSc patients (P < 0.00005). Following ACh iontophoresis, there was a significant increase in the absolute PSD mean value for all the frequency ranges investigated, both in SSc patients and control subjects, with the only exception of the 0.06–0.2 Hz range, related to the myogenic-dependent vasomotion, which did not show any statistically significant PSD value increase in control subjects.

As shown in Fig. 2, there was a significantly lower percentage increase in the absolute PSD mean value of the 0.01–0.02 Hz range, of the 0.02–0.06 Hz range, of the 0.2–0.6 Hz range and of the 0.6–1.6 Hz range following ACh iontophoresis, in SSc patients compared with control subjects (P < 0.005, P < 0.05, P < 0.005 and P < 0.05, respectively). The percentage increase in the absolute PSD mean value of the 0.06–0.2 Hz frequency range did not significantly differ between the two groups.

Table 3 and Fig. 3 show the results for vasomotion investigation performed under basal conditions and following SNP iontophoresis in SSc patients and in control subjects. As in the ACh iontophoresis test, no statistically significant difference was observed under basal conditions in the absolute PSD mean value of all the frequency ranges investigated, with the only exception of the 0.06–0.2 Hz range, which was significantly lower in SSc patients compared with control subjects (P < 0.005). Following SNP iontophoresis, there was a significant increase in the absolute PSD mean value for all the frequency ranges investigated, both in SSc patients and control subjects.


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  		TABLE 3. Absolute and normalized (in parentheses) PSD (PU2/Hz) values (median ± S.D.) of each laser Doppler signal frequency range investigated under basal conditions and during SNP iontophoresis in the SSc patients and in the control subjects recruited in the study

 

Figure 3
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  		FIG. 3. Percentage increase from baseline in PSD (mean ± S.E.M.) following SNP iontophoresis for each of the different skin laser Doppler signal frequency ranges investigated in the 26 SSc patients and in the 20 control subjects enrolled in the study. *P < 0.05, between SSc patients and control subjects. **P < 0.01, between SSc patients and control subjects. ***P < 0.001, between SSc patients and control subjects.

 
As shown in Fig. 3, there was a significantly lower percentage increase in the absolute PSD mean value of the 0.01–0.02 Hz range, of the 0.06–0.02 Hz range and of the 0.6–1.6 Hz range following SNP iontophoresis, in SSc patients compared with control subjects (P < 0.01, P < 0.01 and P < 0.005, respectively). The post-SNP percentage increase in PSD mean value of the 0.02–0.06 Hz range and of the 0.2–0.6 Hz range did not significantly differ between the two groups.

Relation between skin microcirculatory parameters and SSc score index
A negative relation was observed between the normalized PSD value of the 0.01–0.02 Hz frequency range following SNP iontophoresis and the severity SSc score index (r = –0.407, P < 0.05), as well as between the normalized PSD value of the 0.02–0.06 Hz frequency range following SNP iontophoresis and the severity SSc score index (r = –0.459, P < 0.05) (Fig. 4). No significant relation was found between the SSc activity or severity score index and the other skin vasomotion or the skin blood flux parameters investigated.


Figure 4
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  		FIG. 4. (A) Relation between the post-SNP normalized PSD value of the 0.01–0.02 Hz frequency range (related to the endothelial-dependent vasomotion) and SSc severity score index in the SSc patients enrolled in the study. (B) Relation between the post-SNP normalized PSD value of the 0.02–0.06 Hz frequency range (related to the sympathetic-dependent vasomotion) and SSc severity score index in the 26 SSc patients enrolled in the study.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Conclusions
 References
 
To our knowledge, this is the first study which investigated FSV in SSc patients under the effect of the endothelium-dependent agonist ACh and the nitric oxide donor SNP. In a previous study [25], FSV was examined in SSc patients only under basal conditions, showing the absence of vasomotion abnormalities in the studied patients. On the contrary, in the present study, SSc patients exhibited a selective lower finger skin myogenic-dependent vasomotion under basal conditions, together with a selective lower increase in the endothelial-, sympathetic and myogenic-dependent vasomotion during ACh and/or SNP iontophoresis. Moreover, we observed a blunted digital skin vasodilator response to both ACh and SNP iontophoresis in SSc patients, as shown in some previous studies [1, 2, 4, 5].

The parallel blunted skin vasodilator response to ACh and SNP cannot formally be ascribed to vascular endothelium or smooth muscle dysfunction. On the contrary, the simultaneously blunted increase in finger skin endothelial-, sympathetic- and myogenic-dependent vasomotion, in response to the same stimuli observed in the studied SSc patients, is consistent with a parallel and selective dysfunction of the endothelial, sympathetic and myogenic mechanisms that control skin microvascular tone. The selective lower finger skin myogenic-dependent vasomotion observed under basal conditions in the same patients can be considered a further sign of vascular myogenic dysfunction.

In our study, SSc patients also exhibited a blunted post-ACh/SNP spectral increase in finger skin 0.2–0.6 and 0.6–1.6 Hz LDF oscillations, known to reflect central haemodynamic modifications synchronous with respiration and heart activity, respectively [9, 10]. This finding was probably a secondary phenomenon, due to the reduced transmission to the skin microcirculation of the central haemodynamic modifications synchronous with respiration and heart activity. This was in agreement with previous findings showing that the amplitude and kinetics of skin vascular conductance response to occlusive hyperaemia were altered in SSc patients [29].

In order to gain new insights into the potential physio-pathological significance of the skin vasomotion abnormalities observed in SSc patients, we performed regression analysis between the different skin vasomotion data and the SSc activity or severity score index of the studied patients. We found a negative relationship between the SSc severity score index and the normalized post-SNP increase in both the endothelial-dependent and the sympathetic-dependent vasomotion. The first relationship is in keeping with the previous data showing a strong positive relation between free radical damage (a well-known cause of endothelial dysfunction) and the severity of both the lung involvement and of the perturbed video-capillaroscopic pattern in SSc patients [30]. The inverse relationship between the SSc severity score index and the normalized post-SNP increase in the sympathetic-dependent vasomotion is in agreement with the previous data showing that autonomic dysfunction was associated with a more severe microvascular damage in SSc patients [31]. If skin microcirculation mirrors the state of the microcirculation in other vascular beds, as suggested by recent studies [32, 33], then the aforementioned relationships may confirm the role of the endothelial and sympathetic dysfunction in the progression of the overall microvascular involvement in SSc. The parallel absence of any relationship between the severity SSc score index and the finger skin vasodilator response to ACh or to SNP suggests a possible greater sensitivity of skin vasomotion investigation in order to gain new insights in the physiopathology of SSc. However, further studies on FSV in SSc patients should include not only healthy subjects but also patients with primary RP as control groups.

One possible limitation of our study is that we did not formally assess the reproducibility of the data obtained from the spectral analysis of skin LDF signal. However, no significant difference was observed among skin vasomotion data basally obtained from different fingers in control subjects or in SSc patients. This may minimize the aforementioned limitation.

Another potential limitation of the present study is that we cannot exclude a reduction in the effective ACh or SNP delivery to the finger skin during iontophoresis procedures in SSc patients, due to the increased electrical or ‘mechanical’ resistance of sclerodermatous skin to the passage of the vasoactive drug. However, a previous study showed no difference in the finger blood flow response to a transdermal nitro patch between SSc patients and control subjects [34], suggesting that the fibrosis of sclerodermatous skin did not influence the drug delivery to the skin through microcirculation in our patients. On the other hand, SSc patients exhibited a preserved ability of the brachial arteries to dilate in response to sublingual nitroglycerine in another study [35]. This last finding suggests that an increased electrical resistance of the sclerodermatous skin could partly account for the blunted finger skin vasodilator response to SNP observed in SSc patients in the present study.

A possible source of misinterpretation of the findings obtained in the present study could arise from the instability of LDF tracing during ACh or SNP iontophoresis. However, the ACh and SNP iontophoresis protocol we used elicited a rapid and progressive increase in the laser Doppler signal beginning from the first iontophoretic pulse, followed by a ‘steady-state’ laser Doppler tracing. This makes the results of the skin vasomotion investigation sufficiently reliable in our study.

Finally, we cannot formally exclude that the results of the present study have been influenced by nifedipine, methylprednisolone or MTX therapy, which was discontinued for only 1 day before the tests. On the other hand, no study investigated the effects of these drugs on skin vasomotion. However, it is very unlikely that at least nifedipine, which is able to increase blood flow in peripheral microcirculation, could have negatively influenced skin vasomotion in our SSc patients.


   Conclusions
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
References
 
In conclusion, our study showed a perturbed pattern of FSV in SSc patients. This pattern was characterized by a lower myogenic-dependent vasomotion under basal conditions, together with a blunted increase in the endothelial-, sympathetic- and myogenic-dependent vasomotion in response to ACh and/or SNP iontophoresis. A negative relation between the severity of SSc and the normalized spectral increase of the endothelial- and sympathetic-dependent vasomotion was also observed in SSc patients. The first of these findings suggests a parallel and selective dysfunction of the endothelial, sympathetic and myogenic mechanisms that control finger skin microvascular tone in SSc patients. The second finding suggests a role of the endothelial and sympathetic dysfunction in the progression of the overall microvascular involvement in SSc patients.

Formula

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
 References
 

  1. La Civita L, Rossi M, Vagheggini G, et al. Microvascular involvement in systemic sclerosis: laser Doppler evaluation of reactivity to acetylcholine and sodium nitroprusside by iontophoresis. Ann Rheum Dis (1998) 57:52–5.[Abstract/Free Full Text]
  2. Anderson ME, Campbell F, Hollis S, Moore T, Jayson MIV, Herrick AL. Non-invasive assessment of digital vascular reactivity in patients with primary Raynaud's phenomenon and systemic sclerosis. Clin Exp Rheumatol (1999) 17:49–54.[Web of Science][Medline]
  3. Anderson ME, Moore TL, Hollis S, Clark S, Jayson MI, Herrick AL. Endothelial dependent vasodilation is impaired in patients with systemic sclerosis, as assessed by low dose iontophoresis. Clin Exp Rheumatol (2003) 21:403.[Web of Science][Medline]
  4. Anderson ME, Moore TL, Lunt M, Errick AL. Digital iontophoresis of vasoactive substances as measured by laser Doppler imaging—a non-invasive technique by which to measure microvascular dysfunction in Raynaud's phenomenon. Rheumatology (2004) 43:986–91.[Abstract/Free Full Text]
  5. Gunawardena H, Harris ND, Carmichael C, McHugh NJ. Maximum blood flow and microvascular regulatory responses in systemic sclerosis. Rheumatology (2007) 46:1079–82.[Abstract/Free Full Text]
  6. Khan F, Belch JJF. Skin blood flow in patients with systemic sclerosis and Raynaud's phenomenon: effects of oral L-arginine supplementation. J Rheumatol (1999) 26:2389–94.[Web of Science][Medline]
  7. Campbell PM, LeRoy EC. Pathogenesis of systemic sclerosis: a vascular hypothesis. Semin Arthritis Rheum (1975) 4:351–68.[CrossRef][Medline]
  8. Herrick AL. Vascular function in systemic sclerosis. Curr Opin Rheumatol (2000) 12:527–33.[CrossRef][Web of Science][Medline]
  9. Stefanovska A, Kroselj P. Correlation integral and frequency analysis of cardiovascular functions. Open Syst Inf Dyn (1997) 4:457–78.[CrossRef]
  10. Stefanovska A, Bracic M, Kvernmo K. Wavelet analysis of oscillations in the peripheral blood circulation measured by laser Doppler technique. IEEE Trans Biomed Eng (1999) 46:1230–9.[CrossRef][Web of Science][Medline]
  11. Kvandal P, Stefanovska A, Veber M, Kvermmo HD, Kirkeboen KA. Regulation of human cutaneous circulation evaluated by laser Doppler flowmetry, iontophoresis, and spectral analysis: importance of nitric oxide and prostaglandines. Microvasc Res (2003) 65:160–71.[CrossRef][Web of Science][Medline]
  12. Rossi M, Ricco R, Carpi A. Spectral analysis of skin laser Doppler blood perfusion signal during cutaneous hyperemia in response to acetylcholine iontophoresis and ischemia in normal subjects. Clin Hemorheol Microcirc (2004) 31:303–10.[Web of Science][Medline]
  13. Colantuoni A, Bertuglia S, Intaglietta M. Microvascular vasomotion: origin of laser Doppler fluxmotion. Int J Microcirc Clin Exp (1994) 14:151–8.[Web of Science][Medline]
  14. Bertuglia S, Colantuoni A, Coppini G, Intaglietta M. Hypoxia- or hyperoxia-induced changes in arteriolar vasomotion in skeletal muscle microcirculation. Am J Physiol (1991) 260:H362–72.[Web of Science][Medline]
  15. Bertuglia S, Colantuoni A, Intaglietta M. Effects of L-NMMA and indomethacin on arterial vasomotion in skeletal muscle microcirculation of conscious and anesthetized animals. Microcirc Res (1994) 48:68–84.
  16. Ursino M, Fabbri G. Role of the myogenic mechanism in the genesis of microvascular oscillation (vasomotion): analysis with a mathematical model. Microvasc Res (1992) 43:156–77.[CrossRef][Web of Science][Medline]
  17. Ursino M, Cavalcanti S, Bertuglia S, Colantuoni A. Theoretical analysis of complex oscillations in multibranched microvascular networks. Microvasc Res (1996) 23:229–49.
  18. Parthimos D, Edwards DH, Griffith TM. Comparison of chaotic and sinusoidal vasomotion in the regulation of microvascular flow. Cardiovasc Res (1996) 31:388–99.[Abstract/Free Full Text]
  19. Soderstrom T, Stefanovska A, Veber M, Svensson H. Involvement of sympathetic nerve activity in skin blood flow oscillation in humans. Am J Physiol Heart Circ Physiol (2003) 284:H1638–46.[Abstract/Free Full Text]
  20. Stauss HM, Anderson EA, Haynes WG, Kregel KC. Frequency response characteristics of sympathetically mediated vasomotor waves in humans. Am J Physiol (1998) 274:H1277–83.[Web of Science][Medline]
  21. Rossi M, Carpi A, Di Maria C, Galetta F, Santoro G. Spectral analysis of laser Doppler skin blood flow oscillations in human essential arterial hypertension. Microvasc Res (2006) 72:34–41.[CrossRef][Web of Science][Medline]
  22. Stewart J, Kohen A, Brouder D, et al. Non-invasive interrogation of microvasculature for signs of endothelial dysfunction in patients with chronic renal failure. Am J Physiol Heart Circ Physiol (2004) 287:H2687–96.[Abstract/Free Full Text]
  23. Bernardi L, Rossi M, Leuzzi S, et al. Reduction of 0.1 Hz microcirculatory fluctuations as evidence of sympathetic dysfunction in insulin-dependent diabetes. Cardiovasc Res (1997) 34:185–91.[Abstract/Free Full Text]
  24. Lefrandt JD, Bosma E, Oomen PH, et al. Sympathetic mediated vasomotion and skin capillary permeability in diabetic patients with peripheral neuropathy. Diabetologia (2003) 46:40–7.[Web of Science][Medline]
  25. Salvat-Melis M, Carpentier PH, Moreau-Gaudry A, Boignard A, Paris A, Cracowski JL. Fourier transform spectral analysis of cutaneus blood flux in systemic sclerosis. J Mal Vasc (2007) 32:83–9.[Web of Science][Medline]
  26. Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum (1980) 23:581–90.[Web of Science][Medline]
  27. Medsger TA Jr, Silman AJ, Steen VD, et al. A disease severity scale for systemic sclerosis: development and testing. J Rheumatol (1999) 26:2159–67.[Web of Science][Medline]
  28. Della Rossa A, Valentini G, Bombardieri S, et al. European multicentre study to define disease activity criteria for systemic sclerosis: I. Clinical and epidemiological features of 290 patients from 19 centres. Ann Rheum Dis (2001) 60:585–91.[Abstract/Free Full Text]
  29. Boignard A, Salvat-Melis M, Carpentier PH, et al. Local hyperemia to heating is impaired in secondary Raynaud's phenomenon. Arthritis Res Ther (2005) 7:R1103–12.[CrossRef][Web of Science][Medline]
  30. Volpe A, Biasi D, Caramaschi P, et al. Levels of F2-isoprostanes in systemic sclerosis: correlation with clinical features. Rheumatology (2006) 45:314–20.[Abstract/Free Full Text]
  31. Di Franco M, Paradiso M, Riccieri V, Basili S, Mammarella A, Valesini G. Autonomic dysfunction and microvascular damage in systemic sclerosis. Clin Rheumatol (2007) 26:1278–83.[CrossRef][Web of Science][Medline]
  32. Shamim-Uizzaman Q, Pfenninger D, Kehrer C. Altered cutaneous microvascular responses to reactive hyperemia in coronary artery disease: a comparative study with conduit vessel responses. Clin Sci (2002) 103:267–73.[Web of Science][Medline]
  33. Jung F, Mrowietz C, Labarrere C. Primary cutaneous microangiopathy in heart recipients. Microvasc Res (2001) 62:154–63.[CrossRef][Web of Science][Medline]
  34. Anderson ME, Moore TL, Hollis S, Jayson MI, King TA, Herrick AL. Digital vascular response to topical glyceryl trinitrate, as measurement by laser Doppler imaging, in primary Raynaud's phenomenon and systemic sclerosis. Rheumatology (2002) 41:324–8.[Abstract/Free Full Text]
  35. Andersen GN, Mincheva-Nilsson L, Kazzam E, et al. Assessment of vascular function in systemic sclerosis: indications of the development of nitrate tolerance as a result of enhanced endothelial nitric oxide production. Arthritis Rheum (2002) 46:1324–32.[CrossRef][Web of Science][Medline]
Submitted 22 November 2007; revised version accepted 18 February 2008.
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