DOI: 10.1111/eci.12293

ORIGINAL ARTICLE Impact of age and gender on microvascular function Oliver Schlager*, Aura Giurgea*, Alexandra Hammer*, Silvia Charwat-Resl*, Christian Margeta*, Markus Mueller*, Teresa Ehringer*, Sonja Zehetmayer†, Andrea Willfort-Ehringer*, Renate Koppensteiner* and Michael E. Gschwandtner* * †

Division of Angiology, Department of Medicine II, Medical University of Vienna, Vienna, Austria, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria

ABSTRACT Background Microcirculatory function can be assessed by postocclusive reactive hyperaemia (PORH) using laser Doppler fluxmetry. Previous studies have shown that PORH reveals microvascular damage at an early stage. In particular, at younger ages, PORH might depend on age and gender. To implement PORH into a larger scale of clinical studies, one has to be aware of the influence of age and gender on microcirculation. The aim of this study was to assess the impact of age and gender on microcirculatory function during adolescence. Materials and methods Within the scope of an epidemiological project, 896 children and adolescents underwent assessment of PORH by laser Doppler fluxmetry. Microcirculatory parameters during PORH (baseline perfusion, biological zero, peak perfusion, time to peak perfusion and recovery time) were analysed in relation to age (by tertiles) and gender. Results Baseline perfusion, biological zero and peak perfusion were lower in children/adolescents in the upper age tertile (123–181 years) than in the middle (98–122 years) and lower (43–97 years) age tertiles (P < 00001). In the total of participants, baseline perfusion, biological zero and peak perfusion were higher in males than in females (P < 00001). Analysing microcirculatory parameters as a function of age and gender, the sex differences were only apparent in the upper and the middle age tertiles, but not in the lower. Conclusions During adolescence, PORH is a function of age. At higher age, microvascular reactivity considerably depends on gender, whereas no sex differences are present at younger ages. Keywords Endothelial function, epidemiology, laser Doppler, microcirculation, microvascular reactivity. Eur J Clin Invest 2014; 44 (8): 766–774

Introduction To assess microvascular function, postocclusive reactive hyperaemia (PORH) measured by laser Doppler fluxmetry has been established as easily accessible, noninvasive diagnostic test [1,2]. Several studies have shown that PORH – as measured by laser Doppler fluxmetry – reveals early impairments of microvascular reactivity that can often be attributed to metabolic disorders and may also mirror generalized systemic microvascular dysfunction [3–7]. Premature alterations of microvascular PORH can even be detected in children and adolescents with metabolic disorders [5–7]. To prospectively introduce microvascular PORH into a larger scale of clinical studies and to consider its implementation into clinical practice, one has to be aware of changes in microvascular reactivity during physical development. Physical growth is associated with the growth of microvascular networks and an increase of microvascular wall mass [8,9]. Such structural

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changes jointly occur with changes in microvascular perfusion pressure and microvascular blood flow [10]. As a consequence, tissue metabolic requirements may change during juvenile growth subsequently affecting microvascular autoregulation. In addition to growth-related changes – especially in later adolescence – gender might further influence microvascular reactivity. Experimental data have linked juvenile growth with changes in endothelial function and reactivity of arteriolar smooth muscle cells [11,12]. Referring to epidemiological data, previous studies in elderly people suggested impairments of microvascular reactivity upon ageing [13,14]. Notably, the biology of ageing has to be differentiated from the physiological processes during juvenile growth. Therefore, it is still unclear whether and to which extent juvenile growth has an impact on microvascular function. Hence, the aim of the present study was to assess the impact of gender and age on microvascular PORH measured by laser Doppler fluxmetry in an adolescent population.

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Materials and methods Study participants Before initiation of the present study, approval of the local ethical committee was obtained. The study was conducted in accordance with the recommendations of the Declaration of Helsinki and the ICH-GCP guidelines. All study participants were recruited from an Austrian epidemiological project on vascular health in school children. This project was carried out at one Kindergarten and four public schools at two towns in the suburban area of Vienna (Klosterneuburg, Maria Enzersdorf). In collaboration with the Kindergarten and the four schools, the attending children and adolescents as well as their parents were comprehensively informed about this project. Study participation was on a voluntary basis. Prior to study entry, all children and adolescents gave informed assent. Additionally, written informed consent from their parents was mandatory for enrolment. Only nonsmoking children and adolescents without diabetes mellitus were enrolled. Further, study participants had to be free of any previously known cardiovascular or malignant disease, and only children without continuous intake of medication were included in the present study. Included study participants were finally divided into age tertiles (Table 1).

Clinical data In all children and adolescents, a medical history was taken, height and weight were measured and the body mass index (BMI) was calculated. To account for age- and gender-depen-

dent differences of BMI, the respective body mass index–standard deviation scores (BMI-SDS) were determined in accordance with the age- and gender-dependent percentiles [15,16]. Blood pressure was measured on both arms with appropriate cuff sizes after a resting period of 20 min in a supine position. For further analyses, the mean value of both arms was used. Subsequently, z-scores were calculated for systolic and diastolic blood pressure to account for the influence of age, sex and height.

Laboratory data Fasting levels of blood lipids and glucose were determined from whole blood obtained by finger pricks by the Cholestech LDX System (CHOLESTECH Corporation, Hayward, CA, USA) using an enzymatic solid-phase technology. As stated by the manufacturer, the intraday coefficients of variations are 24– 25% for total cholesterol, 34–48% for high-density lipoprotein (HDL) cholesterol, 38–49% for low-density lipoprotein (LDL) cholesterol and 45–62% for blood glucose. Referring to the Cholesterol Reference Method Laboratory Network, the Cholestech LDX System meets the criteria of the National Cholesterol Education Program for accuracy and precision and is comparable to centralized laboratory testing.

Laser Doppler fluxmetry The duplex mode of a laser Doppler device (PIM II with LISCA Opto-Isolation Unit; Perimed, J€ arf€ alla, Sweden) was used to assess skin perfusion (wavelength 632 nm, processor bandwidth 20–13 kHz, time constant 03–04 s, sampling frequency 1–100 Hz). By interfering with moving blood cells of superficial

Table 1 Clinical characteristics of 896 apparently healthy children and adolescents 1st Tertile N

302

Age (years); median (total range)

8 (43–97)

2nd Tertile

3rd Tertile

297

297

108 (98–122)

141 (123–181)

P-value

Female N (%)

138 (457)

153 (515)

183 (616)

Body weight (kg)

262 (226; 307)

372 (33; 44)

534 (463; 618)

< 0001

Body height (cm)

130 (123; 137)

146 (141; 152)

164 (157; 170)

< 0001

BMI (kg/m )

154 (144; 169)

174 (157; 194)

BMI-SDS

03 (09; 046)

2

20 (179; 216)

0 (077; 073)

< 0001

01 (063; 071)

0001

Systolic blood pressure (mmHg)

95 (88; 100)

107 (98; 115)

115 (108; 122)

< 0001

Diastolic blood pressure (mmHg)

55 (50; 60)

69 (60; 75)

72 (65; 79)

< 0001

03 (09; 03)

01 (07; 06)

01 (07; 08)

< 0001

0 (06; 03)

02 (03; 07)

03 (04; 07)

< 0001

Systolic blood pressure z-score Diastolic blood pressure z-score

Data are expressed as counts (+percentages within each tertile) or as median (+interquartile range). BMI, body mass index; BMI-SDS, body mass index – standard deviation score.

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tissue layers, the laser beam gets Doppler shifted and the reflected signal is recorded by the laser Doppler device [17]. The resulting photocurrent scales linearly with tissue perfusion and is given in arbitrary units (AU). In accordance with previous studies, the first interspace between the thumb and the index finger of the dorsum of the participant’ s hand was used as measurement site [5–7]. All measurements were obtained in the morning in a quiet and darkened room and at a constant room temperature of 233  06 °C. For acclimatization, all study participants had to rest in a supine position for 20 min before measurements were initiated. On days of measurements, respective study participants had to refrain from tea or coffee intake.

Postocclusive reactive hyperaemia (PORH) As demonstrated in previous studies, PORH was used to assess microvascular reactivity [5–7]. Baseline perfusion [AU] was recorded over a time period of 3 min using laser Doppler fluxmetry. After that, over another time period of 3 min, a sphygmomanometer cuff on the patients’ upper arm was inflated (10 mm Hg above systolic blood pressure) and

Figure 1

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biological zero [AU] was recorded [18]. Baseline perfusion and biological zero were both determined as mean perfusion values over the predefined time period of 3 min. Following the 3-min occlusion period, a sudden cuff deflation caused an immediate increase of blood flow in major afferent arteries. This sudden increase of blood flow in large afferent arteries provoked a constriction of downstream arteriolar segments to prevent microcirculation from hyperperfusion. The maximum perfusion was defined as peak perfusion [AU], the time span between cuff deflation and peak perfusion as time to peak [s] and the time span between peak perfusion and reacquisition of mean baseline perfusion as recovery time [s]. All parameters were determined using the laser Doppler device-related software (LDPIwin 2 for Windows, www.perimed instruments.com/software/ldpiwin). A schematic time perfusion graph of PORH as measured by laser Doppler fluxmetry is shown in Fig. 1. As previously published, the intrasubject coefficients of variation were 129% for baseline perfusion, 114% for biological zero, 16% for time to peak, 198% for peak perfusion and 183% for recovery time [5].

Schematic time perfusion graph illustrating postocclusive reactive hyperaemia as measured by laser Doppler fluxmetry.

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Statistical analysis Continuous variables are expressed as medians and interquartile ranges (IQR) and categorical variables as absolute and relative frequencies. Tertiles were formed on the basis of age distribution of children and adolescents. Due to a skewed distribution of the microcirculatory target variables (baseline perfusion, biological zero, peak perfusion, time to peak, recovery time), the nonparametric Kruskal–Wallis test was used to assess distribution differences between the age tertiles. In case of statistically significant distribution, differences between the respective age groups – as detected by the Kruskal–Wallis test – we utilized the Mann–Whitney U-test as post hoc test for pairwise comparisons. To compare genderrelated differences in the microvascular variables, the Mann– Whitney U-test was used. Referring to the skewed distribution of the microcirculatory target variables and the accordingly used Kruskal–Wallis test, no multivariate analysis can reliably be applied. Aiming to account for a potential confounding by children0 s BMI, BMISDS, blood glucose, LDL cholesterol, systolic and diastolic blood pressure as well as the blood pressure z-scores, we set up a second model and excluded children with deviations of the respective measures. In this second model, the Kruskal–Wallis test was again applied to assess distribution differences between the microvascular target variables of age tertiles. As an analogy to the first model, the Mann–Whitney U-test was performed as post hoc test for pairwise comparisons. Further, the Mann– Whitney U-test was used to assess gender-related differences. P-values below 005 were considered to indicate statistical significance. Analyses were performed using SPSS, IBM (Armonk, NY, USA) 20.0 software package for Mac and SAS 9.1, SAS Institute Inc (Cary, NC, USA).

Results A total of 1000 children and adolescents from an Austrian epidemiological project on vascular health in children were

eligible for the present study. One hundred and four children had to be excluded according to artefacts of the laser Doppler recordings or incomplete data. Consequently, 896 children and adolescents (468 female (522%), 428 male (478%), age range 43–181 years) were included in the final analysis and divided into age tertiles. Age tertiles as well as the patient’s clinical characteristics are shown in Table 1. Laboratory characteristics (blood glucose, total cholesterol, LDL cholesterol and HDL cholesterol) by age tertiles are shown in Table 2.

Microvascular reactivity In the total of study participants, baseline perfusion was 043 (median, IQR 032; 058) AU and biological zero was 02 (017; 026) AU. During PORH, peak perfusion was 13 (097; 175) AU; time to peak and recovery time were 12 (9; 19) s and 71 (46; 98) s, respectively.

Microvascular reactivity and age Microvascular parameters by age tertiles are shown in Fig. 2a– e: baseline perfusion was lower in the upper age tertile than in the middle and lower tertile; similarly, biological zero and peak perfusion were lower in older than in younger children.

Microvascular reactivity and gender In the total, baseline perfusion was higher in males than in females [males vs. females, 046 (IQR 035; 062) AU vs. 04 (03; 054) AU, P < 0001]. During PORH, biological zero and peak perfusion were also higher in males than in females [males vs. females: biological zero 021 (018; 027) AU vs. 02 (017; 025) AU, P = 003; peak perfusion 145 (103; 194) AU vs. 122 (092; 162) AU, P < 0001]. In contrast, time to peak and recovery time were not different between both sexes [males vs. females: time to peak 12 (9; 20) s vs. 13 (9; 18) s, P = 082; recovery time 75 (49; 99) s vs. 685 (43; 95) s, P = 01]. In the subgroup of females, time to peak and recovery time were prolonged in the upper age tertile.

Table 2 Laboratory characteristics of 896 apparently healthy children and adolescents

N Age (years); median (total range)

1st Tertile

2nd Tertile

3rd Tertile

302

297

297

108 (98–122)

141 (123–181) 472 (439; 5)

8 (43–97)

P-value

< 0001

Blood glucose (mM)

456 (428; 478)

472 (444; 494)

Total cholesterol (mM)

416 (368; 46)

422 (37; 471)

42 (367; 476)

057

LDL cholesterol (mM)

239 (189; 274)

228 (173; 277)

228 (178; 272)

031

HDL cholesterol (mM)

142 (122; 163)

142 (116; 166)

14 (116; 16)

050

Data are expressed as median (+interquartile range). LDL, low-density lipoprotein; HDL, high-density lipoprotein.

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(a)

(b)

(c)

(d)

(e)

Figure 2 Baseline perfusion (a), biological zero (b), peak perfusion (c), time to peak (d) and recovery time (e) during postocclusive reactive hyperaemia using laser Doppler fluxmetry in 896 apparently children and adolescents by age tertiles. Age is given as median (range) for each group. Box plots indicate medians and interquartile ranges (IQR), whiskers display 15 IQRs from the upper and lower quartile and open dots depict outliers.

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Table 3 Microvascular parameters during postocclusive reactive hyperaemia assessed by laser Doppler fluxmetry in 462 children/ adolescents without deviations of body mass index, blood glucose, total cholesterol, low-density lipoprotein cholesterol and systolic/diastolic blood pressure, sorted by age tertiles Age (years); median (total range)

81 (43–97)

Baseline perfusion (AU)

053

IQR Total range Biological zero (AU) IQR Total range Peak perfusion (AU) IQR Total range Time to peak (s) IQR Total range Recovery time (s) IQR Total range

(043; 069)

107 (98–122) 047

143 (123–181) 035

(032; 066)

(028; 045)

023–15

013–164

009–104

024

02

019

(02; 032)

(017; 028)

(017; 021)

01–071

006–055

006–037

157

139

121

(118; 21) 042–417

(099; 2) 035–484

12

12

(8; 19)

(9; 18)

2–114 68 (38; 100) 3–211

3–113 72 (45; 97) 4–193

P-value < 00001

< 00001

0007

(089; 158) 05–269 14

< 00001

(11; 27) 4–162 81

0256

(53; 101) 5–209

Data are given as medians. IQR, interquartile range.

Microvascular reactivity in children without risk factors

Discussion

In a second model, we excluded children who showed deviations in one or more of the parameters BMI, blood pressure and serum lipids [19–23]: 123 (137%) children were excluded because of overweight, 24 (27%) children met the diagnostic criterion for obesity and 24 (27%) children were excluded according to thinness; 123 children (137%) had prehypertensive or hypertensive blood pressure values during their clinical examination, 24 children (27%) were excluded because of elevated fasting blood glucose levels and 160 children (179%) were excluded according to elevated total or LDL cholesterol levels. The remaining 462 subjects were split into three subgroups according to the initially determined ranges of age tertiles (43–97 years: 184 children, 98–122 years: 151 children, 123–181 years: 127 children). Analysing microcirculatory parameters in these subgroups, we again found differences in baseline perfusion, biological zero, peak perfusion and time to peak between the three age subgroups (Table 3). Further, baseline perfusion, peak perfusion and recovery time differed between male and female study participants without risk factors (Table 4).

The findings of this study demonstrate that in children and adolescents, microvascular reactivity is related to age. Further, microvascular reactivity is affected by gender during adolescence. In detail, baseline perfusion and biological zero differed between age tertiles. Baseline perfusion as well as biological zero is determined by spontaneous vasomotion and might thereby depend on the sympathetic nerve activity [18,24,25]. Experimental data have demonstrated that arteriolar responsiveness to sympathetic nerve stimulation increases during juvenile growth [26]. Therefore, the differences in baseline perfusion and biological zero between age tertiles might be attributed to age-depending variations of vascular responsiveness to sympathetic activity. Apart from vasomotion, anatomic properties, such as dermal structure, could influence the power of the reflected laser Doppler signal and might thereby have an impact on baseline perfusion and biological zero [27]. Total cutaneous thickness gradually increases during juvenile growth, which could subsequently result in age-depending variations of baseline perfusion and biological zero [28].

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Table 4 Microvascular parameters during postocclusive reactive hyperaemia assessed by laser Doppler fluxmetry in 462 children/adolescents without deviations of body mass index, blood glucose, total cholesterol, low-density lipoprotein cholesterol and systolic/diastolic blood pressure, sorted by gender Gender N

Male 258

Female 204

P-value

Baseline perfusion (AU)

048

043

0004

IQR

(035; 065)

(032; 06)

Total range

013–164

009–15

021

021

IQR

(018; 028)

(018; 026)

Total range

006–071

006–0–61

153

129

IQR

(107; 204)

(093; 168)

Total range

035–419

041–484

Biological zero (AU)

Peak perfusion (AU)

Time to peak (s)

12

13

IQR

(8; 20)

(10; 20)

Total range

2–114

2–162

80

66

IQR

(54; 102)

(38; 93)

Total range

4–211

3–201

Recovery time (s)

04

0001

027

0005

Data are given as medians. IQR, interquartile range.

Focusing on PORH peak perfusion was higher in young children than at higher ages. To adequately interpret this finding, it appears essential to differentiate between the early phase of PORH, which is supposed to be determined by the neuromuscular axon reflex, and the late phase of PORH, which mostly depends on endothelial and metabolic factors [2,29]. During the early phase of PORH, the sudden increase of blood flow provokes an immediate counter-regulatory constriction of precapillary arteriolar smooth muscle cells [29]. The observed variations of peak perfusion between age tertiles might therefore be attributed to age-depending differences in the primarily neurogenic-mediated arteriolar constriction. Regarding the time to peak, we observed an age-depending change in females, while in males, time to peak did not differ between the respective age tertiles. Within the spectrum of microvascular parameters during PORH, however, time to peak appears to be weaker in relevance than peak perfusion [5–7]. Hence, the observed differences of time to peak might not allow further conclusions to be drawn. Regarding the late phase of PORH, we observed a trend to longer recovery times at higher ages. After an immediate

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regulatory arteriolar constriction, the late phase of PORH is predominantly determined by endothelial-mediated vascular tone regulation. Considering endothelial mediators, the endothelium-derived hyperpolarizing factor and nitric oxide (NO) might contribute to PORH [2]. Referring to a potential impact of age on the expression of endothelial mediators, former studies have shown that the release of NO and asymmetric dimethylarginine changes during juvenile growth [11,30,31]. In contrast, the muscular responsiveness to NO and prostaglandins seems to be hardly influenced by age [32]. Therefore, it remains to be clarified to which extent endothelial mediators contribute to the observed differences in recovery time between distinct age tertiles. Analysing the impact of gender on microvasculature baseline perfusion and peak perfusion differed significantly between males and females in older adolescents, while no significant differences were observed in younger children. This impact of gender on microcirculation in older adolescents seems to be comparable to previous observations in an adult population [33]. Because we observed no impact of gender on microvascular reactivity in younger children, it appears plausible that the microvascular differences between both sexes in older adolescents can be attributed to the hormonal development normally occurring during puberty. As limitation of the present study, we did not investigate the respective phase of the menstrual cycle of the included girls. Although previous studies suggested that variations of sexual hormone levels could affect vascular reactivity [34,35], specific data on the impact of estradiol levels on microvascular PORH are inconsistent [36,37]. Apart from these limitations, the major strength of the present study warrants mention: the introduction of microvascular PORH into an epidemiological project on vascular health allows us to demonstrate the impact of juvenile growth and sex on microvascular reactivity in a large population of children and adolescents. Importantly, data on age- and gender-depending changes in microvascular reactivity are an essential prerequisite, not only to adequately interpret previous studies on premature impairments of microvascular reactivity, but also to implement PORH and laser Doppler fluxmetry into clinical practice. In conclusion, this study shows that age considerably affects microvascular reactivity. During adolescence, microvascular reactivity differs between both sexes at higher age, while in younger children, gender had no impact on PORH.

Disclosures The authors have no further conflict of interest to disclose.

Address Division of Angiology, Department of Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria (O. Schlager, A. Giurgea, A. Hammer, S. Charwat-Resl,

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C. Margeta, M. Mueller, T. Ehringer, A. Willfort-Ehringer, R. Koppensteiner, M. E. Gschwandtner); Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria (S. Zehetmayer). Correspondence to: Michael E. Gschwandtner, MD, Division of Angiology, Department of Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel.: +431404004670; fax: +431404004665; e-mail: michael. [email protected] Received 24 January 2014; accepted 13 June 2014 References 1 Roustit M, Cracowski JL. Assessment of endothelial and neurovascular function in human skin microcirculation. Trends Pharmacol Sci 2013;34:373–84. 2 Roustit M, Cracowski JL. Non-invasive assessment of skin microvascular function in humans: an insight into methods. Microcirculation 2012;19:47–64. 3 Clough GF, L’Esperance V, Turzyniecka M, Walter L, Chipperfield AJ, Gamble J et al. Functional dilator capacity is independently associated with insulin sensitivity and age in central obesity and is not improved by high dose statin treatment. Microcirculation 2011;18:74–84. 4 Kraemer-Aguiar LG, Maranhao PA, Sicuro FL, Bouskela E. Microvascular dysfunction: a direct link among BMI, waist circumference and glucose homeostasis in young overweight/obese normoglycemic women? Int J Obes (Lond) 2010;34:111–7. 5 Schlager O, Hammer A, Willfort-Ehringer A, Fritsch M, RamiMerhar B, Schober E et al. Microvascular autoregulation in children and adolescents with type 1 diabetes mellitus. Diabetologia 2012;55:1633–40. 6 Schlager O, Widhalm K, Hammer A, Giurgea A, Margeta C, Fritsch M et al. Familial hypercholesterolemia affects microvascular autoregulation in children. Metabolism 2013;62:820–7. 7 Schlager O, Willfort-Ehringer A, Hammer A, Steiner S, Fritsch M, Giurgea A et al. Microvascular function is impaired in children with morbid obesity. Vasc Med 2011;16:97–102. 8 Linderman JR, Boegehold MA. Arteriolar network growth in rat striated muscle during juvenile maturation. Int J Microcirc Clin Exp 1996;16:232–9. 9 Wang DH, Prewitt RL. Microvascular development during normal growth and reduced blood flow: introduction of a new model. Am J Physiol 1991;260:H1966–72. 10 Boegehold MA. Endothelium-dependent control of vascular tone during early postnatal and juvenile growth. Microcirculation 2010;17:394–406. 11 Samora JB, Frisbee JC, Boegehold MA. Growth-dependent changes in endothelial factors regulating arteriolar tone. Am J Physiol Heart Circ Physiol 2007;292:H207–14. 12 Samora JB, Frisbee JC, Boegehold MA. Hydrogen peroxide emerges as a regulator of tone in skeletal muscle arterioles during juvenile growth. Microcirculation 2008;15:151–61. 13 Tikhonova IV, Tankanag AV, Chemeris NK. Age-related changes of skin blood flow during postocclusive reactive hyperemia in human. Skin Res Technol 2013;19:e174–81.

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Impact of age and gender on microvascular function.

Microcirculatory function can be assessed by postocclusive reactive hyperaemia (PORH) using laser Doppler fluxmetry. Previous studies have shown that ...
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