**1. Introduction**

In the past two decades, the interest in microcirculatory blood flow in patients with arterial hypertension (AH) has been steadily increasing due to the significant role of microcirculatory disorders in the pathogenesis of this disease [1–3] and unsatisfactory treatment results, when despite achievement of the target blood pressure with antihypertensive therapy, residual cardiovascular risks remain substantial [4]. Laser Doppler flowmetry (LDF) is a modern noninvasive technique for examining the microcirculatory blood flow in humans. Even though the skin vessels are not subjected to baroreflex regulation, the accumulated data suggests that the

microvascular bed of the skin may reflect the microcirculatory system state in other bodily organs and systems [5–8]. The results of functional LDF tests demonstrate a significant correlation between the left ventricular ejection fraction and the enddiastolic volume [9], flow-mediated vasodilation [10], and renal resistive index [11]. Discontinuation of antihypertensive therapy leads to a decrease in post-occlusive reactive hyperemia [12], which, in turn, correlates with the cardiovascular risk factors in the female population [13]. In 2011, the Peripheral Circulation Working Group of the European Society of Cardiology included LDF in the list of the recommended methods to study endothelial function [14].

Arterial hypertension is a hemodynamic disease with a blood pressure (BP) rise due to an increase in the cardiac output and/or peripheral vascular resistance [15]. In the classic work on normo-, hypo-, and hypertensive cats, Zweifach demonstrated that in the mesentery microvessels the greatest pressure gradient is recorded in arterioles <50 μm in diameter [16, 17]; at this level the Reynolds number is less than one and the viscous blood forces prevail over kinetic ones [18]. As in LDF resistive microvessels <50 μm in diameter are included in the probed volume [19], the interest in their functional state in AH is quite natural.

A fundamental feature of resistive arterioles is their high vasomotor activity. The arterioles are in constant motion, changing their tone and their lumen size, which manifests as vasomotions [20] with the respective changes in tissue perfusion. The vasomotion phenomenon is due to the ability of smooth muscle cells to spontaneously contract with an average frequency of 6 times per minute. It is the myogenic resistance at the capillary sphincter level that is the last blood flow control link before the exchange vessels, i.e. capillaries. Myogenic vasomotions are clearly conducted into the capillary bed of the human skin [21], and their amplitude is positively correlated with the number of functioning capillaries [22]. In arterioles, the basal tone and vasomotor activity of smooth muscle cells are modulated from the outer layer of the vessel wall by sympathetic nervous system 2–3 times per minute, and from the lumen by endothelial factors with a frequency of less than once per minute. The vascular tone-forming mechanisms (endothelial, neurogenic, and myogenic) act directly via the smooth muscle cells of microvessels and, as a result of periodic changes in blood flow resistance, generate the corresponding fluctuations in tissue perfusion [23, 24]. Due to the alternating contractions and relaxations of the smooth muscle in the arterioles and capillary sphincters, the arterial blood flowing into the capillaries is modulated to the optimal volume for transcapillary exchange [25–28]. During self-organization of microcirculation, all regulatory mechanisms interact with each other in positive and negative feedback loops that are aimed at maintaining tissue homeostasis. Thus, the tone-forming mechanisms function mainly at the resistive arteriole level, thereby determining not only the capillary hemodynamic parameters but also the peripheral vascular resistance (PVR).

Other microcirculation modulation mechanisms are passive in relation to the arteriolar smooth muscle cells, but they determine the blood filling volume of the microvascular bed (MVB) by changing the longitudinal pressure gradient caused by periodic changes in BP at the "inlet" (pulse BP) and pressure variation in the venules during the respiratory cycles at the "outlet" of MVB. The pulse oscillation amplitude reflects the condition of the inflow tracts (arterioles) and the arterial blood inflow into the MVB, and the amplitude of respiratory-associated blood flow oscillations characterizes the state of the capillary outflow tract, thereby reflecting the blood volume in the venular section of MVB [26, 29–31].

The main aim of this pilot study was to evaluate the functional state of resistive vessels of the skin in patients with essential arterial hypertension according by LDF with an amplitude-frequency wavelet analysis of microcirculation fluctuations.

**137**

**Figure 1.**

*Functional State of the Microvascular Bed of the Skin in Essential Arterial Hypertension…*

The skin perfusion was assessed in the supine position after a 15-min period of adaptation in a laboratory with a constant microclimate (+23 ± 1°С) in the morning (09:00–12:00 AM). The microcirculatory blood flow was recorded by a LAKK-02 single-channel laser analyzer of blood microcirculation in the visible red spectrum (wavelength of 630 nm) and a LAKK-TEST complex (OOO Research and Production Enterprise LAZMA, Russia) that allow evaluating the perfusion

of +32°С. The sensor was located on the outer surface of the right forearm, in the midline 3–4 cm proximal to the wrist joint. The perfusion was recorded for 6 min. After the microcirculation study, all subjects received 24-h ambulatory blood pres-

The initial LDF recording (**Figure 1A**) was subjected to amplitude-frequency wavelet analysis. The time-averaged amplitude of vasomotions was estimated by the maximum values (Amax) in the corresponding [32, 33] blood flow modulation frequency range: endothelial (Ae)—0.0095 − 0.021 Hz; neurogenic (An)—0.021 − 0.052 Hz; myogenic (Am)—0.052 − 0.145 Hz; respiratory-venular (Av)—0.145 − 0.6 Hz; pulse-cardial (Ac) —0.6 – 2 Hz (**Figure 1B**). The perfusion level (M) and the amplitudes of the blood flow modulation mechanisms were

The functional activity of the tone-forming blood flow modulation mechanisms (endothelial, neurogenic, and myogenic) was evaluated as follows – the higher the vasomotion amplitude, the lower the tone, and vice versa, the lower the vasomotion amplitude, the higher the tone generated by this regulatory mechanism. If we take the zero amplitude as the longitudinal axis of a microvessel (LAV), and the maximum vasomotion amplitude as the vascular wall (**Figure 1B**), then the dependence of the microvessel lumen size on the vasomotion amplitude is clearly evident. At the first stage of the study, the main objective was to assess the functional activity of resistive arterioles depending on the blood pressure level. At this stage, the subjects included 90 people (47 men and 43 women) divided into three groups. The control group (NT) consisted of 32 clinically healthy normotensive volunteers. The second group consisted of 32 patients with stage 1 essential AH (AH1). The third group included 26 patients with stage 2 AH (AH2). All patients with AH who were receiving antihypertensive therapy had their therapy discontinued 10–14 days prior to the study (washed out). In the rest of the patients, AH was newly diagnosed

*Laser Doppler flowmetry (LDF). (A) It is a perfusion characteristic during 6 min. (B) It is amplitudefrequency wavelet analysis of blood flow oscillations. Dotted lines indicate a microvessel, arrows mark the activity of tone forming mechanisms in blood flow modulation. LAV, the longitudinal axis of the vessel.*

of skin, at a constant temperature in the studied region

*DOI: http://dx.doi.org/10.5772/intechopen.89852*

sure monitoring (ABPM) on the left shoulder.

**2. Materials, methods and results**

parameters in ~ 1.0–1.5 mm3

assessed in perfusion units (PU).

*Functional State of the Microvascular Bed of the Skin in Essential Arterial Hypertension… DOI: http://dx.doi.org/10.5772/intechopen.89852*

## **2. Materials, methods and results**

*Basic and Clinical Understanding of Microcirculation*

mended methods to study endothelial function [14].

the interest in their functional state in AH is quite natural.

microvascular bed of the skin may reflect the microcirculatory system state in other bodily organs and systems [5–8]. The results of functional LDF tests demonstrate a significant correlation between the left ventricular ejection fraction and the enddiastolic volume [9], flow-mediated vasodilation [10], and renal resistive index [11]. Discontinuation of antihypertensive therapy leads to a decrease in post-occlusive reactive hyperemia [12], which, in turn, correlates with the cardiovascular risk factors in the female population [13]. In 2011, the Peripheral Circulation Working Group of the European Society of Cardiology included LDF in the list of the recom-

Arterial hypertension is a hemodynamic disease with a blood pressure (BP) rise due to an increase in the cardiac output and/or peripheral vascular resistance [15]. In the classic work on normo-, hypo-, and hypertensive cats, Zweifach demonstrated that in the mesentery microvessels the greatest pressure gradient is recorded in arterioles <50 μm in diameter [16, 17]; at this level the Reynolds number is less than one and the viscous blood forces prevail over kinetic ones [18]. As in LDF resistive microvessels <50 μm in diameter are included in the probed volume [19],

A fundamental feature of resistive arterioles is their high vasomotor activity. The arterioles are in constant motion, changing their tone and their lumen size, which manifests as vasomotions [20] with the respective changes in tissue perfusion. The vasomotion phenomenon is due to the ability of smooth muscle cells to spontaneously contract with an average frequency of 6 times per minute. It is the myogenic resistance at the capillary sphincter level that is the last blood flow control link before the exchange vessels, i.e. capillaries. Myogenic vasomotions are clearly conducted into the capillary bed of the human skin [21], and their amplitude is positively correlated with the number of functioning capillaries [22]. In arterioles, the basal tone and vasomotor activity of smooth muscle cells are modulated from the outer layer of the vessel wall by sympathetic nervous system 2–3 times per minute, and from the lumen by endothelial factors with a frequency of less than once per minute. The vascular tone-forming mechanisms (endothelial, neurogenic, and myogenic) act directly via the smooth muscle cells of microvessels and, as a result of periodic changes in blood flow resistance, generate the corresponding fluctuations in tissue perfusion [23, 24]. Due to the alternating contractions and relaxations of the smooth muscle in the arterioles and capillary sphincters, the arterial blood flowing into the capillaries is modulated to the optimal volume for transcapillary exchange [25–28]. During self-organization of microcirculation, all regulatory mechanisms interact with each other in positive and negative feedback loops that are aimed at maintaining tissue homeostasis. Thus, the tone-forming mechanisms function mainly at the resistive arteriole level, thereby determining not only the capillary hemodynamic parameters but also the peripheral vascular

Other microcirculation modulation mechanisms are passive in relation to the arteriolar smooth muscle cells, but they determine the blood filling volume of the microvascular bed (MVB) by changing the longitudinal pressure gradient caused by periodic changes in BP at the "inlet" (pulse BP) and pressure variation in the venules during the respiratory cycles at the "outlet" of MVB. The pulse oscillation amplitude reflects the condition of the inflow tracts (arterioles) and the arterial blood inflow into the MVB, and the amplitude of respiratory-associated blood flow oscillations characterizes the state of the capillary outflow tract, thereby reflecting

The main aim of this pilot study was to evaluate the functional state of resistive vessels of the skin in patients with essential arterial hypertension according by LDF with an amplitude-frequency wavelet analysis of microcirculation fluctuations.

the blood volume in the venular section of MVB [26, 29–31].

**136**

resistance (PVR).

The skin perfusion was assessed in the supine position after a 15-min period of adaptation in a laboratory with a constant microclimate (+23 ± 1°С) in the morning (09:00–12:00 AM). The microcirculatory blood flow was recorded by a LAKK-02 single-channel laser analyzer of blood microcirculation in the visible red spectrum (wavelength of 630 nm) and a LAKK-TEST complex (OOO Research and Production Enterprise LAZMA, Russia) that allow evaluating the perfusion parameters in ~ 1.0–1.5 mm3 of skin, at a constant temperature in the studied region of +32°С. The sensor was located on the outer surface of the right forearm, in the midline 3–4 cm proximal to the wrist joint. The perfusion was recorded for 6 min. After the microcirculation study, all subjects received 24-h ambulatory blood pressure monitoring (ABPM) on the left shoulder.

The initial LDF recording (**Figure 1A**) was subjected to amplitude-frequency wavelet analysis. The time-averaged amplitude of vasomotions was estimated by the maximum values (Amax) in the corresponding [32, 33] blood flow modulation frequency range: endothelial (Ae)—0.0095 − 0.021 Hz; neurogenic (An)—0.021 − 0.052 Hz; myogenic (Am)—0.052 − 0.145 Hz; respiratory-venular (Av)—0.145 − 0.6 Hz; pulse-cardial (Ac) —0.6 – 2 Hz (**Figure 1B**). The perfusion level (M) and the amplitudes of the blood flow modulation mechanisms were assessed in perfusion units (PU).

The functional activity of the tone-forming blood flow modulation mechanisms (endothelial, neurogenic, and myogenic) was evaluated as follows – the higher the vasomotion amplitude, the lower the tone, and vice versa, the lower the vasomotion amplitude, the higher the tone generated by this regulatory mechanism. If we take the zero amplitude as the longitudinal axis of a microvessel (LAV), and the maximum vasomotion amplitude as the vascular wall (**Figure 1B**), then the dependence of the microvessel lumen size on the vasomotion amplitude is clearly evident.

At the first stage of the study, the main objective was to assess the functional activity of resistive arterioles depending on the blood pressure level. At this stage, the subjects included 90 people (47 men and 43 women) divided into three groups. The control group (NT) consisted of 32 clinically healthy normotensive volunteers. The second group consisted of 32 patients with stage 1 essential AH (AH1). The third group included 26 patients with stage 2 AH (AH2). All patients with AH who were receiving antihypertensive therapy had their therapy discontinued 10–14 days prior to the study (washed out). In the rest of the patients, AH was newly diagnosed

#### **Figure 1.**

*Laser Doppler flowmetry (LDF). (A) It is a perfusion characteristic during 6 min. (B) It is amplitudefrequency wavelet analysis of blood flow oscillations. Dotted lines indicate a microvessel, arrows mark the activity of tone forming mechanisms in blood flow modulation. LAV, the longitudinal axis of the vessel.*


*# Differences are significant with respect to AH1 (p < 0.0001).*

#### **Table 1.**

*The main characteristics of the analyzed groups—first stage of the study.*

#### **Figure 2.**

*LDF with amplitude-frequency wavelet analysis of blood flow in the first stage of the study. (A) The functional activity of tone-forming mechanisms (Ae, An, Am) of blood flow modulation. (B) The tissue perfusion (M) and the functional activity of the passive blood flow modulation mechanisms that reflect the condition of the blood inflow tracts to the capillary bed (Ac) and the outflow (Av) tracts. The rectangle indicates a range of 25–75 percentiles, and the median is indicated by a line.*

and they had not received any drug therapy before the inclusion in the study (primary). The main characteristics of the analyzed groups and the hemodynamic parameters at the 10th minute of the adaptation period before LDF are presented in **Table 1**. According to the ABPM, the mean blood pressure (MBP) in the daytime was 89.8 ± 7.8 mm Hg in NT, 101.3 ± 5.2 mm Hg in AH 1, and 112.5 ± 6.9 mmHg in AH 2.

The functional activity of the main tone-forming microcirculation modulation mechanisms is shown in **Figure 2A**. Neither the expected increase in the basal myocyte tone (Am), nor a rise in sympathetic activity (An), nor signs of microvascular endothelial vasomotor dysfunction (Ae) were observed in any of the groups.

**Figure 2B** presents the analysis results of the tissue perfusion (M) and passive blood flow modulation mechanisms (Ac and Av) that determine the blood filling

**139**

*Functional State of the Microvascular Bed of the Skin in Essential Arterial Hypertension…*

of the microvascular bed (MVB). The data obtained demonstrate that statistically significant differences are present only in blood volume in the venular section of the MVB (Av), which indicates a gradual increase in the venular blood volume as AH progresses. It is very important that out of all six parameters analyzed, only the amplitude of respiratory-associated blood flow oscillations (Av) had a weak but significant positive correlation with the MBP in the daytime (r = 0.25; p = 0.035) and night time (r = 0.29; p = 0.013). This correlation means that the more blood

From the results obtained, it can be concluded that the functional state of the blood outflow tracts from the capillary bed plays a more significant role in the total peripheral vascular resistance (TPVR) than the functional state of resistive precapillary arterioles. The obtained data are in agreement with the opinion of Coulson et al. who distinguish two vascular resistance levels: the first is before the capillary plexus with an estimated contribution to TPVR of 67% according to the authors, and the second is after the capillary plexus with a contribution to TPVR of about 33% [34]. Functional disorders were dominant not in the blood inflow to the capillaries (resistive arterioles) but in the outflow system (venules), and that was a completely unexpected finding and does not fit into any of the existing AH development hypotheses (neurogenic, salt, membrane, etc.). It is also highly important that LDF demonstrated changes in tissue perfusion associated with respiratory movements of

And what is the nature of respiratory-associated tissue perfusion oscillations? The blood flow oscillations synchronous with breathing spread into microvessels from the capillary blood outflow side and are recorded in the venules. A mechanical passive transmission of respiratory intrathoracic pressure changes mediated by the

Normally, no respiratory-associated tissue perfusion oscillations are identified in LDF, regardless of the arterial blood volume flowing into the microcirculatory bloodstream. This is due to several factors. Firstly, the cross-sectional area and volume of the venular MVB significantly exceed the cross-sectional area and volume of the arteriolar MVB. Secondly, veins collapse. To maintain a round vein shape, a pressure of about 6–9 mmHg is required, and at lower values, the veins are ellipsoidal. With the same perimeter, the cross-sectional area of an ellipse is much smaller than that of a circle, so when the pressure increases from 0 to 6–9 mmHg, the capacity of the venous segment of the vascular bed increases substantially. Already at 10 mmHg, the increase in venous capacity is more than 60% of the maximum possible. Then the increase in the venous volume decelerates dramatically and is

How can intrathoracic pressure changes during respiration be conducted along the venous vasculature to the periphery, that is, to the postcapillary skin vessels? At low pressures, the collapsed venous walls will obviously dampen the retrograde respiratory wave propagation. Consequently, the propagation of the respiratory wave to the periphery can be observed only with fully expanded veins. Thus, the higher the blood volume in the venous bed, and hence the pressure in them, the better the respiratory waves are propagated to the periphery, and the higher is the Av amplitude. It is obvious that there is a certain critical Av value that reflects the degree of blood filling of the venous bed. During a long period of observation and measurements, the maximum Av value was found empirically to be 0.08 PU, which suggests that the veins are not yet fully expanded because the respiratory waves are not observed during the recording of tissue perfusion. At Av values of 0.09 PU, respiratory-associated oscillations of perfusion begin to appear in the LDF recording. These oscillations have a low amplitude and are not observed at every breath, which most likely depends on the volume and rate of respiratory movements.

*DOI: http://dx.doi.org/10.5772/intechopen.89852*

there is in the venular MVB, the higher the BP.

the chest in far from all AH patients.

venous system is discussed as their origin.

about 30% with a pressure rise from 10 to 80 mmHg [35].

*Functional State of the Microvascular Bed of the Skin in Essential Arterial Hypertension… DOI: http://dx.doi.org/10.5772/intechopen.89852*

of the microvascular bed (MVB). The data obtained demonstrate that statistically significant differences are present only in blood volume in the venular section of the MVB (Av), which indicates a gradual increase in the venular blood volume as AH progresses. It is very important that out of all six parameters analyzed, only the amplitude of respiratory-associated blood flow oscillations (Av) had a weak but significant positive correlation with the MBP in the daytime (r = 0.25; p = 0.035) and night time (r = 0.29; p = 0.013). This correlation means that the more blood there is in the venular MVB, the higher the BP.

From the results obtained, it can be concluded that the functional state of the blood outflow tracts from the capillary bed plays a more significant role in the total peripheral vascular resistance (TPVR) than the functional state of resistive precapillary arterioles. The obtained data are in agreement with the opinion of Coulson et al. who distinguish two vascular resistance levels: the first is before the capillary plexus with an estimated contribution to TPVR of 67% according to the authors, and the second is after the capillary plexus with a contribution to TPVR of about 33% [34].

Functional disorders were dominant not in the blood inflow to the capillaries (resistive arterioles) but in the outflow system (venules), and that was a completely unexpected finding and does not fit into any of the existing AH development hypotheses (neurogenic, salt, membrane, etc.). It is also highly important that LDF demonstrated changes in tissue perfusion associated with respiratory movements of the chest in far from all AH patients.

And what is the nature of respiratory-associated tissue perfusion oscillations? The blood flow oscillations synchronous with breathing spread into microvessels from the capillary blood outflow side and are recorded in the venules. A mechanical passive transmission of respiratory intrathoracic pressure changes mediated by the venous system is discussed as their origin.

Normally, no respiratory-associated tissue perfusion oscillations are identified in LDF, regardless of the arterial blood volume flowing into the microcirculatory bloodstream. This is due to several factors. Firstly, the cross-sectional area and volume of the venular MVB significantly exceed the cross-sectional area and volume of the arteriolar MVB. Secondly, veins collapse. To maintain a round vein shape, a pressure of about 6–9 mmHg is required, and at lower values, the veins are ellipsoidal. With the same perimeter, the cross-sectional area of an ellipse is much smaller than that of a circle, so when the pressure increases from 0 to 6–9 mmHg, the capacity of the venous segment of the vascular bed increases substantially. Already at 10 mmHg, the increase in venous capacity is more than 60% of the maximum possible. Then the increase in the venous volume decelerates dramatically and is about 30% with a pressure rise from 10 to 80 mmHg [35].

How can intrathoracic pressure changes during respiration be conducted along the venous vasculature to the periphery, that is, to the postcapillary skin vessels? At low pressures, the collapsed venous walls will obviously dampen the retrograde respiratory wave propagation. Consequently, the propagation of the respiratory wave to the periphery can be observed only with fully expanded veins. Thus, the higher the blood volume in the venous bed, and hence the pressure in them, the better the respiratory waves are propagated to the periphery, and the higher is the Av amplitude. It is obvious that there is a certain critical Av value that reflects the degree of blood filling of the venous bed. During a long period of observation and measurements, the maximum Av value was found empirically to be 0.08 PU, which suggests that the veins are not yet fully expanded because the respiratory waves are not observed during the recording of tissue perfusion. At Av values of 0.09 PU, respiratory-associated oscillations of perfusion begin to appear in the LDF recording. These oscillations have a low amplitude and are not observed at every breath, which most likely depends on the volume and rate of respiratory movements.

*Basic and Clinical Understanding of Microcirculation*

*Differences are significant with respect to NT (p < 0.000001).*

*Differences are significant with respect to AH1 (p < 0.0001).*

*The main characteristics of the analyzed groups—first stage of the study.*

and they had not received any drug therapy before the inclusion in the study (primary). The main characteristics of the analyzed groups and the hemodynamic parameters at the 10th minute of the adaptation period before LDF are presented in **Table 1**. According to the ABPM, the mean blood pressure (MBP) in the daytime was 89.8 ± 7.8 mm Hg in NT, 101.3 ± 5.2 mm Hg in AH 1, and 112.5 ± 6.9 mmHg in

*25–75 percentiles, and the median is indicated by a line.*

*LDF with amplitude-frequency wavelet analysis of blood flow in the first stage of the study. (A) The functional activity of tone-forming mechanisms (Ae, An, Am) of blood flow modulation. (B) The tissue perfusion (M) and the functional activity of the passive blood flow modulation mechanisms that reflect the condition of the blood inflow tracts to the capillary bed (Ac) and the outflow (Av) tracts. The rectangle indicates a range of* 

**NT (n = 32) AH1 (n = 32) AH2 (n = 26)**

Age (years) 48.9 ± 10.4 48.7 ± 11.2 49.8 ± 10.8 Sex (men/women) 13/19 17/15 17/9 primary/washed – / – 20/12 9/17 SBP (mmHg) 117.5 ± 9.8 141.5 ± 12.8\* 156.0 ± 15.4\*,# DBP (mmHg) 74.5 ± 8.6 86.8 ± 9.8\* 95.2 ± 12.3\*,# HR (beats/min) 65.6 ± 6.9 68.2 ± 8.1 70.6 ± 9.3

The functional activity of the main tone-forming microcirculation modulation mechanisms is shown in **Figure 2A**. Neither the expected increase in the basal myocyte tone (Am), nor a rise in sympathetic activity (An), nor signs of microvascular endothelial vasomotor dysfunction (Ae) were observed in any of the groups.

**Figure 2B** presents the analysis results of the tissue perfusion (M) and passive blood flow modulation mechanisms (Ac and Av) that determine the blood filling

**138**

AH 2.

**Figure 2.**

*\**

*#*

**Table 1.**


#### **Table 2.**

*The main characteristics of the analyzed groups—second stage of the study.*

For the second stage of the study, a homogeneous group of 63 patients with AH was selected with mean daytime SBP of 140–159 mmHg according to ABPM and/or mean daily DBP of 90–99 mmHg. Just as at the first stage, all AH patients receiving antihypertensive therapy had their therapy discontinued 10–14 days prior to the study (washed out), or AH was diagnosed for the first time with no drug therapy before inclusion into the study (primary). The control group (NT) consisted of 30 clinically healthy normotensive volunteers. Based on the functional state of the venular microvessels (Av), the AH patients were divided into two groups. The first (VN) included 30 patients (48%) with no signs of an increased blood volume in the venular MVB (Av ≤ 0.08 PU). The second group (VP) consisted of 33 patients (52%) with signs of hypervolemia in the blood outflow tracts from the capillary bed (Av ≥ 0.09 PU) of varying severity. The groups characteristics and the hemodynamic parameters immediately before LDF (10th minute of the adaptation period) are presented in **Table 2**.

Based on the grouping parameter (Av) value, 8 subjects in the NT group (27%) had a moderate increase in blood volume in the venular MVB – Av = 0.09 PU (n = 3), Av = 0.1 PU (n = 4), Av = 0.12 PU (n = 1).

**Figure 3** presents clinical examples of LDF in the groups analyzed. BP was measured 5 min before the start of LDF. **Figure 3B** shows that not every respiratory movement of a normotensive volunteer from the NT group is accompanied by a distinct change in tissue perfusion, and the main differences are observed in the amplitude of respiratory-associated blood flow oscillations. In a VP patient (**Figure 3D**), the differences are more pronounced not in amplitude but in the frequency of perfusion changes that coincide with the respiration frequency.

An analysis of the perfusion level and microcirculatory blood flow modulation mechanisms which determine the MVB blood filling demonstrated that in the VN group there was no statistically significant difference in tissue perfusion and pulse oscillation amplitude relative to NT, and the blood filling of venules is lower (**Figure 4A**). The situation is totally different in the VP group. A statistically significant rise in tissue perfusion relative to NT (p < 0.0003) can be explained by an increased contribution to the power of the signal reflected from red blood cells in the venular MVB. An unexpected finding was a significant increase in the amplitude of pulse oscillations relative to NT (p < 0.004), which indicates a higher arterial blood inflow to the exchange vessels. The obtained results demonstrate that the increase in the MVB perfusion is caused not only by a larger blood volume in the venular section (disrupted outflow) but also by an increased inflow of arterial blood.

An analysis of the functional activity of the tone-forming mechanisms demonstrated a significant (p < 0.002) decrease was also observed in the amplitude of

**141**

**Figure 4.**

*mechanisms (Ae, an, Am).*

**Figure 3.**

*Functional State of the Microvascular Bed of the Skin in Essential Arterial Hypertension…*

*The first minute of LDF. The functional state of the venular MVB. (A) NT group, BP is 115/70 mmHg: Respiratory-associated blood flow oscillations are not detected, perfusion (M) is 3.81 PU, respiration rate (RR) is 16/min, and Av is 0.05 PU. (B) NT group, BP is 130/80 mmHg: М – 3.82 PU, RR – 16/min, Av – 0.10 PU. (C) VN group, BP is 145/80 mmHg: M – 3.56 PU, RR – 16/min, Av – 0.07 PU. (D) VP group, BP is* 

*150/90 mmHg: M – 3.89 PU, RR – 16/min, Av – 0.20 PU. The dotted lines reflect the changes in tissue perfusion* 

*LDF with amplitude-frequency wavelet analysis of blood flow in the second stage of the study. (A) The tissue perfusion (M) and the functional activity of the microcirculation modulation mechanisms which determine the blood filling of the microcirculatory bloodstream – The pulse (Ac) and respiratory-associated (Av) blood flow oscillation amplitude. (B) The functional activity of the tone-forming microcirculation modulation* 

*DOI: http://dx.doi.org/10.5772/intechopen.89852*

*synchronized with the respiratory chest movements.*

*Functional State of the Microvascular Bed of the Skin in Essential Arterial Hypertension… DOI: http://dx.doi.org/10.5772/intechopen.89852*

#### **Figure 3.**

*Basic and Clinical Understanding of Microcirculation*

*Differences are significant with respect to NT (p < 0.000005).*

*The main characteristics of the analyzed groups—second stage of the study.*

are presented in **Table 2**.

frequency.

*\**

**Table 2.**

For the second stage of the study, a homogeneous group of 63 patients with AH was selected with mean daytime SBP of 140–159 mmHg according to ABPM and/or mean daily DBP of 90–99 mmHg. Just as at the first stage, all AH patients receiving antihypertensive therapy had their therapy discontinued 10–14 days prior to the study (washed out), or AH was diagnosed for the first time with no drug therapy before inclusion into the study (primary). The control group (NT) consisted of 30 clinically healthy normotensive volunteers. Based on the functional state of the venular microvessels (Av), the AH patients were divided into two groups. The first (VN) included 30 patients (48%) with no signs of an increased blood volume in the venular MVB (Av ≤ 0.08 PU). The second group (VP) consisted of 33 patients (52%) with signs of hypervolemia in the blood outflow tracts from the capillary bed (Av ≥ 0.09 PU) of varying severity. The groups characteristics and the hemodynamic parameters immediately before LDF (10th minute of the adaptation period)

Age (years) 44.9 ± 10.4 48.9 ± 10.3 47.8 ± 10.3 Sex (men/women) 15/15 17/13 17/16 primary/washed – / – 12/18 11/22 SBP (mmHg) 118.0 ± 10.1 140.0 ± 14.1\* 142.6 ± 14.7\* DBP (mmHg) 76.5 ± 9.0 88.3 ± 9.8\* 91.1 ± 8.9\* HR (beats/min) 65.8 ± 8.5 68.1 ± 7.9 67.2 ± 9.1

**NT (***n* **= 30) VN (***n* **= 30) VP (***n* **= 33)**

Based on the grouping parameter (Av) value, 8 subjects in the NT group (27%)

**Figure 3** presents clinical examples of LDF in the groups analyzed. BP was measured 5 min before the start of LDF. **Figure 3B** shows that not every respiratory movement of a normotensive volunteer from the NT group is accompanied by a distinct change in tissue perfusion, and the main differences are observed in the amplitude of respiratory-associated blood flow oscillations. In a VP patient (**Figure 3D**), the differences are more pronounced not in amplitude but in the frequency of perfusion changes that coincide with the respiration

An analysis of the perfusion level and microcirculatory blood flow modulation mechanisms which determine the MVB blood filling demonstrated that in the VN group there was no statistically significant difference in tissue perfusion and pulse oscillation amplitude relative to NT, and the blood filling of venules is lower (**Figure 4A**). The situation is totally different in the VP group. A statistically significant rise in tissue perfusion relative to NT (p < 0.0003) can be explained by an increased contribution to the power of the signal reflected from red blood cells in the venular MVB. An unexpected finding was a significant increase in the amplitude of pulse oscillations relative to NT (p < 0.004), which indicates a higher arterial blood inflow to the exchange vessels. The obtained results demonstrate that the increase in the MVB perfusion is caused not only by a larger blood volume in the venular section

An analysis of the functional activity of the tone-forming mechanisms demonstrated a significant (p < 0.002) decrease was also observed in the amplitude of

(disrupted outflow) but also by an increased inflow of arterial blood.

had a moderate increase in blood volume in the venular MVB – Av = 0.09 PU

(n = 3), Av = 0.1 PU (n = 4), Av = 0.12 PU (n = 1).

**140**

*The first minute of LDF. The functional state of the venular MVB. (A) NT group, BP is 115/70 mmHg: Respiratory-associated blood flow oscillations are not detected, perfusion (M) is 3.81 PU, respiration rate (RR) is 16/min, and Av is 0.05 PU. (B) NT group, BP is 130/80 mmHg: М – 3.82 PU, RR – 16/min, Av – 0.10 PU. (C) VN group, BP is 145/80 mmHg: M – 3.56 PU, RR – 16/min, Av – 0.07 PU. (D) VP group, BP is 150/90 mmHg: M – 3.89 PU, RR – 16/min, Av – 0.20 PU. The dotted lines reflect the changes in tissue perfusion synchronized with the respiratory chest movements.*

#### **Figure 4.**

*LDF with amplitude-frequency wavelet analysis of blood flow in the second stage of the study. (A) The tissue perfusion (M) and the functional activity of the microcirculation modulation mechanisms which determine the blood filling of the microcirculatory bloodstream – The pulse (Ac) and respiratory-associated (Av) blood flow oscillation amplitude. (B) The functional activity of the tone-forming microcirculation modulation mechanisms (Ae, an, Am).*

neurogenic vasomotions (An), which can be regarded as an increase in the sympathetic adrenergic tone. Meanwhile, the basal tone of smooth muscle cells (Am) was unchanged and comparable to that in the control group (**Figure 4B**).

The tone-forming mechanisms were in a completely opposite state in the VP group. Relative to NT, there were no significant differences in the functional activity of the endothelial and neurogenic arteriolar tone regulation mechanisms, although there was a trend towards a vasomotion amplitude increase by these regulatory mechanisms. However, the basal tone of the smooth muscle cells in precapillary arterioles and capillary sphincters was significantly reduced (p < 0.05), which was indicated by the myogenic vasomotion amplitude (Am) increase.

Thus, according to the functional state of the skin microcirculatory vessels, we obtained two completely opposite groups of patients with AH that initially seemed homogeneous. The differences between the groups were observed in all the six parameters analyzed: tissue perfusion (p < 0.002), amplitude of pulse (p < 0.002) and respiratory-associated (p < 0.000001) blood flow oscillations, amplitude of endothelial (p < 0.002), neurogenic (p < 0.003), and myogenic (p < 0.003) vasomotions.

From the data obtained it can be assumed that in AH patients without disruptions blood outflow from the capillary bed, hypertension is caused by an increase in the sympathetic adrenergic vascular tone regulation mechanism and by a vasomotor dysfunction of the microvascular endothelium. In patients with impaired blood outflow from the capillary bed associated with a decline in the myogenic tone of precapillary arterioles, an increase in the arterial blood inflow is observed.

The ABPM results were no less interesting. **Figure 5** shows significantly higher BP during both day and nighttime in the VP patients relative to VN, except for the nocturnal diastolic BP. A paradoxical situation arose – BP was higher in patients with a reduced resistive arteriolar tone than in patients with an increased tone.

#### **Figure 5.**

*The results of 24-h arterial blood pressure monitoring (ABPM). (А) Systolic BP (SBP). (B) Diastolic BP (DBP). (C) Mean BP (MBP).*

**143**

*Functional State of the Microvascular Bed of the Skin in Essential Arterial Hypertension…*

arterial hypertension raised fundamental questions that require reflection and

The pilot study of the functional state of the skin microvascular bed in essential

The first fundamental question is the validity of LDF in assessing the functional state of the resistive vascular bed in AH. On the one hand, there is no statistically significant correlation of BP with the functional activity of the tone-forming mechanisms in resistive arterioles. This can be explained by the absence of regulatory baroreflex mechanisms in the skin microvessels in contrast to microvessels in the striated muscle. On the other hand, the amplitude-frequency wavelet analysis of microcirculatory blood flow oscillations demonstrated that the functional state of the regulatory mechanisms in exchange microvessels may differ drastically in the initially homogeneous group of AH patients. This, in turn, not only has different hemodynamic and metabolic effects but quite evidently demands an individual

Let us consider the VN group in terms of the functional state of resistive arterioles. This group has a moderate decrease in the endothelial vasomotion amplitude with a trend towards significance (p = 0.065), indicating vasomotor dysfunction of the microvascular endothelium, which is consistent with the previously obtained results [36]. The group also exhibits a significant reduction in the neurogenic vasomotion amplitude (p < 0.002), which can be regarded as an increase in the sympathetic adrenergic tone. From the data obtained, it can be concluded that the functional state of resistive arterioles in AH patients with normal blood outflow from the capillary bed does not contradict Lang's neurogenic theory and the current ideas about the role of endothelial dysfunction in the AH pathogenesis. In such a functional state of the resistive arterioles, the prescription of drugs which lead to a tone decrease through various regulatory mechanisms can be considered

Now let us consider the VP group, which raises many more questions. Based on the precapillary arteriole functional state, it can be concluded that there is a significant decrease in the basal tone of smooth muscle cells in arterioles and capillary sphincters. The insignificant (relative to NT) trend towards an amplitude increase (tone decline) of endothelial and neurogenic vasomotions can be explained in two ways: 1) changes in the regulatory systems themselves; 2) decreased smooth muscle cell sensitivity to the regulatory effects of the endothelium and the sympathetic adrenergic system. The hemodynamic consequences of the precapillary arteriolar tone are an increase in the arterial blood inflow (Ac), venular blood volume (Av),

Gryglewska et al. [37] also draw attention to a significant increase in the vasomotion amplitude in the neurogenic and myogenic activity range in patients with masked hypertension. The patients analyzed in that study were on average 10 years younger than our subjects. The data presented by the authors demonstrate that a neurogenic tone decline is observed against the background of an increased norepinephrine level. One possible cause for the increased plasma norepinephrine is the neurotransmitter leakage from the neuro-muscular synapses in microvessels in AH patients when the sympathetic nervous system activity is enhanced. This phenomenon is well-established for skeletal muscles [38, 39], but not for the skin microvessels which are not subject to baroreflex regulation [40]. The authors of the study suggest that the vasomotion amplitude increase in patients with masked hypertension is of a compensatory nature, aimed at meeting the metabolic needs of tissues when there is a reduced number of functioning capillaries, while the

and as a result, tissue hyperperfusion, i.e. an increase in M.

*DOI: http://dx.doi.org/10.5772/intechopen.89852*

approach to selecting antihypertensive therapy.

**3. Discussion**

quite justified.

detailed consideration.

*Functional State of the Microvascular Bed of the Skin in Essential Arterial Hypertension… DOI: http://dx.doi.org/10.5772/intechopen.89852*
