Novel Method to Assess Endothelial Function via Monitoring of Perfusion Response to Local Heating by Imaging Photoplethysmography.

Endothelial dysfunction is one of the most important markers of the risk of cardiovascular complications. This study is aimed to demonstrate the feasibility of imaging photoplethysmography to assess microcirculation response to local heating in order to develop a novel technology for assessing endothelial function. As a measure of vasodilation, we used the relative dynamics of the pulsatile component of the photoplethysmographic waveform, which was assessed in a large area of the outer surface of the middle third of the subject's forearm. The perfusion response was evaluated in six healthy volunteers during a test with local skin heating up to 40-42 °C and subsequent relaxation. The proposed method is featured by accurate control of the parameters affecting the microcirculation during the prolonged study. It was found that in response to local hyperthermia, a multiple increase in the pulsation component, which has a biphasic character, was observed. The amplitude of the first phase of the perfusion reaction depends on both the initial skin temperature and the difference between the basal and heating temperatures. The proposed method allows the assessment of a reproducible perfusion increase in response to hyperthermia developed due to humoral factors associated with the endothelium, thus allowing detection of its dysfunction.

Novel capsaicin-induced parameters of microcirculation in migraine patients revealed by imaging photoplethysmography.

BACKGROUND: The non-invasive biomarkers of migraine can help to develop the personalized medication of this disorder. In testing of the antimigraine drugs the capsaicin-induced skin redness with activated TRPV1 receptors in sensory neurons associated with the release of the migraine mediator CGRP has already been widely used. METHODS: Fourteen migraine patients (mean age 34.6 ± 10.2 years) and 14 healthy volunteers (mean age 29.9 ± 9.7 years) participated in the experiment. A new arrangement of imaging photoplethysmography recently developed by us was used here to discover novel sensitive parameters of dermal blood flow during capsaicin applications in migraine patients. RESULTS: Blood pulsation amplitude (BPA) observed as optical-intensity waveform varying synchronously with heartbeat was used for detailed exploration of microcirculatory perfusion induced by capsicum patch application. The BPA signals, once having appeared after certain latent period, were progressively rising until being saturated. Capsaicin-induced high BPA areas were distributed unevenly under the patch, forming "hot spots." Interestingly the hot spots were much more variable in migraine patients than in the control group. In contrast to BPA, a slow component of waveforms related to the skin redness changed significantly less than BPA highlighting the latter parameter as the potential sensitive biomarker of capsaicin-induced activation of the blood flow. Thus, in migraine patients, there is a non-uniform (both in space and in time) reaction to capsaicin, resulting in highly variable openings of skin capillaries. CONCLUSION: BPA dynamics measured by imaging photoplethysmography could serve as a novel sensitive non-invasive biomarker of migraine-associated changes in microcirculation.

Autonomous control of cardiovascular reactivity in patients with episodic and chronic forms of migraine.

BACKGROUND: The autonomous cardiovascular control can contribute to progression of migraine. However, current data on cardiovascular reactivity in migraine, especially severe forms, are essentially contradictory. The main aim of this study was to compare the autonomous regulation of circulation in patients with episodic and chronic migraine and healthy subjects. METHODS: Seventy three migraine patients (mean age 35 ± 10) including episodic migraine (51 patients, 4-14 headache days/months) and chronic migraine (22 patients, ≥15 headache days/month) along with age-match control (71 healthy voluntaries) were examined. The autonomic regulation of circulation was examined with the tilt-table test, a deep breathing and Valsalva Maneuver, handgrip test, cold-stress vasoconstriction, arterial baroreflex and blood pressure variability. RESULTS: The changes in heart rate induced by deep breathing, Valsalva Maneuver, and blood pressure in tilt-table test in patients with migraine did not differ from the control group. In contrast, the values of cold-stress-vasoconstriction forearm blood-flow reactivity (p <0.001), the increase in diastolic blood pressure in handgrip test (p <0.001), mean blood pressure in the late stage of the second phase of Valsalva Maneuver (p <0.001) and blood pressure variability (p <0.005) were all higher in patients with migraine than in the control group. CONCLUSION: Thus, both episodic and chronic migraine are associated with significant disturbances in autonomous control resulting in enhanced vascular reactivity whereas the cardiac regulation remains largely unchanged.

Plethysmographic assessment of vasomotor response in patients with congestive heart failure before and after heart transplantation.

Sympathetic vasomotor response is the most important part of the autonomic regulation of circulation, which determines the quality of life. It is disrupted in a number of diseases, particularly in patients with congestive heart failure (CHF). However, experimental evaluation of reflex vasoconstriction is still a non-trivial task due to the limited set of available technologies. The aim of this study is to assess the dynamics of vasomotor response of forearm vessels due to both the deactivation of cardiopulmonary baroreceptors and cold stress using a newly designed imaging plethysmograph (IPG) and compare its performance with classical air plethysmograph (APG). In both vasoconstriction tests, vasomotor response was assessed as a change in the blood flow rate due to venous occlusion compared to that at rest. Both tests were carried out in 45 CHF patients both before and after heart transplantation, as well as in 11 age-matched healthy volunteers. Prior to transplantation, both APG and IPG showed a significant decrease in vasomotor response in CHF patients due to both tests as compared to the control group. After heart transplantation, an increase in vasomotor reactivity was revealed in both vasoconstriction tests. We have found that both plethysmographic techniques provide correlated assessment of changes in the vasomotor response. In addition, we have found that IPG is more resistant to artifacts than APG. The new IPG method has the advantage of measuring blood flow in a contactless manner, making it very promising for experimental evaluation of vasomotor response in clinical conditions.

Effect of Physical Training on the Morphology of Parasympathetic Atrial Ganglia after Unilateral Vagotomy in Rats.

Cardiac denervation is a serious problem in a number of patients, including patients after heart transplantation. The status of the parasympathetic ganglia after crossing the preganglionic fibers of the vagus nerve has not been enough studied. The aim of our study was to assess the effect of physical training on the morphological parameters of the parasympathetic atrial ganglia and autonomic regulation of heart rate after right- and left-sided vagotomy in rats. Morphometric characteristics of the right atrial ganglia were evaluated using an immunohistochemical method after a study that included a three-time assessment of heart rate variability. It was found that right-sided vagotomy leads to both an increase in the volume of ganglion and autonomic dysfunction. No significant change in the number of nerve cells was found in animals with false and left-sided vagotomy while maintaining preganglionic innervation after the physical training, whereas exercises led to a decrease in the volume of nerve tissue of rats with right-sided denervation. It was also found that in animals with preserved vagal innervation, the volume of atrial ganglion tissue correlates with overall heart rate variability and a normalized parasympathetic component. Therefore, a positive effect from regular physical activity on parasympathetic regulation can be expected only if preganglionic vagal influence is preserved.

Transcutaneous Spinal Cord Stimulation Attenuates Blood Pressure Drops in Orthostasis.

Orthostatic hypotension is a complex medical problem with various underlying pathogenic mechanisms and limited modalities for its correction. Since transcutaneous spinal cord stimulation (t-SCS) leads to immediate blood pressure (BP) elevation in a supine position, we suggested that t-SCS may attenuate blood pressure drops in orthostasis. We aimed to evaluate the hemodynamic effects of t-SCS during tilt testing in a feasibility study in three patients with documented orthostatic hypotension. Four sessions on two different days of tilt testing on and off t-SCS were performed on each patient. While tilting with t-SCS off showed typical significant BP drops in every patient, active t-SCS resulted in systemic vascular resistance (SVR) elevation in all patients and significantly higher values of systolic and diastolic BP in two patients. T-SCS requires further investigation on a larger patient population. However, our preliminary results demonstrate its ability for SVR and BP elevation in subjects with severe orthostatic hypotension.

Study of cerebrovascular reactivity to hypercapnia by imaging photoplethysmography to develop a method for intraoperative assessment of the brain functional reserve.

Intraoperative assessment of cerebrovascular reactivity is a relevant problem of neurosurgery. To assess the functional reserve of cerebral blood flow, we suggest using imaging photoplethysmography for measuring changes in cortical perfusion caused by CO2 inhalation. Feasibility of the technique was demonstrated in three groups of anesthetized rats (n=21) with opened and closed cranial windows. Our study for the first time revealed that the hemodynamic response to hypercapnia strongly depends on the cranial state. However, it was shown that regardless of the direction of changes in local and systemic hemodynamics, the ratio of normalized changes in arterial blood pressure and cortical perfusion could be used as a measure of the cerebrovascular functional reserve.

Animal model of assessing cerebrovascular functional reserve by imaging photoplethysmography.

Assessment of the cerebral blood-flow-reserve in patients with cerebrovascular diseases is extremely important in terms of making prognosis, determining treatment tactics, and controlling the revascularization outcome in the case of reconstructive interventions on the brain vessels. However, there is no easy-to-use, contactless method for either assessing the functional reserve of the cortical vascular network or intraoperative monitoring of surgical intervention. Our study aims to demonstrate feasibility of green-light imaging photoplethysmography (iPPG) to estimate cerebrovascular functional reserve in animal model of craniosurgical intervention. Custom-made iPPG system was exploited to visualize intracranial vessels in anesthetized Wistar rats (n = 15). Video frames of rat's cortex were recorded concurrently with systemic blood pressure, end-tidal CO2, and electrocardiogram. We found that injection of dorzolamide (carbonic-anhydrase inhibitor) significantly increased the blood-pulsations amplitude in all animals by 35 ± 19% (p < 0.001). Such an increase negatively correlated with significant decrease in end-tidal CO2 by 32 ± 7% (p < 0.001). It is noteworthy that the dorzolamide injection did not lead to significant changes in systemic blood pressure. Concluding, pulsations amplitude is a marker of the vascular tone that can be used to evaluate the functional cerebrovascular reserve. Imaging PPG is a simple and convenient method to assess cerebral blood flow, including during various neurosurgical interventions.

Novel instrumental markers of proximal scleroderma provided by imaging photoplethysmography.

OBJECTIVE: Instrumental identification of proximal scleroderma, which is necessary for the early diagnosis of systemic sclerosis (SSD), has not yet been developed. The aim of this study was to assess the potential diagnostic value of the imaging photoplethysmography (IPPG) method in patients with SSD. APPROACH: The study enrolled 19 patients with SSD and 21 healthy subjects matched by age and sex with the patients. Spatial distribution of capillary-blood-flow parameters and their dynamics was estimated in the facial area of patients and subjects. In the IPPG system, a 40 s video of the subject's face illuminated by green polarized light was recorded with a monochrome digital camera in synchronization with the electrocardiogram. Experimental data were processed using custom software allowing assessment of an arrival time of the blood pressure wave (PAT), an amplitude of pulsatile component (APC) of the photoplethysmographic (PPG) waveform, and their variability. MAIN RESULTS: Our study has revealed a significant increase in PAT variability in patients with SSD compared to the control group: 52 ± 47 ms vs 24 ± 13 ms (P =0.01). Similarly, the variability of the PPG-pulse shape was larger in patients with SSD: 0.13 ± 0.07% vs 0.09 ± 0.02% (P < 0.001). In addition, patients with scleroderma showed a significantly greater degree of asymmetry of the APC parameter than the control group: 17.7 ± 9.7 vs 7.9 ± 5.0 (P < 0.001). At the same time, no correlation was found between the PPG waveform parameters and either the form or duration of the disease. Also, no relationship between the characteristics of the PPG waveform and the modified Rodnan skin score was found. SIGNIFICANCE: Novel instrumental markers found in our pilot study showed that the IPPG method can be used for diagnosing SSD in the early stages of the disease.

Analysis of blood pressure-heart rate feedback regulation under non-stationary conditions: beyond baroreflex sensitivity.

The feedback regulation of blood pressure and heart rate is an important indicator of human autonomic function usually assessed by baroreflex sensitivity (BRS). We suggest a new method yielding a higher temporal resolution than standard BRS methods. Our approach is based on a regression analysis of the first differences of inter-heartbeat intervals and blood pressure values. Data are recorded from 23 patients with hypertension and sleep apnoea, 22 patients with diabetes mellitus and 23 healthy subjects. Using the proposed method for 3 min data segments, we obtain average regression coefficients of 9.1 and 3.5 ms mmHg(-1) for healthy subjects in supine and orthostatic positions, respectively. In patients with hypertension, we find them to be 3.8 and 2.6 ms mmHg(-1). The diabetes patients with and without autonomic neuropathy are characterized by 3.1 and 6.1 ms mmHg(-1) in the supine position compared with 1.7 and 3.3 ms mmHg(-1) in the orthostatic position. The results are highly correlated with conventional BRS measures; we find r > 0.9 for the dual sequence method. Therefore, we suggest that the new method can quantify BRS. It is superior in distinguishing healthy subjects from patients both in supine and orthostatic positions for short-term recordings. It is suitable for non-stationary data and has good reproducibility. Besides, we cannot exclude that other regulatory mechanisms than BRS may also contribute to the regression coefficients between the first differences.

The Autonomic Regulation of Circulation and Adverse Events in Hypertensive Patients during Follow-Up Study.

PURPOSE: Comprehensive study of autonomic regulation assessed during follow-up could provide new detailed information about the risks stratification for hypertensive patients. Therefore, we investigated the associations of these indices with death, stroke, and revascularization during the follow-up observation of 55 patients. METHODS: All patients were with target organ damage, and 27 of them had associated clinical conditions (ACC). Mean age of patients with and without ACC was 62.6 ± 4.2 and 51.9 ± 9.9 (mean ± SD) years, respectively. Follow-up was from 66 to 95 months. At entry, autonomic regulation was assessed by the tilt test, Valsalva maneuver, hand-grip test, and cold-stress vasoconstriction. Hemodynamic parameters were measured by continuous blood pressure monitoring, occlusion plethysmography, and electrocardiography. Re-examination of patients was carried out by questioning and physical and laboratory examination. RESULTS: We found that fatal outcomes were associated with a lower Valsalva index (1.34 ± 0.16 vs. 1.69 ± 0.37, P < 0.05) and depressed cold vasoconstriction (0.20 ± 0.02 vs. 0.39 ± 0.16%, P < 0.05) and depressed cold vasoconstriction (0.20 ± 0.02 vs. 0.39 ± 0.16%, P < 0.05) and depressed cold vasoconstriction (0.20 ± 0.02 vs. 0.39 ± 0.16%, P < 0.05) and depressed cold vasoconstriction (0.20 ± 0.02 vs. 0.39 ± 0.16%, P < 0.05) and depressed cold vasoconstriction (0.20 ± 0.02 vs. 0.39 ± 0.16%, P < 0.05) and depressed cold vasoconstriction (0.20 ± 0.02 vs. 0.39 ± 0.16%, P < 0.05) and depressed cold vasoconstriction (0.20 ± 0.02 vs. 0.39 ± 0.16%. CONCLUSIONS: This study shows that such autonomic regulation indices as Valsalva index, blood pressure dynamics in the tilt test, cold-stress vasomotor reactivity, and BPV are important for prognosis of hypertension course.

Contactless Assessment of Cerebral Autoregulation by Photoplethysmographic Imaging at Green Illumination.

Accurate and practical assessment of the brain circulation is needed to adequately estimate the viability of cerebral blood flow regulatory mechanisms in various physiological conditions. The objective of our study was to examine feasibility of the contactless green-light imaging photoplethysmography (PPG) for assessing cerebral autoregulation by revealing the dynamic relationships between cortical microcirculation assessed by PPG and changes in systemic blood pressure caused by visceral and somatic peripheral stimuli. In anesthetized male Wistar rats, the PPG video images of the open parietal cortex (either with unimpaired or dissected dura mater), electrocardiogram, and systemic arterial blood pressure (ABP) in the femoral artery were continuously recorded before, during and after visceral (colorectal distension) or somatic (tail squeezing) stimulation. In the vast majority of experiments with intact and removed dura mater, both spontaneous and peripheral stimulation-evoked changes in ABP negatively correlated with the accompanying alterations in the amplitude of pulsatile PPG component (APC), i.e., an increase of ABP resulted in a decrease of APC and vice versa. The most pronounced ABP and APC alterations were induced by noxious stimuli. Visceral painful stimulation in all cases caused short-term hypotension with simultaneous increase in cortical APC, whereas somatic noxious stimuli in 8 of 21 trials produced hypertensive effect with decreased APC. Animals with pressure 50-70 mmHg possessed higher negative cerebrovascular response rate of ABP-APC gradients than rats with either lower or higher pressure. Severe hypotension reversed the negative ratio to positive one, which was especially evident under visceral pain stimulation. Amplitude of the pulsatile PPG component probably reflects the regulation of vascular tone of cerebral cortex in response to systemic blood pressure fluctuations. When combined with different kinds of peripheral stimuli, the technique is capable for evaluation of normal and elucidation of impaired cerebrovascular system reactivity to particular physiological events, for example pain. The reported contactless PPG monitoring of cortical circulatory dynamics during neurosurgical interventions in combination with recordings of changes in other physiological parameters, such as systemic blood pressure and ECG, has the appealing potential to monitor viability of the cortex vessels and determine the state of patient's cerebrovascular autoregulation.

Visualization of skin capillaries with moving red blood cells in arbitrary area of the body.

Evaluation of skin microcirculation allows for the assessment of functional states for neuroendocrine and endothelial regulation. We present a novel method to visualize skin microvessels in any area of the body, which is in contrast to classical capillaroscopy, in which the application areas are limited to the nailfold and retina capillaries. The technique is based on microscopic video-image analysis. It exploits a specific feature of irregularity of red-blood-cells motion. Feasibility of the method is demonstrated by mapping the skin capillaries in the forearm and face of 11 healthy volunteers. The proposed method is promising for the quantitative assessment of cutaneous microcirculation in a wide range of diseases and functional states.

Contactless monitoring of the blood-flow changes in upper limbs.

Vasomotor reactivity, which is important to estimate neurogenic regulation of blood vessels in patients with different pathologies, is still assessed by occlusion plethysmography using sensors contacting the limbs. Recently we proposed a contactless approach for measuring blood flow changes during venous occlusion using imaging photoplethysmography [Kamshilin et al., Sci. Rep.7, 4642017]. In this work, the response of the vascular system on the occlusion was studied simultaneously by contact air-plethysmography system and remote optical system under illumination by incoherent polarized green light. A high correlation (r > 0.93) between the waveforms measured by both system was observed. Moreover, we found that the response of the optical system on the venous occlusion is uniform at the whole area of the forearm. The new optical technique is more convenient for assessment of the blood flow dynamics because it can be used for measurements in any part of the body. Method of imaging photoplethysmography is very promising for use in equipment intended for evaluation of neurogenic mechanisms of regulation of vascular blood flow.

Alterations of blood pulsations parameters in carotid basin due to body position change.

The velocity of the pulse wave (PWV) propagating through the vascular tree is an essential parameter for diagnostic the state of the cardiovascular system especially when it is measured in the pool of carotid arteries. In this research, we showed for the first time that the time of the blood-pressure-wave propagation from the heart to the face is a function of the body position. Significant asymmetry and asynchronicity of blood pulsations in the facial area were found in a recumbent position. Parameters of blood pulsations were measured by an advanced camera-based photoplethysmography system in 73 apparently healthy subjects. Most likely, observed changes of the blood-pulsation parameters are caused by variations of the arterial blood pressure due to hydrostatic pressure changes, and secondary reaction of blood vessels in response to these variations. Demonstrated feasibility of PWV measurements in the pool of carotid arteries provides considerable advantages over other technologies. Moreover, possibilities of the method to estimate physiological regulation of the peripheral blood flow (particularly, as a response to the gravitational changes) have been demonstrated. The proposed concept allows development of non-invasive medical equipment capable of solving a wide range of scientific and practical problems related to vascular physiology.

Novel contactless approach for assessment of venous occlusion plethysmography by video recordings at the green illumination.

Occlusion plethysmography is an important method for assessment of the status of the cardiovascular system, which provides valuable information concerning arterial and venous blood flow, including mechanisms of their regulation. All up-to-date systems estimate change of the limb's volume during occlusion by contact-type sensors. The objective of the research is demonstration of feasibility of the novel approach to measuring the blood flow during venous occlusion by using imaging photoplethysmography (PPG). Twenty healthy individuals participated in the experiment. We used four synchronized video cameras to record all-around view of the forearm illuminated by the green light. After the recording, the PPG waveform was calculated in more than 4000 non-overlapping Regions of Interest (ROI). In the most of the ROIs, the waveform shape was typical for classical plethysmography with the distinctive linear growth of the signal. Speed of the signal change was the same along the forearm but it varied along the forearm's circumference. These findings allows us to hypothesize that the PPG waveform is the direct consequence of the forearm blood flow. Therefore, the novel technique could be applied to the same medical examinations as the classical plethysmography, but it is more advantageous because of non-contact nature and easiness in implementation.

Arterial hypertension in migraine: Role of familial history and cardiovascular phenotype.

Recent studies indicate that migraine is associated with increased risk of cardiovascular diseases. However, links between autonomic cardiovascular regulation, arterial hypertension (AH) and migraine are still little explored. In this study, we evaluated autonomic regulation in migraine patients with and without hypertension. We studied 104 patients with migraine, aged 34±10 y, including 28 with and 76 without hypertension (M+AH and M-AH groups, respectively). The control group consisted of 88 healthy volunteers matched by age and sex. The autonomic regulation of circulation was examined with the tilt-table test, deep-breathing and Valsalva Maneuver, handgrip test, cold-stress induced vasoconstriction, arterial baroreflex, and blood pressure variability measurements. We found that migraine patients with concomitant hypertension demonstrated reduced arterial baroreflex, whereas other parameters of cardiac autonomic regulation were unchanged. In contrast, most indicators of vasomotor reactivity (blood pressure response to the hand-grip, Valsalva maneuver and cold vasoconstriction) were enhanced in migraine patients with no significant differences between migraine patients with and without hypertension. Patients from both M+AH and M-AH groups more commonly had a family history of cardiovascular disorders. Our data revealed increased vasomotor reactivity in migraine patients, with or without concomitant hypertension. This was associated with the family history of cardiovascular diseases.

Video capillaroscopy clarifies mechanism of the photoplethysmographic waveform appearance.

Photoplethysmography (PPG) devices are widely used in clinical practice but the origin of PPG signal is still under debating. The classical theory assumes that the PPG waveform stems from variations of blood volume in pulsating arteries. In this research we analysed high-speed video recordings of capillaries in a fingernail bed. It was found that speed of erythrocytes in capillaries has pronounced modulation in time, which follows variations of instantaneous blood pressure in arteries. However, the mean speed significantly differs even for neighbour capillaries whereas change of the speed occurs in phase for the most of capillaries. Moreover, the light intensity remitted from the papillary dermis is also modulated at the heartbeat frequency displaying significant correlation with waveforms of the RBC speed. Obtained results can hardly be explained by the classical theory of PPG signal formation. Shallow penetrating visible light acquires modulation of erythrocytes density in the capillary bed without interacting with deeper situated pulsating arteries. Therefore, the capillary bed could serve as a distributed sensor for monitor the status of deep vessels. Better understanding of the photoplethysmography basis will result in a wider range of applications of this fast growing technology in both medical and research practice.

Accurate measurement of the pulse wave delay with imaging photoplethysmography.

Assessment of the cardiovascular parameters using noncontact video-based or imaging photoplethysmography (IPPG) is usually considered as inaccurate because of strong influence of motion artefacts. To optimize this technique we performed a simultaneous recording of electrocardiogram and video frames of the face for 36 healthy volunteers. We found that signal disturbances originate mainly from the stochastically enhanced dichroic notch caused by endogenous cardiovascular mechanisms, with smaller contribution of the motion artefacts. Our properly designed algorithm allowed us to increase accuracy of the pulse-transit-time measurement and visualize propagation of the pulse wave in the facial region. Thus, the accurate measurement of the pulse wave parameters with this technique suggests a sensitive approach to assess local regulation of microcirculation in various physiological and pathological states.