Effect of pulsed laser parameters on photoacoustic flow cytometry efficiency in vitro and in vivo.

Photoacoustic flow cytometry is one of the most effective approaches to detect "alien" objects in the bloodstream, including circulating tumor cells, blood clots, parasites, and emboli. However, the possibility of detecting high-amplitude signals from these objects against the background of blood depends on the parameters of the laser pulse. So, the dependencies of photoacoustic signals amplitude and number on laser pulse energy (5-150 µJ), pulse length (1, 2, 5 ns), and pulse repetition rate (2, 5, 10 kHz) for the melanoma cells were investigated. First, the PA responses of a melanoma cell suspension in vitro were measured to directly assess the efficiency of converting laser light into an acoustic signal. After it, the same dependence with the developed murine model based on constant rate melanoma cell injection into the animal blood flow was tested. Both in vivo and in vitro experiments show that signal generation efficiency increases with laser pulse energy above 15 µJ. Shorter pulses, especially 1 ns, provide more efficient signal generation as well as higher pulse rates. A higher pulse rate also provides more efficient signal generation, but also leads to overheating of the skin. The results show the limits where the photoacoustic flow cytometry system can be effectively used for the detection of circulating tumor cells in undiluted blood both for in vitro experiments and for in vivo murine models.

Directional couplings between the respiration and parasympathetic control of the heart rate during sleep and wakefulness in healthy subjects at different ages.

Cardiorespiratory interactions are important, both for understanding the fundamental processes of functioning of the human body and for development of methods for diagnostics of various pathologies. The properties of cardiorespiratory interaction are determined by the processes of autonomic control of blood circulation, which are modulated by the higher nervous activity. We study the directional couplings between the respiration and the process of parasympathetic control of the heart rate in the awake state and different stages of sleep in 96 healthy subjects from different age groups. The detection of directional couplings is carried out using the method of phase dynamics modeling applied to experimental RR-intervals and the signal of respiration. We reveal the presence of bidirectional couplings between the studied processes in all age groups. Our results show that the coupling from respiration to the process of parasympathetic control of the heart rate is stronger than the coupling in the opposite direction. The difference in the strength of bidirectional couplings between the considered processes is most pronounced in deep sleep.

Directional Couplings Between Electroencephalogram and Interbeat Intervals Signals in Awake State and Different Stages of Sleep.

Purpose of the work is to identify the directional coupling between the structures of the brain and the autonomic control of the heart rate variability, to analyze the changes in these coupling in sleep and in wakefulness. Infra-slow oscillations of the electroencephalograms potential and low-frequency components (0.04-0.15 Hz) of the interbeat intervals signal where analyzed using a sensitive method for identifying the directional coupling. The technique, based on modeling the dynamics of instantaneous phases of oscillations, made it possible to reveal the presence and quantify the directional couplings between the structures of the brain and the autonomic control of the heart rate variability. It was shown that the coupling coefficients in the frequency band of 0.04-0.15 Hz (associated mainly with sympathetic control of blood circulation), on average, decrease with falling asleep. We have also shown the asymmetry of coupling. At the same time, stronger connections were revealed in the direction from the autonomic control of the heart rate variability to the brain structures than in the opposite direction. It has been shown that the strength of such couplings decreases with increasing of sleep depth.

Low-frequency component of photoplethysmogram reflects the autonomic control of blood pressure.

The question of how much information the photoplethysmogram (PPG) signal contains on the autonomic regulation of blood pressure (BP) remains unsolved. This study aims to compare the low-frequency (LF) and high-frequency components of PPG and BP and assess their correlation with oscillations in interbeat (RR) intervals at similar frequencies. The PPG signal from the distal phalanx of the right index finger recorded using a reflective PPG sensor at green light, the BP signal from the left hand recorded using a Finometer, and RR intervals were analyzed. These signals were simultaneously recorded within 15 min in a supine resting condition in 17 healthy subjects (12 males and 5 females) aged 33 ± 9 years (mean ± SD). The study revealed the high coherence of LF components of PPG and BP with the LF component of RR intervals. The high-frequency components of these signals had low coherence. The analysis of the signal instantaneous phases revealed the presence of high-phase coherence between the LF components of PPG and BP. It is shown that the LF component of PPG is determined not only by local myogenic activity but also reflects the processes of autonomic control of BP.

Synchronization of the Processes of Autonomic Control of Blood Circulation in Humans Is Different in the Awake State and in Sleep Stages.

The influence of higher nervous activity on the processes of autonomic control of the cardiovascular system and baroreflex regulation is of considerable interest, both for understanding the fundamental laws of the functioning of the human body and for developing methods for diagnostics and treatment of pathologies. The complexity of the analyzed systems limits the possibilities of research in this area and requires the development of new tools. Earlier we propose a method for studying the collective dynamics of the processes of autonomic control of blood circulation in the awake state and in different stages of sleep. The method is based on estimating a quantitative measure representing the total percentage of phase synchronization between the low-frequency oscillations in heart rate and blood pressure. Analysis of electrocardiogram and invasive blood pressure signals in apnea patients in the awake state and in different sleep stages showed a high sensitivity of the proposed measure. It is shown that in slow-wave sleep the degree of synchronization of the studied rhythms is higher than in the awake state and lower than in sleep with rapid eye movement. The results reflect the modulation of the processes of autonomic control of blood circulation by higher nervous activity and can be used for the quantitative assessment of this modulation.

Mathematical modeling of the cardiovascular autonomic control in healthy subjects during a passive head-up tilt test.

A mathematical model is proposed for the autonomic control of cardiovascular system, which takes into account two separated self-exciting sympathetic control loops of heart rate and peripheral vascular tone. The control loops are represented by self-exciting time-delay systems and their tone depends on activity of the aortic, carotid, and lower-body baroreceptors. The model is used to study the dynamics of the adaptive processes that manifest in a healthy cardiovascular system during the passive head-up tilt test. Computer simulation provides continuous observation of the dynamics of the indexes and variables that cannot be measured in the direct experiment, including the noradrenaline concentration in vessel wall and heart muscle, tone of the sympathetic and parasympathetic control, peripheral vascular resistance, and blood pressure. In the supine and upright positions, we estimated the spectral characteristics of the model variables, especially in the low-frequency band, and the original index of total percent of phase synchronization between the low-frequency oscillations in heart rate and blood pressure signals. The model demonstrates good quantitative agreement with the dynamics of the experimentally observed indexes of cardiovascular system that were averaged for 50 healthy subjects.

Low-frequency variability in photoplethysmographic waveform and heart rate during on-pump cardiac surgery with or without cardioplegia.

We studied the properties of low-frequency (LF) heart rate variability (HRV) and photoplethysmographic waveform variability (PPGV) and their interaction under conditions where the hemodynamic connection between them is obviously absent, as well as the LF regulation of PPGV in the absence of heart function. The parameters of HRV and finger PPGV were evaluated in 10 patients during cardiac surgery under cardiopulmonary bypass (on-pump cardiac surgery) with or without cardioplegia. The following spectral indices of PPGV and HRV were ertimated: the total spectral power (TP), the high-frequency (HF) and the LF ranges of TP in percents (HF% and LF%), and the LF/HF ratio. We assessed also the index S of synchronization between the LF oscillations in finger photoplethysmogram (PPG) and heart rate (HR) signals. The analysis of directional couplings was carried out using the methods of phase dynamics modeling. It is shown that the mechanisms leading to the occurrence of oscillations in the LF range of PPGV are independent of the mechanisms causing oscillations in the LF range of HRV. At the same time, the both above-mentioned LF oscillations retain their activity under conditions of artificial blood circulation and cardioplegia (the latter case applies only to LF oscillations in PPG). In artificial blood circulation, there was a coupling from the LF oscillations in PPG to those in HR, whereas the coupling in the opposite direction was absent. The coupling from the LF oscillations in PPG to those in HR has probably a neurogenic nature, whereas the opposite coupling has a hemodynamic nature (due to cardiac output).

Simulating Dynamics of Circulation in the Awake State and Different Stages of Sleep Using Non-autonomous Mathematical Model With Time Delay.

We propose a mathematical model of the human cardiovascular system. The model allows one to simulate the main heart rate, its variability under the influence of the autonomic nervous system, breathing process, and oscillations of blood pressure. For the first time, the model takes into account the activity of the cerebral cortex structures that modulate the autonomic control loops of blood circulation in the awake state and in various stages of sleep. The adequacy of the model is demonstrated by comparing its time series with experimental records of healthy subjects in the SIESTA database. The proposed model can become a useful tool for studying the characteristics of the cardiovascular system dynamics during sleep.

The intensity of oscillations of the photoplethysmographic waveform variability at frequencies 0.04-0.4 Hz is effective marker of hypertension and coronary artery disease in males.

Background: It is believed that the intensity of oscillations in the photoplethysmographic waveform variability reflects the activity of vascular regulatory mechanisms. However, the relationship of such fluctuations with the state of health is poorly understood.Purpose: The aim of our study was to assess the possibility of using spectral indices that reflect the intensity of oscillations of the photoplethysmographic waveform variability at frequencies 0.04-0.4 Hz as markers of hypertension and coronary artery disease. We did not study women to exclude the influence of menopause and sex hormones on the results.Materials and Methods: We compared synchronous 10-minute records of finger photoplethysmogram and respiration at rest in 30 healthy males (48.8 ± 4.5 years; data presented as Mean ± SD) versus 30 patients with hypertension (aged 49.0 ± 4.3 years) versus 30 patients with stable coronary artery disease (49.2 ± 4.8 years). Percentages of high-frequency and low-frequency ranges in the total power of photoplethysmographic waveform variability spectrum (HF% and LF%), and LF/HF ratio were assessed.Results: HF% are subject to by 2- to 5-fold increase in hypertensive patients (p < .001) and up to an 8-fold increase in patients with coronary artery disease (p < .001) when compared with healthy persons. On the contrary, LF% is reduced by 1.5-5 times in all patients when compared with healthy people (p < .001). We identified cut-off points for each photoplethysmographic index to distinguish patients with coronary artery disease or hypertension from healthy subjects. Multiple logistic regression models based on photoplethysmographic waveform variability indices had sufficient sensitivity and specificity for patients with hypertension or coronary artery disease.Conclusion: Frequency-domain indices of photoplethysmographic waveform variability (in particular, HF%, LF%, and LF/HF) are sufficiently sensitive and specific markers of hypertension and coronary artery disease in adult males.

Comparative study of short-term cardiovascular autonomic control in cardiac surgery patients who underwent coronary artery bypass grafting or correction of valvular heart disease.

Introduction: Our aim was to perform a comparative study of short-term cardiovascular autonomic control in cardiac surgery patients who underwent coronary artery bypass grafting (CABG) or surgical correction of valvular heart disease (SCVHD ). Methods: The synchronous 15 minutes records of heart rate variability (HRV) and finger's photoplethysmographic waveform variability (PPGV) were performed in 42 cardiac surgery patients (12 women) aged 61.8 ± 8.6 years (mean ± standard deviation), who underwent CABG, and 36 patients (16 women) aged 54.2 ± 14.9 years, who underwent SCVHD , before surgery and in 5-7 days after surgery. Conventional time and frequency domain measures of HRV and index S of synchronization between the slow oscillations in PPGV and HRV were analyzed. We also calculated personal dynamics of these indices after surgery. Results: We found no differences (Р > 0.05) in all studied autonomic indices (preoperative and post-surgery) between studied patients' groups, except for the preoperative heart rate, which was higher in patients who underwent SCVHD (P = 0.013). We have shown a pronounced preoperative and post-surgery variability (magnitude of inter-quartile ranges) of all autonomic indices in studied patients. In the cluster analysis based on cardiovascular autonomic indices (preoperative and post-surgery), we divided all patients into two clusters (38 and 40 subjects) which did not differ in all clinical characteristics (except for the preoperative hematocrit, P = 0.038), index S, and all post-surgery HRV indices. First cluster (38 patients) had higher preoperative values of the HR, TP, HF, and HF%, and lower preoperative values of the LF% and LF/HF. Conclusion: The variability of cardiovascular autonomic indices in on-pump cardiac surgery patients (two characteristic clusters were identified based on preoperative indices) was not associated with their clinical characteristics and features of surgical procedure (including cardioplegia).

Interaction between cardiovascular autonomic control and sex hormones in perimenopausal women under menopausal hormone therapy.

OBJECTIVE: The aim of this study was to assess the dynamical interaction between the cardiovascular autonomic control and sex hormones in perimenopausal women under menopausal hormone therapy (MHT). PATIENTS AND METHODS: Seventy women (age: 51.6±2.1 years) were treated with MHT. Standard time and frequency domain measures of heart rate variability (HRV) and index S of synchronization between the slow oscillations in HRV and photoplethysmographic waveform variability were studied during a 6-week treatment with MHT. We assessed also the dynamics of the following sex hormones: estradiol, follicle-stimulating hormone, dehydroepiandrosterone sulfate, and testosterone. RESULTS: MHT increased estradiol and decreased follicle-stimulating hormone. Hot flashes and index S were significantly decreased under MHT (P<0.05). Other autonomic indices were not significantly changed (P>0.05). Changes of index S did not correlate with changes of sex hormones and hot flushes (P>0.05). CONCLUSION: The obtained results may indicate the independence of heart autonomic control (assessed by HRV measures) from women's hormonal status. However, any changes in sex hormones contribute to changes in the systemic control of circulation, which is assessed by index S.

Model of human cardiovascular system with a loop of autonomic regulation of the mean arterial pressure.

A model of human cardiovascular system is proposed which describes the main heart rhythm, the regulation of heart function and blood vessels by the autonomic nervous system, baroreflex, and the formation of arterial blood pressure. The model takes into account the impact of respiration on these processes. It is shown that taking into account nonlinearity and introducing the autonomous loop of mean arterial blood pressure in the form of self-oscillating time-delay system allow to obtain the model signals whose statistical and spectral characteristics are qualitatively and quantitatively similar to those for experimental signals. The proposed model demonstrates the phenomenon of synchronization of mean arterial pressure regulatory system by the signal of respiration with the basic period close to 10 seconds, which is observed in the physiological experiments.

Effects of antihypertensive treatment on cardiovascular autonomic control: a prospective study.

OBJECTIVE: The aim of study was to propose an approach to the control of dynamics of autonomic dysfunction in cardiovascular system (CVS) under antihypertensive treatment (AT) in patients with arterial hypertension (AH), based on individual features of synchronization of 0.1-Hz rhythms in heart rate (HR) and photoplethysmogram (PPG) and spectral indices of heart rate variability (HRV). METHODS: We designed prospective cohort diagnostic accuracy and studied 105 AH patients (66 females) aged 47±8 years during 8 weeks. The HRV spectral indices and the index S of synchronization between the 0.1-Hz rhythms in HR and PPG during a tilt test are compared in their ability to control the AT with angiotensin-converting enzyme inhibitors (ACE-Is) (fosinopril or enalapril) and ß-blockers (atenolol or metoprolol). We apply Shapiro-Wilk, Mann-Whitney U and Wilcoxon tests. RESULTS: It is shown that the power of low-frequency (LF) band in HRV spectrum and index S can be used as criteria for initial assessment of the status of autonomic regulation in AH patients. The patients with S<25% in vertical body's position and LF>250 ms2 in horizontal body's position require ACE-Is treatment. The AH patients with LF<350 ms2 and S<30% in vertical body's position require ß-blocker treatment. The AH patients with S>25% and LF>250 ms2 in horizontal body's position do not require any ACE-Is or ß-blocker treatment. Both drug groups can be used in patients with low values of index S and low power of LF band in HRV spectrum. CONCLUSION: The control of AT can be carried out in AH patients taking into account the individual features of autonomic dysfunction in CVS. Sensitivity and specificity of our approach were 65% and 73%, respectively.

Evaluation of 5-year risk of cardiovascular events in patients after acute myocardial infarction using synchronization of 0.1-Hz rhythms in cardiovascular system.

BACKGROUND: Synchronization between 0.1-Hz rhythms in cardiovascular system is deteriorated at acute myocardial infarction (AMI) leading to a disruption of natural functional couplings within the system of autonomic regulation. OBJECTIVE: This study evaluates the prognostic value of autonomic regulation indices for the 5-year risk of fatal and nonfatal cardiovascular events in patients after AMI. METHODS AND RESULTS: We studied 125 patients (53 [42%] female) after AMI aged between 30 and 83 years. The period of observation was 5 years with checkpoints at the first week after AMI and after each year after AMI. We compared the prognostic value of established clinical characteristics and degree S of synchronization between 0.1-Hz rhythms in heart rate and microcirculation for evaluation of the 5-year risk of mortality and recurrent myocardial infarction (MI) in patients after AMI. Acute heart failure Killip 2-4 at AMI and S < 20% at the first week after AMI were identified as the most important factors for evaluation of the risk of 5-year mortality in patients after AMI (χ(2) = 14.2, P = 0.003). Sensitivity and specificity of low S (<20%) at the first week after AMI were 76% and 43%, respectively. For evaluation of the 5-year risk of recurrent MI index S had no advantage over established clinical characteristics. CONCLUSION: The value of S below 20% in patients with AMI is a sensitive marker of high risk of mortality during the subsequent five years. It is characterized by better prognostic value than most of established clinical characteristics.

Selection of optimal dose of beta-blocker treatment in myocardial infarction patients based on changes in synchronization between 0.1 Hz oscillations in heart rate and peripheral microcirculation.

BACKGROUND: Selection of the optimal dose of beta-blocker treatment in myocardial infarction (MI) patients is problematic because of a lack of well-established guidelines. METHODS: We evaluated changes in synchronization between 0.1 Hz oscillations in heart rate (HR) and plethysmographic peripheral microcirculation in response to a tilt-table test and to 3-month treatment with the highest tolerated beta-blocker (metoprolol) dose in 43 patients aged between 41 and 77 years with acute MI 6 months prior to the start of the study. Before the study the patients were treated with small doses of beta-blocker. Phase differences between HR and peripheral microcirculation oscillations were used to measure the degree of synchronization (S), and relative change in S from horizontal position was used to characterize the response to vertical tilt. RESULTS: Two groups of MI patients matched for clinical characteristics were identified on the basis of the results. The first group was composed of patients with decreased S as a response to vertical tilt at the beginning of the study. The patients with increased S during vertical tilt before treatment with the highest tolerated beta-blocker dose were attributed to the second group. The response to vertical tilt in the first group of patients was postulated to indicate the need to increase beta-blocker dose, and in turn, the response in the second group to indicate an already adequate beta-blocker dose. CONCLUSION: Assessment of synchronization of 0.1  Hz HR and peripheral microcirculation oscillations as a response to a tilt test can possibly be used as a guideline for selecting beta-blocker dose in post-MI patients.