Morphological features of the photoplethysmographic signal: a new approach to characterize the microcirculatory response to photobiomodulation.

Introduction and Objectives: Advanced analysis of the morphological features of the photoplethysmographic (PPG) waveform may provide greater understanding of mechanisms of action of photobiomodulation (PBM). Photobiomodulation is a non-ionizing, red to near-infrared irradiation shown to induce peripheral vasodilatation, promote wound healing, and reduce pain. Using laser Doppler flowmetry combined with thermal imaging we found previously in a clinical study that PBM stimulates microcirculatory blood flow and that baseline palm skin temperature determines, at least in part, why some individuals respond favorably to PBM while others do not. "Responders" (n = 12) had a skin temperature range of 33°C-37.5°C, while "non-responders" (n = 8) had "cold" or "hot" skin temperature (<33°C or >37.5°C respectively). The continuous PPG signals recorded from the index fingers of both hands in the original clinical study were subjected to advanced post-acquisitional analysis in the current study, aiming to identify morphological features that may improve the accuracy of discrimination between potential responders and non-responders to PBM. Methods: The PPG signals were detrended by subtracting the lower envelope from the raw signal. The Root Mean Square (RMS) and Entropy features were extracted as were two additional morphological features -- Smoothness and number of local extrema per PPG beat (#Extrema). These describe the signal jaggedness and were developed specifically for this study. The Wilcoxon test was used for paired comparisons. Correlations were determined by the Spearman correlation test (rs). Results: The PPG waveforms of responders to PBM had increased amplitude and decreased jaggedness (Baseline vs. 10' post-irradiation: Entropy, 5.0 ± 1.3 vs. 3.9 ± 1.1, p = 0.012; #Extrema, 4.0 ± 1.1 vs. 3.0 ± 1.6, p = 0.009; RMS, 1.6 ± 0.9 vs. 2.3 ± 1.2, p = 0.004; Smoothness, 0.10 ± 0.05 vs. 0.19 ± 0.16, p = 0.016). In addition, unilateral irradiation resulted in a bilateral response, although the response of the contralateral, non-irradiated hand was shorter in duration and lower in magnitude. Although subjects with 'cold,' or 'hot,' baseline skin temperature appeared to have morphologically distinct PPG waveforms, representing vasoconstriction and vasodilatation, these were not affected by PBM irradiation. Conclusion: This pilot study indicates that post-acquisitional analysis of morphological features of the PPG waveform provides new measures for the exploration of microcirculation responsiveness to PBM.

Additional predictors of the lower limit of cerebral autoregulation during cardiac surgery.

OBJECTIVES: The lower limit of autoregulation (LLA) of cerebral blood flow was previously shown to vary directly with the Ambulatory Arterial Stiffness Index (AASI) redefined as 1-regression slope of DBP-versus-SBP readings invasively measured from the radial artery before the bypass. We aimed expanding the predictive capacity of the LLA with AASI by combining it with additional predictors and provide new indications whether mean arterial pressure (MAP) is above/below the LLA. DESIGN AND METHOD: In 181 patients undergoing cardiac surgery, mean (SD) age 71 (8) years), we identified from the demographic, preoperative and intraoperative characteristics independent and statistically significant 'single predictors' of the LLA (including AASI). This was achieved using multivariate linear regression with a backward-elimination technique. The single predictors combined with 1-AASI generated new multiplicative and additive composite predictors of the LLA. Indicators for the MAP-to-LLA difference (DIF) were determined using DIF-versus-predictor plots. The odds ratio (OR) for the DIF sign (Outcome = 1 for DIF≤0) and predictor-minus-median sign (Exposure = 1 for Predictor  ≤ Median) were calculated using logistic regression. RESULTS: BMI, 1-AASI and systolic coefficient of variation were identified single predictors that correlated similarly with the LLA ( r  = -0.26 to -0.27, P  < 0.001). The multiplicative and additive composite predictors displayed higher correlation with LLA ( r  = -0.41 and r  = -0.43, respectively, P  < 0.001) and improved LLA estimation. The adjusted OR for the composite predictors was nearly twice that of the single predictors. CONCLUSION: The novel composite predictors may enhance the LLA estimation and the ability to maintain MAP in the cerebral autoregulatory range during cardiac surgery.

Predictive power of 24-h ambulatory pulse pressure and its components for mortality and cardiovascular outcomes in 11 848 participants recruited from 13 populations.

BACKGROUND: The role of pulse pressure (PP) 'widening' at older and younger age as a cardiovascular risk factor is still controversial. Mean PP, as determined from repeated blood pressure (BP) readings, can be expressed as a sum of two components: 'elastic PP' (elPP) and 'stiffening PP' (stPP) associated, respectively, with stiffness at the diastole and its relative change during the systole. We investigated the association of 24-h ambulatory PP, elPP, and stPP ('PP variables') with mortality and composite cardiovascular events in different age classes. METHOD: Longitudinal population-based cohort study of adults with baseline observations that included 24-h ambulatory BP. Age classes were age 40 or less, 40-50, 50-60, 60-70, and over 70 years. Co-primary endpoints were total mortality and composite cardiovascular events. The relative risk expressed by hazard ratio per 1SD increase for each of the PP variables was calculated from multivariable-adjusted Cox regression models. RESULTS: The 11 848 participants from 13 cohorts (age 53 ±â€Š16 years, 50% men) were followed for up for 13.7 ±â€Š6.7 years. A total of 2946 participants died (18.1 per 1000 person-years) and 2093 experienced a fatal or nonfatal cardiovascular event (12.9 per 1000 person-years). Mean PP, elPP, and stPP were, respectively, 49.7, 43.5, and 6.2 mmHg, and elPP and stPP were uncorrelated ( r  = -0.07). At age 50-60 years, all PP variables displayed association with risk for almost all outcomes. From age over 60 years to age over 70 years, hazard ratios of of PP and elPP were similar and decreased gradually but differently for pulse rate lower than or higher than 70 bpm, whereas stPP lacked predictive power in most cases. For age 40 years or less, elPP showed protective power for coronary events, whereas stPP and PP predicted stroke events. Adjusted and unadjusted hazard ratio variations were similar over the entire age range. CONCLUSION: This study provides a new basis for associating PP components with outcome and arterial properties in different age groups and at different pulse rates for both old and young age. The similarity between adjusted and unadjusted hazard ratios supports the clinical usefulness of PP components but further studies are needed to assess the prognostic significance of the PP components, especially at the young age.

Relative and Absolute Risk to Guide the Management of Pulse Pressure, an Age-Related Cardiovascular Risk Factor.

BACKGROUND: Pulse pressure (PP) reflects the age-related stiffening of the central arteries, but no study addressed the management of the PP-related risk over the human lifespan. METHODS: In 4,663 young (18-49 years) and 7,185 older adults (≥50 years), brachial PP was recorded over 24 hours. Total mortality and all major cardiovascular events (MACEs) combined were coprimary endpoints. Cardiovascular death, coronary events, and stroke were secondary endpoints. RESULTS: In young adults (median follow-up, 14.1 years; mean PP, 45.1 mm Hg), greater PP was not associated with absolute risk; the endpoint rates were ≤2.01 per 1,000 person-years. The adjusted hazard ratios expressed per 10-mm Hg PP increments were less than unity (P ≤ 0.027) for MACE (0.67; 95% confidence interval [CI], 0.47-0.96) and cardiovascular death (0.33; 95% CI, 0.11-0.75). In older adults (median follow-up, 13.1 years; mean PP, 52.7 mm Hg), the endpoint rates, expressing absolute risk, ranged from 22.5 to 45.4 per 1,000 person-years and the adjusted hazard ratios, reflecting relative risk, from 1.09 to 1.54 (P < 0.0001). The PP-related relative risks of death, MACE, and stroke decreased >3-fold from age 55 to 75 years, whereas absolute risk rose by a factor 3. CONCLUSIONS: From 50 years onwards, the PP-related relative risk decreases, whereas absolute risk increases. From a lifecourse perspective, young adulthood provides a window of opportunity to manage risk factors and prevent target organ damage as forerunner of premature death and MACE. In older adults, treatment should address absolute risk, thereby extending life in years and quality.

Microcirculatory Response to Photobiomodulation-Why Some Respond and Others Do Not: A Randomized Controlled Study.

BACKGROUND AND OBJECTIVES: Photobiomodulation (PBM), a non-ionizing, non-thermal irradiation, used clinically to accelerate wound healing and inhibit pain, was previously shown to increase blood flow. However, some individuals respond to PBM, but others do not. The purpose of this study was to investigate factors affecting this patient-specific response using advanced, noninvasive methods for monitoring microcirculatory activity. STUDY DESIGN/MATERIALS AND METHODS: In this prospective, randomized controlled clinical trial (NCT03357523), 20 healthy non-smoking volunteers (10:10 males:females, 30 ± 8 years old) were randomized to receive either red- (633 nm and 70 W/cm2 ) or near-infrared light (830 nm and 55 mW/cm2 ) over the wrist for 5 minutes. Photoplethysmography, laser Doppler flowmetry, and thermal imaging were used to monitor palm microcirculatory blood volume, blood flow, and skin temperature, respectively, before, during, and 20 minutes after irradiation. Participants with skin temperature change ≥0.5°C from baseline were considered "responders". RESULTS: Near-infrared PBM was found to induce a 27% increase in microcirculatory flow that increased to 54% during the 20-minute follow-up period (P = 0.049 and P = 0.004, respectively), but red light PBM did not increase the median flow. Only 10 of 20 participants were responders by thermal imaging (i.e., ≥0.5°C from baseline), and their initial skin temperature was between 33 and 37.5°C. The non-responders had either "hot" hands (≥37.5°C) or "cold" hands (≤33°C). In responders, the meantime to 20% increase in microcirculatory blood volume and blood flow was less than 2.5 minutes after initiation of PBM irradiation. CONCLUSIONS: We demonstrated that PBM induces arteriolar vasodilatation that results in both immediate and long-lasting increased capillary flow and tissue perfusion in healthy individuals. This response was wavelength-dependent and modified by skin temperature. These findings regarding physiological parameters associated with sensitivity or resistance to PBM provide information of direct relevance for patient-specific therapy. Lasers Surg. Med. © 2020 Wiley Periodicals, Inc.

Do estimated 24-h pulse pressure components affect outcome? The Ohasama study.

OBJECTIVE: Twenty-four-hour ambulatory pulse pressure (PP) is a powerful predictor of outcome. We attempted to apply the recently described PP components, an elastic (elPP), and systolic stiffening (stPP) components from 24-h ambulatory blood pressure (BP) monitoring (AMBP), and examine their influence on outcome in the Ohasama study population. DESIGN AND METHODS: Included were participants of the Ohasama study without history of cardiovascular disease (CVD), who were followed-up for total and CVD mortality, and for stroke morbidity. The PP components were derived from 24-h SBP and DBP using a model based on the nonlinear pressure--volume relationship in arteries expressing pressure stiffness relationship. Outcome predictive power was estimated by Cox regression models; hazard ratio with 95% confidence interval (CI), applied to elPP, and stPP, adjusted for age, sex, BMI, smoking, alcohol drinking, diabetes mellitus, total cholesterol, antihypertensive treatment, and mean arterial pressure (MAP), whenever appropriate. RESULTS: Of 1745 participants (age 61.4 ±â€Š11.6, 65% women), 580 died, 212 of CVD, and 290 experienced a stroke during 17 follow-up years. PP was strongly correlated with elPP (r = 0.89) and less so with stPP (r = 0.58), and the correlation between the two components was weak (r = 0.15). After the adjustment, hazard ratio of PP per 1 SD increment for total mortality, CVD mortality, and stroke morbidity were 1.095 (95% CI 0.973-1.232), 1.207 (1.000-1.456), and 0.983 (0.829-1.166), respectively. Corresponding hazard ratios and 95% CIs were nonsignificant for elPP, and stPP. However, among participants with median pulse rate 68.5 bpm or less (median, n = 872), total (327 deaths) and CVD (131 deaths) mortality were predicted by elPP (per 1 SD increment), hazard ratio 1.231 (95% CI, 1.082-1.401), and 1.294 (95% CI, 1.069-1.566), respectively. In the subgroup of treated participants with hypertension and pulse rate 68.5 or less bpm (n = 309), total (177 deaths) and CVD (77 deaths) mortality were predicted by elPP, hazard ratio of 1.357 (95% CI, 1.131-1.628), and 1.417 (95% CI, 1.092-1.839), respectively. Stroke morbidity was not predicted by either PP or the PP components. CONCLUSION: In a rural Japanese population, elPP but not stPP was predictive of total and CVD mortality even when adjusted for MAP and conventional risk factors in the subpopulation with slower pulse rate. This was mostly among the treated hypertensive patients.

Ambulatory pulse pressure components: concept, determination and clinical relevance.

BACKGROUND: Ambulatory pulse pressure (PP) a well known predictor of mortality, is widely believed to be a marker for arterial stiffness. However stiffness itself is pressure-dependent. OBJECTIVES: Developing a model-based method for splitting PP into two components expressing the contribution of a pressure-independent stiffness ('elastic', elPP) and the pressure-dependence of stiffness ('stiffening', stPP), and investigating their predictive power for all-cause mortality. METHODS: Deriving quantitative expressions for elPP and stPP assuming an exponential pressure-volume relationship in arteries, calculated from ambulatory blood pressure (BP) data and estimate standardized hazard ratios with Cox proportional hazards regression in selected patient groups. RESULTS: Ambulatory BP records of 1999 consecutive hypertensive patients, of whom 103 died from all causes within 5 years, were analyzed. PP, elPP, stPP and stPP/elPP (PP variables) (mean ±â€ŠSD) were 60 ±â€Š14, 50 ±â€Š10, 10 ±â€Š8 and 0.20 ±â€Š0.14 mmHg, respectively. elPP and stPP were weakly correlated (r = 0.21). Predictive power was found for patients with heart rate less than 70: mean [95% confidence interval] (P value) hazard ratio of PP, stPP and stPP/elPP (adjusted) were 1.48 [1.13-1.95] (P = 0.005), 1.58 [1.20-2.09] (P = 0.001) and 1.78 [1.25-2.52] (P = 0.001), respectively. The elPP (83% of PP) did not show predictive power. None of the PP variables displayed predictive power for the higher-heart-rate subgroup. CONCLUSION: Ambulatory PP components provide a novel and clinically valuable tool bridging between PP and arterial properties. Replacing PP by its components, taken as independent variables, may improve predictive power. The prognostic significance of the PP for all-cause mortality in elderly hypertensive patients with lower heart rates is dominated by its smaller component that quantifies arterial stiffening with pressure.

The response of peripheral microcirculation to gravity-induced changes.

BACKGROUND: The peripheral microcirculation supplies fresh blood to the small blood vessels, providing oxygen and nutrients to the tissues, removing waste, and maintaining normal homeostatic conditions. The goal of this study was to characterize the response of the peripheral microcirculation, in terms of blood flow and tissue oxygenation variables, to gravity-induced changes. METHODS: The study included 20 healthy volunteers and the experiment involved monitoring central and peripheral variables with the right hand positioned at different heights. These positions correspond to various gravitational levels. Peripheral perfusion and oxygenation were monitored using a laser Doppler flowmeter, photoplethysmograph, and transcutaneous oxygen tension monitor. Local blood pressure and respiration rate were also measured. FINDINGS: At the heart level, tissue oxygenation displayed a nadir, while capillary flow displayed a peak. Similar but weaker changes were observed at the control hand. In contrast, the photoplethysmograph's amplitude strongly decreased upon reducing the arm position below heart level. Both systolic and diastolic pressures decreased linearly between the highest to lowest arm position. INTERPRETATION: The results may reflect peripheral compensation mechanisms, as well as an interaction between the central and peripheral cardiovascular systems, in response to local changes in blood pressure. The observed dependence of the oxygenation pattern on height could lead to important new insights for the diagnosis and treatment of problems in the regulation of tissue perfusion.

Association of Blood Pressure Variability Ratio With Glomerular Filtration Rate Independent of Blood Pressure and Pulse Wave Velocity.

BACKGROUND: Blood pressure variability ratio (BPVR)(derived from within-subject SD of 24-hour ambulatory blood pressure [BP]) predicts all-cause mortality independent of BP and has a similar prognostic ability to ambulatory arterial stiffness (AASI). Whether BPVR, and AASI, offer prognostic information beyond measurements of arterial stiffness at a given pressure, as indexed by pulse wave velocity (PWV), is not known. METHODS: We assessed whether BPVR and AASI were associated with indices of subclinical organ damage (TOD) [estimated glomerular filtration rate (eGFR), left ventricular mass index, early-to-late transmitral velocity (E/A), carotid intima-media thickness (IMT)] independent of BP, and whether BPVR-TOD and AASI-TOD relations were independent of PWV (applanation tonometry) in 772 randomly selected participants from an urban, developing community. AASI was derived from 24-hour diastolic BP vs. systolic BP standard linear regression. RESULTS: On bivariate analyses, BPVR, AASI, and PWV were correlated with all indices of TOD (P < 0.0005). However, after adjustments for potential confounders including age and 24-hour mean BP, BPVR, and PWV (P < 0.005 to P < 0.0001), but not AASI (P > 0.25), were independently associated with eGFR, but not other indices of TOD. Importantly, the BPVR-eGFR relation was independent of BP variability (P < 0.005) and PWV (P < 0.001). CONCLUSIONS: BPVR was negatively associated with eGFR independent of mean BP, BP variability, and PWV. Therefore, in the prediction of cardiovascular risk, measurements of arterial stiffening (BPVR) may provide information beyond the impact of arterial stiffness.

The coupling between peripheral microcirculation and slow breathing.

Vasomotion (rhythmic changes in arteriolar diameter) is believed to enhance tissue perfusion at low oxygenation levels. We hypothesized that slow breathing and vasomotion may correlate temporally ("coupling"), especially at low oxygenation levels. We paced down spontaneous breathing to about 5 or 6breaths/min in 14 healthy subjects using device-guided breathing (DGB), and continuously monitored respiration, transcutaneous oxygen pressure ("oxygenation"), and skin capillary blood flow ("microflow") using a laser Doppler flowmeter. The coupling was expressed by cross-correlation calculated in 1-min time windows. Our main results illustrated that: (1) coupling increased gradually upon slowing breathing down in a subgroup, in which initial oxygenation was lower than a threshold of 30mmHg (0.3±0.2 vs. 0.07±0.2, P<10-6); (2) during DGB changes in oxygenation elicited opposite (relative) changes in microflow, with 4-fold higher sensitivity for low initial oxygenation relative to high (regression slope -0.094±0.010mmHg-1 vs. -0.020±0.002mmHg-1, P<10-6); (3) at low initial oxygenation, we observed larger coupling and (relative) microflow changes in younger subjects, and greater oxygenation changes in females (P<10-6 for all); (4) pulse pressure changes from before to after DGB were reduced by increased oxygenation changes during DGB (-5.5±7.4mmHg, r=-0.73, P<0.001). In conclusion, the present methodology can provide the variation trend of respiration-vasomotion coupling during DGB that may characterize microcirculation behavior at tissue oxygenation below a measurable threshold. The potential association of these trends and thresholds with pathologies or specific conditions of the cardiopulmonary system, and the possible role played by the neural sympathetic activity in that coupling, deserve further studies.

Arterial Stiffness: Going a Step Beyond.

Interest in arterial stiffness has been fueled by the scientific and clinical implications of its "vicious cycle" relationship with aging and systolic blood pressure. In physical terms, stiffness is the slope of the relationship between an artery's distending pressure and its cross-sectional area or volume. Pulse wave velocity (PWV, in m/s), the most common arterial stiffness indicator, is usually measured by the foot-to-foot time and distance method and is proportional to [stiffness × area (or volume)]1/2 at a given pressure. Its intrinsic pressure dependency and other flaws in current PWV methods limit its utility. In contrast, the arterial stiffness-arterial pressure relationship is near-linear, with a slope ß, the exponent of the curvilinear arterial pressure-arterial volume relationship. The concept of arterial stiffening is related to ß and describes a more functionally relevant aspect of arterial behavior: the change in stiffness for a given change in pressure. Arterial stiffening can be estimated from the variability of within-individual BP measurements (24-h ambulatory, home BP, or BP measured at different arm heights) and can be expressed as the pulse stiffening ratio (PSR) = [systolic stiffness]/[diastolic stiffness] or the ambulatory arterial stiffness index (AASI or its symmetric form, sAASI). High arterial stiffness (PWV) and stiffening (ß, stiffness index, cardio-ankle vascular index, AASI, and PSR) are associated with increased cardiovascular disease risk, but it remains unclear whether these indicators are useful in improving medical care quality; the standard of care remains stringent BP control.

Effects of gravity-induced upper-limb blood pressure changes on wave transmission and arterial radial waveform.

BACKGROUND: Local blood pressure (BP) changes induced by arm tilting may influence pressure wave transmission and reflection. We investigated the effects of upper-limb tilting on radial augmentation index (rAIx) and related central measures [aortic augmentation index (aAIx)]. METHODS: In 45 volunteers (age 49 ±â€Š19 years), supine brachial BP and radial artery waveforms were obtained by applanation tonometry with the dominant arm stretched and gently supported in three different positions: at the heart level, with the BP cuff 15 cm above heart level (approximately +30°), and 15 cm below heart level (-30°). RESULTS: Brachial SBP/DBP was 120/68 ±â€Š17/8 mmHg. Mean arterial pressure changed predictably with arm tilting (99 ±â€Š12 mmHg at -30°, 88 ±â€Š10 mmHg at 0°, 77 ±â€Š11 mmHg at +30°, all P < 0.001). rAIx decreased at -30° (69 ±â€Š22%), and increased at +30° (93 ±â€Š20%) compared with 0° (82 ±â€Š20%, all P less than 0.001). Changes in rAIx (value at +30° minus value at -30°) showed an inverse relationship with age (r = -0.32, P = 0.03). Heart rate, BP and rAIx did not change in the contralateral arm, which was held at the heart level during the examination. aAIx followed the same pattern as rAIx (123 ±â€Š27% at -30°, 144 ±â€Š33% at +30°, 136 ±â€Š31% at 0°, all P less than 0.001); changes in rAIx and aAIx were strongly related each other (r = 0.82, P < 0.001). CONCLUSION: Acute gravitational upper-limb BP changes generate opposite, profound changes in rAIx, and major artifactual changes in aAIx. These findings provide a rationale for recommending to keep the upper limb at the heart level during radial waveform assessment.

Blood pressure and heart period variability ratios derived from 24-h ambulatory measurements are predictors of all-cause mortality.

OBJECTIVE: The linear relationship between blood pressure (BP) and heart rate (or period) over 24 h has been suggested to be a marker for neural regulation of the circadian variations in BP and heart rate. We investigated the predictive power of indices defined by the ratio between BP and heart period variability that is a known expression for such a relationship. METHODS: We analysed BP and heart rate data obtained by standard 24-h BP monitoring in 1246 hypertensive patients, 76 of whom died from all causes during 5-year follow-up. SBP, DBP and heart period (T) variabilities were estimated by standard deviations. Studied indices were the SBP-T variability ratio (dS/dT) and the DBP-T variability ratio (dD/dT). Standardized hazard ratios and odds ratios were determined using Cox regression and logistic regression, respectively. RESULTS: Significant covariates adjusted hazard ratios for dS/dT and dD/dT that gradually increased across the following cohorts: entire sample, high-median age and high-median age and heart period: mean [95% confidence interval (95% CI)] 1.23 (1.03-1.47), 1.26 (1.05-1.52) and 1.55 (1.19-2.02), and 1.36 (1.07-1.72), 1.40 (1.09-1.80) and 1.57 (1.15-2.14), respectively. The corresponding odd ratios were similar in all cohorts: about 1.5 (1.2-2.0) and 1.3 (1.1-1.5). The adjusted indices size was greater in nonsurvivors (P =0.000001 and P = 0.003, respectively). CONCLUSION: The 24-h BP to heart period variability ratios are powerful independent predictors of all-cause mortality, especially for elderly hypertensive patients with slow heart rate. The results support their interpretation as integrative indices of cardiovascular function and markers for cardiovascular dysregulation during low DBP states, with potential use in clinical practice.