Pulse Pressure is Sex-Specifically Associated with the Ratio of Diastolic and Systolic Arterial Pressure in Healthy Children, and Differently During Night Versus Daytime Recordings.

Noninvasive blood pressure recordings typically focus on systolic blood pressure (SBP) and diastolic pressure (DBP). Derived metrics are often analyzed, e.g. pulse pressure (PP), defined as SBP minus DBP. As the metric PP is not unique, we introduced the PP companion (PPC), calculated using the Pythagorean theorem. PPC is associated with mean arterial pressure (MAP). Another mathematical construct frequently used in hemodynamic studies refers to the ratio of DBP and SBP, denoted as Prat. PP and Prat share the same companion (C). The association between PratC and MAP, as well as the connection between PP and Prat has not been studied in healthy children. We analyzed a large set of daytime (DT) and nighttime (NT) data (N=949, age 5 to 16 years, including 485 girls), published in the literature. Average PP increases with age (in 0.5 year increments), while Prat decreases. Prat vs PP yields R2>0.985 for both DT and NT data, when stratified for boys and girls. PPC is significantly lower (P<0.0001) during the night for both sexes. We conclude that Prat carries no substantial incremental value beyond PP, in contrast to PPC which points to DT/NT, age-dependent and sex-specific differences in these children.Clinical Relevance- Various derived metrics based on blood pressure have been introduced in hemodynamic studies, but not all of them are fully independent. The diastolic to systolic pressure ratio in healthy children is inversely associated with pulse pressure, showing partial sex-specific overlap, but substantial daytime versus night differences.

Sex-specific Evaluation of Ventricular Ejection Fraction and End-Systolic Volume Applied to Cardiac Resynchronization Therapy.

Cardiac resynchronization therapy (CRT) can decrease the risk of heart failure (HF) events in relatively asymptomatic patients with a reduced ejection fraction (EF) and wide QRS complex. However, individual response to this type of therapy varies widely. Often based on either EF increase or end-systolic volume (ESV) decrease as criterion, a subgroup of super-responders has been described. Therefore, it is important to determine factors that can predict a favorable response and identify those patients who may benefit from CRT. With this goal in mind we explored the possible role of ESV.To improve insight in ventricular pump function we previously introduced the volume regulation graph (VRG), relating ESV to end-diastolic volume (EDV). An individual patient is uniquely defined by the prevailing working point in the volume domain. The traditional metric EF can be graphically derived for each working point. The nonlinear association between EF and ESV is given by EF = 1 + γ {ESV / (δ - ESV)}, with empirical constants γ and δ. The impact of CRT super-responders on EF can be evaluated, taking into account sex-specific ESV values. Based on available regression equations we modeled the impact on EF (as percent points) resulting from CRT-induced fractional ESV changes expressed as % of baseline ESV. Our analysis confirms clinical findings, indicating that CRT super-responders are likely to be women, and clarify why a specific reduction of ESV cannot be directly translated into EF improvement. We propose that the EF as CRT criterion should be abandoned and replaced by sex-specific ESV evaluations.Clinical Relevance- Response to CRT should be evaluated in a sex-specific manner. The smaller heart size in women has implications for the interpretation of percentwise reductions of ESV and their translation into an associated increase of EF.

The Ratio of Diastolic and Systolic Arterial Pressure is Associated with Pulse Pressure.

Pulse pressure (PP) is defined as the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP). The metric PP is not unique, as numerous combinations of SBP and DBP yield the same value for PP. Therefore, we introduced the PP companion (PPC) which is calculated using the Pythagorean theorem. Only the combination of PP and PPC offers unique characterization. Interestingly, PPCwas found to be associated with mean arterial pressure (MAP). Another mathematical construct frequently used in hemodynamic studies refers to the ratio of DBP and SBP, or DBP/SBP, denoted as Prat. As Prat and PP share the same companion (C), we investigated the association between PratC and MAP, as well as the connection between PP and Prat. Various patient cohorts were included: A) 52 heart failure patients (16 women), B) 88 patients (11 women) with acute cardiac syndromes, C) 257 patients (68 men) diagnosed with atherosclerosis or any of various types of autoimmune disease, and D) 106 hypertensives (51 men). Linear regression analysis resulted in the following correlations: A: R (PratC, MAP) = 0.94, R (PP, Prat) = -0.91 B: R (PratC, MAP) = 0.98, R (PP, Prat) = -0.85 C: R (PratC, MAP) = 0.97, R (PP, Prat) = -0.86 D: R (PratC, MAP) = 0.92, R (PP, Prat) = -0.82 We conclude that Prat carries no substantial incremental value beyond PP, while both Prat and PP are incomplete metrics, requiring simultaneous consideration of MAP. Clinical Relevance- Various ratio-based metrics have been introduced in hemodynamic studies without paying attention to missing components or even redundant candidates. Here we present a uniform method to provide comprehensive insight.

Various Approaches to Define the Volume Intercept of the Ventricular End-Systolic Pressure-Volume Relationship: Implications for Statistical Analysis.

Ventricular pump function is often characterized by the (non)linear end-systolic pressure-volume relationship (ESPVR). For each working point on that curve the tangent along with the intercept (Vo) reflect contractile state. Vo on the abscissa is an extrapolated point without physiological meaning, and may be negative. To obtain positive values for the intercept, investigators often choose a non-zero pressure level. Although this preference is mathematically sound, we demonstrate that statistical evaluations may yield different results, depending on the pressure level selected. Published data on 17 cardiac patients representing three diagnostic groups were analyzed, showing dicrotic notch pressure based values -14

Machine Learning-Based Continuous Intracranial Pressure Prediction for Traumatic Injury Patients.

Structured Abstract-Objective: Abnormal elevation of intracranial pressure (ICP) can cause dangerous or even fatal outcomes. The early detection of high intracranial pressure events can be crucial in saving lives in an intensive care unit (ICU). Despite many applications of machine learning (ML) techniques related to clinical diagnosis, ML applications for continuous ICP detection or short-term predictions have been rarely reported. This study proposes an efficient method of applying an artificial recurrent neural network on the early prediction of ICP evaluation continuously for TBI patients. Methods: After ICP data preprocessing, the learning model is generated for thirteen patients to continuously predict the ICP signal occurrence and classify events for the upcoming 10 minutes by inputting the previous 20-minutes of the ICP signal. Results: As the overall model performance, the average accuracy is 94.62%, the average sensitivity is 74.91%, the average specificity is 94.83%, and the average root mean square error is approximately 2.18 mmHg. Conclusion: This research addresses a significant clinical problem with the management of traumatic brain injury patients. The machine learning model data enables early prediction of ICP continuously in a real-time fashion, which is crucial for appropriate clinical interventions. The results show that our machine learning-based model has high adaptive performance, accuracy, and efficiency.

Inadequacy of Augmentation Index for Monitoring Arterial Stiffness: Comparison with Arterial Compliance and Other Hemodynamic Variables.

PURPOSE: Augmentation Index (AIx) is used clinically for monitoring both wave reflections and arterial stiffness, which when increased is a risk factor of cardiovascular mortality and morbidity. We hypothesize that AIx is not solely related to vascular stiffness as described by arterial compliance and other hemodynamic parameters since AIx underestimates wave reflections. METHODS: Aortic pressure and flow datasets (n = 42) from mongrel dogs were obtained from our experiments and Mendeley Data under various conditions. Arterial compliances based on the Windkessel model (Ct), the stroke volume (SV) to pulse pressure (PP) ratio (Cv = SV/PP), and at inflection pressure point (CPi) were computed. Other relevant hemodynamic factors are also computed. RESULTS: AIx was poorly associated with arterial stiffness calculated from Ct (r = 0.299, p = 0.058) or CPi (r = 0.203, p = 0.203), even when adjusted for heart rates. Ct and Cv were monotonically associated. Alterations in inflection pressure (Pi) did not follow the changes in pulse pressure (PP) (r = 0.475, p = 0.002), and Pi was quantitatively similar to systolic pressure (r = 0.940, p < 0.001). CONCLUSION: AIx is neither linearly correlated with arterial stiffness, nor with arterial compliance and several cardiac and arterial parameters have to be considered when AIx is calculated.

Investigation into the diversity in the fractal dimensions of arterioles and venules in a microvascular network - A quantitative analysis.

Fractal dimension is a robust fractal parameter for estimating the morphology of vascular networks. It reflects the property of vascular networks that may vary and thus, differentiate between individual networks and/or identify physiological and pathological conditions. As such, fractal dimension differs also between arteriolar and venular compartments, yet the underlying reason is so far unclear. In order to understand the mechanisms behind these differences, we quantitatively analyzed the impacts of vessel attributes on the fractal dimension. Fractal dimension and vessel attributes given by vessel density (VD), vessel length density (VL), and diameter index (DI=VD/VL) were analyzed in three microvascular networks of the rat mesentery, which were reconstructed from experimental data. The results show that differences in diameter between arterioles and venules are primarily responsible for arterio-venous differences in fractal dimension. Moreover, multiple linear regression analysis demonstrates that the sensitivity of the variation of fractal dimension to vessel length and diameter varies with the type of the vessels. While the change of vessel length contributes 57.8 ±â€¯3.4% to the variation of arteriolar dimension, vessel diameter contributes 63.9 ±â€¯4.8% to the variation of venular dimension. The present study provides an explanation for the different fractal dimension and dimension variation in arteriolar and venular compartments. It highlights the importance of estimating the fractal dimensions of arterioles and venules separately, which will enhance the ability of feature extraction by fractal analysis in physiological and clinical application.

Energetically wasteful wave reflections due to impedance mismatching in hypertension and their reversal with vasodilator: Time and frequency domain evaluations.

BACKGROUND: Increased pulse wave reflections in hypertension arise due to impedance mismatching and the effective energy transmission to the vasculature is compromised. Their quantification in the time and the frequency domains are compared and the beneficial effect of vasodilator is evaluated in the study. METHODS: A simple, fast time domain method for the resolution of aortic pressure and flow pulses into their forward and reflected components is presented, together with frequency domain reflection coefficient and impedance calculations. Both steady and pulsatile energy components are quantified during induced hypertension (HBP) and subsequent vasodilator (VSD, nitroprusside) treatment in experimental mongrel dogs. Corresponding power generation and usage are also analyzed. RESULTS: Characteristic impedance and peripheral resistance were not statistically different between the methods (p > 0.05). Time domain reflection coefficient identified significant differences among control, HBP and VSD groups (p < 0.05) while the frequency domain method did not adequately differentiate the control and the HBP groups. Impedance calculations were similar between the two methods. Frequency domain calculations of total, mean and pulsatile power were, on average, 32.6 mW higher, 12.8 mW lower and 45.4 mW higher than their respective time domain calculations (p < 0.05). Hypertension increased energy consumption, on average, by 88.8 mJ (p < 0.05) and subsequent VSD decreased the energy consumption, on average, by 99.4 mJ (p < 0.05). CONCLUSION: Impedance mismatching in hypertension which leads to increased wave reflections and significantly increased pulsatile work, could be effectively alleviated through vasodilator therapy. This can be quantified through the time-domain method, which is fast and equally accurate as the time-consuming frequency domain approach. The time domain method to quantify crucial parameters such as stroke work cannot be readily determined using the frequency domain methods.

Polar Coordinate Description of Blood Pressure Measurements and Implications for Sex-Specific and Personalized Analysis.

Vascular properties and their associated impact on cardiovascular risk factors are often evaluated by metrics such as pulse pressure (PP) and the augmentation index (AIx). All derived metrics are essentially based on the combination of blood pressure recordings. These clinically used metrics typically concern a difference (as in PP) or a ratio (as in AIx). A polar coordinate description reveals the companion (C) of the traditional metric. The aim of this study is to evaluate the impact of PPC and AIxC by analyzing both patient data and a detailed data set on healthy children derived from the literature.Companions are calculated using the Pythagorean theorem, and show that PPC is related to mean arterial pressure, thus complementing the biomarker PP. Also, inflection pressure is tied to systolic pressure, implying a possible simplification of obtaining the numerical value of AIx. Outcomes for adults and children are comparable. We conclude that derived metrics such as PP and AIx are incomplete. The associated companion metrics PPC and AIxC can easily be calculated. They add clinically relevant information without the need to perform additional measurements. Combination of traditional and the newly described companion metrics permits more precise characterization of individual patients.

Myocardial oxygen balance during acute normovolemic hemodilution: A novel compartmental modeling approach.

BACKGROUND: Hemodilution was introduced initially as a blood conservation technique to reduce allogeneic blood transfusion in patients undergoing surgical procedures. Although the technique has been approved by the National Institute of Health consensus panel, limits of hemodilution under anesthetic conditions have not been established as they have in animal models. METHODS: A novel multi-compartmental modeling approach has been proposed that includes the effect of anesthesia to quantify the effect of hemodilution on myocardial oxygen balance during myocardial ischemia. RESULTS: The results showed that isovolemic hemodilution would cause detrimental effects around a hematocrit of 15%. Even though the fall in oxygen content caused by the decrease in hemoglobin concentration was compensated by an increase in coronary blood flow induced by hypoxic vasodilation and decreased viscosity, the endocardial tissue received less oxygen compared to the epicardial regions, and this sub-endocardial ischemia eventually led to cardiac failure. Statistical analysis also showed that the type of acellular replacement fluid failed to affect the heart rate, the stroke index or the cardiac index during hemodilution, and supplemental oxygen improved the endocardial oxygen supply. CONCLUSION: The model validates the clinical conclusions that sub-endocardial ischemia causes cardiac failure under extreme hemodilution conditions and the model can also be easily integrated into other human simulators.

Quantitative cardiology and computer modeling analysis of heart failure in systole and in diastole.

Clinical cardiology diagnosis relies on the assessment of a set of specified parameters. Computer modeling is a powerful tool that can provide a realistic interpretation of the variations of these parameters through computational quantification. Here we present an overview of different aspects of diagnosis that are based on evaluation of either systolic or diastolic cardiac abnormalities. Emphasis is on the quantitative hemodynamic assessment and modeling. For myocardial ischemia and stunning, multi-scale modeling from single fiber to the global ventricular level is demonstrated. The classic force-velocity-length relations are found to be applicable even for modern quantitative cardiac assessment. The reduced systolic shortening and delayed diastolic relaxation associated with stunning and ischemia can be reproduced even at the single muscle fiber level. In addition, ejection fraction (EF) which has been viewed as an important index in assessing the state of the heart, is found to be inadequate for the diagnosis and assessment of heart failure (HF) in differentiation of HF patients with reduced EF (HFrEF) or with preserved EF (HFpEF). Parameters that relate to structural changes whether at fiber or the global levels are found to be most appropriate to quantify the cardiac function, hence for its quantitative diagnosis. Parameters that govern heart-arterial system interaction when the LV is single-loaded with pressure-overloaded LV hypertrophy or double-loaded as in LVH with aortic valve stenosis are also quantified. It is shown that a computational modeling approach can be invaluable in delineating parameters that are critical for quantitative cardiology diagnosis.

Arterial Flow, Pulse Pressure and Pulse Wave Velocity in Men and Women at Various Ages.

The increase in pulse pressure (PP) that occurs with advancing age is predominantly due to reduced arterial distensibility leading to decreased aortic compliance, particularly in the elderly, in whom high blood pressure mainly manifests as isolated systolic hypertension. Since age-related changes in stroke volume are minimal compared with changes in PP, PP is often considered a surrogate measure of arterial stiffness. However, since PP is determined by both cardiac and arterial function, a more precise and reliable means of assessment of arterial stiffness is arterial pulse wave velocity (PWV), a parameter that is only dependent on arterial properties. Arterial stiffness as measured by PWV has been found to be a powerful pressure-related indicator for cardiovascular morbidity and mortality. We analyzed PP and PWV in men and women of various age groups in healthy volunteers as well as cardiac patients with different types of diseases. The findings identified several striking sex-specific differences which demand consideration in guidelines for diagnostic procedures, for epidemiological analysis, and in evaluation of therapeutic interventions.

Cardiovascular Allometry: Analysis, Methodology, and Clinical Applications.

The classic works of "On Growth and Form" and "The Problem of Relative Growth" that began a century ago have so fittingly, albeit unintentionally, become pertinent to the modern-day clinical treatment strategy of the many patients with cardiovascular disease. This chapter uses allometry, which was established for comparative biology, to explore physiological and pathological differences due to differential growth, which may lead to differing diagnostic and treatment approaches for male versus female patients. Men and women have obvious differences in body and heart weights, as well as different geometries and structures of their blood vessels; the analysis in this chapter extends to their hemodynamic functional differences. This includes dimensional analysis to establish criteria for characterizing functions based on allometric formulations. The clinical applications of sex differences are analyzed for arterial stenosis, aneurysm, atherosclerosis, hypertension, and coronary revascularization. Allometric approaches are applied specifically to isolated cases of systolic hypertension to delineate the intermingled relations of aging and sex differences. This chapter aims to provide some preliminary insights into the usefulness of cardiovascular allometry. Its future impact on clinical diagnosis remains largely unexplored.

Arterial Wall Properties in Men and Women: Hemodynamic Analysis and Clinical Implications.

The properties of arterial walls are dictated by their underlying structure, which is responsible for the adequate perfusion of conduit branching arteries and their vascular beds. Beginning with the mechanobiology of arteries in terms of their composition and individual contributions to overall viscoelastic behavior in men and women, pressure-flow relations are analyzed and noted in terms of sex differences. Hemodynamic function in terms of indices of vascular stiffness-such as pressure-strain elastic modulus, pulse wave velocity, augmentation index, and cardio-ankle vascular index-are evaluated. They all showed differences between the sexes, and these differences also were shown among people of different cultures. Recent studies also showed, in heart failure patients, a comparatively greater increase in peripheral resistance and a greater decreased arterial compliance in women. Wave separation into forward and reflected waves allows elucidation of mechanical and drug-treated similarities and differences in induced hypertension. This may provide insight into treatment strategy in terms of improving mechanobiology and designing drug therapy for the sexes. Finally, modeling studies are useful in identifying how arterial compliance and its pressure dependence can be better used in differentiating aging- and hypertension-induced changes that differentially affect the sexes.

A novel compliance-pressure loop approach to quantify arterial compliance in systole and in diastole.

Arterial compliance has been recognized as a critical parameter in governing pulsatile flow dynamics. It has traditionally been assumed constant throughout the cardiac cycle and its computation has been based either on the classic Windkessel model (C) in diastole or the stroke volume over pulse pressure (Cv) method in systole. Other methods using area (Cam) or two-area (Ctam) and exponential (C(P)exp1) methods were used for the cardiac cycle. We proposed a novel compliance-pressure loop (CPP loop) approach for the quantification of arterial compliance and compared it to existing linear and nonlinear methods. Experimental data were gathered in 5 dogs and blood pressure levels were varied (systolic pressure of 100 mmHg-185 mmHg) with induced hypertension and vasodilation. Results showed the limited regime of validity of C (Control:0.4681 ±â€¯0.1270 ml/mmHg, MTX:0.3015 ±â€¯0.1264 ml/mmHg and NTP:1.8323 ±â€¯0.7207 ml/mmHg) and Cv (Control:0.3583 ±â€¯0.0158 ml/mmHg, MTX:0.2602 ±â€¯0.1275 ml/mmHg and NTP:0.4131 ±â€¯0.0589 ml/mmHg), Cam (Control:0.4175 ±â€¯0.0505, MTX:0.3086 ±â€¯0.1568 and NTP:1.4181 ±â€¯0.4812) and Ctam (Control: 0.2064 ±â€¯0.0228 ml/mmHg, MTX:0.1967 ±â€¯0.0884 ml/mmHg, NTP:0.0881 ±â€¯0.0375 ml/mmHg) and that C(P)exp1 underestimates the arterial compliance compared to our method (Control:0.2233 ±â€¯0.0168 ml/mmHg vs 0.4481 ±â€¯0.0515 ml/mmHg, MTX:0.1976 ±â€¯0.0964 ml/mmHg vs 0.3273 ±â€¯0.1443 ml/mmHg and NTP: 0.2177 ±â€¯0.0273 ml/mmHg vs 1.9990 ±â€¯1.8221 ml/mmHg at mean arterial pressure). The CPP method based on the exponential method is superior, as it provides continuous compliance variations and CPP loop area can be readily visualized from hypotension to hypertension conditions. We conclude that the concept of using compliance-pressure loop is advantageous as it can afford continuous and accurate tracking of the dynamic arterial behavior despite greatly varying blood pressure levels.

Aortic Pressure Estimation Using Blind Identification Approach on Single Input Multiple Output Nonlinear Wiener Systems.

Aortic pressure () is important for diagnosis of cardiovascular diseases, but it cannot be directly measured by noninvasive means. We present a method for its estimation by modeling arterial system as multichannel Weiner system with linear finite impulse response filter accounting for larger arteries transmission channel and nonlinear memoryless function block accounting for all nonlinearities due to narrowing of arteries, branching and visco-elastic forces. With this structure when pressure waveforms are measured from two distinct peripheral locations, multichannel blind system identification (MBSI) technique can be used to estimate common input pressure signal or . Nonlinear MBSI method was employed on previously acquired human hemodynamic measurements (seven datasets); results show can be accurately derived. This method by nature is self-calibrating to account for any interpersonal, along with intrapersonal, vascular dynamics inconstancy. Besides Pa estimation, the proposed MBSI method also allows extraction of system dynamics for vascular channels.

Development and Retrospective Clinical Assessment of a Patient-Specific Closed-Form Integro-Differential Equation Model of Plasma Dilution.

A closed-form integro-differential equation (IDE) model of plasma dilution (PD) has been derived which represents both the intravenous (IV) infusion of crystalloid and the postinfusion period. Specifically, PD is mathematically represented using a combination of constant ratio, differential, and integral components. Furthermore, this model has successfully been applied to preexisting data, from a prior human study, in which crystalloid was infused for a period of 30 minutes at the beginning of thyroid surgery. Using Euler's formula and a Laplace transform solution to the IDE, patients could be divided into two distinct groups based on their response to PD during the infusion period. Explicitly, Group 1 patients had an infusion-based PD response which was modeled using an exponentially decaying hyperbolic sine function, whereas Group 2 patients had an infusion-based PD response which was modeled using an exponentially decaying trigonometric sine function. Both Group 1 and Group 2 patients had postinfusion PD responses which were modeled using the same combination of hyperbolic sine and hyperbolic cosine functions. Statistically significant differences, between Groups 1 and 2, were noted with respect to the area under their PD curves during both the infusion and postinfusion periods. Specifically, Group 2 patients exhibited a response to PD which was most likely consistent with a preoperative hypovolemia. Overall, this IDE model of PD appears to be highly "adaptable" and successfully fits clinically-obtained human data on a patient-specific basis, during both the infusion and postinfusion periods. In addition, patient-specific IDE modeling of PD may be a useful adjunct in perioperative fluid management and in assessing clinical volume kinetics, of crystalloid solutions, in real time.

Validation of a novel nonlinear black box Wiener System model for arterial pulse transmission.

Numerous linear dynamic models exist for describing the arterial pulse transmission phenomenon. We introduce a novel Wiener system based model in which a linear filter representing large arteries is coupled with a hysteresis-free nonlinear function representing complex wave transmission of branching arteries and the periphery. Experimental datasets (n = 7) are used to first estimate the Wiener model with linear, quadratic and cubic function for the aorta to radial artery pulse transmission and aorta to femoral artery pulse transmission. To model the nonlinear memoryless monotonic function in the Wiener System model, a correlation study is performed for linear finite impulse response (FIR) filter simulated peripheral pressure vs. measured peripheral pressure waveform. Each of this correlation curves were fitted to linear, quadratic and cubic polynomial equation. Wiener model is then simulated for aortic-to-radial artery as well as aortic-to-femoral artery to reconstruct radial and femoral pressure waveform. It was found that Wiener model with 3rd order polynomial function yielded better modeling accuracy (with average RMSE = 2.187 mmHg for radial and 4.281 mmHg for femoral pressure) than that from 2nd order polynomial function (with average RMSE = 2.242 mmHg for radial and 4.355 mmHg for femoral pressure) which in turn was better than mere linear FIR filter (with average RMSE = 2.604 mmHg for radial and 4.810 mmHg for femoral pressure).

Modeling of pulsatile flow-dependent nitric oxide regulation in a realistic microvascular network.

Hemodynamic pulsatility has been reported to regulate microcirculatory function. To quantitatively assess the impact of flow pulsatility on the microvasculature, a mathematical model was first developed to simulate the regulation of NO production by pulsatile flow in the microcirculation. Shear stress and pressure pulsatility were selected as regulators of endothelial NO production and NO-dependent vessel dilation as feedback to control microvascular hemodynamics. The model was then applied to a real microvascular network of the rat mesentery consisting of 546 microvessels. As compared to steady flow conditions, pulsatile flow increased the average NO concentration in arterioles from 256.8±93.1nM to 274.8±101.1nM (P<0.001), with a corresponding increase in vessel dilation by approximately 7% from 27.5±10.6% to 29.4±11.4% (P<0.001). In contrast, NO concentration and vessel size showed a far lesser increase (about 1.7%) in venules under pulsatile flow as compared to steady flow conditions. Network perfusion and flow heterogeneity were improved under pulsatile flow conditions, and vasodilation within the network was more sensitive to heart rate changes than pulse pressure amplitude. The proposed model simulates the role of flow pulsatility in the regulation of a complex microvascular network in terms of NO concentration and hemodynamics under varied physiological conditions.