Influence of angiotensin II and telmisartan on in vivo high-resolution renal arterial impedance in rats.

Angiotensin II (ANGII) is known to play an important role in regulating renal hemodynamics. We sought to quantify this effect in an in vivo rat model with high-resolution renal arterial (RA) impedance. This study examines the effects of ANGII and its type 1 receptor blocker, telmisartan (TELM), on RA impedance. In baroreflex deactivated rats, we measured RA pressure (Pr) and blood flow (Fr) during random ventricular pacing to induce pressure fluctuation at three different mean Pr (60, 80, and 100 mmHg). We then estimated RA impedance as the transfer function from Fr to Pr. The RA impedance was found to align with a three-element Windkessel model consisting of proximal (Rp) and distal (Rd) resistance and compliance (C). Our study showed Rd reflected the composite characteristics of afferent and efferent arterioles. Rd increased with increasing Pr under the baseline condition with a slope of 1.03 ± 0.21 (× 10-1) min·mL-1. ANGII significantly increased the slope by 0.72 ± 0.29 (× 10-1) min·mL-1 (P < 0.05) without affecting the intercept. TELM significantly reduced the intercept by 34.49 ± 4.86 (× 10-1) mmHg·min·mL-1 (P < 0.001) from the baseline value of 37.93 ± 13.36 (× 10-1) mmHg·min·mL-1, whereas it did not affect the slope. In contrast, Rp was less sensitive than Rd to ANGII or TELM, suggesting Rp may represent the characteristics of elastic large arteries. Our findings provide valuable insights into the influence of ANGII on the dynamics of the renal vasculature.

Novel closed-loop control system of dual rotary blood pumps in total artificial heart based on the circulatory equilibrium framework: a proof-of-concept in vivo study.

OBJECTIVE: Total artificial heart (TAH) using dual rotary blood pumps (RBPs) is a potential treatment for end-stage heart failure. A well-noted challenge with RBPs is their low sensitivity to preload, which can lead to venous congestion and ventricular suction. To address this issue, we have developed an innovative closed-loop control system of dual RBPs in TAH. This system emulates the Frank-Starling law of the heart in controlling RBPs while monitoring stressed blood volume (V) based on the circulatory equilibrium framework. We validated the system in in-vivo experiments. METHODS: In 9 anesthetized dogs, we prepared a TAH circuit using 2 centrifugal-type RBPs. We first investigated whether the flow and inlet atrial pressure in each RBP adhered to a logarithmic Frank-Starling curve. We then examined whether the RBP flows and atrial pressures were maintained stably during aortic occlusion (AO) and pulmonary cannula stenosis (PS), whether averaged flow of dual RBPs and bilateral atrial pressures were controlled to their predefined target values for a specific V, and whether this system could maintain the atrial pressures within predefined control ranges under significant changes in V. RESULTS: This system effectively emulated the logarithmic Frank-Starling curve. It robustly stabilized the flow and atrial pressures during AO and PS without venous congestion or ventricular suction, accurately achieved target values in averaged flow and atrial pressures, and efficaciously maintained these pressures within the control ranges. CONCLUSION: This system controls dual RBPs in TAH accurately and stably. SIGNIFICANCE: This system may accelerate clinical application of TAH with dual RBPs.

Computer-controlled closed-loop norepinephrine infusion system for automated control of mean arterial pressure in dogs under isoflurane-induced hypotension: a feasibility study.

Introduction: Intra-operative hypotension is a common complication of surgery under general anesthesia in dogs and humans. Computer-controlled closed-loop infusion systems of norepinephrine (NE) have been developed and clinically applied for automated optimization of arterial pressure (AP) and prevention of intra-operative hypotension in humans. This study aimed to develop a simple computer-controlled closed-loop infusion system of NE for the automated control of the mean arterial pressure (MAP) in dogs with isoflurane-induced hypotension and to validate the control of MAP by the developed system. Methods: NE was administered via the cephalic vein, whereas MAP was measured invasively by placing a catheter in the dorsal pedal artery. The proportional-integral-derivative (PID) controller in the negative feedback loop of the developed system titrated the infusion rate of NE to maintain the MAP at the target value of 60 mmHg. The titration was updated every 2 s. The performance of the developed system was evaluated in six laboratory Beagle dogs under general anesthesia with isoflurane. Results: In the six dogs, when the concentration [median (interquartile range)] of inhaled isoflurane was increased from 1.5 (1.5-1.5)% to 4 (4-4)% without activating the system, the MAP was lowered from 95 (91-99) to 41 (37-42) mmHg. In contrast, when the concentration was increased from 1.5 (1.0-1.5)% to 4 (4-4.8)% for a 30-min period and the system was simultaneously activated, the MAP was temporarily lowered from 92 (89-95) to 47 (43-49) mmHg but recovered to 58 (57-58) mmHg owing to the system-controlled infusion of NE. If the acceptable target range for MAP was defined as target MAP ±5 mmHg (55 ≤ MAP ≤65 mmHg), the percentage of time wherein the MAP was maintained within the acceptable range was 96 (89-100)% in the six dogs during the second half of the 30-min period (from 15 to 30 min after system activation). The median performance error, median absolute performance error, wobble, and divergence were - 2.9 (-4.7 to 1.9)%, 2.9 (2.0-4.7)%, 1.3 (0.8-1.8)%, and - 0.24 (-0.34 to -0.11)%·min-1, respectively. No adverse events were observed during the study period, and all dogs were extubated uneventfully. Conclusion: This system was able to titrate the NE infusion rates in an accurate and stable manner to maintain the MAP within the predetermined target range in dogs with isoflurane-induced hypotension. This system can be a potential tool in daily clinical practice for the care of companion dogs.

Inverse ESPVR Estimation with Singularity Avoidance via Constrained EDPVR Parameter Optimization.

Left ventricular end-systolic elastance Ees, as an index of cardiac contractility, can play a key role in continuous patient monitoring during cardiac treatment scenarios such as drug therapies. The clinical feasibility of Ees estimation remains challenging because most techniques have been built on left ventricular pressure and volume, which are difficult to measure or estimate in the regular ICU/CCU setting. The purpose of this paper is to propose and validate a novel approach to estimate Ees, which is independent of left ventricular pressure and volume. Our methods first derive an analytical representation of Ees as the inverse function of the gradient of the Frank-Starling Curve based on cardiac mechanics. Second, elucidating the mechanism of singularities in the inverse function, we derive multiple conditions in both end-systolic pressure-volume relationship (ESPVR) and end-diastolic pressure-volume relationship (EDPVR) parameters to avoid these singularities analytically. Third, we formulate a constrained nonlinear least squares problem to optimize both ESPVR and EDPVR parameters simultaneously to avoid singularities. The effectiveness of the proposed method in avoiding singularities was evaluated in an animal experiment. Compared to the conventional Ees estimation by linear regression, our proposed method reproduced in-vivo hemodynamics more accurately when simulating the estimated Ees variation during drug administration. Our method can be applied using the available data in the regular ICU/CCU setting. The improved clinical feasibility can support not only physicians' decision-making, including adjusting drug dosages in current clinical treatment, but also a closed-loop hemodynamic control system requiring accurate continuous Ees estimation.

Analytical Representation of Four-dimensional Hemodynamics for Drug Therapy Simulation in Acute Heart Failure Treatment.

Acute heart failure imperils multiple organs, including the heart. Elucidating the impact of drug therapies across this multidimensional hemodynamic system remains a challenge. This paper proposes a simulator that analyzes the impact of drug therapies on four dimensions of hemodynamics: left atrial pressure, cardiac output, mean arterial pressure, and myocardial oxygen consumption. To mathematically formulate hemodynamics, the analytical solutions of four-dimensional hemodynamics and the direction of its change are derived as functions of cardiovascular parameters: systemic vascular resistance, cardiac contractility, heart rate, and stressed blood volume. Furthermore, a drug library which represents the multi-dependency effect of drug therapies on cardiovascular parameters was identified in animal experiments. In evaluating the accuracy of our derived hemodynamic direction, the average angular error of predicted versus observed direction was 18.85[deg] after four different drug infusions for acute heart failure in animal experiments. Finally, the impact of drug therapies on four-dimensional hemodynamics was analyzed in three different simulation settings. One result showed that, even when drug therapies were simulated with simple rules according to the Forrester classification, the predicted direction of hemodynamic change matched the expected direction in more than 80% in 963 different AHF patient scenarios. Our developed simulator visualizes the impact of drug therapies on four-dimensional hemodynamics so intuitively that it can support clinicians' decision-making to protect multiple organs.

System Design for Optimizing Drug Infusions Using Cardiovascular Space Mapping for Acute Heart Failure.

Acute heart failure is caused by various factors and requires multiple drug therapies to remedy underlying causes. Due to the complexity of pharmacologic effects of cardiovascular agents, few studies have theoretically addressed the multidrug optimization problem. This paper proposes a drug infusion system for acute heart failure that controls cardiovascular performance metrics (cardiac output, left atrial pressure, and mean arterial pressure) within desired ranges as dictated by the cardiovascular parameters (systemic vascular resistance, cardiac contractility, heart rate, and stressed blood volume). The key to our system design is modeling and controlling cardiovascular parameters to yield the desired cardiovascular metrics. A 'tailored drug infusion' technique controls parameters by solving the optimization problem in order to conquer the complexity of multi-dependencies and the different dosage limits among multiple drugs. A 'cardiovascular space mapping' technique identifies the desired parameters from the desired metrics by deriving the analytical solutions of the metrics as functions of the parameters. To facilitate clinical discussions, parameters were set to realistic values in 5,600 simulated patients. Our results showed not only that the optimized drug combinations and dosages controlled the cardiovascular metrics to within the desired ranges, but also that they mostly corresponded to the recommended clinical use guidelines. An additional value of our system is that it proactively predicts the limitations of the tailored drug therapy, which supports the clinical decision of pivoting to alternative treatment strategies such as mechanical circulatory support.

Spatial Feature Extraction of Vectorcardiography via Minimum Volume Ellipsoid Enclosure in Classifying Left Ventricular Hypertrophy.

The voltage criteria used to diagnose left ventricular hypertrophy (LVH) in the chest and limb leads are by no means absolute. In addition to QRS voltages, QRS axis and duration, and P wave characteristics, repolarization (STT) changes have been focused attention due to their representing left ventricular overload. Vectorcardiography (VCG) has been studied specifically on its repolarization abnormality. The present study aims to devise spatial feature extraction of VCG and assess it in the LVH classification task. A minimum volume ellipsoid enclosure was applied to six segments obtained from upstroke and downstroke of each P, QRS, and T loops of a single-beat VCG. For the evaluation, VCG and 12 lead ECG dataset along with LVH labels of 61 subjects were derived from public open data, PTB-XL. These classification performances were compared with the LVH diagnosis criteria in the standard 12 lead ECG. As a result, the Random Forest classifier trained by the proposed spatial VCG feature resulted in accuracy of 0.904 (95% confidence interval: 0.861-0.947) when the classbalanced dataset was evaluated, which slightly exceeded the feature of 12 lead ECG. The feature importance analysis provided the quantitative ranking of the spatial feature of VCG, which were practically similar to those of ECG in the LVH classification task. Since the VCG are spatially comparable with three-dimensional data of CT, MRI, or Echocardiography, VCG will shed light on the spatial behavior of electrical depolarization and repolarization abnormalities in cardiac diseases.

Tonometric Condition of Cellular Polypropylene Film Sensors in Measuring Arterial Pressure Waveform.

Tonometric continuous measurement of arterial pressure becomes feasible using a cellular polypropylene (Cellular PP) film sensor. A pulsatile arterial vascular phantom model was used to find the range of optimal tonometric conditions and the responsiveness to dynamic pressure changes. The optimal tonometric condition was assessed by the correlation coefficient between the hydraulic pressure and the Cellular PP output using two different types of tubes (the latex tube and the hydrogel tube) to simulate arteries. With a setting of the normal blood pressure range, the output of Cellular PP correlated strongly with the level of hydraulic pressure, 0.998 and 0.989 in the latex tube and the hydrogel tube, respectively. For maintaining the optimal tonometric condition, the depressed depths of the latex and the hydrogel tube were less than 1.2 and 0.6 mm, respectively. The phantom model also demonstrated that the Cellular PP sensor followed changes in a hydraulic pressure dynamically under the optimal tonometric conditions. The present results demonstrated the Cellular PP film sensor is applicable to the arterial tonometry in measuring the instantaneous blood pressure while the sensor is adjusted to maintain the minimal flatness of the underlying arterial wall.Clinical Relevance- To understand the physiological characteristics of blood pressure and arterial system, the instantaneous measurement of blood pressure is necessary. The present study suggests that Cellular PP films are applicable to peripheral arteries tonometrically to obtain simultaneously the respective blood pressure waveforms.