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.

Automated control of Impella maintains optimal left ventricular unloading during periods of unstable hemodynamics and prevents myocardial damage in acute myocardial infarction.

BACKGROUND: Left ventricular (LV) unloading by Impella, an intravascular microaxial pump, has been shown to exert dramatic cardioprotective effects in acute clinical settings of cardiovascular diseases. Total Impella support (no native LV ejection) is far more efficient in reducing LV energetic demand than partial Impella support, but the manual control of pump speed to maintain stable LV unloading is difficult and impractical. We aimed to develop an Automatic IMpella Optimal Unloading System (AIMOUS), which controls Impella pump speed to maintain LV unloading degree using closed-feedback control. We validated the AIMOUS performance in an animal model. METHODS: In dogs, we identified the transfer function from pump speed to LV systolic pressure (LVSP) under total support conditions (n = 5). Using the transfer function, we designed the feedback controller of AIMOUS to keep LVSP at 40 mmHg and examined its performance by volume perturbations (n = 9). Lastly, AIMOUS was applied in the acute phase of ischemia-reperfusion in dogs. Four weeks after ischemia-reperfusion, we assessed LV function and infarct size (n = 10). RESULTS: AIMOUS maintained constant LVSP, thereby ensuring a stable LV unloading condition regardless of volume withdrawal or infusion (±8 ml/kg from baseline). AIMOUS in the acute phase of ischemia-reperfusion markedly improved LV function and reduced infarct size (No Impella support: 13.9 ± 1.3 vs. AIMOUS: 5.7 ± 1.9%, P < 0.05). CONCLUSIONS: AIMOUS is capable of maintaining optimal LV unloading during periods of unstable hemodynamics. Automated control of Impella pump speed in the acute phase of ischemia-reperfusion significantly reduced infarct size and prevented subsequent worsening of LV function.

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.

Effects of nitric oxide inhalation on pulmonary arterial impedance: differences between normal and pulmonary hypertension male rats.

Nitric oxide (NO) inhalation improves pulmonary hemodynamics in participants with pulmonary arterial hypertension (PAH). Although it can reduce pulmonary vascular resistance (PVR) in PAH, its impact on the dynamic mechanics of pulmonary arteries and its potential difference between control and participants with PAH remain unclear. PA impedance provides a comprehensive description of PA mechanics. With an arterial model, PA impedance can be parameterized into peripheral pulmonary resistance (Rp), arterial compliance (Cp), characteristic impedance of the proximal arteries (Zc), and transmission time from the main PA to the reflection site. This study investigated the effects of inhaled NO on PA impedance and its associated parameters in control and monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) male rats (6/group). Measurements were obtained at baseline and during NO inhalation at 40 and 80 ppm. In both groups, NO inhalation decreased PVR and increased the left atrial pressure. Notably, its impact on PA impedance was frequency dependent, as revealed by reduced PA impedance modulus in the low-frequency range below 10 Hz, with little effect on the high-frequency range. Furthermore, NO inhalation attenuated Rp, increased Cp, and prolonged transmission time without affecting Zc. It reduced Rp more pronouncedly in MCT-PAH rats, whereas it increased Cp and delayed transmission time more effectively in control rats. In conclusion, the therapeutic effects of inhaled NO on PA impedance were frequency dependent and may differ between the control and MCT-PAH groups, suggesting that the effect on the mechanics differs depending on the pathological state.NEW & NOTEWORTHY Nitric oxide inhalation decreased pulmonary arterial impedance in the low-frequency range (<10 Hz) with little impact on the high-frequency range. It reduced peripheral pulmonary resistance more pronouncedly in pulmonary hypertension rats, whereas it increased arterial compliance and transmission time in control rats. Its effect on the mechanics of the pulmonary arteries may differ depending on the pathological status.

Donepezil attenuates progression of cardiovascular remodeling and improves prognosis in spontaneously hypertensive rats with chronic myocardial infarction.

The acetylcholinesterase inhibitor donepezil restores autonomic balance, reduces inflammation, and improves long-term survival in rats with chronic heart failure (CHF) following myocardial infarction (MI). As arterial hypertension is associated with a significant risk of cardiovascular death, we investigated the effectiveness of donepezil in treating CHF in spontaneously hypertensive rats (SHR). CHF was induced in SHR by inducing permanent MI. After 2 weeks, the surviving SHR were randomly assigned to sham-operated (SO), untreated (UT), or oral donepezil-treated (DT, 5 mg/kg/day) groups, and various vitals and parameters were monitored. After 7 weeks of treatment, heart rate and arterial hypertension reduced significantly in DT rats than in UT rats. Donepezil treatment improved 50-day survival (41% to 80%, P = 0.004); suppressed progression of cardiac hypertrophy, cardiac dysfunction (cardiac index: 133 ± 5 vs. 112 ± 5 ml/min/kg, P < 0.05; left ventricular end-diastolic pressure: 12 ± 3 vs. 22 ± 2 mmHg, P < 0.05; left ventricular +dp/dtmax: 5348 ± 338 vs. 4267 ± 114 mmHg/s, P < 0.05), systemic inflammation, and coronary artery remodeling (wall thickness: 26.3 ± 1.4 vs. 34.7 ± 0.7 µm, P < 0.01; media-to-lumen ratio: 3.70 ± 0.73 vs. 8.59 ± 0.84, P < 0.001); increased capillary density; and decreased plasma catecholamine, B-type natriuretic peptide, arginine vasopressin, and angiotensin II levels. Donepezil treatment attenuated cardiac and coronary artery remodeling, mitigated cardiac dysfunction, and significantly improved the prognosis of SHR with CHF.

The impact of ECPELLA on haemodynamics and global oxygen delivery: a comprehensive simulation of biventricular failure.

BACKGROUND: ECPELLA, a combination of veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) and Impella, a percutaneous left ventricular (LV) assist device, has emerged as a novel therapeutic option in patients with severe cardiogenic shock (CS). Since multiple cardiovascular and pump factors influence the haemodynamic effects of ECPELLA, optimising ECPELLA management remains challenging. In this study, we conducted a comprehensive simulation study of ECPELLA haemodynamics. We also simulated global oxygen delivery (DO2) under ECPELLA in severe CS and acute respiratory failure as a first step to incorporate global DO2 into our developed cardiovascular simulation. METHODS AND RESULTS: Both the systemic and pulmonary circulations were modelled using a 5-element resistance‒capacitance network. The four ventricles were represented by time-varying elastances with unidirectional valves. In the scenarios of severe LV dysfunction, biventricular dysfunction with normal pulmonary vascular resistance (PVR, 0.8 Wood units), and biventricular dysfunction with high PVR (6.0 Wood units), we compared the changes in haemodynamics, pressure-volume relationship (PV loop), and global DO2 under different VA-ECMO flows and Impella support levels. RESULTS: In the simulation, ECPELLA improved total systemic flow with a minimising biventricular pressure-volume loop, indicating biventricular unloading in normal PVR conditions. Meanwhile, increased Impella support level in high PVR conditions rendered the LV-PV loop smaller and induced LV suction in ECPELLA support conditions. The general trend of global DO2 was followed by the changes in total systemic flow. The addition of veno-venous ECMO (VV-ECMO) augmented the global DO2 increment under ECPELLA total support conditions. CONCLUSIONS: The optimal ECPELLA support increased total systemic flow and achieved both biventricular unloading. The VV-ECMO effectively improves global DO2 in total ECPELLA support conditions.

Myeloid derived suppressor cells in peripheral blood can be a prognostic factor in canine transitional cell carcinoma.

Myeloid-derived suppressor cells (MDSCs) are immature cells with immunosuppressive properties found in the tumor microenvironment. MDSCs are divided into two major subsets: polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs). Both MDSC subsets contribute to the creation of an immunosuppressive environment for tumor progression. In humans, patients with high levels of MDSCs show worse outcomes for several types of cancers. However, the association between MDSCs and clinical features has rarely been investigated in canine studies. In the present study, we measured the proportion of PMN-MDSCs and M-MDSCs in the peripheral blood and tumor tissue of dogs with hepatocellular carcinoma (HCC), prostate cancer (PC), transitional cell carcinoma (TCC), lymphoma, and pulmonary adenocarcinoma. Additionally, we examined immunosuppressive ability of PMN-MDSCs and M-MDSCs in peripheral blood mononuclear cells of TCC case on CD4+, CD8+ and interferon-γ+ cells and investigated the relationships of MDSCs with clinical features and outcomes. PMN-MDSCs increased in HCC, PC, TCC, and lymphoma. In contrast, M-MDSCs increased in the TCC. Both PMN-MDSCs and M-MDSCs exhibited immunosuppressive effects on CD8+, CD4+ and interferon-γ+ cells. In dogs with TCC, lymph node metastasis was associated with high level of PMN-MDSCs but not with M-MDSCs. High levels of both PMN-MDSCs and M-MDSCs were related to advanced tumor stage. Kaplan-Meier analysis revealed that high levels of both PMN-MDSCs and M-MDSCs were significantly associated with shorter overall survival. In addition, the Cox proportional hazard regression model showed that M-MDSCs and the tumor stage were independent prognostic factors for TCC. These results suggest that PMN-MDSCs and M-MDSCs may be involved in tumor progression and could be prognostic factors and promising therapeutic targets in dogs with TCC.

Short-term dynamic characteristics of diuresis during exogenous pressure perturbations with and without arterial baroreflex control.

Although body fluid volume control by the kidneys may be classified as a long-term arterial pressure (AP) control system, it does not necessarily follow that the urine flow (UF) response to changes in AP is slow. We quantified the dynamic characteristics of the UF response to short-term AP changes by changing mean AP between 60 mmHg and 100 mmHg every 10 s according to a binary white noise sequence in anesthetized rats (n = 8 animals). In a baro-on trial (the carotid sinus baroreflex was enabled), the UF response represented the combined synergistic effects of pressure diuresis (PD) and neurally mediated antidiuresis (NMA). In a baro-fix trial (the carotid sinus pressure was fixed at 100 mmHg), the UF response mainly reflected the effect of PD. The UF step response was quantified using the sum of two exponential decay functions. The fast and slow components had time constants of 6.5 ± 3.6 s and 102 ± 85 s (means ± SD), respectively, in the baro-on trial. Although the gain of the fast component did not differ between the two trials (0.49 ± 0.21 vs. 0.66 ± 0.22 µL·min-1·kg-1·mmHg-1), the gain of the slow component was greater in the baro-on than in the baro-fix trial (0.51 ± 0.14 vs. 0.09 ± 0.39 µL·min-1·kg-1·mmHg-1, P = 0.023). The magnitude of NMA relative to PD was calculated to be 32.2 ± 29.8%. In conclusion, NMA contributed to the slow component, and its magnitude was approximately one-third of that of the effect of PD.NEW & NOTEWORTHY We quantified short-term dynamic characteristics of the urine flow (UF) response to arterial pressure (AP) changes using white noise analysis. The UF step response approximated the sum of two exponential decay functions with time constants of ∼6.5 s and 102 s. The neurally mediated antidiuretic (NMA) effect contributed to the slow component of the UF step response, with the magnitude of approximately one-third of that of the pressure diuresis (PD) effect.

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.

Acute effects of empagliflozin on open-loop baroreflex function and urinary glucose excretion in rats with chronic myocardial infarction.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have exerted cardioprotective effects in clinical trials, but underlying mechanisms are not fully understood. As mitigating sympathetic overactivity is of major clinical concern in the mechanisms of heart failure treatments, we examined the effects of modulation of glucose handling on baroreflex-mediated sympathetic nerve activity and arterial pressure regulations in rats with chronic myocardial infarction (n = 9). Repeated 11-min step input sequences were used for an open-loop analysis of the carotid sinus baroreflex. An SGLT2 inhibitor, empagliflozin, was intravenously administered (10 mg/kg) after the second sequence. Neither the baroreflex neural nor peripheral arc significantly changed during the last observation period (seventh and eighth sequences) compared with the baseline period although urinary glucose excretion increased from near 0 (0.0089 ± 0.0011 mg min-1 kg-1) to 1.91 ± 0.25 mg min-1 kg-1. Hence, empagliflozin does not acutely modulate the baroreflex regulations of sympathetic nerve activity and arterial pressure in this rat model of chronic myocardial infarction.

Impact of vericiguat on baroreflex-mediated sympathetic circulatory regulation: An open-loop analysis.

AIMS: To quantify in vivo the effects of the soluble guanylate cyclase (sGC) stimulator, vericiguat, on autonomic cardiovascular regulation in comparison with the nitric oxide (NO) donor, sodium nitroprusside. METHODS: In anesthetized Wistar-Kyoto rats, baroreflex-mediated changes in sympathetic nerve activity (SNA), arterial pressure (AP), central venous pressure (CVP), and aortic flow (AoF) were examined before and during the intravenous continuous administration (10 µg·kg-1·min-1) of vericiguat or sodium nitroprusside (n = 8 each). Systemic vascular resistance (SVR) was calculated as SVR = (AP-CVP) / AoF. RESULTS: Neither vericiguat nor sodium nitroprusside affected fitted parameters of the baroreflex-mediated SNA response. Both vericiguat and sodium nitroprusside decreased the AP mainly through their peripheral effects. Vericiguat halved the slope of the SNA-SVR relationship from 0.012 ± 0.002 to 0.006 ± 0.002 mmHg·min·mL-1·%-1 (P = 0.008), whereas sodium nitroprusside caused a near parallel downward shift in the SNA-SVR relationship with a reduction of the SVR intercept from 1.235 ± 0.187 to 0.851 ± 0.123 mmHg·min/mL (P = 0.008). CONCLUSION: Neither vericiguat nor sodium nitroprusside significantly affected the baroreflex-mediated SNA response. The vasodilative effect of vericiguat became greater toward high levels of SNA and AP, possibly reflecting the increased sGC sensitivity to endogenous NO. By contrast, the effect of sodium nitroprusside was more uniform over the range of SNA. These results help better understand cardiovascular effects of vericiguat.

Acute effects of empagliflozin on open-loop baroreflex function and urine glucose excretion in Goto-Kakizaki diabetic rats.

Although suppression of sympathetic activity is suggested as one of the underlying mechanisms for the cardioprotective effects afforded by sodium-glucose cotransporter 2 (SGLT2) inhibitors, whether the modulation of glucose handling acutely affects sympathetic regulation of arterial pressure remains to be elucidated. In Goto-Kakizaki diabetic rats, we estimated the open-loop static characteristics of the carotid sinus baroreflex together with urine glucose excretion using repeated 11-min step input sequences. After the completion of the 2nd sequence, an SGLT2 inhibitor empagliflozin (10 mg kg-1) or vehicle solution was administered intravenously (n = 7 rats each). Empagliflozin did not significantly affect the baroreflex neural or peripheral arc, despite significantly increasing urine glucose excretion (from 0.365 ± 0.216 to 8.514 ± 0.864 mg·min-1·kg-1, P < 0.001) in the 7th and 8th sequences. The possible sympathoinhibitory effect of empagliflozin may be an indirect effect associated with chronic improvements in renal energy status and general disease conditions.

Discordance between fractional flow reserve and instantaneous wave-free ratio in patients with severe aortic stenosis: A retrospective cohort study.

BACKGROUND: Discordance between fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) occurs in approximately 20 % of cases. However, no studies have reported the discordance in patients with severe aortic stenosis (AS). We aimed to evaluate the diagnostic discordance between FFR and iFR in patients with severe AS. METHODS: We examined 140 consecutive patients with severe AS (164 intermediate coronary artery stenosis vessels). FFR and iFR were calculated in four quadrants based on threshold FFR and iFR values of ≤0.8 and ≤0.89, respectively (Group 1: iFR >0.89, FFR >0.80; Group 2: iFR ≤0.89, FFR >0.80; Group 3: iFR >0.89, FFR ≤0.80; and Group 4: iFR ≤0.89, FFR ≤0.80). Concordant groups were Groups 1 and 4, and discordant groups were Groups 2 and 3. Positive and negative discordant groups were Groups 3 and 2, respectively. RESULTS: The median (Q1, Q3) FFR and iFR were 0.84 (0.76, 0.88) and 0.85 (0.76, 0.91), respectively. Discordance was observed in 48 vessels (29.3 %). In the discordant group, negative discordance (Group 2: iFR ≤0.89 and FFR >0.80) was predominant (45 cases, 93.6 %). Multivariate analysis showed that the left anterior descending artery [odds ratio (OR), 3.88; 95 % confidence interval (CI): 1.54-9.79, p = 0.004] and peak velocity ≥5.0 m/s (OR, 3.21; 95%CI: 1.36-7.57, p = 0.008) were independently associated with negative discordance (FFR >0.8 and iFR ≤0.89). CONCLUSIONS: In patients with severe AS, discordance between FFR and iFR was predominantly negative and observed in 29.3 % of vessels. The left anterior descending artery and peak velocity ≥5.0 m/s were independently associated with negative discordance.

Dynamic accentuated antagonism of heart rate control during different levels of vagal nerve stimulation intensity in rats.

Accentuated antagonism refers to a phenomenon in which the vagal effect on heart rate (HR) is augmented by background sympathetic tone. The dynamic aspect of accentuated antagonism remains to be elucidated during different levels of vagal nerve stimulation (VNS) intensity. We performed VNS on anesthetized rats (n = 8) according to a binary white noise signal with a switching interval of 500 ms at three different stimulation rates (low-intensity: 0-10 Hz, moderate-intensity: 0-20 Hz, and high-intensity: 0-40 Hz). The transfer function from VNS to HR was estimated with and without concomitant tonic sympathetic nerve stimulation (SNS) at 5 Hz. The asymptotic low-frequency (LF) gain (in beats/min/Hz) of the transfer function increased with SNS regardless of the VNS rate [low-intensity: 3.93 ± 0.70 vs. 5.82 ± 0.65 (P = 0.021), moderate-intensity: 3.87 ± 0.62 vs. 5.36 ± 0.53 (P = 0.018), high-intensity: 4.77 ± 0.85 vs. 7.39 ± 1.36 (P = 0.011)]. Moreover, SNS slightly increased the ratio of high-frequency (HF) gain to the LF gain. These effects of SNS were canceled by the pretreatment of ivabradine, an inhibitor of hyperpolarization-activated cyclic nucleotide-gated channels, in another group of rats (n = 6). Although background sympathetic tone antagonizes the vagal effect on mean HR, it enables finer HR control by increasing the dynamic gain of the vagal HR transfer function regardless of VNS intensity. When interpreting the HF component of HR variability, the augmenting effect from background sympathetic tone needs to be considered.

A Novel Triple-Bladder Cuff Method for Blood Pressure Estimation Based on Pulse Wave Dynamics in Brachial Artery: Theoretical and Experimental Analyses.

OBJECTIVE: The objective of this study was to develop a novel triple-bladder cuff method for accurate and automated estimation of systolic (SBP) and diastolic (DBP) blood pressure and validate its reliability in animal experiments. METHODS: The cuff is composed of three bladders each measured one-third the width of a conventional BP cuff, which are designed to measure oscillatory pulsation at the proximal, middle, and distal segments of the upper arm. This structure allows evaluation of the pulse wave propagation in the brachial artery under the cuff. SBP is estimated (SBPe) by detecting resumption of systolic arterial flow based on statistical similarity in oscillatory pulse traces between the proximal and distal segments. DBP is estimated (DBPe) based on the relation between pulse wave velocity and transmural pressure at diastole in the brachial artery. In 7 anesthetized goats, we compared SBPe and DBPe to reference SBP and DBP, respectively, measured by an intra-arterial catheter. BP was perturbed by infusing nitroprusside or noradrenaline. RESULTS: SBP correlated strongly with SBPe in each animal [mean coefficient of determination (R2) = 0.98 ± 0.01]. Mean ± standard deviation of errors between SBP and SBPe was 0.0 ± 4.9 mmHg. DBP correlated strongly with DBPe in each animal (R2 = 0.96 ± 0.03). Mean ± standard deviation of errors between DBP and DBPe was 0.0 ± 6.3 mmHg. CONCLUSION: This method estimates SBP and DBP with acceptable accuracy. SIGNIFICANCE: Accurate and automated BP estimation by this method may potentially optimize antihypertensive treatment in patients with hypertension.

Distal Transradial Access For Cardiac Catheterization in Patients Undergoing Hemodialysis.

OBJECTIVES: Although a distal radial artery (DRA) approach has recently been used in patients undergoing cardiac catheterization, no studies have so far investigated the safety and feasibility of DRA in patients undergoing hemodialysis (HD). We aimed to investigate the incidence of conventional radial artery (CRA) occlusion and puncture site complications after DRA puncture in patients undergoing HD. METHODS: We retrospectively analyzed the data of 117 consecutive patients with HD who underwent coronary angiography or percutaneous coronary intervention via a DRA approach at our institution from September 2017 to December 2019. The primary endpoint was the incidence of CRA occlusion after DRA puncture, as assessed via vascular ultrasonography. Secondary endpoints included difficulty achieving hemostasis, DRA occlusion, aneurysm, arteriovenous shunt, and acute ischemia. RESULTS: The DRA puncture was successful in 106 patients (success rate: 90.5%). Because 21 patients lacked postprocedural vascular ultrasonography data, the primary endpoint was evaluated in 85 patients. CRA occlusion occurred in three patients (3.5%) following DRA puncture. DRA occlusion and aneurysm occurred in five patients (5.9%) and one patient (1.2%), respectively. CONCLUSIONS: Catheterization through DRA is feasible in patients undergoing HD, with a clinically acceptable incidence of CRA and complications.

Sorafenib inhibits tumor cell growth and angiogenesis in canine transitional cell carcinoma.

Canine transitional cell carcinoma (cTCC) is the most common naturally occurring bladder cancer and accounts for 1-2% of canine tumors. The prognosis is poor due to the high rate of invasiveness and metastasis at diagnosis. Sorafenib is a multi-kinase inhibitor that targets rapidly accelerated fibrosarcoma (RAF), vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor-ß (PDGFR-ß), and KIT. In previous studies, a somatic mutation of B-rapidly accelerated fibrosarcoma (BRAF) and expressions of VEGFR-2 and PDGFR-ß were observed in over 80% of patients with cTCC. Therefore, in this study, we investigated the anti-tumor effects of sorafenib on cTCC. Five cTCC cell lines were used in the in vitro experiments. All five cTCC cell lines expressed VEGFR-2 and PDGFR-ß and sorafenib showed growth inhibitory effect on cTCC cell lines. Cell cycle arrest at the G0/G1 phase and subsequent apoptosis were observed following sorafenib treatment. In the in vivo experiments, cTCC (Sora) cells were subcutaneously injected into nude mice. Mice were orally administered with sorafenib (30 mg/kg daily) for 14 days. Sorafenib inhibited tumor growth compared to vehicle control. The necrotic area in the tumor tissues was increased in the sorafenib-treated group. Sorafenib also inhibited angiogenesis in the tumor microenvironment. Thus, sorafenib may be potential therapeutic agent for cTCC via its direct anti-tumor effect and inhibition of angiogenesis.

Rehabilitation Nutrition and Exercise Therapy for Sarcopenia.

Sarcopenia is an age-related loss of skeletal muscle associated with adverse outcomes such as falls, fractures, disability, and increased mortality in older people and hospitalized patients. About half of older male nursing home residents have sarcopenia. The diagnostic criteria by the European Working Group on Sarcopenia in Older People (EWGSOP) and the Asian Working Group for Sarcopenia (AWGS) have led to increased interest in sarcopenia. Exercise and nutritional management are crucial for the prevention and treatment of sarcopenia. Nutritional therapy for sarcopenia that includes 20 g of whey protein and 800 IU of vitamin D twice a day improves lower limb strength. Exercise therapy for sarcopenia, such as resistance training and 6 months of home exercises, improves muscle strength and physical function. Combination therapy that includes both nutritional and exercise therapy improves gait speed and knee extension strength more than either exercise alone or nutrition therapy alone. Excessive bedrest and mismanagement of nutrition in medical facilities can lead to iatrogenic sarcopenia. Iatrogenic sarcopenia is sarcopenia caused by the activities of health care workers in health care facilities. Appropriate nutritional management and exercise programs through rehabilitation nutrition are important for prevention and treatment of iatrogenic sarcopenia. Nutritional and exercise therapy should be started very early after admission and adjusted to the level of inflammation and disease status. Repeated assessment, diagnosis, goal setting, interventions, and monitoring using the rehabilitation nutrition care process is important to maximize treatment effectiveness and improve patients' functional recovery and quality of life.

Coronary Access After TAVR With a Cylindrical-Shaped Valve: Learning From LOTUS.

BACKGROUND/PURPOSE: Data on the feasibility of coronary access (CA) through above or outside of the cylindrical shaped-transcatheter heart valve (THV) are very limited. The aims of the present study were to assess the feasibility of CA after transcatheter aortic valve replacement (TAVR) with the LOTUS using multi detector computed tomography (MDCT) and the reliability of algorithm detecting unfavorable CA. METHODS/MATERIALS: Post-TAVR MDCT of 41 patients with 82 coronary arteries were evaluated. The relationship and distance between the THV flame and sinotubular junction (STJ) and coronary ostia were assessed. Unfavorable CA was defined as the valve-to-STJ distance < 2-mm or the valve-to-coronary ostia distance < 2-mm if the THV flame was above STJ or coronary ostia. RESULTS: MDCT-identified unfavorable CA was observed in 29.3% for the left coronary artery and 41.5% for the right coronary artery. In total, 53.7% of patients had at least one unfavorable CA and 14.6% of those had unfavorable CA for both left and right coronary artery. While patients underwent coronary angiography after TAVR, the success rates of selective coronary cannulation were significantly lower in patients with MDCT-identified unfavorable CA in comparison to those with favorable CA for left (20.0% vs. 100%, P = 0.002) and right coronary artery (0% vs. 100%, P < 0.001). CONCLUSIONS: Future CA through above or outside of a cylindrical shaped THV may be challenging with a significant probability. Our algorithm identifying unfavorable CA using post-MDCT seems to be useful for estimating the risk of unsuccessful selective cannulation.