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.

Input-size dependence of the baroreflex neural arc transfer characteristics during Gaussian white noise inputs.

Although Gaussian white noise (GWN) inputs offer a theoretical framework for identifying higher-order nonlinearity, an actual application to the data of the neural arc of the carotid sinus baroreflex did not succeed in fully predicting the well-known sigmoidal nonlinearity. In the present study, we assumed that the neural arc can be approximated by a cascade of a linear dynamic (LD) component and a nonlinear static (NS) component. We analyzed the data obtained using GWN inputs with a mean of 120 mmHg and standard deviations (SDs) of 10, 20, and 30 mmHg for 15 min each in anesthetized rats (n = 7). We first estimated the linear transfer function from carotid sinus pressure to sympathetic nerve activity (SNA) and then plotted the measured SNA against the linearly predicted SNA. The predicted and measured data pairs exhibited an inverse sigmoidal distribution when grouped into 10 bins based on the size of the linearly predicted SNA. The sigmoidal nonlinearity estimated via the LD-NS model showed a midpoint pressure (104.1 ± 4.4 mmHg for SD of 30 mmHg) lower than that estimated by a conventional stepwise input (135.8 ± 3.9 mmHg, P < 0.001). This suggests that the NS component is more likely to reflect the nonlinearity observed during pulsatile inputs that are physiological to baroreceptors. Furthermore, the LD-NS model yielded higher R2 values compared with the linear model and the previously suggested second-order Uryson model in the testing dataset.NEW & NOTEWORTHY We examined the input-size dependence of the baroreflex neural arc transfer characteristics during Gaussian white noise inputs. A linear dynamic-static nonlinear model yielded higher R2 values compared with a linear model and captured the well-known sigmoidal nonlinearity of the neural arc, indicating that the nonlinear dynamics contributed to determining sympathetic nerve activity. Ignoring such nonlinear dynamics might reduce our ability to explain underlying physiology and significantly limit the interpretation of experimental data.

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.

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.

Impact of neurally mediated antidiuretic effect relative to pressure diuresis during acute changes in sympathetic nerve activity.

We examined urine excretion during primary acute sympathetic activation (PASA) in anesthetized Wistar-Kyoto rats. Since arterial pressure (AP) changes with sympathetic nerve activity (SNA) during PASA, urine excretion reflects a neurally mediated antidiuretic effect combined with an effect of pressure diuresis. We hypothesized that preventing AP changes under PASA would enable the direct estimation of the neurally mediated antidiuretic effect alone. We changed the isolated carotid sinus pressure stepwise from 60 to 180 mmHg and compared the relationship of normalized urine flow (nUF, urine flow normalized by body weight) versus SNA between conditions allowing and preventing baroreflex-mediated changes in the mean AP. The slope of the SNA-nUF relationship was [Formula: see text]nUFvar = 0.444 ± 0.074 µL·min-1·kg-1·%-1 when the mean AP was variable, whereas it was [Formula: see text]nUFfix = -0.143 ± 0.032 µL·min-1·kg-1·%-1 when the mean AP was fixed at 100 mmHg (n = 7 rats). The slope associated with the effect of pressure diuresis alone, calculated as [Formula: see text]nUFvar - [Formula: see text]nUFfix, was 0.586 ± 0.105 µL·min-1·kg-1·%-1. Hence, the potency of the neurally mediated antidiuretic effect |[Formula: see text]nUFfix|/([Formula: see text]nUFvar - [Formula: see text]nUFfix) was 0.235 ± 0.014 relative to the effect of pressure diuresis under PASA. Our findings would aid an integrative understanding of the effects of renal hemodynamic and sympathetic modulations on urine output function.

Substantial Reduction of Acute Ischemic Mitral Regurgitation Using Impella in AMI Complicated with Cardiogenic Shock.

A 77-year-old female presented with loss of consciousness, blood pressure of 90/60 mmHg, and heart rate of 47 bpm. At admission, highly sensitive Trop-T and lactate were elevated, and an electrocardiogram revealed an infero-posterior ST elevation myocardial infarction. Echocardiography revealed a depressed left ventricular ejection fraction with abnormal wall motion in the infero-posterior region and hyperkinetic apical movement along with severe mitral regurgitation (MR). Coronary angiography showed a hypoplastic right coronary artery, 100% thrombotic occlusion of the dominant left circumflex (LCx) artery, and 75% stenosis in the left anterior descending (LAD) artery. Substantial hemodynamic improvement with the reduction of acute ischemic MR was achieved by the initiation of an Impella 2.5, which is a transvalvular axial flow pump, and successful percutaneous coronary intervention (PCI) was conducted with stents to the LCx. The patient was weaned off the Impella 2.5 in 5 days, received staged PCI to LAD, and was later discharged after completion of the staged PCI to LAD.

Angiotensin II inhibition increases diuresis during acute sympathetic activation in intact and denervated kidneys in rats with chronic myocardial infarction.

We examined urine excretion during primary acute sympathetic activation (PASA) in Wistar-Kyoto rats with myocardial infarction (MI). The rats underwent unilateral renal denervation (RDN) 7 weeks after coronary artery ligation. 4-10 days later, an acute experiment was performed under anesthetized conditions (n = 8 rats). Isolated carotid sinus pressure was changed stepwise from 60 to 180 mmHg, and the relationship between the arterial pressure (AP) and the normalized urine flow (nUF, urine flow normalized by the body weight) was examined. After obtaining the control data, an angiotensin II type 1 receptor blocker telmisartan (2.5 mg/kg) was intravenously administered. The effects of RDN, telmisartan, and heart weight (biventricular weight) on the relationship between AP and nUF were examined using multiple regression analyses. Regarding the slope of nUF versus AP (nUFslope), the constant term of the regression was positive (0.315 ± 0.069 µL·min-1·kg-1·mmHg-1), indicating that nUF increased with AP. The heart weight had a negative effect on nUFslope (P < 0.05), suggesting that the severity of MI was associated with the impairment of urine excretion. Telmisartan increased nUFslope by 0.358 ± 0.080 µL·min-1·kg-1·mmHg-1 (P < 0.001), whereas RDN had no significant effect on this parameter. The results indicate that unilateral RDN was unable to abolish the effect of the renin-angiotensin system on urine excretion during PASA. Circulating or locally produced angiotensin II, rather than ongoing renal sympathetic nerve activity, played a dominant role in the impairment of urine excretion during PASA in rats with chronic MI.

Development of an automated closed-loop ß-blocker delivery system to stably reduce myocardial oxygen consumption without inducing circulatory collapse in a canine heart failure model: a proof of concept study.

Beta-blockers are well known to reduce myocardial oxygen consumption (MVO2) and improve the prognosis of heart failure (HF) patients. However, its negative chronotropic and inotropic effects limit their use in the acute phase of HF due to the risk of circulatory collapse. In this study, as a first step for a safe ß-blocker administration strategy, we aimed to develop and evaluate the feasibility of an automated ß-blocker administration system. We developed a system to monitor arterial pressure (AP), left atrial pressure (PLA), right atrial pressure, and cardiac output. Using negative feedback of hemodynamics, the system controls AP and PLA by administering landiolol (an ultra-short-acting ß-blocker), dextran, and furosemide. We applied the system for 60 min to 6 mongrel dogs with rapid pacing-induced HF. In all dogs, the system automatically adjusted the doses of the drugs. Mean AP and mean PLA were controlled within the acceptable ranges (AP within 5 mmHg below target; PLA within 2 mmHg above target) more than 95% of the time. Median absolute performance error was small for AP [median (interquartile range), 3.1% (2.2-3.8)] and PLA [3.6% (2.2-5.7)]. The system decreased MVO2 and PLA significantly. We demonstrated the feasibility of an automated ß-blocker administration system in a canine model of acute HF. The system controlled AP and PLA to avoid circulatory collapse, and reduced MVO2 significantly. As the system can help the management of patients with HF, further validations in larger samples and development for clinical applications are warranted.

A novel method of trans-esophageal Doppler cardiac output monitoring utilizing peripheral arterial pulse contour with/without machine learning approach.

Transesophageal Doppler (TED) velocity in the descending thoracic aorta (DA) is used to track changes in cardiac output (CO). However, CO tracking by this method is hampered by substantial change in aortic cross-sectional area (CSA) or proportionality between blood flow to the upper and lower body. To overcome this, we have developed a new method of TED CO monitoring. In this method, TED signal is obtained primarily from the aortic arch (AA). Using AA velocity signal, CO (COAA-CSA) is estimated by compensating changes in the aortic CSA with peripheral arterial pulse contour. When AA cannot be displayed properly or when the quality of AA velocity signal is unacceptable, our method estimates CO (CODA-ML) from DA velocity signal first by compensating changes in the aortic CSA, and by compensating changes in the blood flow proportionality through a machine learning of the relation between the CSA-adjusted CO and a reference CO (COref). In 12 anesthetized dogs, we compared COAA-CSA and CODA-ML with COref measured by an ascending aortic flow probe under diverse hemodynamic conditions (COref changed from 723 to 7316 ml·min-1). Between COAA-CSA and COref, concordance rate in the four-quadrant plot analysis was 96%, while angular concordance rate in the polar plot analysis was 91%. Between CODA-ML and COref, concordance rate was 93% and angular concordance rate was 94%. Both COAA-CSA and CODA-ML demonstrated "good to marginal" tracking ability of COref. In conclusion, our method may allow a robust and reliable tracking of CO during perioperative hemodynamic management.

Impella Motor Current Amplitude Reflects the Degree of Left Ventricular Unloading under ECPELLA Support.

The combination of venoarterial extracorporeal membrane oxygenation (VA-ECMO) and Impella, referred to as ECPELLA, is a powerful transient mechanical circulatory support for patients with severe cardiogenic shock (CS). During ECPELLA support, VA-ECMO loads the left ventricle (LV) and Impella unloads the LV. Therefore, evaluating the degree of LV unloading during ECPELLA may be a prerequisite to protect the injured myocardium. Here we report a patient with CS due to an inferior ST-elevation myocardial infarction in which the degree of LV unloading on ECPELLA was confirmed by direct LV pressure (LVP) measurement. After the percutaneous coronary intervention for the right coronary artery on ECPELLA, the aortic pressure became nonpulsatile and the peak systolic LVP was reduced at approximately 10 mmHg with 20 mA of the Impella motor current (MC) amplitude, which we referred to as the total LV unloading condition. We maintained the condition in the early phase of ECPELLA by monitoring the Impella MC amplitude at 20 mA and less with nonpulsatile aortic pressure. The patient was successfully weaned off VA-ECMO on day 3, and Impella was explanted on day 8. Prior to the Impella explant, the Impella MC amplitude increased more than 100 mA and the estimated pressure gradient between the aortic pressure and LVP was well matched with the directly measured LVP. In this case, the patient was successfully treated by ECPELLA with the total LV unloading condition, and we showed that the degree of LV unloading on ECPELLA can be estimated from the aortic pressure and Impella MC amplitude at given Impella flows.

Prediction of hemodynamics after atrial septal defect closure using a framework of circulatory equilibrium in dogs.

In patients with heart failure, atrial septal defect (ASD) closure has a risk of inducing life-threatening acute pulmonary edema. The objective of this study was to develop a novel framework for quantitative prediction of hemodynamics after ASD closure. The generalized circulatory equilibrium comprises right and left cardiac output (CO) curves and pulmonary and systemic venous return surfaces. We incorporated ASD into the framework of circulatory equilibrium by representing ASD shunt flow (QASD) by the difference between pulmonary flow (QP) and systemic flow (QS). To examine the accuracy of prediction, we created ASD in six dogs. Four weeks after ASD creation, we measured left atrial pressure (PLA), right atrial pressure (PRA), QP, and Qs before and after ASD balloon occlusion. We then predicted postocclusion hemodynamics from measured preocclusion hemodynamics. Finally, we numerically simulated hemodynamics under various ASD diameters while changing left and right ventricular function. Predicted postocclusion PLA, PRA, and QS from preocclusion hemodynamics matched well with those measured [PLA: coefficient of determination (r2) = 0.96, standard error of estimate (SEE) = 0.89 mmHg, PRA: r2 = 0.98, SEE = 0.26 mmHg, QS: r2 = 0.97, SEE = 5.6 mL·min-1·kg-1]. A simulation study demonstrated that ASD closure increases the risk of pulmonary edema in patients with impaired left ventricular function and normal right ventricular function, indicating the importance of evaluation for the balance between right and left ventricular function. ASD shunt incorporated into the generalized circulatory equilibrium accurately predicted hemodynamics after ASD closure, which would facilitate safety management of ASD closure.NEW & NOTEWORTHY We developed a framework to predict the impact of atrial septal defect (ASD) closure on hemodynamics by incorporating ASD shunt flow into the framework of circulatory equilibrium. The proposed framework accurately predicted hemodynamics after ASD closure. Patient-specific prediction of hemodynamics may be useful for safety management of ASD closure.

Roxadustat Markedly Reduces Myocardial Ischemia Reperfusion Injury in Mice.

BACKGROUND: Ischemic preconditioning (IPC) is an effective procedure to protect against ischemia/reperfusion (I/R) injury. Hypoxia-inducible factor-1α (Hif-1α) is a key molecule in IPC, and roxadustat (RXD), a first-in-class prolyl hydroxylase domain-containing protein inhibitor, has been recently developed to treat anemia in patients with chronic kidney disease. Thus, we investigated whether RXD pretreatment protects against I/R injury.Methods and Results:RXD pretreatment markedly reduced the infarct size and suppressed plasma creatinine kinase activity in a murine I/R model. Analysis of oxygen metabolism showed that RXD could produce ischemic tolerance by shifting metabolism from aerobic to anaerobic respiration. CONCLUSIONS: RXD pretreatment may be a novel strategy against I/R injury.

Estimation of the baroreflex total loop gain by the power spectral analysis of continuous arterial pressure recordings.

Baroreflex dysfunction contributes to the pathogenesis of cardiovascular diseases. The baroreflex comprises a negative feedback loop to stabilize arterial pressure (AP); its pressure-stabilizing capacity is defined as the gain ( G) of the transfer function ( H) of the baroreflex total loop. However, no method exists to evaluate G in a clinical setting. A feedback system with H attenuates pressure disturbance (PD) to PD/(1 + H). We hypothesized that the baroreflex attenuates the power spectrum density (PSD) of AP in the baroreflex functioning frequency range. We created graded baroreflex dysfunction in rats using a modified sinoaortic denervation (SAD) method [SAD; control (no SAD): n = 9; partial SAD (SAD in the right carotid sinus): n = 6, and total SAD (SAD in the bilateral carotid sinuses): n = 6] and evaluated the PSD of 12-h telemetric AP recordings in the light phase. Using the ratio of PSD at 0.01-0.1 Hz (PSD slope), we normalized them with the PSD in rats with complete baroreflex failure and derived the baroreflex index (BRI), which directly reflects G. We compared BRI and G obtained from a baroreflex open-loop experiment (reference G). The PSD slope became steeper with progression of baroreflex dysfunction. BRI (control: 2.00 ± 0.31, partial SAD: 1.28 ± 0.30, and total SAD: 0.06 ± 0.10, P < 0.05) was linearly correlated with reference G ( R2 = 0.91, P < 0.01). BRI accurately estimated G of the baroreflex and may serve as a novel tool for estimating the pressure-stabilizing capacity of the baroreflex in clinical settings. NEW & NOTEWORTHY This study proposed a novel method to estimate the gain of the baroreflex total loop, the so-called "baroreflex index" (BRI). BRI focuses on action potential variability in the frequency domain, considering baroreflex low-pass filter characteristics within 0.01-0.1 Hz. We demonstrated that BRI was linearly correlated with the reference gain of baroreflex in rats. Thus, BRI may contribute greatly to the development of a clinical tool for estimating baroreflex pressure-stabilizing capacity.

Diabetes mellitus attenuates the pressure response against hypotensive stress by impairing the sympathetic regulation of the baroreflex afferent arc.

Patients with diabetes mellitus (DM) often show arterial pressure (AP) lability associated with cardiovascular autonomic neuropathy. Because the arterial baroreflex tightly regulates AP via sympathetic nerve activity (SNA), we investigated the systematic baroreflex function, considering the control theory in DM by open-loop analysis. We used Zucker diabetic fatty (ZDF) rats as a type 2 DM model. Under general anesthesia, we isolated the carotid sinuses from the systemic circulation, changed intracarotid sinus pressure (CSP), and recorded SNA and AP responses. We compared CSP-AP (total loop), CSP-SNA (afferent arc), and SNA-AP (efferent arc) relationships between ZDF lean ( n = 8) and ZDF fatty rats ( n = 6). Although the total loop gain of baroreflex (ΔAP/ΔCSP) at the operating point did not differ between the two groups, the average gain in the lower CSP range was markedly reduced in ZDF fatty rats (0.03 ± 0.01 vs. 0.87 ± 0.10 mmHg/mmHg, P < 0.001). The afferent arc showed the same trend as the total loop, with a response threshold of 139.8 ± 1.0 mmHg in ZDF fatty rats. There were no significant differences in the gain of efferent arc between the two groups. Simulation experiments indicated a markedly higher AP fall and lower total loop gain of baroreflex in ZDF fatty rats than in ZDF lean rats against hypotensive stress because the efferent arc intersected with the afferent arc in the SNA unresponsive range. Thus, we concluded that impaired baroreflex sympathetic regulation in the lower AP range attenuates the pressure response against hypotensive stress and may partially contribute to AP lability in DM. NEW & NOTEWORTHY In this study, we investigated the open-loop baroreflex function, considering the control theory in type 2 diabetes mellitus model rats to address the systematic mechanism of arterial pressure (AP) lability in diabetes mellitus. The unresponsiveness of baroreflex sympathetic regulation in the lower AP range was observed in type 2 diabetic rats. It may attenuate the baroreflex pressure-stabilizing function and induce greater AP fall against hypotensive stress.

Suppressed baroreflex peripheral arc overwhelms augmented neural arc and incapacitates baroreflex function in rats with pulmonary arterial hypertension.

NEW FINDINGS: What is the central question of this study? The impact of pulmonary arterial hypertension on open-loop baroreflex function, which determines how powerfully and rapidly the baroreflex operates to regulate arterial pressure, remains poorly understood. What is the main finding and its importance? The gain of the baroreflex total arc, indicating the baroreflex pressure-stabilizing function, is markedly attenuated in rats with monocrotaline-induced pulmonary arterial hypertension. This is caused by a rightward shift of the baroreflex neural arc and a downward shift of the peripheral arc. These findings contribute greatly to our understanding of arterial pressure regulation by the sympathetic nervous system in pulmonary arterial hypertension. ABSTRACT: Sympathoexcitation has been documented in patients with established pulmonary arterial hypertension (PAH). Although the arterial baroreflex is the main negative feedback regulator of sympathetic nerve activity (SNA), the way in which PAH impacts baroreflex function remains poorly understood. In this study, we conducted baroreflex open-loop analysis in a rat model of PAH. Sprague-Dawley rats were injected with monocrotaline (MCT) s.c. to induce PAH (60 mg kg-1 ; n = 11) or saline as a control group (CTL; n = 8). At 3.5 weeks after MCT injection, bilateral carotid sinuses were isolated, and intrasinus pressure (CSP) was controlled while SNA at the coeliac ganglia and arterial pressure (AP) were recorded. To examine the static baroreflex function, CSP was increased stepwise while steady-state AP (total arc) and SNA (neural arc) responses to CSP and the AP response to SNA (peripheral arc) were measured. Monocrotaline significantly decreased the static gain of the baroreflex total arc at the operating AP compared with CTL (-0.80 ± 0.31 versus -0.22 ± 0.22, P < 0.05). Given that MCT markedly increased plasma noradrenaline, an index of SNA, by approximately 3.6-fold compared with CTL, calibrating SNA by plasma noradrenaline revealed that MCT shifted the neural arc to a higher SNA level and shifted the peripheral arc downwards. Monocrotaline also decreased the dynamic gain of the baroreflex total arc (-0.79 ± 0.16 versus -0.35 ± 0.17, P < 0.05), while the corner frequencies that reflect the speed of the baroreflex remained unchanged (0.06 ± 0.02 versus 0.08 ± 0.02 Hz, n.s.). In rats with MCT-induced PAH, the suppressed baroreflex peripheral arc overwhelms the augmented neural arc and, in turn, attenuates the gain of the total arc, which determines the pressure-stabilizing capacity of the baroreflex.

Derangement of open-loop static and dynamic characteristics of the carotid sinus baroreflex in streptozotocin-induced type 1 diabetic rats.

Although diabetes mellitus (DM) is a major risk factor for cardiovascular diseases, changes in open-loop static and dynamic characteristics of the arterial baroreflex in the early phase of DM remain to be clarified. We performed an open-loop systems analysis of the carotid sinus baroreflex in type 1 DM rats 4 to 5 wk after intraperitoneal streptozotocin injection ( n = 9) and we compared the results with control rats ( n = 9). The operating-point baroreflex gain was maintained in the DM rats compared with the control rats (2.07 ± 0.67 vs. 2.66 ± 0.22 mmHg/mmHg, P = 0.666). However, the range of arterial pressure (AP) control was narrower in the DM than in the control group (48.0 ± 5.0 vs. 77.1 ± 4.5 mmHg, P = 0.001), suggesting that the reserve for AP buffering is lost in DM. Although baroreflex dynamic characteristics were relatively preserved, coherences were lower in the DM than in the control group. The decreased coherence in the neural arc may be related to the narrowed quasi-linear range in the static relationship between carotid sinus pressure and sympathetic nerve activity in the DM group. Although the reason for the decreased coherences in the peripheral arc and the total reflex arc was inconclusive, the finding may indicate a loss of integrity of the baroreflex-mediated sympathetic AP control in the DM group. The derangement of the baroreflex dynamic characteristics is progressing occultly in this early stage of type 1 DM in a manner where dynamic gains are relatively preserved around the normal operating point.

Prediction of hemodynamics under left ventricular assist device.

Left ventricular assist device (LVAD) saves lives in patients with severe left ventricular (LV) failure. However, predicting how much LVAD boosts total cardiac output (CO) remains difficult. This study aimed to develop a framework to quantitatively predict the impact of LVAD on hemodynamics. We adopted the circulatory equilibrium framework and incorporated LVAD into the integrated CO curve to derive the circulatory equilibrium. In anesthetized dogs, we ligated left coronary arteries to create LV failure and inserted a centrifugal pump as LVAD. Using CO and right (PRA) and left atrial pressure (PLA) measured before LVAD support, we predetermined the stressed volume (V) and logarithmic slope of right heart CO curve (SR). Next, we initiated LVAD at maximum level and then decreased LVAD flow stepwise while monitoring hemodynamic changes. We predicted LVAD-induced CO and PRA for given PLA from the predetermined SR and V and compared with those measured experimentally. The predicted CO [r2 = 0.907, SE of estimate (SEE) = 5.59 ml·min-1·kg-1, P < 0.001] and PRA (r2 = 0.967, SEE = 0.307 mmHg, P < 0.001) matched well with measured values indicating the validity of the proposed framework. We further conducted simulation using the validated framework to analyze the impact of LVAD on PRA under various right ventricular (RV) functions. It indicated that PRA is relatively insensitive to changes in RV end-systolic elastance or pulmonary arterial resistance, but sensitive to changes in V. In conclusion, the circulatory equilibrium framework predicts quantitatively the hemodynamic impact of LVAD. This knowledge would contribute to safe management of patients with LV failure undergoing LVAD implantation. NEW & NOTEWORTHY: Hemodynamic response to left ventricular assist device (LVAD) has not been quantitatively investigated. This is the first report of quantitative prediction of the hemodynamics on LVAD using circulatory equilibrium framework. The validated framework allows us to simulate the impact of LVAD on right atrial pressure under various right ventricular functions.