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.

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.

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 PAH participants remain unclear. PA impedance provides a comprehensive description of PA mechanics. Using 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 hypertension (MCT-PAH) rats (6 per 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 affecting 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-PH 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.

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.

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.

Efficacy and safety of post-closure technique using Perclose ProGlide/ProStyle device for large-bore mechanical circulatory support access sites.

PURPOSE: Mechanical circulatory support (MCS) using a venoarterial extracorporeal membrane oxygenation (VA-ECMO) device or a catheter-type heart pump (Impella) is critical for the rescue of patients with severe cardiogenic shock. However, these MCS devices require large-bore cannula access (14-Fr and larger) at the femoral artery or vein, which often requires surgical decannulation. METHODS: In this retrospective study, we evaluated post-closure method using a percutaneous suture-mediated vascular closure system, Perclose ProGlide/ProStyle (Abbott Vascular, Lake Bluff, IL, Perclose), as an alternative procedure for MCS decannulation. Closure of 83 Impella access sites and 68 VA-ECMO access sites performed using Perclose or surgical method between January 2018 and March 2023 were evaluated. RESULTS: MCS decannulation using Perclose was successfully completed in all access sites without surgical hemostasis. The procedure time of ProGlide was shorter than surgical decannulation for both Impella and VA-ECMO (13 min vs. 50 min; p < 0.001, 21 min vs. 65 min; p < 0.001, respectively). There were no significant differences in the 30-day survival rate and major adverse events by decannulation including arterial dissection requiring endovascular treatment, hemorrhage requiring a large amount of red blood cell transfusion, and access site infection. CONCLUSION: Our results suggest that the post-closure technique using the percutaneous suture-mediated closure system appears to be a safe and effective method for large-bore MCS decannulation.

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.

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.

Mechanical circulatory support in cardiogenic shock.

Cardiogenic shock is a complex and diverse pathological condition characterized by reduced myocardial contractility. The goal of treatment of cardiogenic shock is to improve abnormal hemodynamics and maintain adequate tissue perfusion in organs. If hypotension and insufficient tissue perfusion persist despite initial therapy, temporary mechanical circulatory support (t-MCS) should be initiated. This decade sees the beginning of a new era of cardiogenic shock management using t-MCS through the accumulated experience with use of intra-aortic balloon pump (IABP) and venoarterial extracorporeal membrane oxygenation (VA-ECMO), as well as new revolutionary devices or systems such as transvalvular axial flow pump (Impella) and a combination of VA-ECMO and Impella (ECPELLA) based on the knowledge of circulatory physiology. In this transitional period, we outline the approach to the management of cardiogenic shock by t-MCS. The management strategy involves carefully selecting one or a combination of the t-MCS devices, taking into account the characteristics of each device and the specific pathological condition. This selection is guided by monitoring of hemodynamics, classification of shock stage, risk stratification, and coordinated management by the multidisciplinary shock team.

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.

How to incorporate tricuspid regurgitation in right ventricular-pulmonary arterial coupling.

Adaptation of the right ventricle (RV) to a progressively increasing afterload is one of the hallmarks of pulmonary arterial hypertension (PAH). Pressure-volume loop analysis provides measures of load-independent RV contractility, i.e., end-systolic elastance, and pulmonary vascular properties, i.e., effective arterial elastance (Ea). However, PAH-induced RV overload potentially results in tricuspid regurgitation (TR). TR makes RV eject to both PA and right atrium; thereby, a ratio of RV end-systolic pressure (Pes) to RV stroke volume (SV) could not correctly define Ea. To overcome this limitation, we introduced a two-parallel compliance model, i.e., Ea = 1/(1/Epa + 1/ETR), while effective pulmonary arterial elastance (Epa = Pes/PASV) represents pulmonary vascular properties and effective tricuspid regurgitant elastance (ETR) represents TR. We conducted animal experiments to validate this framework. First, we performed SV analysis with a pressure-volume catheter in the RV and a flow probe at the aorta in rats with and without pressure-overloaded RV to determine the effect of inferior vena cava (IVC) occlusion on TR. A discordance between the two techniques was found in rats with pressure-overloaded RV, not in sham. This discordance diminished after IVC occlusion, suggesting that TR in pressure-overloaded RV was diminished by IVC occlusion. Next, we performed pressure-volume loop analysis in rats with pressure-overloaded RVs, calibrating RV volume by cardiac magnetic resonance. We found that IVC occlusion increased Ea, suggesting that a reduction of TR increased Ea. Using the proposed framework, Epa was indistinguishable to Ea post-IVC occlusion. We conclude that the proposed framework helps better understanding of the pathophysiology of PAH and associated right heart failure.NEW & NOTEWORTHY This study reveals the impact of tricuspid regurgitation on pressure-volume loop analysis in right ventricle pressure overload. By introducing a novel concept of parallel compliances in the pressure-volume loop analysis, a better description is provided for the right ventricular forward afterload in the presence of tricuspid regurgitation.

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.

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.

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.