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.

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.

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.

Ivabradine augments high-frequency dynamic gain of the heart rate response to low- and moderate-intensity vagal nerve stimulation under ß-blockade.

Our previous study indicated that intravenously administered ivabradine (IVA) augmented the dynamic heart rate (HR) response to moderate-intensity vagal nerve stimulation (VNS). Considering an accentuated antagonism, the results were somewhat paradoxical; i.e., the accentuated antagonism indicates that an activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels via the accumulation of intracellular cyclic adenosine monophosphate (cAMP) augments the HR response to VNS, whereas the inhibition of HCN channels by IVA also augmented the HR response to VNS. To remove the possible influence from the accentuated antagonism, we examined the effects of IVA on the dynamic vagal control of HR under ß-blockade. In anesthetized rats (n = 7), the right vagal nerve was stimulated for 10 min according to binary white noise signals between 0 and 10 Hz (V0-10), between 0 and 20 Hz (V0-20), and between 0 and 40 Hz (V0-40). The transfer function from VNS to HR was estimated. Under ß-blockade (propranolol, 2 mg/kg iv), IVA (2 mg/kg iv) did not augment the asymptotic low-frequency gain but increased the asymptotic high-frequency gain in V0-10 (0.53 ± 0.10 vs. 1.74 ± 0.40 beats/min/Hz, P < 0.01) and V0-20 (0.79 ± 0.14 vs. 2.06 ± 0.47 beats/min/Hz, P < 0.001). These changes, which were observed under a minimal influence from sympathetic background tone, may reflect an increased contribution of the acetylcholine-sensitive potassium channel (IK,ACh) pathway after IVA, because the HR control via the IK,ACh pathway is faster and acts in the frequency range higher than the cAMP-mediated pathway.NEW & NOTEWORTHY Since ivabradine (IVA) inhibits hyperpolarization-activated cyclic nucleotide-gated channels, interactions among the sympathetic effect, vagal effect, and IVA can occur in the control of heart rate (HR). To remove the sympathetic effect, we estimated the transfer function from vagal nerve stimulation to HR under ß-blockade in anesthetized rats. IVA augmented the high-frequency dynamic gain during low- and moderate-intensity vagal nerve stimulation. Untethering the hyperpolarizing effect of acetylcholine-sensitive potassium channels after IVA may be a possible underlying mechanism.

Impact of Peripheral α7-Nicotinic Acetylcholine Receptors on Cardioprotective Effects of Donepezil in Chronic Heart Failure Rats.

PURPOSE: Pharmacological modulation of parasympathetic activity with donepezil, an acetylcholinesterase inhibitor, improves the long-term survival of rats with chronic heart failure (CHF) after myocardial infarction (MI). However, its mechanism is not well understood. The α7-nicotinic acetylcholine receptor (α7-nAChR) reportedly plays an important role in the cholinergic anti-inflammatory pathway. The purpose of this study was to examine whether blockade of α7-nAChR, either centrally or peripherally, affects cardioprotection by donepezil during CHF. METHODS: One-week post-MI, the surviving rats were implanted with an electrocardiogram or blood pressure transmitter to monitor hemodynamics continuously. Seven days after implantation, the MI rats (n = 74) were administered donepezil in drinking water or were untreated (UT). Donepezil-treated MI rats were randomly assigned to the following four groups: peripheral infusion of saline (SPDT) or an α7-nAChR antagonist methyllycaconitine (α7PDT), and brain infusion of saline (SBDT) or the α7-nAChR antagonist (α7BDT). RESULTS: After the 4-week treatment, the role of α7-nAChR was evaluated using hemodynamic parameters, neurohumoral states, and histological and morphological assessment. Between the peripheral infusion groups, α7PDT (vs. SPDT) showed significantly increased heart weight and cardiac fibrosis, deteriorated hemodynamics, increased plasma neurohumoral and cytokine levels, and significantly decreased microvessel density (as assessed by anti-von Willebrand factor-positive cells). In contrast, between the brain infusion groups, α7BDT (vs. SBDT) showed no changes in either cardiac remodeling or hemodynamics. CONCLUSION: Peripheral blockade of α7-nAChR significantly attenuated the cardioprotective effects of donepezil in CHF rats, whereas central blockade did not. This suggests that peripheral activation of α7-nAChR plays an important role in cholinergic pharmacotherapy for CHF.

Contribution of afferent pathway to vagal nerve stimulation-induced myocardial interstitial acetylcholine release in rats.

Vagal nerve stimulation (VNS) has been explored as a potential therapy for chronic heart failure. The contribution of the afferent pathway to myocardial interstitial acetylcholine (ACh) release during VNS has yet to be clarified. In seven anesthetized Wistar-Kyoto rats, we implanted microdialysis probes in the left ventricular free wall and measured the myocardial interstitial ACh release during right VNS with the following combinations of stimulation frequency (F in Hz) and voltage readout (V in volts): F0V0 (no stimulation), F5V3, F20V3, F5V10, and F20V10. F5V3 did not affect the ACh level. F20V3, F5V10, and F20V10 increased the ACh level to 2.83 ± 0.47 (P < 0.01), 4.31 ± 1.09 (P < 0.001), and 4.33 ± 0.82 (P < 0.001) nM, respectively, compared with F0V0 (1.76 ± 0.22 nM). After right vagal afferent transection (rVAX), F20V3 and F20V10 increased the ACh level to 2.90 ± 0.53 (P < 0.001) and 3.48 ± 0.63 (P < 0.001) nM, respectively, compared with F0V0 (1.61 ± 0.19 nM), but F5V10 did not (2.11 ± 0.24 nM). The ratio of the ACh levels after rVAX relative to before was significantly <100% in F5V10 (59.4 ± 8.7%) but not in F20V3 (102.0 ± 8.7%). These results suggest that high-frequency and low-voltage stimulation (F20V3) evoked the ACh release mainly via direct activation of the vagal efferent pathway. By contrast, low-frequency and high-voltage stimulation (F5V10) evoked the ACh release in a manner dependent on the vagal afferent pathway.

Intravenous ivabradine augments the dynamic heart rate response to moderate vagal nerve stimulation in anesthetized rats.

Ivabradine is a selective bradycardic agent that reduces the heart rate (HR) by inhibiting the hyperpolarization-activated cyclic nucleotide-gated channels. Although its cardiovascular effect is thought to be minimal except for inducing bradycardia, ivabradine could interact with cardiovascular regulation by the autonomic nervous system. We tested whether ivabradine modifies dynamic characteristics of peripheral vagal HR control. In anesthetized Wistar-Kyoto rats (n = 7), the right vagal nerve was sectioned and stimulated for 10 min according to a binary white noise sequence with a switching interval of 500 ms. The efferent vagal nerve stimulation (VNS) trials were performed using three different rates (10, 20, and 40 Hz), and were designated as V0-10, V0-20, and V0-40, respectively. The transfer function from the VNS to the HR was estimated before and after the intravenous administration of ivabradine (2 mg/kg). Ivabradine increased the asymptotic dynamic gain in V0-20 [from 3.88 (1.78-5.79) to 6.62 (3.12-8.31) beats·min-1·Hz-1, P < 0.01, median (range)] but not in V0-10 or V0-40. Ivabradine increased the corner frequency in V0-10 [from 0.032 (0.026-0.041) to 0.064 (0.029-0.090) Hz, P < 0.01] and V0-20 [from 0.040 (0.037-0.056) to 0.068 (0.051-0.100) Hz, P < 0.01] but not in V0-40. In conclusion, ivabradine augmented the dynamic HR response to moderate VNS. At high VNS, however, ivabradine did not significantly augment the dynamic HR response, possibly because ivabradine reduced the baseline HR and limited the range for the bradycardic response to high VNS.NEW & NOTEWORTHY Ivabradine is considered to be a pure bradycardic agent that has little effect on cardiovascular function except inducing bradycardia. The present study demonstrated that ivabradine interacts with the dynamic vagal heart rate control in a manner that augments the heart rate response to moderate-intensity efferent vagal nerve stimulation.

Acute ivabradine treatment reduces heart rate without increasing atrial fibrillation inducibility irrespective of underlying vagal activity in dogs.

Ivabradine, a bradycardic agent, has been shown to stably reduce patient's heart rate (HR) in the setting of acute cardiac care. However, an association between atrial fibrillation (AF) risk and acute ivabradine treatment remains a controversial clinical issue, and has not been thoroughly investigated. Bradycardia and abnormal atrial refractoriness induced by ivabradine treatment may enhance vulnerability to AF induction, especially when vagal nerve is concurrently activated. We aimed to experimentally investigate the effects of acute ivabradine treatment with/without concurrent vagal activation on AF inducibility. In 16 anesthetized dogs, cervical vagal nerves were prepared for electrical stimulation (VS). AF induction rate (AFIR) was determined by atrial burst pacing. HR, atrial action potential duration (APD), atrial effective refractory period (ERP), and AFIR were obtained consecutively at baseline, during delivery of VS (VS alone), after intravenous injection of ivabradine 0.5 mg/kg (n = 8, ivabradine group) or saline (n = 8, saline group), and again during VS delivery (drug+VS). In the ivabradine group, ivabradine alone significantly lowered HR compared to baseline, while ivabradine+VS significantly lowered HR compared to VS alone. Contrary to expectations, there were no significant differences in trends of APD, temporal dispersion of APD, ERP, and AFIR between ivabradine and saline groups. Irrespective of whether ivabradine or saline was injected, VS significantly shortened APD and ERP, and increased AFIR. Interestingly, although bradycardia in response to ivabradine injection was more intense than that to VS alone, AFIR was significantly lower after ivabradine injection than during VS alone. We conclude that, despite its intense bradycardic effect, acute ivabradine treatment does not increase AF inducibility irrespective of underlying vagal activity. This study may constitute support for the safety of using ivabradine in the setting of acute cardiac care.

Computer-controlled closed-loop drug infusion system for automated hemodynamic resuscitation in endotoxin-induced shock.

BACKGROUND: Hemodynamic resuscitation in septic shock requires aggressive fluid replacement and appropriate use of vasopressors to optimize arterial pressure (AP) and cardiac output (CO). Because responses to these drugs vary between patients and within patient over time, strict monitoring of patient condition and repetitive adjustment of drug dose are required. This task is time and labor consuming, and is associated with poor adherence to resuscitation guidelines. To overcome this issue, we developed a computer-controlled closed-loop drug infusion system for automated hemodynamic resuscitation in septic shock, and evaluated the performance of the system in a canine model of endotoxin shock. METHODS: Our system monitors AP, CO and central venous pressure, and computes arterial resistance (R), stressed blood volume (V) and Frank-Starling slope of left ventricle (S). The system controls R with noradrenaline (NA), and V with Ringer's acetate solution (RiA), thereby controlling AP and CO. In 4 dogs, AP and CO were measured invasively. In another 4 dogs, AP and CO were measured less invasively using clinically acceptable modalities, aiming to make the system clinically feasible. In all 8 dogs, endotoxin shock was induced by injecting Escherichia coli lipopolysaccharide, which significantly decreased AP from 95 (91-108) to 43 (39-45) mmHg, and CO from 112 (104-142) to 62 (51-73) ml·min-1·kg-1. The system was then connected to the dogs, and activated. System performance was observed over a period of 4 h. RESULTS: Our system immediately started infusions of NA and RiA. Within 40 min, RiA increased V to target level, and NA maintained R at target level, while S was concomitantly increased. These resulted in restoration of AP to 70 (69-71) mmHg and CO to 130 (125-138) ml·min-1·kg-1. Median of absolute performance error, an index of precision of control, was small in AP [2.5 (2.1-4.5) %] and CO [2.4 (1.4-5.5) %], which were not increased even when the variables were measured less invasively. CONCLUSIONS: In a canine model of endotoxin shock, our system automatically improved and maintained AP and CO at their target values with small performance error. Our system is potentially an attractive clinical tool for rescuing patients with septic shock.

Development of a servo pump system for in vivo loading of pathological pulmonary artery impedance on the right ventricle of normal rats.

Pulmonary artery (PA) impedance provides detailed information on right ventricular (RV) afterload in pulmonary hypertension (PH). This study aimed to examine PA impedance in a rat model of monocrotaline-induced PH (MCT-PH) and to develop an experimental system for in vivo loading of pathological PA impedance on the RV of normal rats. PA impedance was quantified in normal (n= 10) and MCT-PH rats (n= 10) using a three-element Windkessel (3-WK) model. Compared with normal rats, MCT-PH rats had higher characteristic impedance (ZC) and peripheral pulmonary resistance (RP) (ZC: 0.121 ± 0.039 vs. 0.053 ± 0.017 mmHg·min·ml(-1), P< 0.001; RP: 0.581 ± 0.334 vs. 0.252 ± 0.105 mmHg·min·ml(-1), P= 0.013) and lower pulmonary artery compliance (CP) (0.242 ± 0.131 vs. 0.700 ± 0.186 ml/mmHg, P< 0.001). In another group of 10 normal rats, a computer-controlled servo pump was connected to the left PA for loading PA impedance with parameters in pathological ranges designed by the 3-WK model. Activation of the servo pump decreased the error of measured vs. target PA impedance (modulus: from 0.047 ± 0.020 without pump activation to 0.019 ± 0.007 with pump activation,P< 0.001; phase: 0.085 ± 0.028 to 0.043 ± 0.012 radians,P< 0.001). In conclusion, MCT-PH increases ZC and RP and decreases CP Our servo pump system, which is capable of imposing arbitrary PA impedance with pathological parameters, may offer a unique opportunity to delineate the pathological significance of PA impedance in PH.

Effects of Proximal Pulmonary Artery Occlusion on Pulsatile Right Ventricular Afterload in Rats.

BACKGROUND: In patients with proximal pulmonary artery (PA) thromboembolism, an increased PA resistance contributes to abnormal right ventricular (RV) afterload. However, the effects of proximal thromboembolism on the dynamic properties of RV afterload, which is determined by PA impedance, have not been analyzed quantitatively. The present study aimed to identify changes in PA impedance after the pulmonary perfusion volume was greatly reduced by unilateral proximal PA occlusion. METHODS AND RESULTS: Ten male Sprague-Dawley rats were used. PA flow and pressure waveforms were recorded during irregular pacing, before and 10 min after left PA occlusion. PA impedance was parameterized by using a three-element Windkessel model consisting of peripheral resistance (RP), arterial compliance (CP) and characteristic impedance (ZC). After proximal PA occlusion, PA impedance modulus increased over a frequency range of interest.ZCincreased significantly (after PA occlusion vs. baseline: 0.128±0.016 vs. 0.074±0.010 mmHg·min/ml, P<0.001), whereasCPandRPdid not change significantly. CONCLUSIONS: Proximal PA occlusion increasedZCwith the attenuation ofRPincrease andCPdecrease predicted from the decreased pulmonary perfusion volume. The insignificant changes inRPandCPindicate that a recruitment phenomenon may result in this attenuation. The existence of compensation by a recruitment mechanism suggests the relative importance of increasedZCin defining abnormal RV afterload in patients with proximal PA thromboembolism. (Circ J 2016; 80: 2010-2018).

A novel technique to predict pulmonary capillary wedge pressure utilizing central venous pressure and tissue Doppler tricuspid/mitral annular velocities.

Assessing left ventricular (LV) filling pressure (pulmonary capillary wedge pressure, PCWP) is an important aspect in the care of patients with heart failure (HF). Physicians rely on right ventricular (RV) filling pressures such as central venous pressure (CVP) to predict PCWP, assuming concordance between CVP and PCWP. However, the use of this method is limited because discordance between CVP and PCWP is observed. We hypothesized that PCWP can be reliably predicted by CVP corrected by the relationship between RV and LV function, provided by the ratio of tissue Doppler peak systolic velocity of tricuspid annulus (S(T)) to that of mitral annulus (S(M)) (corrected CVP:CVP·S(T)/S(M)). In 16 anesthetized closed-chest dogs, S T and S M were measured by transthoracic tissue Doppler echocardiography. PCWP was varied over a wide range (1.8-40.0 mmHg) under normal condition and various types of acute and chronic HF. A significantly stronger linear correlation was observed between CVP·S(T)/S(M) and PCWP (R2 = 0.78) than between CVP and PCWP (R2 = 0.22) (P < 0.01). Receiver-operating characteristic (ROC) analysis indicated that CVP·S(T)/S(M) >10.5 mmHg predicted PCWP >18 mmHg with 85% sensitivity and 88% specificity. Area under ROC curve for CVP·S T/S M to predict PCWP >18 mmHg was 0.93, which was significantly larger than that for CVP (0.66) (P < 0.01). Peripheral venous pressure (PVP) corrected by S T/S M (PVP·S(T)/S(M) also predicted PCWP reasonably well, suggesting that PVP·S(T)/S (M) may be a minimally invasive alternative to CVP·S(T)/S(M) In conclusion, our technique is potentially useful for the reliable prediction of PCWP in HF patients.

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.

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.

Donepezil markedly improves long-term survival in rats with chronic heart failure after extensive myocardial infarction.

BACKGROUND: Vagal activation by electrical stimulation has been shown to improve the long-term survival of rats with chronic heart failure (CHF) after extensive myocardial infarction (MI). Acetylcholinesterase inhibition increases synaptic acetylcholine, and can disproportionately increase vagal tone. To develop an alternative therapy for CHF using a clinically available drug, the present study investigated whether oral donepezil, an acetylcholinesterase inhitor, could reproduce the beneficial effects of electrical vagal stimulation in rats. METHODS AND RESULTS: At 2 weeks after ligation of the proximal left coronary artery, resulting in extensive MI, surviving rats were randomly assigned to donepezil-treated and untreated groups. Donepezil treatment started 14 days after MI significantly decreased the heart rate (325 ± 6 vs. 355 ± 10 beats/min, P<0.05) and improved 140-day survival (29% to 54%, P=0.03) by preventing pump failure (cardiac index: +29%, P<0.001; left ventricular+dp/dtmax: +18%, P<0.01; left ventricular end-diastolic pressue: -26%, P<0.01) and cardiac remodeling (biventricular weight: 2.73 ± 0.04 vs. 3.06 ± 0.08 g/kg, P<0.001). In addition, donepezil treatment lowered the levels of plasma arginine vasopressin, brain natriuretic peptide, catecholamine, and tissue pro-inflammation markers. CONCLUSIONS: Oral donepezil markedly improved the long-term survival of CHF rats by preventing pump failure and cardiac remodeling, indicating that donepezil may be a new alternative therapy for CHF.

A minimally invasive monitoring system of cardiac output using aortic flow velocity and peripheral arterial pressure profile.

BACKGROUND: In managing patients with unstable hemodynamics, monitoring cardiac output (CO) can provide critical diagnostic data. However, conventional CO measurements are invasive, intermittent, and/or inaccurate. The purpose of this study was to validate our newly developed CO monitoring system. METHODS: This system automatically determines peak velocity of the ascending aortic flow using continuous-wave Doppler transthoracic echocardiography and estimates cardiac ejection time and aortic cross-sectional area using the pulse contour of the radial arterial pressure. These parameters are continuously processed to estimate CO (CO(est)). In 10 anesthetized closed-chest dogs instrumented with an aortic flowprobe to measure reference CO (CO(ref)), hemodynamic conditions were varied over wide ranges by infusing cardiovascular drugs or by random atrial pacing. Under each condition, CO(ref) and CO(est) were determined. Absolute changes of CO(ref) (ΔCOref) and CO(est) (ΔCO(est)), and relative changes of CO(ref) (%ΔCO(ref)) and CO(est) (%ΔCO(est)) from the corresponding baseline values were determined in each animal. We calibrated CO(est) against CO(ref) to obtain proportionally scaled CO(est) (CO(est)(N)). RESULTS: A total of 1335 datasets of CO(ref) and CO(est) were obtained, in which CO(ref) ranged from 0.17 to 5.34 L/min. Bland-Altman analysis between CO(ref) and CO(est) indicated that the limits of agreement (the bias ± 1.96 × SD of the difference) and the percentage error (1.96 × [SD of the difference]/[mean CO] × 100) were from -1.01 to 1.13 L/min (95% confidence interval, -1.76 to 1.88 L/min) and 43%, respectively. The agreement between CO(ref) and CO(est)(N) was improved, with limits of agreement from -0.53 to 0.49 L/min (95% confidence interval, -0.62 to 0.59 L/min) and the percentage error of 20%. Polar plot analysis between ΔCO(ref) and ΔCO(est) indicated that mean ± 1.96 × SD of polar angle was -2° ± 22°. Four quadrant plot analysis indicated that %ΔCO(est) correlated tightly with %ΔCO(ref) (R(2) = 0.93). The %ΔCO(est) and %ΔCO(ref) changed in the same direction in 95% of the datasets. Reliability of this system was well preserved under conditions of random atrial pacing and also in a continuous manner. CONCLUSION: Over a wide range of hemodynamic conditions, irrespective of cardiac beat irregularity, this system may allow minimally invasive monitoring of CO with a good trending ability. The present results warrant further research and development of this system for future clinical application.