Yalin Yin

Negative Inotropic and Chronotropic Effects of Oxytocin

Abstract—We have previously shown that oxytocin receptors are present in the heart and that perfusion of isolated rat hearts with oxytocin results in decreased cardiac flow rate and bradycardia. The mechanisms involved in the negative inotropic and chronotropic effects of oxytocin were investigated in isolated dog right atria in the absence of central mechanisms. Perfusion of atria through the sinus node artery with 10−6 mol/L oxytocin over 5 minutes (8 mL/min) significantly decreased both beating rate (−14.7±4.9% of basal levels, n=5, P <0.004) and force of contraction (−52.4±9.1% of basal levels, n=5, P <0.001). Co-perfusion with 10−6 mol/L oxytocin receptor antagonist (n=3) completely inhibited the effects of oxytocin on frequency (P <0.04) and force of contraction (P <0.004), indicating receptor specificity. The effects of oxytocin were also totally inhibited by co-perfusion with 5×10−8 mol/L tetrodotoxin (P <0.02) or 10−6 mol/L atropine (P <0.03) but not by 10−6 mol/L hexamethonium, which implies that these effects are neurally mediated, primarily by intrinsic parasympathetic postganglionic neurons. Co-perfusion with 10−6 mol/L NO synthase inhibitor (L-NAME) significantly inhibited oxytocin effects on both beating rate (−1.85±1.27% versus −14.7±4.9% in oxytocin alone, P <0.05) and force of contraction (−24.9±4.4% versus −52.4±9.1% in oxytocin alone, n=4, P <0.04). The effect of oxytocin on contractility was further inhibited by L-NAME at 10−4 mol/L (−8.1±1.8%, P <0.01). These studies imply that the negative inotropic and chronotropic effects of oxytocin are mediated by cardiac oxytocin receptors and that intrinsic cardiac cholinergic neurons and NO are involved in these actions.

Spinal Cord Stimulation Causes Potentiation of Right Vagus Nerve Effects on Atrial Chronotropic Function and Repolarization in Canines

Spinal Cord Stimulation Modulates Vagal Atrial Influences. Introduction: Experimental evidence suggests that spinal cord stimulation (SCS) can cause augmentation of parasympathetic influences on the heart via enhanced vagus nerve (VgN) activity. Herein, we investigated whether this might lead to enhanced inducibility of vagally mediated atrial tachyarrhythmias (AT) and whether such actions depend on intact autonomic neural connections with central neurons.

Estimating Atrial Action Potential Duration from Electrograms

Electrogram analysis is important in clinical and experimental settings. Activation recovery interval (ARI) has been used to measure ventricular action potential duration (APD) but its suitability for the atria has not been addressed. Mapping of atrial repolarization may be especially important during nerve stimulation since large heterogenous APD changes may manifest. This study assessed the utility of estimating APD in the atria using electrograms. A computer model of the atria was used to compute electrograms. Two different atrial waveforms were used, as well as two ventricular. APD was modulated with an acetylcholine- (ACh) dependent potassium channel and varying the spatial ACh distribution. ARI was computed, as well as the area under the repolarization wave (ATa). APD was measured by four methods. Atrial electrograms were also compared to monophasic action potentials recorded from a dog. ARI computed from atrial action potentials was not very precise, with errors ranging over 30 ms. Determining changes in APD induced by changing [ACh] yielded larger errors. Conversely, ventricular action potentials produced ARIs that very closely correlated with APD, and changes in APD . Positive ATa indicated regions of shortened APD, and islands of ACh release were clearly demarcated by ATa polarity. Experimentally, ARI was able to detect changes in APD, but did not measure APD well. The faster rate of ventricular repolarization produces larger currents that are less susceptible to electrotonic coupling effects, improving correlation with APD. ARI most closely correlated with APD measured as a fixed threshold above rest. Atrial APs produce electrograms that can be used to detect changes in APD. This may be improved by decreasing coupling. The ATa is a robust measure for precisely identifying spatial APD heterogeneities.

Differential effects of cervical vagosympathetic and mediastinal nerve activation on atrial arrhythmia formation in dogs

To investigate the influence of the thoracic autonomic neuronal hierarchy on atrial arrhythmia formation, we compared the characteristics of atrial tachyarrhythmias induced by electrical stimulation of 1) the right vagosympathetic nerve complex at the cervical level and 2) the more caudal juxta-cardiac mediastinal nerves located on the anterior surface of the superior vena cava. Unipolar electrograms were recorded from 191 sites on the entire epicardial atrial surface and, in some experiments, from 63 right atrial endocardial sites. The sites of origin of initial beats at the onset of atrial tachyarrhythmias so induced were investigated analysing atrial activation maps. Neural effects on repolarization were determined by computing the integral surface subtended by unipolar recordings under basal conditions and at maximum neurally induced bradycardia, and calculating differences at each recording site. The mean area affected by nerve stimulation in all animals was significantly greater in response to vagosympathetic than mediastinal nerve stimulation. Atrial cycle length prolongation prior to tachyarrhythmia onset was more pronounced in response to vagosympathetic than mediastinal nerve stimulation. The earliest epicardial activations in early tachyarrhythmia beats were localized in the right atrial free wall and Bachmann bundle region in both cases, but with a higher incidence of double breakthroughs from septal sites of origin in response to vagosympathetic versus mediastinal nerve stimulation. Sites of early activation were associated with the areas of neurally induced repolarization changes. Thus, differential contributions are made to the electrophysiologic substrate of neurally induced atrial tachyarrhythmias depending on the pattern of engagement of neural elements within the autonomic neuronal hierarchy.

Echocardiographic Assessment of Cardiac Performance in Response to High Altitude and Development of Subclinical Pulmonary Edema in Healthy Climbers

BACKGROUND Data regarding the effect of high altitude on heart function are sparse and conflicting. We aimed to assess the right and left ventricular responses to altitude-induced hypoxia and the occurrence of subclinical pulmonary edema. METHODS Echocardiography was performed according to protocol on 14 subjects participating in an expedition in Nepal, at 3 altitude levels: Montreal (30 m), Namche Bazaar (3450 m), and Chukkung (4730 m). Systematic lung ultrasound was performed to detect ultrasound lung comets. RESULTS Pulmonary artery systolic pressure increased in all subjects between Montreal and Chukkung (mean 27.4 ± 5.4 mm Hg vs. 39.3 ± 7.7 mm Hg; P < 0.001). Right ventricular (RV) myocardial performance index (MPI) increased significantly (0.32 ± 0.08 at 30 m vs. 0.41 ± 0.10 at 4730 m; P = 0.046). A trend toward deteriorated RV free wall longitudinal strain was observed between Montreal and Chukkung (-25.9 [5.3%] vs. -21.9 [6.4%]; P = 0.092). The left ventricular early diastolic inflow velocity/atrial mitral inflow velocity and early diastolic inflow velocity/mean of the maximal early diastolic mitral annulus tissue doppler velocities ratios remained unchanged. At 4730 m, ultrasound lung comets were seen in all subjects except 1. None had clinical criteria for high-altitude pulmonary edema (HAPE). All altered parameters normalized after return to sea level. CONCLUSION Subclinical HAPE is frequent in healthy lowlander climbers. This is the first study to document a trend towards decreased RV free wall strain and MPI increment at high altitude. Whether rising RV MPI is a physiologic adaptive mechanism to hypoxia or a pathologic response identifying HAPE-susceptible subjects needs further study.

Automatic detection and classification of human epicardial atrial unipolar electrograms.

This paper describes an unsupervised signal processing method applied to three-channel unipolar electrograms recorded from human atria. These were obtained by epicardial wires sutured on the right and left atria after coronary artery bypass surgery. Atrial (A) and ventricular (V) activations had to be detected and identified on each channel, and gathered across the channels when belonging to the same global event. The algorithm was developed and optimized on a training set of 19 recordings of 5 min. It was assessed on twenty-seven 2 h recordings taken just before the onset of a prolonged atrial fibrillation for a total of 1593697 activations that were validated and classified as normal atrial or ventricular activations (A, V) and premature atrial or ventricular activations (PAA, PVA). 99.93% of the activations were detected, and amongst these, 99.89% of the A and 99.75% of the V activations were correctly labelled. In the subset of the 39705 PAA, 99.83% were detected and 99.3% were correctly classified as A. The false positive rate was 0.37%. In conclusion, a reliable fully automatic detection and classification algorithm was developed that can detect and discriminate A and V activations from atrial recordings. It can provide the time series needed to develop a monitoring system aiming to identify dynamic predictors of forthcoming cardiac events such as postoperative atrial fibrillation.

Electrophysiological changes preceding the onset of atrial fibrillation after coronary bypass grafting surgery.

Background The incidence of Post-CABG atrial fibrillation (AF) lies between 25% and 40%. It worsens morbidity and raises post-operative costs. Detection of incoming AF soon enough for prophylactic intervention would be helpful. The study is to investigate the electrophysiological changes preceding the onset of AF and their relationship to the preoperative risk. Methods and Results Patients were recorded continuously for the first four days after coronary artery bypass grafting surgery (CABG) with three unipolar electrodes sutured to the atria (AEG). The patients experiencing an AF lasting more than 10 minutes were selected and the two hours before the onset were analyzed. Four variables were found to show significant changes in the two hours prior to the first prolonged AF: increasing rate of premature atrial activation, increasing incidence of short transient arrhythmias, acceleration of heart rate, and rise of low frequency content of heart rate. The main contrast was between the first and last hour before AF onset. Preoperative risk was not predictive of the onset time of AF and did not correlate with the amplitude of changes prior to AF. Conclusions Post-CABG AF were preceded by electrophysiological changes occurring in the last hour before the onset of the arrhythmia, whereas none of these changes was found to occur in all AF patients. The risk was a weighted sum of factors related to the density of premature activations and the state of atrial substrate reflected by the sinus rhythm and its frequency content prior to AF. Preoperative risk score seems unhelpful in setting a detection threshold for the AF onset.

Biatrial neuroablation attenuates atrial remodeling and vulnerability to atrial fibrillation in canine chronic rapid atrial pacing

AIMS We investigated the proposition that an intact cardiac nervous system may contribute to electrophysiological remodeling and increased vulnerability to atrial fibrillation (AF) following chronic rapid atrial pacing (RAP). METHODS AND RESULTS Baseline study was conducted prior to ablating right and left ganglionated plexuses (RAGP, LAGP) in 11 anesthetized canines (Neuroablation group) and in 11 canines without neuroablation (Intact GP). After being subjected to RAP (400 beats/min) for 6 weeks, animals were reanesthetized for terminal study. The ERP shortening typical of chronic RAP was significantly more pronounced in the Intact GP (baseline: 112 ± 12 to terminal: 80 ± 11 ms) than in the Neuroablation group (113 ± 18 to 102 ± 21 ms, p < .001), and AF inducibility (extrastimulus protocol) showed significantly greater increment in the Intact GP (baseline: 23 ± 19% to terminal: 60 ± 17% of trials) than in the Neuroablation group (18 ± 15% to 27 ± 17%, p = 0.029). Negative chronotropic responses to right vagus nerve stimulation were markedly reduced immediately after the neuroablation procedure but had recovered at terminal study. Vagally-evoked repolarization changes (from 191 unipolar electrograms) occurred in a majority of Intact GP animals in the superior, middle and inferior RA free wall, and in the LA appendage. In the Neuroablation group, repolarization changes were restricted to the superior RA free wall but none occurred in the inferior RA and only infrequently in the LA appendage, yielding significantly smaller affected areas in Neuroablation than in Intact GP animals. CONCLUSION Persistent functional denervation in LA and RA regions other than RA pacemaker areas may contribute to prevent the development of a tachycardia-dependent AF substrate.