Enhancing respiratory sinus arrhythmia increases cardiac output in rats with left ventricular dysfunction

Key points: Respiratory sinus arrhythmia is physiological pacing of the heart that disappears in cardiovascular disease and is associated with poor cardiac prognosis. In heart failure, cardiac pacing has little, if any, variation in rate at rest. We proposed that reinstatement of respiratory sinus arrhythmia would improve cardiac function in rats with heart failure. Heart failure rats were paced daily for 2 weeks with either respiratory sinus arrhythmia or paced monotonically at a matched heart rate; cardiac function was measured using non-invasive echocardiography. Cardiac output and stroke volume were increased in rats paced with respiratory sinus arrhythmia compared to monotonic pacing, via improvement in systolic function that persisted beyond the pacing treatment period. We propose that respiratory sinus arrhythmia pacing reverse-remodels the heart in heart failure and is worth considering as a new form of cardiac pacemaking. Abstract: Natural pacing of the heart results in heart rate variability, an indicator of good health and cardiac function. A contributor to heart rate variability is respiratory sinus arrhythmia or RSA – an intrinsic respiratory modulated pacing of heart rate. The loss of RSA is associated with poor cardiac prognosis and sudden cardiac death. We tested if reinstatement of respiratory-modulated heart rate (RMH) would improve cardiac performance in heart failure. Heart failure was induced in Wistar rats by ligation of the left anterior descending coronary artery. Rats were unpaced, monotonically paced and RMH paced; the latter had the same average heart rate as the monotonically paced animals. Cardiac function was assessed non-invasively using echocardiography before and after 2 weeks of daily pacing at a time when pacing was turned off. RMH increased cardiac output by 20 ± 8% compared to monotonic pacing (−3 ± 5%; P &lt; 0.05). This improvement in cardiac output was associated with an increase in stroke volume compared to monotonic pacing (P = 0.03) and improvement in circumferential strain (P = 0.02). Improvements in ejection fraction (P = 0.08) and surrogate measures of left ventricle compliance did not reach significance. Increases in contractility (P &lt; 0.05) and coronary blood flow (P &lt; 0.05) were seen in vitro during variable pacing to mimic RMH. Thus, in rats with left ventricular dysfunction, chronic RMH pacing improved cardiac function through improvements in systolic function. As these improvements were made with pacing switched off, we propose the novel idea that RMH pacing causes reverse-remodelling.</p

Utility of a novel biofeedback device for within-breath modulation of heart rate in rats:a quantitative comparison of vagus nerve versus right atrial pacing

In an emerging bioelectronics era, there is a clinical need for physiological devices incorporating biofeedback that permits natural and demand-dependent control in real time. Here, we describe a novel device termed a central pattern generator (CPG) that uses cutting edge analogue circuitry producing temporally controlled, electrical stimulus outputs based on the real time integration of physiological feedback. Motivated by the fact that respiratory sinus arrhythmia (RSA), which is the cyclical changes in heart rate every breath, is an essential component of heart rate variability (an indicator of cardiac health), we have explored the versatility and efficiency of the CPG for producing respiratory modulation of heart rate in anaesthetised, spontaneously breathing rats. Diaphragmatic electromyographic activity was used as the input to the device and its output connected to either the right cervical vagus nerve or the right atrium for pacing heart rate. We found that the CPG could induce respiratory related heart rate modulation that closely mimicked RSA. Whether connected to the vagus nerve or right atrium, the versatility of the device was demonstrated by permitting: (i) heart rate modulation in any phase of the respiratory cycle, (ii) control of the magnitude of heart rate modulation and (iii) instant adaptation to changes in respiratory frequency. Vagal nerve pacing was only possible following transection of the nerve limiting its effective use chronically. Pacing via the right atrium permitted better flexibility and control of heart rate above its intrinsic level. This investigation now lays the foundation for future studies using this biofeedback technology permitting closer analysis of both the function and dysfunction of RSA

Silicon central pattern generators for cardiac diseases

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Silicon central pattern generators for cardiac diseases

Cardiac rhythm management devices provide therapies for both arrhythmias and resynchronisation but not heart failure, which affects millions of patients worldwide. This paper reviews recent advances in biophysics and mathematical engineering that provide a novel technological platform for addressing heart disease and enabling beat-to-beat adaptation of cardiac pacing in response to physiological feedback. The technology consists of silicon hardware central pattern generators (hCPGs) that may be trained to emulate accurately the dynamical response of biological central pattern generators (bCPGs). We discuss the limitations of present CPGs and appraise the advantages of analog over digital circuits for application in bioelectronic medicine. To test the system, we have focused on the cardio-respiratory oscillators in the medulla oblongata that modulate heart rate in phase with respiration to induce respiratory sinus arrhythmia (RSA). We describe here a novel, scalable hCPG comprising physiologically realistic (Hodgkin–Huxley type) neurones and synapses. Our hCPG comprises two neurones that antagonise each other to provide rhythmic motor drive to the vagus nerve to slow the heart. We show how recent advances in modelling allow the motor output to adapt to physiological feedback such as respiration. In rats, we report on the restoration of RSA using an hCPG that receives diaphragmatic electromyography input and use it to stimulate the vagus nerve at specific time points of the respiratory cycle to slow the heart rate. We have validated the adaptation of stimulation to alterations in respiratory rate. We demonstrate that the hCPG is tuneable in terms of the depth and timing of the RSA relative to respiratory phase. These pioneering studies will now permit an analysis of the physiological role of RSA as well as its any potential therapeutic use in cardiac disease

Enhancing respiratory sinus arrhythmia increases cardiac output in rats with left ventricular dysfunction

Key points: Respiratory sinus arrhythmia is physiological pacing of the heart that disappears in cardiovascular disease and is associated with poor cardiac prognosis. In heart failure, cardiac pacing has little, if any, variation in rate at rest. We proposed that reinstatement of respiratory sinus arrhythmia would improve cardiac function in rats with heart failure. Heart failure rats were paced daily for 2 weeks with either respiratory sinus arrhythmia or paced monotonically at a matched heart rate; cardiac function was measured using non-invasive echocardiography. Cardiac output and stroke volume were increased in rats paced with respiratory sinus arrhythmia compared to monotonic pacing, via improvement in systolic function that persisted beyond the pacing treatment period. We propose that respiratory sinus arrhythmia pacing reverse-remodels the heart in heart failure and is worth considering as a new form of cardiac pacemaking. Abstract: Natural pacing of the heart results in heart rate variability, an indicator of good health and cardiac function. A contributor to heart rate variability is respiratory sinus arrhythmia or RSA – an intrinsic respiratory modulated pacing of heart rate. The loss of RSA is associated with poor cardiac prognosis and sudden cardiac death. We tested if reinstatement of respiratory-modulated heart rate (RMH) would improve cardiac performance in heart failure. Heart failure was induced in Wistar rats by ligation of the left anterior descending coronary artery. Rats were unpaced, monotonically paced and RMH paced; the latter had the same average heart rate as the monotonically paced animals. Cardiac function was assessed non-invasively using echocardiography before and after 2 weeks of daily pacing at a time when pacing was turned off. RMH increased cardiac output by 20 ± 8% compared to monotonic pacing (−3 ± 5%; P &lt; 0.05). This improvement in cardiac output was associated with an increase in stroke volume compared to monotonic pacing (P = 0.03) and improvement in circumferential strain (P = 0.02). Improvements in ejection fraction (P = 0.08) and surrogate measures of left ventricle compliance did not reach significance. Increases in contractility (P &lt; 0.05) and coronary blood flow (P &lt; 0.05) were seen in vitro during variable pacing to mimic RMH. Thus, in rats with left ventricular dysfunction, chronic RMH pacing improved cardiac function through improvements in systolic function. As these improvements were made with pacing switched off, we propose the novel idea that RMH pacing causes reverse-remodelling.</p

High-level production of functional muscle alpha-tropomyosin in Pichia pastoris

Although numerous studies have reported the production of skeletal muscle alpha -tropomyosin in E. coli, the protein needs to be modified at the amino terminus in order to be active. Without these modifications the protein does not bind to actin, does not exhibit head-to-tail polymerization, and does not inhibit the actomyosin Mg2+-ATPase in the absence of troponin. on the other hand, the protein produced in insect cells using baculovirus as an expression vector (Urbancikova, M., and Hitchcock-DeGregori, S. E., J. Biol. Chem., 269, 24310-24315, 1994) is only partially acetylated at its amino terminal and therefore is not totally functional. In an attempt to produce an unmodified functional recombinant muscle alpha -tropomyosin for structure-function correlation studies we have expressed the chicken skeletal alpha -tropomyosin cDNA in the yeast Pichia pastoris. Recombinant protein was produced at a high level (20 mg/L) and was similar to the wild type muscle protein in its ability to polymerize, to bind to actin and to regulate the actomyosin S1 Mg2+-ATPase. (C) 2001 Academic Press

Conditions affecting production of functional muscle recombinant alpha-tropomyosin in Saccharomyces cerevisiae

Yeasts are attractive hosts for heterologous protein production as they follow the general eukaryotic post-translational modification pattern. The well-known Saccharomyces cerevisiae has been used to produce a large variety of foreign proteins. The proper function of muscle tropomyosin depends on a specific modification at its N-terminus. Although tropomyosin has been produced in different expression systems, only the recombinant protein produced in the yeast Pichia pastoris has native-like functional properties. In this paper we describe the production of functional skeletal muscle tropomyosin in the yeast S. cerevisiae. The recombinant protein was produced in high amounts and production was strongly affected by genetic and environmental factors, including plasmid copy number, promoter strength, and growth media composition. (C) 2003 Elsevier B.V. (USA). All rights reserved

P2X3 receptor antagonism attenuates the progression of heart failure

Despite medications, heart failure worsens with time with many patients dying within five years of diagnosis. Here the authors show that blocking purinergic receptors in the carotid body stops heart failure progression, improves its function, reduces sleep apneas and systemic inflammation in male rats