Cardiac mechano-electric feedback: past,present, and prospect

Mechanical effects on heart rhythm have been known to the clinical community for well over a century, and documented cases include both arrhythmogenic and pro-rhythmic consequences of mechanical stimulation. The intracardiac pathway that leads from changes in the cardiac mechanical environment to altered electrical activity is referred to as mechano-electric feedback (MEF). Fundamental research into the mechanisms underlying cardiac MEF is ‘engineering-intensive’, and much of the current insight would have been impossible without the introduction of novel techniques for the study of isolated cardiac cells.

Clinical and basic research into MEF have developed over different time scales, often uninformed of each other, and utilizing disparate concepts and terminology. Bridging the gap between the two domains is not straightforward, as physicians and scientists tend to publish in different journals and attend different meetings. There is, however, a growing interest in ‘re-uniting’ the clinic and basic MEF research, as witnessed by an increasing number of dedicated journal issues and international meetings, including events hosted by major European and American professional organisations such as the ESC and NASPE. Last year alone saw an international workshop on Cardiac MEF & Arrhythmias at Oxford, as well as dedicated sessions at NASPE's 23rd annual meeting in San Diego, CardioStim 2002 in Nice, and the UK Physiological Society meeting in Leeds.

This volume of Progress in Biophysics and Molecular Biology incorporates clinical and basic science results, and it is fitting that its publication coincides with a special session on cardiac MEF at the 2003 meeting of NASPE.     

Bradyarrythmias in the obstructive sleep apnea sundrome: a dangerous complication or defense mechanism?

Sleep is characterized by cycling and consecutive alternation of different phases and stages, each of which features intrinsic changes in autonomic regulation with heart rate oscillations; this may cause heart rhythm disorders, especially in the presence of comorbidities. This review addresses the issues of interrelationship between cardiac conduction disorders and obstructive sleep apnea. It is shown that some mechanisms of bradyarrythmia emergence (first of all, features of autonomic regulation with increases in parasympathetic tone) under respiratory arrest during sleep are also inherent to human divers as well as aquatic or para-aquatic mammals that have to hold their breath when diving or staying under water for a long time. These mechanisms may fulfill the defense function.     

Sinus rhythm: mechanisms and function

The normal cardiac rhythm originates in a specialized region of the heart, the sinus node that is part of the nodal tissue. The rhythmic, impulse initiation of sinus node pacemaker cells results from a spontaneous diastolic depolarization that is initiated immediately after repolarization of the preceding actions potential. This slow diastolic depolarisation is typical of automatic cells and essential to their function. Several currents are involved in this diastolic depolarisation: a hyperpolarization activated inward current, termed "pacemaker" I(f) current, two Ca2+ currents (a L type and a T type), a delayed K+ current and a Na/Ca exchange current. The frequency of the automatic discharge is the main determinant of heart rate. However the sinus node activity is regulated by adrenergic and cholinergic neurotransmitters. Acetylcholine provokes the hyperpolarization of pacemaker cells and decreases the speed of the spontaneous diastolic depolarisation, thus slowing the sinus rate. Catecholamines lead to sinus tachycardia by increasing the diastolic depolarisation speed. In normal conditions, the observed resting heart rate is lower than the intrinsic frequency of the sinus node due to a "predominance" of the vagal tone. Neural regulation of the heart rate aims at meeting the metabolic needs of the tissues through a varying blood flow. Differences between diurnal and nocturnal mean heart rates are accounted for by neural influences. During the night, the increased vagal tone results in decreased heart rate. The exercise-induced tachycardia results from the sympathetic stimulation. It allows more blood to reach skeletal muscles, and as a consequence an increased supply of oxygen and nutrients. Compared to the variety of clinical arrhythmias, sinus rhythm is the basis for optimal exercise capacity and quality of life.     

Strategy for control of complex low-dimensional dynamics in cardiac tissue

 Heart rate-dependent alterations in the duration of the electrically active state of cardiac cells, the action potential, are an important determinant of lethal heart rhythm disorders. The relationship between action potential duration and heart rate can be modelled as a nonlinear one-dimensional map. Iteration of the map over a range of physiologically relevant heart rates produces complex changes in action potential duration, including period doubling bifurcations, chaos and period doubling reversals. We present a computer algorithm that ensures, over the same range of heart rates, uniform state variable values (action potential durations) by application of small perturbing stimuli at appropriate intervals. The algorithm succeeds, even though the only parameter in the system (the heart rate) is immutable. Control of the dynamics is achieved by exploiting the inexcitability of the cardiac cells immediately after stimulation. This algorithm may have applications for the prevention of cardiac rhythm disturbances. Received 24 April 1995; received in revised form 7 August 1995     

Qualitative modeling of mechanoelectrical feedback in a ventricular cell

Mechanical changes in the heart muscle can influence its electrical properties through a process called mechanoelectrical feedback (MEF). This feedback can operate via changes in calcium dynamics during the cross-bridge cycle or via mechanosensitive (stretch-activated) channels. We present a four-variable ordinary differential equation (ODE) system that caricatures the electrical and mechanical activity of a ventricular cell and their mutual interactions. A three-variable excitable system with restitution properties of the FitzHugh-Nagumo type is coupled to a fourth equation which describes changes in cell length during a lightly loaded contraction. The resulting four-variable system models MEF in a cell and can be incorporated into spatially distributed models for mechanoelectric behavior during wave propagation in the cardiac tissue.     

Intrinsic and extrinsic influences on cardiac rhythms in crustaceans

Several factors cause predictable changes in heart rate of crustaceans thus affecting basic heart rhythms. In decapod crustaceans these consist of: many internal factors including influences from neural and neurohormonal systems and chemosensory influences; many external factors including startling stimuli and other disturbance; ventilatory (scaphognathite) reversals; tail flips and other postural movements including locomotor activity; and variations in environmental factors such as oxygen level, temperature and air-exposure. In many cases the initial response involves temporary bradycardia or cardiac arrest. These responses may quickly facilitate to sustained low level stimuli although maintained strong stimulation will eventually be associated with cardio-acceleration and escape responses. Measurement of change in heart rate alone is rarely a sensible monitor of cardiac performance in crustaceans since simultaneous changes in cardiac stroke volume occur which may confound diagnosis. Hypoxia for instance causes decrease in heart rate of adult crustaceans but the apparent decrease in cardiac output is offset or reversed by increase in stroke volume. Concomitant changes occur in cardiac output and in the proportion of cardiac output which is delivered to particular tissues. In fact change in heart rhythm is only one factor in a complex suite of responses involving several physiological systems which compensate uniquely for changes in environmental or other stimuli. Both neural and neuro-hormonal factors are known to play a role in control of these complex responses.     

Mechano-electric feedback and arrhythmias

The mechanical state of the heart feeds back to modify cardiac rate and rhythm. Mechanical stretch of myocardial tissue causes immediate and chronic responses that lead to the common end point of arrhythmia. This review provides a brief summary of the author's personal choice of contributions that she considers have fostered our understanding of the role of mechano-electric feedback in arrhythmogenesis.

Acute mechanical stretch reversibly depolarises the cell membrane and shortens the action potential duration. These electrophysiological changes are related to the activation of mechano-sensitive ion channels. Several different ion channels are involved in the sensing of stretch, among them K⁺-selective, Cl⁻-selective, non-selective, and ATP-sensitive K⁺ channels. Sodium and Ca²⁺ entering the cells via non-selective ion channels are thought to contribute to the genesis of stretch-induced arrhythmia. Mechano-sensitive channels have been cloned from non-vertebrate and vertebrate species.

Chronic stress on the heart activates gene expression in cardiomyocytes and non-myocytes. The signal transduction involves atrial natriuretic peptides and growth factors that initiate remodelling processes leading to hypertrophy which in turn may contribute to the electrical instability of the heart by increasing the responsiveness of mechano-sensitive channels. Selective block of these channels could provide some new form of treatment of mechanically induced arrhythmias, although at present there are no drugs available with sufficient selectivity. Detailed understanding of how mechanical strain on myocardial cells is translated into channel activation will allow to identify new targets for putative antiarrhythmic drugs.     

Augmentation of the expression of c-myc and c-fos oncogenes as a function of the mechanical activity of the isolated adult rat heart

c-myc and c-fos oncogenes encode nuclear DNA binding proteins, and are involved in both growth regulation and differentiation. Using the molecular hybridization technique and DNA probes complementary to c-myc and c-fos mRNA, we report an increase in c-myc and c-fos expression level in the isolated beating adult rat heart with reference to the arrested isolated heart. This suggests a causal relationship between mechanical activity of the heart and c-myc and c-fos expression. It evidences for the first time a messenger between mechanical factor and adaptational changes in the phenotype which occurs at the beginning of cardiac hypertrophy.     

Changes in heart rate and circadian cardiac rhythm as physiological biomarkers for estimation of functional state of crayfish <Emphasis Type="Italic">Pontastacus leptodactylus</Emphasis> Esch. upon acidification of the environment

The changes in heart rate and circadian cardiac rhythm of crayfish Pontastacus leptodactylus Esch. kept in a lightning regime that is close to natural under optimal or low pH values were studied. The heart rate was registered in real time using an original noninvasive fiberoptic method. Upon acidification, disorders in circadian cardiac rhythm and organism reaction (by heart rate) in the suspension test were detected. The characteristics of cardiac activity are considered criteria for estimating the crayfish’s functional state at normal and stress conditions caused by the changes in the quality of the environment.     

A Simulation Study of the Role of Mechanical Stretch in Arrhythmogenesis during Cardiac Alternans

The deformation of the heart tissue due to the contraction can modulate the excitation, a phenomenon referred to as mechanoelectrical feedback (MEF), via stretch-activated channels. The effects of MEF on the electrophysiology at high pacing rates are shown to be proarrhythmic in general. However, more studies need to be done to elucidate the underlying mechanism. In this work, we investigate the effects of MEF on cardiac alternans, which is an alternation in the width of the action potential that typically occurs when the heart is paced at high rates, using a biophysically detailed electromechanical model of cardiac tissue. We observe that the transition from spatially concordant alternans to spatially discordant alternans, which is more arrhythmogenic than concordant alternans, may occur in the presence of MEF and when its strength is sufficiently large. We show that this transition is due to the increase of the dispersion of conduction velocity. In addition, our results also show that the MEF effects, depending on the stretch-activated channels’ conductances and reversal potentials, can result in blocking action potential propagation.     

Sex-Based Differences in Cardiac Arrhythmias, ICD Utilisation and Cardiac Resynchronisation Therapy

Many important differences in the presentation and clinical course of cardiac arrhythmias are present between men and women that should be accounted for in clinical practice. In this paper, we review published data on gender differences in cardiac excitable properties, supraventricular tachycardias, ventricular tachycardias, sudden cardiac death, and the utilisation of implantable defibrillators and cardiac resynchronisation therapy. Women have a higher heart rate at rest, and a longer QT interval than men. They further have a narrower QRS complex and lower QRS voltages on the 12-lead ECG with more often non-specific repolarisation abnormalities at rest. Supraventricular tachycardias, such as AV nodal reentrant tachycardia, are twice as frequent in women compared with men. Atrial fibrillation, however, has a 1.5-fold higher prevalence in men. The triggers for idiopathic right ventricular outflow tract tachycardia (VT) initiation are gender specific, i.e. hormonal changes play an important role in the occurrence of these VTs in women. There are clear-cut gender differences in acquired and congenital LQTS. Brugada syndrome affects men more commonly and severely than women. Sudden cardiac death is less prevalent in women at all ages and occurs 10 years later in women than in men. This may be related to the later onset of clinically manifest coronary heart disease in women. Among patients who receive ICDs and CRT devices, women appear to be under-represented, while they may benefit even more from these novel therapies.     

Coupled pacing improves cardiac efficiency during acute atrial fibrillation with or without cardiac dysfunction

Coupled pacing (CP), a method for controlling ventricular rate during atrial fibrillation (AF), consists of a single electrical stimulation applied to the ventricles after each spontaneous activation. CP results in a mechanical contraction rate approximately one-half the rate during AF. Paired stimulation in which two electrical stimuli are delivered to the ventricles has also been proposed as a therapy for heart failure. Although paired stimulation enhances contractility, it greatly increases energy consumption. The primary hypothesis of the present study is that CP improves cardiac function during acute AF without a similar increase in energy consumption because of the reduced rate of ventricular contractions. In a canine model, CP was applied during four stages: sinus rhythm (SR), acute AF, cardiac dysfunction (CD), and AF in the presence of cardiac dysfunction. The rate of ventricular contraction decreased in all four stages as the result of CP. In addition, we determined the changes in external cardiac work, myocardial oxygen consumption, and myocardial efficiency in the each of four stages. CP partially reversed the effects of AF and CD on external cardiac work, whereas myocardial oxygen consumption increased only moderately. In all stages but SR, CP increased myocardial efficiency because of the marked increases in cardiac work compared with the moderate increases in total energy consumed. Thus this pacing therapy may be a viable therapy for patients with concurrent atrial fibrillation and heart failure.     

Mechanical stretch increases L-type calcium channel stability in cardiomyocytes through a polycystin-1/AKT-dependent mechanism

The L-type calcium channel (LTCC) is an important determinant of cardiac contractility. Therefore, changes in LTCC activity or protein levels could be expected to affect cardiac function. Several studies describing LTCC regulation are available, but only a few examine LTCC protein stability. Polycystin-1 (PC1) is a mechanosensor that regulates heart contractility and is involved in mechanical stretch-induced cardiac hypertrophy. PC1 was originally described as an unconventional Gi/o protein-coupled receptor in renal cells. We recently reported that PC1 regulates LTCC stability in cardiomyocytes under stress; however, the mechanism underlying this effect remains unknown. Here, we use cultured neonatal rat ventricular myocytes and hypo-osmotic stress (HS) to model mechanical stretch. The model shows that the Cavβ2 subunit is necessary for LTCC stabilization in cardiomyocytes during mechanical stretch, acting through an AKT-dependent mechanism. Our data also shows that AKT activation depends on the G protein-coupled receptor activity of PC1, specifically its G protein-binding domain, and the associated Gβγ subunit of a heterotrimeric Gi/o protein. In fact, over-expression of the human PC1 C-terminal mutant lacking the G protein-binding domain blunted the AKT activation-induced increase in Cav1.2 protein in cardiomyocytes. These findings provide novel evidence that PC1 is involved in the regulation of cardiac LTCCs through a Giβγ-AKT-Cavβ2 pathway, suggesting a new mechanism for regulation of cardiac function.     

The heart and control of renal excretion: neural and endocrine mechanisms.

There has been a great deal of research concerning the heart being an important regulator of renal fluid and electrolyte excretion. This cardiac-renal connection involves two different types of major mechanisms, both of which are covered in this review. The first of these to be discovered was neural reflex regulation. This type of control is due to the fact that the heart possesses nerve receptors whose activity is altered by changes in the degree of cardiac stretch that occur as a result of changes in blood volume. These receptors affect various humoral, neural, and perhaps hemodynamic mechanisms that modify renal excretion. A second, more recently discovered type of regulation is based on the concept that the heart is also an endocrine gland. Similar to neural receptor activity, cardiac hormone secretion is also linked to the degree of cardiac stretch or filling. These cardiac peptides have been shown to have a variety of physiologic effects, most of which directly or indirectly affect renal excretion. Both of the above cardiorenal control mechanisms, one neural and one humoral, may be important not only in maintaining normal fluid-electrolyte balance but may also have pathophysiologic relevance.