Max J. Lab

Mechanoelectric feedback (transduction) in heart: concepts and implications

It seems that one could regard mechanoelectric feedback in normal heart as an intrinsic regulatory process that modulates normal electromechanical interactions (Fig. 6, left loop). Any physiological mechano-electro-mechano perturbation is self-adjusting and homeostatic. This preserves the status quo, or the heart adapts to form a new electro-mechanoelectric situation. The position in cardiac pathology is different (Fig. 6, right loop), particularly if the disease process produces inhomogeneities. A premature ventricular contraction can be mechanically induced by several of the accepted electrophysiological arrhythmic mechanisms. Thereafter, instantaneous feedback develops within and between regional heterogeneous mechanical conditions. These non-linear recovery processes compound interacting non-linear time courses of recovery of restitution and excitability. Changes in initial loading or mechanical conditions could initiate arrhythmia. Both mechanical and electrical inhomogeneities (also diagrammed in Fig. 5) compound the situation in the intact ventricle. This would enable a milieu of altered excitability, arrhythmogenic current flow and re-entry, to sustain the arrhythmia.

Contribution to Heart Rate Variability by Mechanoelectric Feedback Stretch of the Sinoatrial Node Reduces Heart Rate Variability

BACKGROUND Heart rate variability is an important prognostic indicator for sudden death. An increased risk of sudden death and arrhythmia is associated with reduced heart rate variability in heart failure. In heart failure, there is also dilatation of the atria, which raises the prospect that there could be some physiological basis to possibly link heart rate variability with atrial dilatation. We therefore investigated whether sustained atrial stretch could modulate heart rate variability directly. METHODS AND RESULTS Pigs were anesthetized and their hearts exposed. A specially built device stretched the sinoatrial node before and after vagal section and then after administration of propranolol. Stretch of the sinoatrial node decreases heart rate variability in the following ways: The standard deviation of the beat-to-beat interval decreases (4.2 to 2.6 ms; P = .004), and the high-frequency components are reduced (control, 6.5 +/- 2.2 ms2, during stretch, 1.4 +/- 0.3 ms2, P = .003). After section of both vagi, the high-frequency components are reduced by stretch of the sinoatrial node (2.8 +/- 0.9 ms2 for control versus 1.2 +/- 0.3 ms2 during stretch; P = .05). Similarly, after both vagal section and beta-blockade, stretch of the sinoatrial node reduces the high-frequency components (10.6 +/- 3.5 ms2 for control verses 3.0 +/- 1.5 ms2 during stretch; P = .01). CONCLUSIONS We conclude that stretch of the sinoatrial node reduces high-frequency heart rate variability. This may account in part for the reduced heart rate variability seen in clinical conditions in which the right atrium is dilated, such as congestive cardiac failure.

Human Ventricular Action Potential Duration During Short and Long Cycles Rapid Modulation by Ischemia

BACKGROUND Mechanisms underlying the initiation of ventricular arrhythmias in ischemia by a premature beat or after a pause remain unclear. The kinetics of electrical restitution, which is the modulation of action potential duration (APD) by an abrupt alteration in cycle length, may be important. METHODS AND RESULTS We recorded one or two simultaneous monophasic action potentials (MAPs) from the right ventricular septum during balloon occlusion of the left anterior descending coronary artery (LAD) (14 patients), which is expected to induce ischemia at the recording site, and during occlusion of the right coronary artery (RCA) (7 patients), which is not expected to induce ischemia at the recording area. The latter acted as a control. A test pulse sequence was incorporated whereby during steady-state pacing, test beats of altered cycle length were interpose. During LAD occlusion, APD for basic beats shortened from 260 +/- 4 to 236 +/- 4 ms (P < .0001), whereas the control group (RCA occlusion) showed no significant change (251 +/- 7 to 249 +/- 9 ms; P = NS). LAD occlusion resulted in flattening of the slope relating APD of test beats to diastolic interval (P = .001), whereas in the control group (RCA occlusion) the slope remained unchanged. Similar results were obtained during a second occlusion. CONCLUSIONS LAD occlusion in patients during balloon angioplasty shortened MAP duration of basic beats and minimized, abolished, or reversed the normal APD/diastolic-interval relation of test beats of altered cycle length at sites served by the occluded vessel. The results suggest that ischemia flattens the electrical restitution curve in the human endocardium. These findings may have important implications in arrhythmogenesis.

Electrical alternans and the onset of rate-induced pulsus alternans during acute regional ischaemia in the anaesthetised pig heart

OBJECTIVES Electrical alternans and mechanical alternans are both associated with cardiac ischaemia and in the case of electrical alternans there is a strong link with serious ventricular arrhythmia. We elected to investigate the relationship between electrical and mechanical alternans in control and acutely ischaemic myocardium in the intact porcine heart to determine the nature of their interaction and in particular to determine if abnormal mechanical events play a role in arhythmogenesis as has been suggested in non-ischaemic preparations. METHODS We used rapid atrial pacing to induce regional mechanical alternans and pulsus alternans before and then at 5-min intervals after the onset of acute ischaemia induced by a 30-min ligation of a diagonal branch of the left anterior descending artery. Regional mechanical activity is measured with epicardial tripodal strain gauges and regional electrical activity is measured using suction-based monophasic action potential electrodes. To test whether alternate stretching of ischaemic segments during pulsus alternans contributed to electrical alternans we simulated pulsus alternans by clamping the proximal aorta on alternate beats. RESULTS In control areas there was a constant discordant relationship between peak systolic pressure during alternans and action potential duration. In contrast, the ischaemic areas showed electromechanical alternans that was most frequently concordant. Clamping the proximal aorta on alternate beats produced an electrical alternans in control areas but not in the ischaemic area. CONCLUSIONS Pulsus alternans during acute ischaemia is associated with electrical alternans that can be out of phase in control and ischaemic areas. This could increase electrical dispersion which may be pro-arrhythmic.

Mechanical modulation of stretch-induced premature ventricular beats: induction of a mechanoelectric adaptation period

OBJECTIVE Mechanoelectric Feedback, a mechanical intervention inducing an electrical change, is gaining credence as a cause of cardiac arrhythmia in the clinical situation. However, the precise mechanism is unknown. To elucidate this we investigated mechanical and chemical modulation of stretch-induced premature ventricular beats. METHODS We positioned a balloon in the left ventricle of an isolated heart (New Zealand White rabbit), perfused by the Langendorff technique. Balloon inflation regularly produces premature ventricular beats. Monophasic action potentials, ECGs and pressure recordings monitored changes, during mechanical intervention. The hearts were subjected to (i) variations in the degree of preload and duration of inflation, and (ii) cytoskeletal disrupters, colchicine and cytochalasin-B. RESULTS Mechanical dilation of the left ventricle can not only induce premature ventricular beats, but also induce a period during which premature beats cannot be re-induced on a subsequent inflation, i.e. a mechanoelectric adaptation period. The trigger for the mechanoelectric adaptation period seems to occur immediately on balloon inflation and required up to 60 s to recover. This period started with an undershoot in the diastolic component of the monophasic action potential as well as in the peak systolic pressure, with return to control levels within the period. Deflation produced an overshoot (rather than undershoot) in the monophasic action potential duration, but this also returned to control levels within the period. Changes in preload, duration of inflation and disruption of the cytoskeleton failed to modulate the mechanically induced premature beats, or the mechanoelectric adaptation period. CONCLUSIONS Transient ventricular stretch produces arrhythmia, followed by an antiarrhythmic adaptive period. Possible mechanisms are related to a mechanical influence on stretch-activated channels, changes in ionic concentration or diffusion, or second messenger systems, which influence membrane potential. The arrhythmic adaptation does not appear to be related to the mechanical properties of the cytoskeleton. Final elucidation of the mechanism of the mechanoelectric adaptation period demonstrated, may prove important in determining the mechanism of stretch-induced premature ventricular beats and consequently arrhythmia management.

Mechano-electric feedback.

From humble beginnings, cardiac mechanoelectric transduction or feedback has come of age. The last editorial board (Editor-in-Chief, David Hearse, and concerning the Focussed Issue particularly Associate Editor Michael Shattock) facilitated growth by encouraging the Issue. The present board (Editor-in-Chief, Michiel Janse, and concerning this focussed publication, Associate Editor Tobias Opthof) handled the Issue’s adolesence with patience, fortitude and humour. The reviews in this volume of the journal affirm mechanoelectric feedback’s manifestation. It occurs throughout the heart from membrane to man at manifold anatomical and pathological levels. General reviews by Lab and Crozatier attest to mechanotransduction’s possible functional and conceptual roles, whereas Janvier and Boyett cover some ionic aspects, and Vandenberg et al. point to some cellular aspects related to osmotic changes. Taggart covers its existence in man, with Reiter alluding an arrhythmic role in congestive cardiac failure. Franz reviews experimental evidence in intact ventricle supporting a general role in clinical ventricular arrhythmia. Nazir and Lab do the same for atria1 arrhythmia. Still in the atrium, Kohl and Noble’s review suggests, essentially, that mechanoelectric feedback or transduction in fibroblasts may modulate rate and rhythm.

Sympathomimetic modulation of load-dependent changes in the action potential duration in the in situ porcine heart.

AIMS Increased sympathetic stimulation is known to be arrhythmogenic. Likewise increased loading of the myocardium can directly generate arrhythmias. The interaction between the two on the electrophysiology of the myocardium has not been investigated before. We investigated the effect of dobutamine infusion on the shortening of the monophasic action potential duration secondary to increased loading. This was investigated during steady-state pacing and during an alteration in beat-to-beat interval in the form of a restitution curve. METHODS Pigs were anaesthetised and their hearts exposed. Monophasic action potentials and segment lengths were recorded from the anterior surface of the left ventricle. The loading of the ventricle was increased by transiently occluding the aorta. Steady-state pacing and a restitution curve were performed. Recordings were taken before and during dobutamine infusion. RESULTS At steady state, increased loading of the heart shortened the monophasic action potential duration by a mean (+/- s.e.m.) of 4.0 (+/- 0.5) ms (P < 0.001). During dobutamine infusion this shortening of the monophasic action potential increased. Shortening of the action potential duration increased with the dose of dobutamine up to 10 micrograms/kg/min after which a plateau was reached. By comparison to control, dobutamine depressed the electrical restitution curve at short test pulse intervals did not significantly alter the plateau. Increased loading elevated the initial section of the electrical restitution curve at short test pulse intervals and depressed the plateau in both the control recordings and those taken during dobutamine infusion. Increased loading increased the amplitude of the supernormal phase of the electrical restitution curve in control recordings and those taken during dobutamine infusion. Sympathetic stimulation by dobutamine during the steady state potentiates the effect of mechanoelectric feedback on the myocardium. The effect on the restitution curve varies with test pulse interval. At short test pulse intervals the effect of sympathetic stimulation dominates with only minor antagonistic modification by increased loading. However, at longer test pulse intervals the effect of mechanoelectric feedback is equal to that of sympathetic stimulation and is synergistic with it. CONCLUSIONS The mechanically induced changes we describe in the normal pig heart in situ are relatively small. However, they are in the right direction to possibly contribute to arrhythmia under pathological conditions where mechanical as well as electrophysiological inhomogeneity is prominent.

Myocardial mechanics and arrhythmia

The initialing cause of the first ectopic beat and its precipitation of sustained lethal arrhythmia in acute myocardial ischemia is not clear. Comparable uncertainties surround sudden deaih in myocardial failure. Progress in control of ventricular fibrillation has been slow, perhaps because diagnosis and treatment have been based on the premise that ischemic biochemical changes solely cause the alterations in electrophysiological behavior. Alternative approaches need exploration. Evidence that mechanical changes can initiate electrophysiological changes by a process sometimes referred to as “mechanoelectric feedback” is accumulating. It operates when any primary mechanical change in ventricular muscle, e.g., contraction produces a change in its electrical properties. Mechanical changes are prevalent in ischemia and cardiac failure. If mechanoelectric feedback operates here, it is not surprising that arrhythmias in some of these pathologies parallel the degree of mechanical myocardial dysfunction rather than electrophysiological changes, independent of etiology. This mechanoelectric feedback system may exist as an intrinsic property of normal myocardium, providing a feedback control of activation processes at both the cellular and gross levels. Its disruption during pathological events produces instability in the system and thus ventricular arrhythmia. This concept provides a new potential avenue for arrhythmia therapy.

Load-dependent period-doubling bifurcations in the heart of the anaesthetized pig

Abstract The onset of period-doubling behaviour in cardiac physiology is often associated with pathological states and an adverse prognosis. Changes in myocardial loading frequently accompany cardiac disease, and there is growing evidence that they may be important in the genesis of cardiac arrhythmias. This study investigates the effect of changes in myocardial loading on period-doubling bifurcations of mechanical activity in the heart of the anaesthetized pig. Changes in loading can both produce and abolish period-doubling bifurcations in the mechanical behaviour of the heart. The dual effect of changes in loading may reflect the movement of the system around a bifurcation point.

Regional alternans in relaxation and the onset of pulsus alternans in the heart of the anaesthetized pig.

1. The factors leading to the alternation in myocardial contractility believed primarily responsible for pulsus alternans are not known. We examine regional and global contraction patterns in the in situ heart at stimulation rates just below the threshold for pulsus alternans to determine if events occurring in the transition to alternans can give clues to cellular mechanisms. 2. Twelve pigs were anaesthetized, the chest wall removed and regional contraction measured in three areas of the left ventricle using tripodal strain gauges. We analysed regional and global dynamics during right atrial pacing at cycle lengths 50‐150 ms greater than the threshold for pulsus alternans. 3. At pacing cycle lengths 50 ms greater than that required to produce pulsus alternans seven of twelve pigs showed alternans in the maximum rate of ventricular pressure decay but none showed alternans in the maximum rate of pressure rise. Pigs showing alternans in global relaxation were more likely to show alternans in regional contracility (P < 0.05). 4. Twenty‐six of the thirty‐six areas sampled showed alternans in end‐diastolic length at pacing rates below the threshold for pulsus alternans. In fifteen of these areas alternation in end‐diastolic length occurred in the absence of alternans in measures of contractility. 5. Alternans in global measures of relaxation may simply be a manifestation of regional alternans in contractility. It is therefore not appropriate, from global haemodynamic data, to suppose that alternans in relaxation is the primary abnormality in the generation of pulsus alternans.(ABSTRACT TRUNCATED AT 250 WORDS)