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Putting the Heart Through its Paces-Cellular Insights from Frequency Phenomena
EDITORIAL
Editorial
Putting the Heart Through its Paces-Cellular Insights from Frequency Phenomena Lea M.D. Delbridge, Ph.D.∗ and Claire L. Curl, Ph.D. Department of Physiology, University of Melbourne, Parkville, Vic. 3010, Australia
T
his issue of Heart, Lung and Circulation features a review by Palomeque et al. which provides a detailed update on how recent mechanistic insights into cardiac excitation–contraction coupling have been gained from experimental studies of myocardial contractile responses to altered stimulation frequency. Investigations of this type are not simply esoteric protocol tools employed by bench researchers to extract information about myocardial contractile nuance. A detailed understanding of the way in which the heart responds to alterations in pacing is essential to appreciate how cardiac reserve is altered in disease conditions and what molecular cellular targets can be potentially identified for remedial intervention.
Responding to Rate—An Intrinsic Cardio-regulatory Mechanism Frequency modulation is a primary neurohumoral mechanism relied on physiologically to achieve regulation of stroke volume and cardiac output. In pathological circumstances, the effectiveness of this modulation is often blunted. Indeed, a reduced responsiveness to frequency modulation can be an early sign of subtle impending loss of function, well before any performance deficit is evident under normal operating steady-state conditions. This is because the heart is very successful in recruiting compensatory strategies to ensure preservation of function under normal demand conditions. Only when a more strenuous challenge is applied, can an underlying defect be unmasked. Although heart rate regulation is achieved through neurohumoral modulation, it is important to understand that the myocardial contractile response to frequency modulation per se is intrinsic to the cardiomyocyte and does not rely on the downstream effects of any extrinsic signalling process. Thus, a frequency shift achieved by direct electrical intervention can induce an alteration in myocardial contractile status. In vivo, it is difficult to separate the extrinsic and intrinsic response components associated with altered heart rate, as the frequency-dependent modula∗
Corresponding author. Tel.: +61 3 8344 5853. E-mail address: [email protected] (L.M.D. Delbridge).
tion is combined with the adrenoceptor-driven contractile response. This is why in vitro experimental strategies such as those discussed in detail by Palomeque et al. have been so informative.
Genetic Disease Models Generate a Renewed Interest in Frequency Phenomena Even though it is more than 100 years since Bowditch’s initial description of the phenomenon where a progressive stepping up or down of pacing/stimulation frequency applied to the heart is associated with a graduated contractile response (i.e. a frequency ‘treppe’), the use of this experimental manoeuvre remains as popular as ever.1 One reason for this is the explosion in the number and type of genetically engineered rodent models of cardiovascular disease which have been produced in recent years. As a functional benchmark of intrinsic performance, a Bowditch-style approach to putting the heart through its ‘paces’ is hard to improve on. Both at the level of the isolated cardiomyocyte2 and the intact organ,3 fundamentally important observations about contractile status can be made by careful observation of frequency-dependent responses. Tracking the frequency response profile for an isolated cardiomyocyte is essentially informative about the calcium (Ca) handling dynamics of the cell. Knowledge of how Ca homeostasis may be disturbed assists in quantifying contractile reserve and in identifying arrhythmia vulnerability.
Calcium and Sodium Fluxes—The Fundamentals of Frequency During excitation–contraction coupling, Ca influx via the L-type channel (with some possible augmentation via the sodium–calcium (Na–Ca) exchanger operating in socalled ‘reverse’ mode) directly activates the myofilaments and also serves as the trigger for the release of additional Ca from the sarcoplasmic reticulum—the cell Ca storage organelle. In relaxation, Ca is recycled back into the sarcoplasmic reticulum by an ATP-driven pump, and also exits the cell via the Na–Ca exchanger (with the exchanger
© 2004 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
1443-9506/04/$30.00 doi:10.1016/j.hlc.2004.08.007
362
Delbridge and Curl Putting the heart through its paces-cellular insights from Frequency Phenomena
EDITORIAL
Fig. 1. Excitation–contraction coupling in the cardiomyocyte. Ca and Na fluxes are tightly coupled by the operation of the Na–Ca exchanger which allows Ca removal during relaxation (‘forward’ mode) and Ca entry during activation (‘reverse’ mode).
operating in the so-called ‘forward’ mode during this phase of the contractile cycle). These important ion fluxes are summarised diagrammatically (Fig. 1). In their review, Palomeque et al. present a comprehensive discussion of recent developments in our understanding of how evaluation of the frequency response can be used to assess myocyte Ca handling status. For many species including human, with increasing frequency there is a parallel increase in myocyte contraction (i.e. a positive frequency staircase). With more rapid pacing the peak cytosolic Ca transient is increased and myofilament crossbridge activity is therefore enhanced. On the basis of their own findings and careful analysis of work produced by other laboratories, Palomeque et al. conclude that mechanisms relating to Ca current augmentation are dominant in determining the positive frequency response. In particular, the Ca-dependent facilitation of the L-type Ca current by the Ca–calmodulin dependent protein kinase II appears to be an important player. While sarcoplasmic reticulum loading may be modulated by frequency (tonic
Heart Lung and Circulation 2004;13:361–362
suppression of the Ca ATPase is relieved with elevated Ca), the evidence suggests that this effect may be of secondary importance in determining the slope of the positive frequency–response relation. When a negative frequency response is observed, as is the case for failing human heart and in some rodent tissues, the underlying mechanisms are less well understood. In these situations, myocyte Na regulation significantly impacts on Ca handling. As illustrated, myocyte Na and Ca fluxes are inextricably linked by means of the activity of the Na–Ca exchanger. Ionic fluxes in the micro-environment of the restricted space between the sarcoplasmic reticulum and the sarcolemmal membranes where the Na–Ca exchanger and the Na and Ca channels are localized become crucially important. In a therapeutic setting, the contractile support achieved by digitalis treatment involves elevation of intracellular Na, and relies on the close relationship between Na and Ca levels in the cardiomyocyte. For this reason, rodent models in which a positive frequency relation is absent (and where a negative frequency response could in fact be prominent) may be especially relevant to our developing understanding of how ionic homeostasis is disturbed in human failure. Palomeque et al. focus attention on the importance of understanding how the fundamental events of excitation–contraction coupling in the heart contribute to the contractile outcomes of pacing modulation. A more detailed experimental dissection of the Ca and Na ionic fluxes in particular will be of value in the identification of new molecular targets of therapeutic potential.
References 1. Bers DM. Excitation–contraction coupling and cardiac contractile force. 2nd ed. Dordrecht, The Netherlands: Kluwer Academic Publishers; 2001. 2. Khan SA, et al. Nitric oxide regulation of myocardial contractility and calcium cycling: independent impact of neuronal and endothelial nitric oxide synthases. Circ Res 2003;92:1322–9. 3. Huke S, Liu LH, Biniakiewicz D, Abraham WT, Periasamy M. Altered force–frequency response in non-failing hearts with decreased SERCA pump-level. Cardiovasc Res 2003;59:668–77.
Editorial
Putting the Heart Through its Paces-Cellular Insights from Frequency Phenomena Lea M.D. Delbridge, Ph.D.∗ and Claire L. Curl, Ph.D. Department of Physiology, University of Melbourne, Parkville, Vic. 3010, Australia
T
his issue of Heart, Lung and Circulation features a review by Palomeque et al. which provides a detailed update on how recent mechanistic insights into cardiac excitation–contraction coupling have been gained from experimental studies of myocardial contractile responses to altered stimulation frequency. Investigations of this type are not simply esoteric protocol tools employed by bench researchers to extract information about myocardial contractile nuance. A detailed understanding of the way in which the heart responds to alterations in pacing is essential to appreciate how cardiac reserve is altered in disease conditions and what molecular cellular targets can be potentially identified for remedial intervention.
Responding to Rate—An Intrinsic Cardio-regulatory Mechanism Frequency modulation is a primary neurohumoral mechanism relied on physiologically to achieve regulation of stroke volume and cardiac output. In pathological circumstances, the effectiveness of this modulation is often blunted. Indeed, a reduced responsiveness to frequency modulation can be an early sign of subtle impending loss of function, well before any performance deficit is evident under normal operating steady-state conditions. This is because the heart is very successful in recruiting compensatory strategies to ensure preservation of function under normal demand conditions. Only when a more strenuous challenge is applied, can an underlying defect be unmasked. Although heart rate regulation is achieved through neurohumoral modulation, it is important to understand that the myocardial contractile response to frequency modulation per se is intrinsic to the cardiomyocyte and does not rely on the downstream effects of any extrinsic signalling process. Thus, a frequency shift achieved by direct electrical intervention can induce an alteration in myocardial contractile status. In vivo, it is difficult to separate the extrinsic and intrinsic response components associated with altered heart rate, as the frequency-dependent modula∗
Corresponding author. Tel.: +61 3 8344 5853. E-mail address: [email protected] (L.M.D. Delbridge).
tion is combined with the adrenoceptor-driven contractile response. This is why in vitro experimental strategies such as those discussed in detail by Palomeque et al. have been so informative.
Genetic Disease Models Generate a Renewed Interest in Frequency Phenomena Even though it is more than 100 years since Bowditch’s initial description of the phenomenon where a progressive stepping up or down of pacing/stimulation frequency applied to the heart is associated with a graduated contractile response (i.e. a frequency ‘treppe’), the use of this experimental manoeuvre remains as popular as ever.1 One reason for this is the explosion in the number and type of genetically engineered rodent models of cardiovascular disease which have been produced in recent years. As a functional benchmark of intrinsic performance, a Bowditch-style approach to putting the heart through its ‘paces’ is hard to improve on. Both at the level of the isolated cardiomyocyte2 and the intact organ,3 fundamentally important observations about contractile status can be made by careful observation of frequency-dependent responses. Tracking the frequency response profile for an isolated cardiomyocyte is essentially informative about the calcium (Ca) handling dynamics of the cell. Knowledge of how Ca homeostasis may be disturbed assists in quantifying contractile reserve and in identifying arrhythmia vulnerability.
Calcium and Sodium Fluxes—The Fundamentals of Frequency During excitation–contraction coupling, Ca influx via the L-type channel (with some possible augmentation via the sodium–calcium (Na–Ca) exchanger operating in socalled ‘reverse’ mode) directly activates the myofilaments and also serves as the trigger for the release of additional Ca from the sarcoplasmic reticulum—the cell Ca storage organelle. In relaxation, Ca is recycled back into the sarcoplasmic reticulum by an ATP-driven pump, and also exits the cell via the Na–Ca exchanger (with the exchanger
© 2004 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
1443-9506/04/$30.00 doi:10.1016/j.hlc.2004.08.007
362
Delbridge and Curl Putting the heart through its paces-cellular insights from Frequency Phenomena
EDITORIAL
Fig. 1. Excitation–contraction coupling in the cardiomyocyte. Ca and Na fluxes are tightly coupled by the operation of the Na–Ca exchanger which allows Ca removal during relaxation (‘forward’ mode) and Ca entry during activation (‘reverse’ mode).
operating in the so-called ‘forward’ mode during this phase of the contractile cycle). These important ion fluxes are summarised diagrammatically (Fig. 1). In their review, Palomeque et al. present a comprehensive discussion of recent developments in our understanding of how evaluation of the frequency response can be used to assess myocyte Ca handling status. For many species including human, with increasing frequency there is a parallel increase in myocyte contraction (i.e. a positive frequency staircase). With more rapid pacing the peak cytosolic Ca transient is increased and myofilament crossbridge activity is therefore enhanced. On the basis of their own findings and careful analysis of work produced by other laboratories, Palomeque et al. conclude that mechanisms relating to Ca current augmentation are dominant in determining the positive frequency response. In particular, the Ca-dependent facilitation of the L-type Ca current by the Ca–calmodulin dependent protein kinase II appears to be an important player. While sarcoplasmic reticulum loading may be modulated by frequency (tonic
Heart Lung and Circulation 2004;13:361–362
suppression of the Ca ATPase is relieved with elevated Ca), the evidence suggests that this effect may be of secondary importance in determining the slope of the positive frequency–response relation. When a negative frequency response is observed, as is the case for failing human heart and in some rodent tissues, the underlying mechanisms are less well understood. In these situations, myocyte Na regulation significantly impacts on Ca handling. As illustrated, myocyte Na and Ca fluxes are inextricably linked by means of the activity of the Na–Ca exchanger. Ionic fluxes in the micro-environment of the restricted space between the sarcoplasmic reticulum and the sarcolemmal membranes where the Na–Ca exchanger and the Na and Ca channels are localized become crucially important. In a therapeutic setting, the contractile support achieved by digitalis treatment involves elevation of intracellular Na, and relies on the close relationship between Na and Ca levels in the cardiomyocyte. For this reason, rodent models in which a positive frequency relation is absent (and where a negative frequency response could in fact be prominent) may be especially relevant to our developing understanding of how ionic homeostasis is disturbed in human failure. Palomeque et al. focus attention on the importance of understanding how the fundamental events of excitation–contraction coupling in the heart contribute to the contractile outcomes of pacing modulation. A more detailed experimental dissection of the Ca and Na ionic fluxes in particular will be of value in the identification of new molecular targets of therapeutic potential.
References 1. Bers DM. Excitation–contraction coupling and cardiac contractile force. 2nd ed. Dordrecht, The Netherlands: Kluwer Academic Publishers; 2001. 2. Khan SA, et al. Nitric oxide regulation of myocardial contractility and calcium cycling: independent impact of neuronal and endothelial nitric oxide synthases. Circ Res 2003;92:1322–9. 3. Huke S, Liu LH, Biniakiewicz D, Abraham WT, Periasamy M. Altered force–frequency response in non-failing hearts with decreased SERCA pump-level. Cardiovasc Res 2003;59:668–77.