Does the sinoatrial node conduction time depend on heart rate?]

The informations about the dependence of sinoatrial conduction time (SACT) on heart rate (HR) are unequivocal. The aim of the study was to establish if such a dependence really exists. The study group comprised 24 patients (9 women and 15 men) aged 42-71 years, mean 55.8. All the patients presented atrial premature contractions of various etiology. No agents affecting heart electrophysiology were administered until the study was completed. In every patient SACT was estimated by means of the Strauss formula from the 24-hr ecg and from transoesophageal single impulse stimulation. SACT obtained from 24-hr ecg was 156.2 +/- 33.1 ms; whereas the one respectively, calculated from the transoesophageal stimulation was 119.0 +/- 21.0 ms. Despite a significant difference between the results (p less than 0.001), the SACT values obtained with both methods correlated well with each other (r = 0.712; p less than 0.01). The dependence of SACT on basic heart cycle length was observed in 9 pts during 24-h ecg (37.5%). Among these pts SACT was shortened with higher and lengthened with lower HR. In the remaining 15 pts this dependence didn't occur, neither it occurred in any patients examined with the single impulse stimulation. The results suggest that the dependence of SACT on HR is not a constant phenomenon and that it occurs only in a part of the examined population.     

RGS4 regulates parasympathetic signaling and heart rate control in the sinoatrial node

Heart rate is controlled by the opposing activities of sympathetic and parasympathetic inputs to pacemaker myocytes in the sinoatrial node (SAN). Parasympathetic activity on nodal myocytes is mediated by acetylcholine-dependent stimulation of M(2) muscarinic receptors and activation of Galpha(i/o) signaling. Although regulators of G protein signaling (RGS) proteins are potent inhibitors of Galpha(i/o) signaling in many tissues, the RGS protein(s) that regulate parasympathetic tone in the SAN are unknown. Our results demonstrate that RGS4 mRNA levels are higher in the SAN compared to right atrium. Conscious freely moving RGS4-null mice showed increased bradycardic responses to parasympathetic agonists compared to wild-type animals. Moreover, anesthetized RGS4-null mice had lower baseline heart rates and greater heart rate increases following atropine administration. Retrograde-perfused hearts from RGS4-null mice showed enhanced negative chronotropic responses to carbachol, whereas SAN myocytes showed greater sensitivity to carbachol-mediated reduction in the action potential firing rate. Finally, RGS4-null SAN cells showed decreased levels of G protein-coupled inward rectifying potassium (GIRK) channel desensitization and altered modulation of acetylcholine-sensitive potassium current (I(KACh)) kinetics following carbachol stimulation. Taken together, our studies establish that RGS4 plays an important role in regulating sinus rhythm by inhibiting parasympathetic signaling and I(KACh) activity.     

Depressed pacemaker activity of sinoatrial node myocytes contributes to the age-dependent decline in maximum heart rate

An inexorable decline in maximum heart rate (mHR) progressively limits human aerobic capacity with advancing age. This decrease in mHR results from an age-dependent reduction in “intrinsic heart rate” (iHR), which is measured during autonomic blockade. The reduced iHR indicates, by definition, that pacemaker function of the sinoatrial node is compromised during aging. However, little is known about the properties of pacemaker myocytes in the aged sinoatrial node. Here, we show that depressed excitability of individual sinoatrial node myocytes (SAMs) contributes to reductions in heart rate with advancing age. We found that age-dependent declines in mHR and iHR in ECG recordings from mice were paralleled by declines in spontaneous action potential (AP) firing rates (FRs) in patch-clamp recordings from acutely isolated SAMs. The slower FR of aged SAMs resulted from changes in the AP waveform that were limited to hyperpolarization of the maximum diastolic potential and slowing of the early part of the diastolic depolarization. These AP waveform changes were associated with cellular hypertrophy, reduced current densities for L- and T-type Ca²⁺ currents and the “funny current” (I_f), and a hyperpolarizing shift in the voltage dependence of I_f. The age-dependent reduction in sinoatrial node function was not associated with changes in β-adrenergic responsiveness, which was preserved during aging for heart rate, SAM FR, L- and T-type Ca²⁺ currents, and I_f. Our results indicate that depressed excitability of individual SAMs due to altered ion channel activity contributes to the decline in mHR, and thus aerobic capacity, during normal aging.One of the most insidious aspects of growing older is an inevitable decline in maximum heart rate (mHR), which limits maximum aerobic capacity with advancing age (1–3). The decline in mHR proceeds at approximately the same rate for all individuals, without regard for lifestyle or physical fitness (4–8). For many otherwise healthy elderly people, it is the factor that ultimately restricts the ability to live independently (9, 10).The decrease in mHR with age results primarily from a parallel age-dependent decline in “intrinsic heart rate” (iHR) (11–13), which is measured during autonomic blockade, and thus reflects the spontaneous pacemaker activity of the sinoatrial node of the heart. Although it is known that the intact sinoatrial node from aged animals contracts more slowly (14, 15) and contains fewer pacemaker myocytes (16), little is known about the functional properties of individual myocytes from the sinoatrial node of the aged heart.Sinoatrial myocytes (SAMs) are highly specialized cells that serve a primarily electrical function as cardiac pacemakers via their production of spontaneous action potentials (APs). Sinoatrial APs are characterized by a spontaneous depolarization during diastole that drives the membrane potential to threshold, thereby triggering the subsequent AP. This “diastolic depolarization” (DD) phase of the sinoatrial AP results from the coordinated activity of numerous membrane conductances, including L- and T-type Ca²⁺ currents (I_Ca,L and I_Ca,T, respectively) and the “funny current” (I_f), all of which contribute directly to the DD by conducting inward current at diastolic potentials (17–23). I_Ca,L also contributes indirectly to the DD by stimulating Ca²⁺ efflux from the sarcoplasmic reticulum of SAMs (24), thereby activating the Na⁺-Ca²⁺ exchange current (I_NCX), which is also known to be critical for normal pacemaker activity (25–29).In this study, we determined the effects of aging on heart rates (HRs) and on spontaneous APs and membrane currents in acutely isolated SAMs. We observed age-dependent decreases in AP firing rates (FRs) in SAMs that corresponded to the age-dependent reductions in iHRs and mHRs. The slower AP FRs resulted from changes in the AP waveform that were associated with an increase in cell size and with alterations in I_Ca,L, I_Ca,T, and I_f. These findings indicate that changes in expression and/or regulation of ion channels in SAMs comprise part of the molecular program that limits mHR, and thus aerobic capacity, during normal aging.     

大鼠窦房结功能及其HCN4通道蛋白表达的增龄性变化

目的 观察幼年、成年、老年SD大鼠窦房结功能及HCN4通道蛋白表达的增龄变化,探讨窦房结电生理重构的分子基础.方法 大鼠麻醉后测基础心率、用食管电极测量窦房结恢复时间(SNRT)、校正的窦房结恢复时间(CSNRT)、以及窦房传导时间(SACT),最后测量固有心率(IHR).用SABC-FITC免疫组化法染色测量大鼠窦房结HCN4通道蛋白荧光强度.结果 窦房结功能测定显示,大鼠基础心率及IHR随年龄的增加呈明显减慢趋势,大鼠SACT随年龄增长延长,大鼠SNRT和CSNRT在不同年龄段未发现显著差异.窦房结HCN4通道蛋白荧光强度随年龄增长呈减弱趋势.结论 窦房结HCN4通道蛋白表达增龄性减低可能是构成窦房结功能增龄减退的电生理分子基础之一.     

SCN5A and sinoatrial node pacemaker function

The SCN5A gene encodes specific voltage-dependent Na+ channels abundant in cardiac muscle that open and close at specific stages of cardiac activity in response to voltage change, thereby controlling the magnitude and timecourse of voltage-dependent Na+ currents (iNa) in cardiac muscle cells. Although iNa has been recorded from sinoatrial (SA) node pacemaker cells, its precise role in SA node pacemaker function remains uncertain. This review summarizes recent findings bearing upon: (i) Sinus node dysfunction resulting from genetic mutations in SCN5A; (ii) Sinus node function in the murine cardiac model with targeted disruptions of the SCN5A gene; (iii) Experimental and computational evaluations of the functional roles of iNa in SA node pacemaker function. Taken together, these new observations suggest strong correlations between SCN5A-encoded Na+ channel and SA node pacemaker function.     

An unexpected requirement for brain-type sodium channels for control of heart rate in the mouse sinoatrial node

Voltage-gated Na(+) channels are composed of pore-forming alpha and auxiliary beta subunits. The majority of Na(+) channels in the heart contain tetrodotoxin (TTX)-insensitive Na(v)1.5 alpha subunits, but TTX-sensitive brain-type Na(+) channel alpha subunits are present and functionally important in the transverse tubules of ventricular myocytes. Sinoatrial (SA) nodal cells were identified in cardiac tissue sections by staining for connexin 43 (which is expressed in atrial tissue but not in SA node), and Na(+) channel localization was analyzed by immunocytochemical staining with subtype-specific antibodies and confocal microscopy. Brain-type TTX-sensitive Na(v)1.1 and Na(v)1.3 alpha subunits and all four beta subunits were present in mouse SA node, but Na(v)1.5 alpha subunits were not. Na(v)1.1 alpha subunits were also present in rat SA node. Isolated mouse hearts were retrogradely perfused in a Langendorff preparation, and electrocardiograms were recorded. Spontaneous heart rate and cycle length were constant, and heart rate variability was small under control conditions. In contrast, in the presence of 100 nM TTX to block TTX-sensitive Na(+) channels specifically, we observed a significant reduction in spontaneous heart rate and markedly greater heart rate variability, similar to sick-sinus syndrome in man. We hypothesize that brain-type Na(+) channels are required because their more positive voltage dependence of inactivation allows them to function at the depolarized membrane potential of SA nodal cells. Our results demonstrate an important contribution of TTX-sensitive brain-type Na(+) channels to SA nodal automaticity in mouse heart and suggest that they may also contribute to SA nodal function and dysfunction in human heart.     

Anisotropy of electrotonus in the sinoatrial node of the rabbit heart

In fibers of the sinoatrial node of isolated right atria of rabbits the decay of the electrotonic potential caused by intracellular current injection was measured in two directions: parallel to the crista terminalis and perpendicular to it. A K+-perfused extracellular suction electrode was used to apply current pulses (10(-5) A, 60 ms) to fibers located in the primary center of the SA node every fourth cardiac cycle at a fixed moment during diastole. The decay of the electrotonic spread was measured in a series of impalements on a straight line from the current source. Space constants were calculated by fitting single exponential curves to the data. Considerable regional differences in space constant values were found in either direction. Parallel to the crista terminalis the mean value was 529 +/- 446 microns (S.D., n = 7), perpendicular to it 306 +/- 295 microns (n = 12); the difference was not significant (P less than 0.2). However, a significant anisotropy (P less than 0.05) of the electrotonic spread was found when measurements were taken from small areas of the node. Large abrupt changes in the electrotonic potential within 200 microns were observed in the center of the node. These data indicate a non-uniformity of electrotonic spread in this part of the SA node.     

Role of phosphoinositide 3-kinase in cardiac function and heart failure

Phosphoinositide 3-kinase (PI3K) belongs to a conserved family of lipid kinases that regulate many critical functions in the cell by generating 3'-phosphorylated phosphatidylinositols. Although PI3K has been the focus of intense study in various biologic processes including apoptosis, metastasis, and neuronal differentiation, it is only recently that the focus has shifted to understanding the role of PI3K in cardiac function, hypertrophy, and heart failure. This article reviews the role of PI3K in regulating cardiac growth, contractility, beta-adrenergic receptor function, and hypertrophy, as well as possible novel therapeutic strategies in the treatment of heart failure.     

Morphophysiological organization of the sinoatrial node of the rat heart

A combined morphophysiologic study of the rat heart sinus node pacemaker cells showed this conductive formation to comprise true and latent pacemakers. The latent pacemaker cell population is heterogeneous in terms of electric activity as well as morphology. The electrophysiologic and morphologic characteristics of latent pacemaker cells undergo a smooth change from centre to periphery of the sinus node. No criteria could be identified for accurate correlation of morphologic and electrophysiologic characteristics of sinus node pacemaker cells, not even by intracellular labelling of cardiomyocytes that belonged to definite electric activity types. The differences between these cells are assumed to be largely related to specific membrane structures, such as ion channels and receptors.     

Exercise assessment of sinoatrial node function following the Mustard operation

To screen for sinoatrial node dysfunction following the Mustard procedure for transposition of the great arteries, we studied the chronotropic response to graded maximal treadmill exercise in 29 patients at mean 6.7 years after operation. Although 93% of patients had normal resting heart rate (HR), 83% demonstrated significant depression of maximum HR and/or recovery HR after termination of exercise. These findings were similarly present among a subset of 13 patients with normal exercise tolerance. Resting and exercise-induced HR in 10 patients receiving chronic digoxin therapy were no different than in the 19 patients without medication. Sixteen patients with abnormal chronotropic responses to exercise had intracardiac electrophysiologic evaluation which confirmed sinoatrial node dysfunction in nine. Abnormal HR responses did not correlate with clinical symptoms, cardiac arrhythmias, or postoperative hemodynamics. Maximal exercise testing may be a sensitive noninvasive method to identify sinoatrial node dysfunction in postoperative children.     

Characterization of sinoatrial node in four conduction system marker mice

The specialized cardiac conduction system (CCS) consists of the sinoatrial node (SAN) and the atrioventricular (AV) conduction system (AVCS), which includes proximal (AV node, bundle of His and bundle branches) and distal (Purkinje fibers) components. In four CCS marker mice [two transgenic (cGATA6|lacZ, CCS|lacZ) and two targeted gene knock-in (minK|lacZ, Hop|lacZ)] the expression of the lacZ gene (beta-gal) has been reported to mark portions of the proximal and distal AVCS; the expression of this marker in the adult SAN is unknown. The primary objective of this study was to analyze the utility of these marker mice in the identification of the SAN. Intercaval and interventricular septal regions, containing all the components of the CCS, were freshly dissected from adult mice based on the anatomical landmarks and sectioned. Immunohistochemical characterization was performed with SAN markers (Cx45, HCN4), compared to the reporter expression (beta-gal) and markers of the working myocardium (Cx40 and Cx43). In all four of the CCS marker mice, we found that beta-gal expression is consistently observed in the proximal and distal AVCS. However, the presence of lacZ gene expression in the working myocardium outside the CCS and/or the absence of this reporter expression in the SAN prevent the effective use of these mice to identify the SAN, leading us to conclude that none of the four CCS marker mice we studied specifically mark the SAN.     

Effect of glycolytic inhibitors on the sinoatrial node,atrium and atrioventricular node in the rabbit heart

The effect of unspecific noncompetitive (iodoacetic acid; IAA) and of specific competitive (deoxyglucose) glycolytic inhibitors were studied under aerobic and anaerobic conditions in the isolated sinoatrial (SA) node, right atrium and atrioventricular (AV) node of the rabbit heart. Transmembrane action potentials were recorded simultaneously with the His bundle electrogram. Under aerobic conditions (Po₂ 460 mmHg), 7.5 × 10^?5m IAA caused no significant alterations of sinus rate, intraatrial and AV nodal conduction. Under hypoxic conditions (Po₂ 40 mmHg), 7.5 × 10^?5m IAA resulted in rapid and complete abolition of the SA and AV nodal electrical activity and in a more delayed atrial inexcitability. Similar changes were never observed in the presence of hypoxia alone. Higher concentrations of IAA (5 × 10^?4m) severely depressed the sinus rate and the AV nodal conduction already under aerobic conditions. The action potential amplitude and the rate of diastolic depolarization of the SA nodal fibers was significantly reduced, the maximum diastolic potential remained unchanged. In atrial fibers, 5 × 10^?4m IAA caused predominantly shortening of the action potential duration but had less marked and delayed depressant effects on the action potential amplitude. Electrophysiologic abnormalities included Mobitz type II sinoatrial block. The electrophysiological effects of deoxyglucose (50 mm) under aerobic and hypoxic conditions resembled those obtained with 7.5 × 10^?5m IAA. The results suggest that the “normal” nodal function is predominantly related to aerobic metabolism but that under hypoxic conditions glycolytic energy production can effectively contribute to the maintenance of nodal electrical activity. Also that the specific relation between cardiac metabolism and electrical activity of nodal and atrial cells may at least partly be explained by the particular electrical membrane properties of the various fiber types.     

Functional and morphological organization of the guinea-pig sinoatrial node compared with the rabbit sinoatrial node

The primary pacemaker, i.e. the group of pacemaker cells discharging the sinoatrial node comprises less than 1000 cells in the guinea-pig and about 5000 cells in the rabbit. These primary pacemaker cells are described as 'central nodal' cells in light microscopy and as 'typical nodal' cells in electron microscopy. The action potential of the leading cells has a higher upstroke velocity in the guinea-pig than in the rabbit (6.2 v. 1.9 V/s). Gap junctions have been observed even in the very center of the node in both species. A zone of double-component action potentials at the septal margin of the node was observed in the rabbit, but not in the guinea-pig. Evidence is presented for abrupt transitions in electrophysiological as well as in ultrastructural characteristics in the guinea-pig sinoatrial node. The differences in intrinsic cycle length between both species but also between individuals of the same species are discussed.