Atrial natriuretic peptide has dose-dependent, autonomically mediated effects on atrial refractoriness and repolarization in anesthetized dogs

INTRODUCTION: Atrial natriuretic peptide (ANP) may alter electrophysiological properties of the heart and possibly have a role in arrhythmogenesis. However, previous studies have yielded conflicting results and have not fully considered whether ANP's cardiac electrophysiological effects are mediated via direct actions and/or indirectly via the autonomic nervous system. This study's aim was to establish whether ANP infused at pathophysiological and pharmacological doses has significant in vivo cardiac electrophysiological effects and to determine whether these effects are directly or autonomically mediated. METHODS AND RESULTS: Electrophysiologic and hemodynamic effects of ANP infusion (human ANP at 15-600 ng/kg per minute) were examined in chloralose-anesthetized dogs under conditions of varying autonomic blockade. In autonomically intact dogs (n = 12), low-dose ANP (15 ng/kg per minute) shortened atrial effective refractory period (ERP) (P < 0.001) and monophasic action potential duration (MAPD90) (P < 0.05) at 600, 500, and 400 msec atrial paced cycle lengths and reduced right atrial pressure (P < 0.05) but did not alter mean arterial pressure. After either combined vagal and beta-adrenergic blockade (vagotomy plus atropine plus propranolol, n = 7) or selective vagal blockade (n = 9), low-dose ANP no longer altered atrial ERP or MAPD90. Higher ANP doses (150 and 600 ng/kg per minute) decreased mean arterial and right atrial pressures (P < 0.001) but did not alter atrial ERP, MAPD90, or other electrophysiological parameters including atrial fibrillation threshold, ventricular ERP, and MAPD90. CONCLUSION: ANP has dose-dependent, autonomically mediated effects on atrial refractoriness and repolarization.     

Unsuccessful internal defibrillation in Brugada syndrome: focus on refractoriness and ventricular fibrillation cycle length

INTRODUCTION: In patients with Brugada syndrome, implantable cardioverter defibrillator (ICD) is the only reliable treatment to prevent sudden death though, in some cases, internal defibrillation may be unsuccessful. The aim of this study was to examine the determinants of defibrillation failure, with a focus on electrophysiologic characteristics. METHODS: The study included 51 patients treated with ICD: 22 with Brugada syndrome and 29 with structural heart disease (SHD). The prevalence of defibrillation energy requirement precluding the programming of a 10-J safety margin, the mean right ventricular effective refractory period (ERP), and mean induced ventricular fibrillation cycle length (VFCL) from the stored ICD electrograms, were compared between the two patient groups. RESULTS: High defibrillation requirements were observed in 18% of patients with Brugada syndrome versus 0% of patients with SHD. However, the patients with SHD had larger heart size than those with Brugada syndrome. Mean VFCL and mean ERP were both significantly shorter in patients with Brugada syndrome than in patients with SHD, and ERP and VFCL were significantly correlated. CONCLUSION: Patients with Brugada syndrome have a high prevalence of high defibrillation energy requirement, and short ventricular ERP and VFCL.     

阈下条件电刺激对患者心脏不应期和起搏节律的影响

目的研究阈下条件电刺激对心脏不应期的影响。方法通过右心电极导管法,在24例心律失常患者中,观察阈下条件单个刺激（Ss）和串刺激（St）对心房或心室不应期和心房或心室起搏节律的影响。结果在SlS2间期中加发St,可使人心房及心室相对不应期和有效不应期延长;且随St强度的增加,不应期延长量增加。在SlS2间期中加发Ss,只有6/18例,心房相对不应期延长;另6/18例,心室相对及有效不应期延长。另外,St和Ss可抑制心房及心室起搏节律。结论阈下条件电刺激具有抑制心肌兴奋性的作用。     

Sympathomimetic infusion and cardiac repolarization: the normative effects of epinephrine and isoproterenol in healthy subjects

Introduction: Catecholamines are known to affect cardiac repolarization, and provocation with either isoproterenol or epinephrine has been proposed as a tool for uncovering latent repolarization abnormalities. This study systematically compares the effects of isoproterenol and epinephrine infusions on QT interval (QT), T waves and U waves in normal subjects.
Methods and Results: Twenty-four normal subjects (29 ± 8 years) were evaluated during graded infusions of up to 0.30 μg/kg/minute epinephrine and 5.0 μg/minute isoproterenol. Heart rates at peak doses were 81 ± 13 bpm at 0.28 ± 0.04 μg/kg/minute epinephrine and 104 ± 5 bpm at 2.4 μg/minute isoproterenol. The longest absolute QT increase was 4 ± 5 msec above baseline during isoproterenol (P < 0.001) and 12 ± 23 msec during epinephrine (P = 0.07), while the longest corrected QT interval (QTc) increase was 67 ± 28 msec (P < 0.0001) and 79 ± 40 msec (P < 0.0001) above baseline during isoproterenol and epinephrine, respectively (P = 0.12 for difference). There was a 2-fold increase in U-wave amplitude during each intervention (P < 0.001). The specificity of paradoxical QT prolongation (≥30 msec at 0.05 μg/kg/minute or ≥35 msec at 0.10 μg/kg/minute epinephrine) and an increase in QTc ≥600 msec at any dose epinephrine were 100%. However, the specificity of other proposed criteria that utilized QTc measurement (≥30 msec at 0.10 μg/kg/minute or ≥65 msec at any dose) was poor whether all leads or only lead II were assessed.
Conclusion: Both epinephrine and isoproterenol are associated with QTc prolongation and amplification of the U wave in normal subjects. The specificity of proposed criteria for epinephrine provocation in diagnosis of the long-QT syndrome is variable; however, paradoxical QT prolongation at low-dose epinephrine or a QTc ≥600 msec is highly specific.     

Reduction of dispersion of repolarization and prolongation of postrepolarization refractoriness explain the antiarrhythmic effects of quinidine in a model of short QT syndrome

Background: Short QT syndrome (SQTS) is a newly described ion channelopathy, characterized by a short QT interval resulting from an accelerated cardiac repolarization, associated with syncope, atrial fibrillation, and sudden cardiac death due to ventricular fibrillation. As therapeutic options in SQTS are still controversial, we examined antiarrhythmic mechanisms in an experimental model of SQTS. Methods and Results: Pinacidil, an I_K‐ATP channel opener, was administered in increasing concentrations (50–100 μM) in 48 Langendorff‐perfused rabbit hearts and led to a significant reduction of action potential duration and QT interval, thereby mimicking SQTS. Eight simultaneously recorded monophasic action potentials demonstrated an increase in dispersion of repolarization, especially between the left and the right ventricle. During programmed ventricular stimulation with up to two extrastimuli, pinacidil significantly increased the inducibility of ventricular fibrillation (1 heart under baseline conditions, 29 hearts during pinacidil administration; P = 0.0001). Additional treatment with the I_Kr blocker sotalol (100 μM) and the class I antiarrhythmic drugs flecainide (2 μM) and quinidine (0.5 μM) randomly assigned to three groups of 16 hearts led to prolongation of repolarization as well as refractory period. Sotalol or flecainide did not reduce the rate of inducibility of ventricular fibrillation significantly (P = 0.63; P = 0.219). However, quinidine reduced the inducibility of ventricular fibrillation by 73% (P = 0.008). The antiarrhythmic potential of quinidine was associated with a significantly greater prolongation of MAP duration, refractoriness, and postrepolarization refractoriness (PRR) as compared with sotalol and flecainide. Moreover, quinidine, in contrast to sotalol and flecainide, reduced dispersion of repolarization. Conclusion: Pinacidil mimics SQTS via increasing potassium outward currents, thereby facilitating inducibility of ventricular fibrillation. Quinidine demonstrates superior antiarrhythmic properties in the treatment of ventricular fibrillation in this model as compared with sotalol and flecainide because of its effects on refractoriness, PRR, and by reducing dispersion of repolarization.     

Effects of successful cardioversion of persistent atrial fibrillation on right ventricular refractoriness and repolarization.

AIM: Changes in ventricular refractoriness and repolarization after successful electrical cardioversion to sinus rhythm in persistent atrial fibrillation (AF) patients were studied. METHODS AND RESULTS: In 33 AF patients with controlled ventricular response, right ventricular ERP (VERP) at three basic cycle lengths (600, 500, 400 ms), as well as monophasic action potential duration (MAPd(90)) at a drive cycle length of 500 ms, were measured just before, 20 min and 24 h after cardioversion. VERP at 600 ms changed from 241+/-19 ms to 249+/-21 ms to 253+/-24 ms (P<0.001), VERP at 500 ms changed from 234+/-19 ms to 242+/-22 ms to 246+/-23 ms (P<0.001) and VERP at 400 ms changed from 224+/-20 ms to 232+/-23 ms to 236+/-24 ms (P<0.001). MAPd(90) changed from 247+/-16 ms preconversion to 252+/-17 ms 20 min postconversion to 253+/-19 ms after 24 h (P<0.05). Change in refractoriness at 500 ms was well correlated with change of mean RR interval before and 20 min after conversion (R=0.616, P<0.001). There was no correlation between RR variability and VERP before cardioversion. CONCLUSION: Restoration of sinus rhythm in persistent AF patients is followed by significant effects on ventricular refractoriness and repolarization related to cycle length change. No AF related ventricular electrophysiological alterations were found.     

Experimental model simulating right ventricular outflow tract tachycardia: a novel technique to initiate RVOT-VT

BACKGROUND: The mechanism(s) whereby a discrete area of myocardium in the RVOT becomes arrhythmogenic remains unknown. METHODS: In 13 dogs, a circular catheter was placed in the proximal pulmonary artery (PA) to contact the endovascular circumference of the PA. A 50-msec train of high-frequency stimulation (HFS, 200 Hz), coupled to atrial pacing, was applied at each bipolar pair of the circular catheter. The coupling interval was adjusted so that the 50-msec train occurred during the ventricular refractory period, that is, the QRS complex, in order to prevent stimulation of the myocardial sleeve within the proximal PA. RESULTS: In all dogs, HFS induced ventricular premature depolarizations and VTs with a left bundle branch block (LBBB) morphology and inferior axis (average 6.8 +/- 1.6 V). Earliest activation was consistently recorded from the proximal PA. Esmolol, a short-acting beta-blocker (1 mg/kg), was administered intravenously in 11 dogs. The inducible ventricular ectopy was abolished in 10 dogs (>12 V, P < 0.05) and the response to HFS was blunted in one dog (10-11 V). After 30 minutes, the response to HFS returned to pre-esmolol levels. CONCLUSIONS: Stimulation of the sympathetic input to the proximal PA induces ventricular ectopy and VTs exhibiting a left bundle branch block morphology and inferior axis, closely simulating clinical RVOT-VT. Beta-blockade either abolishes or blunts this response, corroborating the sympathetic etiology in this model and in some clinical cases of RVOT tachycardias.     

Effects of carvedilol on left ventricular function, mass, and scintigraphic findings in isolated left ventricular non-compaction

A four month old infant with isolated left ventricular non-compaction was treated with carvedilol. Haemodynamic studies and various types of imaging—including echocardiography, radiographic angiography, magnetic resonance imaging, and single photon emission computed tomography with ²⁰¹Tl, ¹²³I-β-methyliodophenylpentadecanoic acid (BMIPP), and ¹²³I-metaiodobenzylguanidine (MIBG)—were performed before and 14 months after treatment. Left ventricular ejection fraction increased from 30% to 57%, and left ventricular end diastolic volume, end systolic volume, and end diastolic pressure showed striking reductions during treatment. Left ventricular mass decreased to about two thirds of the baseline value after treatment. Per cent wall thickening increased after carvedilol in the segments corresponding to non-compacted myocardium. A mismatch between ²⁰¹Tl and BMIPP uptake in the area of non-compaction observed before carvedilol disappeared after treatment. Impaired sympathetic neuronal function shown by MIBG recovered after treatment. Thus carvedilol had beneficial effects on left ventricular function, hypertrophy, and both metabolic and adrenergic abnormalities in isolated left ventricular non-compaction.


Keywords: isolated left ventricular non-compaction; carvedilol; cardiac sympathetic nerve; ventricular remodelling     

阵发性房室折返性心动过速对人心房有效不应期的影响

目的 :探讨阵发性房室折返性心动过速 （AVRT）对人心房有效不应期 （ERP）的影响。方法 :对 5 5例阵发性AVRT患者 ,采用 S1- S2程控刺激法 ,在 AVRT发生前及发生后 ,分别测量其心房 ERP。结果 :AVRT后即刻的ERP较发生前缩短 ,该缩短可在 5 min内恢复。AVRT后 5和 10 min的 ERP与 AVRT前比较无明显改变。结论 :阵发性 AVRT能导致人心房 ERP缩短 ,该缩短可在 5 m in内恢复     

Effects of adalat (nifedipine) on left ventricular hemodynamics in angina pectoris: Comparative study with propranolol

The hemodynamic effects of nifedipine and propranolol administered intravenously were studied in 17 patients with angina pectoris. Nine patients received nifedipine and eight received propranolol. The hemodynamic parameters were compared at rest and during supine bicycle exercise at work loads known to produce angina. Exercise-induced angina improved in four out of nine patients following nifedipine and in one out of eight patients following propranolol. Nifedipine significantly reduced the increment of left ventricular end-diastolic pressure and V_max during exercise. Intravenous propranolol significantly suppressed the increment of heart rate, max dp/dt, tension time index, and V_max during exercise. Although the exact mode of action of nifedipine remains uncertain, it is suggested that it decreases myocardial oxygen requirements primarily through a reduction of left ventricular volume, whereas propranolol suppresses the positive chronotropic and inotropic responses of the heart muscle to exercise.     

Differential effects of eplerenone versus amlodipine on muscle metaboreflex function in hypertensive humans

Numerous studies have demonstrated that sympathetic nervous system overactivation during exercise in hypertensive rodents and humans is due, in part, to an exaggerated reflex response known as the exercise pressor reflex. Our prior studies have implicated a key role of mineralocorticoid receptor activation in mediating an augmented exercise pressor reflex in spontaneously hypertensive rats, which is mitigated by blockade with eplerenone. However, the effect of eplerenone on exercise pressor reflex has not been assessed in human hypertension. Accordingly, the authors performed a randomized crossover study to compare the effects of eplerenone to another antihypertensive drug from a different class amlodipine on sympathetic nerve activity (SNA) in 14 patients with uncomplicated hypertension. The authors found that amlodipine unexpectedly augmented the increase in SNA during the second minute of isometric handgrip, which persisted into the post‐exercise circulatory arrest period (∆ SNA, from rest of 15 ± 2 vs. 9 ± 2 vs. 10 ± 2 bursts/min, amlodipine vs. baseline vs. eplerenone, respectively, p < .01), suggesting an exaggerated muscle metaboreflex function. Eplerenone did not alter sympathetic responses to exercise or post‐exercise circulatory arrest in the same hypertensive individuals. In conclusions, our studies provide the first direct evidence for a potentially unfavorable potentiation of muscle metaboreflex by amlodipine during isometric handgrip exercise in hypertensive patients whereas eplerenone has no significant effect. Our study may have clinical implications in terms of selection of antihypertensive agents that have the least detrimental effects on sympathetic neural responses to isometric exercise.     

Effects of premature excitation and tachycardia on the spatial distribution of refractoriness and propagation of excitation in a computer model

In this study, the spatial pattern of refractoriness and its effects on propagation of excitation during premature responses and tachycardia have been investigated using a computer model. The model simulated propagation, cycle length-dependent refractoriness, and slow propagation during the relative refractory period. Findings showed slow propagation near the origin of premature responses resulting in longer cycle lengths distal to the slowing. The nonuniform cycle lengths terminated by a premature response also represented the onset of the subsequent cycle, so the pattern of refractoriness was altered after both the premature and following cycle. This occurred even though cycle length affected only the immediately following refractory period in the model. The effect of nonuniform cycle lengths during a premature response on refractory periods after the subsequent response occurred with all cycle lengths of the later response. When the cycle length of that and further responses was sufficiently shortened to result in slowed propagation, changing spatial patterns of refractoriness and propagation occurred. The findings are evidence that responses with slow propagation during incomplete recovery of excitability can affect conduction velocity and refractoriness during multiple subsequent cycles. These effects are likely to occur in the heart but are modified by features such as sustained effects of cycle length on refractoriness, anisotropy, and electrotonic interactions.     

The link between acute haemodynamic adrenergic beta-blockade and long-term effects in patients with heart failure: A study on diastolic function, heart rate and myocardial metabolism following intravenous metoprolol

The present study was performed to find possible mechanismslinking the early effects of beta-blockade with the observedlong-term effects in patients with heart failure. In 57 patients with heart failure, 13±3.1 mg of metoprololwas given intravenously. The patients were investigated by invasivehaemodynamics (n = 34), including collection of myocardial metabolicdata during atrial pacing stress (n = 16), by radionuclide angiographyduring physiological atrial pacing (n = 13), and by a bedsideevaluation (n = 10). Diastolic function, measured by early peak filling rate, followedchanges in heart rate, but was similar when heart rate was heldconstant by atrial pacing before and after beta-blockade. Followingbeta-blockade and slower heart rates, diastolic filling volumeswere redistributed to late diastole. Metoprolol induced a paralleldecrease in coronary sinus flow and myocardial oxygen consumption.Myocardial oxygen consumption following beta-blockade decreasedboth during spontaneous rhythm (25±15 to 16±8.8ml. min^–1; P = 0.006), and during atrial pacing stress(30±13 to 23±11 ml.min^–1; P = 0.004). Cardiacindex decreased owing to reduction of heart rate (2.3±1.0to 1.9±0.64 l.min^–1.m²; P = 0.0003), while leftventricular filling pressure was unchanged. Ejection fractionand ventricular volumes were unaltered following atrial pacingor beta-blockade. There was a reflex increase in noradenalineconcentration after beta-blockade injection (0.96±0.66to 1.20±0.91 nmol.l^–1; P = 0.002), whereas myocardialnoradrenaline overflow was unchanged. There was a trend towardsan increase in myocardial lactate consumption after beta-blockadeadministration during atrial pacing stress. It is suggested that the surprisingly good tolerability seenafter acute administration of beta-blockers to patients withsevere heart failure may be explained by prolongation of thediastolic filling phase, which outweighs the negative ino tropiceffects. The reduced myocardial metabolic demand may allow thefailing myocardium to recover and explain the excellent long-termeffect on heart function following beta-blockade treatment.     

自主神经系统对在体犬跨室壁复极不均一性影响的研究

目的　探讨自主神经系统对在体犬跨室壁复极离散度的影响。方法　用单相动作电位(MAP)记录技术 ,同步记录 12只开胸犬左心室游离壁心外膜心肌 (epicardium ,Epi)、中层心肌(midmyocardium ,Mid)和心内膜心肌 (endocardium ,Endo)的MAP。对自主神经刺激前和刺激过程中 ,三层心肌的跨室壁复极离散度和早期后除极的发生率进行比较。结果　起搏周长为 10 0 0ms时 ,在未刺激自主神经的情况下 ,Epi、Mid和Endo的单相动作电位时程 (MAPD)复极 90 %的时限 (MAPD90 )分别是 (2 78± 11)ms、(316± 16 )ms和 (2 70± 12 )ms;其中Mid的MAPD90 明显长于Epi和Endo的MAPD90 (P<0 0 1)。刺激交感神经时 ,Epi、Mid和Endo细胞的MAPD90 分别缩短 (19± 4 )ms、(45± 6 )ms、(18± 3)ms。与刺激前相比 ,跨室壁复极离散度由 (44± 4 )ms减少到 (15± 3)ms(P <0 0 1) ;但是交感神经刺激时 ,有 5只犬 (41% )的中层心肌出现了早期后除极。迷走神经刺激对三层心肌的MAPD90 值无明显影响。结论　 (1)在体犬心室肌存在跨室壁复极不均一性 ;(2 )交感神经刺激可减少跨室壁复极离散度 ,但易在Mid诱发早期后除极 ;(3)迷走神经刺激对跨室壁复极离散度无明显影响。     

Gene-specific response of dynamic ventricular repolarization to sympathetic stimulation in LQT1, LQT2 and LQT3 forms of congenital long QT syndrome.

AIMS: Differences in the sensitivity of the genotype of the congenital long QT syndrome to sympathetic stimulation have been suggested. This study compared the influence of sympathetic stimulation on continuous corrected QT (QTc) intervals between LQT1, LQT2 and LQT3 forms of the congenital long QT syndrome. METHODS AND RESULTS: We recorded a 12-lead electrocardiogram continuously before and after bolus injection (0.1 microg x kg(-1)) of epinephrine followed by continuous infusion (0.1 microg x kg(-1) min(-1)) in 12 LQT1, 10 LQT2, 6 LQT3, and 13 control patients. The QT intervals and previous RR intervals of all beats were measured semi-automatically, and the QTc intervals of all beats were calculated by Bazett's method. The dynamic response of the RR interval to epinephrine was no different between the four groups. The QTc was prolonged remarkably (477+/-42 to 631+/- 59 ms; P<0.0005, % delta prolongation =+32%) as the RR was maximally decreased (at peak of epinephrine), and remained prolonged at steady state conditions of epinephrine (556+/-56 ms; P<0.0005 vs baseline, +17%) in LQT1 patients. Epinephrine also prolonged the QTc dramatically (502+/-23 to 620+/-39 ms; P<0.0005, +24%) at peak of epinephrine in LQT2 patients, but this shortened to baseline levels at steady state (531+/-25 ms; P=ns vs baseline, +6%). The QTc was much less prolonged at peak of epinephrine in LQT3 (478+/-44 to 532+/-41 ms; P<0.05, +11%) and controls (394+/-21 to 456+/-18 ms; P<0.0005, +16%) than in LQT1 and LQT2 patients, and shortened to the baseline levels (LQT3; 466+/-49 ms, -3%, controls; 397+/-16 ms, +1%; P=ns vs baseline) at steady state. CONCLUSION: Our data suggest that the dynamic response of ventricular repolarization to sympathetic stimulation differs between LQT1, LQT2 and LQT3 syndromes, and may explain why the trigger of cardiac events differs between the genotypes.     

Sympathetic Nervous System Activity and Ventricular Tachyarrhythmias: Recent Advances

Sympathetic nervous system activity (SNSA) is believed to participate in the genesis of ventricular tachyarrhythmias (VTA) but understanding has been impeded by the number and complexity of effects and the paucity of data from humans. New information from studies of genetic disorders, animal models, and spontaneous human arrhythmias indicates the importance of the temporal pattern of SNSA in arrhythmia development. The proarrhythmic effects of short‐term elevations of SNSA are exemplified by genetic disorders and include enhancement of early and delayed afterdepolarizations and increased dispersion of repolarization. The role of long‐term elevations of SNSA is suggested by animal models of enhanced SNSA signaling that results in apoptosis, hypertrophy, and fibrosis, and sympathetic nerve sprouting caused by infusion of nerve growth factor. Processes that overlap short‐ and long‐term effects are suggested by changes in R‐R interval variability (RRV) that precede VTA in patients by several hours. SNSA‐mediated alterations in gene expression of ion channels may account for some intermediate‐term effects. The propensity for VTA is highest when short‐, intermediate, and long‐term changes are superimposed. Because the proarrhythmic effects are related to the duration and intensity of SNSA, normal regulatory processes such as parasympathetic activity that inhibits SNSA, and oscillations that continuously vary the intensity of SNSA may provide vital antiarrhythmic protection that is lost in severe heart failure and other disorders. These observations may have therapeutic implications. The recommended use of β‐adrenergic receptor blockers to achieve a constant level of inhibition does not take into account the temporal patterns and regional heterogeneity of SNSA, the proarrhythmic effects of α‐adrenergic receptor stimulation, or the potential proarrhythmic effects of β‐adrenergic receptor blockade. Further research is needed to determine if other approaches to SNSA modulation can enhance the antiarrhythmic effects.