Sinoatrial Node Recovery Time Research Articles

Tachy-brady arrhythmias: The critical role of adenosine-induced sinoatrial conduction block in post-tachycardia pauses

In patients with sinoatrial nodal (SAN) dysfunction, atrial pauses lasting several seconds may follow rapid atrial pacing or paroxysmal tachycardia (tachy-brady arrhythmias). Clinical studies suggest that adenosine may play an important role in SAN dysfunction, but the mechanism remains unclear. To define the mechanism of SAN dysfunction induced by the combination of adenosine and tachycardia. We studied the mechanism of SAN dysfunction produced by a combination of adenosine and rapid atrial pacing in isolated coronary-perfused canine atrial preparations by using high-resolution optical mapping (n = 9). Sinus cycle length and sinoatrial conduction time (SACT) were measured during adenosine (1-100 μM) and DPCPX (1 μM; A1 receptor antagonist; n = 7) perfusion. Sinoatrial node recovery time was measured after 1 minute of "slow" pacing (3.3 Hz) or tachypacing (7-9 Hz). Adenosine significantly increased sinus cycle length (477 ± 62 ms vs 778 ± 114 ms; P<.01) and SACT during sinus rhythm (41 ± 11 ms vs 86 ± 16 ms; P<.01) in a dose-dependent manner. Adenosine dramatically affected SACT of the first SAN beat after tachypacing (41 ± 5 ms vs 221 ± 98 ms; P<.01). Moreover, at high concentrations of adenosine (10-100 μM), termination of tachypacing or atrial flutter/fibrillation produced atrial pauses of 4.2 ± 3.4 seconds (n = 5) owing to conduction block between the SAN and the atria, despite a stable SAN intrinsic rate. Conduction block was preferentially related to depressed excitability in SAN conduction pathways. Adenosine-induced changes were reversible on washout or DPCPX treatment. These data directly demonstrate that adenosine contributes to post-tachycardia atrial pauses through SAN exit block rather than slowed pacemaker automaticity. Thus, these data suggest an important modulatory role of adenosine in tachy-brady syndrome.

Ageing-dependent remodelling of ion channel and Ca2+clock genes underlying sino-atrial node pacemaking

The function of the sino-atrial node (SAN), the pacemaker of the heart, is known to decline with age, resulting in pacemaker disease in the elderly. The aim of the study was to investigate the effects of ageing on the SAN by characterizing electrophysiological changes and determining whether changes in gene expression are involved. In young and old rats, SAN function was characterized in the anaesthetized animal, isolated heart and isolated right atrium using ECG and action potential recordings; gene expression was characterized using quantitative PCR. The SAN function declined with age as follows: the intrinsic heart rate declined by 18 ± 3%; the corrected SAN recovery time increased by 43 ± 13%; and the SAN action potential duration increased by 11 ± 3% (at 75% repolarization). Gene expression in the SAN changed considerably with age, e.g. there was an age-dependent decrease in the Ca(2+) clock gene, RYR2, and changes in many ion channels (e.g. increases in Na(v)1.5, Na(v)β1 and Ca(v)1.2 and decreases in K(v)1.5 and HCN1). In conclusion, with age, there are changes in the expression of ion channel and Ca(2+) clock genes in the SAN, and the changes may provide a partial explanation for the age-dependent decline in pacemaker function.

Changes in Ion Channel Gene Expression Underlying Heart Failure-Induced Sinoatrial Node Dysfunction

Heart failure (HF) causes a decline in the function of the pacemaker of the heart-the sinoatrial node (SAN). The aim of the study was to investigate HF-induced changes in the expression of the ion channels and related proteins underlying the pacemaker activity of the SAN. HF was induced in rats by the ligation of the proximal left coronary artery. HF animals showed an increase in the left ventricular (LV) diastolic pressure (317%) and a decrease in the LV systolic pressure (19%) compared with sham-operated animals. They also showed SAN dysfunction wherein the intrinsic heart rate was reduced (16%) and the corrected SAN recovery time was increased (56%). Quantitative polymerase chain reaction was used to measure gene expression. Of the 91 genes studied during HF, 58% changed in the SAN, although only 1% changed in the atrial muscle. For example, there was an increase in the expression of ERG, K(v)LQT1, K(ir)2.4, TASK1, TWIK1, TWIK2, calsequestrin 2, and the A1 adenosine receptor in the SAN that could explain the slowing of the intrinsic heart rate. In addition, there was an increase in Na(+)-H(+) exchanger, and this could be the stimulus for the remodeling of the SAN. SAN dysfunction is associated with HF and is the result of an extensive remodeling of ion channels; gap junction channels; Ca(2+)-, Na(+)-, and H(+)-handling proteins; and receptors in the SAN.

Role of Polyamines and cAMP-dependent Mechanisms on 5α-dihydrotestosterone-elicited Functional Effects in Isolated Right Atria of Rat

Androgens produce acute vasodilation of systemic, pulmonary, and coronary arteries in several mammal preparations and increase cardiomyocyte contractility. A decrease of the spontaneous beating of sinoatrial cells has also been described. The aim of this study was to characterize the direct effect of 5alpha-dihydrotestosterone on the spontaneous chronotropism and inotropism in the same preparation as an approach to establish the effect on cardiac output and their mechanism of action. The effects were studied on isolated right atria of Wistar rats placed in an organ bath in Tyrode solution at 37 degrees C and bubbled with carbogen. In male rats, the acute administration of 5alpha-dihydrotestosterone, a nonaromatizable derivate of testosterone, elicited a positive inotropism, which was associated with a negative chronotropism. As reported in the left atria, polyamines and beta-adrenoceptors played a role in 5alpha-dihydrotestosterone-elicited positive inotropism because the effect was antagonized by alpha-difluoromethylornithine, an inhibitor of polyamine synthesis, and atenolol, a beta1-adrenoceptor blocker, but not on the negative effect on chronotropism. The androgen increased the sinoatrial node recovery time, suggesting an effect on the mechanisms of spontaneous diastolic depolarization involved in atria pacemaking. These effects of 5alpha-dihydrotestosterone are not hormonally regulated because they are similarly produced in estrogenized females and gonadectomized male and female rats. These results suggest that the androgen could acutely improve cardiac performance.

Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation

The mechanism of sinoatrial node (SAN) dysfunction in atrial fibrillation (AF) is unclear. The purpose of this study was to test the hypothesis that defective spontaneous sarcoplasmic reticulum (SR) Ca(2+) release (Ca(2+) clock) is in part responsible for SAN dysfunction in AF. Arrhythmic events and SAN function were evaluated in pacing-induced AF dogs (n = 7) and in normal dogs (n = 19) with simultaneous intracellular calcium (Ca(i)) and membrane potential recording. AF dogs had frequent sinus pauses during Holter monitoring. Isolated right atrium (RA) from AF dogs showed slower heart rate (P = .001), longer SAN recovery time (P = .001), and longer sinoatrial conduction time (P = .003) than normal. In normal RAs, isoproterenol 0.3 and 1 mumol/L increased heart rate by 96% and 105%, respectively. In contrast, in RAs from AF dogs, isoproterenol increased heart rate by only 60% and 72%, respectively. Isoproterenol induced late diastolic Ca(i) elevation (LDCAE) at superior SAN in all 19 normal RAs but in only 3 of 7 AF RAs (P = .002). In AF RAs without LDCAE (n = 4), heart rate increased by the acceleration of ectopic foci. Caffeine (20 mmol/L) injection increased heart rate with LDCAE in all 6 normal RAs but did not result in LDCAE in any of the 5 AF RAs (P = .002). Type 2 ryanodine receptor (RyR2) in the superior SAN of AF dogs was decreased to 33% of normal (P = .02). SAN dysfunction in AF is associated with Ca(2+) clock malfunction, characterized by unresponsiveness to isoproterenol and caffeine and down-regulation of RyR2 in SAN.

Funny Current Downregulation and Sinus Node Dysfunction Associated With Atrial Tachyarrhythmia

Sinoatrial node (SAN) dysfunction is frequently associated with atrial tachyarrhythmias (ATs). Abnormalities in SAN pacemaker function after termination of ATs can cause syncope and require pacemaker implantation, but underlying mechanisms remain poorly understood. This study examined the hypothesis that ATs impair SAN function by altering ion channel expression. SAN tissues were obtained from 28 control dogs and 31 dogs with 7-day atrial tachypacing (400 bpm). Ionic currents were measured from single SAN cells with whole-cell patch-clamp techniques. Atrial tachypacing increased SAN recovery time in vivo by approximately 70% (P<0.01), a change which reflects impaired SAN function. In dogs that underwent atrial tachypacing, SAN mRNA expression (real-time reverse-transcription polymerase chain reaction) was reduced for hyperpolarization-activated cyclic nucleotide-gated subunits (HCN2 and HCN4) by >50% (P<0.01) and for the beta-subunit minK by approximately 42% (P<0.05). SAN transcript expression for the rapid delayed-rectifier (I(Kr)) alpha-subunit ERG, the slow delayed-rectifier (I(Ks)) alpha-subunit KvLQT1, the beta-subunit MiRP1, the L-type (I(CaL)) and T-type (I(CaT)) Ca2+-current subunits Cav1.2 and Cav3.1, and the gap-junction subunit connexin 43 (were unaffected by atrial tachypacing. Atrial tachypacing reduced densities of the HCN-related funny current (I(f)) and I(Ks) by approximately 48% (P<0.001) and approximately 34% (P<0.01), respectively, with no change in voltage dependence or kinetics. I(Kr), I(CaL), and I(CaT) were unaffected. SAN cells lacked Ba2+-sensitive inward-rectifier currents, irrespective of AT. SAN action potential simulations that incorporated AT-induced alterations in I(f) accounted for slowing of periodicity, with no additional contribution from changes in I(Ks). AT downregulates SAN HCN2/4 and minK subunit expression, along with the corresponding currents I(f) and I(Ks). Tachycardia-induced remodeling of SAN ion channel expression, particularly for the "pacemaker" subunit I(f), may contribute to the clinically significant association between SAN dysfunction and supraventricular tachyarrhythmias.

Bradycardia and Slowing of the Atrioventricular Conduction in Mice Lacking Ca V 3.1/α 1G T-Type Calcium Channels

The generation of the mammalian heartbeat is a complex and vital function requiring multiple and coordinated ionic channel activities. The functional role of low-voltage activated (LVA) T-type calcium channels in the pacemaker activity of the sinoatrial node (SAN) is, to date, unresolved. Here we show that disruption of the gene coding for CaV3.1/alpha1G T-type calcium channels (cacna1g) abolishes T-type calcium current (I(Ca,T)) in isolated cells from the SAN and the atrioventricular node without affecting the L-type Ca2+ current (I(Ca,L)). By using telemetric electrocardiograms on unrestrained mice and intracardiac recordings, we find that cacna1g inactivation causes bradycardia and delays atrioventricular conduction without affecting the excitability of the right atrium. Consistently, no I(Ca,T) was detected in right atrium myocytes in both wild-type and CaV3.1(-/-) mice. Furthermore, inactivation of cacna1g significantly slowed the intrinsic in vivo heart rate, prolonged the SAN recovery time, and slowed pacemaker activity of individual SAN cells through a reduction of the slope of the diastolic depolarization. Our results demonstrate that CaV3.1/T-type Ca2+ channels contribute to SAN pacemaker activity and atrioventricular conduction.

Inhibition by E-4031 of the prolongation of the first returning cycle length after overdrive in anesthetized dog hearts.

Prolongation of the functional recovery of the sinoatrial (SA) nodal pacemaker activity after overdrive, "overdrive suppression," is determined by intrinsic pacemaker activity, pacemaker site, and SA conduction. We investigated the effects of E-4031, a blocker of a rapid type of the delayed rectifier K+ current (Ikr) and stimulation of the intracardiac parasympathetic nerves to the SA nodal region (SAP) on the prolongation of the first returning cycle length (1st RCL) after overdrive in autonomically decentralized hearts of open-chest anesthetized dogs. Second and third RCLs also were measured. We determined SA node recovery time (SNRT) and corrected SNRT (CSNRT) after atrial pacing at rates of 120, 150, and 200% of the control rate for 1 min and also determined SA conduction time (SACT) by the constant-atrial-pacing method. E-4031 (0.1-3 micromol/kg i.v.) increased the sinus cycle length (SCL) and SNRT dose dependently. However, E-4031 decreased CSNRT when the pacing rate was low or the number of pacing stimuli was small, although the agent did not induce a significant change in CSNRT when sufficient pacing stimuli were applied. E-4031 decreased SACT dose dependently. After E-4031 treatment. we observed changes in atrial electrical configurations, suggesting the possibility of pacemaker shift. When SAP stimulation increased SCL, SNRT, CSNRT, and SACT, E-4031 selectively inhibited the prolongation of SCL by SAP stimulation but did not affect the prolongation of CSNRT or SACT. These results suggest that functional recovery of the SA nodal pacemaker activity after overdrive is regulated by Ikr at least in part and that Ikr inhibition attenuates prolongation of the SCL but not the 1st RCL induced by parasympathetic nerve activation in the heart in situ.

Classificaion of sinus node dysfunction

The Sick Sinus Syndrome (SSS) is a serious life-threatening heart disease. It is important to establish a credible and stable sinus node damage model. In this study, we use two methods to construct an SSS damage model in rats. One is to inject sodium hydroxide to the SSS area through internal jugular vein. Another is to cause ischemia-reperfusion injury on the SSS area. 43 healthy SD rats were randomly divided into 4 groups, namely ischemia-reperfusion injury group (IRIG), inject sodium hydroxide group (ISHG), and propranolol group (PG) and the control group (CG). The achievement ratio of modeling was 67% in the IRIG and 83% in the ISHG. The HR significantly decreased after operation in the IRIG and ISHG compared with pre-operation (P＜0.01). The HR was reduced by above 30% in these 2 groups after modeling, while the reduction was better maintained in IRIG. Additionally, the sinoatrial node recovery time (SNRT) and sinoatrial conduction time (SACT) were significantly prolonged compared with pre-modeling in 2 groups (P < 0.01). Morphology results showed blurry in structure and boundaries with pale cytoplasm. It is speculated that IRIG and ISHG modeling might influence the calcium concentration and damage the sinus node function by decrease the expression of HCN4 and SCN5A, which impaired the driving ability of sinus node and leading to apoptosis. Ischemia reperfusion injury and sodium hydroxide injury could construct stable SSS models which could represent clinic pathological damage. Thus, both methods could be used for further studies of the SSS mechanisms and drugs.

Electrophysiologic manifestations in so-called "sick sinus syndrome".

Electrophysiologic disorders in 17 patients with sick sinus syndrome (SSS) were assessed by recording of intracardiac electrograms, atrial overdrive pacing and extrastimulus technique. Significant suppression of the sinoatrial node (SAN) by overdrive pacing (maximum corrected SAN recovery time of longer than 560 msec) was noted in 14 or 16 patients studied. In nine patients, scanning with atrial extrastimuli, sinus rest was defined in all. In one patient there was a longer interpolation zone. Calculated sinoatrial conduction time (SACT) in individual patients varied considerably. The mean SACT was over 110 msec in 5 of 9 patients (56%). Sinus echo was demonstrated in 3; one manifested SAN- re-entrant tachycardia with rates of 72 to 77 beats/min. AV nodal echo was demonstrated in 3, two of them manifested AV nodal re-entrant tachycardia. Intracardiac electrograms revealed prolonged AV conduction time in 2 of 15 patients and prolonged His-Purkinje system conduction time in 2 of 17 patients studied. Two patients disclosed what we thought to be manifestation of intraatrial conduction disturbance. Both had considerable time interval between pacing impulse and atrial response. In one of them Mobitz type 1 and 2:1 intraatrial blocks were observed on atrial pacing and a possible internodal tract depolarization was also recorded. It is concluded that the electrophysiologic manifestations of patients with SSS cover a wide spectrum. The machanism of tachycardia can be due to either SAN or AV nodal re-entry.

The Effect of Pharmacologic Doses of Steroids on Atrioventricular Conduction in Man

His bundle electrograms were performed in ten patients with organic heart disease. Recordings were made at various rates using right atrial pacing. Two grams of methylprednisolone were infused intravenously over a 20-minute period. The PI-A, A-H, H-Q, and H-S intervals were obtained before and up to 1 hour after the infusion of the steroid. The maximum effect was seen at 1 hour. All patients showed a significant prolongation in the A-H interval with negligible effects on other intervals. At the atrial pacing rate of 120 beats/minute, the average A-H interval increased from control of 119 milliseconds to 159 milliseconds after steroids (P smaller than 0.01). Second-degree heart block occurred at lower pacing rates after steroids in six patients as compared with the control state. The postsuppressive sinoatrial node recovery time was increased in seven cases after steroid infusion. Pharmacologic doses of steroids can impair conduction through the atrioventricular node.