Impaired Sinus Node Function Research Articles

Electrophysiological differences of deep sedation with dexmedetomidine versus propofol

Abstract Funding Acknowledgements Type of funding sources: None. Background Dexmedetomidine and propofol are commonly used drugs for deep sedation during cardiovascular interventions. Patients undergoing these interventions often have impaired sinus node function or atrioventricular (AV) conduction disease. Anesthetics used for deep sedation may further compromise sinus node function and AV nodal conduction, and thereby interfere with the intervention. Purpose To compare the electrophysiological effects of dexmedetomidine and propofol on the function of the sinus node and AV conduction. Methods We randomized patients undergoing first atrial fibrilation ablation 1:1 to deep sedation by dexmedetomidine (DEX group) versus propofol (PRO group), according to a standardized protocol. At the end of the ablation procedure with the patients still deeply sedated and hemodynamically stable, we conducted a standard electrophysiological study and assessed sinus node function, properties of AV conduction and atrial refractoriness. Results Of 160 patients (65±11 years old; 32% female) included into the study, 80 patients were randomized to the DEX and PRO group each. Procedure duration (128±59 minutes) and sedation depth, as assessed by the "Modified Observer’s Assessment of Alertness/Sedation" score (median 3; interquartile range 2, 3), was not different among groups. DEX group patients received a mean of 231±111 mcg of dexmedetomidine and PRO group patients a mean of 657±356 mg of propofol. The table shows the results of the electrophysiological study. DEX group patients had lower sinus rate and longer unadjusted sinus node recovery time (SNRT) at pacing cycle lengths of 600, 500 and 400 ms. However, both corrected (SNRT-RR) and normalized (SNRT/RR) SNRT did not differ among groups. Compared to PRO group patients, AV nodal conduction was slower in DEX group patients as evidenced by longer PR and AH intervals, and a higher Wenckebach cycle length and AV node effective refractory period (ERP) was observed. Conduction properties in the His-Purkinje system were not different among groups, as QRS width and HV interval were similar. An arrhythmia, mainly atrial fibrillation, was induced in 33 patients (21%) during the electrophysiological study, without differences among groups. Conclusions Sinus rate and AV conduction are slower during deep sedation with dexmedetomidine compared to propofol. These differences in electrophysiological effects need to be taken into account when using these anesthetics during cardiovascular interventions.

Abstract 10429: Atrial Pitx2c Overexpression Increased Atrial Arrhythmias with Altered Calcium Handling

Introduction: We have previously reported that the atrial cardiomyocyte-specific Pitx2c overexpression impaired sinus node function. It is well known that sinus node dysfunction is associated with atrial fibrillation (AF) and PITX2C increases in patients with chronic AF. Although Pitx2c overexpression in the atrium may be susceptible to atrial arrhythmias, the mechanism is not well understood. Hypothesis: Pitx2c overexpression in the atrium induces atrial arrhythmias with altered calcium handling. Methods: We generated the atrial cardiomyocyte-specific Pitx2c overexpression mice by crossing two types of mice. Then, we examined AF inducibilities, the expressions of genes related to left-right axis determination and AF, and monophasic action potential durations of B6-Tg ( CAG-LSL-Pitx2c ); SLN Cre/+ (overexpression: OE) and B6 (wild type: WT) mice. Results, Conclusions: Pitx2c was up-regulated in the right atrium (RA) of OE than WT mice. AF increased significantly following burst pacing in OE (52%, n=6) than WT (7%, n=9) mice. Furthermore, episodes of atrial arrhythmias such as premature atrial conduction and AF were increased in OE mice. TBX3 , Shox2 and Scn5a were down-regulated, and Kcne1 was up-regulated significantly in the atrium of OE than WT mice (n=8, each group). Especially in the RA of OE mice, Cacna1c and Serca2 , which were calcium regulatory genes, were significantly down-regulated. In addition, we found that monophasic action potential duration was shorter in RA of the OE mice than WT mice. In conclusion, cardiomyocyte-specific Pitx2c overexpression in RA induces atrial arrhythmias with altered calcium handling. The transcription factor Pitx2c promotes electrical remodeling similar to clinical data.

Deficiency of cyclase-associated protein 2 promotes arrhythmias associated with connexin43 maldistribution and fibrosis

IntroductionCyclase-associated protein 2 (CAP2) plays a major role in regulating the actin cytoskeleton. Since inactivation of CAP2 in a mouse model by a gene trap approach (Cap2gt/gt) results in cardiomyopathy and increased mortality, we hypothesized that CAP2 has a major impact on arrhythmias and electrophysiological parameters.Material and methodsWe performed long-term-ECG recordings in transgenic CAP2 deficient mice (C57BL/6) to detect spontaneous arrhythmias. In vivo electrophysiological studies by right heart catheterization and ex vivo epicardial mapping were used to analyze electrophysiological parameters, the inducibility of arrhythmias, and conduction velocities. Expression and distribution of cardiac connexins and the amount of cardiac fibrosis were evaluated.ResultsSpontaneous ventricular arrhythmias could be detected in Cap2gt/gt during the long-term-ECG recording. Cap2gt/gt showed marked conduction delays at atrial and ventricular levels, including a reduced heart rate (421.0 ±40.6 bpm vs. 450.8 ±27.9 bpm; p < 0.01), and prolongations of PQ (46.3 ±4.1 ms vs. 38.6 ±6.5 ms; p < 0.01), QRS (16.2 ±2.6 ms vs. 12.6 ±1.4 ms; p < 0.01), and QTc interval (55.8 ±6.0 ms vs. 45.2 ±3.3 ms; p = 0.02) in comparison to wild type mice. The PQ prolongation was due to an infra-Hisian conduction delay (HV: 9.7 ±2.1 ms vs. 6.5 ±3.1 ms; p = 0.02). The inducibility of ventricular tachycardias during the electrophysiological studies was significantly elevated in the mutant mice (inducible animals: 88% vs. 33%; p = 0.04). Cap2gt/gt showed more abnormal distribution of connexin43 compared to WT (23.0 ±4.7% vs. 2.9 ±0.8%; p < 0.01). Myocardial fibrosis was elevated in Cap2gt/gt hearts (9.1 ±6.7% vs. 5.5 ±3.3%; p < 0.01).ConclusionsLoss of CAP2 results in marked electrophysiological disturbances including impaired sinus node function, conduction delays, and susceptibility to malignant arrhythmias. Structural changes in Cap2gt/gt are associated with alterations in myocardial connexins and fibrosis.

Arrhythmogenic cardiomyopathy with reduction of connexin40 and altered ion channel expression due to an inactivation of cyclase-associated protein 2

Purpose: The inactivation of Cyclase Associated Protein 2 (CAP2) by a gene trap approach (gt) in the mouse leads to a cardiomyopathy with morphological predominance of the right ventricle resulting in an increased mortality. The purpose of our investigation was to identify potential arrhythmogenic reasons leading to this premature cardiac death. Methods: We performed in vivo electrophysiological studies in CAP2gt/+, CAP2gt/gt and corresponding Wild Type (WT) mice to determine surface and intracardiac ECG parameters and to test the inducibility of Ventricular Tachycardias (VTs). Long-term-ECG recordings were used to detect spontaneous arrhythmias. mRNA expression analysis of Cardiac Connexins (Cx) and ion channels were carried out as well as quantitative cardiac fibrosis determination. Immunofluorescence of Cx40 and Cx43 was performed to visualise their distribution pattern. Results: In comparison to WT, CAP2gt/gt showed marked conduction delays on atrial and ventricular level (reduced heart rate, prolonged PQ, QRS and QT time). AV-time prolongation was due to an infra Hisian conduction delay. Functional testing revealed a trend towards a prolonged ventricular refractory period. The inducibility of VTs was significantly higher in the mutant mice. Long-term-ECG recordings showed polymorphic premature ventricular contractions and spontaneous VTs in the CAP2 deficient mice. Compared to WT, the ventricles of CAP2gt/gt mice presented enhanced myocardial fibrosis (9.1±6.7% vs. 5.6±3.3%; p=0.01) that was found predominantly in the left ventricle. CAP2gt/gt resulted in a significant reduction of Cx40 expression (septum area) and elevated ventricular expression of Cx43, desmin and the calcium channel Cav 1.2. Conclusions: Loss of CAP2 results in marked electrophysiological disturbances leading to malignant ventricular arrhythmias. Impaired sinus node function, conduction delays, and susceptibility to arrhythmias are in accordance with a reduction of Cx40 and alterations in Cx43 and calcium channel expression. Cases of right ventricular cardiomyopathy may be due to dysfunction of CAP2, so further evaluation of its influence on cardiomyopathy and arrhythmogenesis should ensue to fully understand its functioning.

Enalapril Preserves Sinus Node Function in a Canine Atrial Fibrillation Model Induced by Rapid Atrial Pacing

Seventeen beagles were pretreated with either placebo (group I, n = 9) or enalapril 1 mg/kg/day (group II, n = 8) and paced at 500/min from the right atrial appendage for 4 weeks. Every week, corrected sinus node recovery time (CSNRT) and sinus cycle length (SCL) were measured. Quantitative analysis of interstitial fibrosis (IF) and adipose tissue (AT) in the SN was performed with Masson's trichrome stain, and apoptosis of the sinus nodal cells were detected with terminal deoxynucleotidyl transferase nick end-labeling. In group I, rapid atrial pacing prolonged both CSNRT and SCL. After 4 weeks of pacing, CSNRT and SCL were significantly shorter in group II (CSNRT, 410 +/- 37 msec; SCL, 426 +/- 34 msec) than in group I (CSNRT, 717 +/- 52 msec, P < 0.005; SCL, 568 +/- 73 msec, P < 0.05). Both IF and AT of the SN were greater in group I (IF, 9.7 +/- 1.9%; AT, 32.6 +/- 5.9%) than in seven sham dogs (IF, 2.4 +/- 0.9%, P < 0.05; AT, 4.0 +/- 1.7%, P < 0.05) and in group II dogs (IF, 4.0 +/- 2.0%, P < 0.05; AT, 4.0 +/- 1.7%, P < 0.05). End-labeling assay was positive in three of nine dogs in group I, but negative in group II and sham dogs. Rapid atrial pacing impaired SN function through IF and AT of the SN. Enalapril prevented these pacing-induced degenerative changes and improved SN function.

Exercise chronotropy in patients with normal and impaired sinus node function after cardiac transplantation.

The chronotropic response during graded, symptom limited exercise was investigated in 32 cardiac transplant recipients a mean of 49 +/- 18 days after transplantation. All patients had systematic evaluation of postoperative donor sinus node (SN) function and the cardioacceleratory response was compared according to the SN function. Twenty-one patients had normal postoperative SN studies (corrected SN recovery time < 520 msec, group I) while the SN function was impaired postoperatively in the remainder (n = 11, group II; corrected SN recovery time 4,149 +/- 6,283 msec in 5 patients, junctional escape rhythm in 6 patients). All patients had regained sinus rhythm at time of the exercise test. Patients in group II had lower basal sinus rates at the beginning of exercise (91.5 +/- 11 vs 101.4 +/- 7 beats/min, P < 0.02). This lower chronotropy was maintained over every incremental step (F rate between groups = 30, P = 0.0001, F rate vs workload = 15, P = 0.0001 by two-way ANOVA) and resulted in a significantly lower heart rate at individual peak exercise (108.3 +/- 20 vs 124.2 +/- 13 beats/min, P < 0.02). A total of 14/16 patients in group I but only 2/16 patients in group II accomplished a peak heart rate > or = 120 beats/min (P = 0.009). The workload achieved did not differ between the groups (107 +/- 29 vs 102 +/- 32 watts, P > 0.5). These data show a lower SN chronotropy during rest and at peak exercise in cardiac transplant recipients with postoperative SN deficiency and apparent normalization of SN function.

Normal AV Node Function in Patients with Sinus Node Dysfunction After Cardiac Transplantation

Postoperative atrioventricular nodal (AVN) function was compared in 55 patients with normal and 50 patients with impaired sinus node (SN) function after cardiac transplantation (corrected SN recovery time > 520 msec or sinus arrest +/- escape rhythm). Fifty-two patients had fixed atrial pacing at cycle lengths between 600 and 430 msec, and 53 patients at cycle lengths from 600 to 300 msec between postoperative weeks 1 to 3. Relative (stimulus-R interval; AVNRRP) and effective AVN refractory period (AVNERP) were determined in 53 patients at a cycle length of 500 msec. Only one of 105 recipients had high degree AVN conduction disturbance characterized by a Wenckebach phenomenon at cycle length < 630 msec in the first postoperative week. Three patients with normal and two patients with impaired SN function had Wenckebach cycle lengths > 430 msec while the Wenckebach cycle lengths were < or = 430 msec in the remainder (p = NS). Resting PQ interval (146 +/- 18 vs 162 +/- 32; p = 0.09), Wenckebach cycle length (350 +/- 53 vs 362 +/- 50 msec), AVNRRP (356 +/- 38 vs 367 +/- 37 msec), and AVNERP (217 +/- 48 vs 244 +/- 49 msec) did not differ significantly between patients with normal and impaired SN function. AVN conduction did not deteriorate during 318 +/- 130 days of follow-up (PQ at follow-up 154 +/- 17 and 158 +/- 22 msec, patients with normal and impaired SN function, respectively). One DDD pacemaker was placed for AVN conduction disturbance while 22 pacemakers were implanted for SN deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Sinus node dysfunction after orthotopic cardiac transplantation: postoperative incidence and long-term implications.

We investigated incidence, normalization rates, and clinical significance of sinus node (SN) dysfunction after cardiac transplantation. Thirty-nine of 90 patients systematically evaluated presented with impaired SN function in the postoperative period. Of these, 22 normalized their SN function during follow-up while 17 remained impaired after 3 months. The proportion normalized was higher in patients with prolonged SN recovery time (11/16, 68.8%) and those reverting from escape rhythm to sinus rhythm until discharge (5/8, 62.5%) when compared to patients in escape rhythm throughout the postoperative period (5/11, 45.5%) or pacemaker dependence (1/4, 25%). There was no reliable postoperative predictor of normalization and necessity of long-term pacing. A postoperative heart rate consistently less than 70 beats/min (irrespective of the native rhythm) was significantly related to outcome (P = 0.01), but revealed unacceptable sensitivity (61.5%) and specificity (81%). After all, both patients with severe symptoms (near syncopes and syncope), were derived from this group. These two patients, who had been discharged in sinus rhythm, had late pacemakers implanted. An additional 17 patients had early pacemaker placement, only seven of which were constantly paced during follow-up. Given the low normalization rates, patients with postoperative escape rhythm are those most likely to benefit from pacemaker therapy over the long term. Even those in, or reverting back to, sinus rhythm until discharge may experience severe symptoms, particularly in the setting of a postoperative rate consistently less than 70 beats/min since this indicates a relatively lower probability of recovery.

DEMOGRAPHIC AND PERIOPERATIVE FACTORS ASSOCIATED WITH INITIAL AND PROLONGED SINUS NODE DYSFUNCTION AFTER ORTHOTOPIC HEART TRANSPLANTATION

The etiology of sinus node (SN) dysfunction after orthotopic heart transplantation as assessed by the origin of rhythm, heart rate (HR), and, provided the origin of rhythm was sinus, by corrected sinus node recovery time (CSNRT) was studied in 50 patients. The possible influences on postoperative donor SN function of donor age, recipient age, underlying pretransplant heart disease, pretransplant amiodarone (AMIO) treatment, date of surgery, ischemic time, surgical technique of atrial incision, the use of different cardioplegic solutions during the study period, and rejection were evaluated. The results thus obtained indicate that SN dysfunction is common after cardiac transplantation and pinpoint to a different etiology of transient (restoration of normal SN function within 4 postoperative weeks) and persistent (SN function still impaired at 3 months) SN dysfunction. Of the several demographic and perioperative variables evaluated, only ischemic time had an influence on postoperative SN function in that ischemic times were significantly longer in patients with impaired SN function when compared with patients exhibiting normal SN function (148 +/- 39 min vs. 110.5 +/- 36 min, respectively, P = 0.001). Further stratification according to the duration of SN dysfunction revealed significantly longer ischemic times in patients with transiently impaired SN function only (156.3 +/- 35 min vs. 110.5 +/- 36 min, P = 0.0026). No relation to persistent SN dysfunction of ischemic time (130.5 +/- 36 min vs. 110.5 +/- 36 min, P = ns) or any other factor investigated was found.

Electrophysiological Properties of Isradipine (PN200–110) in Humans

Isradipine (PN 200-110) is a new dihydropyridine calcium-entry blocker with powerful vasodilating properties. Therapeutic concentrations do not affect myocardial contractility. However, in vitro studies have demonstrated at higher concentrations negative chronotropic action with only minor dromotropic influence. For this reason we studied the effect of intravenous isradipine (0.3 microgram/kg/min during 30 min) on sinus node and atrioventricular (AV) nodal function in 25 patients. Nine of these patients had normal sinus node function (group I), nine patients were treated with a beta blocker (group II), and seven patients had a sick sinus syndrome (group III). Mean supine arterial blood pressure decreased in all groups; however, in group I not significantly. Spontaneous sinus cycle length decreased significantly in all groups. In none of the patients effective refractory periods of atrium or ventricle were depressed. QRS duration was not significantly affected in any of the groups. There was only a slight, but significant, prolongation of the QTc of maximal 4% (except in group III). We concluded that isradipine has no depressant effect on sinus and AV nodal function in humans, not even in the presence of beta blockade or impaired sinus node function.

HV interval in calcific aortic stenosis. Relation to left ventricular function and effect of valve replacement.

Intracardiac electrography and 24 hour ambulatory electrocardiographic monitoring were carried out in 20 patients with calcific aortic stenosis (mean pressure gradient 86 mm Hg) to investigate (a) the role of bradycardia and tachycardia in the pathogenesis of syncope in aortic stenosis, (b) the relation between haemodynamic data and electrophysiological abnormalities, and (c) whether valve replacement corrects electrophysiological abnormalities. Intracardiac electrograms showed impaired sinus node function in five patients and a prolonged HV interval (greater than or equal to 50 ms) in 11 but there was no difference in the findings of 13 patients with syncope and seven without. Ambulatory monitoring showed short pauses in three patients and brief episodes of tachycardia in four, but there was no difference in the findings of patients with and without syncope. The HV interval correlated inversely with the left ventricular ejection fraction, whereas no correlation was found between the HV interval and the pressure gradient. Nine patients were re-evaluated 15 months after aortic valve replacement. No change was found in sinus node function, but the HV interval had increased by 7.8 ms. It is concluded that in calcific aortic stenosis neither bradycardia nor tachycardia is shown to be a frequent cause of syncope, a prolonged HV interval is a frequent finding and further prolongation occurs after valve replacement, and contractility and conductivity appear to deteriorate in parallel.