Sinus Node Automaticity Research Articles

A framework for the interpretation of heart rate variability applied to transcutaneous auricular vagus nerve stimulation and osteopathic manipulation.

Reports on autonomic responses to transcutaneous auricular vagus nerve stimulation (taVNS) and osteopathic manipulative techniques have been equivocal, partly due to inconsistent interpretation of heart rate variability (HRV). We developed a mechanistic framework for the interpretation of HRV based on a model of sinus node automaticity that considers autonomic effects on Phase 3 repolarization and Phase 4 depolarization of the sinoatrial action potential. The model was applied to HRV parameters calculated from ECG recordings (healthy adult humans, both genders) before (30 min), during (15 min), and after (30 min) a time control intervention (rest, n = 23), taVNS (10 Hz, 300 μs, 1-2 mA, cymba concha, left ear, n = 12), or occipitoatlantal decompression (OA-D, n = 14). The experimental protocol was repeated on 3 consecutive days. The model simulation revealed that low frequency (LF) HRV best predicts sympathetic tone when calculated from heart rate time series, while high frequency (HF) HRV best predicts parasympathetic tone when calculated from heart period time series. Applying our model to the HRV responses to taVNS and OA-D, revealed that taVNS increases cardiac parasympathetic tone, while OA-D elicits a mild decrease in cardiac sympathetic tone.

Pacing or ablation for vasovagal syncope: one size does not fit all.

Practical decision pathway for the management of vasovagal syncope. Please see text for details. White circles demonstrate sites of grouping of autonomic ganglia defined as ganglionated plexi (GP). The superior right atrial GP (RSGP) located on the posterosuperior surface of the right atrium adjacent to the junction of the superior vena cava and the right atrium; the superior left atrial GP (LSGP) is on the posterosuperior surface of the left atrium between the pulmonary veins; the inferior (posterior) right atrial GP (RIGP) located adjacent to the interatrial groove; the inferior left atrial GP (LIGP) is identified on the posterolateral surface of the left atrium; and the Marshall tract GP (MTGP) located adjacent the vein of Marshall. *Response to atropine which accelerates sinus node automaticity and increases the speed of atrioventricular conduction should be evaluated in all cases prior recommending CNA to confirm adequate procedural response. A sinus rate increase of ≥25% or a sinus rate ≥90 bpm in the first 15 min after infusion should be considered as a positive response.7,13 CLS, closed loop stimulation; CNA, cardioneuroablation; HUT, head-up tilt table test; and ILR, implantable loop recorder.

Metalloprotease Nardilysin regulates sinus node automaticity through modulating ion channel transcription.

Metalloprotease Nardilysin regulates sinus node automaticity through modulating ion channel transcription.

Time and frequency domain analysis of long-term heart rate variability in an experimental model of diet-induced metabolic syndrome

Abstract Background Metabolic syndrome (MetS) is defined as the set of at least three of the following conditions: central obesity, elevation of triglycerides, decreased in high-density lipoproteins, systemic hypertension and glucose intolerance. MetS is linked with a high prevalence of cardiovascular disease, including sudden cardiac death and atrial arrhythmias, which may be a consequence of changes related to the structure, function and autonomic control of the heart. One of the underlying mechanisms responsible could be the alteration of sinus node automaticity. Heart rate variability (HRV) analysis is a useful non-invasive tool for evaluating alterations in neural control of cardiac automaticity. Purpose To examine the changes in long-term HRV using time- and frequency- domain analyses in an experimental model of diet-induced MetS which develops all its components. Methods Male NZW rabbits were randomly assigned to control (n=10) or MetS group (n=10), fed with high-fat (10% coconut oil and 5% lard) and high sucrose (15% dissolved in water) diet during 28 weeks. At week 28, 24 hour ECG recording was performed (eMotion Faros 180, Mega Electronics®, 1 kHz). We analyzed 60 minutes of RR time series, comparing day (from 8:00 to 19:59 h) and night (from 20:00 to 7:59 h), and quantified the standard parameters of time and frequency domains: 1) Time domain: RR, SDNN, triangular index (Ti), RMSSD and TINN; 2) Frequency domain: very low (VLF), low (LF), high frequency (HF), and LF/HF index. Multivariate analysis of variance (MANOVA, factorial model) was used for statistical analysis (p<0.05). Results Time domain analysis showed a decrease in RR interval (p<0.001) and geometrical Ti (p=0.036) in MetS animals (Figure, A-B), indicative of an increased heart rate. The rest of parameters in the time domain (SDNN, RMSSD, TINN) were not modified. Further, in the frequency domain at FFT spectrum, we did find a significant decrease in the LF band (p=0.032) in MetS animals (Figure, C). The rest of the frequency domain parameters (VLF, HF and LF/HF index) remained unchanged. Conclusion MetS decreased RR interval duration and triangular index, suggesting an increased sympathetic activity during day and night. Those changes were reflected in LF modifications, and might be attributable to a deficiency in sympathetic-parasympathetic control, which requires adjustments to maintain normal autonomic balance. Collectively, these results could give insight into the autonomic mechanisms that underlie increased atrial arrhythmia susceptibility in MetS. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Generalitat Valenciana, University of Valencia

COCAINE-INDUCED COMPLETE HEART BLOCK THAT WAS REVERSED BY NALOXONE

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Cocaine is largely known for its abuse potential and its toxicity. We present a unique case of cocaine induced complete heart block (CHB) that resolved with IV naloxone administration. CASE PRESENTATION: 49-year-old woman with history of coronary artery disease, mechanical mitral valve, heart failure, anxiety, and depression on aspirin, warfarin, furosemide, gabapentin, citalopram, quetiapine, and clonazepampresented with 3 days history of abdominal pain, diarrhea, and vomiting. The initial vital signs showed heart rate of 32 bpm and blood pressure of 133/69 mmHg. Examination remarkable for epigastric tenderness. Initial labs were significant for WBC of 13.6 x10(3)/mcL, hemoglobin of 8.3 gm/dL, elevated creatinine of 1.24 mg/dL, BUN of 40.6 mg/dL, AST of 206 IU/L, ALT of 280 IU/L and lactic acid 3.7 mmol/L. EKG showed CHB. Urine toxicology was positive for cocaine and benzodiazepines. CT scan of abdomen and pelvis showed mild colitis. Patient was started on IV fluids, IV antibiotics for acute colitis and morphine for pain. Transvenous pacing and dopamine infusion were initiated for bradycardia and hypotension. Patient underwent permanent pacemaker placement due to persistent CHB and during the procedure, patient received fentanyl. Post procedure patient became lethargic, IV naloxone 0.4 mg was given for opioid toxicity with observed conversion of heart rhythm to normal sinus rhythm. Narcotics were discontinued. Patient was discharged in stable condition after 13 days of hospitalization. On follow up visits her EKG recordings showed normal sinus rhythm with no dependency on pacemaker. DISCUSSION: One of the very detrimental effects of cocaine toxicity is cardiovascular sequalae including tachyarrhythmias as well as bradyarrhythmias. Cocaine blocks the fast sodium current and reduces sinus node automaticity and leads to bradycardia. The treatment of tachyarrhythmia related to cocaine intoxication includes benzodiazepine which blunts the hyper sympathetic state mediated by cocaine. From literature review there is no clear guidelines in the management of cocaine induced bradyarrhythmia.Naloxone is used for opioid intoxication, thought to be competitive antagonist at opioid receptors. Our patient received IV naloxone with immediate resolution of CHB. From literature review, we found a case report on perindoprilintoxication inducing severe bradycardia and profound hypotension completely resolved with naloxone infusion. This is the first case of cocaine induced bradycardia that was treated with IV naloxone. We are not sure of the exact mechanism, but administration of naloxone has been associated with increase heart rate, cardiac output, and arterial blood pressure due to increased catecholamines. CONCLUSIONS: In conclusion, naloxone might be a possible treatment for cocaine induced CHB, but further studies are required to further elicit this observed effect. REFERENCE #1: Kariyanna PT, Jayarangaiah A, Al-Sadawi M, Ahmed R, Green J, Dubson I, McFarlane SI. A Rare Case of Second Degree Mobitz Type II AV Block Associated with Cocaine Use. Am J Med Case Rep. 2018;6(7):146-148. doi: 10.12691/ajmcr-6-7-7. Epub 2018 Aug 21. PMID: 30294672; PMCID: PMC6173318. REFERENCE #2: Robert M, De Bels D, Chaumont M, Honoré PM, Gottignies P. Angiotensin converting enzyme inhibitor intoxication: Naloxone to the rescue? Naloxone for ACE inhibitor intoxication. Am J Emerg Med. 2019 Jun;37(6):1217.e1-1217.e2. doi: 10.1016/j.ajem.2019.03.046. Epub 2019 Mar 28. PMID: 30952604. REFERENCE #3: Franklin SM, Thihalolipavan S, Fontaine JM. Sinus Bradycardia in Habitual Cocaine Users. Am J Cardiol. 2017 May 15;119(10):1611-1615. doi: 10.1016/j.amjcard.2017.02.018. Epub 2017 Mar 1. PMID: 28341362. DISCLOSURES: No relevant relationships by Oluwafemi Ajibola, source=Web Response No relevant relationships by Matthew Apedo, source=Web Response No relevant relationships by Susan Collins, source=Web Response No relevant relationships by Ayesha Iqbal, source=Web Response No relevant relationships by Pang Lam, source=Web Response

Mechanism of and strategy to mitigate liraglutide-mediated positive chronotropy

AimAn adverse side-effect of Liraglutide (LG), a Glucagon-Like Peptide 1 (GLP1)-analog commonly used in treatments for diabetes, is positive chronotropy. The goal of this study is to investigate on the mechanism of this drug-induced chronotropy and explore potential means to mitigate this side-effect so as to maximize the therapeutic benefits from LG. Main methodsExperiments were conducted with: 1) Isolated rabbit hearts in a Langendorff set-up to assess for direct effects of drug actions and 2) Murine cardiomyocytes isolated from the sino-atrial node (SAN) to assess the effects of LG on spontaneous action potential (AP) firing and the hyperpolarization-activated current If. Key findingsLG induced a dose-dependent increase in heart rate. Its effects on sinus node automaticity, which were not suppressed during β-blockade with Propranolol, were abolished by If blockade with Ivabradine. In isolated murine SAN myocytes, LG increased spontaneous AP firing frequency by an increase in diastolic depolarization slope without changing other electrophysiological parameters. SignificanceLG-induced positive chronotropy is partly due to a direct effect on the SAN and is independent of the adrenergic cascade and extrinsic autonomic reflex mechanisms. The direct LG-associated increase in heart rate should be mitigated with If blockers rather than β-blockade.

The Cardiac Pacemaker Story-Fundamental Role of the Na+/Ca2+ Exchanger in Spontaneous Automaticity.

The electrophysiological mechanism of the sinus node automaticity was previously considered exclusively regulated by the so-called “funny current”. However, parallel investigations increasingly emphasized the importance of the Ca2+-homeostasis and Na+/Ca2+ exchanger (NCX). Recently, increasing experimental evidence, as well as insight through mechanistic in silico modeling demonstrates the crucial role of the exchanger in sinus node pacemaking. NCX had a key role in the exciting story of discovery of sinus node pacemaking mechanisms, which recently settled with a consensus on the coupled-clock mechanism after decades of debate. This review focuses on the role of the Na+/Ca2+ exchanger from the early results and concepts to recent advances and attempts to give a balanced summary of the characteristics of the local, spontaneous, and rhythmic Ca2+ releases, the molecular control of the NCX and its role in the fight-or-flight response. Transgenic animal models and pharmacological manipulation of intracellular Ca2+ concentration and/or NCX demonstrate the pivotal function of the exchanger in sinus node automaticity. We also highlight where specific hypotheses regarding NCX function have been derived from computational modeling and require experimental validation. Nonselectivity of NCX inhibitors and the complex interplay of processes involved in Ca2+ handling render the design and interpretation of these experiments challenging.

Challenges in Treatment of Inappropriate Sinus Tachycardia.

Background: Inappropriate Sinus Tachycardia (IST) is a clinical syndrome characterized by a sinus heart rate inexplicably higher than one hundred beats per minute at rest that is associated with symptoms like palpitations, dyspnea or dizziness in the absence of primary causes of tachycar-dia.The diagnosis requires exclusion of other causes of tachycardia including medications/substances (such as anti-cholinergic, beta-blocker withdrawal, caffeine, and alcohol) or medical conditions (such as panic attacks, pulmonary embolism, fever, hyperthyroidism, hypovolemia, anemia, and pain).Methods: Work up should include an EKG to differentiate other causes of tachycardia, 24 hour-Holter monitor if indicated, serum thyroid levels, hemoglobin levels and toxicology screen. Electro-physiological studies are not routinely recommended, but should be considered in certain patients in whom concurrent supraventricular tachycardia is suspected.Conclusion: The underlying pathology in IST is yet to be completely understood. However, it is thought that the causes of IST can be broadly classified into two groups; either as an intrinsic increase in sinus node automaticity or an extrinsic cause. Among extrinsic causes, there is evolving evidence that IgG anti-β receptor antibodies are found in IST causing tachycardia.Managing patients with IST includes lifestyle modification, non-pharmacological and pharmacologi-cal interventions. Ivabradine has recently emerged as an effective treatment of IST and was shown to be superior to beta-blockers.

Sinus bradycardia and syncope: what pathophysiological mechanism and what management of the patient?

Sick sinus syndrome (SSS) can be diagnosed only when there is a clear correlation between symptoms and sinus node dysfunction. In the absence of such correlation, the mechanism of undocumented intermittent symptoms such as syncopal spells in patients with permanent mild sinus bradycardia remains uncertain. Some clinical data suggest that a reflex mechanism is likely to be involved in many patients with syncope and sinus bradycardia: the course of syncopal recurrences is very variable from patient to patient and transient loss of consciousness does not recur in more than half of unpaced patients during an observation period of several years. The results of some studies seem to confirm a reflex mechanism as the cause of syncope in most cases: in patients with SSS and syncope the prevalence of positive response to tilt testing was high (~60%) and significantly higher than in patients with SSS without syncope and in other control groups. However, a depressed sinus node automaticity, roughly expressed by very prolonged sinus node recovery time, suggests a role of sinus node dysfunction in the origin of syncope. Patients with permanent mild sinus bradycardia and syncope as an isolated symptom should undergo tilt testing and electrophysiological study. In the presence of positive tilt test without very prolonged sinus node recovery time, the patient should be managed as the patients with neurally mediated syncope and normal sinus rate.

Electrocardiographic RR and QT Interval Variability in Patients with Atrial Septal Defect and Healthy Children.

Atrial septal defect is a common congenital heart disease. In patients with atrial septal defect, left-to-right shunting increases the right atrial and right ventricular preload. This pathological change affects sinus node automaticity and myocardial depolarization and repolarization, and has the potential to evoke arrhythmogenic substrates. We examined the effect of atrial septal defect on sinus node automaticity and myocardial repolarization by investigating the variability in the repolarization interval, namely the QT variability index (QTVI) and variability ratio (VR). This retrospective study included 38 patients (mean age, 2.2 ± 1.9 years; mean left-to-right shunt ratio, 2.1 ± 0.70) and 40 age-matched healthy control subjects evaluated from 2008 to 2015. QTVI was calculated using the ratio of the repolarization parameter variance to heart rate variance, and VR was calculated as the ratio of the standard deviation (SD) of QT intervals to the SD of RR intervals on electrocardiography. There was a significant difference in the SD of all normal RR intervals, heart rate variance, VR, and QTVI of control subjects or patients with low shunt ratio compared with patients with high shunt ratio (all P < 0.05). Linear regression analysis revealed strong positive correlations between the left-to-right shunt ratio and VR (r = 0.662, P < 0.0001) or QTVI (r = 0.808, P < 0.0001). These repolarization indices provide information on alteration of sinus node autonomic control and the pathophysiology of myocardial repolarization, and could be used as a noninvasive indicator of the shunt ratio in children with atrial septal defect.

Acute Oestradiol Increases the Propensity for Atrial Arrhythmias in the Isolated Mouse Heart

Atrial fibrillation (AF) is the most common sustained arrhythmia, significantly contributing to cardiovascular morbidity/mortality. Epidemiological studies have reported sex differences in AF incidence and outcomes. The influence of sex steroids on AF vulnerability is poorly understood, though clinical trial findings (ie WHI) have indicated that hormone supplementation using oestrogen-only therapy significantly increased AF risk. Experimental data addressing oestrogenic influence on atrial arrhythmias are lacking. We have previously shown that oestrogen influences ventricular electromechanical properties and arrhythmia vulnerability. The aim of this study was to assess the influence of acute oestradiol treatment on atrial arrhythmias in isolated mouse hearts. Bipolar electrograms were recorded from hearts subjected to programmed pulse stimulations in the presence/absence of 10 nM estradiol (vs vehicle control). Oestradiol significantly increased the incidence of atrial arrhythmias (# episodes; 2.8 ± 0.5 vs 0.9 ± 0.3), with the mean duration of each arrhythmic episode exhibiting similar trend. The total duration of atrial arrhythmias throughout the pulse stimulation protocol was significantly increased in the presence of oestradiol (s; 6.9 ± 3.2 vs 1.0 ± 0.4). Augmented atrial arrhythmia vulnerability was likely not due to oestrogenic action on sinus node automaticity, as no effect was observed on sinus node recovery time (ms; 424 ± 46 vs 397 ± 47). These data show for the first time in an experimental setting that acute oestrogen exposure increases cardiac vulnerability to atrial arrhythmia. This finding demonstrates potential cardiac vulnerability to local increase in oestrogen of endogenous and exogenous origin. Further studies are required to identify and target the cellular mechanisms by which oestrogen exerts this arrhythmogenic influence.

Present trends and controversies in the use of beta-blockers in cardiovascular diseases

In this paper we summarize present trends and controversies in the use of beta-blockers in cardiovascular diseases. Beta-blockers are catecolamine competitive inhibitors and act through alpha and beta adrenergic receptors blockade. Different agents have a dose-dependent affinity for different beta adrenergic receptors (beta 1, beta 2, beta 3) which is less with higher doses. The most important therapeutic effects of beta-blockers are on cardiovascular system, where they act as negative chronotropic and inotropic agents, lowering cardiac work and improving oxygen demand /supply ratio. Clinical indications are numerous. For their anti-ischemic activity beta-blockers are used as anti-anginal drugs and in acute and previous myocardial infarction for preventing total and cardiovascular mortality. Combined use of beta-blockers and ACE inhibitors slows down heart failure progression and reduces cardiovascular mortality. Beta-blockers are useful in treating focal atrial tachycardia and supra ventricular paroxysmal tachycardia, by reducing sinus node automaticity and delay atrio-ventricular conduction; they also prevent sudden cardiac death and ventricular tachycardia associated with increased sympathetic activity. There is no indication in treating primary non-complicated hypertension with beta-blockers as first-line drugs. Different metabolic effects of selective and non-selective beta-blockers are actually debated. In conclusion, beta-blockers have indication in the treatment of many cardiovascular diseases. Further studies are needed for better understanding the differences in cardiac and peripheral beta-blockers effects depending on their selectivity.

ECG Response: October 1, 2013

HomeCirculationVol. 128, No. 14ECG Response: October 1, 2013 Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBECG Response: October 1, 2013 Originally published1 Oct 2013https://doi.org/10.1161/CIRCULATIONAHA.113.005949Circulation. 2013;128:1586–1587ECG Challenge: A 66-year-old woman with a history of diabetes mellitus, hyperlipidemia, and rheumatoid arthritis presents to her primary care physician with complaints of intermittent lightheadedness. She has not experienced syncope. With the lightheadedness, she has noted her heart rate to be slow, often at ≈40 bpm. She denies any other cardiac symptoms. While in the office, she has a sudden onset of lightheadedness, and an ECG is obtained.Download figureDownload PowerPointThere is a regular rhythm at a rate of 32 bpm. The QRS complex has a normal duration (0.08 second) and a normal morphology. The axis is extremely leftward between −30° and −90° (positive QRS complex in lead I and negative QRS complex in leads II and aVF with an rS morphology). Causes of an extreme left axis include an inferior wall myocardial infarction in which there is a deep Q wave in leads II and aVF or a left anterior fascicular block in which there is an rS morphology in leads II and aVF. This is a left anterior fascicular block. The QT/QTc intervals are normal (460/340 milliseconds). P waves are seen before each QRS complex (+), with a stable PR interval of 0.40 second. The P wave is positive in leads I, II, aVF, and V4 through V6. This represents a sinus rhythm with a first-degree atrioventricular (AV) block or prolonged AV conduction. A second sinus P wave is seen after each QRS complex (*); it is not followed by a QRS complex and hence is nonconducted. The presence of an occasional on time but not conducted P wave defines a second-degree AV block, and because every other P wave is nonconducted, this represents a 2:1 AV block or AV conduction. The second-degree AV block may be either Mobitz type I or Wenckebach, which is attributable to a conduction abnormality in the AV node, or Mobitz type II, which is attributable to a conduction abnormality within the His-Purkinje system. When there is a continuous pattern of 2:1 AV block, the block may be Mobitz type I or II. The etiology can only be established if there is a change in the pattern of conduction, ie two sequentially conducted P waves (if PR interval stable it is Mobitz II, if PR interval lengthens it is Mobitz I) or the development of complete heart block (escape junctional rhythm it is Mobitz I, escape ventricular rhythm it is Mobtiz II). It can be seen that the PP interval is not constant, but there is a repeating pattern such that the PP interval surrounding the QRS complex is slightly shorter (↔, 0.80 sec) than the PP interval without a QRS complex (└┘, 0.96 sec). This is called ventriculophasic arrhythmia. Proposed mechanisms include enhanced sinus node artery pulsatile blood flow with ventricular contraction that increased the automaticity of the sinus node, stretch of the right atrium and sinus node with ventricular contraction that augments sinus node automaticity, and changes in baroreceptor output resulting from the stroke volume caused by ventricular contraction.FootnotesCorrespondence to Philip J. Podrid, MD, West Roxbury VA Hospital, Section of Cardiology, 1400 VFW Pkwy, West Roxbury, MA 02132. E-mail [email protected] Previous Back to top Next FiguresReferencesRelatedDetails October 1, 2013Vol 128, Issue 14 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.113.005949PMID: 24081954 Originally publishedOctober 1, 2013 PDF download Advertisement

Noninvasive Assessment of Autonomic Cardiovascular Activity in Patients With Inappropriate Sinus Tachycardia

Inappropriate sinus tachycardia (IST) is a clinical syndrome characterized by excessive resting heart rate (HR) or disproportional HR increase during exercise. The etiology of IST has not been fully elucidated and remains controversial. The aim of the present study was to assess autonomic function by means of noninvasive tests and commonly available electrocardiographic methods in a series of consecutive patients with symptomatic IST. Twenty-four patients (37 ± 12 years; 20 women) with IST were enrolled. Six cardiovascular reflex tests were performed: (1) HR variation during slow deep breathing, (2) 30-to-15 ratio during active standing, (3) blood pressure response to standing, (4) cold face test, (5) Valsalva maneuver, and (6) blood pressure response to sustained handgrip. Intrinsic HR was calculated and compared with HR after pharmacologic denervation. Additionally, spontaneous baroreflex sensitivity and 24-hour HR variability indices were analyzed. In IST patients, intrinsic HR was significantly higher compared with control subjects. Most cardiovascular autonomic tests revealed abnormal or borderline results, particularly those reflecting mainly parasympathetic function. The spontaneous baroreflex gain was significantly reduced in IST patients. After controlled orthostatic stress and during Valsalva maneuver, impaired baroreflex function was observed. The sympathovagal balance from HR variability was preserved, but altered activity in both bands of frequency domain analysis was recorded. In conclusion, IST is a heterogenic syndrome with enhanced sinus node automaticity modulated by complex alterations of autonomic tone.

症例 洞結節電位直接記録法による洞自動能,洞房伝導の評価

症例 洞結節電位直接記録法による洞自動能,洞房伝導の評価

Region- and Condition-Dependence of the Membrane and Ca2+ Clocks in the Sinus Node

The results presented by Shinohara et al(1) suggests that both the membrane clock and the Ca(2+) clock contribute to sinus node automaticity. Which is dominant depends on the region within the sinus node and the condition of the SNS. When you change the way you look at things, the things you look at change. This new hypothesis is very attractive, because it combines the membrane and Ca(2+) clocks. In fact, supporting data have been reported by the same parties.(11,12) Supportive studies by others are warranted.

Atrial fibrillatory rate and irregularity of ventricular response as predictors of clinical outcome in patients with atrial fibrillation

Atrial fibrillation (AF) remains the most common arrhythmia encountered in clinical practice. Electrocardiogram (ECG)-based predictors of clinical outcome, however, have mostly been studied during sinus rhythm, whereas noninvasive risk stratification of patients with AF remains largely unexplored. Advances in ECG signal processing have led to the development of noninvasive methods of atrial fibrillatory rate (AFR) assessment using spatiotemporal QRST cancellation and time frequency analysis that demonstrated its predictive value for the outcome of pharmacologic and catheter-based interventions for AF. Recently, the prognostic value of AFR was evaluated in patients with congestive heart failure and indicated that reduced AFR may be an independent predictor of total and congestive heart failure–related mortality. A high degree of irregularity of the RR intervals during AF and its dependence on the modulation of the atrioventricular conduction rather than sinus node automaticity hampers the use of conventional heart rate variability approach in patients with AF. However, RR irregularity measures that can be applied to short-time ECG recordings appear to be promising predictors of clinical outcome.

Cardiac involvement in juvenile neuronal ceroid lipofuscinosis (Batten disease)

To explore the onset and progression of cardiac involvement in juvenile neuronal ceroid lipofuscinosis (JNCL). The study population comprised an unselected group of 29 children and adolescents with genetically verified JNCL. We focused on T-wave abnormalities on an EKG, cardiac hypertrophy, and left ventricular systolic function on echocardiography, and heart rates and heart rate variability (HRV) on 24-hour EKG recordings. The surviving patients were observed for 7&frac12; years. The 24-hour EKG recording was repeated after 3 years. Abnormally deeply inverted T waves were present in one-third of the initial EKG recordings and were reported as early as 14 years of age. We found coherence between the presence of repolarization disturbances of the ventricular myocardium at the initial recordings and risk of death during the observation period. At increasing age, heart rate and HRV, expressed as the vagal index (number of adjacent RR intervals deviating more than 6%), were significantly reduced, suggesting an age-dependent bidirectional effect of JNCL on heart rate: one through decreasing parasympathetic activity on the heart and the other through a direct negative influence on sinus node automaticity. Coherence between bradycardia and arrhythmia and occurrence of sinus arrests and atrial flutter with increasing age indicated an age-dependent decrease in sinus node activity also. In the early 20s, a high frequency of ventricular hypertrophy occurred. Progressive cardiac involvement with repolarization disturbances, ventricular hypertrophy, and sinus node dysfunction occur in JNCL. We recommend that the attention on heart involvement in JNCL and other neuronal ceroid lipofuscinosis subtypes should be intensified.

High-Dose Remifentanil Suppresses Sinoatrial Conduction and Sinus Node Automaticity in Pediatric Patients Under Propofol-Based Anesthesia

We sought to determine the effect of remifentanil on sinus node function and the atrial-His (AH) interval in pediatric patients undergoing radiofrequency catheter ablation. Sixty pediatric patients with Wolff-Parkinson-White syndrome were prospectively enrolled in this study. General anesthesia was induced and maintained with a continuous infusion of propofol. We recorded the calculated sinoatrial conduction time (CSACT), corrected sinus node recovery time (CSNRT), and AH interval when the patients were in a stable anesthetic state and compared the values before and during remifentanil administration at a moderate dose (0.2 μg · kg(-1) · min(-1)) or a high dose (0.4 μg · kg(-1) · min(-1)). Data are expressed as mean (95% confidence interval). At the moderate dose, remifentanil prolonged CSNRT (from 177 [117-237] milliseconds to 245 [167-322] milliseconds after administration; P=0.016), but had no effect on either CSACT (P=0.59) or AH interval (P=0.11). However, high-dose remifentanil prolonged both CSNRT (from 201 [144-260] milliseconds to 307 [232-382] milliseconds after administration; P=0.019) and CSACT (from 48 [31-65] milliseconds to 78 [59-96] milliseconds after administration; P=0.038), but had no effect on the AH interval (P=0.058). The interaction in CSNRT between remifentanil administration and its dose was not different (P=0.44). Remifentanil may inhibit both intraatrial conduction and sinus node automaticity, but it has no effect on conduction through the atrioventricular node. Dose dependency was not observed within the range of 0.2 to 0.4 μg · kg(-1) · min(-1) of remifentanil.

Sinus node revisited

Sinus node disease (SND) is a common clinical condition and is the most common indication for permanent pacemaker implantation. This review aims to revisit the complex sinus node anatomy, the evolving understanding of its pacemaking mechanisms, the atrial myopathy in SND and sinus node remodeling. Recent high-density noncontact mapping of the human sinus node showed multiple origins of sinus activation and exit sites with preferential pathways of conduction. Perhaps, a newly described discrete paranodal area containing a molecular mixture of nodal and atrial cells may account for this long recognized discrepancy between the anatomical and functional sinus node. The funny current (I(f)) driven 'membrane clock' is not solely responsible for sinus node automaticity, following recent recognition of the importance of the 'calcium clock'. Several molecular links to sinus node remodeling have recently been identified: loss of connexin-43 expression and down-regulation of I(ca,L) in aging; reduced I(f) and down-regulation of I(f) encoding HCN4 and HCN2 subunits in heart failure; and calcium clock malfunction with down-regulated HCN4, HCN2 and minK in atrial fibrillation. Ongoing research with improved technology and techniques continues to unravel new understandings and challenges to the century old discovery of the anatomical sinus node.