Pacemaker Channels and the Chronotropic Response in Health and Disease.

Loss or dysregulation of the normally precise control of heart rate via the autonomic nervous system plays a critical role during the development and progression of cardiovascular disease-including ischemic heart disease, heart failure, and arrhythmias. While the clinical significance of regulating changes in heart rate, known as the chronotropic effect, is undeniable, the mechanisms controlling these changes remain not fully understood. Heart rate acceleration and deceleration are mediated by increasing or decreasing the spontaneous firing rate of pacemaker cells in the sinoatrial node. During the transition from rest to activity, sympathetic neurons stimulate these cells by activating ß-adrenergic receptors and increasing intracellular cyclic adenosine monophosphate. The same signal transduction pathway is targeted by positive chronotropic drugs such as norepinephrine and dobutamine, which are used in the treatment of cardiogenic shock and severe heart failure. The cyclic adenosine monophosphate-sensitive hyperpolarization-activated current (If) in pacemaker cells is passed by hyperpolarization-activated cyclic nucleotide-gated cation channels and is critical for generating the autonomous heartbeat. In addition, this current has been suggested to play a central role in the chronotropic effect. Recent studies demonstrate that cyclic adenosine monophosphate-dependent regulation of HCN4 (hyperpolarization-activated cyclic nucleotide-gated cation channel isoform 4) acts to stabilize the heart rate, particularly during rapid rate transitions induced by the autonomic nervous system. The mechanism is based on creating a balance between firing and recently discovered nonfiring pacemaker cells in the sinoatrial node. In this way, hyperpolarization-activated cyclic nucleotide-gated cation channels may protect the heart from sinoatrial node dysfunction, secondary arrhythmia of the atria, and potentially fatal tachyarrhythmia of the ventricles. Here, we review the latest findings on sinoatrial node automaticity and discuss the physiological and pathophysiological role of HCN pacemaker channels in the chronotropic response and beyond.

Association of Sinoatrial Node Radiation Dose With Atrial Fibrillation and Mortality in Patients With Lung Cancer.

Importance: Atrial fibrillation (AF) can develop following thoracic irradiation. However, the critical cardiac substructure responsible for AF has not been properly studied. Objective: To describe the incidence of AF in patients with lung cancer and determine predictive cardiac dosimetric parameters. Design, Setting, and Participants: This retrospective cohort study was performed at a single referral center and included 239 patients diagnosed with limited-stage small cell lung cancer (SCLC) and 321 patients diagnosed with locally advanced non-small cell lung cancer (NSCLC) between August 2008 and December 2019 who were treated with definitive chemoradiotherapy. Exposures: Radiation dose exposure to cardiac substructures, including the chambers, coronary arteries, and cardiac conduction nodes, were calculated for each patient. Main Outcomes and Measures: Main outcomes were AF and overall survival. Results: Of the 239 and 321 patients with SCLC and NSCLC, the median (IQR) age was 68 (60-73) years and 67 (61-75) years, and 207 (86.6%) and 261 (81.3%) were men, respectively. At a median (IQR) follow-up time of 32.7 (22.1-56.6) months, 9 and 17 patients experienced new-onset AF in the SCLC and NSCLC cohorts, respectively. The maximum dose delivered to the sinoatrial node (SAN Dmax) exhibited the highest predictive value for prediction of AF. A higher SAN Dmax significantly predicted an increased risk of AF in patients with SCLC (adjusted hazard ratio [aHR], 14.91; 95% CI, 4.00-55.56; P < .001) and NSCLC (aHR, 15.67; 95% CI, 2.08-118.20; P = .008). However, SAN Dmax was not associated with non-AF cardiac events. Increased SAN Dmax was significantly associated with poor overall survival in patients with SCLC (aHR, 2.68; 95% CI, 1.53-4.71; P < .001) and NSCLC (aHR, 1.97; 95% CI, 1.45-2.68; P < .001). Conclusions and Relevance: In this cohort study, results suggest that incidental irradiation of the SAN during chemoradiotherapy may be associated with the development of AF and increased mortality. This supports the need to minimize radiation dose exposure to the SAN during radiotherapy planning and to consider close follow-up for the early detection of AF in patients receiving thoracic irradiation.

cAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells.

It is highly debated how cyclic adenosine monophosphate-dependent regulation (CDR) of the major pacemaker channel HCN4 in the sinoatrial node (SAN) is involved in heart rate regulation by the autonomic nervous system. We addressed this question using a knockin mouse line expressing cyclic adenosine monophosphate-insensitive HCN4 channels. This mouse line displayed a complex cardiac phenotype characterized by sinus dysrhythmia, severe sinus bradycardia, sinus pauses and chronotropic incompetence. Furthermore, the absence of CDR leads to inappropriately enhanced heart rate responses of the SAN to vagal nerve activity in vivo. The mechanism underlying these symptoms can be explained by the presence of nonfiring pacemaker cells. We provide evidence that a tonic and mutual interaction process (tonic entrainment) between firing and nonfiring cells slows down the overall rhythm of the SAN. Most importantly, we show that the proportion of firing cells can be increased by CDR of HCN4 to efficiently oppose enhanced responses to vagal activity. In conclusion, we provide evidence for a novel role of CDR of HCN4 for the central pacemaker process in the sinoatrial node.

Isoform-specific regulation of HCN4 channels by a family of endoplasmic reticulum proteins.

Ion channels in excitable cells function in macromolecular complexes in which auxiliary proteins modulate the biophysical properties of the pore-forming subunits. Hyperpolarization-activated, cyclic nucleotide-sensitive HCN4 channels are critical determinants of membrane excitability in cells throughout the body, including thalamocortical neurons and cardiac pacemaker cells. We previously showed that the properties of HCN4 channels differ dramatically in different cell types, possibly due to the endogenous expression of auxiliary proteins. Here, we report the discovery of a family of endoplasmic reticulum (ER) transmembrane proteins that associate with and modulate HCN4. Lymphoid-restricted membrane protein (LRMP, Jaw1) and inositol trisphosphate receptor-associated guanylate kinase substrate (IRAG, Mrvi1, and Jaw1L) are homologous proteins with small ER luminal domains and large cytoplasmic domains. Despite their homology, LRMP and IRAG have distinct effects on HCN4. LRMP is a loss-of-function modulator that inhibits the canonical depolarizing shift in the voltage dependence of HCN4 in response to the binding of cAMP. In contrast, IRAG causes a gain of HCN4 function by depolarizing the basal voltage dependence in the absence of cAMP. The mechanisms of action of LRMP and IRAG are independent of trafficking and cAMP binding, and they are specific to the HCN4 isoform. We also found that IRAG is highly expressed in the mouse sinoatrial node where computer modeling predicts that its presence increases HCN4 current. Our results suggest important roles for LRMP and IRAG in the regulation of cellular excitability, as tools for advancing mechanistic understanding of HCN4 channel function, and as possible scaffolds for coordination of signaling pathways.

Selective inhibition of electrical conduction within the pulmonary veins by α1-adrenergic receptors activation in the Rat.

Pulmonary veins (PV) are involved in the pathophysiology of paroxysmal atrial fibrillation. In the rat, left atrium (LA) and PV cardiomyocytes have different reactions to α1-adrenergic receptor activation. In freely beating atria-PV preparations, we found that electrical field potential (EFP) originated from the sino-atrial node propagated through the LA and the PV. The α1-adrenergic receptor agonist cirazoline induced a progressive loss of EFP conduction in the PV whereas it was maintained in the LA. This could be reproduced in preparations electrically paced at 5 Hz in LA. During pacing at 10 Hz in the PV where high firing rate ectopic foci can occur, cirazoline stopped EFP conduction from the PV to the LA, which allowed the sino-atrial node to resume its pace-making function. Loss of conduction in the PV was associated with depolarization of the diastolic membrane potential of PV cardiomyocytes. Adenosine, which reversed the cirazoline-induced depolarization of the diastolic membrane potential of PV cardiomyocytes, restored full over-shooting action potentials and EFP conduction in the PV. In conclusion, selective activation of α1-adrenergic receptors results in the abolition of electrical conduction within the PV. These results highlight a potentially novel pharmacological approach to treat paroxysmal atrial fibrillation by targeting directly the PV myocardium.

A case report of sinoatrial arrest caused by temporal lobe epilepsy in subclinical glioblastoma.

BACKGROUND: Atrial fibrillation with symptomatic bradycardia, higher grade atrioventricular block, and sinus node disease are all common indications for permanent pacemaker implantation. The most frequent causes of sinus node disease treated with pacemaker implantation involve degenerative structural changes of the sinus node; less often, extrinsic causes (such as damage due to myocardial infarction or heightened parasympathetic nervous system activity) lead to pacemaker implantation. CASE PRESENTATION: A 50-year-old patient with syncope and documented sinoatrial arrest was referred. Neurologic exams (including CT and EEG) revealed no pathologies, so a pacemaker was implanted. Postoperatively, syncope occurred again due to a focal seizure during which sinus rhythm transitioned to atrial pacing by the device. Further neurologic testing revealed focal epilepsy. Six months later, stage IV glioblastoma was diagnosed and the patient was treated surgically. CONCLUSION: Intracerebral tumors should be considered in the differential diagnosis for patients with unexplained sinoatrial block, as well as in patients with repeat syncope after pacemaker implantation. Cranial MRI could aid the diagnostic workup of such cases.

Sinus Node Sparing Novel Hybrid Approach for Treatment of Inappropriate Sinus Tachycardia/Postural Orthostatic Sinus Tachycardia With New Electrophysiological Finding.

The ideal treatment of Inappropriate Sinus Tachycardia (IST) and Postural Orthostatic Tachycardia Syndrome (POTS) still needs to be defined. Medical treatment yields suboptimal results, endocardial ablation of the sinus node (SN) may risk phrenic nerve damage and open heart surgery may be accompanied by unjustified invasive risks. We describe our first experience of 50 consecutive patients (41 females, 22.83 ± 3.91 years) having undergone a novel hybrid thoracoscopic ablation for drug resistant IST (n = 39, 78%) or POTS (n = 11, 22%). The SN was identified with the help of 3D mapping. Surgery was performed through 3 (5 mm) ports from the right side. A minimally invasive approach with a radio frequency bipolar clamp was utilized to a new target sparing the SN region, to isolate the superior and the inferior caval veins, and a crista terminalis line was made. All lines were interconnected. Normal SR was restored in all patients at the end of the procedure. All patients discontinued medication during the follow-up. After a blanking period of 6 months all patients presented stable SR. At a mean of 28.4 ± 1.2 months, normal SN ruction and chronotropic response to exercise was present. In the 11 patients initially diagnosed with POTS, no syncope occurred. During the follow-up, pericarditis was the most common complication (39 patients; 78%) with complete resolution in all cases. In conclusions the preliminary results of our first experience with a SN sparing novel hybrid ablation of IST/POTS, using surgical thoracoscopic video-assisted epicardial ablation combined with concomitant endocardial 3D mapping may prove an efficient and safe therapeutic option in patients with symptomatic drug resistant IST and POTS. Importantly, in our study all patients had a complete resolution of the symptoms and restored normal SN activity.

In utero exposure to nicotine abolishes the postnatal response of the cardiac sodium current to isoproterenol in newborn rabbit atrium.

BACKGROUND: In utero exposure to tobacco smoke is associated with sudden infant death syndrome (SIDS) and cardiac arrhythmias in newborns. The arrhythmogenic mechanisms seem linked to alterations of the cardiac sodium current (INa). We previously reported that in utero exposure to nicotine delays the postnatal development of the heart sinoatrial node in rabbits and altered expression of the sodium channels NaV1.5 and NaV1.1 in the atrium surrounding it. These channels react differently to sympathetic stimulation. OBJECTIVE: The purpose of this study was to test whether nicotine altered the response of INa to stimulation by the ß-adrenoreceptor agonist isoproterenol in atrial myocytes. Our hypothesis is that changes in the sympathetic response of sinoatrial node peripheral cells may create a substrate for arrhythmia. METHODS: Using the patch-clamp technique we measured the effect of nicotine on the response of INa to adrenergic stimulation in isolated cardiomyocytes. RESULTS: Isoproterenol increased INa by 50% in newborn sham rabbits but had no effect in newborn rabbits exposed to nicotine in utero. Our data also show that nicotine increases the late sodium current, an effect that may promote QT prolongation. CONCLUSION: We provide the first evidence linking fetal exposure to nicotine to long-term alterations of INa response to isoproterenol. These changes may impair INa adaptation to sympathetic tone and prevent awakening from sleep apnea, thus leading to arrhythmias that could potentially be involved in SIDS. Our data also raise concerns about the use of nicotine replacement therapies for pregnant women.

An automated hybrid bioelectronic system for autogenous restoration of sinus rhythm in atrial fibrillation.

Because of suboptimal therapeutic strategies, restoration of sinus rhythm in symptomatic atrial fibrillation (AF) often requires in-hospital delivery of high-voltage shocks, thereby precluding ambulatory AF termination. Continuous, rapid restoration of sinus rhythm is desired given the recurring and progressive nature of AF. Here, we present an automated hybrid bioelectronic system for shock-free termination of AF that enables the heart to act as an electric current generator for autogenous restoration of sinus rhythm. We show that local, right atrial delivery of adenoassociated virus vectors encoding a light-gated depolarizing ion channel results in efficient and spatially confined transgene expression. Activation of an implanted intrathoracic light-emitting diode device allows for termination of AF by illuminating part of the atria. Combining this newly obtained antiarrhythmic effector function of the heart with the arrhythmia detector function of a machine-based cardiac rhythm monitor in the closed chest of adult rats allowed automated and rapid arrhythmia detection and termination in a safe, effective, repetitive, yet shock-free manner. These findings hold translational potential for the development of shock-free antiarrhythmic device therapy for ambulatory treatment of AF.

Interleukin-10 treatment attenuates sinus node dysfunction caused by streptozotocin-induced hyperglycaemia in mice.

Aims: Diabetes, characterized by hyperglycaemia, causes sinus node dysfunction (SND) in several rodent models. Interleukin (IL)-10, which is a potent anti-inflammatory cytokine, has been reported to decrease in obese and diabetic patients. We tested the hypothesis that administration of IL-10 inhibits the development of SND caused by hyperglycaemia in streptozotocin (STZ)-induced diabetic mice. Methods and results: Six-week old CL57/B6 (WT) mice were divided into the following groups: control, STZ injection, and STZ injection with systemic administration of IL-10. IL-10 knockout mice were similarly treated. STZ-induced hyperglycaemia for 8 weeks significantly depressed serum levels of IL-10, but increased several proinflammatory cytokines in WT mice. STZ-induced hyperglycaemia-reduced resting heart rate (HR), and attenuated HR response to isoproterenol in WT mice. In isolated perfused heart experiments, corrected-sinus node recovery time was prolonged in WT mice with STZ injection. Sinus node tissue isolated from the WT-STZ group showed fibrosis, abundant infiltration of macrophages, increased production of reactive oxygen species (ROS), and depressed hyperpolarization activated cyclic nucleotide-gated potassium channel 4 (HCN4). However, the changes observed in the WT-STZ group were significantly attenuated by IL-10 administration and were further exaggerated in IL-10 knockout mice. In cultured cells, preincubation of IL-10 suppressed hyperglycaemia-induced apoptotic and profibrotic signals, and overproduction of ROS. IL-10 markedly inhibited the high glucose-induced p38 activation, and activated signal transducer and activator of transcription (STAT) 3 phosphorylation. Conclusions: Our results suggest that IL-10 attenuates ROS production, inflammation and fibrosis, and plays an important role in the inhibition of hyperglycaemia-induced SND by suppression of HCN4 downregulation. In addition, IL-10-mediated inhibition of p38 is dependent on STAT3 phosphorylation.

Development of a Rat Model of Sick Sinus Syndrome Using Pinpoint Press Permeation.

OBJECTIVE: Sick sinus syndrome (SSS) is one of the most common causes of cardiac impairment necessitating pacemaker implantation. However, studies of SSS pathogenesis are neither comprehensive nor conclusive due to limited success in achieving a stable rat SSS model. Here, we modified pinpoint press permeation to establish a stable rat SSS model. METHODS: We randomly assigned 138 male Sprague-Dawley rats into three groups: normal control (n = 8), sham (n = 10), and SSS (n = 120). Postoperatively, the SSS group was further divided into SSSA (n = 40), SSSB (n = 40), and SSSC (n = 40), based on reduction in heart rates by 20-30%, 31-40%, and 41-50%, respectively. We also assessed histomorphological characteristics and hyperpolarization-activated cyclic nucleotide-gated cation channel 4 (HCN4) expression in the sinoatrial node (SAN) at 1, 2, 3, and 4 weeks after surgery. RESULTS: Mortality was statistically higher in SSSC compared to SSSA and SSSB (7.5% versus 90.0% and 87.5%; P < 0.05). Heart rate in SSSA was gradually restored to preoperative levels by week 4 after surgery. In contrast, heart rate in SSSB was stable at 2-3 weeks after surgery. However, we observed that the tissues and cells in SAN were severely injured and also found a time-dependent increase in collagen content and atrium myocardium in SSSB. HCN4 expression was significantly reduced at all 4 time points in SSSB, with statistically significant differences among the groups (P < 0.01). CONCLUSION: We successfully developed a rat SSS model that was sustainable for up to 4 weeks.

Sinoatrial node toxicity after stereotactic ablative radiation therapy to lung tumors.

PURPOSE: Stereotactic ablative radiation therapy (SABR) is an established treatment for selected lung tumors. Sinoatrial node (SAN) toxicity after thoracic SABR has not been reported in the literature. We sought to understand the risk of SAN toxicity owing to incidental dose to the SAN from SABR. METHODS AND MATERIALS: We conducted a retrospective review of patients with early-stage lung cancer or limited pulmonary metastases who underwent thoracic SABR to a right-sided central lung tumor (within 2 cm of the mainstem bronchus or other mediastinal structures) between January 2008 and December 2014, analyzed a subset whose treatment imparted dose to the SAN exceeding 10% of the prescription dose, and examined patient and treatment dosimetric characteristics. Mean follow-up interval was 28 months. Time to toxicity was defined from start of SABR. RESULTS: Of 47 patients with central tumors in the right lung treated with SABR reviewed, 13 met our study criteria. A contouring atlas of regional cardiac anatomy was created. One patient treated with SABR for non-small cell lung cancer at the right hilum developed symptomatic sick sinus syndrome, requiring pacemaker placement 6 months after treatment. Her acute presentation and short interval between SABR and onset of symptoms suggest that SAN toxicity was likely due to radiation-induced injury. Both her age and mean dose to her SAN were the third highest in our cohort. She remained free from cancer progression at 24 months' follow-up. Twelve additional patients who received significant dose to the SAN from SABR did not develop toxicity. CONCLUSION: While uncommon, SAN toxicity from SABR to right-sided central thoracic tumors should be recognized and followed in future studies.

In-utero exposure to nicotine alters the development of the rabbit cardiac conduction system and provides a potential mechanism for sudden infant death syndrome.

In-utero exposure to tobacco smoke remains the highest risk factor for sudden infant death syndrome (SIDS). To alleviate the risks, nicotine replacement therapies are often prescribed to women who wish to quit smoking during their pregnancy. Cardiac arrhythmias is considered the final outcome leading to sudden death. Our goal in this study was to determine if exposing rabbit fetus to nicotine altered the cardiac conduction system of newborn kittens in a manner susceptible to cause SIDS. Using neuronal markers and a series of immunohistological and electrophysiological techniques we found that nicotine delayed the development of the cardiac pacemaker center (sinoatrial node) and decreased its innervation. At the molecular level, nicotine favored the expression of cardiac sodium channels with biophysical properties that will tend to slow heart rate and diminish electrical conduction. Our results show that alterations of the cardiac sodium current may contribute to the bradycardia, conduction disturbances and other cardiac arrhythmias often associated to SIDS and raise awareness on the use of replacement therapy during pregnancy.

Prolonged Sinus Pauses upon Termination of Paroxysmal Atrial Fibrillation: Abnormal Right Atrial Electrophysiologic and Electroanatomic Findings.

The efficacy of pulmonary vein antral isolation for patients with prolonged sinus pauses (PSP) on termination of atrial fibrillation has been reported. We studied the right atrial (RA) electrophysiologic and electroanatomic characteristics in such patients. Forty patients underwent electroanatomic mapping of the RA: 13 had PSP (group A), 13 had no PSP (group B), and 14 had paroxysmal supraventricular tachycardia (control group C). Group A had longer P-wave durations in lead II than did groups B and C (115.5 ± 15.4 vs 99.5 ± 10.9 vs 96.5 ± 10.4 ms; P=0.001), and RA activation times (106.8 ± 13.8 vs 99 ± 8.7 vs 94.5 ± 9.1 s; P=0.02). Group A's PP intervals were longer during adenosine triphosphate testing before ablation (4.6 ± 2.3 vs 1.7 ± 0.6 vs 1.5 ± 1 s; P <0.001) and after ablation (4.7 ± 2.5 vs 2.2 ± 1.4 vs 1.6 ± 0.8 s; P <0.001), and group A had more complex electrograms (11.4% ± 5.4% vs 9.3% ± 1.6% vs 5.8% ± 1.6%; P <0.001). Compared with group C, group A had significantly longer corrected sinus node recovery times at a 400-ms pacing cycle length after ablation, larger RA volumes (100.1 ± 23.1 vs 83 ± 22.1 mL; P=0.04), and lower conduction velocities in the high posterior (0.87 ± 0.13 vs 1.02 ± 0.21 mm/ms; P=0.02) and high lateral RA (0.89 ± 0.2 vs 1.1 ± 0.35 mm/ms; P=0.04). We found that patients with PSP upon termination of atrial fibrillation have RA electrophysiologic and electroanatomic abnormalities that warrant post-ablation monitoring.

Biological pacemakers: Concepts and techniques.

The sinoatrial (SA) node is the dominant pacemaker of the heart which initiates the process of impulse generation in the cardiac tissue, thereby defining the rate and rhythm of cardiac contraction. The automaticity of the conduction cells in the SA node is due to ion channels which are inter-linked by molecular, histological and electrophysiological mechanisms causing spontaneous diastolic depolarization and generation of an impulse. The SA nodal action potentials are then transmitted to the ventricles by electrical coupling of the myocytes in different areas of the heart. Regulatory pathways overseeing cardiac impulse generation and conduction provide effective and safe pacing, and help maintain the rate according to the physiological demands of the individual's body. Failure of physiological pacing due to any pathology in the SA or atrioventricular node necessitates implantation of a permanent pacemaker. Implantable pacemakers, despite technological advances, are not without practical limitations including a defined battery life leading to lead and/or generator replacement at periodic intervals, vascular complications, occasional component failure, electronic interference from external/ internal sources, e.g. myopotentials, electromechanical interference, etc., inadequate or incomplete physiological rate response to autonomic influences (devices have certain algorithms to address these issues) and most importantly the risk of infection. A biological pacemaker is therefore emerging as a promising technique to counter these challenges.

Differential effect of ganglionic plexi ablation in a patient with neurally mediated syncope and intermittent atrioventricular block.

AIMS: In patients with severe neurally mediated syncope (NMS), radiofrequency catheter ablation (RFA) of ganglionic plexi (GP) has been proposed as a new therapeutic approach. Cardio-inhibitory response during NMS is usually related to the sinoatrial (SA) and less frequently to atrioventricular (AV) node. Differential effect of GP ablation on SA and AV node is poorly understood. METHODS AND RESULTS: We report a case of a 35-year-old female with frequent symptomatic episodes of advanced AV block treated by anatomically guided RFA at empirical sites of GPs. After RFA at the septal portion of the right atrium-superior vena cava junction, heart rate accelerated from 62 to 91 beats/min and PR interval prolonged from 213 to 344 ms. Sustained first-degree AV block allowed to observe directly the effects of subsequent RFA on the AV nodal properties. Subsequent RFA at right- and left-sided aspects of the inter-atrial septum had no further effect on heart rate and PR interval. Ablation at the inferior left GP was critical for restoration of normal AV conduction (final PR interval of 187 ms). No bradycardia episodes were observed by implantable loop recorder during the follow-up of 10 months and the patient was symptomatically improved. CONCLUSION: This is the first clinical case showing the differential effect of GP ablation on SA and AV nodal function, and critical importance of targeting the GP at the postero-inferior left atrium. The successful procedure corroborates clinical utility of ablation treatment instead of pacemaker implantation in selected patients with cardio-inhibitory NMS.

Outcome and survival in canine sick sinus syndrome and sinus node dysfunction: 93 cases (2002-2014).

INTRODUCTION: To evaluate the clinical presentation, diagnosis, treatment, and outcomes of a group of dogs with sinoatrial node abnormalities. ANIMALS: Ninety-three client-owned dogs at a referral institution. MATERIALS AND METHODS: Medical records were reviewed for clinical history, diagnostic testing, and medical or permanent artificial pacemaker (PAP) treatment. Owners or veterinarians were contacted for long-term follow-up. RESULTS: Sixty-one dogs were symptomatic for their bradyarrhythmia and were diagnosed with sick sinus syndrome (SSS). Thirty-two dogs were asymptomatic for their bradyarrhythmia and were diagnosed with sinus node dysfunction (SND). Miniature Schnauzers, West Highland White terriers, Cocker spaniels, and female dogs were overrepresented. Medical management with positive chronotropic drugs successfully controlled syncope long-term in 54% of SSS dogs, and acted as a bridge to PAP in 20%. Positive atropine response predicted medical treatment success. Forty-six percent of SSS dogs eventually underwent PAP implantation. Median survival time was approximately 18 months in SND and SSS dogs regardless of treatment strategy. Congestive heart failure (CHF) associated with progressive valvular heart disease occurred commonly in all groups, particularly in dogs with bradycardia-tachycardia syndrome. CONCLUSIONS: Sinus node dysfunction and SSS represent a spectrum of sinoatrial node disease, which for some dogs may also involve a component of autonomic dysfunction. Dogs with SND do not require treatment. Dogs with SSS often require treatment to reduce the frequency of syncope; medical management is often useful, particularly in atropine responsive dogs. Prognosis of SSS with treatment is good, though development of CHF does not appear to be mitigated by treatment.

Zebrafish heart as a model to study the integrative autonomic control of pacemaker function.

The cardiac pacemaker sets the heart's primary rate, with pacemaker discharge controlled by the autonomic nervous system through intracardiac ganglia. A fundamental issue in understanding the relationship between neural activity and cardiac chronotropy is the identification of neuronal populations that control pacemaker cells. To date, most studies of neurocardiac control have been done in mammalian species, where neurons are embedded in and distributed throughout the heart, so they are largely inaccessible for whole-organ, integrative studies. Here, we establish the isolated, innervated zebrafish heart as a novel alternative model for studies of autonomic control of heart rate. Stimulation of individual cardiac vagosympathetic nerve trunks evoked bradycardia (parasympathetic activation) and tachycardia (sympathetic activation). Simultaneous stimulation of both vagosympathetic nerve trunks evoked a summative effect. Effects of nerve stimulation were mimicked by direct application of cholinergic and adrenergic agents. Optical mapping of electrical activity confirmed the sinoatrial region as the site of origin of normal pacemaker activity and identified a secondary pacemaker in the atrioventricular region. Strong vagosympathetic nerve stimulation resulted in a shift in the origin of initial excitation from the sinoatrial pacemaker to the atrioventricular pacemaker. Putative pacemaker cells in the sinoatrial and atrioventricular regions expressed adrenergic ß2 and cholinergic muscarinic type 2 receptors. Collectively, we have demonstrated that the zebrafish heart contains the accepted hallmarks of vertebrate cardiac control, establishing this preparation as a viable model for studies of integrative physiological control of cardiac function by intracardiac neurons.

Registro de arritmias em pacientes com marcapassos e doença renal crônica de leve a moderada (RYCKE): resultados de um estudo de coorte observacional / Register of arrhythmias in patients with pacemakers and mild to moderate chronic kidney disease (RYCKE): results from an observational cohort study

O presente estudo examinou pacientes submetidos a implante de marcapasso dupla-câmara em decorrência de doença do nó sinusal ou bloqueio atrioventricular de 3o ou 2o graus do tipo 2 na doençarenal crônica em estágios 2, 3 e 4. O estudo teve como objetivo registrar os eventos arrítmicos durante 12 mesesde acompanhamento e comparar a incidência e a gravidade deles nas diferentes fases da doença renal crônica.Método: No total, 305 pacientes foram avaliados a cada 4 meses até 12 meses de acompanhamento. Os eventosarrítmicos foram avaliados em cada visita de acompanhamento. Resultados: Dentro do mesmo grupo de estágio da doença renal crônica não houve diferença entre as causas doença do nó sinusal e bloqueio atrioventricular, a respeito da ocorrência de qualquer arritmia. No entanto, menor incidência de taquicardia atrial/fibrilação atrial foi observada para todas as comparações entre todos os pacientes e os mesmos subgrupos em pacientes no estágio 2 (total: 58%; doença do nó sinusal: 63%; bloqueio atrioventricular: 51%), comparativamente aos estágios 3 (total:87%, P < 0,0001; doença do nó sinusal: 89%, P = 0,0020; bloqueio atrioventricular: 84%, P = 0,0019) e 4 (total: 85%, P < 0,0001; doença do nó sinusal: 81%, P = 0,0409; bloqueio atrioventricular: 90%, P < 0,0001). Em relação à taquicardia ventricular não sustentada/taquicardia ventricular sustentada, foi observada incidência mais elevada para todas as comparações entre todos os pacientes e os mesmos subgrupos em pacientes no estágio 4 (total: 32%; doença do nó sinusal: 16%; bloqueio atrioventricular: 16%), comparativamente aos estágios 3 (total: 11%, P = 0,0007; doença do nó sinusal: 9%, P = 0,0110; bloqueio atrioventricular: 14%, P = 0,0441) e 2 (total: 3%, P < 0,0001; doença do nó sinusal: 3%, P < 0,0001; bloqueio atrioventricular: 4%, P < 0,0001). Conclusão: Nossos resultados sugerem que quanto mais avançado o estágio da doença renal crônica maior a incidência de arritmias malignas...

The present study evaluated patients who had received a dual chamber pacemaker implant due to sinus node disease or 3rd/2nd degree type 2 atrioventricular block in chronic kidney disease stages 2, 3 and 4. The study was aimed at registering arrhythmic events for 12 months of follow-up and comparing their incidence and severity in different stages of chronic kidney disease. Method: Three hundred and five patients were evaluated every 4 months up to 12 months of follow-up. Arrhythmic events were assessed at each follow-up visit. Results: Within the same chronic kidney disease stage group there was no difference between the causes ofsinus node disease and atrioventricular block for the occurrence of any arrhythmia. However, a lower incidence of atrial fibrillation/tachycardia was observed for all comparisons among all patients and the same subgroups in stage 2 patients (total: 58%; sinus node disease: 63%; atrioventricular block: 51%) compared to stages 3 (total: 87%,P < 0.0001; sinus node disease: 89%, P = 0.0020; atrioventricular block: 84%, P = 0.0019) and 4 (total: 85%,P < 0.0001; sinus node disease: 81%, P = 0.0409; atrioventricular block: 90%, P < 0.0001). Regarding nonsustained/ sustained ventricular tachycardia, a higher incidence was observed for all comparisons among all patients and the same subgroups in stage 4 patients (total: 32%; sinus node disease: 16%; atrioventricular block: 16%) compared to stages 3 (total: 11%, P = 0.0007; sinus node disease: 9%, P = 0.0110; atrioventricular block: 14%, P = 0.0441) and 2 (total: 3%, P < 0.0001; sinus node disease: 3%, P < 0.0001; atrioventricular block: 4%,P < 0.0001). Conclusion: Our findings suggest that the more advanced the stage of chronic kidney disease, thegreater the incidence of malignant arrhythmias...

Hyperhomocysteinemia Alters Sinoatrial and Atrioventricular Nodal Function: Role of Magnesium in Attenuating These Effects.

Patients with hyperhomocysteinemia (HHcy), or elevated plasma homocysteine (Hcy), are at higher risk of developing arrhythmias and sudden cardiac death; however, the mechanisms are unknown. In this study, the effects of HHcy on sinus node function, atrioventricular conduction, and ventricular vulnerability were investigated by electrophysiological (EP) analysis, and the role of magnesium (Mg(2+)), an endogenous N-methyl-D-aspartate (NMDA) receptor antagonist, in attenuating EP changes due to HHcy was explored. Wild-type mice (WT) and mice receiving Hcy in the drinking water for 12 weeks (DW) were subjected to electrocardiographic and EP studies. DW compared to WT had significantly shorter RR, PR, QT, and HV intervals, corrected sinus node recovery times (CSNRT), Wenckebach periodicity (WP), atrioventricular nodal effective refractory periods (AVNERP), and right ventricular effective refractory periods (RVERP). To examine the role of Mg(2+) in mitigating conduction changes in HHcy, WT, DW, and heterozygous cystathionine-ß-synthase knockout mice (CBS (+/-) ) were subjected to repeat EP studies before and after administration of low-dose magnesium sulfate (20 mg/kg). Mg(2+) had no effect on EP variables in WT, but significantly slowed CSNRT, WP, and AVNERP in DW, as well as WP and AVNERP in CBS (+/-) . These findings suggest that ionic channels modulated by Mg(2+) may contribute to HHcy-induced conduction abnormalities.