Disruption of mitochondria-sarcoplasmic reticulum microdomain connectomics contributes to sinus node dysfunction in heart failure.

The sinoatrial node (SAN), the leading pacemaker region, generates electrical impulses that propagate throughout the heart. SAN dysfunction with bradyarrhythmia is well documented in heart failure (HF). However, the underlying mechanisms are not completely understood. Mitochondria are critical to cellular processes that determine the life or death of the cell. The release of Ca2+ from the ryanodine receptors 2 (RyR2) on the sarcoplasmic reticulum (SR) at mitochondria-SR microdomains serves as the critical communication to match energy production to meet metabolic demands. Therefore, we tested the hypothesis that alterations in the mitochondria-SR connectomics contribute to SAN dysfunction in HF. We took advantage of a mouse model of chronic pressure overload-induced HF by transverse aortic constriction (TAC) and a SAN-specific CRISPR-Cas9-mediated knockdown of mitofusin-2 (Mfn2), the mitochondria-SR tethering GTPase protein. TAC mice exhibited impaired cardiac function with HF, cardiac fibrosis, and profound SAN dysfunction. Ultrastructural imaging using electron microscope (EM) tomography revealed abnormal mitochondrial structure with increased mitochondria-SR distance. The expression of Mfn2 was significantly down-regulated and showed reduced colocalization with RyR2 in HF SAN cells. Indeed, SAN-specific Mfn2 knockdown led to alterations in the mitochondria-SR microdomains and SAN dysfunction. Finally, disruptions in the mitochondria-SR microdomains resulted in abnormal mitochondrial Ca2+ handling, alterations in localized protein kinase A (PKA) activity, and impaired mitochondrial function in HF SAN cells. The current study provides insights into the role of mitochondria-SR microdomains in SAN automaticity and possible therapeutic targets for SAN dysfunction in HF patients.

Inherited and Acquired Rhythm Disturbances in Sick Sinus Syndrome, Brugada Syndrome, and Atrial Fibrillation: Lessons from Preclinical Modeling.

Rhythm disturbances are life-threatening cardiovascular diseases, accounting for many deaths annually worldwide. Abnormal electrical activity might arise in a structurally normal heart in response to specific triggers or as a consequence of cardiac tissue alterations, in both cases with catastrophic consequences on heart global functioning. Preclinical modeling by recapitulating human pathophysiology of rhythm disturbances is fundamental to increase the comprehension of these diseases and propose effective strategies for their prevention, diagnosis, and clinical management. In silico, in vivo, and in vitro models found variable application to dissect many congenital and acquired rhythm disturbances. In the copious list of rhythm disturbances, diseases of the conduction system, as sick sinus syndrome, Brugada syndrome, and atrial fibrillation, have found extensive preclinical modeling. In addition, the electrical remodeling as a result of other cardiovascular diseases has also been investigated in models of hypertrophic cardiomyopathy, cardiac fibrosis, as well as arrhythmias induced by other non-cardiac pathologies, stress, and drug cardiotoxicity. This review aims to offer a critical overview on the effective ability of in silico bioinformatic tools, in vivo animal studies, in vitro models to provide insights on human heart rhythm pathophysiology in case of sick sinus syndrome, Brugada syndrome, and atrial fibrillation and advance their safe and successful translation into the cardiology arena.

A Multicenter External Validation of a Score Model to Predict Risk of Events in Patients With Brugada Syndrome.

A multivariate risk score model was proposed by Sieira et al in 2017 for sudden death in Brugada syndrome; their validation in 150 patients was highly encouraging, with a C-index of 0.81; however, this score is yet to be validated by an independent group. A total of 192 records of patients with Brugada syndrome were collected from 2 centers in the United Kingdom and retrospectively scored according to a score model by Sieira et al. Data were compiled summatively over follow-up to mimic regular risk re-evaluation as per current guidelines. Sudden cardiac death survivor data were considered perievent to ascertain the utility of the score before cardiac arrest. Scores were compared with actual outcomes. Sensitivity in our cohort was 22.7%, specificity was 57.6%, and C-index was 0.58. In conclusion, up to 75% of cardiac arrest survivors in this cohort would not have been offered a defibrillator if evaluated before their event. This casts doubt on the utility of the score model for primary prevention of sudden death. Inherent issues with modern risk scoring strategies decrease the likelihood of success even in robustly designed tools such as the Sieira score model.

Patient with sick sinus syndrome and implanted dual-chamber pacemaker with reduced P-wave duration following low interatrial septal pacing: Case report.

INTRODUCTION: A dual-chamber pacemaker (DDD/R) for a sinus node disease is sometimes referred to as a physiological pacemaker as it maintains atrioventricular synchrony, however several clinical trials have proved its inferiority to a nonphysiological single-chamber ventricular back-up pacing. PATIENT CONCERNS: A subject of the study is a 74-year-old woman with a sick sinus syndrome (SSS) and a previously implanted physiological DDD/R pacemaker. The SSS was diagnosed because of patient's very slow sinus rhythm of about 36 bpm, and due to several episodes of dizziness. After the DDD/R implantation the percentage of atrial pacing approached 100%, with almost none ventricular pacing. DIAGNOSES: Sick sinus syndrome, complete Bachmann's bundle block, atrial fibrillation, atrial flutter. INTERVENTIONS: The patient was previously implanted with a physiological DDD/R pacemaker. Several years after the implantation, the atrial fibrillation was diagnosed and the pulmonary vein isolation was then performed by cryoablation. During the follow-up after pulmonary vein isolation, the improvement of mitral filling parameters was assessed using echocardiography. Shortly thereafter the patient developed the persistent paroxysm of a typical atrial flutter which was successfully terminated using a radiofrequency ablation. No recurrence thereof has been observed ever since (24 months). OUTCOMES: The atrial electrode of the pacing system was implanted within the low interatrial septal region that resulted in a reduced P-wave duration compared to native sinus rhythm P-waves. The said morphology was deformed because of the complete Bachmann bundle block. That approach, despite a nonphysiological direction of an atrial activation, yielded relatively short P-waves (paced P-wave: 179 ms vs intrinsic sinus P-wave: 237 ms). It also contributed to a significantly shorter PR interval (paced PR: 204 ms vs sinus rhythm PR: 254 ms). CONCLUSIONS: The authors took into consideration different aspects of alternative right atrial pacing sites. This report has shown that in some patients with a sinus node disease, low interatrial septal pacing can reduce the P-wave duration but does not prevent from the development of atrial arrhythmias.

Sinus Node Dysfunction.

Sinus node dysfunction, previously known as sick sinus syndrome, describes disorders related to abnormal conduction and propagation of electrical impulses at the sinoatrial node. An abnormal atrial rate may result in the inability to meet physiologic demands, especially during periods of stress or physical activity. Sinus node dysfunction may occur at any age, but is usually more common in older persons. The causes of sinus node dysfunction are intrinsic (e.g., degenerative idiopathic fibrosis, cardiac remodeling) or extrinsic (e.g., medications, metabolic abnormalities) to the sinoatrial node. Many extrinsic causes are reversible. Electrocardiography findings include sinus bradycardia, sinus pauses or arrest, sinoatrial exit block, chronotropic incompetence, or alternating bradycardia and tachycardia (i.e., bradycardia-tachycardia syndrome). Clinical symptoms result from the hypoperfusion of end organs. About 50% of patients present with cerebral hypoperfusion (e.g., syncope, presyncope, lightheadedness, cerebrovascular accident). Other symptoms include palpitations, decreased physical activity tolerance, angina, muscular fatigue, or oliguria. A diagnosis is made by directly correlating symptoms with a bradyarrhythmia and eliminating potentially reversible extrinsic causes. Heart rate monitoring using electrocardiography or ambulatory cardiac event monitoring is performed based on the frequency of symptoms. An exercise stress test should be performed when symptoms are associated with exertion. The patient's inability to reach a heart rate of at least 80% of their predicted maximum (220 beats per minute - age) may indicate chronotropic incompetence, which is present in 50% of patients with sinus node dysfunction. First-line treatment for patients with confirmed sinus node dysfunction is permanent pacemaker placement with atrial-based pacing and limited ventricular pacing when necessary.

Bradyarrhythmias in patients with SARS-CoV-2 infection: A narrative review and a clinical report.

Several cardiovascular diseases and arrhythmic disorders have been described in COVID-19 era as likely related to SARS-CoV-2 infection. The prognostic relevance of bradyarrhythmias during the infection has not been yet described and no data are available about long-term heart conduction disorders. A review of literature concerning the association between hypokinetic arrhythmias and COVID-19 from January 2020 to February 2021 was performed. The key-words used for the research were: "sinus node disfunction," "sick sinus syndrome (SSS)," "sino-atrial block," "atrio-ventricular block (AVB)," "bradyarrhythmias," and "COVID-19″ or "SARS-CoV-2.″ Excluding "relative bradycardia," a total of 38 cases of bradyarrhythmia related to SARS-CoV-2 infection have been described, even in very young people, requiring in many cases a definitive pacemaker implantation. Furthermore, we report a case of non-hospitalized 47-years old man with a SSS developed as a consequence of mild SARS-CoV-2 infection. While in all described cases heart conduction disorders were found at presentation of the infection or during hospitalization for COVID-19, in our case the diagnosis of SSS was made after the resolution of the infection. Although rarely, heart conduction disorders may occur during COVID-19 and the present case highlights that a cardiological follow up may be desirable even after the resolution of infection, especially in the presence of symptoms suggesting a possible heart involvement.

Yixin-Fumai granules improve sick sinus syndrome in aging mice through Nrf-2/HO-1 pathway: A new target for sick sinus syndrome.

ETHNOPHARMACOLOGICAL RELEVANCE: Yixin-Fumai granules (YXFMs)-composed of Ginseng quinquefolium (L.) Alph. Wood, Ophiopogon japonicus (Thunb.) Ker Gawl, Schisandra arisanensis Hayata, Astragalus aaronsohnianus Eig, Salvia cryptantha Montbret & Aucher ex Benth, and Ligusticum striatum DC-are compound granules used in traditional Chinese medicine to increase heart rate and thus treat bradyarrhythmia. It may be effective in treating sick sinus syndrome (SSS). AIM: To observe the effect of YXFMs on aging-induced SSS in mice and explore whether this effect is related to the Nrf-2/HO-1 signaling pathway. MATERIALS AND METHODS: Mice with a significant decrease in the heart rate due to natural aging were selected to construct an SSS model. After the mice were administered YXFMs, the damage to their sinoartrial node (SAN) was assessed through electrocardiography, Masson's trichrome staining, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Dihydroethidium staining and immunofluorescence staining were used to assay reactive oxygen species (ROS) content and HCN4, respectively. Moreover, to observe the effects of YXFMs in vitro, the HL-1 cell line, derived from mouse atrial myocytes, was used to simulate SAN pacemaker cells, with H2O2 used as the cellular oxidative stress (OS) inducer. 2,7-Dichlorodihydrofluorescein diacetate staining was used to assay ROS content, whereas immunofluorescence staining and Western blotting were used to elucidate the related protein expression. Finally, mice were injected the Nrf-2 inhibitor ML385 to reversely verify the effects of YXFMs. RESULTS: In our in vivo experiments, YXFMs significantly inhibited aging-induced SSS, shortened the R-R interval, increased heart rate, alleviated fibrosis, reduced apoptosis rate and ROS content, and promote HCN4 expression in the SAN. In our in vitro experiments, YXFMs significantly inhibited H2O2-induced cell peroxidation damage, promoted Nrf-2 activation and nuclear metastasis, increased HO-1 expression- thereby inhibiting ROS accumulation-and finally, upregulated HCN4 expression through the inhibition of histone deacetylase 4 (HDAC4) expression and its nuclear metastasis. Finally, injection of the Nrf-2 inhibitor ML385 after YXFMs administration inhibited their protective effect in the mice. CONCLUSION: Here, we elaborated on the relationship between aging-induced SSS and the Nrf-2/HO-1 pathway for the first time and proposed that YXFMs improve SSS via the Nrf-2/HO-1 axis. Specifically, YXFMs promoted Nrf-2 activation and plasma-nuclear transfer to enhance HO-1 expression via the Nrf-2/HO-1 axis. This inhibited OS and reduced ROS accumulation in the SAN, and then, through the ROS/HDAC4 axis, reduced HDAC4 expression and plasma-nuclear transfer. Thereby, the OS-induced HCN4 loss in the SAN was inhibited-improving the function of If channel and thus producing SAN protection effect against SSS and improving the heart rate and R-R interval. In the future, we plan to use bioinformatics analysis technology to execute the next step of our research, namely to determine the effect of isolated, purified components of YXFMs in SSS, to increase its efficiency and reduce the toxicity of YXFMs.

Durable Physiological Changes and Decreased Syncope Burden 12 Months After Unifocal Right-Sided Ablation Under Computed Tomographic Guidance in Patients With Neurally Mediated Syncope or Functional Sinus Node Dysfunction.

[Figure: see text].

Sleep Rate Mode of Pacemaker-Dependent Patients with Sick Sinus Syndrome Increases Dipper Blood Pressure and Dipper Heart Rate Patterns.

Cardiovascular event rates of patients with a dipper blood pressure (BP) and dipper heart rate (HR) pattern are lower than those of patients with nondipper BP and HR patterns. However, how the pacemaker mode affects the diurnal BP and HR patterns remains unclear.We enrolled nine patients (average age 74.4 ± 6.6 years, 4 males and 5 females) with sick sinus syndrome who required atrial pacing. We investigated sequential 6-month pacing regimens (DDD mode at 60 bpm and sleep rate mode). We set the lower rate of sleep rate mode as follows: 60 bpm during the daytime and 50 bpm during the nighttime. The order of pacing mode was randomized, with crossover design. Ambulatory BP monitoring was performed at baseline, 6 months, and 12 months, BP category was classified into four groups (extreme dipper, dipper, nondipper, and riser pattern), and HR was classified into dipper and nondipper patterns.Nighttime HR during the sleep rate mode was significantly lower than that at DDD (57.1 ± 6.2 versus 63.5 ± 3.8 bpm, P = 0.001). The dipper HR pattern was increased in the sleep rate mode compared with those at baseline or DDD mode (versus baseline: 89% versus 44%, P = 0.035; versus DDD: 89% versus 22%, P = 0.004). The dipper BP pattern significantly increased in the sleep rate mode compared with the baseline (56% versus 11%, P = 0.035), but the difference between the sleep rate mode and DDD mode was statistically marginal (56% versus 22%, P = 0.081).The pacemaker settings in the sleep rate mode increased the dipper HR and BP patterns in pacemaker-dependent patients with sick sinus syndrome.

Instantaneous and averaged heart rate profiles: Developing strategies for programming pacing rates in dogs.

Pacemakers use heart rate histograms (% beats) and sensor indicated rate histograms (% time) to illustrate rate distributions. When programmed to the rate adaptive modes, these data are used to determine the appropriateness of rate response to activity. These histograms are generated from instantaneous heart rate calculations. In humans, such data are compared to known histographic rate profiles. Such rate profiles during 24 h in the dog are not available. Moreover, data representation differ between Holter monitoring and pacemakers making comparisons challenging. The rate distribution in dogs >7-years of age was determined over 24 h using instantaneous and rolling average heart rate. Such data could serve as a guide to programming pacing rates for dogs. Sinus arrhythmia resulted in dissimilar heart rate profiles depending on the method of determining rate. The long intervals of sinus arrhythmia resulted in median values for the percent of time with an instantaneous heart rate of <50 beats/min (bpm) of 15%, whereas a rolling average heart rate of <50 bpm was 0.2%. Based on the cumulative time of the rolling average rate, dogs spent 26.3% of the day between 70-90 bpm with rates <65 bpm and >90 bpm approximating 30% for each. Rates >160 bpm were uncommon (<1%). However, high variability existed between dogs. This study demonstrated the shortcomings of both instantaneous and averaging methods to evaluate heart rate profiles in the dog and that both methods should be incorporated when making pacing rate decisions during programming.

Adaptation of ventricular repolarization time following abrupt changes in heart rate: comparisons and reproducibility of repeated atrial and ventricular pacing.

Adequate adaptation of ventricular repolarization (VR) duration to changes in heart rate (HR) is important for cardiac electromechanical function and electrical stability. We studied the QT and QTpeak adaptation in response to abrupt start and stop of atrial and ventricular pacing on two occasions with an interval of at least 1 mo in 25 study subjects with permanent pacemakers. Frank vectorcardiography was used for data collection. Atrial or ventricular pacing was performed for 8 min aiming at a cycle length (CL) of 500 ms. We measured the immediate response (IR), the time constant (τ) of the exponential phase, and T90 End, the time to reach 90% change of QT and QTpeak from baseline to steady state during and after pacing. During atrial pacing, the CL decreased on average 45% from mean (SD) 944 (120) to 518 (46) ms and QT decreased on average 18% from 388 (20) to 318 (17) ms. For QT, T90 End was 103 (24) s and 126 (15) s after start versus stop of atrial pacing; a difference of 24 (27) s (P = 0.006). The response pattern was similar for τ but IR did not differ significantly between pacing start and stop. The response pattern was similar for QTpeak and also for QT and QTpeak following ventricular pacing start and stop. The coefficients of variation for repeated measures were 7%-21% for T90 End and τ. In conclusion, the adaptation of VR duration was significantly more rapid following increasing than decreasing HR and intraindividually a relatively reproducible process.NEW & NOTEWORTHY We studied the duration of ventricular repolarization (VR) adaptation and its hysteresis, following increasing and decreasing heart rate by abrupt start and stop of 8-min atrial or ventricular pacing in study subjects with permanent pacemakers and repeated the protocol with ≥1 mo interval, a novel approach. VR adaptation was significantly longer following decreasing than increasing heart rate corroborating previous observations. Furthermore, VR adaptation was intraindividually a reproducible and, hence, robust phenomenon, a novel finding.

Baroreflex Sensitivity in Patients With Atrial Fibrillation.

Background It has been reported that atrial fibrillation (AF) may contribute to impairment of baroreflex sensitivity (BRS). However, the difference of BRS between patients with persistent AF (PeAF) and those with paroxysmal AF (PAF) is unknown. We tested the hypothesis that patients with PeAF have a more impaired BRS compared with those with PAF. Methods and Results From October 2015 onwards, a total of 67 patients (14 women [20.9%]; mean age 65.2±10.1 years) with PAF (n=46, 68.7%) and PeAF (n=21, 31.3%), who underwent catheter ablation, were prospectively enrolled. The baseline BRS was evaluated during sinus rhythm. The baseline BRS in patients with PeAF was significantly lower than those with PAF (2.97 [0.52-6.62] ms/mm Hg versus 4.70 [2.36-8.37] ms/mm Hg, P=0.047). The BRS was significantly depressed after catheter ablation in all the patients (4.66 [1.80-7.37] ms/mm Hg versus 0.55 [-0.15 to 1.22] ms/mm Hg, P<0.001). However, the depression of BRS because of catheter ablation appeared attenuated in patients with PeAF when compared with those with PAF. The number of patients who did not show depression of BRS was significantly greater, that is, patients with PeAF (3/12, 25%) than those with PAF (0/46, 0%, P<0.01). Conclusions Our findings demonstrated that the baseline BRS was more depressed in patients with PeAF compared with PAF. Catheter ablation depressed BRS irrespective of the type of AF, with a greater effect in patients with PAF than PeAF.

VVI pacing with normal QRS duration and ventricular function: MOST trial findings relevant to leadless pacemakers.

BACKGROUND: Leadless pacemakers (LPs) provide ventricular pacing without the risks associated with transvenous leads and device pockets. LPs are appealing for patients who need pacing, but do not need defibrillator or cardiac resynchronization therapy. Most implanted LPs provide right ventricular pacing without atrioventricular synchrony (VVIR mode). The Mode Selection Trial in Sinus Node Dysfunction (MOST) showed similar outcomes in patients randomized to dual-chamber (DDDR) versus ventricular pacing (VVIR). We compared outcomes by pacing mode in LP-eligible patients from MOST. METHODS: Patients enrolled in the MOST study with an left ventricular ejection fraction (LVEF) >35%, QRS duration (QRSd) <120 ms and no history of ventricular arrhythmias or prior implantable cardioverter defibrillators were included (LP-eligible population). Cox proportional hazards models were used to test the association between pacing mode and death, stroke or heart failure (HF) hospitalization and atrial fibrillation (AF). RESULTS: Of the 2010 patients enrolled in MOST, 1284 patients (64%) met inclusion criteria. Baseline characteristics were well balanced across included patients randomized to DDDR (N = 630) and VVIR (N = 654). Over 4 years of follow-up, there was no association between pacing mode and death, stroke or HF hospitalization (VVIR HR 1.28 [0.92-1.75]). VVIR pacing was associated with higher risk of AF (HR 1.32 [1.08-1.61], P = .007), particularly in patients with no history of AF (HR 2.38 [1.52-3.85], P < .001). CONCLUSION: In patients without reduced LVEF or prolonged QRSd who would be eligible for LP, DDDR, and VVIR pacing demonstrated similar rates of death, stroke or HF hospitalization; however, VVIR pacing significantly increased the risk of AF development.

Positive chronotropic effects of theophylline and cilostazol in patients with symptomatic sick sinus syndrome who have declined permanent pacing.

Pacemakers are more commonly recommended than theophylline for sick sinus syndrome (SSS) treatment. The positive effects of cilostazol on bradyarrhythmias also have been reported. However, no comparison of cilostazol and theophylline has been previously reported found. We retrospectively enrolled SSS patients, who refused a pacemaker implantation. Theophylline or cilostazol was administered, and the heart rate (HR) was evaluated in 4-8 weeks using a digital sphygmomanometer and the electrocardiogram (ECG). A 200-400 mg of theophylline or 100-200 mg of cilostazol were administered per day in 50 and 30 patients, respectively. The baseline HR was 54.8 ± 13.5 beats per minute (bpm) on using sphygmomanometry and 51.9 ± 11.8 bpm using the ECG. In the theophylline group, the HR increased by 12.0 ± 16.3 bpm by sphygmomanometry (P < 0.001) and 8.4 ± 12.0 bpm by the ECG (P < 0.001). In the cilostazol group, the HR increased by 16.8 ± 13.9 bpm by sphygmomanometry (P < 0.001) and 12.4 ± 13.4 bpm using the ECG (P < 0.001). In 15 of the 50 theophylline patients, the medication was switched to cilostazol. The HR increased from 61.4 ± 13.8 bpm to 64.0 ± 12.6 bpm (P = 0.338). Symptoms such as dyspnea, chest discomfort, dizziness, and syncope significantly improved after the administration of the medications. There were no significant differences in the improvement in the symptoms except for dizziness between the two agents. Cilostazol was as effective as theophylline for increasing the HR in SSS patients.

Complex Arrhythmia Syndrome in a Knock-In Mouse Model Carrier of the N98S Calm1 Mutation.

BACKGROUND: Calmodulin mutations are associated with arrhythmia syndromes in humans. Exome sequencing previously identified a de novo mutation in CALM1 resulting in a p.N98S substitution in a patient with sinus bradycardia and stress-induced bidirectional ventricular ectopy. The objectives of the present study were to determine if mice carrying the N98S mutation knocked into Calm1 replicate the human arrhythmia phenotype and to examine arrhythmia mechanisms. METHODS: Mouse lines heterozygous for the Calm1N98S allele (Calm1N98S/+) were generated using CRISPR/Cas9 technology. Adult mutant mice and their wildtype littermates (Calm1+/+) underwent electrocardiographic monitoring. Ventricular de- and repolarization was assessed in isolated hearts using optical voltage mapping. Action potentials and whole-cell currents and [Ca2+]i, as well, were measured in single ventricular myocytes using the patch-clamp technique and fluorescence microscopy, respectively. The microelectrode technique was used for in situ membrane voltage monitoring of ventricular conduction fibers. RESULTS: Two biologically independent knock-in mouse lines heterozygous for the Calm1N98S allele were generated. Calm1N98S/+ mice of either sex and line exhibited sinus bradycardia, QTc interval prolongation, and catecholaminergic bidirectional ventricular tachycardia. Male mutant mice also showed QRS widening. Pharmacological blockade and activation of ß-adrenergic receptors rescued and exacerbated, respectively, the long-QT phenotype of Calm1N98S/+ mice. Optical and electric assessment of membrane potential in isolated hearts and single left ventricular myocytes, respectively, revealed ß-adrenergically induced delay of repolarization. ß-Adrenergic stimulation increased peak density, slowed inactivation, and left-shifted the activation curve of ICa.L significantly more in Calm1N98S/+ versus Calm1+/+ ventricular myocytes, increasing late ICa.L in the former. Rapidly paced Calm1N98S/+ ventricular myocytes showed increased propensity to delayed afterdepolarization-induced triggered activity, whereas in situ His-Purkinje fibers exhibited increased susceptibility for pause-dependent early afterdepolarizations. Epicardial mapping of Calm1N98S/+ hearts showed that both reentry and focal mechanisms contribute to arrhythmogenesis. CONCLUSIONS: Heterozygosity for the Calm1N98S mutation is causative of an arrhythmia syndrome characterized by sinus bradycardia, QRS widening, adrenergically mediated QTc interval prolongation, and bidirectional ventricular tachycardia. ß-Adrenergically induced ICa.L dysregulation contributes to the long-QT phenotype. Pause-dependent early afterdepolarizations and tachycardia-induced delayed afterdepolarizations originating in the His-Purkinje network and ventricular myocytes, respectively, constitute potential sources of arrhythmia in Calm1N98S/+ hearts.

Aging-associated sinus arrest and sick sinus syndrome in adult zebrafish.

Because of its powerful genetics, the adult zebrafish has been increasingly used for studying cardiovascular diseases. Considering its heart rate of ~100 beats per minute at ambient temperature, which is very close to human, we assessed the use of this vertebrate animal for modeling heart rhythm disorders such as sinus arrest (SA) and sick sinus syndrome (SSS). We firstly optimized a protocol to measure electrocardiogram in adult zebrafish. We determined the location of the probes, implemented an open-chest microsurgery procedure, measured the effects of temperature, and determined appropriate anesthesia dose and time. We then proposed an PP interval of more than 1.5 seconds as an arbitrary criterion to define an SA episode in an adult fish at ambient temperature, based on comparison between the current definition of an SA episode in humans and our studies of candidate SA episodes in aged wild-type fish and Tg(SCN5A-D1275N) fish (a fish model for inherited SSS). With this criterion, a subpopulation of about 5% wild-type fish can be considered to have SA episodes, and this percentage significantly increases to about 25% in 3-year-old fish. In response to atropine, this subpopulation has both common SSS phenotypic traits that are shared with the Tg(SCN5A-D1275N) model, such as bradycardia; and unique SSS phenotypic traits, such as increased QRS/P ratio and chronotropic incompetence. In summary, this study defined baseline SA and SSS in adult zebrafish and underscored use of the zebrafish as an alternative model to study aging-associated SSS.

Is transjugular insertion of a temporary pacemaker a safe and effective approach?

Temporary pacemakers (TPMs) are usually inserted in an emergency situation. However, there are few reports available regarding which route of access is best or what the most preferred approach is currently in tertiary hospitals. This study aimed to compare procedure times, complication rates, and indications for temporary pacing between the transjugular and transfemoral approaches to TPM placement. We analyzed consecutive patients who underwent TPM placement. Indications; procedure times; and rates of complications including localized infection, any bleeding, and pacing wire repositioning rates were analyzed. A total of 732 patients (361 treated via the transjugular approach and 371 treated via the transfemoral approach) were included. Complete atrioventricular block was the most common cause of TPM placement in both groups, but sick sinus syndrome was especially common in the transjugular approach group. Separately, procedure time was significantly shorter in the transjugular approach group (9.0 ± 8.0 minutes vs. 11.9 ± 9.7 minutes; P < 0.001). Overall complication rates were not significantly different between the two groups, and longer duration of temporary pacing was a risk factor for repositioning. The risk of reposition was significantly increased when the temporary pacing was continued more than 5 days and 3 days in the transjugular approach group and the transfemoral approach group, respectively. The transjugular approach should be considered if the TPM is required for more than 3 days.

Ischemic Stroke in Patients With Sinus Node Disease, Atrial Fibrillation, and Other Cardiac Conditions.

Background and Purpose- Atrial fibrillation (AF) is known to increase risk of ischemic stroke (IS), but the risk of IS in isolated sinus node disease (SND) is unclear. We compared the incidence of IS in patients with SND, patients with AF, and in a control population with other cardiac diseases (disease of the circulatory system using the International Classification of Diseases, Tenth Revision). Methods- This French longitudinal cohort study was based on the national database covering hospital care for the entire population from 2008 to 2015. Results- Of 1 692 157 patients included in the cohort, 100 366 had isolated SND, 1 564 270 had isolated AF, and 27 521 had AF associated with SND. Incidence of IS during follow-up was higher in isolated patients with AF than in AF associated with SND (yearly rate 2.22% versus 2.06%) and in isolated patients with AF than in isolated patients with SND (yearly rate 2.22% versus 1.59%). The incidence of IS was lower in a control population with other cardiac conditions (n=479 108) compared with SND and patients with AF (0.96%/y, 1.59%/y, and 2.22%/y, respectively). After 1:1 propensity score matching, SND was associated with lower incidence of IS compared to AF (hazard ratio, 0.77 [95% CI, 0.73-0.82]) but higher incidence of IS compared to control population (hazard ratio, 1.27 [95%CI, 1.19-1.35]). Conclusions- Patients with SND had a lower risk of thromboembolic events than patients with AF but a higher risk than a control population with other cardiac diseases. Randomized clinical trial in a selected SND population, with, for example, a high CHA2DS2-VASc score, would be required to determine the value of IS prevention by anticoagulation.

Delayed-onset sinus node dysfunction in a child victim of Russell's viper bite.

Cardiac complications following envenomation by Russell's viper venom are uncommon. We describe a 14-year-old girl who developed delayed-onset sinus node dysfunction. She presented with mucosal bleeding, ptosis, and muscle weakness. Her 20-min whole blood clotting time and international normalized ratio were prolonged. The initial electrocardiogram showed sinus tachycardia. Her systemic manifestations responded to antivenom serum. After 24 h, she developed bradycardia and electrocardiography showed sinus node dysfunction with sinus arrest and an atrial escape rhythm. This case shows that arrhythmias can have a delayed onset even after resolution of other systemic manifestations, and even after treatment with antivenom serum.