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Concept: Cardiac pacemaker


The introduction of the so-called newer-generation transcatheter aortic valve implantation (TAVI) devices has led to a dramatic reduction in the incidence of complications associated with the procedure. However, preliminary data suggest that conduction abnormalities (particularly new-onset atrioventricular block and left bundle branch block) remain a frequent complication post TAVI. Although inconsistencies across studies are apparent, new-onset conduction abnormalities post TAVI may be associated with higher incidences of mortality, sudden cardiac death and left ventricular dysfunction. Strategies intended both to reduce the risk and to improve the management of such complications are clearly warranted. In fact, the indication and timing of permanent pacemaker implantation are frequently individualised according to centre and/or operator preference. Currently, studies assessing the impact of these complications and the optimal indications for permanent cardiac pacing are underway. In this article, we review the data available on the incidence and impact of conduction disturbances following TAVI, and propose a strategy for the management of such complications.

Concepts: Cardiology, Heart, Cardiac arrest, Cardiac electrophysiology, Left ventricle, Cardiac pacemaker, Sinoatrial node, Transcutaneous pacing


Synchronization occurs in many natural and technological systems, from cardiac pacemaker cells to coupled lasers. In the synchronized state, the individual cells or lasers coordinate the timing of their oscillations, but they do not move through space. A complementary form of self-organization occurs among swarming insects, flocking birds, or schooling fish; now the individuals move through space, but without conspicuously altering their internal states. Here we explore systems in which both synchronization and swarming occur together. Specifically, we consider oscillators whose phase dynamics and spatial dynamics are coupled. We call them swarmalators, to highlight their dual character. A case study of a generalized Kuramoto model predicts five collective states as possible long-term modes of organization. These states may be observable in groups of sperm, Japanese tree frogs, colloidal suspensions of magnetic particles, and other biological and physical systems in which self-assembly and synchronization interact.

Concepts: Colloid, Emergence, Cardiac pacemaker, Swarm, Flocking


Background Cardiac pacemakers are limited by device-related complications, notably infection and problems related to pacemaker leads. We studied a miniaturized, fully self-contained leadless pacemaker that is nonsurgically implanted in the right ventricle with the use of a catheter. Methods In this multicenter study, we implanted an active-fixation leadless cardiac pacemaker in patients who required permanent single-chamber ventricular pacing. The primary efficacy end point was both an acceptable pacing threshold (≤2.0 V at 0.4 msec) and an acceptable sensing amplitude (R wave ≥5.0 mV, or a value equal to or greater than the value at implantation) through 6 months. The primary safety end point was freedom from device-related serious adverse events through 6 months. In this ongoing study, the prespecified analysis of the primary end points was performed on data from the first 300 patients who completed 6 months of follow-up (primary cohort). The rates of the efficacy end point and safety end point were compared with performance goals (based on historical data) of 85% and 86%, respectively. Additional outcomes were assessed in all 526 patients who were enrolled as of June 2015 (the total cohort). Results The leadless pacemaker was successfully implanted in 504 of the 526 patients in the total cohort (95.8%). The intention-to-treat primary efficacy end point was met in 270 of the 300 patients in the primary cohort (90.0%; 95% confidence interval [CI], 86.0 to 93.2, P=0.007), and the primary safety end point was met in 280 of the 300 patients (93.3%; 95% CI, 89.9 to 95.9; P<0.001). At 6 months, device-related serious adverse events were observed in 6.7% of the patients; events included device dislodgement with percutaneous retrieval (in 1.7%), cardiac perforation (in 1.3%), and pacing-threshold elevation requiring percutaneous retrieval and device replacement (in 1.3%). Conclusions The leadless cardiac pacemaker met prespecified pacing and sensing requirements in the large majority of patients. Device-related serious adverse events occurred in approximately 1 in 15 patients. (Funded by St. Jude Medical; LEADLESS II number, NCT02030418 .).

Concepts: Clinical trial, Heart, Right ventricle, Ventricle, Left ventricle, Cardiac pacemaker, Artificial pacemaker, Transcutaneous pacing


The heartbeat originates within the sinoatrial node (SAN), a small structure containing <10,000 genuine pacemaker cells. If the SAN fails, the ∼5 billion working cardiomyocytes downstream of it become quiescent, leading to circulatory collapse in the absence of electronic pacemaker therapy. Here we demonstrate conversion of rodent cardiomyocytes to SAN cells in vitro and in vivo by expression of Tbx18, a gene critical for early SAN specification. Within days of in vivo Tbx18 transduction, 9.2% of transduced, ventricular cardiomyocytes develop spontaneous electrical firing physiologically indistinguishable from that of SAN cells, along with morphological and epigenetic features characteristic of SAN cells. In vivo, focal Tbx18 gene transfer in the guinea-pig ventricle yields ectopic pacemaker activity, correcting a bradycardic disease phenotype. Myocytes transduced in vivo acquire the cardinal tapering morphology and physiological automaticity of native SAN pacemaker cells. The creation of induced SAN pacemaker (iSAN) cells opens new prospects for bioengineered pacemakers.

Concepts: Gene, Cardiology, Heart, Cardiac electrophysiology, Cardiac anatomy, Cardiac pacemaker, Sinoatrial node, Artificial pacemaker


The sinoatrial node is the main impulse-generating tissue in the heart. Atrioventricular conduction block and arrhythmias caused by sinoatrial node dysfunction are clinically important and generally treated with electronic pacemakers. Although an excellent solution, electronic pacemakers incorporate limitations that have stimulated research on biological pacing. To assess the suitability of potential biological pacemakers, we tested the hypothesis that the spontaneous electric activity of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) exhibit beat rate variability and power-law behavior comparable to those of human sinoatrial node.

Concepts: Myocardial infarction, Cardiology, Heart, Embryonic stem cell, Cardiac pacemaker, Sinoatrial node, Atrioventricular node, Heart block


-Risks associated with pediatric reconstructive heart surgery include injury of the sinoatrial node (SAN) and atrioventricular node (AVN), requiring cardiac rhythm management using implantable pacemakers. These injuries are result of difficulties in identifying nodal tissues intraoperatively. Here, we describe an approach based on confocal microscopy and extracellular fluorophores to quantify tissue microstructure and identify nodal tissue.

Concepts: Cardiology, Heart, Cardiac anatomy, Identification, Cardiac pacemaker, Sinoatrial node, Atrioventricular node, Electrical conduction system of the heart


Somatic reprogramming by reexpression of the embryonic transcription factor T-box 18 (TBX18) converts cardiomyocytes into pacemaker cells. We hypothesized that this could be a viable therapeutic avenue for pacemaker-dependent patients afflicted with device-related complications, and therefore tested whether adenoviral TBX18 gene transfer could create biological pacemaker activity in vivo in a large-animal model of complete heart block. Biological pacemaker activity, originating from the intramyocardial injection site, was evident in TBX18-transduced animals starting at day 2 and persisted for the duration of the study (14 days) with minimal backup electronic pacemaker use. Relative to controls transduced with a reporter gene, TBX18-transduced animals exhibited enhanced autonomic responses and physiologically superior chronotropic support of physical activity. Induced sinoatrial node cells could be identified by their distinctive morphology at the site of injection in TBX18-transduced animals, but not in controls. No local or systemic safety concerns arose. Thus, minimally invasive TBX18 gene transfer creates physiologically relevant pacemaker activity in complete heart block, providing evidence for therapeutic somatic reprogramming in a clinically relevant disease model.

Concepts: DNA, Gene, Genetics, Heart, Cardiac electrophysiology, Cardiac pacemaker, Sinoatrial node, Artificial pacemaker


Daphnia magna heartbeat is myogenic-originating within the animal’s heart. However, the mechanism for this myogenic automaticity is unknown. The mechanism underlying the automaticity of vertebrate myogenic hearts involves cells (pacemaker cells), which have a distinct set of ion channels that include hyperpolarization activated cyclic nucleotide-gated (HCN) and T-type calcium ion channels. We hypothesized that these ion channels also underlie the automatic myogenic heartbeat of Daphnia magna. The drugs, ZD7288 and mibefradil dihydrochloride, block HCN and T-type calcium ion channels respectively. Application of these drugs, in separate experiments, show that they inhibit the heartbeat of Daphnia magna in a dose-dependent manner. Calculation of the percent difference between the heart rate of pretreatment (before drug application) and heart rate following drug application (post-treatment) allowed us to graph a dose-response curve for both ZD7288 and mibefradil, revealing that ZD7288 produces a greater effect on decreasing heart rate. This indicates the HCN ion channels play a foremost role in generating Daphnia magna heartbeat. Our results show conclusively that HCN and T-type calcium ion channels underlie the automatic myogenic heartbeat in Daphnia magna-and suggest a conserved mechanism for generating myogenic heartbeat within the animal kingdom. Thus, Daphnia magna represents a credible model system for further exploration of cardiac physiology.

Concepts: Pharmacology, Bone, Heart, Action potential, Sodium, Heart rate, Potassium, Cardiac pacemaker


Human ether-à-go-go related gene (hERG) 1 channels conduct the rapid delayed rectifier K(+) current (IKr) and are essential for the repolarization of the cardiac action potential. hERG1 inhibition by structurally diverse drugs may lead to life threatening arrhythmia. Putative binding determinants of hERG1 channel blockers include T623, S624 and V625 on the pore helix, and residues G648, Y652 and F656, located on segment S6. We and others have previously hypothesized that additional binding determinants may be located on helix S5, which is in close contact with the S6 segments. In order to test this hypothesis, we performed a detailed investigation combining ionic current measurements with two-microelectrode voltage clamp and molecular modeling techniques. We identified a novel aromatic high affinity binding determinant for blockers located in helix S5, F557, which is equally potent as Y652. Modeling supports a direct interaction with the outer pore helix.

Concepts: Action potential, Electrophysiology, Direct current, Potassium channel, HERG, Cardiac pacemaker, Inward-rectifier potassium ion channel, Cardiac action potential


Parasympathetic regulation of sinoatrial node (SAN) pacemaker activity modulates multiple ion channels to temper heart rate. The functional role of the G-protein-activated K(+) current (IKACh) in the control of SAN pacemaking and heart rate is not completely understood. We have investigated the functional consequences of loss of IKACh in cholinergic regulation of pacemaker activity of SAN cells and in heart rate control under physiological situations mimicking the fight or flight response. We used knockout mice with loss of function of the Girk4 (Kir3.4) gene (Girk4(-/-) mice), which codes for an integral subunit of the cardiac IKACh channel. SAN pacemaker cells from Girk4(-/-) mice completely lacked IKACh. Loss of IKACh strongly reduced cholinergic regulation of pacemaker activity of SAN cells and isolated intact hearts. Telemetric recordings of electrocardiograms of freely moving mice showed that heart rate measured over a 24-h recording period was moderately increased (10%) in Girk4(-/-) animals. Although the relative extent of heart rate regulation of Girk4(-/-) mice was similar to that of wild-type animals, recovery of resting heart rate after stress, physical exercise, or pharmacological β-adrenergic stimulation of SAN pacemaking was significantly delayed in Girk4(-/-) animals. We conclude that IKACh plays a critical role in the kinetics of heart rate recovery to resting levels after sympathetic stimulation or after direct β-adrenergic stimulation of pacemaker activity. Our study thus uncovers a novel role for IKACh in SAN physiology and heart rate regulation.

Concepts: Gene, Cardiology, Heart, Action potential, Heart rate, Parasympathetic nervous system, Cardiac pacemaker, Sinoatrial node