Modulation Scheme Analysis for Low-Power Leadless Pacemaker Synchronization Based on Conductive Intracardiac Communication

Conductive intracardiac communication (CIC) has been demonstrated as a promising concept for the synchronization of multi-chamber leadless cardiac pacemakers (LLPMs). To meet the 2–5 μ W power budget of a LLPM, highly specialized CIC-transceivers, which make optimal use of the cardiac communication channel, need to be developed. However, a detailed investigation of the optimal communication parameters for CIC-based LLPM synchronization is missing so far. This work analyzes the intracardiac communication performance of two low-power modulation techniques, namely On-Off-Keying (OOK) and Manchester-encoded baseband transmission (BB-MAN), as a function of the transmitted bit-energy. The bit error rate (BER) of a prototype dual-chamber LLPM was determined both in simulation and in-vitro experiments on porcine hearts. A BER of 1e − 4 was achieved with a median bit-energy in the range of 3-16 pJ (interquartile range: 4-15 pJ) for data rates from 75-500 kbps and a receiver input noise density of 7 nV/ √Hz . Both modulation schemes showed comparable performance, with BB-MAN having a slight bit-energy advantage (1-2 dB at 150-500 kbps) under equalized transceiver characteristics. This study demonstrates that reliable CIC-based LLPM synchronization is feasible at transmitted power levels < 10 nW under realistic channel conditions and receiver noise performance. Therefore, modulation techniques such, as BB-MAN or OOK, are preferable over recently proposed alternatives, such as pulse position modulation or conductive impulse signaling, since they can be realized with fewer hardware resources and smaller bandwidth requirements. Ultimately, a baseband communication approach might be favored over OOK, due to the more efficient cardiac signal transmission and reduced transceiver complexity

Leadless pacemaker technology: clinical evidence of new paradigm of pacing

Despite continuous technological developments, transvenous pacemakers (PM) are still associated with significant immediate and long-term complications, mostly lead or pocket-related. Recent technological advances brought to the introduction in clinical practice of leadless PM for selected cohort of patients. These miniaturize devices are implanted through the femoral vein and advanced to the right ventricle, without leaving leads in place. Lack of upper extremity vascular access and/or high infective risk in patients requiring VVI pacing are the most common indications to leadless PM. The recently introduced MICRA AV leadless PM also allows ventricular synchronization through mechanical sensing of atrial contraction waves, thus solving the problem of AV synchronization. This review will discuss and summarize available clinical evidence on leadless PM, their performance compared to transvenous devices, current applications and future perspectives

Bridging the future of cardiac stimulation: physiologic or leadless pacing?

Cardiac simulation has moved from early life-saving pacemakers meant only to prevent asystole to current devices capable of physiologic stimulation for the treatment of heart rhythm and heart failure, that are also intended for remote patient and disease-progression monitoring. The actual vision of contemporary pacing aims to correct the electrophysiologic roots of mechanical inefficiency regardless of underlying structural heart diseases. The awareness of the residual cardiac dyssynchrony related to customary cardiac pacing has changed the concept of what truly represents “physiologic pacing”. On a different perspective, leadless stimulation to abolish CIED surgery and prevent lead-related complications is becoming a priority both for young device recipients and for frail, elderly patients. Careful clinical evaluation attempts to bridge decision-making to patient-tailored therapy

Five-year safety and efficacy of leadless pacemakers in a Dutch cohort

BACKGROUND: Adequate real-world safety and efficacy of leadless pacemakers (LPs) have been demonstrated up to 3 years after implantation. Longer-term data are warranted to assess the net clinical benefit of leadless pacing.OBJECTIVE: The purpose of this study was to evaluate the long-term safety and efficacy of LP therapy in a real-world cohort.METHODS: In this retrospective cohort study, all consecutive patients with a first LP implantation from December 21, 2012, to December 13, 2016, in 6 Dutch high-volume centers were included. The primary safety endpoint was the rate of major procedure- or device-related complications (ie, requiring surgery) at 5-year follow-up. Analyses were performed with and without Nanostim battery advisory-related complications. The primary efficacy endpoint was the percentage of patients with a pacing capture threshold ≤2.0 V at implantation and without ≥1.5-V increase at the last follow-up visit.RESULTS: A total of 179 patients were included (mean age 79 ± 9 years), 93 (52%) with a Nanostim and 86 (48%) with a Micra VR LP. Mean follow-up duration was 44 ± 26 months. Forty-one major complications occurred, of which 7 were not advisory related. The 5-year major complication rate was 4% without advisory-related complications and 27% including advisory-related complications. No advisory-related major complications occurred a median 10 days (range 0-88 days) postimplantation. The pacing capture threshold was low in 163 of 167 patients (98%) and stable in 157 of 160 (98%).CONCLUSION: The long-term major complication rate without advisory-related complications was low with LPs. No complications occurred after the acute phase and no infections occurred, which may be a specific benefit of LPs. The performance was adequate with a stable pacing capture threshold.</p

Leadless Pacemakers

Leadless or transcatheter pacemakers have recently been introduced to market with important benefits and some limitations. Implanted entirely within the right ventricle, these devices eliminate the need for transvenous pacing leads and pacemaker pockets and thus reduce the risk of infections and lead-related problems. Currently, they offer only VVI/R pacing and they cannot provide atrial sensing, antitachycardia pacing, or AV synchrony. They offer a number of features (such as rate response) and electrogram storage, albeit more limited than in a transvenous system. Real-world clinical data are needed to better comment on projected battery life, which manufacturers suggest will be at least equivalent to transvenous devices. Extracting an implanted leadless pacemaker remains a challenge, although proprietary snare and removal systems are available. However, a leadless pacemaker at end of service may be programmed to OOO and left in place; a revised device may be implanted adjacent. These innovative new devices may have important uses in special populations. Initial data on implant success and adverse events are favorable. Currently, there are two leadless pacemakers available: the Micra™ device by Medtronic and the Nanostim™ device by Abbott (formerly St. Jude Medical)

Differentiable PKC activation on pacemaking activity of cardiomyocytes derived from mouse embryonic stem cells

Les maladies cardiovasculaires sont souvent causées par des arythmies qui proviennent d'une obstruction du système de conduction cardiaque. L'intervenant clé de ce système est le nœud sinu-atrial (SA), qui est responsable de l’initiation de chaque battement cardiaque. L’activation électrique à intervalles réguliers, assurant que le rythme cardiaque est un rythme normal. Le dysfonctionnement du nœud SA entraînerait des instabilités électriques dans le cœur. Une maladie cardiaque acquise, comme la cardiopathie rhumatismale, ou un bloc de conduction ne sont que quelques-uns des nombreux cas qui nécessitent un stimulateur cardiaque électronique pour surveiller la fréquence cardiaque et générer une impulsion lorsqu'elle bat anormalement. Bien que le stimulateur cardiaque électrique soit considéré comme une thérapie fiable, il n'est pas sans limites. Ces limites comprennent les complications chirurgicales, l'infection au plomb ainsi que la durée de vie limitée de la batterie, qui doit être remplacée à intervalles de quelques années, ce qui alourdit le fardeau hospitalier. Plusieurs approches ont été adoptées pour développer une méthode thérapeutique plus adéquate. Une stratégie qui sera étudiée implique l'utilisation d'une greffe de cellules de stimulateur cardiaque, créant fondamentalement un stimulateur biologique. Les approches de thérapie cellulaire utilisent des cellules souches embryonnaires pour évoluer vers les lignées de cellules cardiaques, y compris les cellules stimulatrices cardiaques. Ces cellules de stimulation sont caractérisées par une dépolarisation spontanée qui crée les impulsions rythmiques dans le cœur et contrôle la fréquence cardiaque. Un élément important des cellules du stimulateur cardiaque qui donne lieu à la dépolarisation spontanée sont les canaux « hyperpolarization-activated and cyclic nucleotide-gated » qui sont activés pendant l’hyperpolarisation et conduisent le courant sous le nom de « funny current ». Ce courant augmente la perméabilité intérieure de la cellule aux courants de sodium et de potassium conduisant à la dépolarisation de la cellule. D'autre part, le taux de conduction est déterminé par la connexine 30.2 et la connexine 45, qui sont des protéines transmembranaires qui s’assemblent pour former des jonctions lacunaires. L'expression de HCN et l'expression de la connexine ont toutes deux étés liés au facteur T-box 3 (Tbx3) dans le développement des myocytes auriculaires. Une approche praticable pour moduler l'expression des gènes et par conséquent l'expression des protéines est l'utilisation du conditionnement chimique. Le Phorbol 12- myristate 13-acétate (PMA) est un activateur de Protéine Kinase C (PKC) lié à l'expression de Tbx3, et par conséquent à l'expression de HCN et de connexine, et entraînant une modification de l'activité spontanée. Les cellules souches embryonnaires de souris sont des cellules qui sont isolées de la masse cellulaire interne des embryons. Ces cellules ont la capacité de se différencier en tous les types de cellules somatiques. En combinant les facteurs de croissance, ces cellules peuvent se différencier en cardiomyocytes. Nous émettons l'hypothèse que le conditionnement chronique de cardiomyocytes de souris avec PMA entraîne une régulation à la hausse de l'expression de Tbx3 et par conséquent une régulation à la hausse de l'expression de HCN et de l'expression de connexine, favorisant ainsi le développement des cellules stimulatrices cardiaques dans la population des cardiomyocytes. Afin de vérifier notre hypothèse, nous avons acheté des cellules de la lignée cellulaire E14TG2A de souris. Ces cellules ont été cultivées dans des pétris et différenciées en cardiomyocytes à l'aide d'un protocole en trois étapes (voir la section Méthodes). Les cardiomyocytes sont ensuite exposés à la PMA à des concentrations variables (0.1 µM vs 1 µM) pendant 1h (exposition aiguë) ou 24 h (exposition chronique). Les résultats variaient d'un groupe expérimental à l'autre par rapport au groupe témoin. Dans toutes les conditions expérimentales, il semble y avoir une augmentation initiale de l'activité spontanée, mais elle s'inverse rapidement à la marque des 24 heures, où le rythme diminue. Différentes concentrations jouent un rôle dose-dépendant dans l'effet inhibiteur de longue durée sur la stimulation des cellules.Cardiovascular diseases are often caused by arrhythmias that originate from an obstruction within the cardiac conduction system. The key player within that system is the sinoatrial (SA) node, which is responsible for initiation the electrical impulses at a regular interval, insuring the heartbeat at a normal pace. Dysfunction of the SA node would lead to electrical instabilities in the heart. An acquired heart disease, such as rheumatic heart disease, or a conduction block are just some of many cases that would require an electronic pacemaker to monitor the heart rate and generate an impulse when it beats abnormally. Although the electric pacemaker is considered as a reliable therapy, it is not without limitations. These limitations include surgery complication, lead infection as well as limited battery lifespan, which requires replacement every few years thus adding to the hospital burden. Several approaches have been taken to develop a more adequate therapeutic method. A strategy that will be investigated involves using a graft of pacemaker cells, fundamentally creating a biological pacemaker. Cell therapy approaches use embryonic stem cells to evolve into the cardiac cell lines, including pacemaker cells. These pacing cells are characterized by spontaneous depolarization that create the rhythmic impulses in the heart and control the heart rate. An important element of the pacemaker cells that give rise to the spontaneous depolarization are the hyperpolarization- activated and cyclic nucleotide-gated (HCN) channels that are activated during hyperpolarization and conduct the funny current by increasing the cell’s inward permeability to sodium-potassium currents. On the other hand, the conduction rate is determined by connexin 30.2 and connexin 45, which are transmembrane proteins that assemble to form gap junctions. Both HCN expression and connexin expression has been linked to T-box factor 3 (Tbx3) in the development of atrial myocytes. A practicable approach to modulate gene expression and consequently protein expression is using chemical conditioning. Phorbol 12-myristate 13-acetate (PMA) is a Protein Kinase C (PKC) activator that has linked to Tbx3 expression, and consequently HCN and connexin expression, and lead to a modification in spontaneous activity. Mouse embryonic stem cells (ESCs) are cells that are isolated from the inner cell mass of early embryos. These cells can differentiate into all somatic cell types. Given the proper combination of growth factors, these cells can differentiate into cardiomyocytes. We hypothesize that chronic conditioning of mice cardiomyocytes with PMA lead to an upregulation of Tbx3 expression and consequently an upregulation of HCN expression and connexin expression, therefore promoting the development of pacemaker cells within the cardiomyocyte population. In order to test our hypothesis, we purchased cells from the mouse E14TG2A cell line. These cells were cultured in glass bottom petri dishes and differentiated into cardiomyocytes using a three-step protocol (shown in Methods section). The cardiomyocytes are then exposed to PMA in varying concentration (0.1 µM vs 1 µM) for either 1h (acute exposure) or 24 h (chronic exposure). The results varied between the experimental groups compared to the control. In all experimental conditions there seems to be an initial increase in spontaneous activity, but this is quickly reversed at the 24 h mark, where pacing decreased. Different concentration plays a dose-dependent role in long-lasting inhibitory effect on the pacing of the cell

Pacing the heart:one site fits all?

In a healthy heart, contraction/pumping is controlled by an electrical stimulus. This ensures that the heart contracts synchronously. When a problem arises with generating or conducting this electrical stimulus, people are fitted with a pacemaker. Our research shows that - in contrast to current technology - stimulating the ventricular septum is safer and better for the pump function. Stimulation of the ventricular septum can prevent (symptoms of) heart failure. Survival also improves

Current Issues and Recent Advances in Pacemaker Therapy

Patients with implanted pacemakers or defibrillators are frequently encountered in various healthcare settings. As these devices may be responsible for, or contribute to a variety of clinically significant issues, familiarity with their function and potential complications facilitates patient management. This book reviews several clinically relevant issues and recent advances of pacemaker therapy: implantation, device follow-up and management of complications. Innovations and research on the frontiers of this technology are also discussed as they may have wider utilization in the future. The book should provide useful information for clinicians involved in the management of patients with implanted antiarrhythmia devices and researchers working in the field of cardiac implants