Myocardial Refractory Period Research Articles

M6A reader YTHDF2 governs the onset of atrial fibrillation by modulating Cacna1c translation.

Atrial fibrillation (AF) is the most common arrhythmia, which is tightly associated with the abnormal expression and function of ion channels in the atrial cardiomyocytes. N6-methyladenosine (m6A), a widespread chemical modification in eukaryotic mRNA, is known to play a significant regulatory role in the pathogenesis of heart disease. However, the significance of m6A regulatory proteins in the onset of AF remains unclear. Here, we demonstrate that the m6A reader protein YTHDF2 regulates atrial electrical remodeling and AF onset by modulating the Cav1.2 expression. Firstly, YTHDF2 expression was selectively upregulated in rat atrial cardiomyocytes with AF. Secondly, YTHDF2 knockout reduced AF susceptibility in mice. Thirdly, the knockout of YTHDF2 increased Cav1.2 protein levels in an m6A-in-dependent manner, ultimately prolonging the atrial myocardial refractory period, a critical electrophysiological substrate for the onset of AF. Fourthly, the N-terminal domain of YTHDF2 was identified as critical for Cacna1c mRNA translation regulation. Overall, our findings unveil that YTHDF2 can alter Cav1.2 protein expression in an m6A-independent manner, thereby facilitating the onset of AF. Our study suggests that YTHDF2 may be a potential intervention target for AF.

PO-04-018 RECOGNITION AND INTERPRETATION OF IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR INTERVAL CHANGES ON REMOTE MONITORING FOLLOWING A CARDIAC CONTRACTILITY MODULATION IMPLANT.

Cardiac contractility modulation (CCM) devices aim to improve the quality of life in chronic heart failure patients by delivering an electrical stimulus during the absolute myocardial refractory period in hopes of improving contractility without additional myocardial oxygen consumption. With 7,000 patients receiving the benefits of CCM by May 2022, it becomes increasingly important to remain educated regarding purpose, functionality, and potential for implantable device interactions. Investigate abnormal implantable cardioverter-defibrillator (ICD) remote monitoring (RM) transmissions to eliminate device interactions. Patient (73 yr) received an ICD in 2017 for non-ischemic cardiomyopathy and ventricular tachycardia and is compliant with RM and in-person follow-up. A CCM device was implanted December 2021 with no ICD re-programming post-iterative testing. Multiple RM transmissions reviewed January – May 2022 noted changes (Table 1), including “noise” visualized on both atrial and ventricular channels; however, only atrial over-sensing occurred (Figure 1). The RM team inquired about possible external stimuli in May 2022’s transmission and from clinic correspondence, learned of the patient’s CCM implant. Patient was seen in-clinic with appropriate company representatives present. ICD re-programming completed: Post Ventricular Atrial Blanking shortened to 110 ms; PVAB Method to Absolute; V Blanking post VS increased to 140 ms, and VF detection decreased to 214 bpm. CCM changes made: 8 hours to 9 hours and pulse delivery from 40 ms to 35 ms. ICD changes observed via RM over 5-month period post-CCM implant include false-positive (FP) AT/AF detections, short V-V intervals, and PVC burden (unclear if accurate or FP due to RV over-sensing). The increased sensed R-waves initially assumed to be an inappropriate measurement of CCM output were 15mV via in-office automatic testing. Changes recognized via RM allowed the clinic to non-urgently schedule simultaneous assessment and adjustment of both implanted devices with the hope of preventing over-sensing, specifically RV over-sensing resulting in inappropriate ICD therapies. While an in-office ICD evaluation did occur immediately post CCM implant, it is imperative to continue RM to assess for concomitant device interactions.Tabled 1Table 1DateRV SensingShort interval counter (SIC)PVC Runs/Singles CountEpisodes11/26/21 2:28 am RM3.6mV0Runs 7.3Singles 126.6 since 11/07/21No episodes01/18/22 in-clinic4.1mVnot available (n/a)n/aNo episodes01/18/22 8:09 pm RM4.1mV127 since 12/16/21Runs 5.6Singles 108.7 since 12/18/21No episodes01/18/22 8:12 pm RM4.1mV127 since 12/16/21Runs 5.6Singles 108.7 since 12/18/21No episodes01/20/22 6:11 pm RM3.5mV10 since 01/18/22Runs 2.2Singles 59.5 since 01/18/22No episodes02/25/22 1:23 am RM3.9mV158 since 01/18/22Runs 7.1Singles 110.8 since 01/20/221 AT/AF (FP)05/26/22 3:34 am RM15.6mV1060 since 01/18/22Runs 18.4Singles 161.3 since 02/25/221 high rate NST (true positive)4 AT/AF (FP)05/31/22 in clinic16.5mVn/aRuns 15.9Singles 150.7 since 01/18/22n/a Open table in a new tab

Shortness of breath in a patient with complete heart block and permanent pacemaker: A case of effective pacemaker reprogramming

An 82-year-old frail woman with a prior history of hypertension, complete heart block, and dual permanent pacemaker (Sensia DR SEDR01, Medtronic Inc., Minneapolis, MN) presented to pacemaker clinic with symptoms of shortness of breath (SOB), dizziness, and “low pulse rate”. Pacemaker interrogation showed underlying normal sinus rhythm, sinus rate of around 74 beats/ min with atrial sensed events, and ventricular paced rhythm with frequent symptomatic premature ventricular complexes (PVC). Pacemaker parameters were DDD, lower rate limit (LRL) of 60 beats/min, and maximum tracking rate of 120 beats/min, along with paced/sensed AV delay of 300/250 ms. Also noted was high pacing threshold of 3.5 V at 1 ms in the atrial lead with normal sensing parameters. In view of these, the pacemaker mode was reprogrammed to VDD mode and the patient was given betablocker therapy for frequent PVCs. She presented to arrhythmia clinic a few weeks later because of worsening SOB, light-headedness, and transient ischemic attacklike symptoms. Electrocardiography (ECG) performed in the clinic showed ventricular paced rhythmwith retrograde P waves (Fig. 1). What was the underlying arrhythmia mechanism? What treatment options are available? 2. Discussion

Functional Properties of the Superior Vena Cava (SVC)‐Aorta Ganglionated Plexus: Evidence Suggesting an Autonomic Basis for Rapid SVC Firing

the mechanism underlying spontaneous rapid superior vena cava (SVC) firing that initiates atrial fibrillation (AF) remains poorly understood. We investigated the role of the SVC-aorta-ganglionated plexus (SVC-Ao-GP) in AF initiated by rapid firing from the SVC. in 42 dogs, a circular catheter was positioned above the SVC-atrial junction. Multielectrode catheters were sutured on atria, atrial appendages and pulmonary veins. The effective refractory period (ERP) and window of vulnerability (WOV) for AF were measured at all sites in the baseline state, during cervical vagosympathetic trunk stimulation and during SVC-Ao-GP stimulation, before and after SVC-Ao-GP ablation. AF inducibility was also assessed by delivering high-frequency stimulation (HFS) within myocardial refractory period to the SVC before and after SVC-Ao-GP ablation. HFS applied to the SVC-Ao-GP slowed the sinus rate and/or atrioventricular conduction. HFS of the SVC-Ao-GP induced more significant shortening of ERP and a greater increase in WOV at the SVC than other sites. Ablation of the SVC-Ao-GP significantly increased the baseline ERP and decreased the baseline WOV only at the SVC. AF induced at the SVC by HFS during refractoriness was eliminated by ablation of the SVC-Ao-GP but was not altered by ablation of the 4 major atrial GP. Direct injection of acetylcholine into the SVC-Ao-GP initiated rapid firing from the SVC in every case. the SVC-Ao-GP preferentially modulates the electrophysiological function of the SVC sleeves and may contribute to rapid firing from the SVC.

EP News: Basic and Translational

Meyer et al (Circulation 2010;121:1286, PMID 20212280) administered high-frequency stimulation (200 Hz) during the myocardial refractory period with electrode catheters inside the coronary sinus in 20 sheep. The results showed that stimulation evoked a systolic left ventricular pressure increase without changes in sinus rate or PR interval. Likewise, the rate of systolic pressure development, rate of diastolic relaxation, slope of the end-systolic pressure–volume relationship, and cardiac output increased.

Augmentation of Left Ventricular Contractility by Cardiac Sympathetic Neural Stimulation

Electric stimulation of mediastinal sympathetic cardiac nerves increases cardiac contractility but is not selective for the left ventricle because it elicits sinus tachycardia and enhanced atrioventricular conduction. The aim of this study was to identify sympathetic neural structures inside the heart that selectively control left ventricular inotropy and can be accessed by transvenous catheter stimulation. In 20 sheep, high-frequency stimulation (200 Hz) during the myocardial refractory period with electrode catheters inside the coronary sinus evoked a systolic left ventricular pressure increase from 97+/-20 to 138+/-32 mm Hg (P<0.001) without changes in sinus rate or PR time. Likewise, the rate of systolic pressure development (1143+/-334 versus 1725+/-632 mm Hg/s; P=0.004) and rate of diastolic relaxation (531+/-128 versus 888+/-331 mm Hg/s; P=0.001) increased. The slope of the end-systolic pressure-volume relationship increased (2.3+/-0.8 versus 3.1+/-0.6 mm Hg/mL; P=0.04), as did cardiac output (3.5+/-0.8 versus 4.4+/-0.8 L/min; P<0.001). Systemic vascular resistance and right ventricular pressure remained unchanged. There was a sigmoid dose-response curve. Ultrasound analysis revealed an increase in circumferential and radial strain in all left ventricular segments that was significant for the posterior, lateral, and anterior segments. Pressure effects were maintained for at least 4 hours of continued high-frequency stimulation and abolished by beta1-receptor blockade. Histology showed distinct adrenergic nerve bundles at the high-frequency stimulation site. Cardiac nerve fibers that innervate the left ventricle are amenable to transvenous electric catheter stimulation. This may permit direct interference with and modulation of the sympathetic tone of the left ventricle.

Autologous skeletal myoblasts restore the myocardial electrical impedance, but not the refractory period of infarcted myocardium: engraftment versus integration?

Introduction: Autologous skeletal myoblasts (ASM) can survive within areas of myocardial infarct. However, little evidence exists as to whether these skeletal fibers develop and become integrated (electromechanically coupled) with the host myocardium. Myocardial electrical impedance (MEI) is sensitive to physiological changes in regional tissue metabolism, while the myocardial refractory period (RP) is sensitive to changes in integrated intercellular electrochemistry of the myocardium. Methods: Myocardial infarction was created in sheep (N = 7) by means of coronary microembolization. Myocardial impedance electrodes were placed in remote (CTRL) and infarcted areas. Animals were injected (in the infarct) with up to 5.0 × 10^8 ASM (INF+ASM; N = 4) or cell-media (INF; N = 3). MEI and RP were measured in awake, unsedated animals at 1, 7, 14 and 21 days following ASM/cell-media injection. Random night-time ECG (telemetry) monitoring was conducted to evaluate for the presence of premature ventricular contractions (PVCs) or other ectopy. Results: ASM-derived myofibers were found aligned and apposed to cardiac myocytes, however, no connexin 43 was identified in skeletal myocytes. At Day 1, the MEI and RP of infarcted myocardium (361±20Ω & 178±4ms) differed (P<0.05) from that of remote myocardium (480±25Ω & 205±8ms). After 21 days, the MEI difference remained unchanged in cell-media animals (470±71Ω vs. 584±27Ω) but decreased significantly with ASM, reaching control (remote) values (503±20Ω vs. 522±24Ω, see figure). However, no significant change in RP or PVC count (21 pvc/hr; range: 3–38) was observed after Day 1. Discussion: The normalization of passive electrical properties (MEI) of the infarcted myocardium after ASM injection may represent ASM development, engraftment, and the revitalization of myocardial scar by skeletal myofibers. However, the lack of changes in measured RP suggests that engrafted skeletal myofibers may not impact active electrochemical properties of the myocardium.

The significance of QT interval in drug development.

The duration of QT interval of the surface electrocardiogram (ECG) reflects the ventricular action potential duration (APD) which is determined mainly by the rapid component of the outward repolarizing current (IKr). This current is mediated primarily by the delayed rectifying potassium channel. Thus, the QT interval is congenitally prolonged when this current is diminished as a result of genetic mutations of this channel as for example in the Romano–Ward syndrome [1]. Reduction in this current and hence, the prolongation of the QT interval may also be acquired, resulting from electrolyte imbalance (especially hypokalaemia and/or hypomagnesaemia), endocrine dysfunction (e.g. hypothyroidism), autonomic imbalance, various disease states or most frequently, following clinical administration of drugs. Drug-induced prolongation of the QTc interval may be followed by potentially fatal proarrhythmias. More than any other adverse drug reaction in recent times, it has been responsible for the withdrawal of many drugs from the market and yet as a surrogate of proarrhythmias, it is not well understood. Regulatory decisions have resulted in rejection of some new drugs or the restriction on the clinical use of many old and other new drugs over the last decade because of their potential to prolong the QTc interval. Therefore, there are regulatory and clinical expectations of better preapproval characterization of new chemical entities (NCEs) for this potential risk which have had a very profound influence on drug development. This paper will focus on the issues that need to be addressed during drug development, strategies aimed at identifying this risk during early preclinical and clinical phases of drug development and the regulatory assessment of the potential risk, particularly the electrocardiographic data from the clinical trials. Because the actually measured QT interval changes with heart rate in the absence of any intervention, it is usual to correct the measured interval for changes in heart rates (RR interval) to derive a rate-corrected (QTc) interval, which is then used when evaluating the effect of an intervention. Clinically, the rate-correction applied most widely, and almost exclusively for years, is the Bazett’s correction (QTc = QT/RR0.50), which divides the measured QT interval by the square root of the preceding RR interval. A less frequently applied rate-correction is that of Fridericia (QTc = QT/RR0.33) which divides the measured QT interval by the cube root of the preceding RR interval. Both these corrections standardize the measured QT interval to an RR interval of 1 s (heart rate of 60 beats min−1). When corrected by Bazett’s formula, on historical and epidemiological grounds, the widely accepted upper limits of normal QTc interval are 450 ms in adult males, 470 ms in adult females and 460 ms in children between 1 and 15 years of age (regardless of gender). Unless stated otherwise, the QTc interval referred to in this paper is the interval as corrected by Bazett’s formula. Drug-induced prolongation of QTc interval is expected with class III antiarrhythmic drugs which are intended to produce their desired therapeutic benefit by blocking IKr, delaying ventricular repolarization and, therefore, increasing myocardial refractory period. Typical examples of these drugs include sotalol, bretylium, ibutilide, dofetilide, azimilide, sematilide, ambasilide, almokalant, N-acetyl-procainamide, fenoxedil and terikalant.

Bolus administration of intrapericardial ibutilide: its dynamic effect on myocardial refractory period and defibrillation threshold

Bolus administration of intrapericardial ibutilide: its dynamic effect on myocardial refractory period and defibrillation threshold

Repetitive reentrant and non‐reentrant ventriculoatrial synchrony in dual chamber pacing

Repetitive retrograde ventriculoatrial (VA) conduction in patients with dual chamber pacemakers may cause two forms of VA synchrony. (1) Endless loop tachycardia (pacemaker-mediated tachycardia) or repetitive reentrant VA synchrony occurs when the pacemaker senses retrograde P waves. Appropriate programming can prevent pacemaker reentrant tachycardia in almost all cases. However, the measures used to control tachycardia may themselves create new problems. (2) AV desynchronization arrhythmia or repetitive non-reentrant AV synchrony occurs when the pacemaker does not sense retrograde P waves. In this form of VA synchrony, the atrial stimulus is ineffectual because it falls in the atrial myocardial refractory period generated by the preceding unsensed retrograde P wave. A long atrioventricular interval and a relatively fast lower rate (or sensor-driven rate with DDDR pacing) favor the development of AV desynchronization arrhythmia and its unfavorable hemodynamic consequences.

Magnet unresponsive pacemaker endless loop tachycardia

Endless loop tachycardia is a well-known complication of DDD pacing and is almost invariably terminated by conversion to the asynchronous DOO mode upon application of a magnet over the pulse generator. Occasionally magnet application is ineffectual because the ventriculoatrial (VA) synchrony of endless loop tachycardia is converted directly or indirectly to an atrioventricular (AV) desynchronization arrhythmia, another form of VA synchrony. This occurs when a paced ventricular beat engenders an unsensed retrograde P wave and the continual delivery of an ineffectual atrial stimulus during the atrial myocardial refractory period creates self-perpetuating VA synchrony. Upon magnet removal, AV desynchronization arrhythmia reverts immediately to endless loop tachycardia. In the absence of access to programmers, magnet unresponsive endless loop tachycardia can be easily and reliably terminated by chest wall stimulation through inhibition of the ventricular channel of the DDD pulse generator.

A special adrenergic receptor mediating ventricular fibrillation and shortening of the effective ventricular myocardial refractory period and its blocking.

The incidence of ventricular fibrillation (VF) was compared to the degree of shortening of ventricular myocardial effective refractory period (ERP) produced by sympathomimetics Epinephrine (E) and norepinephrine (NE) markedly shortened ERP (58.3 and 60.9 %, respectively), and produced VF in 100 % of the cases. The other which slightly shortened ERP: Mechanism of arrhythmia isoproterenol (20.6%), phentetramine (11.8%), and phenylephrine (7.6%) did not produce VF. <i>α</i> (‘Se 2’, dibenamine) and <i>β </i>(propranolol) adrenergic blocking agents (ABA) antagonized both VF and ERP shortening. Their relative pharmacological potencies were comparable both in antagonism towards ERP shortening and VF produced by E or NE. Both phenomena are thus intimately connected. Such sympathomimetic actions could not be classified either as <i>α</i> or <i>β, </i>exerted upon an admittedly special <i>&#917;</i>-adrenergic receptor inspecific as to its blocking and different from the mediator of inotropic and chronotropic positive actions of sympathomimetic agents.

Mechanisms of ventricular fibrillation during hypothermia: Relative changes in myocardial refractory period and conduction velocity

Summary Experimental studies of the effect of hypothermia on myocardial refractory period and conduction time during induced hypothermia have been performed. The following observations were made. 1. There was progressive and proportionate increase in refractory period and conduction time down to approximately 20° C. 2. At temperatures below 25° C., there was progressive impairment of conduction with development of partial and, subsequently, complete atrioventricular block with multifocal ectopic beats. 3. On the basis of these observations, it is felt that hypothermic ventricular fibrillation cannot be explained by disproportionate changes in conduction time and refractory period leading to re-entry of the impulse. This tends to refute the circus movement theory of fibrillation during hypothermia. 4. It is believed that hypothermic fibrillation at temperatures below approximately 25° C. is primarily a result of progressive interference with conduction, resulting in cessation of normal coordinated myocardial activation.

A comparison study of drugs in experimental and clinical auricular fibrillation

Each of four basic theories for the genesis of auricular fibrillation and flutter is supported by experimental procedures using laboratory animals. These procedures were used to evaluate certain compounds felt to have antifibrillatory properties. Drugs with high experimental antifibrillatory potency did not necessarily exhibit therapeutic action when subjected to clinical test. No basic theory as yet has sufficient experimental proof to explain completely the mechanism of auricular fibrillation. Hypervagotonia is undoubtedly an important factor in the initiation of auricular fibrillation but not in the maintenance of the arrhythmia. An unknown factor (or factors) appears to be responsible for the maintenance of auricular fibrillation. Diphenhydramine hydrochloride (Benadryl) may be added to the list of successful therapeutic agents for clinical auricular fibrillation. Although our results do not indicate it for routine use in place of quinidine, its use may prove valuable in selected patients. Banthine, while possessing the ability to prolong the myocardial refractory period and to prevent or reverse auricular fibrillation in experimental animals, did not prove effective in the treatment of auricular fibrillation in humans.