Repolarization Stability Research Articles

Comparison of electrocardiogram parameters and echocardiographic response between distinct left bundle branch area pacing modes in heart failure patients.

Left bundle branch area pacing (LBBAP) has become an alternative method for cardiac resynchronization therapy. Various modes of LBBAP have been determined, including left bundle trunk pacing (LBTP), left anterior branch pacing (LAFP) and left posterior branch pacing (LPFP). However, whether the outcomes of various pacing modes differ in heart failure (HF) patients is still unclear. This study aimed to compare the electrophysiological characteristics and echocardiographic response rate among those distinct modes of LBBAP. HF patients undergoing successful LBBAP were retrospectively included. Distinct modes of pacing were determined based on paced QRS morphology. The fluoroscopic images were collected to compare the lead tip position between the groups. The electrocardiograms (ECG) before and after LBBAP were used to measure the depolarization (QRS duration [QRSd] and the interventricular delay [IVD]), and the repolarization parameters [QTc, TpeakTend(TpTe), and TpTe/QTc]. The left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDD) of patients were also recorded. In addition, the lead parameters and certain complications were compared. A total of 64 HF patients were finally included, consisting of 16 (25.0%) patients in the LBTP group, 22 (34.4%) patients in the LAFP group, and 26 (40.6%) patients in the LPFP group. The distribution features of LBBAP lead tips were significantly related to pacing modes: LBTP was more likely to be in zone 4 while LAFP or LPFP was prone to locate in zone 5. After LBBAP, the ventricular ECG parameters were significantly improved, regardless of pacing modes. Besides, the LVEF of the patients was significantly increased (P < 0.001), and LVEDD was significantly decreased (P < 0.001). There was no difference in the response rate and super-response rate among groups (P > 0.05). In addition, the lead parameters remained stable and no significant difference was observed among groups. LPFP was the main pacing mode among HF patients after LBBAP. The paced QRS morphology was significantly related to the position of lead tips. After LBBAP, the ventricular depolarization synchronization and repolarization stability were both significantly improved, regardless of pacing modes. There was no significant difference in the echocardiographic response rate among distinct LBBAP modes.

The electrical restitution of the non-propagated cardiac ventricular action potential.

Sudden changes in pacing cycle length are frequently associated with repolarization abnormalities initiating cardiac arrhythmias, and physiologists have long been interested in measuring the likelihood of these events before their manifestation. A marker of repolarization stability has been found in the electrical restitution (ER), the response of the ventricular action potential duration to a pre- or post-mature stimulation, graphically represented by the so-called ER curve. According to the restitution hypothesis (ERH), the slope of this curve provides a quantitative discrimination between stable repolarization and proneness to arrhythmias. ER has been studied at the body surface, whole organ, and tissue level, and ERH has soon become a key reference point in theoretical, clinical, and pharmacological studies concerning arrhythmia development, and, despite criticisms, it is still widely adopted. The ionic mechanism of ER and cellular applications of ERH are covered in the present review. The main criticism on ERH concerns its dependence from the way ER is measured. Over the years, in fact, several different experimental protocols have been established to measure ER, which are also described in this article. In reviewing the state-of-the art on cardiac cellular ER, I have introduced a notation specifying protocols and graphical representations, with the aim of unifying a sometime confusing nomenclature, and providing a physiological tool, better defined in its scope and limitations, to meet the growing expectations of clinical and pharmacological research.

Abstract 12538: Intermittent Hypoxemia Progressively Destabilizes Ventricular Repolarization in Healthy Awake Subjects

Introduction : Obstructive sleep apnea (OSA) is highly prevalent in the general population. OSA is associated with adverse cardiovascular events, including sudden cardiac death, but the mechanism is unclear. Intermittent hypoxemia, a pathognomonic feature of OSA, could increase the propensity for abnormal ventricular repolarization. We previously found that short-term exposure of awake healthy subjects to recurrent hypoxic episodes increased their heart rate (HR) and HR variability. Hypothesis: Exposure to intermittent hypoxia increases ventricular repolarization instability in awake healthy subjects. Methods: Healthy adults (N = 19) were exposed to either intermittent hypoxia or air for 4 hours on two different days in a randomized order. Intermittent hypoxia was induced with exposure to hypoxic gas (95% N 2 and 5% O 2 ) or ambient air in an alternative fashion at a frequency of ⁓ 25 times/hour, mimicking moderate to severe OSA. Repolarization stability was assessed using the QT variability index (QTVI), a validated predictor of cardiac arrhythmias and mortality. HR and QTVI were measured from one-lead ECG over consecutive 5-min epochs. Paired sample t - test was used to assess statistical associations. Results: Mean oxygen saturation levels were lower during exposure to intermittent hypoxia (90.86 ± 0.19%) versus normoxia (97.37 ± 0.20%, P &lt; 10 -13 ). Electrocardiographic measures at baseline were similar between the two conditions. No changes in these measures were noted during the conditions of normoxia. However, with intermittent hypoxia, mean HR and QTVI steadily increased (HR: 63.31 ± 1.51 initial, 69.21 ± 2.14 final, P &lt; 0.001; QTVI: -1.85 ± 0.04 initial, -1.64 ± 0.07 final, P = 0.016). By the end of the 4-hour experiment, QTVI was greater in hypoxia vs. normoxia (final QTVI in hypoxia: -1.64 ± 0.07, in normoxia: -1.86 ± 0.06, P = 0.021). Conclusion: Four hours of intermittent hypoxia in awake normal healthy subjects progressively destabilized ventricular repolarization. Chronic exposure to recurrent periods of intermittent hypoxemia in OSA can increase ventricular repolarization and contribute to the OSA-associated adverse cardiovascular events, including sudden cardiac death.

Comparison of immediate changes of repolarization parameters after left bundle branch area pacing and traditional biventricular pacing in heart failure patients.

Comparison of immediate changes of repolarization parameters after left bundle branch area pacing and traditional biventricular pacing in heart failure patients.

Depolarization and repolarization dynamics after His-bundle pacing: Comparison with right ventricular pacing and native ventricular conduction.

BackgroundThe current study aimed to evaluate changes in electrical depolarization and repolarization parameters after His‐bundle pacing (HBP) compared with right ventricular pacing (RVP) and its association with ventricular arrhythmia (VA).MethodsForty‐one patients (13 with HBP, 14 with RVP, and 14 controls [AAI mode]) were evaluated. After continuous pacing algorithm, QRS duration, QT interval, QTc, JT interval, T‐peak to T‐end (Tpe), and Tpe/QT ratio were measured on electrocardiography at baseline and 1 week, 1 month, and 6 months postoperatively. We investigated VA occurrence and adverse events after implantation.ResultsAt 6 months, QRS duration was significantly shorter in the HBP (121.6 ± 15.6 ms) than in the RVP (150.1 ± 14.9 ms) group. The QT intervals were lower in the HBP (424.0 ± 40.9 ms) and control (405.9 ± 23.0 ms) groups than in the RVP (453.0 ± 40.2 ms) group. The Tpe and Tpe/QT ratios at 6 months differed significantly between the HBP and RVP groups (Tpe, 69.8 ± 19.7 ms vs 87.4 ± 11.9 ms and Tpe/QT, 0.16 ± 0.03 vs 0.19 ± 0.02, respectively). The Tpe and Tpe/QT ratios were similarly shortened in the HBP and control groups. VA occurred less frequently in the HBP (15%) and control (7.1%) groups than in the RVP (50%) group (p = 0.020). The non‐RVP group showed significantly lower rates of VA and major adverse events than the RVP group. Patients with VA demonstrated significantly longer QRS duration, QT interval, Tpe, and Tpe/QT at 6 months than those without VA.ConclusionHBP showed better depolarization and repolarization stability than RVP.

Balance Between Rapid Delayed Rectifier K+ Current and Late Na+ Current on Ventricular Repolarization: An Effective Antiarrhythmic Target?

Rapid delayed rectifier K+ current (IKr) and late Na+ current (INaL) significantly shape the cardiac action potential (AP). Changes in their magnitudes can cause either long or short QT syndromes associated with malignant ventricular arrhythmias and sudden cardiac death. Physiological self AP-clamp was used to measure INaL and IKr during the AP in rabbit and porcine ventricular cardiomyocytes to test our hypothesis that the balance between IKr and INaL affects repolarization stability in health and disease conditions. We found comparable amount of net charge carried by IKr and INaL during the physiological AP, suggesting that outward K+ current via IKr and inward Na+ current via INaL are in balance during physiological repolarization. Remarkably, IKr and INaL integrals in each control myocyte were highly correlated in both healthy rabbit and pig myocytes, despite high overall cell-to-cell variability. This close correlation was lost in heart failure myocytes from both species. Pretreatment with E-4031 to block IKr (mimicking long QT syndrome 2) or with sea anemone toxin II to impair Na+ channel inactivation (mimicking long QT syndrome 3) prolonged AP duration (APD); however, using GS-967 to inhibit INaL sufficiently restored APD to control in both cases. Importantly, INaL inhibition significantly reduced the beat-to-beat and short-term variabilities of APD. Moreover, INaL inhibition also restored APD and repolarization stability in heart failure. Conversely, pretreatment with GS-967 shortened APD (mimicking short QT syndrome), and E-4031 reverted APD shortening. Furthermore, the amplitude of AP alternans occurring at high pacing frequency was decreased by INaL inhibition, increased by IKr inhibition, and restored by combined INaL and IKr inhibitions. Our data demonstrate that IKr and INaL are counterbalancing currents during the physiological ventricular AP and their integrals covary in individual myocytes. Targeting these ionic currents to normalize their balance may have significant therapeutic potential in heart diseases with repolarization abnormalities. Visual Overview: A visual overview is available for this article.

Restitution and Stability of Human Ventricular Action Potential at High and Variable Pacing Rate

Despite the key role of beat-to-beat action potential (AP) variability in the onset of ventricular arrhythmias at high pacing rate, the knowledge of the involved dynamics and of effective prognostic parameters is largely incomplete. Electrical restitution (ER), the way AP duration (APD) senses changes in preceding cycle length (CL), has been used to monitor transition to arrhythmias. The use of standard ER (sER), though, is controversial, not always suitable for in vivo and only rarely for clinical applications. By means of simulations on a human ventricular AP model, I investigate the dynamics of APD at high pacing rate under sinusoidally, saw-tooth, and randomly variable pacing CLs. AP sequences were compared in terms of beat-to-beat restitution (btb-ER) and of the collections of sER curves generated from each beat. A definition of APD stability is also proposed, based on successive APD changes introduced in an AP sequence by a premature beat. The explored CL range includes values leading to APD alternans under constant pacing. Three different types of response to CL variability were found, corresponding to progressively higher rate of beat-to-beat CL changes. Low rates (∼1 ms/beat) generate a btb-ER dominated by steady-state rate dependence of APD (type 1), intermediate rates (∼5 ms/beat) lead to a btb-ER similar to a single sER (type 2), and high rates (∼20 ms/beat) to hysteretic btb-ER under periodic pacing and to a vertically spread btb-ER in the case of random pacing (type 3). Stability of AP repolarization always increases with the rate of CL changes. Thus, rather than looking at sER slope, which requires additional interventions during the recording of cardiac electrical activity, this study provides rationale for the use of btb-ER representations as predictors of repolarization stability under extreme pacing conditions, known to be critical for the arrhythmia development.

Predisposition of functional genetic variants of A-kinase anchoring protein 10 toward acquired repolarization disorders in high-risk vascular surgery patients

PurposeWe aimed at assessing the predisposition of A-kinase anchoring protein 10 (AKAP10) polymorphism toward acquired repolarization disorders in high-risk vascular surgery patients.Patients and methodsOne hundred adult patients (age =44–85 years), scheduled for an elective high-risk “open” vascular surgery procedure, were recruited. The electrocardiogram Holter monitor was used to assess repolarization stability from the beginning of the operation up to 24 hours afterward. The AKAP10 gene rs203462 polymorphism and cardiac complications were analyzed.ResultsRepolarization disturbances defined as QT interval duration corrected for heart rate (QTc) interval prolongation >500 ms and QTc interval dispersion >65 ms were recorded in 46 patients. A model of multivariate logistic regression showed that only the presence of allele G of the AKAP10 polymorphism was an independent risk factor for repolarization disturbances in the perioperative period (odds ratio =14.35; 95% CI =4.65–44.23; p<0.0001).ConclusionWhen the acquired QTc interval prolongation or QTc dispersion is associated with AKAP10 polymorphism, it may remain clinically silent.

Short-term action potential memory and electrical restitution: A cellular computational study on the stability of cardiac repolarization under dynamic pacing.

Electrical restitution (ER) is a major determinant of repolarization stability and, under fast pacing rate, it reveals memory properties of the cardiac action potential (AP), whose dynamics have never been fully elucidated, nor their ionic mechanisms. Previous studies have looked at ER mainly in terms of changes in AP duration (APD) when the preceding diastolic interval (DI) changes and described dynamic conditions where this relationship shows hysteresis which, in turn, has been proposed as a marker of short-term AP memory and repolarization stability. By means of numerical simulations of a non-propagated human ventricular AP, we show here that measuring ER as APD versus the preceding cycle length (CL) provides additional information on repolarization dynamics which is not contained in the companion formulation. We focus particularly on fast pacing rate conditions with a beat-to-beat variable CL, where memory properties emerge from APD vs CL and not from APD vs DI and should thus be stored in APD and not in DI. We provide an ion-currents characterization of such conditions under periodic and random CL variability, and show that the memory stored in APD plays a stabilizing role on AP repolarization under pacing rate perturbations. The gating kinetics of L-type calcium current seems to be the main determinant of this safety mechanism. We also show that, at fast pacing rate and under otherwise identical pacing conditions, a periodically beat-to-beat changing CL is more effective than a random one in stabilizing repolarization. In summary, we propose a novel view of short-term AP memory, differentially stored between systole and diastole, which opens a number of methodological and theoretical implications for the understanding of arrhythmia development.

A Novel Approach to Measure Short Term Cardiac Ventricular Action Potential Memory: Comparison between Five Numerical Models

Rate-dependence (RD) and electrical restitution (ER) describe the dependence of cardiac action potential duration (APD) from the average or from the previous pacing cycle length (CL). We know however that in certain dynamic conditions APD depends not only from the average of from the previous, but from a given small number (3 to 5) of CLs preceding each beat. Such dependence is usually called short term AP memory (STAM) and has been shown to control repolarization stability. Despite the relevance of STAM for the transition to arrhythmias, a clear definition of it and a way to measure it are still lacking, making it difficult to compare findings from different preparations/laboratories. By means of simulations carried out on 5 different human cardiac ventricular AP models, I provide a novel general definition of STAM which is substantially different from those proposed in literature so far, and is based on the collective behavior of the family of ER curves that describe the system during dynamic pacing. I show how STAM can predict repolarization stability under high- and beat-to-beat-variable pacing rate after singular perturbations of the rhythm. The measure of STAM in the 5 AP models shows that memory involves a number of preceding beats up to 15 at high pacing rate (CL = 320 ms). I monitored STAM over consecutive beats during periodic and random pacing trains in a compact representation that allows comparison between models. STAM, as measured here, compactly represents otherwise hidden dynamic properties of cardiac AP at high pacing rate, which is of great interest in a variety of cardiac electrophysiological issues, like the mechanism underlying latent instability of repolarization in LQT1 syndrome, to cite one.

Memory and Stability of the Cardiac Action Potential Repolarization in the Space of its Allowed States: A Single Cell Simulation Study

The rate-dependent partition of the cardiac cycle into diastole and systole is measured at the cellular level as rate-dependence (RD) and electrical restitution (ER) of the action potential (AP) duration (APD), the first describing changes in APD after steady state changes in cycle length (CL), and the second APD changes after a sudden switch from constant to a variably delayed CL, as a function of the pre-switch CL (or DI). A dynamic ER curve (DER) can also be measured under beat-to-beat changes in pacing rate, and the increase in its slope is a recognized predictor of electrical alternance and ventricular fibrillation. An hysteretic behavior has been described previously in DER curve and associated with cardiac memory and repolarization stability. In the present study, by means of simulations with three numerical models of the human ventricular AP, I measure DER as APD vs DI and APD vs CL plots from high frequency paced AP series, and find that both show hysteresis with remarkably different phase shifts. Based on both representations, I define and measure a space of states (SPoS) for APs elicited, in turn, at constant, periodically changing, and randomly changing (1, 2, and 3 dimensional SPoS) pacing rates, and use them to study perturbations (a single missing beat) of the pacing protocol. I show how the maximum conductance and gating kinetics of three plateau ion currents (IKs, IKr, and ICaL), change shape and size of SPoS. I show how geometrical parameters of SPoS, for a given AP type and a given pacing law, can be used to numerically quantify memory and stability of its dynamics.

Change of QT variability index during general anesthesia.

BackgroundThe QT variability index (QTVI)–a non-invasive measure of beat-to-beat QT interval (QTI) fluctuations–is related to myocardial repolarization lability. The QTVI represents the relationship between QTI and the RR interval. Elevated QTVI is associated with an increased risk of malignant ventricular arrhythmias and sudden death. We investigated the influence of general anesthesia and tourniquets on the QTVI.MethodsWe studied fifty patients who received total knee replacement arthroplasty under sevoflurane anesthesia. We measured QTI, corrected QTI (QTc), T-wave peak-to-end interval (TPE), QTVI, and heart rate variability. All variables were calculated at baseline (B), 30 min after general anesthesia (A), 30 min (TQ1) and 60 min (TQ2) after tourniquet inflation, and at tourniquet deflation (TQR).ResultsProlongation of QTI was detected at all times, and QTc was significantly prolonged TQR. TPE was unchanged during general anesthesia. The QTVI was significantly decreased and more negative during anesthesia and tourniquet inflation. After deflation of the tourniquet, the QTVI was restored to preanesthetic values. Low frequency (LF) was significantly decreased during general anesthesia, but high frequency (HF) was somewhat maintained, except at TQ2. The LF/HF ratio was significantly decreased at A and TQ2.ConclusionsSevoflurane based general anesthesia induced repolarization stability and, more negativity of the QTVI, in patients undergoing total knee replacement arthroplasty.

Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure.

The role of IKCa in cardiac repolarization remains controversial and varies across species. The relevance of the current as a therapeutic target is therefore undefined. We examined the cellular electrophysiologic effects of IKCa blockade in controls, chronic heart failure (HF) and HF with sustained atrial fibrillation. We used perforated patch action potential recordings to maintain intrinsic calcium cycling. The IKCa blocker (apamin 100 nM) was used to examine the role of the current in atrial and ventricular myocytes. A canine tachypacing induced model of HF (1 and 4 months, n = 5 per group) was used, and compared to a group of 4 month HF with 6 weeks of superimposed atrial fibrillation (n = 7). A group of age-matched canine controls were used (n = 8). Human atrial and ventricular myocytes were isolated from explanted end-stage failing hearts which were obtained from transplant recipients, and studied in parallel. Atrial myocyte action potentials were unchanged by IKCa blockade in all of the groups studied. IKCa blockade did not affect ventricular myocyte repolarization in controls. HF caused prolongation of ventricular myocyte action potential repolarization. IKCa blockade caused further prolongation of ventricular repolarization in HF and also caused repolarization instability and early afterdepolarizations. SK2 and SK3 expression in the atria and SK3 in the ventricle were increased in canine heart failure. We conclude that during HF, IKCa blockade in ventricular myocytes results in cellular arrhythmias. Furthermore, our data suggest an important role for IKCa in the maintenance of ventricular repolarization stability during chronic heart failure. Our findings suggest that novel antiarrhythmic therapies should have safety and efficacy evaluated in both atria and ventricles.

Processes of Ageing and Fatigue in Lead Titanate Thin Films

Processes of ageing and fatigue in lead titanate thin films are experimentally investigated. The films under discussion were synthesized by plasma-enhanced magnetron sputtering of titanium and lead on titanium, silicon and polycor substrates in an argon environment, and subsequent annealing in an oxygen atmosphere. High temperature resistance, long shelf ageing and repolarization stability of lead titanate films on polycor substrates was shown. Reduction of polarization under cyclic switching in sine wave electric field to the minimal value happens after 10 11 cycles. Partial recovery of the basic dielectric characteristics of lead titanate thin films was observed during relaxation without external influences.

Rate dependency of beta-adrenergic modulation of repolarizing currents in the guinea-pig ventricle.

Beta-adrenergic stimulation modulates ventricular currents and sinus cycle length (CL). We investigated how changes in CL affect the current induced by isoprenaline (Iso) during the action potential (AP) of guinea-pig ventricular myocytes. Action-potential clamp was applied at CLs of 250 and 1000 ms to measure: (1) the net current induced by 0.1 microm Iso (I(Iso)); (2) the L-type Ca2+ current I(CaL) and slow delayed rectifier current I(Ks) components of I(Iso) (I(IsoCa) and I(IsoK)), identified as the Iso-induced current sensitive to nifedipine and HMR1556, respectively; and (3) I(Iso) persisting after inhibition of both I(Ca) and I(Ks) (I(isoR)). The pause dependency of I(Ks) and its modulation were evaluated in voltage-clamp experiments. The rate dependency of the duration of the action potential at 90% repolarization (APD90) and its modulation by isoprenaline were tested in current-clamp experiments. At a CL of 250 ms I(Iso) was inward during initial repolarization and reversed at 59% of APD90. At a CL of 1000 ms I(Iso) became mostly inward in all cells. Switching to shorter CL did not change I(IsoCa) and I(IsoK) amplitudes, but moved their peak amplitudes to earlier repolarization; I(IsoR) was independent of CL. Acceleration of I(IsoK) at shorter CL was based on faster pause dependency of I(Ks) activation rate. The 'restitution' of activation rates was modulated by isoprenaline. The APD90-CL relation was rotated anticlockwise by isoprenaline and crossed the control curve at a CL of 150 ms (400 beats min(-1)). We conclude that: (1) isoprenaline induced markedly different current profiles according to pacing rate, involving CL-dependent I(Ca) and I(Ks) modulation; (2) the effect of isoprenaline on APD90 was CL dependent, and negligible during tachycardia; and (3) during sympathetic activation, repolarization stability may involve matched modulation of sinus rate and repolarizing currents.

Usefulness of magnesium sulfate in stabilizing cardiac repolarization in heart failure secondary to ischemic cardiomyopathy

Experimental heart failure is associated with cardiac magnesium loss, causing increased beat-to-beat variability in the action potential. Unstable repolarization contributes to sudden death, but no therapy has been shown to reduce repolarization variability safely. We sought to test whether a prolonged infusion of magnesium sulfate (MgSO4; 40 mmol/24 hours) would normalize QT interval variability in patients with compensated heart failure. Fifteen patients (New York Heart Association class II to III; mean age 63 years) were enrolled in a placebo-controlled, double-blind study. Surface electrocardiograms were recorded and digitized at entry and at 48 and 168 hours (drug washout). Repolarization stability was assessed using an automated method measuring each QT interval in a 5-minute epoch. The QT variability index was derived as the ratio of normalized QT-to-normalized heart rate variability. Seven of 15 patients received MgSO4. Mean heart rate and QT did not change in either group. The QT variability index was stable in the placebo group (−0.69 ± 0.15 at entry, −0.71 ± 0.22 at 48 hours, −0.70 ± 0.18 at 168 hours), but decreased significantly in the treated group at 48 hours (−0.95 ± 0.19 to −1.36 ± 0.13, p <0.05 repeated-measures analysis of variance), returning to baseline at 168 hours (−0.84 ± 0.18). Regression analyses showed that administration of MgSO4 resulted in a stronger correlation between the QT and RR interval (p <0.01). Thus, MgSO4 stabilizes cardiac repolarization in patients with compensated heart failure due to ischemic heart disease. Magnesium therapy may be useful in altering the proarrhythmic substrate in heart failure.