Cessation Of Pacing Research Articles

Abstract 10194: Pacing Site- and Rate-Dependent Shortening of Retrograde Conduction Time Over the Slow Pathway After Atrial Entrainment of Fast-Slow Atrioventricular Nodal Reentrant Tachycardia

Introduction: The entrainment rule by which the site of entrainment has no effect on the orthodromic conduction time across the reentry circuit immediately after cessation of pacing has not been unequivocally verified in atypical atrioventricular nodal reentrant tachycardia (AVNRT). We have recently observed a unique electrophysiological response upon atrial induction of fast-slow (F/S-) AVNRT, characterized by a shortening of the retrograde conduction time across the slow pathway (SP) (retro-SP-time). Hypothesis: Atrial entrainment pacing (EP) of a) the common-type (com-) F/S-AVNRT using a typical SP, or b) the superior-type (sup-) F/S-AVNRT using a superior SP, both might modify the retro-SP-time immediately after termination of EP. Methods: In 16 patients of com-F/S-AVNRT and 11 patients of sup-F/S-AVNRT in whom successful EP from the high right atrium (EP-HRA) and the proximal coronary sinus (EP-CS) was obtained at 2±2 rates, we evaluated the difference in the His-atrial (HA) interval measured immediately after cessation of each EP attempt (HA difference) between EP-HRA and EP-CS (HA[1]-HRA and HA[1]-CS, respectively) and also measured atrial-His and HA intervals in the 1st and 2nd cycles immediately after the EP, and during tachycardia stabilized. Results: >20 ms HA difference, defined as an atypical difference, at ≥1 rates of EP was observed in 16 patients (56%), including 7 with com- and 9 with sup-F/S-AVNRT. Irrespective of the EP rate, the atypical response of com-F/S-AVNRT was always due to a shorter HA[1]-CS than HA[1]-HRA, with a 39±22 ms HA difference, whereas the atypical response of sup-F/S-AVNRT was always due to a longer HA[1]-CS than HA[1]-HRA, with a 51±26 ms HA difference. Moreover, the atypical response disappeared within 2 cycles after the cessation of EP. The atypical difference, although its exact mechanism remains unclear, might attribute to a shortening of the retro-SP-time according to decremental properties of the SP with deeper antidromic penetration during EP provoked depending on the site and rate of pacing. Conclusions: We have identified a little-known pacing site- and pacing rate-dependent shortening of the retro-SP-time. This phenomenon may affect an interpretation of post-pacing interval after EP of F/S-AVNRT.

Surface ECG criteria can discriminate post-septal pacing cardiac memory from ischemic T wave inversions

Cardiac memory (CM) refers to transient T wave changes that appear after cessation of a period of abnormal ventricular activation, such as right ventricular (RV) pacing. ECG criteria for differentiating post-pacing CM from ischemia-induced T wave changes were previously published only for apical, but not for septal RV pacing. AimTo find ECG criteria for discriminating post-septal pacing CM from ischemic T wave inversions. MethodsECGs were analyzed in 2 groups: CM (n = 23) and ischemia (n = 26). CM was induced by 2 weeks of DDD pacing with a short AV delay. Ischemic patients were grouped by culprit vessel: left anterior descending (LAD), circumflex (Cx), right coronary artery (RCA). ResultsCM was visible on the ECG after 1 week of ventricular pacing, started to disappear in <1 week after pacing cessation and was completely reversible within 4 weeks of pacing cessation. T wave axis differed between CM (75.8 ± 18.5°) and Cx (−25.2 ± 25.5°, p < 0.01) and RCA (−18.3 ± 18.9°, p < 0.01) groups, but not compared to LAD group (96.4 ± 65.0°, p = 0.17). The combination of (1) positive T wave in aVF; and (2) (i) T wave amplitude in aVF ≥ the absolute value of the most negative precordial T wave, or (ii) positive T wave in V5 and positive or isoelectric T wave in lead I identified CM from all ischemia with a sensitivity of 91% and a specificity of 92%. ConclusionECG criteria can discriminate post-septal RV pacing CM from ischemic changes with high sensitivity and specificity.

Anterograde His bundle activation during right ventricular overdrive pacing in supraventricular tachycardia.

Differentiation between atrioventricular nodal re-entrant tachycardia (AVNRT), atrioventricular re-entrant tachycardia (AVRT), and atrial tachycardia (AT) is often challenging during electrophysiology studies. This study compared the sensitivity and specificity of identifying anterograde His bundle activation during entrainment with commonly used right ventricular (RV) pacing maneuvers to differentiate between these types of supraventricular tachycardia (SVT). Out of 112 consecutive patients with SVT, 90 (36 males [40%], age 37 ± 16 years) were prospectively studied. After entrainment during RV pacing, atrial response upon cessation of pacing, anterograde His activation during entrainment, stimulus-atrial (SA), ventriculoatrial (VA) intervals, and post-pacing interval minus tachycardia cycle length (PPI-TCL) were determined. Ventricular extrastimulation during tachycardia and para-Hisian pacing were performed. The final diagnosis was AVNRT in 54, AVRT in 33, and AT in 3 patients. Entrainment was achieved in 87(96%) patients. Anterograde His bundle activation predicted AVRT (sensitivity: 62.5%, specificity: 100%). PPI-TCL ≥129ms predicted AVNRT (sensitivity: 83%, specificity: 84%), as did SA-VA value ≥85ms (sensitivity: 91%, specificity: 87%). Atria were advanced during transition zone in 57% of AVRTs. Atrial pre-excitation in response to progressively premature ventricular extrastimuli identified AVRT (sensitivity: 90%, specificity: 85%). Pre-excitation index ≥87ms identified AVNRT (sensitivity: 80%, specificity: 100%). Para-Hisian pacing identified AVRT (sensitivity: 25%, specificity: 100%). RV pacing maneuvers, applied in isolation, can misclassify a significant proportion of SVTs. Identifying anterograde His bundle activation during entrainment can complement other discriminators in differential diagnosis of SVT, with greatest sensitivity in septal and right-sided accessory pathways.

Cessation of pacing in super-responders of cardiac resynchronization therapy: A randomized controlled trial.

The consequence of cessation of biventricular pacing in super-responders of cardiac resynchronization therapy (CRT) has not been fully investigated. In this prospective, single-blinded clinical trial, 21 super-responders were randomly assigned to the ceased pacing (CeP, 11 patients) group or the continued pacing (CoP, 10 patients) group. Patients randomized to the CeP group underwent cessation of biventricular pacing. New York Heart Association (NYHA) class, quality of life (QOL) assessed with Minnesota questionnaire, 6-minute walking distance (6MWD), left ventricular end systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and left ventricular ejection fraction (LVEF) were compared between groups at 3- and 6-month follow-up. No significant difference was observed between the CeP and CoP groups regarding NYHA class, QOL, 6MWD, LVESV, LVEDV, or LVEF after 3 months (all P > 0.05). After 6 months, there existed no significant difference between the CeP and CoP groups with regard to NYHA class, QOL, 6MWD, LVESV, and LVEDV (all P > 0.05); however, LVEF was significantly lower in the CeP group than that of the CoP group (0.49 ± 0.10 vs 0.60 ± 0.11, P = 0.04), and LVEF was significantly reduced in the CeP group compared with the baseline value at randomization (0.49 ± 0.10 vs 0.54 ± 0.06, P = 0.04). LVEF was significantly reduced in super-responders of CRT 6 months after cessation of pacing. Super-responders to CRT should receive continued, long-term pacing to preserve recovered LV function.

Regional Mechanical Changes Assessed by 2D Speckle-Tracking Longitudinal Strain do not Parallel Electrical Post-Pacing Cardiac Memory.

Cardiac memory (CM) refers to persistent T-wave changes that appear after cessation of a period of abnormal ventricular activation, such as ventricular pacing. Prior animal studies using tagged magnetic resonance imaging have suggested that CM is associated with prolonged action potential duration and increased strain of late-activated myocardial segments. The aim of the present study is to determine whether CM induced by ventricular pacing in human subjects is accompanied by regional mechanical changes in late-activated myocardial segments, assessed by left ventricular (LV) longitudinal strain (peak LS) and time-to-peak longitudinal strain (TTP-LS), using 2D-speckle tracking echocardiography (2DSE). We included 20 patients (16 women, age 71±11 years), with DDD pacemakers and with normal AV conduction and QRS/T morphology at baseline. CM was induced by DDD pacing with a short AV delay. ECGs and 2DSE were performed before pacing (baseline), at peak CM (immediately after two weeks of pacing), and at CM washout (4 weeks after cessation of pacing). We measured by echocardiography: left ventricular (LV) ejection fraction, LV diastolic function (E, A, E/E'), peak LS and TTP-LS for the earliest (i.e. adjacent to the pacing site) and latest (i.e. latest-activated during ventricular pacing) segments, using an 18-segment LV model. All patients had electrical (ECG) CM changes, which disappeared by CM washout. LV global systolic and diastolic functions, as well as regional LS (peak LS for both the latest and earliest activated segments) were similar between evaluations. TTP for the latest and earliest activated segments, as well as mean TTP-LS, increased from baseline to peak CM, but did not decrease at CM washout. The dispersion of TTP-LS was not changed. These results suggest that regional mechanical changes, as can be assessed by 2DSE longitudinal strain, do not overlap electrical CM.

Effect of α7nAChR mediated cholinergic anti-inflammatory pathway on inhibition of atrial fibrillation by low-level vagus nerve stimulation

Objective: To investigate the effect of α7nAChR mediated cholinergic anti-inflammatory pathway on inhibition of atrial fibrillation by low-level vagus nerve stimulation(LL-VNS). Methods: Eighteen beagles were randomized into control group (n=6), LL-VNS group (n=6) and methyllycaconitine (MLA) + LL-VNS group (n=6). All the beagles were subjected to rapid atrial pacing at 800 beats/min for 6 hours.And the effective refractory period (ERP) of atriums and pulmonary veins and induced atrial fibrillation (AF) were measured hourly during non-pacing.After cessation of pacing for 3 hours, the beagles in control group were injected with saline into four ganglionated plexis (GPs), the beagles in LL-VNS group were given LL-VNS and saline injected into four GPs, and the beagles in MLA+ LL-VNS group were injected with MLA into four GPs combined with LL-VNS.And the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and acetylcholine (ACh) in the plasma at baseline condition, 3 h and 6 h were measured.At the end of this experiment, atrial tissues were collected to examine the levels of TNF-α, IL-6, ACh, NF-κBp65 and STAT3 proteins. Results: During the right atrium pacing for the first 3 hours, the ERPs were gradually decreased while AF inducibility were gradually increased in all groups. At the end of this experiment, compared with the control group and MLA+ LL-VNS group, the ERPs in LL-VNS group were increased, and the induced times and duration of AF were significantly decreased. The levels of TNF-α and IL-6 in plasma were all significantly decreased in LL-VNS group and MLA+ LL-VNS group when compared with the control group(pg/ml) [IL-6: (101±6) vs (119±7), P<0.05; (102±5) vs (119±7), P<0.05; TNF-α: (17.8±1.7) vs (22.1±2.0), P<0.05; (17.9±2.2) vs (22.1±2.0), P<0.05]. And the levels of ACh were higher than in the control group(μg/ml)[(151±13) vs (123±10), P<0.05; (145±5) vs (123±10), P<0.05]. After cessation of pacing for 6 hours, compared with the control groupand MLA+ LL-VNS group, the tissue levels of TNF-α and IL-6 were significantly decreased in LL-VNS group (P<0.05). The concentrations of NF-κBp65 proteins in atrial tissues were lower in the LL-VNS group (P<0.05), and the levels of STAT3 proteins in those tissues were higher in the LL-VNS group than in thein the two other groups (P<0.05). Conclusion: LL-VNS could inhibit the atrial electrical remodeling and atrial fibrillation induction; cholinergic anti-inflammatory pathway mediated by α7nAChR may be the important mechanism in vagal nerve regulated AF.

Tachycardia-Induced Cardiomyopathy As a Chronic Heart Failure Model in Swine.

A stable and reliable model of chronic heart failure is required for many experiments to understand hemodynamics or to test effects of new treatment methods. Here, we present such a model by tachycardia-induced cardiomyopathy, which can be produced by rapid cardiac pacing in swine. A single pacing lead is introduced transvenously into fully anaesthetized healthy swine, to the apex of the right ventricle, and fixated. Its other end is then tunneled dorsally to the paravertebral region. There, it is connected to an in-house modified heart pacemaker unit that is then implanted in a subcutaneous pocket. After 4 - 8 weeks of rapid ventricular pacing at rates of 200 - 240 beats/min, physical examination revealed signs of severe heart failure - tachypnea, spontaneous sinus tachycardia, and fatigue. Echocardiography and X-ray showed dilation of all heart chambers, effusions, and severe systolic dysfunction. These findings correspond well to decompensated dilated cardiomyopathy and are also preserved after the cessation of pacing. This model of tachycardia-induced cardiomyopathy can be used for studying the pathophysiology of progressive chronic heart failure, especially hemodynamic changes caused by new treatment modalities like mechanical circulatory supports. This methodology is easy to perform and the results are robust and reproducible.

Benefits of Cardiac Resynchronization Therapy in an Asynchronous Heart Failure Model Induced by Left Bundle Branch Ablation and Rapid Pacing

It is now well recognized that heart failure (HF) patients with left bundle branch block (LBBB) derive substantial clinical benefits from cardiac resynchronization therapy (CRT), and LBBB has become one of the important predictors for CRT response. The conventional tachypacing-induced HF model has several major limitations, including absence of stable LBBB and rapid reversal of left ventricular (LV) dysfunction after cessation of pacing. Hence, it is essential to establish an optimal model of chronic HF with isolated LBBB for studying CRT benefits. In the present study, a canine model of asynchronous HF induced by left bundle branch (LBB) ablation and 4 weeks of rapid right ventricular (RV) pacing is established. The RV and right atrial (RA) pacing electrodes via the jugular vein approach, together with an epicardial LV pacing electrode, were implanted for CRT performance. Presented here are the detailed protocols of radiofrequency (RF) catheter ablation, pacing leads implantation, and rapid pacing strategy. Intracardiac and surface electrograms during operation were also provided for a better understanding of LBB ablation. Two-dimensional speckle tracking imaging and aortic velocity time integral (aVTI) were acquired to validate the chronic stable HF model with LV asynchrony and CRT benefits. By coordinating ventricular activation and contraction, CRT uniformed the LV mechanical work and restored LV pump function, which was followed by reversal of LV dilation. Moreover, the histopathological study revealed a significant restoration of cardiomyocyte diameter and collagen volume fraction (CVF) after CRT performance, indicating a histologic and cellular reverse remodeling elicited by CRT. In this report, we described a feasible and valid method to develop a chronic asynchronous HF model, which was suitable for studying structural and biologic reverse remodeling following CRT.

Triggered intracellular calcium waves in dog and human left atrial myocytes from normal and failing hearts.

Abnormal intracellular Ca2+ cycling contributes to triggered activity and arrhythmias in the heart. We investigated the properties and underlying mechanisms for systolic triggered Ca2+ waves in left atria from normal and failing dog hearts. Intracellular Ca2+ cycling was studied using confocal microscopy during rapid pacing of atrial myocytes (36 °C) isolated from normal and failing canine hearts (ventricular tachypacing model). In normal atrial myocytes (NAMs), Ca2+ waves developed during rapid pacing at rates ≥ 3.3 Hz and immediately disappeared upon cessation of pacing despite high sarcoplasmic reticulum (SR) load. In heart failure atrial myocytes (HFAMs), triggered Ca2+ waves (TCWs) developed at a higher incidence at slower rates. Because of their timing, TCW development relies upon action potential (AP)-evoked Ca2+ entry. The distribution of Ca2+ wave latencies indicated two populations of waves, with early events representing TCWs and late events representing conventional spontaneous Ca2+ waves. Latency analysis also demonstrated that TCWs arise after junctional Ca2+ release has occurred and spread to non-junctional (cell core) SR. TCWs also occurred in intact dog atrium and in myocytes from humans and pigs. β-adrenergic stimulation increased Ca2+ release and abolished TCWs in NAMs but was ineffective in HFAMs making this a potentially effective adaptive mechanism in normals but potentially arrhythmogenic in HF. Block of Ca-calmodulin kinase II also abolished TCWs, suggesting a role in TCW formation. Pharmacological manoeuvres that increased Ca2+ release suppressed TCWs as did interventions that decreased Ca2+ release but these also severely reduced excitation-contraction coupling. TCWs develop during the atrial AP and thus could affect AP duration, producing repolarization gradients and creating a substrate for reentry, particularly in HF where they develop at slower rates and a higher incidence. TCWs may represent a mechanism for the initiation of atrial fibrillation particularly in HF.

Response to exercise and mechanical efficiency in non-ischaemic stunning, induced by short-term rapid pacing in dogs: a role for calcium?

Rapid pacing (RP) is a regularly used model to induce heart failure in dogs. The aim of the study was to evaluate Ca2+ handling, left ventricular (LV) contractile response during Ca2+ administration compared to exercise, as well as oxygen consumption and mechanical efficiency after 48h of RP. Fifty-three mongrel dogs were instrumented to measure LV pressure, LV fractional shortening, regional wall thickening and coronary blood flow. Contractile reserve was measured with isoproterenol and intravenous (IV) Ca2+ administration. To assess the function of the sarcoplasmic reticulum (SR), post-extrasystolic potentiation (PESP) and SR Ca2+ uptake were measured. A graded treadmill test was performed in baseline and after RP (n=14). In a separate group of animals (n=5), myocardial performance and oxygen consumption were measured using a wide range of loading conditions. Left ventricular contractility was significantly decreased upon cessation of pacing. The contractile response to isoproterenol was blunted compared to a preserved response to IV Ca2+ . Post-extrasystolic potentiation was slightly increased after RP. Maximal velocity (Vmax ) of SR Ca2+ uptake was unchanged. Contractile response during exercise is attenuated after RP. External work is reduced, whereas oxygen consumption is preserved, provoking a reduced mechanical efficiency. Forty-eight-hours RP provokes a reversible LV dysfunction, while the SR function and response to exogenous Ca2+ are preserved. This is compatible with an intracellular functional remodelling to counteract Ca2+ overload provoked by RP. Left ventricular dysfunction is accompanied by a reduced contractile reserve, but an unchanged oxygen consumption, illustrating an alteration in oxygen utilization.

Distinguishing between overdrive excited and suppressed ventricular beats in guinea pig ventricular myocardium.

Rapid ventricular pacing rates induces two types of beats following pacing cessation: recovery cycle length (RCL) prolongation (overdrive suppression) and RCL shortening (overdrive excitation). The goals of this study were to compare common experimental protocols for studying triggered activity in whole-heart preparations and differentiate between recovery beats using a new methodology. Post-pacing recovery beat cycle length (RCL) and QRS were normalized to pre-paced R-R and QRS intervals and analyzed using a K-means clustering algorithm. Control hearts only produced suppressed beats: RCL ratio increased with rapid pacing (25 ± 4.0%, n = 10) without changing QRS duration. Rapid pacing during hypercalcemia + hypothermia (5.5 mM and 34°C) produced significantly earlier excited beats (53 ± 14%, n = 5) with wider QRS durations (58 ± 6.3%, n = 5) than suppressed beats. Digoxin + hypothermia (0.75 μM) produced the most excited beats with significantly earlier RCL (44 ± 3.2%, n = 6) and wider QRS (60 ± 3.1%, n = 6) ratios relative to suppressed beats. Increasing pacing further shortened RCL (30 ± 7.8%, n = 6). In a prospective study, TTX (100 nM) increased RCL ratio (15 ± 6.0%, n = 10) without changing the QRS duration of excited beats. The algorithm was compared to a cross-correlation analysis with 93% sensitivity and 94% specificity. This ECG based algorithm distinguishes between triggered and automatic activity.

ASSA13-03-7 Renal Sympathetic Denervation Changes the Distribution of Atrial Substrate and Inhibites the Inducibility of Atrial Fibrillation

Objective Whether renal sympathetic denervation has effect on changes of atrial substrate and inducilibity of atrial fibrillation is unknown. The purpose of this study was to determine the effect of renal denervation on the inducibility atrial fibrillation. Methods Thirteen dogs were randomly divided into control group (7 dogs) and renal artery ablation group (6 dogs). In control group, at first, atrial fibrillation was induced by anterior right ganglionated plexi stimulation. Then, rapid atrial pacing was performed for 7 hours. Atrial effective refractory period and atrial fibrillation were measured each hour. In renal artery ablation group, after renal artery ablation, dogs were raised for 6 weeks. After that, the procedure of pacing and electrophysiological measurement was same as in the control group. Results The voltage in the sinus rate slowing response and the threshold of inducilibity atrial fibrillation increased during ganglionated plexi stimulation after renal artery ablation (3.5 ± 1.6V vs 1.6 ± 0.3V; 5.1V ± 1.0V vs 2.1V ± 0.7V, P = 0.03). Induced number of times and duration of atrial fibrillation was higher in control group than that in renal artery ablation group after cessation of pacing. Levels of ANP in right atrium and densities of Cx43 were lower in renal artery ablation group than that in control group (ANP: 220.5 ± 37.6 pg/mg vs 164.4 ± 22.0 pg/mg, P = 0.02; Cx43: 0.52, 0.63, 0.87 vs 1, 1.02, 1.91, P Conclusions Renal sympathetic denervation results in changes of atrial substrate and markedly decrease the inducilibity of atrial fibrillation by inhibiting activity of renin-angiotensin-aldosterone system.

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E0096 The study on the relations between aldosterone and atrial interstitial remodelling and atrial fibrillation

ObjectiveTo investigate the relations between aldosterone (Ald) and atrial interstitial remodelling and atrial fibrillation (AF).Methods18 healthy male hybrid dogs aged 15–18 months were divided into three groups randomly, the control...

Is “Hyper Response” to Cardiac Resynchronization Therapy in Patients with Nonischemic Cardiomyopathy a Recovery, a Remission, or a Control?

Some patients treated by cardiac resynchronization therapy (CRT) recover "normal" left ventricular (LV) function and functional status. However, whether this "normalization" persists or reverts over time remains unknown. The aim of the present study was to evaluate the long-term outcomes of LV function in patients hyper responder to CRT. Eleven consecutive patients with nonischemic dilated cardiomyopathy, sinus rhythm, left bundle branch block (LBBB), New York Heart Association (NYHA) class III or IV, and optimal pharmacological treatment were hyper responder as they fulfilled concurrently the two following criteria: functional recovery (NYHA class I or II) and normalization of LV ejection fraction (LVEF). After a mean follow-up of 65 ± 30 months between CRT implantation and last evaluation LVEF improved from 26 ± 9 to 59 ± 6% (P < 0.0001). One patient died from pulmonary embolism 31 months after implantation. Three patients exhibited LVEF ≤ 50% at their last follow-up visit (two at 40% and one at 45%). In eight patients, brief cessation of pacing was feasible (three were pacemaker-dependent). Mean QRS duration decreased from 181 ± 23 ms to 143 ± 22 ms (P = 0.006). In one patient, pacing was interrupted for 2 years and LVEF decreased markedly (from 65% to 31%) but returned to normal after a few months when pacing was resumed. In hyper responder patients, "normalization" of LV function after CRT persists as long as pacing is maintained with an excellent survival.

Ovine Models for Chronic Heart Failure

Testing and optimizing of surgical therapies for chronic heart failure (CHF) requires large animal models. CHF has been induced in several large animal species. Sheep have modest body mass increase and demonstrate docile behavior and are therefore a preferred species in research on surgical therapies for CHF METHODS: A literature search for existing ovine CHF models was performed, using search terms "sheep" and "heart failure". Relevant secondary references were traced. Rapid ventricular pacing produces rapid-onset CHFE Its severity ranges from moderate left ventricular failure to severe biventricular failure, depending on length and frequency of pacing. Its counterpart in human CHF is tachycardia-induced HF since it is reversible upon cessation of pacing. Myocardial damage models include CHF induced by cardiototoxic drugs and ischemia. Ischemia-based models include coronary microembolization, occlusion and ischemia/reperfusion models. The microembolization model is relevant to diabetic cardiomyopathy. Coronary occlusion models exhibit variable functional impairment, some with aneurysm formation, and some with mitral valve regurgitation, depending on occlusion localization. They are relevant to CHF following non-reperfused myocardial infarction. Coronary occlusion/reperfusion models are relevant to the occurrence of human ãã despite coronary artery recanalization. Pressure overload of left and right ventricle is induced by aortic and pulmonary artery banding, respectively. Hypertrophy precedes CHF as in patients with valve stenosis and hypertension. Volume overload is induced by valve damage or shunt creation. Atrioventricular valve regurgitation is the most important clinical counterpart. Several ovine CHF models exist. Since they exhibit important cardiac pathology differences, the choice of model should be based on the specific experimental question.

Sarcomere Shortening Destabilizes the Ca2+ Control System in Ventricular Myocytes: Implications for Understanding Arrhythmias in Familial Hypertrophic Cardiomyopathy

Familial hypertrophic cardiomyopathy (FHC) results from mutations of contractile proteins. Certain forms of FHC are linked with a surprisingly high incidence of sudden cardiac death. It is a long-standing conundrum how mutations in motor proteins give rise to electrical arrhythmias. Quantitative modeling studies using large-scale simulations reveal an intimate link between the contractile system and the Ca2+ control system. This insight may help resolve this conundrum. Our simulations show that a small decrease in sarcomere length (SL) can destabilize the Ca2+ control system and increase the probability of spontaneous Ca2+ waves. FHC mutations on cardiac troponin T (cTnT) increase myofilament Ca2+ sensitivity, which may account for the shortened SL in cardiomyocytes from mice harboring the cTnT mutations. To test the model predictions we conducted experiments using the myofilament Ca2+ sensitizer EMD 57033 (Merck) to reduce the resting SL length. EMD in the range of 1-3 μM reduced the resting SL from 1.9 to 1.5 μm without altering sarcoplasmic reticulum Ca2+ load, systolic, or diastolic Ca2+ levels. Upon cessation of pacing (1 Hz), control myocytes (0 EMD) were quiescent but EMD treated myocytes exhibited spontaneous contractions and Ca2+ release. These results are consistent with the model predictions lending support to the idea that FHC mutations destabilize the Ca2+ control system, which in turn, become a substrate for arrhythmias.

Heart Rate Variability in a Progressive Heart Failure Model with Rapid Ventricular Pacing

Heart rate variability (HRV) is an indicator of autonomic nervous system functionality and a recognized predictor of cardiac death; however, the changes in HRV occurring in progressive heart failure are not fully understood. The purpose of this study was to evaluate the progressive changes of autonomic system activity in progressive heart failure by rapid ventricular pacing in an animal model. Heart failure was induced in 13 mongrel dogs (27.8 +/- 3.7 kg) by rapid ventricular pacing (230 beats/min) for 4 weeks and maintenance of pacing at a reduced rate (190 beats/min) for 2 weeks. Time domain analysis and spectral analysis of HRV were performed with the MemCalc system after 30 minutes of pacing cessation every week. Hemodynamic and echocardiographic data were obtained before and after induction of heart failure. Cardiac output decreased significantly (3.6 L/min versus 1.6 L/min, P < .001) after 6 weeks of ventricular pacing. Significantly increased were the heart rate (126 beats/min versus 138 beats/min, P < .05), left ventricular end-diastolic pressure (9.1 mm Hg versus 30.9 mm Hg, P < .001), and pulmonary capillary wedge pressure (8.0 mm Hg versus 18.7 mm Hg, P < .001). High-frequency components progressively decreased. Low-frequency components progressively decreased except at 5 weeks after the pacing. A ratio of low- to high-frequency components increased in moderate heart failure and decreased in severe heart failure. Changes in the high-frequency component and low-frequency component are important for assessing heart failure in progressive heart failure. Serial follow-up measurements of HRV might be helpful for patients with such disease.

Abstract 3071: Reversible Transmural Electrical Dyssynchrony in Pacing-Induced Congestive Heart Failure

Introduction: Inter and Intra-ventricular dyssynchrony can develop during congestive heart failure (CHF). We investigated transmural electrical conduction properties within the LV wall during CHF and subsequent recovery. Methods: Biventricular pacemakers were implanted in 8 normal mongrel dogs (mean weight: 38 kg), and continuous RV pacing (230 –250 bpm) was initiated to induce CHF. Echocardiography, catheterization, and LV myocardial biopsy were performed biweekly while pacing was temporarily stopped. At each catheterization, an intracardiac electrode-catheter was placed at the LV endocardium against the pacemaker coronary sinus lead tip located at the LV epicardium. Intrinsic transmural electrical conduction delay was measured by recording endocardial electrograms via the electrode-catheter and epicardial electrograms via the pacemaker coronary sinus lead, both in posterolateral LV. The conduction delay was also assessed during LV pacing via the endocardial catheter and measuring the time to the coronary sinus lead tip. Pacing was stopped in 4 dogs with CHF to allow for recovery of function. All times were corrected for heart rate. Results: All dogs developed CHF within 2– 4 wks of pacing from baseline (EF: 27±8 vs. 49±4%; LVEDP: 20±9 vs. 6±3 mmHg; QRS: 98±8 vs. 70±14 msec with no LBBB). There was no change in LV wall thickness during CHF compared to baseline (0.9 cm), while LV myocyte size increased (21.7±6.6 vs. 16.2±1.5 μm). Transmural endocardial-to-epicardial intrinsic electrical conduction time lengthened during CHF compared to baseline (35±13 vs. 10±5msec, P&lt;0.001). In dogs recovering from CHF 2– 4 wks after cessation of pacing, intrinsic transmural endocardial-to-epicardial conduction time shortened compared to CHF (10±9 vs. 39±1ms, n=4), which was consistent with LV endocardial pacing (recovery: 47.5±6 ms; CHF: 70.7±9 ms, n=3). Conclusions: Electrical transmural dyssynchrony develops as a consequence of pacing-induced CHF, and is reversible upon recovery of cardiac function. These changes are not associated with LV wall thickness. This novel finding suggests another aspect of ventricular dyssynchrony that may not be reflected by routine noninvasive modalities and warrants further investigation.

Electrical pacing counteracts intrinsic shortening of action potential duration of neonatal rat ventricular cells in culture

Previous studies have demonstrated the relationship between the functional electrophysiological properties of cultured neonatal rat ventricular myocytes (NRVMs) and the ability of the substrate to induce and sustain arrhythmia. The goal of this study was to examine the effects of chronic pacing at a constant rate akin to that in vivo, on the functional electrophysiological properties of NRVM monolayers. Confluent NRVM monolayers grown on 20 mm diameter cover slips were left either unpaced or were stimulated at 3 Hz for the duration of the culture, and were optically mapped on days 4, 6, or 8. Action potential duration at 80% repolarization (APD 80), conduction velocity (CV), and Kv4.3 ( I to) and NCX protein expression were measured. The effects of the excitation–contraction uncoupler 2,3-butadione monoxime (BDM) were also investigated. The 2 Hz APD 80 of non-paced monolayers decreased significantly on days 6 (137.1 ± 13.9 ms) and 8 (109.8 ± 9.0 ms) compared with day 4 (197.0 ± 11.8 ms), while that of paced monolayers did not (206.8 ± 9.7, 209.1 ± 9.2, and 210.6 ± 9.9 ms, respectively). The 2 Hz CV of non-paced monolayers increased significantly on days 6 (26.0 ± 1.6 cm/s) and 8 (26.5 ± 1.0 cm/s) compared with day 4 (20.0 ± 1.0 cm/s), while that of paced monolayers did not change significantly (26.0 ± 2.0, 26.0 ± 1.0, and 23.8 ± 1.2 cm/s, respectively). The restitution curves of APD 80 and CV of paced monolayers were also unchanging from days 4 through 8. Despite the unchanging APD 80 and CV, a decrease in Kv4.3 expression and an increase in NCX expression were observed in paced compared with non-paced monolayers. Cessation of pacing or administration of BDM caused a reversal of phenotype back to that of non-paced monolayers. In summary, chronic electrical stimulation of confluent NRVM monolayers results in stabilization of APD 80 and an advancement of the developmental rise of CV that is mediated by electromechanical coupling. These effects produce a steadier functional phenotype that may be beneficial for electrophysiological studies.