Preventing ventricular fibrillation by flattening cardiac restitution

Ventricular fibrillation is the leading cause of sudden cardiac death. In fibrillation, fragmented electrical waves meander erratically through the heart muscle, creating disordered and ineffective contraction. Theoretical and computer studies, as well as recent experimental evidence, have suggested that fibrillation is created and sustained by the property of restitution of the cardiac action potential duration (that is, its dependence on the previous diastolic interval). The restitution hypothesis states that steeply sloped restitution curves create unstable wave propagation that results in wave break, the event that is necessary for fibrillation. Here we present experimental evidence supporting this idea. In particular, we identify the action of the drug bretylium as a prototype for the future development of effective restitution-based antifibrillatory agents. We show that bretylium acts in accord with the restitution hypothesis: by flattening restitution curves, it prevents wave break and thus prevents fibrillation. It even converts existing fibrillation, either to a periodic state (ventricular tachycardia, which is much more easily controlled) or to quiescent healthy tissue.     

快速起搏诱发心室颤动过程中的倍周期分岔和浑沌

目的：探讨室心动过速（VT）向心室颤动（VF）的转化是否表现为浑沌动力学特征。方法：用快速速起和搏法造成犬在体心脏驱动性VT并诱发VF；用非线性分析方法研究VT向VF转化时，心肌电生理学参数的震荡特点，结果：在VT向VF的转化过程中，激动周期（CL），冲动传导速度（CV）和R波振幅出现了交替节律，倍周期分岔，半周期等非线性震荡并最终陷入浑沌，结论：驱动性VT向VF的转化遵循非线性途径，因而VF是心肌激动陷入浑沌所致。     

Experimental congestive heart failure produced by rapid ventricular pacing in the dog: cardiac effects

Chronic rapid ventricular pacing in the dog reportedly produces a useful preparation of low-output heart failure. However, little information is available regarding cardiac changes in this preparation. Accordingly, we evaluated the effects of both short-term (3 weeks) and prolonged (2 months) rapid ventricular pacing on cardiac hemodynamics, mass, and chamber size. The effects of short-term pacing on left ventricular wall thickening, blood flow, and metabolism were also examined. Compared with 16 control dogs, dogs paced for either 3 weeks (n = 8) or 2 months (n = 13) exhibited reduced cardiac outputs (control 130 +/- 20 ml/min/kg, 3 week pacing 112 +/- 19 ml/min/kg, 2 month pacing 116 +/- 14 ml/min/kg) and elevated pulmonary wedge pressures (control 10 +/- 3 mm Hg, 3 week pacing 26 +/- 5 mm Hg, 2 month pacing 26 +/- 8 mm Hg) and right atrial pressures (control 4 +/- 1 mm Hg, 3 week pacing 13 +/- 3 mm Hg, 2 month pacing 9 +/- 3 mm Hg) (all p less than .01 vs control). At the postmortem examination, both groups of paced dogs also exhibited increased left ventricular volumes (control 13 +/- 6 ml, 3 week pacing 27 +/- 6 ml, 2 month pacing 26 +/- 8 ml), right ventricular volumes (control 13 +/- 5 ml, 3 week pacing 27 +/- 9, 2 month pacing 24 +/- 7 ml), and right ventricular mass (control 27 +/- 5 g, 3 week pacing 32 +/- 6 g, 2 month pacing 34 +/- 6 g) (all p less than .03 vs control) but had normal left ventricular mass. Three weeks of pacing also decreased percent left ventricular shortening (34 +/- 6% to 17 +/- 7%) associated with a disproportionate deterioration of posterior wall thickening (58 +/- 16% to 17 +/- 18%) (both p less than .01), as assessed by echocardiography. This left ventricular dysfunction was associated with no change in myocardial lactate extraction (prepacing 40 +/- 10%, 3 week pacing 36 +/- 10%), myocardial arteriovenous O2 difference, or myocardial histology, suggesting that it was not due to myocardial ischemia. These data indicate that rapid ventricular pacing in the dog produces a useful experimental preparation of low-output heart failure characterized by biventricular pump dysfunction, biventricular cardiac dilation, and nonischemic impairment of left ventricular contractility.     

Cardioprotection: intermittent ventricular fibrillation and rapid pacing can induce preconditioning in the blood-perfused rat heart

The aim of the study was to use the isolated blood-perfused rat heart to: (i) determine whether brief intermittent rapid pacing and ventricular fibrillation are able to mimic preconditioning by ischemia and thereby protect the isolated blood-perfused heart against ischemia-induced injury and (ii) characterize the effects of these interventions on cardiac metabolism. To this end, isolated, blood-perfused (2.4 ml/min), paced (360 beats/min) rat hearts (n = 6/group), were aerobically perfused for 20 min. Hearts were then randomized to four groups: (i) a further 16 min aerobic perfusion (UC, untreated controls), (ii) ischemic preconditioning (IP, 3 min ischemia + 3 min reperfusion followed by 5 min ischemia + 5 min reperfusion), (iii) electrically induced ventricular fibrillation (VF, 3 min fibrillation + 3 min sinus rhythm followed by 5 min fibrillation + 5 min sinus rhythm) and (iv) rapid pacing at > or = 600 beats/min (RP, 3 min rapid pacing + 3 min normal heart rate followed by 5 min rapid pacing + 5 min normal heart rate). Hearts were then subjected to 35 min of zero-flow, global ischemia (37 degrees C) and 40 min reperfusion. In parallel studies, blood samples were collected during the first 3 min of treatment and plasma taken for the analysis of noradrenaline. The hearts were then immediately frozen and assayed for high energy phosphates and noradrenaline content. Time-to-50% contracture during ischemia was 13.2 +/- 0.8 min in controls; this was reduced to 6.3 +/- 1.1 min by IP but was unaffected by VF or RP (12.4 +/- 1.1 and 12.8 +/- 1.2 min respectively). Post-ischemic left ventricular developed pressure (LVDP) in untreated controls recovered to only 19.9 +/- 8.4% of its pre-ischemic value whereas with IP, VF and RP substantial and similar improvements were observed (60.3 +/- 7.4, 56.2 +/- 5.7 and 45.3 +/- 10.3%, respectively, P < 0.01). This protection was achieved without any significant depletion of high energy phosphates during VF or RP. Noradrenaline was essentially unchanged in controls and with RP, but VF caused a loss from tissue and a large elevation in the plasma. Our results suggest that both RP and VF are as effective as brief ischemia in protecting the heart against injury during ischemia and reperfusion. In contrast to IP, this protection can be achieved without the exacerbation of ischemic contracture and without inducing ischemia during the preconditioning period.     

Induction of atrial fibrillation with rapid high voltage ventricular pacing for ventricular fibrillation conversion testing. The Ventak AV II DR Study

OBJECTIVE: To assess whether rapid high voltage ventricular pacing can also induce atrial fibrillation, and whether the induction of atrial fibrillation during ventricular fibrillation conversion testing is related to the patient's heart disease. DESIGN: Prospective study of 50 patients who received the dual chamber implantable cardioverter-defibrillator (ICD) Ventak AV II DR (Guidant) as a first implant. This device can record atrial activity even during a ventricular fibrillation episode and can induce atrial fibrillation by rapid atrial bursts. MAIN OUTCOME MEASURES: Frequency of atrial fibrillation after induction of ventricular fibrillation; clinical characteristics of patients with and without induced atrial fibrillation; frequency of atrial fibrillation induced by rapid atrial bursts during predischarge testing. RESULTS: Atrial fibrillation was observed in 40 of the 217 ventricular fibrillation episodes (18%) that could be detected immediately after delivery of high voltage pacing. The biphasic ICD shock for termination of ventricular fibrillation also terminated the atrial fibrillation in all cases. The 40 episodes of simultaneous atrial and ventricular fibrillation occurred in 18 patients (36%). The distribution of the clinical characteristics of the patients and the inducibility of atrial fibrillation during predischarge testing were similar in those with and without induced atrial fibrillation. CONCLUSIONS: Rapid high voltage ventricular pacing frequently induces atrial fibrillation, which was terminated by the subsequent biphasic ICD shock. The induction of atrial fibrillation seems to be a non-specific phenomenon, unrelated to the clinical status of the patient.     

均匀心肌组织中心室颤动机制的仿真研究

目的研究心肌中的局部传导阻滞现象,在细胞水平上解释颤动中螺旋波的形成和破裂为多重子螺旋波的机制,强调动作电位时程(APD)恢复特性对心室颤动的诱发和维系具有重要意义。方法从心肌细胞APD恢复特性和传导速度(CV)恢复特性出发,利用非线性动力学方法,基于一维均匀心肌组织模型,观察不同起搏频率下的APD现象。结果证明了单个心肌细胞的APD交替以及均匀心肌组织中的非同步交替现象,并在起搏位置的远端发现了局部传导阻滞。结论均匀心肌组织中,由于APD和CV恢复特性的相互作用,在高频率起搏时,足以产生局部传导阻滞,从而可能进一步诱发螺旋波及破裂成心室颤动。     

急性心肌梗死后快速刺激诱发心室颤动的“混沌机制”的研究

目的探讨急性心肌梗死后心室颤动（室颤）的发病机制，观察室颤过程中“混沌”的非线性动力学特征，为临床预防急性心肌梗死后室颠的发生提供理论依据。方法2003—06～2005—12对中国医科大学附属第二医院心内科制造的急性心肌梗死模型，快速起搏刺激犬的在体心肌并诱发室颤，用64导心外膜标测系统记录室颤过程中心肌的电生理学参数，观察激动周期的动态改变。结果急性心肌梗死时，诱发室颤的刺激间期明显提高；快速刺激诱发室颤的过程中，激动周期呈现倍周期分叉、准周期乃致混沌等非线性动力学特征，其Poincar＇e作图为环状结构。结论心肌急性缺血导致室颤的阅值明显升高；室颤是由于系统呈现倍周期分叉、准周期乃致混沌而导致。     

急性心肌梗死后快速刺激诱发心室颤动的"混沌机制"的研究

目的探讨急性心肌梗死后心室颤动(室颤)的发病机制,观察室颤过程中“混沌”的非线性动力学特征,为临床预防急性心肌梗死后室颤的发生提供理论依据。方法2003-06～2005-12对中国医科大学附属第二医院心内科制造的急性心肌梗死模型,快速起搏刺激犬的在体心肌并诱发室颤,用64导心外膜标测系统记录室颤过程中心肌的电生理学参数,观察激动周期的动态改变。结果急性心肌梗死时,诱发室颤的刺激间期明显提高;快速刺激诱发室颤的过程中,激动周期呈现倍周期分叉、准周期乃致混沌等非线性动力学特征,其Poincare作图为环状结构。结论心肌急性缺血导致室颤的阈值明显升高;室颤是由于系统呈现倍周期分叉、准周期乃致混沌而导致。     

Induction of atrial fibrillation in mice by rapid transesophageal atrial pacing

Objective: Atrial fibrillation (AF) as an “indicator arrhythmia” for enhanced atrial vulnerability in mouse hearts has not yet been systematically examined. We therefore evaluated a transesophageal rapid atrial stimulation protocol for the induction of AF in C57Bl/6 mice. Methods: 40 C57Bl/6 mice (19 female and 21 male; 5.2 ± 2.1 months; 18 – 27 g) were examined by closed chest transesophageal atrial stimulation. Baseline ECG and electrophysiological parameters, AF-inducing stimulation cycle length (CL) and AF duration were analyzed. Results: The surface ECG demonstrated a significantly faster heart rate in female mice (R-R: 138.7 ± 19.9 ms versus 150.5 ± 15.7 ms, P < 0.05). AF was inducible in 90 % of the population and not inducible in 4 mice, all female (21 % in this subgroup). Mean induction CL was 27.4 ± 7.3 ms. Mean AF duration was 26.9 ± 42.6 s before spontaneous termination. In a subgroup of 4 female and 4 male mice (mean age 7.5 months), successive testing of AF induction showed a range of higher susceptibility to AF at stimulus amplitudes of 3.0 – 4.0 mA and stimulation CLs between 15 – 25 ms. AF induction was observed to be constantly reproducible in the individual animals. No correlation to pacing stimulus length and amplitude was found. Conclusions: This study demonstrates that it is possible to reproducibly induce self-terminating AF and supraventricular arrhythmias in mice by transesophageal atrial burst stimulation. The presented method allowing serial testings of the same animal can be a useful tool in further investigations with transgenic mice and might be helpful in the characterization of underlying genetic or molecular mechanisms of AF. Received: 26 April 2002, Returned for revision: 21 May 2002, Revision received: 17 June 2002, Accepted: 24 June 2002 Correspondence to: J. W. Schrickel, MD     

Apparent suppression of ventricular parasystole by cardiac pacing

Complete disappearance of ventricular parasystolic beats by cardiac pacing with the rates of near multiples of the parasystolic rate was observed in 2 patients with ventricular parasystole. This finding represents a clinical counterpart of recently demonstrated experimental and mathematical models of electrotonic modulation of the parasystolic discharge.     

Regional control of atrial fibrillation by rapid pacing in conscious dogs

BACKGROUND. In five chronically instrumented conscious dogs, we studied the effects of rapid pacing on sustained electrically induced atrial fibrillation. METHODS AND RESULTS. Twenty-three unipolar atrial electrograms were recorded simultaneously from the bundle of Bachmann and the lateral wall of the right and left atria. During sustained atrial fibrillation, the surface electrocardiogram showed continuous irregularities of the baseline without P or F waves as well as an irregular ventricular rhythm with narrow QRS complexes. The atrial electrograms showed rapid irregular activity with a median cycle length of 85 +/- 8 msec and a range (P5-95) of 33 +/- 18 msec. Overdrive pacing of atrial fibrillation was performed using symmetric biphasic rectangular stimuli (2-msec duration, sixfold that of threshold) applied to a pair of stimulating electrodes at the left atrial appendage. Stimulation was started at pacing intervals of about 10 msec longer than the local median fibrillation interval and subsequently shortened in steps of 1 msec. At a critical pacing interval slightly shorter than the median fibrillation interval, the atrium around the pacing site was suddenly captured by the electrical stimuli. The area of local capture had a diameter of 6.1 +/- 1.6 cm. The time window of capture was 12 +/- 4 msec. CONCLUSIONS. These observations show that during electrically induced atrial fibrillation in chronically instrumented conscious dogs, a short excitable gap is present, permitting regional control of the fibrillatory process by rapid pacing.     

Influence of aortic elastic properties on pulse pressure changes induced by rapid ventricular pacing

The mechanism of aortic pulse pressure decline induced by acute rapid ventricular pacing remains incompletely understood. It has been ascribed to changes in stroke volume or aortic compliance. This becomes more complicated by the dependence of aortic compliance on the level of the mean aortic pressure as well as the aortic wall properties. To test the role of such mechanical factors, aortic pressure-diameter hemodynamics, derived from simultaneous tip-micromanometer aortic pressure recordings and high-fidelity ultrasonic intravascular aortic diameter recordings, were measured in 15 normal subjects during and after abrupt cessation of rapid ventricular pacing (up to 160 bpm). Immediately after terminating the pacing, diastolic aortic pressure declined (–9%, from 87.4±1.2 to 79.5±1.7 mmHg,P<0.0001) while systolic aortic pressure increased (+19%, from 109.5±1.6 to 130.1±2.8 mmHg,P<0.0001). Thus, pulse pressure increased from 22.1±2.2 to 50.6±3.1 mmHg,P<0.0001. To quantify systolic and diastolic aortic pressure differences we compared the first postpaced beat (a) and the last paced beat (b). To estimate what the aortic pressure would have been for the paced beats had the aortic diameter differences due to the different heart rate not occurred we calculated the theoretical pressure of the paced beat P_b=E_b·D_a, where E_b was the instantaneous aortic elastance of the paced beat and D_a was the aortic diameter for the postpaced beat. The corrected pressure difference was then calculated by the following: P_cor=(D_a·E_b)–P_a. It was found that systolic P_cor was 25% of systolic P_raw and diastolic P_cor was 89% of diastolic P_raw. P_raw was the pressure difference between paced and spontaneous beat measured from the raw data. P_cor indicates the portion of P_raw that results from a change in aortic stiffness as a consequence of viscous behavior or aorto-ventricular coupling. These data indicate that the majority of diastolic pressure decline after pacing was terminated, may reflect a change in aortic stiffness while the majority of systolic pressure rise, and may be attributable to differences in hemodynamics alone.     

Transient ischaemia induced by rapid cardiac pacing results in myocardial preconditioning.

STUDY OBJECTIVE--The aim was to determine whether rapid ventricular pacing can protect against the ventricular arrhythmias occurring during a subsequent coronary artery occlusion. DESIGN--The effect was examined of two 2 min periods of pacing (300 beats.min-1) in chloralose-urethane anaesthetised dogs on a subsequent 25 min coronary artery occlusion. Ventricular arrhythmias, ST segment elevation, and inhomogeneity of conduction were analysed. EXPERIMENTAL MATERIAL--25 anaesthetised mongrel dogs in a restricted body weight range were used. MEASUREMENTS AND MAIN RESULTS--Preocclusion pacing reduced the severity of occlusion induced ST segment elevation, degree of inhomogeneity, and arrhythmias: ventricular premature beats were reduced from 528(SEM 40) to 136(45), and there were lower incidences of ventricular fibrillation (0% v 47%) and ventricular tachycardia (30% v 80%). CONCLUSIONS--Rapid ventricular pacing "preconditions" the myocardium in a manner similar to that following short coronary artery occlusions. Short periods of ischaemia no matter how induced protect the heart against the arrhythmogenic effect of a prolonged coronary artery occlusion.     

不同起搏方式对高右室起搏比例患者心功能及心房颤动的影响

目的：探讨不同起搏部位对高右室起搏比例、缓慢性心律失常患者新发心房颤动（AF）及心功能的影响。方法：入选我院心内科2005年1月至2011年1月期间置入 DDD 永久起搏器的缓慢性窦房结功能失调或Ⅱ度以上房室传导阻滞患者,选择其中高右室起搏比例者（右室起搏累积百分比＞50％）共120例,随机分为右室心尖部（RVA）起搏组（n＝47）及右室间隔部（RVS）起搏组（n ＝73）。随访内容包括起搏器置入术前、术后3年 AF 发生情况和超声心动图参数。结果：随访期间 RVA 组新发 AF 患者比例高于 RVS 组（23．40％对16．43％,P ＝0．03）。术后3年,与 RVA 组相比,RVS 组左房内径（LAD）、左室舒张末期内径（LVEDD）明显缩小,左室射血分数（LVEF）则明显升高（P ＜0．05）。结论：对于 DDD 起搏模式下高右室起搏比例患者,与 RVA 起搏相比,RVS 起搏可显著改善患者心功能,减少 AF 的发生。