Pacing-induced Congestive Heart Failure Research Articles

Global Bi-ventricular endocardial distribution of activation rate during long duration ventricular fibrillation in normal and heart failure canines

BackgroundThe objective of this study was to detect differences in the distribution of the left and right ventricle (LV & RV) activation rate (AR) during short-duration ventricular fibrillation (SDVF, <1 min) and long-duration ventricular fibrillation VF (LDVF, >1 min) in normal and heart failure (HF) canine hearts.MethodsVentricular fibrillation (VF) was electrically induced in six healthy dogs (control group) and six dogs with right ventricular pacing-induced congestive HF (HF group). Two 64-electrode basket catheters deployed in the LV and RV were used for global endocardium electrical mapping. The AR of VF was estimated by fast Fourier transform analysis from each electrode.ResultsIn the control group, the LV was activated faster than the RV in the first 20 s, after which there was no detectable difference in the AR between them. When analyzing the distribution of the AR within the bi-ventricles at 3 min of LDVF, the posterior LV was activated fastest, while the anterior was slowest. In the HF group, a detectable AR gradient existed between the two ventricles within 3 min of VF, with the LV activating more quickly than the RV. When analyzing the distribution of the AR within the bi-ventricles at 3 min of LDVF, the septum of the LV was activated fastest, while the anterior was activated slowest.ConclusionsA global bi-ventricular endocardial AR gradient existed within the first 20 s of VF but disappeared in the LDVF in healthy hearts. However, the AR gradient was always observed in both SDVF and LDVF in HF hearts. The findings of this study suggest that LDVF in HF hearts can be maintained differently from normal hearts, which accordingly should lead to the development of different management strategies for LDVF resuscitation.

Regulation of Coronary Blood Flow During Exercise in Failing Heart

PURPOSE: Myocardial ischemia is one of the most common causes of exercise associated cardiac arrest in adults. The purpose of this study was to explore the pathophysiological mechanism of exercise associated cardiac arrest by investigating the regulation of coronary blood flow (CBF) during exercise in failing heart. METHODS: Studies were performed in 11 adult mongrel dogs trained to run on a treadmill. A Doppler velocity probe was positioned on the left anterior descending coronary artery for the measurement of CBF. CBF and the endothelium dependent vasodilator response to acetylcholine were studied in dogs in which congestive heart failure (CHF) was produced by rapid ventricular pacing for 4 weeks. Tissue homogenates of left ventricular myocardium from normal dogs and dogs with pacing-induced CHF were investigated by routine Western blot analysis. RESULTS: The CBF at rest and during treadmill exercise were significantly decreased after development of CHF (36.7±2.44 vs 20.1±2.87 ml/min at rest, 49.9±3.88 vs 24.2±3.48 ml/min during exercise). The CBF responses to exercise were gradually decreased at different stages of pacing. The effect of acetylcholine-induced coronary vasodilatation was significantly suppressed by nitric oxide synthase (NOS) blocker L-NNA (p<0.05). Western blot analysis showed that endothelial NOS (eNOS) protein was increased by 43±12 % significantly in failing heart. CONCLUSIONS: Our findings of the decreased CBF response to exercise and the increased eNOS expression in the failing heart may suggest that NO signaling play an important role in the regulation of CBF during exercise and this may be a novel approach to protect heart from exercise associated cardiac arrest.

Exogenous midkine administration prevents cardiac remodeling in pacing-induced congestive heart failure of rabbits.

Midkine (MK), a heparin-binding growth factor, has been shown to prevent cardiac remodeling after ischemic injury through its anti-apoptotic effect. Cell apoptosis is central to the pathophysiology of cardiac remodeling in congestive heart failure (CHF) of ischemic as well as non-ischemic origin. We hypothesized that MK exerts the anti-apoptotic cardioprotective effect in CHF of non-ischemic etiology. MK protein or vehicle (normal saline) was subcutaneously administered in tachycardia-induced CHF rabbits (right ventricular pacing, 350 beats/min, 4 weeks). The vehicle-treated rabbits (n = 19, control) demonstrated severe CHF and high mortality rate, whereas MK (n = 16) demonstrated a well-compensated state and a lower mortality rate. In echocardiography, left ventricular (LV) end-diastolic dimension decreased in MK versus control, whereas LV systolic function increased. In histological analysis (picrosirius red staining), MK decreased collagen deposition area compared with control. TUNEL staining showed that MK prevented cell apoptosis and minimized myocyte loss in the CHF rabbit ventricle, associated with activation of PI3-K/Akt signaling, producing a parallel decrease of Bax/Bcl-2 ratio. MK prevented progression of cardiac remodeling in the CHF rabbit, likely by activation of anti-apoptotic signaling. Exogenous MK application might be a novel therapeutic strategy for CHF due to non-ischemic origin.

Carotid body denervation improves autonomic and cardiac function and attenuates disordered breathing in congestive heart failure

In congestive heart failure (CHF), carotid body (CB) chemoreceptor activity is enhanced and is associated with oscillatory (Cheyne-Stokes) breathing patterns, increased sympathetic nerve activity (SNA) and increased arrhythmia incidence. We hypothesized that denervation of the CB (CBD) chemoreceptors would reduce SNA, reduce apnoea and arrhythmia incidence and improve ventricular function in pacing-induced CHF rabbits. Resting breathing, renal SNA (RSNA) and arrhythmia incidence were measured in three groups of animals: (1) sham CHF/sham-CBD (sham-sham); (2) CHF/sham-CBD (CHF-sham); and (3) CHF/CBD (CHF-CBD). Chemoreflex sensitivity was measured as the RSNA and minute ventilatory (VE) responses to hypoxia and hypercapnia. Respiratory pattern was measured by plethysmography and quantified by an apnoea-hypopnoea index, respiratory rate variability index and the coefficient of variation of tidal volume. Sympatho-respiratory coupling (SRC) was assessed using power spectral analysis and the magnitude of the peak coherence function between tidal volume and RSNA frequency spectra. Arrhythmia incidence and low frequency/high frequency ratio of heart rate variability were assessed using ECG and blood pressure waveforms, respectively. RSNA and VE responses to hypoxia were augmented in CHF-sham and abolished in CHF-CBD animals. Resting RSNA was greater in CHF-sham compared to sham-sham animals (43±5% max vs. 23 ± 2% max, P<0.05), and this increase was not found in CHF-CBD animals (25±1% max, P<0.05 vs. CHF-sham). Low frequency/high frequency heart rate variability ratio was similarly increased in CHF and reduced by CBD (P<0.05). Respiratory rate variability index, coefficient of variation of tidal volume and apnoea-hypopnoea index were increased in CHF-sham animals and reduced in CHF-CBD animals (P<0.05). SRC (peak coherence) was increased in CHF-sham animals (sham-sham 0.49±0.05; CHF-sham 0.79±0.06), and was attenuated in CHF-CBD animals (0.59±0.05) (P<0.05 for all comparisons). Arrhythmia incidence was increased in CHF-sham and reduced in CHF-CBD animals (213±58 eventsh(-1) CHF, 108±48 eventsh(-1) CHF-CBD, P<0.05). Furthermore, ventricular systolic (3.8±0.7 vs. 6.3±0.5ml, P<0.05) and diastolic (6.3±1.0 vs. 9.1±0.5ml, P<0.05) volumes were reduced, and ejection fraction preserved (41±5% vs. 54±2% reduction from pre-pace, P<0.05) in CHF-CBD compared to CHF-sham rabbits. Similar patterns of changes were observed longitudinally within the CHF-CBD group before and after CBD. In conclusion, CBD is effective in reducing RSNA, SRC and arrhythmia incidence, while improving breathing stability and cardiac function in pacing-induced CHF rabbits.

Autonomic nerve activity and the short-term variability of the Tpeak-Tend interval in dogs with pacing-induced heart failure

In congestive heart failure (CHF), autonomic nervous system (ANS) activity is known to modulate arrhythmic risk through its effects on myocardial repolarization. An increased interval between the peak and the end of the T wave (T(peak)-T(end)) has been reported to increase the incidence of sudden cardiac death. However, the ANS influence on the T(peak)-T(end) interval remains unclear. We directly measured ANS nerve activity in ambulatory dogs with pacing-induced CHF to test the hypothesis that ANS activity modulates the T(peak)-T(end) variability index (T(peak)-T(end)VI), the short-term variability of the T(peak)-T(end) interval obtained on 30 beats (T(peak)-T(end)STV(30)), and the short-term variability of the T(peak)-T(end) interval obtained on 5-minute ECG recording (T(peak)-T(end)STV(T)). By using data previously recorded in 6 ambulatory dogs before and after pacing-induced CHF, we assessed ANS activity recorded with an implanted radiotransmitter that monitored integrated left stellate ganglion nervous activity (iSGNA), integrated vagus nerve activity (iVNA), and electrocardiogram (ECG). We selected for analysis 36 segments recorded at baseline and 36 after pacing-induced CHF with similar iSGNA. During CHF, T(peak)-T(end)STV(30) (P<.001) and T(peak)-T(end)STV(T) (P<.05) were significantly higher than those at baseline. The multiple linear mixed regression analysis disclosed a significant positive correlation between iSGNA and T(peak)-T(end)STV(T) (baseline: β 2.92, P<.001; CHF: β 1.13, P<.001) and a significant negative correlation between iVNA and T(peak)-T(end)STV(T) (baseline: β-6.74, P<.001; CHF: β-1.42, P< .001). In a canine model of pacing-induced CHF, iSGNA correlates positively while iVNA correlates negatively with T(peak)-T(end)STV(T). These findings suggest that SGNA increases while VNA decreases the dispersion of ventricular repolarization in ambulatory dogs with CHF.

Arrhythmogenic Difference between the Left and Right Atria in a Canine Ventricular Pacing‐Induced Heart Failure Model of Atrial Fibrillation

The detail of biatrial activation during sustained atrial fibrillation (AF) has not been investigated until now. Five dogs with right ventricular pacing-induced congestive heart failure (CHF) and five normal dogs were included. Biatrial endocardiac mapping was performed using noncontact mapping system. Noncontact mapping of the right atrium (RA) showed CHF dogs had a higher frequency of focal discharge from Bachmann's bundle, sinoatrial region, and crista terminalis. CHF dogs also had a higher frequency of wave break, wave fusion, and reentry. CHF dogs had greater effective refractory period (ERP) dispersion. Noncontact mapping of the left atrium (LA) showed CHF dogs had more frequent focal discharge from left superior pulmonary vein (PV), right superior PV, and left atrial appendage. CHF dogs had a higher frequency of wave break, wave fusion, and reentry. CHF dogs had greater ERP dispersion. Comparison between RA and LA showed LA had a higher frequency of focal discharge, wave break, wave fusion, and leading circle reentry than the RA. LA also had greater ERP dispersion than RA. CHF dogs had a higher frequency of focal discharge and reentry, suggesting that CHF provided an arrhythmogenic substrate. LA had a higher frequency of focal discharge and reentry, suggesting that LA is more important to maintain AF.

Modulation of endoplasmic reticulum stress and cardiomyocyte apoptosis by mulberry leaf diet in experimental autoimmune myocarditis rats

Mulberry is commonly used as silkworm diet and an alternative medicine in Japan and China, has recently reported to contain many antioxidative flavanoid compounds and having the free radical scavenging effects. Antioxidants reduce cardiac oxidative stress and attenuate cardiac dysfunction in animals with pacing-induced congestive heart failure. Hence we investigated the cardioprotective effect of mulberry leaf powder in rats with experimental autoimmune myocarditis. Eight-week-old Lewis rats immunized with cardiac myosin were fed with either normal chow or a diet containing 5% mulberry leaf powder and were examined on day 21. ML significantly decreased oxidative stress, myocyte apoptosis, cellular infiltration, cardiac fibrosis, mast cell density, myocardial levels of sarco/endo-plasmic reticulum Ca2+ ATPase2, p22phox, receptor for advanced glycation end products, phospho-p38 mitogen activated protein kinase, phospho-c-Jun NH2-terminal protein kinase, glucose regulated protein78, caspase12 and osteopontin levels in EAM rats. These results may suggest that mulberry diet can preserve the cardiac function in experimental autoimmune myocarditis by modulating oxidative stress induced MAPK activation and further afford protection against endoplasmic reticulum stress mediated apoptosis.

Rate-dependent shortening of action potential duration increases ventricular vulnerability in failing rabbit heart

Congestive heart failure (CHF) predisposes to ventricular fibrillation (VF) in association with electrical remodeling of the ventricle. However, much remains unknown about the rate-dependent electrophysiological properties in a failing heart. Action potential properties in the left ventricular subepicardial muscles during dynamic pacing were examined with optical mapping in pacing-induced CHF (n=18) and control (n=17) rabbit hearts perfused in vitro. Action potential durations (APDs) in CHF were significantly longer than those observed for controls at basic cycle lengths (BCLs)>1,000 ms but significantly shorter at BCLs<400 ms. Spatial APD dispersions were significantly increased in CHF versus control (by 17-81%), and conduction velocity was significantly decreased in CHF (by 6-20%). In both groups, high-frequency stimulation (BCLs<150 ms) always caused spatial APD alternans; spatially concordant alternans and spatially discordant alternans (SDA) were induced at 60% and 40% in control, respectively, whereas 18% and 82% in CHF. SDA in CHF caused wavebreaks followed by reentrant excitations, giving rise to VF. Incidence of ventricular tachycardia/VFs elicited by high-frequency dynamic pacing (BCLs<150 ms) was significantly higher in CHF versus control (93% vs. 20%). In CHF, left ventricular subepicardial muscles show significant APD shortenings at short BCLs favoring reentry formations following wavebreaks in association with SDA. High-frequency excitation itself may increase the vulnerability to VF in CHF.

Arrhythmogenic Foci and the Mechanisms of Atrial Fibrillation

In this issue of the Circulation: Arrhythmia and Electrophysiology , Kurotobi et al1 determined the number of arrhythmogenic foci in atria provocable with isoproterenol infusion in patients with paroxysmal, persistent, and permanent atrial fibrillation (AF). The results show that persistent AF has more foci than paroxysmal AF. However, when AF persists for >12 months, the number of foci were reduced. The authors suggest that the increased number of foci probably is involved in the development of persistent AF. However, because this association is not observed for AF that persists for >12 months, the importance of these foci in AF maintenance remains unclear. Article see p 39 In ambulatory canine models, simultaneous sympathovagal discharges (rather than isolated sympathetic activation) are typical triggers of paroxysmal atrial tachycardia (AT) and AF.2,3⇓ These observations are explained by the late phase-3 early afterdepolarization (EAD), which depends on the coexistence of increased amplitude and duration of intracellular calcium (Cai) transient and the shortened action potential duration (APD).4,5⇓ Vagal stimulation shortens APD and therefore is needed to promote the late phase-3 EAD. In the Kurotobi study, however, arrhythmogenic foci were induced by isoproterenol alone, without the need of vagal stimulation or the use of parasympathomimetic agents. These results are different from that obtained in canine studies. The first possible explanation is that the pulmonary veins (PVs) naturally have shorter APDs with elevated (less negative) membrane potentials.6,7⇓ Rapid activation may further shorten the APD in the PVs.8 These changes are independent of the vagal tone. Jais et al9 reported the effective refractory periods of the PVs were shorter …

Frequency Analysis of Atrial Electrograms Identifies Conduction Pathways from the Left to the Right Atrium During Atrial Fibrillation—Studies in Two Canine Models

Studies of atrial fibrillation (AF) have demonstrated that a stable rhythm of very short cycle length in the left atrium (LA) can cause fibrillatory conduction in the rest of the atria. We tested the hypothesis that fast Fourier transform (FFT) analysis of atrial electrograms (AEGs) during this AF will rapidly and reliably identify LA-to-right atrium (RA) conduction pathway(s) generated by the driver. During induced atrial tachyarrhythmias in the canine sterile pericarditis and rapid ventricular pacing-induced congestive heart failure models, 380-404 AEGs were recorded simultaneously from epicardial electrodes on both atria. FFT analysis of AEGs during AF demonstrated a dominant frequency peak in the LA (driver), and multiple frequency peaks in parts of the LA and the most of the RA. Conduction pathways from the LA driver to the RA varied from study-to-study. They were identified by the presence of multiple frequency peaks with one of the frequency peaks at the same frequency as the driver, and traveled (1) inferior to the inferior vena cava (IVC); (2) between the superior vena cava and the right superior pulmonary vein (RSPV); (3) between the RSPV and the right inferior pulmonary vein (RIPV); (4) between the RIPV and the IVC; and (5) via Bachmann's bundle. Conduction pathways identified by FFT analysis corresponded to the conduction pathways found in classical sequence of activation mapping. Computation time for FFT analysis for each AF episode took less than 5 minutes. FFT analysis allowed rapid and reliable detection of the LA-to-RA conduction pathways in AF generated by a stable and rapid LA driver.

Power spectral analysis of heart rate variability and autonomic nervous system activity measured directly in healthy dogs and dogs with tachycardia-induced heart failure

Heart rate variability (HRV), calculated in the frequency or time domain, decreases in congestive heart failure (CHF). In HRV power spectral analysis, the low-frequency (LF) component diminishes in patients with CHF and the decrease is related to an increased risk of sudden death. Our aim was to clarify the nature of HRV power spectral analysis in normal and CHF dogs. Using an implanted radiotransmitter, we directly studied integrated left stellate ganglion nerve activity (iSGNA), integrated vagal nerve activity (iVNA), and electrocardiographic tracings before and after pacing-induced CHF in 6 ambulatory dogs. In a short-term power spectral analysis of HRV, we measured power spectral density during high, medium, and low sympathetic and vagal nerve activity. We analyzed 38 data segments characterized by the same autonomic nerve activity patterns at baseline and after pacing-induced CHF. As compared with baseline, the spectral variables during CHF showed decreased total power (P = .002), LF power (P < .0001), and the LF/high frequency (HF) ratio (P = .005) and increased iVNA and iSGNA (P < .0001 for both). Only at baseline, iSGNA correlated positively with LF power (P < .05, r = 0.314). Under the same condition iVNA correlated positively with the HF component expressed as normalized units (P < .05, r = 0.394) and negatively with the LF component expressed both as absolute power (P < .05, r = -0.464) and normalized units (P < .05, r = -0.425). The spectral variables (LF power and the LF/HF ratio) and direct variables measuring sympathetic nerve activity (iSGNA) correlate at baseline but not during CHF. At baseline, the vagal activity (iVNA) is associated with an increase in HFnu and a decrease in LFnu. These data indicate that the reduction in LF power and LF/HF ratio observed in heart failure dogs are likely to reflect a diminished sinus node responsiveness to autonomic modulation or an abnormal baroreflex function rather than an increased sympathetic activity.

Left Ventricular Twist Mechanics in a Canine Model of Reversible Congestive Heart Failure: A Pilot Study

Left ventricular (LV) twist dynamics play an important role in LV systolic and diastolic function. The aim of this preliminary study was to investigate LV twist dynamics in a canine model of reversible congestive heart failure (CHF). Pacing systems were implanted in adult dogs, and continuous chronic right ventricular pacing (230-250 beats/min) was applied until CHF induction. Pacing was then stopped to allow the heart to recover. Echocardiography and LV catheterization were performed at baseline, during CHF while pacing was temporarily switched off, and during recovery. LV twist was computed as the difference between apical and basal rotation measured using 2-dimensional speckle tracking. Torsion was further calculated as LV twist divided by the LV long axis. The untwisting rate was computed as the peak diastolic time derivative of twist. In 6 dogs that completed the study, we found that CHF developed after 2 to 4 weeks of pacing, with LV end-diastolic volume, end-systolic volume, end-diastolic pressure, and the time constant of relaxation during isovolumic relaxation period (tau) all increasing significantly compared with baseline and recovering to normal levels 2 to 4 weeks after pacing was stopped. LV twist, torsion, and untwisting rate decreased significantly with CHF compared with baseline and improved during recovery from CHF. LV twist dynamics reflect pacing-induced CHF and its reversal as assessed by echocardiographic speckle tracking.

Abstract 2474: Dynamic Change in LV Twist Mechanics in a Canine Model of Pacing-Induced Heart Failure

Background : LV twist may reflect LV contractility under different conditions. This study investigated LV twist dynamics and its determinants in a canine model of congestive heart failure (CHF). Methods : Pacemakers and percutaneous leads were implanted in 8 adult hound dogs (mean weight, 38 kg), and continuous chronic RV pacing was applied at 230–250 bpm until CHF induction. Subsequently, pacing was turned off to allow the heart to recover. Echocardiography and LV catheterization were performed simultaneously at baseline, during CHF while pacing was temporarily switched off, and during recovery from CHF after pacing was stopped. CHF induction by pacing was repeated in 4 dogs. Apical and basal rotations were measured using 2D speckle tracking, and LV twist was calculated as the difference between apical and basal rotations. Untwisting rate was calculated as the peak diastolic time derivative of LV twist. Results : CHF developed after 2–4 wks of pacing with LV end-diastolic volume (LVEDV), end-systolic volume (LVESV), end-diastolic pressure (LVEDP), and time constant of LV relaxation during isovolumic relaxation period (tau) all increasing significantly compared to baseline (Table ), and recovering to baseline levels 2–4 wks after pacing was stopped. LV twist and untwisting rate decreased with CHF compared to baseline, and improved during recovery from CHF although the change in untwisting rate between CHF and baseline was not significant. In pooled data, LV twist was significantly related to LVEDV (r=-0.60, P&lt;0.001), LVESV (r=-0.59, P=0.001), LVEF (r=0.81, P&lt;0.001), LVEDP (r=0.41, P=0.03) and +dp/dt (r=0.71, P&lt;0.001), but not with end-systolic pressure (r=0.06, P=0.77). In multiple analysis, +dp/dt was the only independent predictor of twist (P &lt; 0.001). Conclusions : LV twist dynamics can reflect the presence of pacing-induced CHF and its recovery. LV contractility appears to be the only determinant of LV twist in CHF.

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.

Intramural Electrical Dyssynchrony in Pacing-Induced Congestive Heart Failure

Intramural Electrical Dyssynchrony in Pacing-Induced Congestive Heart Failure

Left Stellate Ganglion and Vagal Nerve Activity and Cardiac Arrhythmias in Ambulatory Dogs With Pacing-Induced Congestive Heart Failure

The purpose of this study was to determine the patterns of autonomic nerve activity in congestive heart failure (CHF). The relationship between autonomic nerve activity and cardiac arrhythmias in CHF is unclear. We implanted radiotransmitters in 6 dogs for continuous (24/7) simultaneous monitoring of left stellate ganglion nerve activity (SGNA), vagal nerve activity (VNA), and electrocardiography before and after pacing-induced CHF. Congestive heart failure increased both SGNA and VNA. The SGNA but not VNA manifested a circadian variation pattern. There was extensive sinus node fibrosis. We analyzed 2,263 episodes of prolonged (>3 s) sinus pauses (PSP) and 1,420 long (>10 s) episodes of paroxysmal atrial tachycardia (PAT). Most (95.3%) PSP episodes occurred at night, and 56% were preceded by a short burst of SGNA that induced transient sinus tachycardia. Long PAT episodes were typically (83%) induced by simultaneous SGNA and VNA discharge, followed by VNA withdrawal. Premature ventricular contractions and ventricular tachycardia were preceded by elevated SGNA. The reduction of sympathovagal balance at night in ambulatory dogs was due to reduced sympathetic discharge rather than a net increase of vagal discharge. The tachybrady syndrome in CHF might be triggered by an intermittent short burst of SGNA that resulted in tachycardia and sinus node suppression. Simultaneous sympathovagal discharge is a cause of long PAT episodes. These data indicate that there is an association between the specific patterns of autonomic nerve discharges and cardiac arrhythmia during CHF.

Effect of K + ATP Channel and Adenosine Receptor Blockade During Rest and Exercise in Congestive Heart Failure

K(+)(ATP) channels are important metabolic regulators of coronary blood flow (CBF) that are activated in the setting of reduced levels of ATP or perfusion pressure. In the normal heart, blockade of K(+)(ATP) channels results in a approximately 20% reduction in resting CBF but does not impair the increase in CBF that occurs during exercise. In contrast, adenosine receptor blockade fails to alter CBF or myocardial oxygen consumption (MVO(2)) in the normal heart but contributes to the increase in CBF during exercise when vascular K(+)(ATP) channels are blocked. Congestive heart failure (CHF) is associated with a decrease in CBF that is matched to a decrease in MVO(2) suggesting downregulation of myocardial energy utilization. Because myocardial ATP levels and coronary perfusion pressure are reduced in CHF, this study was undertaken to examine the role of K(+)(ATP) channels and adenosine in dogs with pacing-induced CHF. Myocardial blood flow (MBF) and MVO(2) were measured during rest and treadmill exercise before and after K(+)(ATP) channel blockade with glibenclamide (50 microg/kg/min ic) or adenosine receptor blockade with 8-phenyltheophylline (8-PT; 5 mg/kg iv). Inhibition of K(+)(ATP) channels resulted in a decrease in CBF and MVO(2) at rest and during exercise without a change in the relationship between CBF and MVO(2). In contrast, adenosine receptor blockade caused a significant increase in CBF that occurred secondary to an increase of MVO(2). These findings demonstrate that coronary K(+)(ATP) channel activity contribute to the regulation of resting MBF in CHF, and that endogenous adenosine may act to inhibit MVO(2) in the failing heart.

Use of Fast Fourier Transform Analysis of Atrial Electrograms for Rapid Characterization of Atrial Activation—Implications for Delineating Possible Mechanisms of Atrial Tachyarrhythmias

Different analysis techniques have been developed to help understand and characterize the mechanisms responsible for atrial arrhythmias. We tested the hypothesis that Fast Fourier Transform (FFT) analysis of recorded atrial electrograms (AEGs) will rapidly and accurately identify regular and irregular patterns of atrial activation, and, thereby, may provide evidence suggestive of underlying mechanisms of atrial tachyarrhythmias. During induced atrial tachyarrhythmias in both the canine sterile pericarditis model and canine rapid ventricular pacing-induced congestive heart failure model; 380-404 AEGs were recorded simultaneously from epicardial electrodes on both atria. From AEGs, atrial activation sequences were determined during atrial flutter (AFL), focal atrial tachycardia (AT), and atrial fibrillation (AF). Four-second recording segments of each AEG were subjected to FFT analysis. Frequencies found during FFT analyses in all studies precisely corresponded to the cycle lengths of the AEGs. In AFL and AT, one dominant frequency peak was found throughout both atria. In AF due to multiple unstable reentry circuits, multiple and broad frequency peaks were found in both atria. In AF due to a stable rapid rhythm (driver) in the left atrium with fibrillatory conduction to the rest of the atria, one dominant frequency peak in areas with 1:1 conduction from the driver, and multiple and/or broad frequency peaks in areas with fibrillatory conduction produced by the driver were found. Computation time for all FFT analyses took <5 minutes. FFT analysis accurately and rapidly identifies global atrial activation patterns during AFL, AT, and AF, thereby assisting in determining arrhythmia mechanisms.

Mechanisms of Ventricular Fibrillation in Canine Models of Congestive Heart Failure and Ischemia Assessed by In Vivo Noncontact Mapping

Much of the research performed studying the mechanism of ventricular fibrillation (VF) has been in normal ventricles rather than under a pathological condition predisposing to VF. We hypothesized that different ventricular substrates would alter the mechanism and characteristics of VF. Three groups of dogs were studied: (1) control (n=8), (2) pacing-induced congestive heart failure (n=7), and (3) acute ischemia produced by 30 minutes of mid left anterior descending artery ligation (n=5). A noncontact mapping catheter (Ensite 3000, ESI) was placed via transseptal into the left ventricle (LV), along with an electrophysiology catheter. A multielectrode basket catheter (EP Technologies) was placed in the right ventricle, along with an electrophysiology catheter. Several episodes of VF were recorded in each animal. In addition to constructing isopotential and isochronal maps of the VF episodes, signals underwent frequency domain analysis as a fast Fourier transform was performed over a 2-second window every 1 second. From the fast Fourier transform, the dominant frequency was determined, and the organization was calculated. In control dogs, meandering, reentrant spiral wave activity was the main feature of the VF. The congestive heart failure group showed evidence of a stable rotor (n=3), evidence of a focal source (n=3), or no evidence of a driver in the LV (n=1). The ischemic group showed evidence of an initial focal mechanism that transitioned into reentry. In the control and ischemic groups, the LV always had higher dominant frequencies than the right ventricle. Different ventricular substrates produced by the different animal models altered the characteristics of VF. Thus, different mechanisms of VF may be present in the LV, depending on the animal model.

Giant Flow Reversal in Pulmonary Venous Flow as a Possible Mechanism for Asynchronous Pacing-induced Heart Failure

Mechanistic roles of the immediate increase in left atrial (LA) pressure in pacing-induced congestive heart failure have not been clearly understood. We evaluated the impact of asynchronous rapid ventricular pacing on LA hemodynamics in this model. Transthoracic and transesophageal echocardiography and hemodynamic assessment were performed in 23 healthy mongrel dogs. Data were acquired before and 5 minutes after initiation of rapid right ventricular pacing (200/min). At 5 minutes after initiation of the pacing, giant pulmonary venous (PV) flow reversal (-76 cm/s) was observed in association with 1:1 ventriculoatrial conduction or complete atrioventricular dissociation. This giant PV flow reversal corresponded to an inappropriately timed atrial contraction, especially during systole. Cardiac output (3.21 vs 2.00 L/min, P < .001) was decreased corresponding to the decrease in the forward blood volumes as described by decrease in the Doppler left ventricular (LV) outflow (8.99 vs 4.73 cm, P < .0001), mitral inflow (6.89 vs 3.19 cm, P < .0001), and PV flow (14.15 vs 7.22 cm, P < .0001) velocity integrals. As a result, there was a marked elevation of the mean pulmonary capillary wedge (9.1 vs 17.1 mm Hg, P < .001) and LV end-diastolic (8.2 vs 17.4 mm Hg, P < .01) pressures leading to congestive heart failure. The giant PV flow reversal seen during asynchronous rapid right ventricular pacing corresponds to an inappropriate atrial contraction, immediately elevates LA pressure, and may initially promote congestive heart failure. The increase in LV end-diastolic pressure associated with decreased LV ejection fraction caused decrease in the LV filling volume leading to further increase in the LA pressure. This sustained marked elevation in the LA pressure and LV end-diastolic pressure could contribute to the heart failure process.