Establishing a multicenter, preclinical consortium in resuscitation: A pilot experimental trial evaluating epinephrine in cardiac arrest.

BACKGROUND: Large animal studies are an important step in the translation pathway, but single laboratory experiments do not replicate the variability in patient populations. Our objective was to demonstrate the feasibility of performing a multicenter, preclinical, randomized, double-blinded, placebo-controlled cardiac arrest trial. We evaluated the effect of epinephrine on coronary perfusion pressure (CPP) as previous single laboratory studies have reported mixed results. METHODS: Forty-five swine from 5 different laboratories (Ann Arbor, MI; Baltimore, MD; Los Angeles, CA; Pittsburgh, PA; Toronto, ON) using a standard treatment protocol. Ventricular fibrillation was induced and left untreated for 6 min before starting continuous cardiopulmonary resuscitation (CPR). After 2 min of CPR, 9 animals from each lab were randomized to 1 of 3 interventions given over 12 minutes: (1) Continuous IV epinephrine infusion (0.00375 mg/kg/min) with placebo IV normal saline (NS) boluses every 4 min, (2) Continuous placebo IV NS infusion with IV epinephrine boluses (0.015 mg/kg) every 4 min or (3) Placebo IV NS for both infusion and boluses. The primary outcome was mean CPP during the 12 mins of drug therapy. RESULTS: There were no significant differences in mean CPP between the three groups: 14.4 ± 6.8 mmHg (epinephrine Infusion), 16.9 ± 5.9 mmHg (epinephrine bolus), and 14.4 ± 5.5 mmHg (placebo) (p = NS). Sensitivity analysis demonstrated inter-laboratory variability in the magnitude of the treatment effect (p = 0.004). CONCLUSION: This study demonstrated the feasibility of performing a multicenter, preclinical, randomized, double-blinded cardiac arrest trials. Standard dose epinephrine by bolus or continuous infusion did not increase coronary perfusion pressure during CPR when compared to placebo.

Study of the Effects of Epinephrine on Cerebral Oxygenation and Metabolism During Cardiac Arrest and Resuscitation by Hyperspectral Near-Infrared Spectroscopy.

OBJECTIVES: Epinephrine is routinely administered to sudden cardiac arrest patients during resuscitation, but the neurologic effects on patients treated with epinephrine are not well understood. This study aims to assess the cerebral oxygenation and metabolism during ventricular fibrillation cardiac arrest, cardiopulmonary resuscitation, and epinephrine administration. DESIGN: To investigate the effects of equal dosages of IV epinephrine administrated following sudden cardiac arrest as a continuous infusion or successive boluses during cardiopulmonary resuscitation, we monitored cerebral oxygenation and metabolism using hyperspectral near-infrared spectroscopy. SETTINGS: A randomized laboratory animal study. SUBJECTS: Nine healthy pigs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Our study showed that although continuous epinephrine administration had no significant impact on overall cerebral hemodynamics, epinephrine boluses transiently improved cerebral oxygenation (oxygenated hemoglobin) and metabolism (cytochrome c oxidase) by 15% ± 6.7% and 49% ± 18%, respectively (p < 0.05) compared with the baseline (untreated) ventricular fibrillation. Our results suggest that the effects of epinephrine diminish with successive boluses as the impact of the third bolus on brain oxygen metabolism was 24.6% ± 3.8% less than that of the first two boluses. CONCLUSIONS: Epinephrine administration by bolus resulted in transient improvements in cerebral oxygenation and metabolism, whereas continuous epinephrine infusion did not, compared with placebo. Future studies are needed to evaluate and optimize the use of epinephrine in cardiac arrest resuscitation, particularly the dose, timing, and mode of administration.

Effects of Renal Artery Denervation on Ventricular Arrhythmias in a Postinfarct Model.

BACKGROUND: The therapeutic potential of renal denervation (RDN) for arrhythmias has not been fully explored. Detailed mechanistic evaluation is in order. The objective of the present study was to determine the antiarrhythmic potential of RDN in a postinfarct animal model and to determine whether any benefits relate to RDN-induced reduction of sympathetic effectors on the myocardium. METHODS AND RESULTS: Pigs implanted with single-chamber implantable cardioverter defibrillators to record ventricular arrhythmias (VAs) were subjected to percutaneous coronary occlusion to induce myocardial infarction. Two weeks later, a sham or real RDN treatment was performed bilaterally using the St Jude EnligHTN basket catheter. Parameters of ventricular remodeling and modulation of cardio-renal sympathetic axis were monitored for 3 weeks after myocardial infarction. Histological analysis of renal arteries yielded a mean neurofilament score of healthy nerves that was significantly lower in the real RDN group than in sham controls; damaged nerves were found only in the real RDN group. There was a 100% reduction in the rate of spontaneous VAs after real RDN and a 75% increase in the rate of spontaneous VAs after sham RDN (P=0.03). In the infarcted myocardium, presence of sympathetic nerves and tissue abundance of neuropeptide-Y, an indicator of sympathetic nerve activities, were significantly lower in the RDN group. Peak and mean sinus tachycardia rates were significantly reduced after RDN. CONCLUSIONS: RDN in the infarcted pig model leads to reduction of postinfarction VAs and myocardial sympathetic effectors. This may form the basis for a potential therapeutic role of RDN in postinfarct VAs.

Cerebral Hemodynamics and Metabolism During Cardiac Arrest and Cardiopulmonary Resuscitation Using Hyperspectral Near Infrared Spectroscopy.

BACKGROUND: Maintaining cerebral oxygen delivery and metabolism during cardiac arrest (CA) through resuscitation is essential to improve the survival rate while avoiding brain injury. The effect of CA and cardiopulmonary resuscitation (CPR) on cerebral and muscle oxygen delivery and metabolism is not clearly quantified.Methods and Results:A novel hyperspectral near-infrared spectroscopy (hNIRS) technique was developed and evaluated to measure cerebral oxygen delivery and aerobic metabolism during ventricular fibrillation (VF) CA and CPR in 14 pigs. The hNIRS parameters were measured simultaneously on the dura and skull to investigate the validity of non-invasive hNIRS measurements. In addition, we compared the hNIRS data collected simultaneously on the brain and muscle. Following VF induction, oxygenated hemoglobin (HbO2) declined with a 9.9 s delay and then cytochrome-c-oxidase (Cyt-ox) decreased on average 4.4 s later (P<0.05). CPR improved cerebral metabolism, which was reflected by an average 0.4 µmol/L increase in Cyt-ox, but had no significant effect on HbO2, deoxygenated hemoglobin (HHb) and tissue oxygen saturation (tSO2). Cyt-ox had greater correlation with HHb than HbO2. Muscle metabolism during VF and CPR was significantly different from that of the brain. The total hemoglobin concentration (in the brain only) increased after ~200 s of untreated CA, which is most likely driven by cerebral autoregulation through vasodilation. CONCLUSIONS: Overall, hNIRS showed consistent measurements of hemodynamics and metabolism during CA and CPR.

Characterization of the ultrashort-TE (UTE) MR collagen signal.

Although current cardiovascular MR (CMR) techniques for the detection of myocardial fibrosis have shown promise, they nevertheless depend on gadolinium-based contrast agents and are not specific to collagen. In particular, the diagnosis of diffuse myocardial fibrosis, a precursor of heart failure, would benefit from a non-invasive imaging technique that can detect collagen directly. Such a method could potentially replace the need for endomyocardial biopsy, the gold standard for the diagnosis of the disease. The objective of this study was to measure the MR properties of collagen using ultrashort TE (UTE), a technique that can detect short T2* species. Experiments were performed in collagen solutions. Via a model of bi-exponential T2* with oscillation, a linear relationship (slope = 0.40 ± 0.01, R(2) = 0.99696) was determined between the UTE collagen signal fraction associated with these properties and the measured collagen concentration in solution. The UTE signal of protons in the collagen molecule was characterized as having a mean T2* of 0.75 ± 0.05 ms and a mean chemical shift of -3.56 ± 0.01 ppm relative to water at 7 T. The results indicated that collagen can be detected and quantified using UTE. A knowledge of the collagen signal properties could potentially be beneficial for the endogenous detection of myocardial fibrosis.

Dantrolene improves survival after ventricular fibrillation by mitigating impaired calcium handling in animal models.

BACKGROUND: Resistant ventricular fibrillation, refibrillation. and diminished myocardial contractility are important factors leading to poor survival after cardiac arrest. We hypothesized that dantrolene improves survival after ventricular fibrillation (VF) by rectifying the calcium dysregulation caused by VF. METHODS AND RESULTS: VF was induced in 26 Yorkshire pigs for 4 minutes. Cardiopulmonary resuscitation was then commenced for 3 minutes, and dantrolene or isotonic saline was infused at the onset of cardiopulmonary resuscitation. Animals were defibrillated and observed for 30 minutes. To study the effect of VF on calcium handling and its modulation by dantrolene, hearts from 14 New Zealand rabbits were Langendorff-perfused. The inducibility of VF after dantrolene administration was documented. Optical mapping was performed to evaluate diastolic spontaneous calcium elevations as a measure of cytosolic calcium leak. The sustained return of spontaneous circulation (systolic blood pressure ≥60 mm Hg) was achieved in 85% of the dantrolene group in comparison with 39% of controls (P=0.02). return of spontaneous circulation was achieved earlier in dantrolene-treated pigs after successful defibrillation (21 ± 6 s versus 181 ± 57 s in controls, P=0.005). The median number of refibrillation episodes was lower in the dantrolene group (0 versus 1, P=0.04). In isolated rabbit hearts, the successful induction of VF was achieved in 83% of attempts in controls versus 41% in dantrolene-treated hearts (P=0.007). VF caused diastolic calcium leaks in the form of spontaneous calcium elevations. Administration of 20 µmol/L dantrolene significantly decreased spontaneous calcium elevation amplitude versus controls. (0.024 ± 0.013 versus 0.12 ± 0.02 arbitrary unit [200-ms cycle length], P=0.001). CONCLUSIONS: Dantrolene infusion during cardiopulmonary resuscitation facilitates successful defibrillation, improves hemodynamics postdefibrillation, decreases refibrillation, and thus improves survival after cardiac arrest. The effects are mediated through normalizing VF-induced dysfunctional calcium cycling.

Dronedarone and Captisol-enabled amiodarone in an experimental cardiac arrest.

OBJECTIVE: To compare the energy required for defibrillation and postshock outcomes after the administration of dronedarone, amiodarone, and placebo in a porcine model of cardiac arrest. METHODS: Forty-two pigs were randomized to amiodarone, dronedarone, or control treatments. After induction of ventricular fibrillation, compressions and ventilations were performed for 3 minutes and treatment was administered over 30 seconds. If defibrillation was unsuccessful, cardiopulmonary resuscitation continued and repeated shocks were administered every 2 minutes with continual hemodynamic monitoring for a total duration of 30 minutes. RESULTS: The cumulative energy required for defibrillation was 570 ± 422 J for dronedarone, 441 ± 365 J for amiodarone, and 347 ± 281 J for control (P = not significant). Survival at 30 minutes was 1 (7.1%) for dronedarone compared with 11 (78.6%) for control (P = 0.001). Mortality in the dronedarone group was because of refibrillation in 3 (21.4%) cases, atrioventricular block in 1 (7.1%) case, and hypotension not because of bradycardia in 9 (64.3%) cases. Two minutes after successful defibrillation, systolic aortic pressure was lower in dronedarone versus control (86.6 ± 26.9 vs. 110 ± 15.1 mm Hg; P = 0.035). CONCLUSIONS: The administration of dronedarone resulted in a significant reduction in survival and both systolic aortic and coronary perfusion pressure compared with control.

The effects of an automatic, low pressure and constant flow ventilation device versus manual ventilation during cardiovascular resuscitation in a porcine model of cardiac arrest.

BACKGROUND: Cardiac arrest is an important cause of mortality. Cardiopulmonary resuscitation (CPR) improves survival, however, delivery of effective CPR can be challenging and combining effective chest compressions with ventilation, while avoiding over-ventilation is difficult. We hypothesized that ventilation with a pneumatically powered, automatic ventilator (Oxylator(®)) can provide adequate ventilation in a model of cardiac arrest and improve the consistency of ventilations during CPR. METHODS/RESULTS: Twelve pigs (∼40 kg, either sex) underwent 3 episodes each of cardiac arrest and resuscitation consisting of 30s of untreated ventricular fibrillation, followed by 5 min of CPR, defibrillation, and ∼30 min of recovery. During CPR in each episode, pigs were ventilated in 1 of 3 ways in random balanced order: manual ventilation using AMBU bag (12 breaths/min), low pressure Oxylator(®) (maximum airway pressure 15 cm H2O with 20 L/min constant flow in automatic mode [Ox15/20]), or high pressure Oxylator(®) (maximum airway pressure 20 cm H2O with 30 L/min constant flow in automatic mode [Ox20/30]). During CPR, both Ox15/20 and Ox20/30 resulted in higher levels of positive end expiratory pressure than manual ventilation. Ox15/20 ventilation also resulted in higher arterial pCO2 than manual ventilation. Ox20/30 ventilation yielded higher arterial pO2 and a lower arterial-alveolar gradient than manual ventilation. All pigs were successfully defibrillated, and no measured haemodynamic variables were different between the groups. CONCLUSION: Ventilation with an automatic ventilation device during CPR is feasible and provides adequate ventilation and comparable haemodynamics when compared to manual bag ventilation.

How Are n-3 LCPUFAs Antiarrhythmic? A Reassessment of n-3 LCPUFAs in Cardiac Disease.

Long-chain n-3-polyunsaturated fatty acids (n-3 LCPUFAs), referring particularly to marine-derived eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to be effective in treating arrhythmias in some clinical trials and animal studies. The mechanism for this effect of n-3 LCPUFAs is not well understood. Experimental studies and clinical trials published in the 1980s and 1990s suggested that n-3 LCPUFAs may be antiarrhythmic drugs, but more recent trials have not confirmed this. In this paper, we examine evidence for, and against, the direct antiarrhythmic action of n-3 LCPUFAs and suggest that antistructural remodeling effects of n-3 LCPUFAs may be more relevant in accounting for their clinical effects.

Docosahexaenoic acid, but not eicosapentaenoic acid, supplementation reduces vulnerability to atrial fibrillation.

BACKGROUND: The potential health benefits of ω-3 polyunsaturated fatty acids (PUFAs) usually are studied using a combination of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). This combination reduces vulnerability to experimentally induced atrial fibrillation (AF). It is unknown whether EPA and DHA have differential effects when taken alone. Using a model of pacing-induced atrial hemodynamic overload, we investigated the individual effects of EPA and DHA on vulnerability to AF and atrial remodeling. METHODS AND RESULTS: Thirty-four dogs were randomized into 3 groups, all of which underwent simultaneous atrial and ventricular pacing at 220 beats per minute for 14 days. One group received purified DHA (≈1 g/d) orally for 21 days beginning 7 days before pacing began. Similarly, 1 group received ≈1 g/d purified EPA. In a third (control) group (No-PUFAs), 8 dogs received ≈1 g/d olive oil, and 12 were unsupplemented. Electrophysiological and echocardiographic measurements were taken at baseline and 21 days. Atrial tissue samples were collected at 21 days for histological and molecular analyses. Persistent AF inducibility was significantly reduced by DHA compared with No-PUFAs median [25-75 percentiles], 0% [0%-3%] for DHA versus 3.1% [2.2%-11%] for No-PUFAs; P=0.007) but not by EPA (3.4% [1.9%-8.9%]). DHA also reduced atrial fibrosis compared with No-PUFAs (11 ± 6% versus 20 ± 4%, respectively; P<0.05), whereas EPA did not (15 ± 5%; P>0.05). CONCLUSIONS: DHA is more effective than EPA in attenuating AF vulnerability and atrial remodeling in structural remodeling-induced AF.

N-3 polyunsaturated fatty acid supplementation does not reduce vulnerability to atrial fibrillation in remodeling atria.

BACKGROUND: Prophylactic supplementation with omega-3 polyunsaturated fatty acids (PUFAs) reduce vulnerability to atrial fibrillation (AF). The effect of PUFAs given after cardiac injury has occurred is unknown. OBJECTIVE: To investigate using a model of pacing-induced cardiac injury, the time course of development of injury and whether it was altered by postinjury PUFAs. METHODS: Sixty-five dogs were randomized to undergo simultaneous atrial and ventricular pacing (SAVP, 220 beats/min) for 0, 2, 7, or 14 days. Twenty-two dogs received PUFAs (850 mg/d) either prophylactically or after some pacing had occurred (postinjury). Electrophysiologic and echocardiographic measurements were taken at baseline and sacrifice. Atrial tissue samples were collected at sacrifice for histologic and molecular analyses. RESULTS: With no PUFAs, the inducibility of AF increased with pacing duration (P < .001). Postinjury PUFAs (started after 7 days of pacing) did not reduce the inducibility of AF after 14 days of pacing (9.3% ± 8.8% no PUFAs vs 9.7% ± 9.9% postinjury PUFAs; P = .91). Atrial myocyte size and fibrosis increased with pacing duration (P < .05). Postinjury PUFAs did not significantly attenuate the cell size increase after 14 days of pacing (no PUFAs 38% ± 30% vs postinjury PUFAs 19% ± 28%; P = .11). Similarly, postinjury PUFAs did not attenuate the increase in fibrosis after 14 days of pacing (no PUFAs 66% ± 51% vs postinjury PUFAs 63% ± 76%; P = .90). CONCLUSION: PUFA supplementation begun after cardiac injury has already occurred does not reduce atrial structural remodeling or vulnerability to AF.

n-3 Polyunsaturated fatty acids alter expression of fibrotic and hypertrophic genes in a dog model of atrial cardiomyopathy.

BACKGROUND: We previously showed that omega-3 polyunsaturated fatty acids (PUFAs) reduce vulnerability to atrial fibrillation (AF). The mechanisms underlying this effect are unknown. OBJECTIVE: The purpose of this study was to use a genome-wide approach to identify gene expression profiles involved in a new model of AF vulnerability and to determine whether they were altered by PUFA therapy. METHODS: Thirty-six dogs were randomized evenly into three groups. Two groups were paced using simultaneous atrioventricular pacing (SAVP) at 220 bpm for 14 days to induce atrial enlargement, fibrosis, and susceptibility to AF. One group was supplemented with oral PUFAs (850 mg/day) for 21 days, commencing 7 days before the start of pacing (SAVP-PUFAs). The second group received no PUFAs (SAVP-No PUFAs). The remaining dogs were unpaced, unsupplemented controls (CTRL). Atrial tissue was sampled at the end of the protocol. Gene expression was analyzed in four dogs randomly selected from each group (n = 12) via microarray. Results were confirmed with quantitative real-time polymerase chain reaction (RT-PCR) and histology on all 36 dogs. RESULTS: Microarray or quantitative RT-PCR results showed that SAVP-No PUFAs dogs had significantly increased mRNA levels of protein kinase B (Akt), epidermal growth factor (EGF), JAM3, myosin heavy chain alpha (MHCalpha), and CD99 and significantly decreased levels of Smad6 compared with CTRL dogs. Quantitative RT-PCR showed that PUFA supplementation was associated with significant down-regulation of Akt, EGF, JAM3, MHCalpha, and CD99 levels compared with SAVP-No PUFAs dogs. CONCLUSION: The effect of PUFAs on these fibrosis, hypertrophy, and inflammation related genes suggests that, in this model, PUFA-mediated prevention of AF may be due to attenuation of adverse remodeling at the genetic level in response to mechanical stress.

Effects of chronic gap junction conduction-enhancing antiarrhythmic peptide GAP-134 administration on experimental atrial fibrillation in dogs.

BACKGROUND: Abnormal intercellular communication caused by connexin dysfunction may contribute to atrial fibrillation (AF). The present study assessed the effect of the gap junction conduction-enhancing antiarrhythmic peptide GAP-134 on AF inducibility and maintenance in a dog model of atrial cardiomyopathy. METHODS AND RESULTS: Twenty-four dogs subject to simultaneous atrioventricular pacing (220 bpm for 14 days) were randomly assigned to placebo treatment (PACED-CTRL; 12 dogs) or oral GAP-134 (2.9 mg/kg BID; PACED-GAP-134; 12 dogs) starting on day 0. UNPACED-CTRL (4 dogs) and UNPACED-GAP-134 (4 dogs) served as additional control groups. Change in left atrial (LA) systolic area from baseline to 14 days was calculated using transoesophageal echocardiography. At 14 days, animals underwent an open-chest electrophysiological study. PACED-CTRL dogs (versus UNPACED-CTRL) had a shorter estimated LA wavelength (8.0+/-1.4 versus 24.4+/-2.5 cm, P<0.05) and a greater AF vulnerability (mean AF duration, 1588+/-329 versus 25+/-34 seconds, P<0.05). Oral GAP-134 had no effect on AF vulnerability in UNPACED dogs. Compared with PACED-CTRL dogs, PACED-GAP-134 dogs had a longer estimated LA wavelength (10.2+/-2.8 versus 8.0+/-1.4 cm, respectively, P<0.05). Oral GAP-134 did not significantly reduce AF inducibility or maintenance in the entire group of 24 PACED dogs; in a subgroup of dogs (n=11) with less than 100% increase in LA systolic area, oral GAP-134 reduced AF induction from 100% to 40% and mean AF duration from 1737+/-120 to 615+/-280 seconds (P<0.05). CONCLUSIONS: Oral GAP-134 reduces pacing-induced decrease in LA wavelength and appears to attenuate AF vulnerability in dogs with less atrial mechanical remodeling. Gap junction modulation may affect AF in some circumstances.

Influence of ventriculoatrial timing on hemodynamics and symptoms during supraventricular tachycardia.

AIMS: Patients with reentrant supraventricular tachycardia (SVT) are often highly symptomatic and the mechanism of symptoms is not well understood. We hypothesized that variation in ventriculoatrial interval (QRS to P) modulates the left atrial pressure and symptoms during tachycardia. METHODS AND RESULTS: Three hundred twenty-six patients awaiting electrophysiological study completed a questionnaire regarding "neck pounding" or "shirt flapping" during tachycardia. Mean left atrial pressure was measured during simulated atrioventricular reentry tachycardia (AVRT) and atrioventricular nodal reentry tachycardia (AVNRT) in 18 patients. Pulmonary venous flow reversal was assessed using transesophageal echocardiography in 12 dogs when pacing at 220 bpm with different VA delays (0 to 250 ms). "Shirt flapping" is present more often during AVNRT than during AVRT (58.6% vs 43.8%, respectively, P < 0.05). Simulated AVNRT is associated with higher left atrial pressure compared with AVRT (19.4 +/- 4.8 mmHg vs 13.7 +/- 3.9 mmHg, respectively, P < 0.05). In dogs, pulmonary venous flow reversal during atrial systole was observed with significantly decreasing amplitude as VA delays increased: 668 +/- 167% at 0 ms; 492 +/- 138% at 100 ms; 278 +/- 148% at 180/ms; and 134 +/- 91% at 220 ms. CONCLUSION: "Shirt flapping" and "neck pounding" frequently occur during AVNRT. LA contractions during AV valve closure increase left atrial pressure and may explain differences in certain symptoms between AVNRT and AVRT.

Simultaneous right atrioventricular pacing: a novel model to study atrial remodeling and fibrillation in the setting of heart failure.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia which contributes to morbidity and mortality in patients with heart failure (HF). Atrial remodeling is a key substrate for the development of AF in HF. However, experimental models that study AF in the setting of HF have important limitations. We evaluated a new dog model of atrial remodeling and AF. METHODS AND RESULTS: Twenty-two mongrel dogs were randomized into 2 groups: 14 dogs with simultaneous atrioventricular pacing (SAVP) for 2 weeks (220 beats/min, no AV delay) and 8 control dogs with no pacing. SAVP for 2 weeks induced marked changes in atrial mechanical function and conduction. Left atrial area fractional shortening decreased 61 +/- 17%, whereas left ventricular area fractional shortening decreased by 38 +/- 18% from baseline (both P < .05). Conduction slowed and conduction heterogeneity increased. AF was induced in 83% of SAVP dogs, lasting a median of 1600 seconds, versus no dogs with induced AF in the controls. SAVP significantly increased nonfibrillar collagen in the mid-myocardium of both atrial appendages and matrix metalloproteinase-9 activity. CONCLUSIONS: SAVP in dogs induces structural and electrical remodelling that form the substrate for reproducibly inducible AF. This novel model may be useful for studies of the pathophysiology and treatment of AF in heart failure.

Experimental studies of atrial fibrillation: a comparison of two pacing models.

Rapid ventricular pacing (RVP) is a well-established animal model of atrial fibrillation (AF). However, this model is limited by a high mortality rate and severe heart failure. The purpose of our study was to assess a new canine model of inducible AF. We performed acute, short-term, simultaneous atrioventricular pacing (SAVP) and RVP (in random order) in 14 dogs for 30 s. SAVP produced more echocardiographic pulmonary venous flow reversal, a greater increase in mean pulmonary capillary wedge pressure, and a significantly greater decrease in left atrial emptying function (-84.4 +/- 38.6% vs. -23.7 +/- 27.1%, P < 0.05) than RVP. Thirty dogs were randomized to three, longer-term, study groups: eight dogs in the control group (no pacing), eight dogs in the RVP group (2 wk at 240 beats/min followed by 3 wk at 220 beats/min), and fourteen dogs in the SAVP group (2 wk at 220 beats/min). SAVP induced less left ventricular dysfunction but more left atrial dysfunction than RVP. SAVP dogs had similar atrial effective refractory periods as RVP dogs but more heterogeneity in conduction and more AF inducibility (83% vs. 40%, P < 0.05) and maintenance (median 1,660 vs. 710 s, P < 0.05) than RVP dogs. SAVP induced more collagen turnover and was associated with a significantly greater increase in type III collagen in the atria compared with RVP dogs (6.9 +/- 1.5 vs. 4.8 +/- 1.6, respectively, P < 0.05 vs. 1.1 +/- 0.7 in unpaced control dogs). In conclusion, the SAVP model induced profound mechanical and substrate atrial remodeling and reproducible sustained AF. This new model is clinically relevant and may be useful for testing AF interventions.