Postoperative atrial fibrillation: The role of the inflammatory response.

OBJECTIVE: Abnormal atrial conduction has been shown to be a substrate for postoperative atrial fibrillation (POAF). This study aimed to determine the relationship between the location of the atrial reentry responsible for POAF, and degree of atrial inflammation. METHODS: Normal mongrel dogs (n = 18) were divided into 3 groups: anesthesia alone (anesthesia), lateral right atriotomy (atriotomy), and lateral right atriotomy with anti-inflammatory therapy (steroid). Conduction properties of the right and left atria (RA and LA) were examined 3 days postoperatively by mapping. Activation was observed during burst pacing-induced AF. The RA and LA myeloperoxidase activity was measured to quantitate the degree of inflammation. RESULTS: Sustained AF (>2 minutes) was induced in 5 of 6 animals in the atriotomy group, but in none in the anesthesia or steroid groups. All sustained AF originated from around the RA incision. Three of these animals had an incisional reentrant tachycardia around the right atriotomy and 2 had a focal activation arising from the RA during AF. The LA activations in these animals were passive from the RA activation. The RA activation of the atriotomy group was more inhomogeneous than that of the anesthesia group (inhomogeneity index: 2.0 ± 0.2 vs 1.0 ± 0.1, P < .01). Steroid therapy significantly normalized the RA activation after the atriotomy (1.2 ± 0.1, P < .01). The inhomogeneity of the atrial conduction correlated with the myeloperoxidase activity (r = 0.774, P < .001). CONCLUSIONS: Reentrant circuits responsible for POAF are dependent on the degree of inflammation and rotate around the atriotomy. Anti-inflammatory therapy decreased the risk of postoperative AF.

Potassium and Magnesium Supplementation Do Not Protect Against Atrial Fibrillation After Cardiac Operation: A Time-Matched Analysis.

BACKGROUND: Despite a lack of demonstrated efficacy, potassium and magnesium supplementation are commonly thought to prevent postoperative atrial fibrillation (POAF) after cardiac operation. Our aim was to evaluate the natural time course of electrolyte level changes after cardiac operation and their relation to POAF occurrence. METHODS: Data were reviewed from 2,041 adult patients without preoperative AF who underwent coronary artery bypass grafting, valve operation, or both between 2009 and 2013. In patients with POAF, the plasma potassium and magnesium levels nearest to the first AF onset time were compared with time-matched electrolyte levels in patients without AF. RESULTS: POAF occurred in 752 patients (36.8%). At the time of AF onset or the matched time point, patients with POAF had higher potassium (4.30 versus 4.21 mmol/L, p < 0.001) and magnesium (2.33 versus 2.16 mg/dL, p < 0.001) levels than controls. A stepwise increase in AF risk occurred with increasing potassium or magnesium quintile (p < 0.001). On multivariate logistic regression analysis, magnesium level was an independent predictor of POAF (odds ratio 4.26, p < 0.001), in addition to age, Caucasian race, preoperative ß-blocker use, valve operation, and postoperative pneumonia. Prophylactic potassium supplementation did not reduce the POAF rate (37% versus 37%, p = 0.813), whereas magnesium supplementation was associated with increased POAF (47% versus 36%, p = 0.005). CONCLUSIONS: Higher serum potassium and magnesium levels were associated with increased risk of POAF after cardiac operation. Potassium supplementation was not protective against POAF, and magnesium supplementation was even associated with increased POAF risk. These findings help explain the poor efficacy of electrolyte supplementation in POAF prophylaxis.

Multistage electrotherapy delivered through chronically-implanted leads terminates atrial fibrillation with lower energy than a single biphasic shock.

OBJECTIVES: The goal of this study was to develop a low-energy, implantable device-based multistage electrotherapy (MSE) to terminate atrial fibrillation (AF). BACKGROUND: Previous attempts to perform cardioversion of AF by using an implantable device were limited by the pain caused by use of a high-energy single biphasic shock (BPS). METHODS: Transvenous leads were implanted into the right atrium (RA), coronary sinus, and left pulmonary artery of 14 dogs. Self-sustaining AF was induced by 6 ± 2 weeks of high-rate RA pacing. Atrial defibrillation thresholds of standard versus experimental electrotherapies were measured in vivo and studied by using optical imaging in vitro. RESULTS: The mean AF cycle length (CL) in vivo was 112 ± 21 ms (534 beats/min). The impedances of the RA-left pulmonary artery and RA-coronary sinus shock vectors were similar (121 ± 11 Ω vs. 126 ± 9 Ω; p = 0.27). BPS required 1.48 ± 0.91 J (165 ± 34 V) to terminate AF. In contrast, MSE terminated AF with significantly less energy (0.16 ± 0.16 J; p < 0.001) and significantly lower peak voltage (31.1 ± 19.3 V; p < 0.001). In vitro optical imaging studies found that AF was maintained by localized foci originating from pulmonary vein-left atrium interfaces. MSE Stage 1 shocks temporarily disrupted localized foci; MSE Stage 2 entrainment shocks continued to silence the localized foci driving AF; and MSE Stage 3 pacing stimuli enabled consistent RA-left atrium activation until sinus rhythm was restored. CONCLUSIONS: Low-energy MSE significantly reduced the atrial defibrillation thresholds compared with BPS in a canine model of AF. MSE may enable painless, device-based AF therapy.

Importance of atrial surface area and refractory period in sustaining atrial fibrillation: testing the critical mass hypothesis.

OBJECTIVE: The critical mass hypothesis for atrial fibrillation (AF) was proposed in 1914; however, there have been few studies defining the relationship between atrial surface area and AF. This study evaluated the effect of tissue area and effective refractory period (ERP) on the probability of sustaining AF in an in vivo model. METHODS: Domestic pigs (n = 9) underwent median sternotomy. Epicardial activation maps were constructed from bipolar electrograms recorded from form-fitting electrode templates placed on the atria. Baseline ERPs were determined. ERP was lowered with a continuous infusion of acetylcholine (0.005-0.04 mg/Kg/min) until AF could be sustained after burst pacing. The atria were sequentially partitioned using bipolar radiofrequency ablation. ERPs were lowered using acetylcholine until AF could be sustained in each subdivision of atrial tissue. Each subdivision was further divided until AF was no longer inducible. At study completion, the heart was excised and the surface area of each section was measured. RESULTS: Over a range of ERPs from 75 to 250 ms, the probability of AF was correlated with increasing tissue area (range, 19.5-105 cm(2)) and decreasing ERP. Logistic regression analysis identified shorter ERP (P < .001) and larger area (P = .006) as factors predictive of an increased probability of sustained AF (area under the curve of the receiver-operator characteristic = 0.878). CONCLUSIONS: The probability of sustained AF was significantly associated with increasing tissue area and decreasing ERP. These data may lead to a greater understanding of the mechanism of AF and help to design better interventional procedures.

A novel low-energy electrotherapy that terminates ventricular tachycardia with lower energy than a biphasic shock when antitachycardia pacing fails.

OBJECTIVES: The authors sought to develop a low-energy electrotherapy that terminates ventricular tachycardia (VT) when antitachycardia pacing (ATP) fails. BACKGROUND: High-energy implantable cardioverter-defibrillator (ICD) shocks are associated with device failure, significant morbidity, and increased mortality. A low-energy alternative to ICD shocks is desirable. METHODS: Myocardial infarction was created in 25 dogs. Sustained, monomorphic VT was induced by programmed stimulation. Defibrillation electrodes were placed in the right ventricular apex, and coronary sinus and left ventricular epicardium. If ATP failed to terminate sustained VT, the defibrillation thresholds (DFTs) of standard versus experimental electrotherapies were measured. RESULTS: Sustained VT ranged from 276 to 438 beats/min (mean 339 beats/min). The right ventricular-coronary sinus shock vector had lower impedance than the right ventricular-left ventricular patch (54.4 ± 18.1 Ω versus 109.8 ± 16.9 Ω; p < 0.001). A single shock required between 0.3 ± 0.2 J to 5.9 ± 2.5 J (mean 2.64 ± 3.22 J; p = 0.008) to terminate VT, and varied depending upon the phase of the VT cycle in which it was delivered. By contrast, multiple shocks delivered within 1 VT cycle length were not phase dependent and achieved lower DFT compared with a single shock (0.13 ± 0.09 J for 3 shocks, 0.08 ± 0.04 J for 5 shocks, and 0.09 ± 0.07 J for 7 shocks; p < 0.001). Finally, a multistage electrotherapy (MSE) achieved significantly lower DFT compared with a single biphasic shock (0.03 ± 0.05 J versus 2.37 ± 1.20 J; respectively, p < 0.001). At a peak shock amplitude of 20 V, MSE achieved 91.3% of terminations versus 10.5% for a biphasic shock (p < 0.001). CONCLUSIONS: MSE achieved a major reduction in DFT compared with a single biphasic shock for ATP-refractory monomorphic VT, and represents a novel electrotherapy to reduce high-energy ICD shocks.

Chronic performance of a novel radiofrequency ablation device on the beating heart: Limitations of conduction delay to assess transmurality.

OBJECTIVE: The creation of consistently transmural lesions with epicardial ablation on the beating heart has represented a significant challenge for current technology. This study examined the chronic performance of the AtriCure Coolrail device (AtriCure Inc, West Chester, Ohio), an internally cooled, bipolar radiofrequency ablation device designed for off-pump epicardial ablation. The study also examined the reliability of using acute intraoperative conduction delay to evaluate lesion integrity. METHODS: Seven swine underwent median sternotomy. The right atrial appendage and inferior vena cava were isolated with a bipolar radiofrequency clamp. Linear ablation lines were created between these structures with the AtriCure Coolrail. Paced activation maps were recorded with epicardial patch electrodes acutely before and after ablation and after keeping the animals alive for 4 weeks. The conduction time across the linear ablation was calculated from these maps. The lesions were histologically evaluated with trichrome staining. RESULTS: Only 76% of cross-sections of Coolrail lesions were transmural, and only 1 of 12 ablation lines was transmural in every cross-section examined. Mapping data were available in 5 of the animals. Significant conduction delay was present after the creation of each line of ablation acutely; however, after 4 weeks, conduction time returned to preablation values, demonstrating lack of transmurality. CONCLUSIONS: The AtriCure Coolrail failed to reliably create transmural lesions. Although the Coolrail was able to create acute conduction delay, its failure to transmurally ablate the atrial myocardium left gaps along the length of the lesion, which resulted in neither chronic conduction block nor delay across any line of ablation.

The effects of inflammation on heart rate and rhythm in a canine model of cardiac surgery.

BACKGROUND: Heart rate (HR) and rhythm disturbances are common after cardiac surgery. This study tests the hypothesis that the inflammation caused by cardiac surgery is an underlying mechanism for postoperative changes in HR, rhythm, and HR variability (HRV). METHOD AND RESULTS: Normal canines (n = 6 per group) were divided into 4 groups: (1) anesthesia, (2) sternotomy and pericardiotomy, (3) atriotomy, and (4) corticosteroids combined with an atriotomy. Continuous electrocardiographic recordings were done preoperatively and for 3 postoperative days. Electrophysiologic testing was done at the initial and terminal surgeries. C-reactive protein level was assessed at each study day, and tissue myeloperoxidase activity was assessed at the terminal study. Measurements of HRV were determined daily to detect changes in autonomic tone. Postoperatively, the HR increased in the pericardiotomy (P = .0005) and atriotomy (P = .001) groups and HRV decreased in both the groups. No significant change occurred in either the HR or HRV in the anesthesia (P = .52) and steroid (P = .16) groups. HRV (triangular index) on postoperative day 3 was correlated with the tissue myeloperoxidase levels (r = -.83; P = .0004). Autonomic blockade with atropine and esmolol resulted in an HR and HRV that were not significantly different between groups. Atrial premature beats occurred postoperatively in the all the groups except the anesthesia group and were independent of the degree of inflammation. CONCLUSION: Cardiac surgery increases the postoperative HR by reducing HRV, mostly because of a reduction in vagal tone. Furthermore, the magnitude of these changes is dependent on the degree of inflammation and is normalized by corticosteroids.

Low-energy multistage atrial defibrillation therapy terminates atrial fibrillation with less energy than a single shock.

BACKGROUND: Implantable device therapy of atrial fibrillation (AF) is limited by pain from high-energy shocks. We developed a low-energy multistage defibrillation therapy and tested it in a canine model of AF. METHODS AND RESULTS: AF was induced by burst pacing during vagus nerve stimulation. Our novel defibrillation therapy consisted of 3 stages: stage (ST) 1 (1-4 low-energy biphasic [BP] shocks), ST2 (6-10 ultralow-energy monophasic [MP] shocks), and ST3 (antitachycardia pacing). First, ST1 testing compared single or multiple MP and BP shocks. Second, several multistage therapies were tested: ST1 versus ST1+ST3 versus ST1+ST2+ST3. Third, 3 shock vectors were compared: superior vena cava to distal coronary sinus, proximal coronary sinus to left atrial appendage, and right atrial appendage to left atrial appendage. The atrial defibrillation threshold (DFT) of 1 BP shock was <1 MP shock (0.55 ± 0.1 versus 1.38 ± 0.31 J, P=0.003). Two to 3 BP shocks terminated AF with lower peak voltage than 1 BP or 1 MP shock and with lower atrial DFT than 4 BP shocks. Compared with ST1 therapy alone, ST1+ST3 lowered the atrial DFT moderately (0.51 ± 0.46 versus 0.95 ± 0.32 J, P=0.036), whereas 3-stage therapy (ST1+ST2+ST3) dramatically lowered the atrial DFT (0.19 ± 0.12 versus 0.95 ± 0.32 J for ST1 alone, P=0.0012). Finally, the 3-stage therapy was equally effective for all studied vectors. CONCLUSIONS: Three-stage electrotherapy significantly reduces the AF DFT and opens the door to low-energy atrial defibrillation at or below the pain threshold.

An open sarcolemmal adenosine triphosphate-sensitive potassium channel is necessary for detrimental myocyte swelling secondary to stress.

BACKGROUND: Stress (exposure to hyperkalemic cardioplegia, metabolic inhibition, or osmotic) results in significant myocyte swelling and reduced contractility. In contrast to wild-type mice, these detrimental consequences are not observed in mice lacking the Kir6.2 subunit of the sarcolemmal ATP-sensitive potassium (sK(ATP)) channel after exposure to hyperkalemic cardioplegia. The hypothesis for this study was that an open sK(ATP) channel (Kir6.2 and SUR2A subunits) is necessary for detrimental myocyte swelling to occur in response to stress. METHODS AND RESULTS: To investigate the role of the sK(ATP) channel in stress-induced myocyte swelling, high-dose pharmacological sK(ATP) channel blockade and genetic deletion (knockout of Kir6.2 subunit) were used. Myocytes were exposed sequentially to Tyrode control (20 minutes), test (stress) solution (20 minutes), and Tyrode control (20 minutes). To evaluate pharmacological channel blockade, myocytes were exposed to hyperkalemic cardioplegia (stress) with and without a K(ATP) channel blocker. To evaluate the effects of genetic deletion, wild-type and sK(ATP) knockout [Kir6.2(-/-)] myocytes were exposed to metabolic inhibition (stress). Myocyte volume was recorded using image-grabbing software. Detrimental myocyte swelling was prevented by high-dose sK(ATP) channel blockade (glibenclamide or HMR 1098) but not mitochondrial K(ATP) channel blockade (5-hydroxydecanoate) during exposure to hyperkalemic cardioplegia. Genetic deletion of the sK(ATP) channel prevented significant myocyte swelling in response to metabolic inhibition. CONCLUSIONS: K(ATP) channel openers prevent detrimental myocyte swelling and reduce contractility in response to stress through an unknown mechanism. Paradoxically, the present data support a role for sK(ATP) channel activation in myocyte volume derangement in response to stress.

Vagal denervation and reinnervation after ablation of ganglionated plexi.

OBJECTIVE: Surgical ablation of ganglionated plexi has been proposed to increase efficacy of surgery for atrial fibrillation. This experimental canine study examined electrophysiologic attenuation and recovery of atrial vagal effects after ganglionated plexi ablation alone or with standard surgical lesion sets for atrial fibrillation. METHODS: Dogs were divided into 3 groups: group 1 (n = 6) had focal ablation of the 4 major epicardial ganglionated plexi fat pads, group 2 (n = 6) had pulmonary vein isolation with ablation, and group 3 (n = 6) had posterior left atrial isolation with ablation. All fat pads were ablated. Sinus and atrioventricular interval changes during bilateral vagosympathetic trunk stimulation were examined before and both immediately and 4 weeks after ablation. Vagally induced effective refractory period changes and mean QRST area changes (index of local innervation) were examined in 5 atrial regions. RESULTS: Sinus and atrioventricular interval changes and heart rate variability decreased immediately after ablation, but only sinus interval changes were restored significantly after 4 weeks in all groups. Ablation-modified vagal effects on effective refractory period or QRST area changed heterogeneously in groups 1 and 2. In group 3, regional vagal effects were attenuated extensively postablation in both atria. Posterior left atrial isolation with ablation incrementally denervated the atria. In the long term, vagal stimulation increased QRST area changes relative to control values in all groups. Heart rate variability was also assessed. CONCLUSIONS: Ganglionated plexi ablation significantly reduced atrial vagal innervation. Restoration of vagal effects at 4 weeks suggests early atrial reinnervation.

Structural and functional evidence for discrete exit pathways that connect the canine sinoatrial node and atria.

Surface electrode recordings cannot delineate the activation within the human or canine sinoatrial node (SAN) because they are intramural structures. Thus, the site of origin of excitation and conduction pathway(s) within the SAN of these mammals remains unknown. Canine right atrial preparations (n=7) were optically mapped. The SAN 3D structure and protein expression were mapped using immunohistochemistry. SAN optical action potentials had diastolic depolarization and multiple upstroke components that corresponded to the separate excitations of the node and surface atrial layers. Pacing-induced SAN exit block eliminated atrial optical action potential components but retained SAN optical action potential components. Excitation originated in the SAN (cycle length, 557+/-72 ms) and slowly spread (1.2 to 14 cm/sec) within the SAN, failing to directly excite the crista terminalis and intraatrial septum. After a 49+/-22 ms conduction delay within the SAN, excitation reached the atrial myocardium via superior and/or inferior sinoatrial exit pathways 8.8+/-3.2 mm from the leading pacemaker site. The ellipsoidal 13.7+/-2.8/4.9+/-0.6 mm SAN structure was functionally insulated from the atrium. This insulation coincided with connexin43-negative regions at the borders of the node, connective tissue, and coronary arteries. During normal sinus rhythm, the canine SAN is functionally insulated from the surrounding atrial myocardium except for 2 (or more) narrow superior and inferior sinoatrial exit pathways separated by 12.8+/-4.1 mm. Conduction failure in these sinoatrial exit pathways leads to SAN exit block and is a modulator of heart rate.

Mechanisms of delayed electrical uncoupling induced by ischemic preconditioning.

Electrical uncoupling of cardiac myocytes during ischemia is delayed by ischemic preconditioning. This presumably adaptive response may limit development of arrhythmia substrates. To elucidate responsible mechanisms, we studied isolated, perfused rat hearts subjected to a standard preconditioning protocol of 3 cycles of 3 minutes of global no-flow ischemia each followed by 5 minutes of reperfusion before a 30-minute interval of ischemia. Changes in coupling were monitored by measuring whole-tissue resistance. Changes in phosphorylation and subcellular distribution of connexin43 (Cx43) were defined by quantitative immunoblotting and confocal microscopy. Preconditioning caused a 34% decrease in the maximal rate of uncoupling and delayed the time to plateau in uncoupling. Dephosphorylation of Cx43, known to occur during uncoupling induced by ischemia, was dramatically decreased in preconditioned hearts. Translocation of Cx43 from gap junctions to the cytosol, also known to occur during ischemia, was reduced by >5-fold in preconditioned hearts. The KATP channel blockers glybenclamide and 5-hydroxydecanoate prevented these effects in preconditioned hearts, whereas the KATP channel agonist diazoxide mimicked these effects in nonpreconditioned hearts. Intracellular translocation of Cx43 was blocked, but Cx43 dephosphorylation was not blocked during ischemia in preconditioned hearts treated with the PKC inhibitors chelerythrine and calphostin C. Uncoupling during ischemia was accelerated by PKC and KATP channel inhibition. Thus, delayed uncoupling in preconditioned hearts is likely related to diminished dephosphorylation and intracellular redistribution of Cx43 during prolonged ischemia. Both of these effects are regulated by activation of KATP channels, whereas PKC plays a role in internalization of Cx43.