Differential effects of sevoflurane and propofol on swine cardiac conduction system.

OBJECTIVE: To compare the effects of sevoflurane and propofol on the porcine cardiac conduction system. STUDY DESIGN: A prospective, comparative study of electrophysiological properties of anaesthetics agents in an experimental porcine model. ANIMALS: A total of 36 hybrid Landrace-Large White pigs. METHODS: After premedication with 20 mg kg-1 of intramuscular ketamine, anaesthesia was induced with 4.5 mg kg-1propofol intravenously. In 18 consecutive animals, anaesthesia was maintained with propofol (13 mg kg-1 hour-1) and in the remaining 18 animals with 2.66% sevoflurane. The femoral artery and vein were canalized for invasive monitoring, analytical blood gas sampling and intracardiac catheter insertion. Following instrumentation and after a period of stabilization, a customary electrophysiological evaluation was performed. We compared the electrophysiology of the sinus and atrioventricular node (AV) node under sevoflurane or propofol anaesthesia, and the effects of both anaesthetics on atrial and ventricular refractoriness. RESULTS: There was a significant difference in sinus node recovery time between sevoflurane and propofol (907 ± 231 versus 753 ± 146 ms, p = 0.02). Sevoflurane in comparison with propofol significantly prolonged specialized AV conduction times, represented by an increased Wenckebach cycle length (272 ± 54 versus 235 ± 40 ms, p = 0.03) and AV nodal refractoriness (327 ± 34 versus 287 ± 30 ms, p = 0.002). In addition, sevoflurane prolonged ventricular refractoriness (298 ± 27 versus 255 ± 38 ms, p = 0.007) and the QT corrected interval (0.50 ± 0.05 versus 0.46 ± 0.09 ms, p = 0.005). CONCLUSIONS AND CLINICAL RELEVANCE: Sevoflurane in comparison with propofol, depresses several parameters of sinus and AV nodal function and prolongs the ventricular refractoriness of the porcine cardiac conduction system. These findings should be taken into consideration for the choice of anaesthetic agents in clinical and experimental settings.

Effects of angiotensin-neprilysin inhibition compared to angiotensin inhibition on ventricular arrhythmias in reduced ejection fraction patients under continuous remote monitoring of implantable defibrillator devices.

BACKGROUND: Angiotensin-neprilysin inhibition compared to angiotensin inhibition decreased sudden cardiac death in patients with reduced ejection fraction heart failure (rEFHF). The precise mechanism remains unclear. OBJECTIVE: The purpose of this study was to explore the effect of angiotensin-neprilysin inhibition on ventricular arrhythmias compared to angiotensin inhibition in rEFHF patients with an implantable cardioverter-defibrillator (ICD) and remote monitoring. METHODS: We prospectively included 120 patients with ICD and (1) New York Heart Association functional class ≥II; (2) left ventricular ejection fraction ≤40%; and (3) remote monitoring. For 9 months, patients received 100% angiotensin inhibition with angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), beta-blockers, and mineraloid antagonist. Subsequently, ACEi or ARB was changed to sacubitril-valsartan in all patients, who were followed for 9 months. Appropriate shocks, nonsustained ventricular tachycardia (NSVT), premature ventricular contraction (PVC) burden, and biventricular pacing percentage were analyzed. RESULTS: Patients were an average age of 69 ± 8 years and had mean left ventricular ejection fraction of 30.4% ± 4% (82% ischemic). Use of beta-blockers (98%), mineraloid antagonist (97%) and antiarrhythmic drugs was similar before and after sacubitril-valsartan. Sacubitril-valsartan significantly decreased NSVT episodes (5.4 ± 0.5 vs 15 ± 1.7 in angiotensin inhibition; P <.002), sustained ventricular tachycardia, and appropriate ICD shocks (0.8% vs 6.7% in angiotensin inhibition; P <.02). PVCs per hour decreased after sacubitril-valsartan (33 ± 12 vs 78 ± 15 in angiotensin inhibition; P <.0003) and was associated with increased biventricular pacing percentage (from 95% ± 6% to 98.8% ± 1.3%; P <.02). CONCLUSION: Angiotensin-neprilysin inhibition decreased ventricular arrhythmias and appropriate ICD shocks in rEFHF patients under home monitoring compared to angiotensin inhibition.

Treating Refractory Hypertension: Renal Denervation With High-Resolution 3D-Angiography.

A 53-year-old male was referred to our Department for refractory primary hypertension. Despite high doses of 6 anti-hypertensive drugs, ambulatory monitoring of blood pressure (BP) revealed a mean BP of 160/90 mmHg. Under local anaesthesia, renal denervation with radiofrequency was performed supported by high-resolution 3D angiography, which helped confirm the position of the applications in a spiroid fashion.

Relationship between mechanical and electrical remodelling in patients with cardiac resynchronization implanted defibrillators.

AIMS: Cardiac resynchronization therapy (CRT) is associated with reverse left ventricular (LV) remodelling. However, the effects of CRT-induced mechanical remodelling on electrical remodelling, and the occurrence of ventricular arrhythmias have not been clearly established. We studied the relationship between mechanical remodelling, electrical remodelling, and the occurrence of appropriate implantable cardioverter-defibrillator (ICD) therapy 1 year after CRT. METHODS AND RESULTS: We analysed data from 45 patients who underwent ICD-CRT implantation at our centre. Significant LV reverse remodelling was defined by a minimum 10% decrease in the LV end-diastolic diameter (LVEDd) at 1 year of follow-up. Electrocardiographic indices of dispersion of repolarization [QTc, Tpeak-Tend (Tp-e) and their dispersion] were measured immediately and 1 year post-CRT implantation. The occurrence of appropriate ICD therapy was noted for each patient. Patients with (n= 21) and without (n= 24) significant LV reverse remodelling had similar baseline characteristics. At 1 year of follow-up, patients with mechanical reverse LV remodelling exhibited a significant decrease in QTc (505 ± 42 vs. 485 ± 52 ms, P < 0.05) and Tp-e (107 ± 26 vs. 92 ± 22 ms, P < 0.0001). However, patients without mechanical LV reverse remodelling exhibited a significant increase in QT dispersion (29 ± 43 vs. 98 ± 47 ms, P = 0.002) and Tp-e dispersion (22 ± 21 vs. 54 ± 36 ms, P = 0.0001). Finally patients with mechanical LV reverse remodelling experienced a lower rate of ICD therapy (P = 0.0025) after a mean follow-up of 19 months. CONCLUSION: Reverse LV mechanical remodelling is associated with reversal of electrical remodelling and a lower rate of appropriate ICD therapy following CRT.

Electrophysiological differences between the epicardium and the endocardium of the left atrium.

BACKGROUND: Electrophysiological properties of the atrial endocardium compared to epicardium are not well understood. The purpose of this study was to compare the electrophysiological properties and vulnerability to arrhythmia induction from these regions. METHODS AND RESULTS: Transseptal endocardial and percutaneous epicardial mapping were performed in a porcine model (n = 7). Two opposing 4-mm electrophysiological catheters were positioned endocardially and epicardially. A circular mapping catheter (CMC) was positioned at the ostium of the common inferior pulmonary vein (CIPV) recording left atrial (LA)-PV potentials. Endocardial and epicardial effective refractory periods (ERPs) at two basic cycle lengths (CLs) of 600 and 400 ms were recorded from four anatomic locations (CIPV, LA appendage, right superior PV, and LA posterior wall). Atrial repetitive response (ARR) induction was also tested from endocardial and epicardial sites. Overall, 254 ERP measurements (mean 36.3 per animal) and 84 induction attempts (mean 12 per animal) were performed. The ERP was significantly shorter in the epicardium compared to the endocardium at basic CL of 400 ms (P = 0.006) but not at CL of 600 ms (P = 0.2). In addition, only the epicardium demonstrated ERP shortening when the CL of the basic drive was shortened (P = 0.03). ARR could be induced more often from the epicardium (P = 0.002) and fibrillatory activity with epicardial/endocardial dissociation was recorded (n = 3). Also, the earliest PV activation site on the CMC was noted to be different in 16.5% of cases during epicardial and endocardial pacing. CONCLUSION: The electrophysiological characteristics of the atrial epicardium are different from the endocardium with a shorter ERP and more frequent ARR induction by programed stimulation.

Anisotropic conduction block and reentry in neonatal rat ventricular myocyte monolayers.

Anisotropy can lead to unidirectional conduction block that initiates reentry. We analyzed the mechanisms in patterned anisotropic neonatal rat ventricular myocyte monolayers. Voltage and intracellular Ca (Ca(i)) were optically mapped under the following conditions: extrastimulus (S1S2) testing and/or tetrodotoxin (TTX) to suppress Na current availability; heptanol to reduce gap junction conductance; and incremental rapid pacing. In anisotropic monolayers paced at 2 Hz, conduction velocity (CV) was faster longitudinally than transversely, with an anisotropy ratio [AR = CV(L)/CV(T), where CV(L) and CV(T) are CV in the longitudinal and transverse directions, respectively], averaging 2.1 ± 0.8. Interventions decreasing Na current availability, such as S1S2 pacing and TTX, slowed CV(L) and CV(T) proportionately, without changing the AR. Conduction block preferentially occurred longitudinal to fiber direction, commonly initiating reentry. Interventions that decreased gap junction conductance, such as heptanol, decreased CV(T) more than CV(L), increasing the AR and causing preferential transverse conduction block and reentry. Rapid pacing resembled the latter, increasing the AR and promoting transverse conduction block and reentry, which was prevented by the Ca(i) chelator 1,2-bis oaminophenoxy ethane-N,N,N',N'-tetraacetic acid (BAPTA). In contrast to isotropic and uniformly anisotropic monolayers, in which reentrant rotors drifted and self-terminated, bidirectional anisotropy (i.e., an abrupt change in fiber direction exceeding 45°) caused reentry to anchor near the zone of fiber direction change in 77% of monolayers. In anisotropic monolayers, unidirectional conduction block initiating reentry can occur longitudinal or transverse to fiber direction, depending on whether the experimental intervention reduces Na current availability or decreases gap junction conductance, agreeing with theoretical predictions.

Atrioventricular conduction and arrhythmias at the initiation of beating in embryonic mouse hearts.

To investigate cardiac physiology at the onset of heart beating in embryonic mouse hearts, we performed optical imaging of membrane potential (Vm) and/or intracellular calcium (Ca(i)). Action potentials and Ca(i) transients were detected in approximately 50% of mouse embryo hearts at E8.5, but in all hearts at E9.0, indicating that beating typically starts between E8-E9. Beating was eliminated by Ca channel blocker nifedipine and the I(f) blocker ZD7288, unaffected by tetrodotoxin and only mildly depressed by disabling sarcoplasmic (SR) and endoplasmic (ER) reticulum Ca cycling. From E8.5 to E10, conduction velocity increased from 0.2-1 mm/s to >5 mm/s in first ventricular and then atrial tissue, while remaining slow in other areas. Arrhythmias included atrioventricular reentry induced by adenosine. In summary, at the onset of beating, I(f)-dependent pacemaking drives both AP propagation and Ca(i) transient generation through activation of voltage-dependent Ca channels. Na channels and intracellular Ca cycling have minor roles.

A simple pacing method to diagnose postero-anterior (clockwise) cavo-tricuspid isthmus block after radiofrequency ablation.

AIMS: Bidirectional block of the cavo-tricuspid isthmus (CTI) is a widely accepted endpoint for typical atrial flutter ablation, but its evaluation may be difficult, especially in the postero-anterior (clockwise) direction. The main goal was to evaluate pacing at the septal edge of the ablation line as an indicator of clockwise CTI block and as a predictor for flutter recurrence. METHODS AND RESULTS: In 94 patients undergoing flutter ablation, CTI block in the antero-posterior (counterclockwise) direction was determined by differential pacing from several levels of the anterior right atrial (RA). CTI block in the clockwise direction was evaluated by analysing electrograms (EGM) at the ablation line during differential pacing of the septal RA (differential septal pacing) or by anterior sequence of RA during pacing septal isthmus, next to the ablation line (septal CTI pacing). Ablation produced bidirectional block in 78% of the patients, unidirectional counterclockwise block in 9% and bidirectional conduction persisted in 13%. After follow-up (37 +/- 23 months), flutter recurrence occurred in 13% (48% if persistent conduction vs. 3% if bidirectional block, P < 0.001). During differential septal pacing, EGMs were difficult to interpret in 36% of the patients; in these cases, the diagnosis of CTI block or conduction in the clockwise direction was clearly established by using septal CTI pacing. CONCLUSION: Activation sequence of anterior RA during septal CTI pacing, next to the ablation line, is a reliable and simple method to diagnose clockwise CTI block and is associated with a low flutter recurrence.

Intrapericardial balloon placement for prevention of collateral injury during catheter ablation of the left atrium in a porcine model.

BACKGROUND: Catheter ablation of the left atrium (LA) is associated with potential collateral injury to surrounding structures, especially the esophagus and the right phrenic nerve (PN). OBJECTIVES: The purpose of this study was to evaluate the efficacy and feasibility of intrapericardial balloon placement (IPBP) for the protection of collateral structures adjacent to the LA. METHODS: Electroanatomic mapping was performed in porcine hearts using a transseptal endocardial approach in eight swine weighing 40-50 kg. An intrapericardial balloon was inflated in the oblique sinus, via percutaneous epicardial access, to displace the esophagus. Similarly, with the balloon positioned in the transverse sinus, IPBP was used to displace the right PN. Esophageal temperature was monitored while endocardial radiofrequency (RF) energy was delivered to the distal inferior PV. RESULTS: In all cases, balloon placement was successful with no significant effects on hemodynamic function. Balloon inflation increased the distance between the esophagus and posterior LA by 12.3 +/- 4.0 mm. IPBP significantly attenuated increases in luminal esophageal temperature during endocardial RF application (6.1 +/- 2.4 degrees C vs. 1.2 +/- 1.1 degrees C; P<.0001). High-output endocardial pacing from the right superior pulmonary vein ostium stimulated PN activity. After displacement of the right PN with IPBP, PN capture was abolished in 30 (91%) of 33 sites. CONCLUSIONS: These findings demonstrate that in an animal model, IPBP is feasible in the setting of catheter ablation procedures and has the potential to decrease the risk of collateral damage to the esophagus and PN during LA ablation.

Electrophysiological consequences of acute regional ischemia/reperfusion in neonatal rat ventricular myocyte monolayers.

BACKGROUND: Electrophysiological changes promoting arrhythmias during acute regional ischemia/reperfusion are challenging to study in intact cardiac tissue because of complex 3-dimensional myocardial and vascular geometry. We characterized electrophysiological alterations and arrhythmias during regional ischemia/reperfusion in a simpler 2-dimensional geometry of cultured neonatal rat ventricular myocyte monolayers. METHODS AND RESULTS: Optical mapping of intracellular Ca (Ca(i)) and voltage was performed with the use of Rhod 2-AM and Rh-237, respectively. Regional ischemia was mimicked by covering the central portion of monolayer with a glass coverslip, and reperfusion was mimicked by removing the coverslip. Monolayers were stained with fluorescent antibodies to detect total and dephosphorylated connexin-43 at various time points. During coverslip ischemia, action potential duration shortened, Ca(i) transient duration was prolonged, and local conduction velocity (CV) slowed progressively, with loss of excitability after 10.6 +/- 3.6 minutes. CV slowing was accompanied by connexin-43 dephosphorylation. During ischemia, spontaneous reentry occurred in 5 of 11 monolayers, initiated by extrasystoles arising from the border zone or unidirectional conduction block of paced beats. On reperfusion, excitability recovered within 1.0 +/- 0.8 minutes, but CV remained depressed for 9.0 +/- 3.0 minutes, promoting reentry in the reperfused zone. As connexin-43 phosphorylation recovered in the reperfused zone, CV normalized, and arrhythmias resolved. CONCLUSIONS: Acute regional ischemia/reperfusion in neonatal rat ventricular myocyte monolayers recapitulates electrophysiological alterations and arrhythmias similar to those observed during acute coronary occlusion/reperfusion in intact hearts. During early reperfusion, slow recovery from connexin-43 dephosphorylation leads to persistent CV slowing, creating a highly arrhythmogenic substrate.

Muscleblind-like 2 (Mbnl2) -deficient mice as a model for myotonic dystrophy.

Myotonic dystrophy (DM), the most common adult-onset muscular dystrophy, is caused by CTG or CCTG microsatellite repeat expansions. Expanded DM mRNA microsatellite repeats are thought to accumulate in the nucleus, sequester Muscleblind proteins, and interfere with alternative mRNA splicing. Muscleblind2 (Mbnl2) is a member of the family of Muscleblind RNA binding proteins (that also include Mbnl1 and Mbnl3) that are known to bind CTG/CCTG RNA repeats. Recently, it was demonstrated that Mbnl1-deficient mice have characteristic features of human DM, including myotonia and defective chloride channel expression. Here, we demonstrate that Mbnl2-deficient mice also develop myotonia and have skeletal muscle pathology consistent with human DM. We also find defective expression and mRNA splicing of the chloride channel (Clcn1) in skeletal muscle that likely contributes to the myotonia phenotype. Our results support the hypothesis that Muscleblind proteins and specifically MBNL2 contribute to the pathogenesis of human DM.

Spatially discordant alternans in cardiomyocyte monolayers.

Repolarization alternans is a harbinger of sudden cardiac death, particularly when it becomes spatially discordant. Alternans, a beat-to-beat alternation in the action potential duration (APD) and intracellular Ca (Cai), can arise from either tissue heterogeneities or dynamic factors. Distinguishing between these mechanisms in normal cardiac tissue is difficult because of inherent complex three-dimensional tissue heterogeneities. To evaluate repolarization alternans in a simpler two-dimensional cardiac substrate, we optically recorded voltage and/or Cai in monolayers of cultured neonatal rat ventricular myocytes during rapid pacing, before and after exposure to BAY K 8644 to enhance dynamic factors promoting alternans. Under control conditions (n = 37), rapid pacing caused detectable APD alternans in 81% of monolayers, and Cai transient alternans in all monolayers, becoming spatially discordant in 62%. After BAY K 8644 (n = 28), conduction velocity restitution became more prominent, and APD and Cai alternans developed and became spatially discordant in all monolayers, with an increased number of nodal lines separating out-of-phase alternating regions. Nodal lines moved closer to the pacing site with faster pacing rates and changed orientation when the pacing site was moved, as predicted for the dynamically generated, but not heterogeneity-based, alternans. Spatial APD gradients during spatially discordant alternans were sufficiently steep to induce conduction block and reentry. These findings indicate that spatially discordant alternans severe enough to initiate reentry can be readily induced by pacing in two-dimensional cardiac tissue and behaves according to predictions for a predominantly dynamically generated mechanism.

Cardiac alternans in embryonic mouse ventricles.

T-wave alternans, an important arrhythmogenic factor, has recently been described in human fetuses. Here we sought to determine whether alternans can be induced in the embryonic mouse hearts, despite its underdeveloped sarcoplasmic reticulum (SR) and, if so, to analyze the response to pharmacological and autonomic interventions. Immunohistochemistry confirmed minimal sarcoplasmic-endoplasmic reticulum Ca-ATPase 2a expression in embryonic mouse hearts at embryonic day (E) 10.5 to E12.5, compared with neonatal or adult mouse hearts. We optically mapped voltage and/or intracellular Ca (Ca(i)) in 99 embryonic mouse hearts (dual mapping in 64 hearts) at these ages. Under control conditions, ventricular action potential duration (APD) and Ca(i) transient alternans occurred during rapid pacing at an average cycle length of 212 +/- 34 ms in 57% (n = 15/26) of E10.5-E12.5 hearts. Maximum APD restitution slope was steeper in hearts developing alternans than those that did not (2.2 +/- 0.6 vs. 0.8 +/- 0.4; P < 0.001). Disabling SR Ca(i) cycling with thapsigargin plus ryanodine did not significantly reduce alternans incidence (44%, n = 8/18, P = 0.5), whereas isoproterenol (n = 14) increased the incidence to 100% (P < 0.05), coincident with steepening APD restitution slope. Verapamil abolished Ca(i) transients (n = 9). Thapsigargin plus ryanodine had no major effects on Ca(i)-transient amplitude or its half time of recovery in E10.5 hearts, but significantly depressed Ca(i)-transient amplitude (by 47 +/- 8%) and prolonged its half time of recovery (by 18 +/- 3%) in E11.5 and older hearts. Embryonic mouse ventricles can develop cardiac alternans, which generally is well correlated with APD restitution slope and does not depend on fully functional SR Ca(i) cycling.

Cardiac resynchronization therapy response is associated with shorter duration of atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is commonly associated with heart failure. The benefit of cardiac resynchronization therapy (CRT) on atrial remodeling has been demonstrated. However, biventricular pacing did not reduce the global incidence of AF. We evaluated the relationship between CRT response and AF duration. METHODS: We retrospectively analyzed data from 96 patients (59 +/- 15 years; 78% male) who underwent CRT. All patients had class III-IV New York Heart Association (NYHA) symptoms despite maximal medical therapy, left ventricular ejection fraction (LVEF) < or = 35%, QRS >130 ms, and sinus rhythm before implantation. CRT response in patients who survived at six months of follow-up was defined as: (1) no hospitalization for heart failure and (2) improvement of one or more grades in the NYHA classification. RESULTS: CRT responders (n = 54) and non-responders (n = 42) had similar baseline characteristics, including the incidence of persistent AF within six months before implantation. Six months after implantation, when compared to baseline, CRT responders exhibited a significant decrease in left atrial size (47.5 +/- 7.1 mm vs 44.6 +/- 7.7 mm, P < 0.01) and in the incidence of persistent AF (17% vs 2%, P = 0.02). At six months, CRT responders demonstrated shorter mean AF duration (7.5 +/- 43.3 hours vs 48.8 +/- 129.0 hours, P = 0.03) and lower incidence of persistent AF (2% vs 19%, P = 0.004) compared to nonresponders. CONCLUSION: CRT response is associated with a reversal of atrial remodeling and a shorter AF duration.

Changes and predictive value of dispersion of repolarization parameters for appropriate therapy in patients with biventricular implantable cardioverter-defibrillators.

BACKGROUND: The impact of cardiac resynchronization therapy (CRT) on dispersion of repolarization is controversial. The benefit of CRT on sudden cardiac death has been demonstrated only after 3 years follow-up. OBJECTIVE: The purpose of this study was to explore the immediate effect of CRT on dispersion of repolarization and to define the value of dispersion of repolarization parameters as predictors of appropriate implantable cardioverter-defibrillator (ICD) therapy. METHODS: Data from 100 patients who underwent CRT-ICD placement were analyzed retrospectively. Patients had symptoms of New York Heart Association functional class III or IV heart failure, left ventricular ejection fraction < or =35%, and QRS duration >130 ms or QRS < or =130 ms with left intraventricular dyssynchrony. ECG indices of dispersion of repolarization before and immediately after CRT implantation (QT dispersion, Tpeak-Tend [Tp-e], and Tp-e dispersion) were measured. RESULTS: In patients who were upgraded to a biventricular system, Tp-e did not increase significantly after CRT. However, Tp-e increased significantly after CRT in patients with left bundle branch block or narrow QRS at baseline. After 12-month follow-up, 22 patients had received appropriate ICD therapy. ICD therapy and no ICD therapy groups had similar baseline characteristics, such as secondary prevention and ischemic cardiomyopathy. Postimplantation Tp-e was the only independent predictor of future ICD therapy (P = .02). CONCLUSION: Immediately after CRT, Tp-e did not increase in patients who received a biventricular upgrade; however, Tp-e did increase in patients with preimplantation left bundle branch block or narrow QRS. Postimplantation Tp-e was the only independent predictor of appropriate ICD therapy.

Left ventricular apical wall motion abnormality is associated with lack of response to cardiac resynchronization therapy in patients with ischemic cardiomyopathy.

BACKGROUND: Many patients with appropriate indications fail to respond to cardiac resynchronization therapy (CRT). OBJECTIVE: The purpose of our study was to determine the relationship between CRT response and preimplantation apical wall motion abnormality. METHODS: We analyzed data from 83 patients with ischemic cardiomyopathy who underwent CRT. All patients had New York Heart Association class III or IV symptoms despite maximal medical therapy, left ventricular ejection fraction (LVEF) < or =35%, and QRS duration > or =130 ms or <130 ms with left ventricular dyssynchrony. CRT responders at 6 months were defined as surviving patients with: (1) no hospitalization for heart failure, and (2) improvement of New York Heart Association classification. Patients underwent echocardiography before and 6 months after implantation to assess changes in regional wall motion and LVEF. RESULTS: At baseline, CRT responders (n = 39) and nonresponders (n = 44) had similar LVEF (22.9% +/- 6.9% vs 23.1% +/- 8.3%), QRS duration (159 +/- 43 ms vs 159 +/- 36 ms), and medical treatment. CRT nonresponders had a higher prevalence of preimplantation apical wall motion abnormality (68% vs 33%, P = .003). Patients with baseline apical wall motion abnormalities (n = 43) were less likely than others (n = 40) to show improvement in wall motion at 6 months (30% vs 81%, P < .001) or clinical response to CRT (31% vs 64%, P = .003). CONCLUSION: The presence of a preimplantation apical wall motion abnormality was associated with a lower rate of CRT response in patients with ischemic cardiomyopathy.

Functional characterization of atrial electrograms in sinus rhythm delineates sites of parasympathetic innervation in patients with paroxysmal atrial fibrillation.

OBJECTIVES: This study sought to characterize left atrial (LA) sinus rhythm electrogram (EGM) patterns and their relationship to parasympathetic responses during atrial fibrillation (AF) ablation. BACKGROUND: The mechanistic basis of fractionated LA EGMs in patients with paroxysmal AF is not well understood. METHODS: We analyzed 1,662 LA ablation sites from 30 patients who underwent catheter ablation for paroxysmal AF. Pre-ablation EGM characteristics (number of deflections, amplitude, and duration) were measured in sinus rhythm. Parasympathetic responses during radiofrequency application (increase of atrial-His interval by > or =10 ms or decrease of sinus rate by > or =20%) were assessed at all sites. We also prospectively studied the effect of adenosine, a pharmacological agent mimicking acetylcholine signaling in myocytes, on LA EGMs. Finally, we performed mathematical simulations of atrial tissue to delineate possible mechanisms of fractionated EGMs in sinus rhythm. RESULTS: A specific pattern of pre-ablation sinus rhythm EGM (deflections > or =4, amplitude > or =0.7 mV, and duration > or =40 ms) was strongly associated with parasympathetic responses (sensitivity 72%, specificity 91%). The sites associated with these responses were found to be located mainly in the posterior wall of the LA. Adenosine administration and mathematical simulation of the effect of acetylcholine were able to reproduce a similar EGM pattern. CONCLUSIONS: Parasympathetic activation during AF ablation is associated with the presence of pre-ablation high-amplitude fractionated EGMs in sinus rhythm. Local acetylcholine release could potentially explain this phenomenon.

Effects of metabolic inhibition on conduction, Ca transients, and arrhythmia vulnerability in embryonic mouse hearts.

Developing myocardium is more dependent on glycolysis than adult myocardium, yet the effects of selectively inhibiting glycolysis versus oxidative phosphorylation on embryonic heart function have not been well characterized. Accordingly, we investigated how selective metabolic inhibition affects membrane voltage and intracellular Ca (Ca(i)) transients in embryonic mouse hearts, including their susceptibility to arrhythmias. A total of 136 isolated embryonic mouse hearts were exposed to either 1) 2-deoxyglucose (2DG; 10 mM) or iodoacetate (IAA; 0.1 mM) with 10 mM pyruvate in place of glucose to selectively inhibit glycolysis or 2) the mitochondrial uncoupler protonophore carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP; 500 nM) with 10 mM glucose present to selectively inhibit oxidative phosphorylation. Using confocal imaging, we found that mitochondrial membrane potential monitored with tetramethylrhodamine methyl ester (200 nM) remained stable with 2DG or IAA but depolarized within 5 min after exposure to FCCP. IAA and FCCP decreased heart rate, inhibited Ca(i) transient amplitude, shortened action potential duration at 80% repolarization (APD(80)), and prolonged atrioventricular conduction time to similar extents. Although 2DG decreased heart rate and Ca(i) transient amplitude, it did not significantly affect APD(80) and AV conduction time. In addition, spontaneous arrhythmias occurred in 77 of 136 embryonic hearts (57%) after exposure to IAA (28/53) or FCCP (49/83). There were no significant differences in the types or incidence of arrhythmias induced by IAA and FCCP. These data support the idea that both glycolysis and oxidative phosphorylation play critical metabolic roles in regulating cardiac function in the embryonic mouse heart.

Usefulness of preimplantation B-type natriuretic peptide level for predicting response to cardiac resynchronization therapy.

Nearly 1/3 of patients with heart failure (HF) fail to respond to cardiac resynchronization therapy (CRT). The purpose of this study was to evaluate the value of preimplantation brain natriuretic peptide (BNP) in predicting the clinical response to CRT. We retrospectively analyzed 164 patients who underwent CRT. Patients with New York Heart Association functional class III or IV HF symptoms despite maximal medical therapy, who were not on inotropic medications, had left ventricular ejection fraction < or =35%, and QRS duration >130 ms were included in the study. CRT response in patients who survived at 6-month follow-up was defined as no HF hospitalization and improvement of > or =1 grades in the New York Heart Association classification. BNP assays were performed before implantation and at 6-month follow-up. Patients had ischemic (47%) or nonischemic (53%) cardiopathy. Responders (n = 107) and nonresponders (n = 57) had similar baseline characteristics. Cardiac death and hospitalization for HF occurred in 5 (4.7%) and 18 (31.6%) patients, respectively. CRT responders compared with nonresponders exhibited higher preimplantation BNP levels (800 +/- 823 vs 335 +/- 348 pg/ml, p = 0.0002) and a significant reduction in the QRS duration after implantation (-6 +/- 34 vs +7 +/- 32 ms, p = 0.048). The preimplantation BNP was the only independent predictor of the CRT response (p = 0.001). A BNP value > or =447 pg/ml demonstrated a sensitivity of 62% and specificity of 79% in identifying CRT response. In a subgroup of 41 patients who underwent Doppler tissue imaging analysis, the preimplantation BNP was higher in patients presenting with intraventricular dyssynchrony (845 +/- 779 vs 248 +/- 290 pg/ml, p = 0.04). In conclusion, the preimplantation BNP value independently predicts CRT response and was superior to QRS duration reduction in identifying CRT responders.