ALEXANDRE AMATRUDA MARUM
Índice h a partir de 2011
4
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- Accelerated conversion of atrial fibrillation to normal sinus rhythm by pulmonary delivery of flecainide acetate in a porcine model(2018) VERRIER, Richard L.; BORTOLOTTO, Alexandre L.; SILVA, Bruna A.; MARUM, Alexandre A.; STOCCO, Fernando G.; EVARISTO, Ederson; ANTONIO, Victor Z. de; SILVA, Anderson C.; BELARDINELLI, LuizBACKGROUND Pulmonary delivery of antiarrhythmic agents has the potential to increase rapidly targeted drug concentrations in pulmonary veins and left atrium to terminate atrial fibrillation (AF). OBJECTIVE We evaluated the efficacy of flecainide administered via intratracheal instillation in terminating AF in a reliable preclinical model. METHODS In 11 closed-chest anesthetized Yorkshire pigs, AF was induced by intrapericardial administration of acetylcholine (1 mL of 102.5 mM solution) followed by burst pacing and allowed to continue for 2 minutes before intratracheal flecainide (0.4 or 0.75 mg/kg) administration. RESULTS Both the 0.4-and 0.75-mg/kg doses of intratracheal flecainide significantly reduced AF duration by 35% (P = .02) and 54% (P = .001), respectively, compared to no-drug baseline. There was a strong inverse correlation (r(2) = 0.87; P = .03) between the duration of AF and the change in atrial depolarization duration in response to intratracheal flecainide. Induction of AF resulted in a marked increase in ventricular rate and corresponding reduction in mean arterial pressure, which returned to baseline levels within 5 minutes after conversion. CONCLUSION Intratracheal flecainide instillation is effective in rapidly converting AF to normal sinus rhythm and restoring mean arterial pressure and heart rate to baseline values. The basis for this efficacy is likely rapid absorption of the drug through the lungs and delivery as a first-pass bolus to the left atrial and ventricular chambers and then to the coronary arterial circulation. The antiAF effect of flecainide is inversely correlated with the drug's prolongation of atrial depolarization, implicating slowing of intra-atrial conduction as an important mechanism underlying conversion of AF to normal sinus rhythm.
conferenceObject Pre-implantation interlead EKG heterogeneity is superior to QRS complex duration in predicting mechanical super-response and survival in patients receiving cardiac resynchronization therapy(2020) BORTOLOTTO, A. L.; VERRIER, R. L.; NEARING, B. D.; MARUM, A. A.; SILVA, B. Araujo; PEDREIRA, G.; SILVA, F. Tessarolo; MEDEIROS, S. A.; SROUBEK, J.; ZIMETBAUM, P.; CHANG, J. D.- Pulmonary Delivery of Metoprolol Reduces Ventricular Rate During Atrial Fibrillation and Accelerates Conversion to Sinus Rhythm(2020) MARUM, Alexandre A.; SILVA, Bruna Araujo; BORTOLOTTO, Alexandre L.; PEDREIRA, Giovanna C.; SILVA, Fernanda Tessarolo; MEDEIROS, Sofia A.; NEARING, Bruce D.; BELARDINELLI, Luiz; VERRIER, Richard L.Background: Safe, effective pulmonary delivery of cardioactive agents in humans is under development. Objectives: We examined whether intratracheal delivery of metoprolol can reduce ventricular rate during atrial fibrillation (AF) and accelerate conversion to sinus rhythm. Methods: In 7 closed-chest, anesthetized Yorkshire pigs, AF was induced by intrapericardial infusion of acetylcholine (1 mL of 102.5-mM solution) followed by atrial burst pacing and was allowed to continue for 2 minutes before intratracheal instillation of sterile water or metoprolol (0.2-mg/kg bolus) using a catheter positioned at the bifurcation of the main bronchi. High-resolution electrograms were obtained from catheters fluoroscopically positioned in the right atrium and left ventricle. Results: Rapid intratracheal instillation of metoprolol caused a 32-beat/min reduction in ventricular rate during AF (from 272 +/- 13.7 to 240 +/- 12.6 beats/min, P = 0.008) and a 2.3-minute reduction in AF duration (from 10.3 +/- 2.0 to 8.0 +/- 1.4 minutes, P = 0.018) compared with sterile water control. Conversion of AF to sinus rhythm was associated with rapid restoration (5-6 minutes) of heart rate and arterial blood pressure toward control values. Intratracheal metoprolol reduced AF dominant frequency by 31% (from 8.7 +/- 0.9 to 6.0 +/- 1.1 Hz, P = 0.04) compared with control and resulted in a trend toward a 5% increase in PR interval (from 174 +/- 11.2 to 182 +/- 11.4 ms, P = 0.07). Conclusions: Intratracheal delivery of metoprolol effectively reduces ventricular rate during AF and accelerates conversion to normal sinus rhythm in a pig model of acetylcholine-induced AF.
conferenceObject Targeting atrial depolarization (Pa) duration with pulmonary delivery of flecainide for rapid AF conversion(2018) VERRIER, R. L.; BORTOLOTTO, A. L.; SILVA, B. A.; MARUM, A.; STOCCO, F. G.; SILVA, A. C.; ANTONIO, V. Z. De; BELARDINELLI, A.- Regadenoson-induced T-wave heterogeneity complements coronary stenosis detection by myocardial perfusion imaging in men and women(2021) SILVA, Bruna Araujo; HAUSER, Thomas H.; NEARING, Bruce D.; BORTOLOTTO, Alexandre L.; MARUM, Alexandre A.; SILVA, Fernanda Tessarolo; MEDEIROS, Sofia A.; PEDREIRA, Giovanna C.; V, Ernest Gervino; VERRIER, Richard L.Aims We analysed whether incorporating electrocardiographic interlead T-wave heterogeneity (TWH) with myocardial perfusion imaging (MPI) during pharmacologic stress improves detection of flow-limiting lesions (FLL). Methods and results Medical records of all 103 patients at our institution who underwent stress testing with regadenoson (0.4 mg IV bolus) within 3 months of coronary angiography from September 2017 to March 2019 were studied. Cases (N = 59) had angiographically significant FLL (>= 50% of left main or >= 70% of other epicardial coronary arteries >= 2 mm in diameter); controls (N = 44) were normal or had non-FLL. TWH, i.e., interlead splay of T waves, was assessed from precordial leads V4-6 by second central moment analysis. Maximum TWHV(4-6 )levels during regadenoson stress were 68% higher in cases than in controls (P < 0.0001). TWHV4-6 generated areas under the receiver-operating characteristic (ROC) curve of 0.79 in men (P < 0.0001) and 0.71 in women (P = 0.007). In men, the ROC-guided 54-mu V TWHV4-6 cut-point for FLL produced adjusted odds of 7.3 [95% confidence interval (CI): 1.3-41.5, P = 0.03], 79% sensitivity, and 78% specificity. In women, the ROC-guided 35-mu V TWHV4-6 cut-point produced adjusted odds of 4.5 (95% CI: 1.1-18.9, P = 0.04), 84% sensitivity, and 52% specificity. Adding TWHV4-6 to MPI determinations reduced false-positive results by 70%, more than doubled true-negative results, and improved adjusted odds ratio to 6.8 (95% CI: 2.2-21.4, P = 0.001) with specificity of 78% in men and 86% in women. Conclusion This observational study is the first to demonstrate the benefit of combining TWHV4-6 with MPI to enhance FLL detection during MPI with regadenoson in both men and women.
- Preimplantation interlead ECG heterogeneity is superior to QRS complex duration in predicting mechanical super-response in patients with non-left bundle branch block receiving cardiac resynchronization therapy(2020) BORTOLOTTO, Alexandre L.; VERRIER, Richard L.; NEARING, Bruce D.; MARUM, Alexandre A.; SILVA, Bruna Araujo; PEDREIRA, Giovanna C.; SILVA, Fernanda Tessarolo; MEDEIROS, Sofia A.; SROUBEK, Jakub; ZIMETBAUM, Peter J.; CHANG, James D.BACKGROUND Reliable quantitative preimplantation predictors of response to cardiac resynchronization therapy (CRT) are needed. OBJECTIVE We tested the utility of preimplantation R-wave and T-wave heterogeneity (RWH and TWH, respectively) compared to standard QRS complex duration in identifying mechanical super-responders to CRT and mortality risk. METHODS We analyzed resting 12-lead electrocardiographic recordings from all 155 patients who received CRT devices between 2006 and 2018 at our institution and met class I and IIA American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines with echocardiograms before and after implantation. Super-responders (n=35, 23%) had >= 20% increase in left ventricular ejection fraction and/or >= 20% decrease in left ventricular end-systolic diameter and were compared with non-super-responders (n=120, 77%), who did not meet these criteria. RWH and TWH were measured using second central moment analysis. RESULTS Among patients with non-left bundle branch block (LBBB), preimplantation RWH was significantly lower in super-responders than in non-super-responders in 3 of 4 lead sets ( P=.001 to P=.038) and TWH in 2 lead sets (both, P=.05), with the corresponding areas under the curve (RWH: 0.810-0.891, P<.001; TWH: 0.759-0.810, P <=.005). No differences were observed in the LBBB group. Preimplantation QRS complex duration also did not differ between super-responders and non-super-responders among patients with ( P=.856) or without ( P=.724) LBBB; the areas under the curve were nonsignificant (both, P=.69). RWH V1-3LILII >= 420 mu V predicted 3-year all-cause mortality in the entire cohort ( P=.037), with a hazard ratio of 7.440 (95% confidence interval 1.015-54.527; P=.048); QRS complex duration >= 150 ms did not predict mortality ( P=.27). CONCLUSION Preimplantation interlead electrocardiographic heterogeneity but not QRS complex duration predicts mechanical super-response to CRT in patients with non-LBBB.
- STRESS-INDUCED T-WAVE HETEROGENEITY WITH REGADENOSON DETECTS CLINICALLY SIGNIFICANT CORONARY ARTERY STENOSIS(2019) SILVA, Bruna Araujo; NEARING, Bruce; BORTOLOTTO, Alexandre; MARUM, Alexandre; GERVINO, Ernest; VERRIER, Richard
- Pulmonary delivery of flecainide causes a rate-dependent predominant effect on atrial compared with ventricular depolarization duration revealed by intracardiac recordings in an intact porcine model(2018) ANTONIO, Victor Z. de; SILVA, Anderson C.; STOCCO, Fernando G.; SILVA, Bruna A.; MARUM, Alexandre A.; BORTOLOTTO, Alexandre L.; BELARDINELLI, Luiz; VERRIER, Richard L.Background Pulmonary delivery of flecainide results in the rapid conversion of atrial fibrillation (AF) to normal sinus rhythm in large-animal models and is safe and well-tolerated by normal human volunteers. Objective Methods We investigated the effects of pulmonary delivery of flecainide on atrial and ventricular depolarization and repolarization duration. Intratracheal instillation (1.5 mg/kg, rapid push) of flecainide or sterile water (placebo) was performed in 12 closed-chest, anesthetized Yorkshire pigs with a catheter positioned at the bifurcation of the main bronchi. High-resolution electrograms obtained from catheters fluoroscopically positioned in the right atrium and left ventricle circumvented measurement errors due to the fusion of P and T waves in surface leads when rapid heart rates shortened the TP interval. Pacing was achieved using electrical stimuli delivered via right atrial catheter electrodes. Results Conclusion During sinus rhythm (98 +/- 4.7 beats/min), intratracheal flecainide caused comparable (P = 0.56) increases in atrial depolarization (P-a) duration by 22% (39.8 +/- 3.2 to 48.7 +/- 3.3 milliseconds) and left ventricular (LV) QRS complex duration by 20% (47.9 +/- 1.6 to 57.3 +/- 1.8 milliseconds) at peak effect at 2 minutes post-dosing. During right atrial pacing at 180 beats/min, P-a duration increased by 55% (37.0 +/- 2.0 to 57.2 +/- 1.6 milliseconds; P < 0.0001). The atrial response was greater (p = 0.001) than the 30% increase in LV QRS complex duration (46.6 +/- 1.7 to 60.6 +/- 2.5 milliseconds; P = 0.005). P-a duration and QRS complex duration were unchanged by placebo independent of pacing (P >= 0.4 for both). Atrial repolarization duration (PTa; P = 0.46) and QT(c) interval (P = 0.49) remained unchanged. Intratracheal flecainide exerts a rate-dependent, predominant effect on atrial compared with ventricular depolarization duration. Pulmonary delivery of flecainide could facilitate AF conversion to sinus rhythm with reduced ventricular proarrhythmia risk.
- Optimizing flecainide plasma concentration profile for atrial fibrillation conversion while minimizing adverse ventricular effects by rapid, low-dose intratracheal or intravenous administration(2019) MARUM, Alexandre A.; SILVA, Bruna A.; BORTOLOTTO, Alexandre L.; SILVA, Anderson C.; ANTONIO, Victor Z. de; BELARDINELLI, Luiz; VERRIER, Richard L.Background: We investigated whether rapid administration of a low dose of flecainide, either intratracheally or intravenously (IV), could accelerate conversion of atrial fibrillation (AF) while reducing adverse ventricular effects. Methods: Flecainide was delivered via intratracheal administration at 1.5 mg/kg bolus and compared to IV infusion at 1.0 mg/kg over 2 min (lower-dose, rapid) and 2.0 mg/kg over 10 min (ESC guideline) in closed-chest, anesthetized Yorkshire pigs. Catheters were fluoroscopically positioned in right atrium to measure atrial depolarization (P-a) duration and left ventricle (LV) to measure QRS complex duration and contractility (LV dP/dt) during atrial pacing at 140 beats/min. Flecainide was delivered intratracheally via a catheter positioned at the bifurcation of the main bronchi. AF was induced by intrapericardial administration of acetylcholine followed by burst pacing. Results: Flecainide reduced AF duration similarly by intratracheal and IV delivery. Peak plasma levels were comparable but T-max differed and coincided with peaks in P-a prolongation. The area under the curve indicating sustained plasma levels was greater for higher-dose, slow IV flecainide than for either intratracheal instillation (by 32%) or lower-dose, rapid IV infusion (by 88%). As a result, higher-dose, slow IV flecainide caused 58% (p < 0.03) and 48% (p < 0.006) greater increases in QRS complex duration and 61% and 96% (both, p < 0.02) greater reductions in contractility compared to intratracheal and lower-dose, rapid IV flecainide, respectively. Conclusion: Lower-dose, rapid flecainide, delivered either intratracheally or IV, optimizes the plasma concentration profile for effective conversion of AF while minimizing adverse effects on QRS complex duration and LV contractility.