Drug and herb-induced liver injury: A critical review of Brazilian cases with proposals for the improvement of causality assessment using RUCAM.

INTRODUCTION AND OBJECTIVES: Although hepatotoxicity accounts for 10% of adverse drug reactions, it remains poorly understood and underreported. This study aimed to summarize case reports of herb- and drug-induced liver injury in Brazil. METHODOLOGY: Systematic review in the following databases: PubMed, SciELO, Science Direct, CAPES, and gray literature. RESULTS: Twenty-seven studies reporting 32 cases were identified. Brazilian cases were primarily detected in hospitals, and occurred mainly in young males suffering from chronic diseases. Drugs (n=29) were a more frequent cause of liver injury than herbs (n=3). Almost a third of these drugs were anticonvulsants, and 15 appear in the Brazilian List of Essential Medicines. In 50% of the cases, clinical manifestations started within 30 days of drug ingestion. Regarding the decline of liver enzymes, 50% of the cases reached normality after drug withdrawal. However, 7 deaths and 2 liver transplantations were reported. Only one study assessed causality using RUCAM. CONCLUSION: Given the severe outcomes of DILI and HILI, early detection and management of hepatotoxicity to increase drug safety are necessary, as well as pharmacotherapeutic monitoring of patients with chronic diseases. Moreover, the application of the RUCAM algorithm in clinical practice has to be further disseminated.

In vitro evaluation of ice-cold saline irrigation during catheter radiofrequency ablation.

INTRODUCTION: Irrigated radiofrequency (RF) catheters allow tissue-electrode interface cooling, decreasing thrombus risk while enabling higher RF power delivery. The impact of irrigation with ice-cold saline (ICS) instead of conventional ambient-temperature saline (ATS) on lesion formation is unknown. METHODS AND RESULTS: We performed 120 RF ablations in vitro on porcine left ventricles, using ICS (<5 °C) or ATS (21 °C) irrigation. For ICS irrigation, the irrigation circuit was cooled externally to maintain delivery of cooled saline at the catheter's tip. We applied 20 g of contact force, and delivered 20 W (irrigation 8 or 17 mL/min) or 30 W (irrigation 17 or 30 mL/min) RF power. Temperatures at tissue-electrode interface and 3-mm depth were assessed by fluoroptic probes. Lesion dimensions were assessed. ICS irrigation cooled the tissue-electrode interface better than ATS (53.9 ± 9.6 °C vs. 63 ± 11.4 °C, P < 0.001). Temperatures at 3-mm depth were similar at 30 W using ICS and ATS (104.2 ± 9.3 °C vs. 105.8 ± 7.3 °C, P = 0.5), but were cooler at 20 W using ICS (71.3 ± 11.6 °C vs. 100.2 ± 11.9 °C, P < 0.001). This translated into smaller lesions at 20 W with ICS versus ATS. At 30 W with 17 mL/min flow rate, lesions had the same depth with ICS and ATS (4.9 ± 0.8 mm vs. 5.4 ± 0.7 mm, P = 0.13) but were narrower with ICS (7.7 ± 0.8 mm vs. 9.3 ± 1.2 mm, P = 0.001). At 30 mL/min, lesions had the same dimensions. Steam pop rate was similar using ICS or ATS irrigation. CONCLUSION: ICS irrigation more effectively cools tissue-electrode interface than ATS. This may improve RF safety by potentially decreasing thrombus formation, thus facilitating safe ablation at a low saline volume load. However at lower RF power, ICS reduced lesion size compared to ATS.

Use of a novel endoscopic catheter for direct visualization and ablation in an ovine model of chronic myocardial infarction.

BACKGROUND: Defining the arrhythmogenic substrate is essential for successful ablation of scar-related ventricular tachycardia. The visual characteristics of endocardial ischemic scar have not been described in vivo. The goal of this study was (1) to quantify the visual characteristics of normal tissue, scar border zone, and dense scar in vivo with the use of a novel endoscopic catheter that allows direct endocardial visualization and (2) to correlate visual attributes of myocardial scar with bipolar voltage. METHODS AND RESULTS: Percutaneous transient balloon occlusion (150 minutes) of the mid left anterior descending coronary artery was performed in an ovine model. Animals survived for 41.5±0.7 days. Detailed bipolar voltage maps of the left ventricle were acquired with the use of NavX. Video snapshots of the endocardium were acquired at sites distributed throughout the left ventricle. Visual tissue characteristics of normal (>1.5 mV), border (0.5-1.5 mV), and dense scar (<0.5 mV) were quantified with the use of image processing. Radiofrequency lesions (10-20 W, 30 seconds) were delivered under direct visualization. Mean white-threshold pixel area was lowest in normal tissue (189 969±41 478 pixels(2)), intermediate in scar border zone (255 979±36 016 pixels(2)), and highest in dense scar (324 452±30 152 pixels(2); P<0.0001 for all pairwise comparisons). Tissue whiteness, characteristic of scar, was inversely correlated with bipolar voltage (P<0.0001). During radiofrequency lesions, there was a significant increase in white-thresholded pixel area of the visual field after ablation (average increase, 85 381±52 618 pixels(2); P<0.001). CONCLUSIONS: Visual characteristics of chronic infarct scar in vivo observed with the use of a novel endoscopic catheter correlate with bipolar electrogram voltage. Irrigated radiofrequency lesions in normal endocardial tissue and postinfarction zone can be visualized and quantified with the use of image processing. This technology shows promise for visually based delivery of radiofrequency lesions for the treatment of scar-based ventricular tachycardia.

Comparison of epicardial cryoablation and irrigated radiofrequency ablation in a Swine infarct model.

UNLABELLED: Epicardial Cryoablation in Swine. INTRODUCTION: Cryoablation is an alternative to radiofrequency (RF) energy used in some ablation procedures. Its role and effectiveness compared to irrigated RF in epicardial tissue and epicardial substrates is not yet fully established. METHODS AND RESULTS: Using a swine chronic infarct model, we compared RF lesions produced by an open-irrigated 3.5 mm tip catheter with those produced by an 8 mm tip cryocatheter in epicardial infarct border zone, epicardial normal tissue, and normal endocardium. In the infarct border zone, cryolesions were larger than RF lesions in maximum diameter (9.3 ± 2.9 mm vs 6.2 ± 2 mm, P < 0.001) and volume (171.7 ± 173.1 mm(3) vs 77 ± 53.5 mm(3) , P = 0.021). In normal epicardial tissue, cryolesions were larger in maximum diameter (11.2 ± 4.3 mm vs 7.7 ± 3.1 mm, P = 0.012), depth (5.8 ± 1.6 mm vs 4.7 ± 1.4 mm, P = 0.034), and volume (274.7 ± 242.2 mm(3) vs 112 ± 102.9 mm(3) , P = 0.002). In normal endocardium, no significant differences were found. CONCLUSIONS: Epicardial cryoablation with an 8 mm tip cryocatheter led to larger lesion volume in infarcted myocardium compared to a 3.5 mm irrigated RF catheter. This is likely related to a combination of cryoadherence, more efficient energy delivery with horizontal orientation, and lack of warming by circulating blood. Cryoablation merits further investigation as a modality for treating ventricular tachycardia of epicardial origin in humans. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1016-1023, September 2012).

Mechanism of complex fractionated electrograms recorded during atrial fibrillation in a canine model.

BACKGROUND: Complex fractionated atrial electrograms (CFEs) have been described as a target during atrial fibrillation (AF) ablation; however, the mechanism leading to CFEs is poorly understood. We used noncontact mapping in a canine model of AF to determine the activation patterns in areas of CFEs. METHODS: Sustained AF was induced in 10 canines with 10-12 weeks of atrial tachy-pacing at 440 ppm. A roving mapping catheter and noncontact multielectrode array (MEA) were deployed in the left atrium (LA). NavX software was used to construct a contact bipolar CFE LA map. The MEA was then used to reconstruct wavefront propagation in proximity to CFE regions. Wavefront propagation was assessed during three separate recording segments for each site. RESULTS: There were 34 CFE regions identified (3.4/dog) and 102 noncontact CFE regional activation sequences studied. The CFE regions were stereotypically located at the junctions of (1) the left pulmonary vein (PV)/posterior LA, (2) right inferior PV/posterior LA, (3) right superior PV/anterior LA, and (4) the LA roof. The majority (47%) of CFE recordings were characterized by wavefront collision, usually between circulating LA wavefronts and entry/exit from the PVs. Thirty-eight (38%) CFE recordings were noted to be the central functional barrier of a reentrant wavefront. Ablation through CFE regions due to reentry led to AF termination and noninducibility in 3/5 animals. CONCLUSIONS: In this pacing-induced AF model, common causes of CFEs include: (1) wavefront collision, (2) conduction through channels of functional block, (3) reentry. The vast majority of these CFE regions were caused by wavefront collision rather than true "drivers" of AF.

Pulmonary vein isolation using a compliant endoscopic laser balloon ablation system in a swine model.

INTRODUCTION: The incidence of pulmonary vein reconnection and recurrent atrial fibrillation after a single catheter ablation procedure is unacceptably high. We studied the ability of a novel endoscopic laser balloon ablation system (EAS) to achieve acute and chronic pulmonary vein (PV) isolation in a swine model. METHODS: Eight swine underwent EAS ablation and two underwent standard radiofrequency ablation for comparison. In the EAS arm, laser energy was delivered under visual guidance around the PV antrum in overlapping 30-degree arcs. In the standard ablation arm, radiofrequency energy was delivered via a 4-mm-tip catheter. PV isolation was confirmed acutely after 30 min, and reassessed after 4-6 weeks. Animals were then sacrificed for histopathologic analysis of the PVs. RESULTS: For the EAS animals, 44 ± 10 overlapping lesions were required to achieve acute RSPV isolation. Chronic PV isolation was documented with the circular mapping catheter a mean of 28 ± 9 days after ablation in 7/8 animals (83%). In the standard ablation arm, 30 ± 3 RF lesions were delivered to achieve acute PV isolation. There was evidence of PV reconnection in both animals during the chronic study. Histologically, completely transmural circumferential lesions were found in 7/8 EAS animals, with 99% circumferentiality in the remaining animal. Both control RF animals had evidence of gaps, with isolation of 90% and 75% of the targeted PV segments, respectively. CONCLUSION: Visually guided laser ablation using light energy via a compliant balloon catheter is feasible and achieved chronic isolation in 83% of targeted PVs.

A comparison of intracardiac and transesophageal echocardiography to detect left atrial appendage thrombus in a swine model.

PURPOSE: Transesophageal echocardiography (TEE) is the gold standard in the evaluation for left atrial appendage (LAA) thrombus in patients with atrial fibrillation (AF) and is often performed prior to AF ablation. We routinely use intracardiac echocardiography (ICE) to assist in AF ablation; however, standard right atrial views do not provide adequate visualization of the LAA. As the incidence of thrombus in this population is relatively low, TEE incurs additional risk, cost, and patient discomfort. Novel views of the LAA with ICE may obviate the need for TEE in this population. We tested the hypothesis that due to their proximity, imaging the LAA from the pulmonary artery (PA) would provide equivalent sensitivity and specificity to TEE in detecting LAA thrombus in a swine model. METHODS: Five domestic swine were utilized. Baseline images of the LAA with TEE were obtained. An 8Fr ICE catheter was placed in the left main PA, and imaging of the LAA was repeated. After transseptal puncture, an admixture of 2 cm(3) blood and 1,000 IU of thrombin was injected into the LAA, and imaging of the LAA was repeated. Two blinded, independent reviewers experienced in ICE assessed the images and adjudicated both the presence of thrombus and the subjective image quality. RESULTS: The presence or absence of thrombus was correctly identified in all cases by both reviewers. Both reviewers rated the subjective quality of ICE images superior to TEE. CONCLUSIONS: ICE is equivalent to TEE in imaging LAA thrombus in a porcine model. Whether ICE can provide similar diagnostic accuracy and safety for detecting LAA thrombus in humans remains unproven.

Dominant frequency mapping of atrial fibrillation: comparison of contact and noncontact approaches.

INTRODUCTION: The ability to acquire a dominant frequency (DF) map during atrial fibrillation (AF) instantaneously using noncontact mapping has significant advantages over the current sequential contact mapping approach; however, the relationship between DFs determined from contact bipolar and noncontact unipolar recordings is unknown. We sought to determine the difference between DFs determined using contact bipolar, contact unipolar, noncontact unipolar, and noncontact pseudobipolar recordings. METHODS: Sustained AF was induced in 5 canines with 10 weeks of atrial tachy-pacing at 440 ppm. A noncontact multielectrode array was positioned in the left atrium (LA). Two simultaneous contact signals (unipolar and bipolar) and 3 noncontact signals (unipolar, pseudobipolar, and pseudobipolar Laplacian) were recorded from multiple LA sites. Fourier analysis was performed, and the DFs of contact and noncontact signals were compared. RESULTS: Recordings were obtained from 389 LA locations in 5 canines. The correlation was best between contact bipolar and noncontact QRS-subtracted unipolar signals (r = 0.58, P < 0.001), and weaker between contact bipolar and noncontact best-fit pseudobipolar (r = 0.50, P < 0.01) and noncontact Laplacian bipolar (r = 0.49, P < 0.01). There was no significant difference in the mean DFs between contact bipolar and noncontact unipolar signals; however, there was a significant difference in the DFs comparing contact bipolar to noncontact pseudobipolar signals (11.6 +/- 1.8 vs 11.2 +/- 2.5 Hz; P = 0.004) and a small nonsignificant difference comparing contact bipolar DF and noncontact pseudobipolar Laplacian DF (11.4 +/- 1.8 vs 11.1 +/- 1.6 Hz; P = NS). CONCLUSIONS: We found that estimation of DFs using noncontact mapping is feasible and that QRS-subtracted noncontact unipolar signals perform better than noncontact pseudobipolar signals at estimating contact bipolar DFs. This has important implications for developing algorithms for noncontact frequency mapping of AF.

Comparison of high power, medium power, and irrigated-tip ablation strategies for pulmonary vein isolation in a canine model.

BACKGROUND: We sought to compare the efficacy and collateral damage during pulmonary vein (PV) isolation in a canine model using three different ablation strategies. METHODS: Normal dogs (three each) were randomized to high power (70 W, 20 seconds, 60 degrees C, Hi), medium power (50 W, 60 seconds, 50 degrees C; Med), or irrigated-tip (35 W, 60 seconds, 45 degrees C; Cool) ablation. Two transseptal punctures were performed and right and left superior PV electrical isolation was performed using the assigned ablation strategy. Animals survived for 30 days. RESULTS: There was no difference in the number of lesions required to achieve PV isolation (Hi vs Med vs Cool; 43 vs 38 vs 44 lesions; P = NS). At sacrifice, Hi and Med lesions showed gross evidence of endocardial cratering and eschar formation. Corresponding histopathology showed transmural atrial necrosis with granulation tissue and fibrosis. Cool lesions demonstrated superficial endocardial white patches. The corresponding histopathology was subendocardial fibrosis with full and partial thickness necrosis of the atrial wall. One Hi animal had a large thrombus adherent to the left atrial wall above the left superior PV. PV stenosis was noted in one of three Hi and one of three Med, and none of three Cool. There were visible burns to the lung overlying the left atrial wall in one of three Hi, one of three Med, and none of three Cool. The esophagus demonstrated no evidence of serosal injury. CONCLUSIONS: The Hi and Med power 8-mm-tip ablation strategies for achieving PV isolation appear to result in excessive tissue destruction. Irrigated-tip lesions resulted in less endocardial eschar formation, PV stenosis, and damage to collateral structures.

Characterization of the infarct substrate and ventricular tachycardia circuits with noncontact unipolar mapping in a porcine model of myocardial infarction.

BACKGROUND: Conventional mapping of ventricular tachycardia (VT) after myocardial infarction is limited in patients with hemodynamically untolerated or noninducible VT. OBJECTIVES: The purpose of this study was to develop a unique strategy using noncontact unipolar mapping to define infarct substrate and VT circuits. METHODS: Dynamic substrate mapping (DSM) was performed in seven pigs with healed anterior myocardial infarction. This technique defined substrate as the intersection of low-voltage areas identified in sinus rhythm and during pacing around the infarct. Pacing was also performed within the substrate to determine exit sites. RESULTS: Anteroapical transmural scar was identified in all animals. A mean of three pacing sites was used for substrate definition. The mean area (+/- SD) was 18.4 +/- 8.8 cm2 by DSM and 15.4 +/- 6.9 cm2 by pathology (P >.5). A mean of 4.5 sites was paced within substrate. Ten of 18 paced wavefronts exited substrate adjacent to the pacing area, seven exited at distant areas, and one had two exits. VT was induced in five animals (1.6 morphologies per animal). Except for one VT, circuit exit sites were identified at substrate borders on the endocardium. VT exit sites were at (n = 6) or near (n = 3) a pacing exit site. Electrogram voltages differed significantly between substrate, border, and nonsubstrate areas in infarcted animals and in comparison with control animals. No substrate was identified in two control animals. CONCLUSION: DSM is a reliable method for infarct substrate localization in this model. Pacing within substrate can predict VT exit sites and may prove useful for ablation of unmappable VT after myocardial infarction.

Left ventricular catheter ablation using direct, intramural ethanol injection in swine.

INTRODUCTION: Limitations in lesion volume and particularly lesion depth may negatively effect the efficacy of catheter ablation procedures using radiofrequency energy. This study evaluated the safety and efficacy of myocardial ablation using direct intramural injection of ethanol with a novel injection catheter system. METHODS: Left ventricular lesions were performed in 9 male swine (80-85 pounds); two animals were studied 6 weeks following anterior infarction produced by agarose gel embolization. An 8 Fr deflectable catheter equipped with a 27 gauge adjustable depth, retractable needle was directed to the LV using a retrograde aortic approach. Lesion deployment was guided by fluoroscopy and intracardiac echocardiography (ICE). Lesion characteristics were assessed with ICE imaging and pathologic analysis. RESULTS: Ethanol lesions were confined to the tissue directly adjacent to the injection port. Lesions were intramural with no evidence of overlying thrombus. Lesions delivered with a single port injection needle in normal myocardium (n = 24) averaged 1910 +/- 1066 mm(3) with a depth of 8.9 +/- 3.3 mm. Lesions directed to infarct border zones (n = 4) averaged 929 +/- 882 mm(3) with a depth of 4.3 +/- 2.8 mm. Lesions were immediately evident on ICE imaging, and were visualized by increased echo density and tissue swelling. Pathological analysis revealed homogenous lesions with intramural hemorrhage and contraction band necrosis. CONCLUSIONS: Myocardial catheter ablation using direct ethanol injection is feasible, and relatively large and deep intramural lesions can be delivered, even in the infarct border zone. This technique may prove useful in ablation of arrhythmia substrates that are deep to the endocardial surface.

Multiplane Transesophageal and Intracardiac Echocardiography in Large Swine: Imaging Technique, Normal Values, and Research Applications.

Transthoracic echocardiographic imaging has been difficult to attain in the swine model. This study: (1) compares multiplane transesophageal echocardiography (TEE) with single plane TEE and intracardiac catheter echocardiography (ICE) for imaging of the swine cardiovascular system; and (2) defines normal values using these techniques in a closed chest large swine model (n = 24, body weight 50-114 kg). Multiplane TEE increased success rate over the single plane (the variable plane array only at 0 degrees ) TEE (P < 0.01) for imaging the left ventricular (LV) long-axis view (100% vs 50%), LV outflow tract (100% vs 33%), right atrium and its appendage (79% vs 33%), ascending aorta (100% vs 58%), and aortic arch (100% vs 17%). TEE-derived normal values at end-diastole (ED) and end-systole (ES) were: LV internal diameter (ID) = 49 +/- 3 mm (ED) and 33 +/- 4 mm (ES); LV wall thickness = 7 +/- 1 mm (ED); right ventricular (RV) ID = 24 +/- 4 mm (ED); RV wall thickness = 4 +/- 2 mm (ED); left atrial ID = 48 +/- 6 mm (ES); aortic root ID = 26 +/- 3 mm (ES); LV volume = 157 +/- 49 ml (ED) and 57 +/- 22 ml (ES). Baseline LV ejection fraction (64% +/- 6%), Doppler-derived stroke volume (86 +/- 14 ml), and cardiac index (107 ml/min per kg) were determined. Basal normal values, except for an elevated cardiac index in swine, are comparable to those reported for human adults. Multiplane TEE provided better overall cardiac imaging than did single plane TEE. ICE provided higher resolution imaging of individual cardiac chambers and structures when the ultrasound catheter was introduced into the right or left heart, but whole heart imaging was limited by ultrasound penetration at 12.5 MHz. Normal indices of chamber size and function provide a reference for the physiological significance of induced pathological states in this relevant animal model.