Facilitated Myocardial Ablation Using Heat-Sensitive Liposomes Containing Doxorubicin: A Proof-of-Concept Preclinical Study.

The authors sought to evaluate a method for improving radiofrequency (RF) lesion durability using doxorubicin encased in heat-sensitive liposomes (HSL-dox). Using a porcine model, RF ablations were performed in the right atrium after systemic infusion of either HSL-dox or saline control given immediately before mapping and ablation. Lesion geometry was measured with voltage mapping immediately postablation and after 2 weeks of survival. After 2 weeks, lesions demonstrated less regression in scar area in HSL-dox-exposed animals compared with control animals. We demonstrate improved RF lesion durability in animals treated with HSL-dox, and the cardiotoxic effect was more pronounced after RF applications with higher power and longer duration.

Electrophysiologic testing for diagnostic evaluation and risk stratification in patients with suspected cardiac sarcoidosis with preserved left and right ventricular systolic function.

INTRODUCTION: While cardiac sarcoidosis (CS) carries a risk of ventricular arrhythmias (VAs) and sudden cardiac death (SCD), risk stratification of patients with CS and preserved left ventricular/right ventricular (LV/RV) systolic function remains challenging. We sought to evaluate the role of electrophysiologic testing and programmed electrical stimulation of the ventricle (EPS) in patients with suspected CS with preserved ventricular function. METHODS: One hundred twenty consecutive patients with biopsy-proven extracardiac sarcoidosis and preserved LV/RV systolic function underwent EPS. All patients had either probable CS defined by an abnormal cardiac positron emission tomography or cardiac magnetic resonance imaging, or possible CS with normal advanced imaging but abnormal echocardiogram (ECG), SAECG, Holter, or clinical factors. Patients were followed for 4.5 ± 2.6 years for SCD and VAs. RESULTS: Seven of 120 patients (6%) had inducible ventricular tachycardia (VT) with EPS and received an implantable cardioverter defibrillator (ICD). Three patients (43%) with positive EPS later had ICD therapies for VAs. Kaplan-Meier analysis stratified by EPS demonstrated a significant difference in freedom from VAs and SCD (P = 0.009), though this finding was driven entirely by patients within the cohort with probable CS (P = 0.018, n = 69). One patient with possible CS and negative EPS had unrecognized progression of the disease and unexplained death with evidence of CS at autopsy. CONCLUSIONS: EPS is useful in the risk stratification of patients with probable CS with preserved LV and RV function. A positive EPS was associated with VAs. While a negative EPS appeared to confer low risk, close follow-up is needed as EPS cannot predict fatal VAs related to new cardiac involvement or disease progression.

Use of half-normal saline irrigant with cooled radiofrequency ablation within the great cardiac vein to ablate premature ventricular contractions arising from the left ventricular summit.

A 62-year-old man was referred to our institution for high-density, symptomatic premature ventricular contractions (PVCs) with resultant decrease in left ventricular (LV) function having failed prior ablation attempts. Successful, durable ablation of the patient's mid-myocardial PVC arising from the LV summit region was achieved through the proximal great cardiac vein with ablation depth augmented by use of half-normal saline irrigant. Though standard ablation of ventricular arrhythmias using normal saline irrigation from the coronary venous system has been well-reported, this may be of limited value in addressing mid-myocardial sites of origin. This novel case describes the safe use of cooled radiofrequency ablation with use of half-normal saline irrigant from the distal coronary sinus as an option to address complex sites of PVC origin such as the LV summit.

Repeat ablation of refractory ventricular arrhythmias in patients with nonischemic cardiomyopathy: Impact of midmyocardial substrate and role of adjunctive ablation techniques.

INTRODUCTION: Multiple ablations are often necessary to manage ventricular arrhythmias (VAs) in nonischemic cardiomyopathy (NICM) patients. We assessed characteristics and outcomes and role of adjunctive, nonstandard ablation in repeat VA ablation (RAbl) in NICM. METHODS AND RESULTS: Consecutive NICM patients undergoing RAbl were analyzed, with characteristics of the last VA ablations compared between those undergoing 1 versus multiple-repeat ablations (1-RAbl vs. >1RAbl), and between those with or without midmyocardial substrate (MMS). VA-free survival was compared. Eighty-eight patients underwent 124 RAbl, 26 with > 1RAbl, and 26 with MMS. 1-RAbl and > 1-RAbl groups were similar in age (57 ± 16 vs. 57 ± 17 years; P = 0.92), males (76% vs. 69%; P = 0.60), LVEF (40 ± 17% vs. 40 ± 18%; P = 0.96), and amiodarone use (31% vs. 46%, P = 0.22). One-year VA freedom between 1-RAbl vs. > 1RAbl was similar (82% vs. 80%; P = 0.81); adjunctive ablation was utilized more in >1RAbl (31% vs. 11%, P = 0.02), and complication rates were higher (27% vs. 7%, P = 0.01), most due to septal substrate and anticipated heart block. >1-RAbl patients had more MMS (62% vs. 16%, P < 0.01). Although MMS was associated with worse VA-free survival after 1-RAbl (43% vs. 69%, P = 0.01), when >1RAbl was performed, more often with nonstandard ablation, VA-free survival was comparable to non-MMS patients (85% vs. 81%; P = 0.69). More RAbls were required in MMS versus non-MMS patients (2.00 ± 0.98 vs. 1.16 ± 0.37; P < 0.001). CONCLUSION: For NICM patients with recurrent, refractory VAs despite previous ablation, effective arrhythmia control can safely be achieved with subsequent ablation, although >1 repeat procedure with adjunctive ablation is often required, especially with MMS.

Clinical and biophysical evaluation of variable bipolar configurations during radiofrequency ablation for treatment of ventricular arrhythmias.

BACKGROUND: Bipolar radiofrequency ablation (bRFA) has been used to create larger ablation lesions and to treat refractory arrhythmias. However, little is known about optimal bRFA settings. OBJECTIVE: The purpose of this study was to evaluate various bRFA settings, including active and ground catheter tip orientation and use of variable active and ground catheters during bRFA. METHODS: Two ablation catheters, 1 active and 1 ground, were oriented across from each other, with viable bovine myocardium in between. The catheter tips were placed in various combinations perpendicular or parallel to the myocardium. The active catheter was either a 3.5-mm externally irrigated or 8-mm tip, and the ground catheter was either a 4-mm, 3.5-mm irrigated, or 8-mm tip. Retrospective analysis was undertaken for all bRFA performed at University of Colorado. RESULTS: The largest and deepest lesions were produced using irrigated active and ground tips, oriented perpendicularly. In 14 cases (10 patients) of bRFA for ventricular tachycardia and premature ventricular complexes, acute success was achieved in 13 of 14 procedures. Long-term success was achieved in 7 of 10 patients, but 3 patients required multiple bRFA ablations. CONCLUSION: Active and ground catheter tip orientation and type are important determinants of lesion sizes during bRFA. The largest and deepest lesions, without a higher incidence of steam pops, were achieved using 2 irrigated catheters. As the largest published series to date, bRFA ablation can be performed safely and effectively in humans. Larger studies are necessary to better evaluate bRFA efficacy and safety.

Enhanced Radiofrequency Ablation With Magnetically Directed Metallic Nanoparticles.

BACKGROUND: Remote heating of metal located near a radiofrequency ablation source has been previously demonstrated. Therefore, ablation of cardiac tissue treated with metallic nanoparticles may improve local radiofrequency heating and lead to larger ablation lesions. We sought to evaluate the effect of magnetic nanoparticles on tissue sensitivity to radiofrequency energy. METHODS AND RESULTS: Ablation was performed using an ablation catheter positioned with 10 g of force over prepared ex vivo specimens. Tissue temperatures were measured and lesion volumes were acquired. An in vivo porcine thigh model was used to study systemically delivered magnetically guided iron oxide (FeO) nanoparticles during radiofrequency application. Magnetic resonance imaging and histological staining of ablated tissue were subsequently performed as a part of ablation lesion analysis. Ablation of ex vivo myocardial tissue treated with metallic nanoparticles resulted in significantly larger lesions with greater impedance changes and evidence of increased thermal conductivity within the tissue. Magnet-guided localization of FeO nanoparticles within porcine thigh preps was demonstrated by magnetic resonance imaging and iron staining. Irrigated ablation in the regions with greater FeO, after FeO infusion and magnetic guidance, created larger lesions without a greater incidence of steam pops. CONCLUSIONS: Metal nanoparticle infiltration resulted in significantly larger ablation lesions with altered electric and thermal conductivity. In vivo magnetic guidance of FeO nanoparticles allowed for facilitated radiofrequency ablation without direct infiltration into the targeted tissue. Further research is needed to assess the clinical applicability of this ablation strategy using metallic nanoparticles for the treatment of cardiac arrhythmias.

Incidence of Atrial Fibrillation following Alcohol Septal Ablation for Hypertrophic Cardiomyopathy.

BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) are at a fourfold to sixfold higher risk of developing atrial fibrillation (AF) compared to the general population, though incidence rates among patients undergoing alcohol septal ablation (ASA) are not well characterized. The purpose of this study was to evaluate atrial fibrillation incidence following ASA. METHODS: We studied 132 consecutive HCM patients without comorbid AF that underwent 154 ASA procedures. The incidence of AF in follow-up was assessed through chart abstraction including electrocardiography. Survival free of AF was estimated using Kaplan-Meier methodology. RESULTS: Over a mean follow-up of 3.6 ± 2.7 years (maximum 11.3 years), 10 (7.6%) patients developed new-onset AF. Of those who developed AF, both resting and provoked left ventricular outflow tract (LVOT) gradients had improved significantly (difference -79.78 mm Hg, P ≤ 0.005). Severity of mitral regurgitation improved in 7 (70%) patients. Survival free of AF was estimated to be 99.1%, 93.7%, and 91.7% at 1, 3, and 5 years. CONCLUSIONS: Despite relieving LVOT obstruction and improving mitral regurgitation severity via ASA, new-onset AF remained a common complication of hypertrophic cardiomyopathy.

Incidence and predictors of late complete heart block after alcohol septal ablation treatment of hypertrophic obstructive cardiomyopathy.

OBJECTIVES: This study was designed to identify the incidence of late complete heart block (CHB) first identified at least 48 hours post alcohol septal ablation (ASA). BACKGROUND: Septal reduction with ASA is a therapeutic option for patients with symptomatic hypertrophic obstructive cardiomyopathy (HCM). CHB, resulting from the septal infarct, is a known complication with a reported incidence of 9-22%. The incidence of CHB more than 48 hours post-procedure is unknown. METHODS: Consecutive patients who underwent ASA were analyzed and clinical characteristics associated with late CHB were assessed. Late CHB was defined as first identification of CHB more than 48 hours after ASA. RESULTS: From 2002-2013, 145 subjects underwent 168 ASA procedures and were followed for a mean of 3.2 +/- 2.3 years. The incidence of late CHB was 8.9% (15/168 ASA procedures). Heart block occurred from 48 hours to 3-years post-procedure. In a multivariable model, patients with any CHB were more likely to have had multiple ASA procedures (OR 4.14; 95% CI: 1.24, 13.9; P < 0.05) and high resting and provoked left ventricular outflow tract (LVOT) gradient assessed by catheterization (OR per 10 mmHg gradient 1.14; 95% CI: 1.0, 1.20; P < 0.05). After multivariable adjustment, only a high provokable LVOT gradient remained an independent predictor of late CHB (OR per 10 mmHg gradient 1.14 [95% CI 1.02-1.29]). CONCLUSIONS: Late CHB is a common complication of ASA for treatment of symptomatic HCM. Post-discharge electrocardiographic surveillance for atrioventricular conduction disease should be considered after ASA, especially for those with a high provokable LVOT gradient.

Measured Lead Parameters and Electrogram Sensing Over Time in Patients With Cardiac Sarcoidosis and an Implanted Cardiac-Defibrillator.

OBJECTIVES: The study sought to characterize the performance of implanted leads among a cohort of patients with cardiac sarcoidosis (CS) and implantable cardiac-defibrillators (ICDs). BACKGROUND: An ICD is indicated for some patients with CS for the prevention of sudden cardiac death. CS can lead to myocardial inflammation and scar that may interfere with lead performance. METHODS: We performed a case-control study within the cohort of patients at the University of Colorado Hospital with CS and an ICD (n = 48) compared with randomly selected controls (n = 117) who had other indications for an ICD. We compared the measured lead parameters at the time of routine interrogation to assess the differences between groups over time. The mean duration of follow-up was 51 months. Survival analysis was performed by the method of Kaplan and Meier and by Cox proportional hazards regression. RESULTS: There was no significant difference in measured lead impedance, capture thresholds, or sensed electrograms at implantation between the CS and control groups. There were no significant differences between the mean parameters between groups over the follow-up period. However, patients with CS have a high incidence of significant (>50%) drop in measured electrograms (16 of 46 [33%] CS patients vs. 4 of 117 [3.4%] controls; hazard ratio: 10.49, 95% confidence interval: 3.47 to 31.67). As a result of alterations in lead parameters, 2 patients (4.3%) required lead revision, and 6 patients (13%) required ICD testing to ensure adequate detection of induced ventricular fibrillation. CONCLUSIONS: Reductions over time in ICD sensing of P- and/or R-wave electrograms are common in patients with CS. Although further investigation is needed to determine the mechanism of these changes, these findings suggest that patients with CS who have an ICD should be closely monitored for clinically relevant changes in P- and R-wave amplitudes.

Syncope and cardiac arrest during strenuous exercise associated with a novel mutation in LQTS1.

Exercise-induced syncope should alert clinicians to the possibility of LQTS and must be distinguished from other malignant causes of syncope such as hypertrophic cardiomyopathy, catecholaminergic ventricular tachycardia, and arrhythmogenic right ventricular cardiomyopathy. Emerging genotype-phenotype links have connected mutations resulting in LQTS with risk of developing atrial fibrillation and cardiomyopathy.

Macrolide antibiotics and the risk of cardiac arrhythmias.

Randomized, controlled trials have demonstrated that chronic therapy with macrolide antibiotics reduces the morbidity of patients with cystic fibrosis, non-cystic fibrosis bronchiectasis, chronic obstructive pulmonary disease, and nontuberculous mycobacterial infections. Lower levels of evidence indicate that chronic macrolides are also effective in treating patients with panbronchiolitis, bronchiolitis obliterans, and rejection after lung transplant. Macrolides are known to cause torsade des pointes and other ventricular arrhythmias, and a recent observational study prompted the FDA to strengthen the Warnings and Precautions section of azithromycin drug labels. This summary describes the electrophysiological effects of macrolides, reviews literature indicating that the large majority of subjects experiencing cardiac arrhythmias from macrolides have coexisting risk factors and that the incidence of arrhythmias in absence of coexisting risk factors is very low, examines recently published studies describing the relative risk of arrhythmias from macrolides, and concludes that this risk has been overestimated and suggests an approach to patient evaluation that should reduce the relative risk and the incidence of arrhythmias to the point that chronic macrolides can be used safely in the majority of subjects for whom they are recommended.

Left ventricular systolic function following alcohol septal ablation for symptomatic hypertrophic cardiomyopathy.

Because alcohol septal ablation (ASA) for the treatment of symptomatic hypertrophic cardiomyopathy (HC) with left ventricular (LV) outflow tract (LVOT) obstruction results in a myocardial infarct of up to 10% of ventricular mass, LV systolic function could decline over time. We evaluated LV function during longitudinal follow-up in a cohort of patients who underwent ASA. We studied 145 consecutive patients with HC that underwent 167 ASA procedures from 2002 to 2011. Echocardiographic follow-up was available in 139 patients (96%). Echocardiographic indexes included LV ejection fraction (LVEF), mitral regurgitation severity, systolic anterior motion of the anterior mitral leaflet, and resting and provoked LVOT gradients. All patients had a baseline LVEF of >55%. LVEF was preserved in 97.1% of patients over a mean follow-up time of 3.1±2.3 years (maximum 9.7). Mild LV systolic dysfunction was observed (LVEF range 44% to 54%) in only 4 patients. Mitral regurgitation severity improved in 67% (n=112 of 138 with complete data). Resting LVOT gradient declined from a mean of 75 to 19 mm Hg (p<0.001), and provoked gradient declined from a mean of 101 to 33 mm Hg (p<0.001). New York Heart Association class improved from a mean of 2.9±0.4 to 1.3±0.5 (p<0.001). In conclusion, LV systolic function is only mildly reduced in a minority of patients after ASA for symptomatic HC; other echocardiographic and functional measures were significantly improved.

Ranolazine for the suppression of ventricular arrhythmia: a case series.

BACKGROUND: Premature ventricular complexes (PVCs) and ventricular tachycardia (VT) are associated with persistent symptoms and ventricular dysfunction. Approved medical therapies have undesirable side effects and proarrhythmic liability. Ranolazine is a novel antianginal that preferentially blocks the late sodium current. This current is enhanced among patients with cardiomyopathy; a promising target population for ranolazine. The utility of ranolazine, however, for ventricular arrhythmia suppression has not been well characterized. OBJECTIVES: We sought to determine the effectiveness of ranolazine for suppression of ventricular ectopy, particularly in the setting of ventricular dysfunction where enhanced efficacy might be expected. METHODS: We retrospectively evaluated eight patients (six with >10% PVC burden and two with incessant VT) treated with ranolazine. Arrhythmia frequency was evaluated by continuous monitoring before and after ranolazine initiation and the correlation between ventricular function and reduction in PVC burden was assessed. RESULTS: Among six patients with PVCs, ranolazine resulted in a median decrease in PVC burden of 60.2% (P = 0.06). In two cases of apparent PVC-induced cardiomyopathy, normalization of ventricular function was observed. A significant, inverse correlation between baseline ejection fraction and percentage reduction in PVCs was observed (rho = -0.89, P = 0.02). In two patients treated for incessant VT despite Class III antiarrhythmic therapy, ranolazine eliminated VT and prevented recurrent defibrillator therapy. CONCLUSIONS: Although not approved for this indication, ranolazine appears effective for symptomatic ventricular arrhythmias. The reduction in PVC burden was greatest among individuals with reduced ventricular function, perhaps due to enhanced late sodium current associated with cardiomyopathy. A confirmatory prospective trial seems warranted.

Effect of catheter movement and contact during application of radiofrequency energy on ablation lesion characteristics.

BACKGROUND: The efficient delivery of radiofrequency (RF) energy through an endocardial ablation catheter is affected by variable tissue contact due to cardiac motion with myocardial contraction and respiration. In addition, many operators intentionally move an ablation catheter during the delivery of radiofrequency energy when targeting specific arrhythmias that require lines of conduction block such as atrial flutter and atrial fibrillation. We sought to characterize and quantify any effects of catheter movement and intermittent ablation catheter contact on lesion characteristics. METHODS: An ex vivo model consisting of recently excised viable bovine myocardium, a circulating saline bath at 37 °C, a submersible load cell, and a deflectable sheath with an ablation catheter was assembled. A stepper motor attached to an ablation catheter apparatus was programmed to simulate linear drag lesions and series of point lesions with variable contact using constant force. Lesion volumes were analyzed using a digital micrometer by measuring depth, max width, depth at max width, and surface width and compared. RESULTS: The drag lesion was significantly larger than a pointby-point linear lesion using a constant force of 15 g (2,088± 122 mm3 vs. 1,595±121.6; p =0.01) when controlling for RF time and power. For single point lesion assessment, constant contact lesions were significantly larger than lesions created with intermittent contact using the same duration of RF (194± 68 mm3 vs. 112.5±53; p =0.03). There was no significant difference in lesion size between the constant contact at 60 s and 90-s intermittent contact lesions (194±68 mm3 vs.186±69). CONCLUSIONS: In our ex vivo model, externally irrigated radiofrequency catheters produced drag lesion volumes equal to or larger than those created by a point-by-point method.We also found decreased lesion size due to intermittent contact can be overcome by increasing duration of ablation time.

Endocardial electrogram characteristics of epicardial ventricular arrhythmias.

INTRODUCTION: While most ventricular arrhythmias (VA) can be ablated successfully using an endocardial (endo) approach, epicardial (epi) mapping and ablation is sometimes required. There may be suggestive clues on the surface electrocardiogram; however, identification of an epi origin of VA with certainty remains problematic. METHODS AND RESULTS: All patients referred for ablation of ventricular tachycardia or frequent ventricular ectopy from June 2007 to July 2011 were evaluated. Patients with completed endo and epi electroanatomical activation maps of an epi VA were included (n = 10). Bipolar electrograms (EGMs) in the area of earliest endo activation were analyzed and compared to the area of early epi activation. An EGM component was characterized as far field if it was monophasic and there was inability to capture. We identified 3 characteristics from endo mapping that consistently indicated need for epi ablation: (1) Diffusely early activation (>2 cm(2) region of sites with equally earliest activation within 10 milliseconds). (2) Sequence of a far-field EGM followed by a near-field EGM in the region of earliest endo activation. (3) Inability to capture the far-field component of the earliest EGM (stim-QRS < egm-QRS time) or reproduce morphological features of the VA complex with stimulation at the earliest endo site of activation. CONCLUSIONS: The presence of a diffusely early area of activation and inability to capture a far-field endo EGM indicates that epi ablation may be needed to eliminate a VA.

Use of stored implanted cardiac defibrillator electrograms in catheter ablation of ventricular fibrillation.

BACKGROUND: Ventricular fibrillation (VF) can be abolished by targeting triggering ventricular ectopy, most often originating in the Purkinje network or right ventricular outflow tract (RVOT). This strategy relies upon the induction of premature ventricular complex (PVC) and/or VF. We sought to evaluate a VF ablation strategy that utilizes analysis of stored implantable cardioverter defibrillator (ICD) electrograms. METHODS: Eleven consecutive patients experiencing frequent VF episodes (≥three episodes in prior month) underwent electrophysiology study and ablation of VF triggers. PVC and VF induction was intentionally avoided or not possible in all of these patients. Pacemapping at likely sites for PVC triggers of VF using an analysis of the morphology and relative timing of the stored far- and near-field ICD electrograms of VF triggers was used to identify potential culprit locations. Radiofrequency energy was applied to these sites for ablation of the identified VF trigger. RESULTS: Areas targeted for ablation included the left posterior fascicle (six), left anterior fascicle (three), RVOT (three) and left ventricular outflow tract (one); two patients had two separate triggers. Ablation was completed successfully without any complications. With a mean follow-up of 288 days (range 45-649), 10 patients are free of VF. CONCLUSION: Ablation of VF triggers can be performed successfully with good short-term outcomes in patients with and without underlying heart disease. Use of stored ICD electrograms with a focus on likely target areas permit ablation without the need for PVC or VF induction. This can be useful when ectopy is not present for mapping and to avoid potentially dangerous initiation of multiple episodes of VF.

Implantable cardioverter defibrillator therapy in patients with cardiac sarcoidosis.

UNLABELLED: ICD Shocks in Cardiac Sarcoidosis. BACKGROUND: An implantable cardioverter defibrillator (ICD) is indicated for some patients with cardiac sarcoidosis (CS) for prevention of sudden death. However, there are little data regarding the event rates of ICD therapies in these patients. We sought to identify the incidence and characteristics of ICD therapies in this patient population. METHODS: We performed a cohort study of patients with ICDs at 3 institutions. Cases were those patients with CS and an ICD implanted for primary or secondary prevention of sudden death. Additionally, we included a comparison with historical controls of ICD therapy rates reported in clinical trials evaluating the ICD for primary and secondary prevention of sudden death. RESULTS: Of the 112 CS subjects identified, 36 (32.1%) received appropriate therapies for ventricular tachyarrhythmias (VT) over a mean follow-up period of 29.2 months. VT storm (>3 episodes in 24 hours) occurred in 16 (14.2%) CS subjects. Inappropriate therapies occurred in 13 CS subjects (11.6%). Covariates associated with appropriate ICD therapies included left ventricular ejection fraction (LVEF) <55% (OR 6.52 [95% CI 2.43-17.5]), right ventricular dysfunction (OR 6.73 [95% CI 2.69-16.8]), and symptomatic heart failure (OR 4.33 [95% CI 1.86-10.1]). CONCLUSIONS: In our cohort of patients with CS and ICDs, almost one-third receive appropriate therapies. This may be due to a myocardial inflammatory process leading to increased triggered activity and subsequent scarring leading to reentrant tachyarrhythmias. Adjusted predictors of ICD therapies in this population include left or right ventricular dysfunction. (J Cardiovasc Electrophysiol, Vol. 23, pp. 925-929, September 2012).