Covalently tethering siRNA to hydrogels for localized, controlled release and gene silencing.

Small interfering RNA (siRNA) has found many applications in tissue regeneration and disease therapeutics. Effective and localized siRNA delivery remains challenging, reducing its therapeutic potential. Here, we report a strategy to control and prolong siRNA release by directly tethering transfection-capable siRNA to photocrosslinked dextran hydrogels. siRNA release is governed via the hydrolytic degradation of ester and/or disulfide linkages between the siRNA and hydrogels, which is independent of hydrogel degradation rate. The released siRNA is shown to be bioactive by inhibiting protein expression in green fluorescent protein-expressing HeLa cells without the need of a transfection agent. This strategy provides an excellent platform for controlling nucleic acid delivery through covalent bonds with a biomaterial and regulating cellular gene expression, which has promising potential in many biomedical applications.

Use of microelectrode near-field signals to determine catheter contact.

BACKGROUND: The utility of standard distal bipolar electrograms (sEGMs) for assessing catheter-tissue contact may be obscured by the presence of far-field signals. Microelectrode electrograms (mEGMs) may overcome this limitation. METHODS: We compared 5 mEGM characteristics (amplitude, frequency content, temporal signal variability, presence of injury current, and amplitude differential between bipoles) with the sEGM for determining tissue contact in 20 patients undergoing ablation of typical atrial flutter. Visualization of catheter-tissue contact by intracardiac echocardiography (ICE) served as the gold standard for assessing contact. Correlation between electrograms and ICE-verified contact level was reported as percent concordance. RESULTS: Three of 5 mEGM characteristics demonstrated significantly better concordance with ICE-verified contact level than the sEGM (52% concordance with ICE): mEGM frequency content (59% concordance with ICE, P < .001 for comparison with sEGM); mEGM amplitude (concordance 59%, P < .001); and mEGM presence of injury current (56% concordance, P = .001). Concordance of amplitude differential between mEGM bipoles with ICE (49%) was not significantly different than the sEGM (P = .638) whereas mEGM temporal variability (39%) was significantly worse than the sEGM. Using a median of all 5 mEGM characteristics provided additive information (concordance with ICE 64%) and was significantly better than all of the individual mEGM characteristics except frequency content (P = .976). CONCLUSION: Microelectrode EGMs (in particular frequency content, amplitude, and presence of injury current) can improve real-time assessment of catheter contact compared to the use of standard bipolar EGMs. Broader use of mEGMs may enhance ablation efficacy.

Clinical and anatomic predictors of need for repeat atrial fibrillation ablation.

AIM: To identify predictors of need for repeat procedures after initial atrial fibrillation (AF) ablation. METHODS: We identified a cohort undergoing first time AF ablation at our institution from January 2004 to February 2014 who had cardiac magnetic resonance (CMR) imaging performed prior to ablation. Clinical variables and anatomic characteristics (determined from CMR) were assessed as predictors of need for repeat ablation. The decision regarding need for and timing of repeat ablation was at the discretion of the treating physician. RESULTS: From a cohort of 331 patients, 142 patients (43%) underwent repeat ablation at a mean of 13.6 ± 18.4 mo after the index procedure. Both male gender (81% vs 71%, P = 0.05) and lower ejection fraction (57.4% ± 10.3% vs 59.8% ± 9.4%, P = 0.04) were associated with need for repeat ablation. On pre-ablation CMR, mean pulmonary vein (PV) diameters were significantly larger in all four PVs among patients requiring repeat procedures. In multivariate analysis, increased right superior PV diameter significantly predicted need for repeat ablation (odds ratio 1.08 per millimeter increase in diameter, 95%CI: 1.00-1.16, P = 0.05). There were also trends toward significance for increased left and right inferior PV sizes among those requiring repeat procedures. CONCLUSION: Increased PV size predicts the need for repeat AF ablation, with each millimeter increase in PV diameter associated with an approximately 5%-10% increased risk of requiring repeat procedures.

Pulmonary Vein Remodeling Following Atrial Fibrillation Ablation: Implications For The Radiographic Diagnosis Of Pulmonary Vein Stenosis.

Background: Pulmonary vein (PV) reverse remodeling has been recognized following atrial fibrillation (AF) ablation. However, the extent of physiologic reverse remodeling after AF ablation and the potential impact of reverse remodeling on the radiographic diagnosis of PV stenosis have not been well characterized. Methods: From January 2004 to February 2014, 186 patients underwent paired cardiac magnetic resonance imaging (MRI) to delineate PV orifice dimensions before and after (mean 109 ± 61 days) an initial AF ablation. Results: Negative remodeling of the PV orifice cross sectional area occurred in 67.8% of veins with a mean reduction in area of 21.0 ± 14.1%, and positive remodeling was seen in the remaining PVs with an increase in area of 22.1 ± 23.4% compared to baseline. No PVs demonstrated a reduction in cross-sectional area of > 75% (maximum reduction observed was 58%). Negative remodeling of the PV long axis dimension was observed in 55.2% of veins with a mean reduction of 14.6 ± 9.2% compared to pre-ablation and positive remodeling was observed in 25.3% of PVs with a mean increase in diameter of 14.7 ± 12.6%. Only 1 PV demonstrated a reduction in orifice diameter of > 50%. There were no clinically evident or suspected cases of PV stenosis in this cohort. Conclusions: Negative remodeling of the PV orifice area was noted in the majority of PVs following AF ablation. However, in almost all cases, the extent of negative remodeling was well below commonly used thresholds for the radiographic diagnosis of PV stenosis.

Management of New-Onset Postoperative Atrial Fibrillation Utilizing Insertable Cardiac Monitor Technology to Observe Recurrence of AF (MONITOR-AF).

BACKGROUND: New-onset postoperative atrial fibrillation (POAF) occurs in up to 30% of patients undergoing coronary artery bypass grafting (CABG). POAF is associated with short- and long-term mortality. METHODS: To identify the true incidence and time course of recurrent atrial fibrillation (AF) in patients with POAF, we prospectively assigned 23 patients with POAF to receive an implantable loop recorder (ILR; Medtronic Inc., Minneapolis, MN, USA) for the detection of recurrent AF. Two electrophysiologists independently adjudicated monthly ILR transmissions to classify recurrent AF. We defined AF as any episode lasting ≥6 minutes. RESULTS: The cohort included 23 subjects averaging 69.1 ± 7.2 years of age. Their mean CHADS2 score averaged 1.9 ± 0.8. Note that 26.1% underwent direct current cardioversion prior to discharge; 95.7% left the hospital taking amiodarone and 26.1% warfarin. A total of 14 patients (60.9%) experienced recurrent AF. AF first recurred within 3 months in nine patients (39.1%), and in 10 patients AF emerged or continued beyond 3 months. Eight of 17 (47.1%) patients followed for at least 1 year experienced AF recurrence beyond 1 year of CABG. The time from surgery to first AF episode averaged 143 ± 22.5 days. Long-term monitoring shows that 60.9% of patients with POAF develop recurrent AF. CONCLUSION: POAF may represent a propensity for recurrent paroxysmal atrial fibrillation, and not simply a transient consequence of postoperative stress and inflammation. Better detection of recurrent AF might identify patients at risk for stroke who would benefit from continuing anticoagulation.

Clinical and electrocardiographic predictors of T wave oversensing in patients with subcutaneous ICD.

BACKGROUND: T wave oversensing (TWOS) is a major drawback of the subcutaneous implantable cardioverter defibrillator (S-ICD). Data on predictors of TWOS in S-ICD recipients are limited. We sought to investigate predictors of TWOS in a cohort of patients receiving an S-ICD at our institution. METHODS: S-ICD recipients at our center were identified retrospectively and stratified based on the presence or absence of TWOS. Clinical and electrocardiographic parameters were collected and compared between the 2 groups. RESULTS: Ninety-two patients underwent an S-ICD implantation at our institution between April 2010 and January 2015. Six (6.5%) patients had TWOS. These patients were younger (38.1±13.7 vs. 52.3±16.1 years, p=0.04) and had higher left ventricle ejection fractions (48.5±14.9% vs. 28.4±12.2%, p<0.01) than patients without a history of TWOS. Baseline 12-lead electrocardiogram (ECG) parameters were not different between the 2 groups. Leads I, II, and avF (which mimic the sensing vectors of the S-ICD) were further inspected to identify ECG characteristics that could predict TWOS. The QRS amplitude in ECG lead I was significantly smaller in the TWOS group than in the non-TWOS group (3.7 vs. 7.4 mV, p=0.02). CONCLUSION: In this study, younger age, higher ejection fraction, and lower QRS amplitude were associated with TWOS. These findings could help identify patients referred for S-ICD at high-risk of TWOS.

Pulmonary vein anatomy assessed by cardiac magnetic resonance imaging in patients undergoing initial atrial fibrillation ablation: implications for novel ablation technologies.

BACKGROUND: Novel atrial fibrillation (AF) ablation tools have been designed to facilitate "single-shot" pulmonary vein (PV) isolation using multi-electrode or balloon-based catheters. However, in contrast to point-by-point radiofrequency ablation, these tools may be more dependent on suitable PV anatomy to achieve circumferential PV isolation. METHODS: Three hundred and twenty-two patients underwent gadolinium-enhanced cardiac magnetic resonance angiography to delineate PV anatomy prior to initial AF ablation. Long (a) and short (b) axis measurements of the PV orifice were used to calculate the eccentricity index of the PV ostium. RESULTS: Long axis dimensions of the left superior PV were 18.2 ± 3.3 mm, left inferior PV 17.7 ± 3.9 mm, right superior PV (RSPV) 20.4 ± 4.3, and right inferior PV 18.7 ± 4.7 mm. The long axis dimension of the RSPV was significantly larger than other PVs (p < 0.001). Forty-two patients (13 %) had at least one PV with a long axis dimension >25 mm and 16 patients (5 %) had at least one PV with a long axis dimension >28 mm. Left-sided PV ostia were significantly more ellipse-shaped than the right-sided PVs, which tended to be more spherical. A significant positive correlation was noted between increasing PV size and increased orifice eccentricity. CONCLUSIONS: In this large cohort undergoing initial AF ablation, over 10 % of patients had at least one standard PV with a dimension >25 mm. Additionally, significant differences were noted between left- and right-sided veins with regard to orifice eccentricity. These findings have implications for the design of AF ablation tools and may account for differential isolation rates between PVs noted in some recent studies of novel ablation technologies.

Predictors of Long-Term Survival Following Transvenous Extraction of Defibrillator Leads.

BACKGROUND: Little data exist on long-term outcomes following extraction of implantable cardioverter defibrillator (ICD) leads, particularly for noninfectious indications. We sought to identify predictors of long-term survival after ICD lead extraction. METHODS: We retrospectively reviewed ICD lead extractions at our institution (n = 508). Procedural outcomes and long-term survival were ascertained by medical records review. RESULTS: Indication for lead extraction was infection in 32.5% and lead failure in 61.8%. Mean dwell time of the oldest extracted lead was 5.1 ± 5.9 years. Complete procedural success was achieved in 96.5% of cases. Major procedure-related complications occurred in 1.6% with six periprocedural deaths. During a mean follow-up of 866 ± 798 days, survival was significantly worse among patients with infection as the indication for extraction. At 1 year after extraction, survival among those with infection was 88.2%, compared to 95.0% in the lead failure cohort (P < 0.001). Procedural failure was a significant predictor of long-term mortality, even after excluding periprocedural deaths. In multivariate models, the presence of chronic kidney disease, increased number of leads requiring extraction, lower ejection fraction, and procedural failure were predictors of mortality. CONCLUSION: Despite high rates of procedural success, infectious indication for ICD lead extraction is associated with increased long-term mortality. In contrast, among patients undergoing extraction for lead failure, long-term survival was excellent. The presence of procedural failure was a significant predictor of long-term mortality. Further studies will be necessary to better understand the mechanisms by which procedural failure may adversely impact long-term outcomes.

Pulse Generator Exchange Does Not Accelerate the Rate of Electrical Failure in a Recalled Small Caliber ICD Lead.

BACKGROUND: St. Jude Riata/Riata ST defibrillator leads (St. Jude Medical, Sylmar, CA, USA) were recalled by the Food and Drug Administration in 2011 for an increased rate of failure. More than 227,000 leads were implanted and at least 79,000 patients still have active Riata leads. Studies have examined clinical predictors of lead failure in Riata leads, but none have addressed the effect of implantable cardioverter defibrillator (ICD) generator exchange on lead failure. The purpose of this study is to assess the effect of ICD generator exchange on the rate of electrical failure in the Riata lead at 1 year. METHODS: A retrospective chart review was conducted in patients who underwent implantation of a Riata/Riata ST lead at one center. Patients with a functioning Riata lead (with/without externalized conductor) at the time of ICD exchange were compared to controls with Riata leads implanted for a comparable amount of time who did not undergo generator replacement. RESULTS: Riata leads were implanted in 1,042 patients prior to the recall and 153 of these patients underwent generator exchange without lead replacement. Conductor externalization was noted in 21.5% of Riata leads in the ICD exchange cohort, which was not different from the control group (19.2%; P = 0.32). Two leads failed in the first year after generator replacement (1.5%) which did not significantly differ from the control group (2.0%; P = 0.57). At change-out, 54% received a commanded shock (18.6 ± 0.9 J) that did not result in any change in the high-voltage lead impedance (46.1 ± 1.1 ohms). CONCLUSIONS: Conductor externalization was seen frequently in our cohort of patients. ICD generator exchange did not accelerate the rate of Riata lead failure at 1 year. Although both the control and the change-out cohorts failed at a rate much greater than nonrecalled leads, generator exchange did not appear to add to the problem.

Effect of Surgical Atrial Fibrillation Ablation at the Time of Cardiac Surgery on Risk of Postoperative Pacemaker Implantation.

The aim of this study was to retrospectively investigate whether performing surgical atrial fibrillation (AF) ablation in conjunction with cardiac surgery (CS) increases the risk for postoperative permanent pacemaker (PPM) requirement. The 30-day risk for PPM requirement was analyzed in consecutive patients who underwent CS from January 2007 to August 27, 2013. Patients were divided into 3 groups: (1) those who underwent AF ablation concomitant with CS (AF ABL), (2) patients with any history of AF who underwent surgery who did not undergo ablation (AF NO ABL), and (3) those with no histories of AF who underwent surgery (NO AF). Logistic regression analysis was performed adjusting for age, gender, and surgery type. Of 13,453 CS patients, 353 (3%) were in the AF ABL group, 1,701 (12%) in the AF NO ABL group, and 11,399 (85%) in the NO AF group. A total of 7,651 patients (57%) underwent coronary artery bypass grafting, 4,384 (33%) underwent valve surgery, and 1,418 (10%) underwent coronary artery bypass grafting and valve surgery. The overall PPM risk was 1.6% (212 of 13,453); risk was 5.7% (20 of 353) in the AF ABL group, 3.1% (53 of 1,701) in the AF NO ABL group, and 1.2% (139 of 11,399) in the NO AF group. The unadjusted and adjusted odds of PPM were higher in the AF ABL and AF NO ABL groups than in the NO AF group (adjusted odds ratio [OR] 2.7, 95% confidence interval [CI] 1.7 to 4.4, and adjusted OR 1.7, 95% CI 1.2 to 2.4, respectively). The unadjusted OR comparing the AF ABL group and the AF NO ABL group was significant (unadjusted OR 1.9, 95% CI 1.9 to 3.2); however, the OR adjusted for surgery type, age, and gender showed a trend toward significance (adjusted OR 1.6, 95% CI 0.9 to 2.7). In conclusion, in this large cohort of patients who underwent CS, surgical AF ablation appeared to carry an increased risk for postoperative PPM implantation.

Outcomes of Sprint Fidelis and Riata lead extraction: Data from 2 high-volume centers.

BACKGROUND: The Sprint Fidelis (SF) and the Riata (RT) implantable cardioverter-defibrillator leads have been recalled for premature failure. OBJECTIVE: Data on SF and RT extractions are limited; therefore, we performed a pooled analysis to compare the safety and efficacy of lead extraction for the SF and RT lead families. METHODS: We retrospectively reviewed consecutive patients undergoing transvenous extraction of SF and RT leads at Emory University and the University of Pittsburgh Medical Center from January 2007 to October 2013. Patients were placed into 2 groups based on the presence of an SF or RT lead. The primary endpoint was a major procedural complication, defined as death, need for urgent cardiac surgery, and hemopericardium or hemothorax that required an intervention. RESULTS: A total of 462 patients underwent extraction of recalled leads (SF, n = 360; RT, n = 102). The mean number of leads extracted in the RT group was higher than in the SF group (1.8 ± 0.9 vs 1.3 ± 0.7, P < .001), and there was a longer implantation time in the RT group (5.5 ± 2.5 vs 4.3 ± 2.0 years, P < .001). Complete procedural success was higher in the SF group (99.4% vs 96.1%, P =.024). Clinical success was similar (SF 99.4% vs RT 97.1%, P = .075). There were 6 major procedural complications in the entire cohort (1.3%). The rate of major complications was not different between the SF and RT groups (SF 1.1% vs RT 2.0%, P = .618). Total mortality was 0.65%, with no difference between the groups CONCLUSION: Our data from 2 high-volume centers suggest that extraction of SF and RT leads is associated with excellent clinical success and a similar rate of major procedural complications.

Outcome of Subcutaneous Implantable Cardioverter Defibrillator Implantation in Patients with End-Stage Renal Disease on Dialysis.

BACKGROUND: Although the subcutaneous ICD (S-ICD®) is an attractive alternative in patients with end-stage renal disease (ESRD), data on S-ICD outcomes in dialysis patients are lacking. METHODS: Patients with cardiomyopathy undergoing S-ICD implantation in our center were stratified by need for chronic dialysis at the time of implant. The primary endpoint was incidence of death, heart failure hospitalization or appropriate S-ICD shocks, and secondary endpoints were incidence of inappropriate shocks or implant related complications requiring surgical re-intervention. Mean follow-up was longer in the nondialysis cohort (514 ± 495 vs. 227 ± 233 days, P = 0.006), so all endpoints were analyzed using time-dependent comparisons and reported as annual event rates. RESULTS: Out of 79 S-ICD implants included in this analysis, 27 patients were on dialysis. Dialysis patients were older and more likely to be diabetic. Mean ejection fraction across the entire cohort was 26.9% without significant difference between dialysis and nondialysis groups. Although not significant, the incidence of the primary endpoint was higher in the dialysis cohort (23.8%/year vs. 10.9%/year, P = 0.317), driven primarily by a higher rate of appropriate shocks. The rate of inappropriate shocks was similar between groups (dialysis 6.0%/year vs. nondialysis 6.8%/year, P = 0.509). No patients in the dialysis cohort had complications requiring surgical re-intervention versus 6 patients in the nondialysis cohort (P = 0.086). CONCLUSIONS: Our data suggest that S-ICD implantation in dialysis patients is not associated with an excess risk of implant related complications or inappropriate shocks.

Assessing pediatric and young adult substance use through analysis of prehospital data.

INTRODUCTION: Substance use in young adults is a significant and growing problem. Emergency Medical Services (EMS) personnel often encounter this problem, yet the use of prehospital data to evaluate the prevalence and magnitude of substance abuse has been limited. HYPOTHESIS/PROBLEM: This study evaluated drug and alcohol use through the use of prehospital and EMS data in one suburban county in Maryland (USA). The primary hypothesis was that the type of drug being abused is associated with age. The secondary hypothesis was substance abuse incidence is associated with location. The tertiary hypothesis was that substance abuse is associated with a history of mental illness. METHODS: Deidentified patient care reports (PCRs) were obtained during a 24-month period from October 2010 through September 2012 for patients 0 through 25 years of age. Inclusion criteria included chief complaint of alcohol overdose, drug overdose, or the use of naloxone. RESULTS: The primary hypothesis was supported that age was associated with drug category (P < .001). Younger adolescents were more likely to use household items, prescription drugs, or over-the-counter drugs, whereas older adolescents were more likely to use illicit drugs. The secondary hypothesis was supported that both alcohol (P < .001) and drugs (P < .001) were associated with location of call. Calls involving alcohol were more likely to be at a home or business, whereas calls involving drugs were more likely to be at home or at a public venue. The tertiary hypothesis was supported that both alcohol (P = .001) and drug use (P < .001) were associated with history of mental illness. Older adolescents were more likely to report a history of mental illness. Chi-squared tests indicated there were significant differences between genders and drug category (P = .002) and gender and current suicide attempt (P = .004). Females were more likely to use prescription drugs, whereas males were more likely to use illicit drugs. Calls involving younger adolescents under 18 were more likely to be at school or the mall, whereas calls involving older adolescents were likely to be at a prison, public venue, or a business. CONCLUSION: All three hypotheses were supported: the type of substance being abused was associated with both age and location, and substance abuse was associated with a history of mental illness. This research has important implications for understanding how EMS resources are utilized for substance use. This information is valuable in not only the education and training of prehospital care providers, but also for the targeting of future public health interventions.