Divyang Patel

Relaxin Suppresses Atrial Fibrillation by Reversing Fibrosis and Myocyte Hypertrophy, and Increasing Conduction Velocity and Sodium Current in Spontaneously Hypertensive Rat Hearts

Rationale: Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly and hypertensive patients and has been correlated to enhanced atrial fibrosis. Despite a lack of direct evidence that fibrosis causes AF, reversal of fibrosis is considered a plausible therapy. Objective: To evaluate the efficacy of the antifibrotic hormone relaxin (RLX) in suppressing AF in spontaneously hypertensive rats (SHR). Methods and Results: Normotensive Wistar-Kyoto (WKY) and SHR were treated for 2 weeks with vehicle (WKY+V and SHR+V) or RLX (0.4 mg/kg per day, SHR+RLX) using implantable mini-pumps. Hearts were perfused, mapped optically to analyze action potential durations, intracellular Ca2+ transients, and restitution kinetics, and tested for AF vulnerability. SHR hearts had slower conduction velocity (CV; P<0.01 versus WKY), steeper CV restitution kinetics, greater collagen deposition, higher levels of transcripts for transforming growth factor-&bgr;, metalloproteinase-2, metalloproteinase-9, collagen I/III, and reduced connexin 43 phosphorylation (P<0.05 versus WKY). Programmed stimulation triggered sustained AF in SHR (n=5/5) and SHR+V (n=4/4), but not in WKY (n=0/5) and SHR+RLX (n=1/8; P<0.01). RLX treatment reversed the transcripts for fibrosis, flattened CV restitution kinetics, reduced action potential duration at 90% recovery to baseline, increased CV (P<0.01), and reversed atrial hypertrophy (P<0.05). Independent of antifibrotic actions, RLX (0.1 µmol/L) increased Na+ current density, INa (≈2-fold in 48 hours) in human cardiomyocytes derived from inducible pluripotent stem cells (n=18/18; P<0.01). Conclusions: RLX treatment suppressed AF in SHR hearts by increasing CV from a combination of reversal of fibrosis and hypertrophy and by increasing INa. The study provides compelling evidence that RLX may provide a novel therapy to manage AF in humans by reversing fibrosis and hypertrophy and by modulating cardiac ionic currents.

Failure-free survival of the Durata defibrillator lead

AIMS Given design similarities and a common manufacturer, there have been suspicions regarding the Durata™ defibrillator (ICD) lead, in the aftermath of the Riata™ class I recall. We therefore examined the failure-free survival rates of the Durata™ compared with the Riata™ and Sprint Quattro™ ICD leads. METHODS AND RESULTS All patients (n = 2475) implanted with a Durata (n = 828), Riata [n = 627; 8 Fr. (n = 472) and 7 Fr. (n = 155)], or Sprint Quattro (n = 1020) leads at our institution were included and Kaplan-Meier failure-free survival curves were constructed for all leads. Lead failure was defined as electrical malfunction resulting in lead replacement, excluding dislodgements or perforations. Annual electrical failure rates were 0.3%, 1.7, and 0.3% for the Durata, Riata, and Sprint Quattro leads, respectively (P < 0.0001 for the comparison of Durata to Riata and P = 0.1.0 for the comparison of Durata to Sprint Quattro). The failure-free survival of the Durata lead was significantly better than that of the Riata lead (P < 0.0001) and similar to that of the Sprint Quattro (P = 0.94). The 7 Fr. Riata ST lead had better survival compared with the 8 Fr. Riata lead (P = 0.050) and comparable survival with the Durata lead (P = 0.12). CONCLUSION The Durata lead failure-free survival is significantly better than the 8 Fr. Riata, albeit at a shorter follow-up time. Riata and comparable with that of the 7 Fr. Riata ST and the Sprint Quattro ICD leads. These data provide an insight into the mechanism of electrical failure of Riata leads and have implications for patient management.

Relaxin suppresses atrial fibrillation in aged rats by reversing fibrosis and upregulating Na+ channels

BACKGROUND Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly patients and has been correlated with enhanced age-dependent atrial fibrosis. Reversal of atrial fibrosis has been proposed as therapeutic strategy to suppress AF. OBJECTIVE To test the ability of relaxin to reverse age-dependent atrial fibrosis and suppress AF. METHODS Aged F-344 rats (24 months old) were treated with subcutaneous infusion of vehicle or relaxin (0.4 mg/kg/day) for 2 weeks. Rat hearts were excised, perfused on a Langendorff apparatus, and stained with voltage and Ca(2+) indicator dyes. Optical mapping and programmed electrical stimulation was used to test arrhythmia vulnerability and changes in electrophysiological characteristics. Changes in protein expression and Na(+) current density (INa) were measured by tissue immunofluorescence and whole-cell patch clamp technique. RESULTS In aged rats, sustained AF was readily induced with a premature pulse (n = 7/8) and relaxin treatment suppressed sustained AF by a premature impulse or burst pacing (n = 1/6) (P < .01). Relaxin significantly increased atrial action potential conduction velocity and decreased atrial fibrosis. Relaxin treatment increased Nav1.5 expression (n = 6; 36% ± 10%) and decreased total collagen and collagen I (n = 5-6; 55%-66% ± 15%) in aged atria (P < .05) and decreased collagen I and III and TGF-β1 mRNA (P < .05). Voltage-clamp experiments demonstrated that relaxin treatment (100 nM for 2 days) increased atrial INa by 46% ± 4% (n = 12-13/group, P < .02). CONCLUSION Relaxin suppresses AF through an increase in atrial conduction velocity by decreasing atrial fibrosis and increasing INa. These data provide compelling evidence that relaxin may serve as an effective therapy to manage AF in geriatric patients by reversing fibrosis and modulating cardiac ionic currents.

Complex excitation dynamics underlie polymorphic ventricular tachycardia in a transgenic rabbit model of long QT syndrome type 1

BACKGROUND Long QT syndrome type 1 (LQT1) is a congenital disease arising from a loss of function in the slowly activating delayed potassium current IKs, which causes early afterdepolarizations (EADs) and polymorphic ventricular tachycardia (pVT). OBJECTIVE The purpose of this study was to investigate the mechanisms underlying pVT using a transgenic rabbit model of LQT1. METHODS Hearts were perfused retrogradely, and action potentials were recorded using a voltage-sensitive dye and CMOS cameras. RESULTS Bolus injection of isoproterenol (140 nM) induced pVT initiated by focal excitations from the right ventricle (RV; n = 16 of 18 pVTs). After the pVT was initiated, complex focal excitations occurred in both the RV and the left ventricle, which caused oscillations of the QRS complexes on ECG, consistent with the recent proposal of multiple shifting foci caused by EAD chaos. Moreover, the action potential upstroke in pVT showed a bimodal distribution, demonstrating the coexistence of 2 types of excitation that interacted to produce complex pVT: Na(+) current (INa)-mediated fast conduction and L-type Ca(2+) current (ICa)-mediated slow conduction coexist, manifesting as pVT. Addition of 2 μM tetrodotoxin to reduce INa converted pVT into monomorphic VT. Reducing late INa in computer simulation converted pVT into a single dominant reentry, agreeing with experimental results. CONCLUSION Our study demonstrates that pVT in LQT1 rabbits is initiated by focal excitations from the RV and is maintained by multiple shifting foci in both ventricles. Moreover, wave conduction in pVT exhibits bi-excitability, that is, fast wavefronts driven by INa and slow wavefronts driven by ICa co-exist during pVT.

Comparative effectiveness of antiarrhythmic drugs for rhythm control of atrial fibrillation

INTRODUCTION Although there are many different antiarrhythmic drugs (AADs) approved for rhythm management of atrial fibrillation (AF), little comparative effectiveness data exist to guide drug selection. METHODS We followed 5952 consecutive AF patients who were prescribed amiodarone (N=2266), dronedarone (N=488), dofetilide (N=539), sotalol (N=1718), or class 1C agents (N=941) to the primary end point of AF recurrence. RESULTS Median follow-up time was 18.2 months (range 0.1-101.6 months). Patients who were prescribed amiodarone had the highest, while patients on class 1C agents had the lowest baseline CHA2DS2-VASc score, Charlson comorbidity index, and burden of comorbid illnesses including coronary artery disease, congestive heart failure, diabetes mellitus, hyperlipidemia, chronic obstructive lung disease, chronic kidney disease, or cancer (p<0.05 for all comparisons). After adjusting for baseline characteristics, using dronedarone as benchmark, amiodarone [hazard ratio (HR) 0.58, p<0.001], class 1C agents (HR 0.70, p<0.001), and sotalol (HR 0.79, p=0.008), but not dofetilide (HR 0.87, p=0.178) were associated with less AF recurrence. In addition, compared to dronedarone, amiodarone and class 1C agents were associated with lower rates of admissions for AF (HR 0.55, p<0.001 for amiodarone; HR 0.71, p=0.021 for class 1C agents) and all-cause mortality was lowest in patients treated with class 1C agents (HR 0.42, p=0.018). The risk of stroke was similar among all groups. CONCLUSION Compared with dronedarone, amiodarone, class 1C agents, and sotalol are more effective for rhythm control, while dofetilide had similar efficacy. These findings have important implications for clinical practice.

Risk of Stroke and Death in Atrial Fibrillation by Type of Anticoagulation: A Propensity‐Matched Analysis

We examined the effect of novel oral anticoagulants (NOACs) compared to warfarin on the risk of death or stroke in atrial fibrillation (AF) patients in every day clinical practice.

Patient Outcomes According to Adherence to Treatment Guidelines for Rhythm Control of Atrial Fibrillation

Background Although guidelines for antiarrhythmic drug therapy in atrial fibrillation (AF) were published in 2006, it remains uncertain whether adherence to these guidelines affects patient outcomes. Methods and Results We retrospectively evaluated the records of 5976 consecutive AF patients who were prescribed at least 1 antiarrhythmic drug between 2006 and 2013. Patients with 1 or more prescribed antiarrhythmic drugs that did not comply with guideline recommendations comprised the non–guideline‐directed group (=2920); the remainder constituted the guideline‐directed group (=3056). Time to events was assessed using the survival analysis method and adjusted for covariates using Cox regression. Rates of adherence to the guidelines increased significantly with a higher degree of prescriber specialization in arrhythmias (49%, 55%, and 60% for primary care physicians, general cardiologists, and cardiac electrophysiologists, respectively, P=0.001) for the first prescribed antiarrhythmic drug. Compared to the non–guideline‐directed group, the guideline‐directed group had higher rates of heart failure, but lower baseline CHADS2‐VASc scores (P<0.001) and lower rates of coronary artery disease, valvular disease, hypertension, hyperlipidemia, pulmonary disease, and renal insufficiency (P<0.05 for all). During 45±26 months follow‐up, the guideline‐directed group had a lower risk of AF recurrence (hazard ratio=0.86, 95% CI=0.80 to 0.93), fewer hospital admissions for AF (hazard ratio=0.87, 95% CI=0.79 to 0.97), and fewer procedures for recurrent AF, including electrical cardioversion, pacemaker implantation, and atrioventricular nodal ablation (P<0.01 for all). The mortality and stroke risks were similar between the groups. Conclusions Adherence to published guidelines in the antiarrhythmic management of AF is associated with improved patient outcomes.

RELAXIN SUPPRESSES ATRIAL FIBRILLATION IN 24 MONTH OLD RATS BY REVERSING ATRIAL FIBROSIS AND UPREGULATING SODIUM CHANNELS

Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly patients and AF has been strongly correlated with the development of atrial fibrosis. Therefore, the antifibrotic hormone relaxin (RLX) was studied as a novel therapy for AF and age related fibrosis. 24 month

Cardiac implantable electronic device lead extraction in patients with underlying infection using open thoracotomy or percutaneous techniques

BACKGROUND Explanting infected cardiac implantable electronic devices (CIEDs) and extracting their associated leads can be performed percutaneously (EP) or via open-thoracotomy (OR) approach. In this study, we examined the characteristics and outcomes of infected CIED patients undergoing EP vs. OR extraction procedures. METHODS All patients (EP: n = 329 and OR: n = 24) who received lead extraction in the presence of an infected CIED from 2005 to 2010 at the University of Pittsburgh Medical Center were included in this study. Demographic and clinical characteristics were obtained from the electronic medical records. The Charlson comorbidity index (CCI) was used to adjust for severity of co-morbid conditions. RESULTS Compared to the EP group, OR patients were more likely to have positive blood cultures, larger vegetations, and worse CCI scores. They also had higher total mortality rates at 1 (p = 0.036), 6 (p = 0.020), and 12 months (p = 0.012) after the procedure. One-year survival after lead extractions was significantly better for the EP compared to the OR group (p = 0.002) even after adjusting for other comorbid illnesses (HR = 2.6, p = 0.010) in a Cox regression model. CONCLUSIONS Infected CIED patients undergoing open-chest lead extraction are sicker and have higher mortality rates compared to those undergoing percutaneous extraction. Randomized, prospective data are needed to determine whether the procedural strategy for lead extraction accounts in part for the difference in outcome.

Effect of Cardiac Resynchronization Therapy on Left Ventricular Remodeling in Patients with Cardiac Sarcoidosis

Cardiac resynchronization therapy (CRT) has been shown to be beneficial in patients with medically refractory heart failure. Although it has been found to be effective in a wide range of etiologies for nonischemic cardiomyopathy, its role in improving remodeling and survival of patients with cardiac sarcoidosis (CS) remains undefined. We performed a retrospective review of all patients at our institution with CS who underwent implantation of a CRT device from 2007 to 2017. The outcomes of this population were compared with the outcomes of a cohort of patients with nonischemic cardiomyopathy with an etiology other than sarcoidosis. Nineteen patients in our institution with CS underwent CRT implantation during the time period. This group was compared with 311 consecutive patients with other etiologies of nonischemic cardiomyopathy who underwent CRT implantation. CRT improved left ventricular ejection fraction (LVEF) from 28.8% to 35.9% (p <0.05) in CS, whereas it improved LVEF from 25% to 36.6% (p <0.01) in non-CS group (difference in means of 0.13). CRT significantly improved diastolic and systolic LV diameters, mitral regurgitation, and right ventricular systolic function in non-CS patients but failed to improve same parameters in CS patients. In conclusion, CRT significantly improved LVEF in patients with CS. There is no significant evidence that survival outcomes of CRT patients with CS are significantly worse than other etiologies of nonischemic cardiomyopathy.