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Abstract Background : Non‐motor symptoms are well established phenotypic components of adult‐onset idiopathic, isolated, focal cervical dystonia (AOIFCD). However, improved understanding of their clinical heterogeneity is needed to better target therapeutic intervention. Here, we examine non‐motor phenotypic features to identify possible AOIFCD subgroups. Methods : Participants diagnosed with AOIFCD were recruited via specialist neurology clinics (dystonia wales: n = 114, dystonia coalition: n = 183). Non‐motor assessment included psychiatric symptoms, pain, sleep disturbance, and quality of life, assessed using self‐completed questionnaires or face‐to‐face assessment. Both cohorts were analyzed independently using Cluster, and Bayesian multiple mixed model phenotype analyses to investigate the relationship between non‐motor symptoms and determine evidence of phenotypic subgroups. Results : Independent cluster analysis of the two cohorts suggests two predominant phenotypic subgroups, one consisting of approximately a third of participants in both cohorts, experiencing increased levels of depression, anxiety, sleep impairment, and pain catastrophizing, as well as, decreased quality of life. The Bayesian approach reinforced this with the primary axis, which explained the majority of the variance, in each cohort being associated with psychiatric symptomology, and also sleep impairment and pain catastrophizing in the Dystonia Wales cohort. Conclusions : Non‐motor symptoms accompanying AOIFCD parse into two predominant phenotypic sub‐groups, with differences in psychiatric symptoms, pain catastrophizing, sleep quality, and quality of life. Improved understanding of these symptom groups will enable better targeted pathophysiological investigation and future therapeutic intervention.

Background: The use of direct current electroporation has the potential for significant utility because of its non-thermal approach to tissue destruction. However, the fear of inducibility of cardiac arrhythmias (particular ventricular fibrillation) when using electroporation remains of concern due to membrane poration and ion flux during periods of vulnerability occurring in ventricular repolarization. Objectives: Critically examine the incidence of arrhythmias in a series of acute canine studies to retrospectively determine cause and safe electoporative dosing margins. Methods: We performed electroporation ablation in 6 acute canine studies. These were experimental studies performed at sites critical in arrhytmogenesis. Sites included the pulmonary veins, left atrial appendage, superior vena cavae, right atrium and ventricle. Electroporation was delivered using an ECG gating algorithm so that QRS complexes are tagged and direct current energy is not delivered during the vulnerable portion of the T wave. Results: In 6 acute canine experiments, we delivered a total of 62 electroporation applications for ablation purposes. The average electroporation dosage delivered involved an average of 1427 Volts (range 750-3000 V), Pulse length of 100 ms, and number of pulses of 20.2 (range 10-100). AF was induced in 27.4% of electroporiatve applications. Atrial flutter/tachycardia occurred in 8.1%. VF occurred in only one application at a location of the left superior pulmonary vein. Conclusion: These data suggest that induction of VF is relatively uncommon with ECG gating and highlight its importance when using this modality. However, the induction of AF occurs with higher frequency. The actual mechanism as to why this occurs requires further systematic study.

Introduction: Warfarin and non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran are effective for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). However, few analyses have compared persistence rates of warfarin vs. dabigatran-treated patients. Methods: The ORBIT-AF registry enrolled patients with AF from 173 clinical practices across the US. One-year persistence of warfarin vs. dabigatran was defined as treatment at baseline visit and at 1-year follow-up. Multivariable logistic regression analysis was used to identify characteristics associated with warfarin or NOAC persistent use. Results: At baseline, 6.4% (N=459/7,150) were treated with dabigatran and 93.6% (N=6,691/7,150) with warfarin. Patients treated with warfarin at baseline were older (74 vs. 71, p<.0001), had more NYHA class III/IV heart failure (7 vs. 5, p=.0007), lower creatinine clearance (77 vs. 88, p<.0001), higher CHA2DS2-VASc risk scores, and more prior CVA/TIA events (16 vs. 11, p=.003). Patients treated with dabigatran had more severe symptoms (EHRA class III: 20 vs. 14, p<.0001), higher rates of treatment with a rhythm control strategy (42.7 vs. 28.2, p<.0001), more attempts at cardioversion (38.3 vs. 32.1, p<.006), and catheter ablation of AF (9.8 vs. 5.2, p<.0001). At 12 months, adjusted persistence rates for warfarin were higher than dabigatran [82% (80-84) vs. 67% (61-73) p<.0001]. Factors independently associated with one year persistence were: African American race (OR 1.53, 95% C.I. 1.07-2.19, p=0.02), Hispanic race (OR 1.66, 95% C.I. 1.06-2.60), paroxysmal AF (vs. new onset) (OR 1.68, 95% C.I. 1.21-2.33, p=.002), LVH (OR 1.40, 95% C.I. 1.08-1.81, p=.01), persistent AF (vs. new onset) (OR 1.91, 95% C.I. 1.35-2.69, p=.0002), and CHA2DS2-VASc risk scores ≥ 2 (OR 1.94, 95% C.I. 1.18-3.19, p=.009). Conclusion: Persistence rates for warfarin were higher at one year than those on dabigatran. In addition, factors associated with persistence of warfarin include: African American and Hispanic race, type of AF including permanent and persistent, LVH, and CHA2DS2-VASc risk scores ≥ 2.

Background: Novel therapies for stroke prevention in atrial fibrillation (AF) are emerging. However, data on use and outcomes of these agents in the community are limited, particularly in patients newly diagnosed with AF or recently transitioned to a novel anticoagulant. Methods: Phase II of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF II) is a multicenter, national, AF registry. We are enrolling 15,000 patients with new-onset AF, or those with known AF recently-transitioned to a novel anticoagulant. The primary objective is to evaluate the safety of novel anticoagulants, with specific focus on use, transitions, and management around invasive procedures and bleeding events. An adaptive design is used to ensure diversity of enrollment across geographic, provider, and treatment groups. The primary outcomes are major bleeding and thromboembolic events. Results: Of 1,011 patients in ORBIT-AF II, the median age was 73, 44% were female, 23% had a history of heart failure, 34% had a prior MI, and 11% had a prior stroke/TIA. The mean CHADS2 score was 2. Overall, 76% had AF new-onset, and a range of anticoagulant strategies was used in these patients (Figure). Among the 24% with known AF transitioned to a novel agent, 66% received rivaroxaban, versus 8.1% dabigatran, and 26% apixaban. Compared with patients having new-onset AF, those with known AF recently-transitioned to a novel anticoagulant were slightly older (median age 74 vs. 72), had higher CHADS2 scores (>2 in 70% vs. 62%), but less severe kidney disease (0 vs. 1.7%). Conclusions: Patients with new-onset AF are frequently treated with novel anticoagulants and these patients have lower risk scores than those with known AF transitioned to a novel drug. These data will provide insights into clinical management and patient centered outcomes among those treated with novel anticoagulants in real world practice settings.

Objective: Time in the therapeutic range (TTR) of INR 2.0-3.0 is an important measurement of warfarin anticoagulation quality. There are few reports on TTR in United States (US) clinical practice. Methods: Using the US ORBIT AF registry, we analyzed TTR for patients on warfarin with at least 5 recorded INR measurements. The Rosendaal method of linear interpolation was used between each pair of measured INR values. Patients were stratified into quartiles based on TTR. Results: We studied 5,451 patients treated at 169 US sites with 48% of patients being followed at an anticoagulation clinic. Patients had a median age of 76 years [interquartile range (IQR) 68-82 years] and median follow-up was 18.9 months [IQR 12.7-23.3 months], and patients were 42% women. The median number of INR draws was 21 [IQR 12-30]. Patients had an overall median TTR of 68% [IQR 52-80%]. The median TTR by quartile was 40%, 60%, 73%, and 87%. Patients were more likely to be subtherapeutic (median time of 17%) than supratherapeutic (median time of 10%). Patients age 61-80 years and those with a college education had the highest TTRs. Patients with their INR followed at an anticoagulation clinic were more likely to be in the highest TTR quartile than in the lowest (27% vs 23%, p=0.0002). Patients with worsening renal function and higher risk for bleeding (ATRIA) or stroke (CHADS2 score) had lower TTR (p<0.0001 for all) (Figure). Conclusions: In US clinical practices, warfarin patients have therapeutic INR levels about 2/3 of the time. Those at highest risk for stroke and bleeding paradoxically were the least likely to be in the therapeutic range.

Background Oral anticoagulation (OAC) can reduce stroke risk at the cost of increased bleeding risk in those with atrial fibrillation (AF). Observational data have shown that higher-risk patients with AF most likely to benefit from OAC are less likely to receive OAC at hospital discharge. Methods We used data from ORBIT-AF Registry, a cohort of 9,589 AF patients enrolled among 173 participating outpatient practices. OAC was defined as warfarin or dabigatran use at study enrollment. Stroke and bleeding risk were calculated using the CHADS2 and ATRIA scores, respectively. Results The study population had a mean age of 73.5 years; 57.8% were men. Overall, 76.4% of patients received OAC. Use of OAC rose with increasing CHADS2 stroke risk, from 67% for CHADS2 <1 to 80% for CHADS2 ≥2 (p<0.0001). OAC use fell slightly with increasing ATRIA bleeding risk, from 77% for ATRIA score ≤3 to 74% with ≥5 (p=0.002 for trend). Among patients with low bleeding risk, rates of OAC increased commensurate with stroke risk (p<0.0001 for interaction; see figure). Higher bleeding risk tended to decrease rates of OAC among patients with a CHADS2 score ≥2 (p=0.13 for interaction). Conclusions In community-based outpatients with AF, use of OAC rose with increasing thromboembolic risk and declined with higher bleeding risk. These findings suggest that the risk-treatment paradox may be less that previously reported. Provision of OAC in community practice appears to appropriately consider patients' stroke and bleeding risks. Further research is required to understand how quality improvement initiatives can further improve stroke prevention.

Introduction: Pulmonary hypertension (PH) is associated with increased mortality after surgical or transcatheter aortic valve replacement (TAVR) for aortic stenosis (AS). Hypothesis: We hypothesized that clinical or hemodynamic factors might influence the relationship between significant PH and increased mortality. Methods: Among patients with symptomatic AS at high or prohibitive surgical risk receiving TAVR in the PARTNER I randomized trial or registry, 2180 patients with an invasive measurement of mean pulmonary artery pressure (mPAP) recorded were included. PH was defined as: none (mPAP<25 mmHg), mild (25 to <35), and mod/sev (≥35). Results: One year all-cause mortality was worse with increasing severity of PH: none (n=785, 18.6%), mild (n=838, 22.7%), and mod/sev (n=557, 25.0%) (p=0.01). The association between mod/sev PH (vs. no PH) and 1y mortality varied by sex and renal function (interaction p=0.03 and p=0.06, respectively). In females, mod/sev PH was associated with increased mortality (24.6% vs. 14.1%, HR 1.89, 95% CI 1.32-2.73); in males it was not (24.9% vs. 22.2%, HR 1.12, 95% CI 0.82-1.52). Additionally, mod/sev PH was associated with mortality in those with glomerular filtration rate (GFR) <40 (HR 1.76, 95% CI 1.28-2.42), but not in those with GFR ≥40. In a multivariable Cox PH model of patients with mod/sev PH, oxygen dependent lung disease, cerebrovascular disease, lower GFR, and lower baseline transvalvular mean gradient were each independently associated with increased 1y mortality (p<0.05 for all), whereas pulmonary artery compliance was the only hemodynamic variable associated with mortality (p=0.043) (Table). Conclusions: The relationship between mod/sev PH and increased mortality after TAVR is altered by sex and renal function. While lower pulmonary artery compliance is associated with increased mortality in patients with significant PH, clinical factors appear to be more influential in stratifying risk than hemodynamic indices.

Introduction: Long QT syndrome (LQTS) is a genetic disorder associated with abnormal ventricular repolarization and a predisposition for torsade de pointes and sudden cardiac death. Identification of markers to elucidate high risk patients is of major practical importance. Our aim was to use a novel, automated quantitative T wave analysis program to distinguish symptomatic from asymptomatic LQTS patients. Methods: We analyzed a genotyped cohort of 420 patients (22 ± 15.7years, 43% male) with either LQT1 (61%) or LQT2 (39%). ECG analysis was conducted using novel software that we created to automatically detect subtle changes in T wave morphology. Symptomatic patients were defined as those with a history of syncope or resuscitated cardiac arrest that was suspected of being LQTS triggered. Classification was performed using the top three T wave features in a linear discriminant classifier by 10x10 cross-validation. Results: Symptomatic LQT1 patients have a greater QTc duration in lead aVF (437 msec vs 416 msec, p <0.0001), a greater T wave center of gravity on the x axis (COGx) in lead V2 (0.304 vs 0.280, p <0.0001) and longer Tpeak-Tend/QT in lead II (0.208 vs 0.188, p < 0.0001) than asymptomatic patients with LQT1. Use of these 3 features enabled classification of symptomatic status in 72% of LQT1 cases, compared to 68% when QTc was used to classify alone. Symptomatic LQT2 patients had a longer QTc in Lead 1 (460 vs 418 msec, p < 0.0001), COGx in 4th segment of T wave was greater in lead V5 (0.399 vs 0.350, p<0.0001), and the Tpeak-Tend interval in V2 was longer (126 vs 99 msec, P =0.0004). Use of these 3 features enabled correct classification in 73% of LQT2 cases, compared to 67% when QTc was used alone. Conclusions: Application of an automated T wave analysis program was able to identify T wave features that distinguished the patients who presented as symptomatic LQTS, associated with syncope or resuscitated cardiac arrest. Use of these features could help assess arrhythmic risk and guide management strategies for patients with LQTS.

Introduction: The T peak - T end interval (Tpe) is a measure of transmural dispersion of repolarisation with prolongation of this interval linked to an increased risk of ventricular arrhythmias and sudden death. Patients with cardiac amyloid experience a high rate of sudden cardiac death. Objective: To determine the prognostic utility of the Tpeak-Tend interval in patients with transthyretin (TTR) cardiac amyloidosis. Methods: Of the 240 patients who underwent evaluation for TTR amyloidosis at our tertiary referral center from 1966 to 2010, 39 met inclusion criteria (65 excluded for AF, 66 BBB/Paced Rhythm, 25 CAD, 21 other). Inclusion criteria were presence of histological diagnosis of TTR amyloid and confirmed cardiac involvement by echocardiogram or biopsy and absence of atrial fibrillation (AF) or bundle branch block/paced rhythm on the index surface ECG, or history of coronary heart disease (CAD). Tpe was measured in leads V3 and V5. Cox proportional hazards model were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Kaplan-Meier curves were used to estimate overall survival and differences between curves were estimated using log rank. Primary endpoints were death or heart transplantation. Results: Of the 39 patients, 85% were male, and 69% were mTTR. Mean age 66.4 ± 13.9 years. Mean follow up period of 4.2 ± 3.2 years, 25 died and 5 received heart transplants. Median survival was 3.8 years, with 5 year survival 34%. On univariate analysis, Tpe in lead V3 was predictive of adverse outcome, HR per 10msec, 1.195 (1.051-1.370). Further multivariate analysis, in a model accounting for age, gender, Lead V3 Tpe was independently associated with survival, HR per 10msec, 1.207, (1.094-1.411, p=0.009). Conclusions: The Tpe interval in Lead V3 at diagnosis is a novel, noninvasive independent predictor of survival in transthyretin cardiac amyloidosis patients in sinus rhythm.

Background: In 2007, the American Heart Association (AHA) infective endocarditis (IE) prevention guidelines recommended that antibiotic prophylaxis before invasive dental procedures for the “moderate risk” (MR) group, which represented the bulk of patients who were to receive prophylaxis before 2007, be eliminated. This decision was met with much concern among some healthcare providers and that concern persists today. We therefore evaluated dental office records in Olmsted County (OC), Minnesota to determine whether patients included in the MR group continue to receive antibiotic prophylaxis despite the 2007 AHA recommendations. Methods: Eligible patients include all adult (≥18 years) residents of OC, classified as having MR cardiac condition for IE (i.e. mitral valve prolapse [MVP], bicuspid aortic valve [BAV], hypertrophic obstructive cardiomyopathy [HOCM], acquired valvular dysfunction [AVD]), with at least one dental visit between January 1, 2005 and June 1, 2015. Eight dental offices located within OC were sampled to identify both dental procedures and whether antibiotic prophylaxis was administered according to AHA guidelines. Results: We identified 334 MR patients. Approximately 62% of MR patients received antibiotic prophylaxis prior to the change in AHA guidelines in 2007. There was a decrease to 7% post-2007 AHA guidelines (P<.001). The magnitude of decline was greater among visits for dental cleanings (from 63% to 6%), as compared to other invasive procedures (57% to 11%; P=0.003) (Figure 1). AVD was the most common cardiac condition (85%), followed by MVP (8%), and BAV (4%). Conclusion: Following publication of the 2007 AHA IE prevention guidelines, there was a rapid, 9-fold decrease in antibiotic prophylaxis in patients with MR cardiac conditions who underwent invasive dental procedures in OC. These data are also critical as we attempt to evaluate the impact, if any, of this practice on the incidence of IE due to viridans group streptococci.