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Non-vitamin K antagonist oral anticoagulants (NOACs) are frequently used to prevent stroke in patients with atrial fibrillation. These patients are often also on aspirin or other antiplatelet agents. It is possible that treatment with both NOACs and aspirin or other antiplatelet drug may be effective in decreasing stroke, but data are sparse regarding the efficacy and safety of using both agents for stroke prevention. To address these issues, data were pooled from the 4 recent randomized, controlled trials of NOACs: apixaban, rivaroxaban, dabigatran, and edoxaban, which included 42,411 patients; 14,148 (33.4%) were also on aspirin or other antiplatelet drug. The number of thromboembolic events among participants on NOAC and aspirin/antiplatelet was compared with the number of events in patients on NOAC alone. Bleeding rates were also compared between those on NOAC + aspirin/antiplatelet and on NOAC alone. These results were compared with thromboembolic and bleeding events in the warfarin + aspirin/antiplatelet versus warfarin alone. No greater risk for thromboembolism was seen in patients on NOACs compared with patients on both NOACs and aspirin/antiplatelet drug. In this nonrandomized comparison, there was initially a signal toward higher thromboembolic rates among NOAC users also on aspirin/antiplatelet drugs (relative risk, 1.16; 95% confidence intervals, 1.05, 1.29) when compared with NOAC alone. This likely reflected the higher CHADS2 scores of those on aspirin/antiplatelet drugs. When the analysis was limited to studies that included aspirin rather than other antiplatelet drugs, no difference was seen for thromboembolic rates comparing dual therapy to NOAC alone (relative risk, 1.02; 95% confidence intervals, 0.90, 1.15). Higher rates of bleeding were seen with aspirin/antiplatelet drug in conjunction with NOAC. In this meta-analysis and nonrandomized comparison of aspirin/antiplatelet users and nonusers also on anticoagulation, there was no additional benefit seen of anticoagulation and antiplatelet therapy for stroke prevention when compared with anticoagulation alone. There was, however, an increased risk of bleeding. Careful assessment of the indications for antiplatelet drugs in patients with atrial fibrillation who are also receiving oral anticoagulants is warranted, and future randomized comparisons are needed.

Background Myocardial scar is a substrate for ventricular tachycardia and sudden cardiac death. Late enhancement CT imaging can detect scar, but it remains unclear whether newer late enhancement dual-energy (LE-DECT) acquisition has benefit over standard single-energy late enhancement (LE-CT). Objective We aim to compare late enhancement CT using newer LE-DECT acquisition and single-energy LE-CT acquisitions with pathology and electroanatomic map (EAM) in an experimental chronic myocardial infarction (MI) porcine study. Methods In 8 pigs with chronic myocardial infarction (59 ± 5 kg), we performed dual-source CT, EAM, and pathology. For CT imaging, we performed 3 acquisitions at 10 minutes after contrast administration: LE-CT 80 kV, LE-CT 100 kV, and LE-DECT with 2 postprocessing software settings. Results Of the sequences, LE-CT 100 kV provided the best contrast-to-noise ratio (all P ≤ .03) and correlation to pathology for scar (ρ = 0.88). LE-DECT overestimated scar (both P = .02), whereas LE-CT images did not (both P = .08). On a segment basis (n = 136), all CT sequences had high specificity (87%–93%) and modest sensitivity (50%–67%), with LE-CT 100 kV having the highest specificity of 93% for scar detection compared to pathology and agreement with EAM (κ = 0.69). Conclusions Standard single-energy LE-CT, particularly 100 kV, matched better to pathology and EAM than dual-energy LE-DECT for scar detection. Larger human trials as well as more technical studies that optimize varying different energies with newer hardware and software are warranted.

Optimal left ventricular (LV) lead position has emerged as an important determinant of response after cardiac resynchronization therapy (CRT). Comparatively, strategy for right ventricular (RV) lead optimization remains uncertain. Three variations of RV lead position (apex, mid-septal, and high septal) were tested in seven consecutive patients. At each location, intra-procedural measurement of LV lead electrical delay (LVLED) was obtained during intrinsic rhythm and RV pacing (RV-LVLED). Simultaneous cardiac output assessment was performed using the LiDCO™ (lithium chloride indicator dilution) system. Final RV lead location was selected based on best-measured cardiac output. Clinical and echocardiographic outcomes were assessed at baseline and 6 months. Adjustment of RV lead position after securing a LV lead site led to an incremental change of 30 ± 18 % (range, 7–52 %) in the cardiac index (CI). There was substantial variation in acute hemodynamic response (∆CI, 14 ± 13 %; range, 3–41 %) seen with pacing from each patient’s worst to best RV lead position; no single RV lead position emerged as optimal across all patients. Paced RV-LVLED was not correlated with percent change in CI (r = 0.18; p = NS). LV ejection fraction (LVEF) increased significantly (28 ± 4 to 40 ± 8 %, p = 0.006) at 6 months. LVLED measured during intrinsic rhythm, but not during RV pacing, correlated with percent change in LVEF (r = 0.88, p = 0.02). RV lead position adjustment can be used to enhance acute hemodynamic response during CRT. Measurement of paced RV-LVLED, however, does not reliably predict change in cardiac output.

Electrical Delay in Apically Positioned LV Leads. Introduction: In recent studies, an anatomical apical left ventricular (LV) lead pacing location has been associated with deleterious outcome after cardiac resynchronization therapy (CRT). The differential impact of the LV lead electrical location in these patients remains unknown. Methods and Results: Thirty-one consecutive CRT patients (mean age 71.7 ± 12.7 years, 55% left bundle-branch block [LBBB] morphology) with an apical LV lead and LV lead electrical delay (LVLED) were studied. Anatomical LV lead location was determined via review of coronary venography and chest radiographs. Electrical location was assessed through intraprocedural LVLED measurement. Patients were dichotomized into either “long” LVLED (LVLED ≥ 50% of QRS) or “short” LVLED groups (LVLED < 50%). Patients in the long LVLED group demonstrated significantly greater freedom from a primary composite endpoint of all-cause death, heart failure hospitalization, and cardiac transplantation at 2 years (81% vs 30%, P = 0.007 vs short LVLED patients). Longer LVLED was also associated with more favorable LV remodeling (LV end-systolic volume –41.9 ± 10.3 mL vs –4.3 ± 17.2 mL; P = 0.05), and greater improvement in LV ejection fraction (+9.4 ± 2.9% vs +2.3 ± 7.5%; P = 0.04). Even after multivariate adjustment, LVLED remained an independent predictor of the primary composite endpoint (HR 0.47, P = 0.031). Conclusions: Electrical lead localization, as estimated by LVLED ≥ 50%, is associated with improved long-term clinical outcome and measures of LV remodeling in patients with apical LV leads. Intraprocedural LVLED assessment may provide incremental utility in targeting lead placement even in conventionally unfavorable anatomical segments. (J Cardiovasc Electrophysiol, Vol. 24, pp. 182-187, February 2013)

Patients with diabetes and heart failure (HF) have worse clinical outcomes compared to patients with HF without diabetes after cardiac resynchronization therapy (CRT). Patients with HF and diabetes represent a growing population at high risk for cardiovascular events and are increasingly treated with CRT. Although patients with diabetes and HF appear to benefit from CRT, their clinical outcomes are worse than those of patients without diabetes after CRT. The aim of this study was to identify clinical predictors that explain the differential hazard in patients with diabetes. We studied 442 patients (169 with diabetes) with systolic HF referred to the Massachusetts General Hospital CRT clinic from 2003 to 2010 to identify predictors of outcomes after CRT in patients with HF and diabetes. Patients with diabetes were more likely to have ischemic causes of HF than those without diabetes, but there was no difference in the left ventricular ejection fraction or HF classification at implantation. Patients with diabetes had poorer event-free survival (death or HF hospitalization) compared to those without diabetes (log-rank p = 0.04). The presence of diabetes was the most important independent predictor of differential outcomes in the entire population (hazard ratio 1.65, 95% confidence interval 1.10 to 2.51). Patients with diabetes receiving insulin therapy had poorer survival, whereas those not receiving insulin therapy had similar survival to patients without diabetes. Patients with peri-implantation glycosylated hemoglobin >7% had worse outcomes, whereas patients with glycosylated hemoglobin ≤7% had improved survival (hazard ratio 0.36, 95% confidence interval 0.15 to 0.86) equivalent to that of patients without diabetes. In conclusion, although the presence of diabetes, independent of other variables, increases the hazard of worse outcomes after CRT, there is additional risk conferred by insulin use and suboptimal peri-implantation glycemic control.

Background— Patients undergoing cardiac resynchronization therapy (CRT) are at high risk for ventricular arrhythmias (VAs), and risk stratification in this population remains poor. Methods and Results— This study followed 269 patients (left ventricular ejection fraction 120 ms; New York Heart Association class III/IV) undergoing CRT with a defibrillator for 553±464 days after CRT with defibrillator implantation to assess for independent predictors of appropriate device therapy for VAs. Baseline medication use, medical comorbidities, and echocardiographic parameters were considered. The 4-year incidence of appropriate device therapy was 36%. A Cox proportional hazard model identified left ventricular end-systolic diameter >61 mm as an independent predictor in the entire population (hazard ratio [HR], 2.66; P =0.001). Those with left ventricular end-systolic diameter >61 mm had a 51% 3-year incidence of VA compared with a 26% incidence among those with a less dilated ventricle ( P =0.001). Among patients with left ventricular end-systolic diameter ≤61 mm, multivariate predictors of appropriate therapy were absence of β-blocker therapy (HR, 6.34; P P P =0.013). Early (P P Conclusions— Among patients with CRT and a defibrillator, left ventricular end-systolic diameter >61 mm is a powerful predictor of VAs, and further risk stratification of those with less dilated ventricles can be achieved based on assessment of ejection fraction, history of sustained VA, and absence of β-blocker therapy.

A decade of research has established the role of cardiac resynchronization therapy (CRT) in medically refractory, moderate to severe systolic heart failure (HF) with intraventricular conduction delay. CRT is an electrical therapy instituted to reestablish ventricular synchronization in order to improve cardiac function and favorably modulate the neurohormonal system. CRT confers a mortality benefit, improved HF hospitalizations, and functional outcome in this population, but not all patients consistently demonstrate a positive CRT response. The nonresponder rate varies from 20% to 40%, depending on the defined response criteria. Efforts to improve response to CRT have focused on a number of fronts. Methods to optimize the correction of electrical and mechanical dyssynchrony, which is the primary target of CRT, has been the focus of research, in addition to improving patient selection and optimizing post-implant care. However, a major issue in dealing with improving nonresponse rates has been finding an accurate and generally accepted definition of "response" itself. The availability of a standard consensus definition of CRT response would enable the estimation of nonresponder burden accurately and permit the development of strategies to improve CRT response. In this review, we define various aspects of "response" to CRT and outline variability in the definition criteria and the problems with its inconsistencies. We describe clinical, laboratory, and pacing predictors that influence CRT response and outcome and how to optimize response.

Cardiac resynchronization therapy (CRT) nonresponders have poor outcomes. The significance of progressive ventricular dysfunction among nonresponders remains unclear.We sought to define predictors of and clinical outcomes associated with progressive ventricular dysfunction despite CRT.We conducted an analysis of 328 patients undergoing CRT with defibrillator for standard indications. On the basis of 6-month echocardiograms, we classified patients as responders (those with a ≥5% increase in ejection fraction) and progressors (those with a ≥5% decrease in ejection fraction), and all others were defined as nonprogressors. Coprimary end points were 3-year (1) heart failure, left ventricular assist device (LVAD), transplantation, or death and (2) ventricular tachycardia (VT) or ventricular fibrillation (VF).Multivariable predictors of progressive ventricular dysfunction were aldosterone antagonist use (hazard ratio [HR] 0.23; P = .008), prior valve surgery (HR 3.3; P = .005), and QRS duration (HR 0.98; P = .02). More favorable changes in ventricular function were associated with lower incidences of heart failure, LVAD, transplantation, or death (70% vs 54% vs 33%; P.0001) and VT or VF (66% vs 38% vs 28%; P = .001) for progressors, nonprogressors, and responders, respectively. After multivariable adjustment, progressors remained at increased risk of heart failure, LVAD, transplantation, or death (HR 2.14; P = .0029) and VT or VF (HR 2.03; P = .046) as compared with nonprogressors. Responders were at decreased risk of heart failure, LVAD, transplantation, or death (HR 0.44; P.0001) and VT or VF (0.51; P = .015) as compared with nonprogressors.Patients with progressive deterioration in ventricular function despite CRT represent a high-risk group of nonresponders at increased risk of worsened clinical outcomes.

Reported here is how modified oligonucleotides with increased affinity for DNA or RNA target strands can be selected from small combinatorial libraries via spectrometrically monitored selection experiments (SMOSE). The extent to which target strands retard the degradation of 5'-acyl-, 5'-aminoacyl-, and 5'-dipeptidyl-oligodeoxyribonucleotides by phosphodiesterase I (EC 3.1.4.1) was measured via quantitative MALDI-TOF mass spectrometry. Oligonucleotide hybrids were prepared on solid support, and nuclease selections were performed with up to 10 modified oligonucleotides in one solution. The mass spectrometrically monitored experiments required between 120 and 300 pmol of each modified oligonucleotide, depending on whether HPLC-purified or crude compounds were employed. Data acquisition and analysis were optimized to proceed in semiautomated fashion, and functions correcting for incomplete degradation during the monitoring time were developed. Integration of the degradation kinetics provided "protection factors" that correlate well with melting points obtained with traditional UV melting curves employing single, pure compounds. Among the components of the five libraries tested, three were found to contain 5'-substituents that strongly stabilize Watson--Crick duplexes. Selecting and optimizing modified oligonucleotides via monitored nuclease assays may offer a more efficient way to search for new antisense agents, hybridization probes, and biochemical tools.

Aims Several studies have reported a poor outcome with cardiac resynchronization therapy (CRT) in non-left bundle branch block (LBBB) patients. Although the left ventricular (LV) lead location is an important determinant of the clinical outcome, there is scant information regarding its role in non-LBBB patients. This study sought to examine the impact of electrical and anatomical location of the LV lead in relation to baseline QRS morphology on the CRT outcome. Methods and results A left ventricular lead electrical delay (LVLED) was measured intra-procedurally as an interval between QRS onset on the surface electrocardiogram (ECG) to the peak of sensed electrogram on LV lead and corrected for QRS width. The impact of the LVLED on time to first heart failure hospitalization (HFH), and composite outcome of all-cause mortality, HFH, LVAD implantation, and cardiac transplantation at 3 years was assessed. Among 144 patients (age 67 ± 12 years, QRS duration 156 ± 28 ms, non-LBBB 43%), HFH was higher in non-LBBB compared with LBBB (43.5 vs. 24%, P = 0.015). Within LBBB, patients with the long LVLED (≥50%) had 17% HFH vs. 53% in the short LVLED (

Non-operator controlled forward motion of an ablation catheter within a deflectable sheath (Mobicath, Biosense-Webster) is illustrated in Figure 1 and Supplementary material online, Video …

Both anatomic and electrical locations of the left ventricular (LV) lead have been identified as important predictors of clinical outcomes in cardiac resynchronization therapy (CRT). The impact of LV lead location on incident device-treated ventricular arrhythmia (VA), however, is not well understood.To assess the relationship between electrical and anatomic LV lead location and device treated VAs in CRT.Sixty-nine patients undergoing CRT implantation for standard indications were evaluated. Anatomic LV lead location was assessed by means of coronary venography and chest radiography and categorized as apical or nonapical. Electrical LV lead location was assessed by LV electrical delay (LVLED) and was calculated as the time between the onset of the native QRS on the surface electrocardiogram and sensed signal on the LV lead during implantation and corrected for native QRS. Incident appropriate device-treated VA was assessed via device interrogation.Apical lead placement was an independent predictor of VAs (hazard ratio 5.29; 95% confidence interval 1.69-16.5; P = .004). Among patients with a nonapical lead, LVLED50% native QRS was an independent predictor of VAs (hazard ratio 6.90; 95% confidence interval 1.53-31.1; P = .012). Those with a nonapical lead and LVLED ≥ 50% native QRS were at substantially lower risk for first incident and recurrent VAs when compared to all other patients.The apical lead position is associated with an increased risk of VAs in CRT patients. Among patients with a nonapical lead position, an LVLED of50% of the native QRS is associated with an increased risk of VAs.

Although cardiac resynchronization therapy (CRT) reduces morbidity and mortality in patients with heart failure, a significant minority of patients do not respond adequately to this therapy. The objective of this study was to examine the impact of a 'multidisciplinary care' (MC) approach on the clinical outcome in CRT patients. Methods and results The clinical outcome in patients prospectively receiving MC (n ¼ 254) was compared with a control group of patients who received conventional care (CC, n ¼ 173). The MC group was followed prospectively in an integrated clinic setting by a team of subspecialists from the heart failure, electrophysiology, and echocardiography service at 1-, 3-, and 6-months post-implant. All patients had echocardiographic-guided optimization at their 1-month visit. The pro- portional hazards model (adjusting for all covariates) and Kaplan-Meier time to first event curves were compared between the two groups, over a 2-year follow-up. The long-term outcome was measured as a combined endpoint of heart failure hospitalization, cardiac transplantation, or all-cause mortality. The clinical characteristics between the MC and CC groups at baseline were comparable (age, 68+13 vs. 69+12; NYHA III, 90 vs. 82%; ischaemic cardio- myopathy 55 vs. 64%, P ¼ NS, respectively). The event-free survival was significantly higher in the multidisciplinary vs. the CC group (P ¼ 0.0015). A significant reduction in clinical events was noted in the MC group vs. the CC group (hazard ratio: 0.62, 95% CI: 0.46-0.83, P ¼ 0.001). Conclusion Integrated MC may improve 2-year event-free survival in patients receiving cardiac resynchronization therapy. Prospective randomized studies are needed to validate our findings.

Although scar has been associated with poor outcome after CRT, the impact of coronary artery disease (CAD) severity or ischemia on CRT response remains uncertain. A prospective cohort of CRT patients with ischemic cardiomyopathy was evaluated for ischemia and scar with nuclear perfusion imaging.

To the Editor: Therapeutic hypothermia has been promoted as an effective strategy for the preservation of life and neuroprotection in unconscious survivors of out-of-hospital cardiac arrest ([1–3][1]), largely in patients age >50 years with myocardial infarction, stroke, acute encephalopathy

A substantial proportion of patients who meet the current guidelines for cardiac resynchronization therapy (CRT) fail to respond to this pacing modality. Although appropriate patient selection and left ventricular (LV) lead location have been ascribed as determinants of CRT response, the interaction among contractile reserve, dynamics of dyssynchrony, and lead location is not well understood. The present study prospectively evaluated the effect of contractile reserve and dobutamine-induced changes in LV synchrony, in relation to the LV lead location, as predictors of the response to CRT. In the present study, 31 patients were prospectively evaluated and underwent low-dose dobutamine echocardiography. The dobutamine-induced increase in ejection fraction (contractile reserve [CR]) was measured, and the most mechanically delayed segment was identified to classify patients into 2 groups. Group 1 had a CR of >20% and a LV lead position concordant with the mechanically delayed segment. Group 2 included the remaining patients (i.e., low CR, discordant LV lead position, or both). Patients in group 1 were significantly more likely to have an echocardiographic response at 6 months (80% of group 1 vs 29% of group 2, p = 0.018) and had an improved 2-year heart failure hospitalization-free survival rate (90% in group 1 vs 33% in group 2, p = 0.006). In conclusion, low-dose dobutamine echocardiography provides information that can help to predict responders to CRT. The response rates and heart failure hospitalization-free survival were improved in those patients with a CR >20% and an LV lead tip concordant with the most delayed mechanical segment.

The impact of left ventricular ejection fraction (LVEF) on outcome in patients with heart failure (HF) undergoing noncardiac surgery has not been extensively evaluated. In this study, 174 patients (mean age, 75+/-12 years, 47% male, mean LVEF (47%+/-18%) underwent intermediate- or high-risk noncardiac surgery. Patients were stratified by LVEF, and adverse perioperative complications were identified and compared. Adverse perioperative events occurred in 53 patients (30.5%), including 14 (8.1%) deaths within 30 days, 26 (14.9%) myocardial infarctions, and 44 (25.3%) HF exacerbations. Among the factors associated with adverse perioperative outcomes in the first 30 days were advanced age (80 years), diabetes, and a severely decreased LVEF (30%). Long-term mortality was high, and Cox proportional hazards analysis demonstrated that LVEF was an independent risk factor for long-term mortality.

Background: One-third of patients who receive cardiac resynchronization therapy (CRT) are classified as nonresponders. Characteristics of responders to CRT have been studied in multiple clinical trials. Hypothesis: Independent predictors of CRT response may be identified by studying a series of patients in routine clinical practice. Method: One hundred twenty-five patients were examined retrospectively from a multidisciplinary CRT clinic program. Echocardiographic CRT response was defined as a decrease in left ventricular (LV) end-systolic volume of ≥15% and/or absolute increase of 5% in LV ejection fraction at the 6-month visit. Results: There were 81 responders and 44 nonresponders. By univariate analyses, female sex, nonischemic cardiomyopathy etiology, baseline QRS duration, the presence of left bundle branch block (LBBB), and left ventricular end-diastolic volume (LVEDV) index predicted CRT response. However, multivariate analysis demonstrated that only QRS duration, LBBB, and LVEDV index were independent predictors (QRS width, odds ratio [OR]: 1.027, 95% confidence interval [CI]: 1.004–1.050, P = 0.023; LBBB, OR: 3.568, 95% CI: 1.284–9.910, P = 0.015; LVEDV index, OR: 0.970, 95% CI: 0.953–0.987, P = 0.001). Although female sex and nonischemic etiology were associated with an improved CRT response on univariate analyses, after adjusting for LV volumes they were not independent predictors. Conclusions: QRS width, LBBB, and LVEDV index are independent predictors for echocardiographic CRT response. Previously reported differences in CRT response for sex and cardiomyopathy etiology are associated with differences in baseline LV volumes in our clinical practice. Dr. Heist has received research grants (modest) from Biotronik, Boston Scientific, and St. Jude Medical; honoraria (modest) from Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical; and consultant/advisory board positions (modest) from Boston Scientific, Sorin and St. Jude Medical. Dr. Singh has received research grants (significant) from Biotronik, Boston Scientific, Medtronic, and St. Jude Medical; and consultant/advisory board positions (modest) from Biosense Webster, Biotronik, Boston Scientific, CardioInsight, Medtronic, Sorin, St. Jude Medical, and Thoratec Inc. The statistical analysis was conducted with support from Harvard Catalyst. The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 RR 025758, and financial contributions from Harvard University and its affiliated academic healthcare centers). The authors have no other funding, financial relationships, or conflicts of interest to disclose.

With the increasing use of novel oral anticoagulants (NOAC), patients are often on both NOACs (apixaban, rivaroxaban and dabigatran) and antiplatelet therapy (aspirin or clopidogrel). However, it remains unclear how the addition of antiplatelet therapy to NOACs impacts stroke prevention and bleeding