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Adolescent military-dependents are an understudied population who face unique stressors due to their parents’ careers. Research suggests tat adolescent military-dependents report more anxiety and disordered-eating than their civilian counterparts. While anxiety symptoms predict the onset and worsening of disordered-eating attitudes, the mechanisms underlying this relationship remain unclear. One factor that may underlie this relationship, and be particularly relevant for military-dependent youth, is coping. Therefore, we examined adolescent military-dependents (N = 136; 14.5 ± 1.5 years; 59.6% female; BMI-z: 1.9 ± 0.4) who were at-risk for adult obesity and binge-eating disorder due to an age- and sex-adjusted BMI ≥ 85(th) percentile and loss-of-control eating and/or elevated anxiety. Participants completed an interview assessing disordered-eating attitudes and questionnaires on anxiety symptoms and coping strategies at a single time point. Bootstrapping models were conducted to examine the indirect paths between anxiety symptoms and disordered-eating attitudes through five coping subscales (aggression, distraction, endurance, self-distraction, and stress-recognition). Adjusting for relevant covariates, no significant indirect paths through the coping subscales (ps > .05) were found in any models. General coping, nonspecific to eating, may not be a pathway between anxiety symptoms and disordered-eating attitudes among adolescents. Future research should examine other potential mediators of this relationship.Abbreviations: BMI-z, BMI standard deviation score, adjusted for age and sex; LECI-C, Life Events and Coping Inventory – Coping

PURPOSE: Evidence suggests that difficulties identifying and describing one’s feelings, core components of alexithymia, are positively associated with attitudinal and behavioral symptoms of disordered eating; depressive symptoms also may underlie these associations. Specifically, research indicates that alexithymia is positively related to depressive symptoms, which in turn may promote both disordered-eating attitudes and certain disinhibited eating behaviors (e.g., emotional eating). Findings also suggest that military dependent youth with high weight may exhibit elevated depressive symptoms and disordered eating. As such, understanding associations among alexithymia, depressive symptoms, and disordered eating is particularly relevant for this vulnerable population. METHODS: We examined 149 adolescent military dependents (14.4±1.6y; 55.0% female; 20.0% non-Hispanic Black; BMIz: 1.9±0.4) at high-risk for binge-eating disorder and obesity in adulthood. Participants completed questionnaires assessing two components of alexithymia (difficulty identifying feelings [DIF] and difficulty describing feelings [DDF]), depressive symptoms, emotional eating, and trait anxiety; disordered-eating attitudes were assessed via semi-structured interview. RESULTS: A series of regression-based models examined indirect relationships of DIF and DDF with disordered-eating attitudes and emotional eating through depressive symptoms. Bootstrapped 95% confidence intervals revealed a significant indirect path from each of the alexithymia components to disordered-eating attitudes via depressive symptoms; indirect paths to emotional eating were non-significant. CONCLUSION: Results support the salience of depressive symptoms in the relationship between alexithymia and disordered-eating attitudes. Future research should utilize prospective designs and explore direct and indirect associations of alexithymia with other disordered-eating behaviors. LEVEL OF EVIDENCE: Level III, evidence obtained from a well-designed cohort study.

Whether to repair nonsevere tricuspid regurgitation (TR) during surgery for ischemic mitral valve regurgitation (IMR) remains uncertain.The goal of this study was to investigate the incidence, predictors, and clinical significance of TR progression and presence of ≥moderate TR after IMR surgery.Patients (n = 492) with untreated nonsevere TR within 2 prospectively randomized IMR trials were included. Key outcomes were TR progression (either progression by ≥2 grades, surgery for TR, or severe TR at 2 years) and presence of ≥moderate TR at 2 years.Patients' mean age was 66 ± 10 years (67% male), and TR distribution was 60% ≤trace, 31% mild, and 9% moderate. Among 2-year survivors, TR progression occurred in 20 (6%) of 325 patients. Baseline tricuspid annular diameter (TAD) was not predictive of TR progression. At 2 years, 37 (11%) of 323 patients had ≥moderate TR. Baseline TR grade, indexed TAD, and surgical ablation for atrial fibrillation were independent predictors of ≥moderate TR. However, TAD alone had poor discrimination (area under the curve, ≤0.65). Presence of ≥moderate TR at 2 years was higher in patients with MR recurrence (20% vs. 9%; p = 0.02) and a permanent pacemaker/defibrillator (19% vs. 9%; p = 0.01). Clinical event rates (composite of ≥1 New York Heart Association functional class increase, heart failure hospitalization, mitral valve surgery, and stroke) were higher in patients with TR progression (55% vs. 23%; p = 0.003) and ≥moderate TR at 2 years (38% vs. 22%; p = 0.04).After IMR surgery, progression of unrepaired nonsevere TR is uncommon. Baseline TAD is not predictive of TR progression and is poorly discriminative of ≥moderate TR at 2 years. TR progression and presence of ≥moderate TR are associated with clinical events. (Comparing the Effectiveness of a Mitral Valve Repair Procedure in Combination With Coronary Artery Bypass Grafting [CABG] Versus CABG Alone in People With Moderate Ischemic Mitral Regurgitation, NCT00806988; Comparing the Effectiveness of Repairing Versus Replacing the Heart's Mitral Valve in People With Severe Chronic Ischemic Mitral Regurgitation, NCT00807040).

The effects of stroke and delirium on postdischarge cognition and patient-centered health outcomes after surgical aortic valve replacement (SAVR) are not well characterized. Here, we assess the impact of postoperative stroke and delirium on these health outcomes in SAVR patients at 90 days.Patients (N = 383) undergoing SAVR (41% received concomitant coronary artery bypass graft) enrolled in a randomized trial of embolic protection devices underwent serial neurologic and delirium evaluations at postoperative days 1, 3, and 7 and magnetic resonance imaging at day 7. Outcomes included 90-day functional status, neurocognitive decline from presurgical baseline, and quality of life.By postoperative day 7, 25 (6.6%) patients experienced clinical stroke and 103 (28.5%) manifested delirium. During index hospitalization, time to discharge was longer in patients experiencing stroke (hazard ratio, 0.62; 95% confidence interval [CI], 0.42-0.94; P = .02) and patients experiencing delirium (hazard ratio, 0.68; 95% CI, 0.54-0.86; P = .001). At day 90, patients experiencing stroke were more likely to have a modified Rankin score2 (odds ratio [OR], 5.9; 95% CI, 1.7-20.1; P = .01), depression (OR, 5.3; 95% CI, 1.6-17.3; P = .006), a lower 12-Item Short Form Survey physical health score (adjusted mean difference -3.3 ± 1.9; P = .08), and neurocognitive decline (OR, 7.8; 95% CI, 2.3-26.4; P = .001). Delirium was associated with depression (OR, 2.2; 95% CI, 0.9-5.3; P = .08), lower 12-Item Short Form Survey physical health (adjusted mean difference -2.3 ± 1.1; P = .03), and neurocognitive decline (OR, 2.2; 95% CI, 1.2-4.0; P = .01).Stroke and delirium occur more frequently after SAVR than is commonly recognized, and these events are associated with disability, depression, cognitive decline, and poorer quality of life at 90 days postoperatively. These findings support the need for new interventions to reduce these events and improve patient-centered outcomes.

Objectives Adolescent military-dependents experience distinct risk and protective factors, which may necessitate additional clinical considerations. In civilian youth, overweight/obesity is associated with eating, internalizing, and externalizing difficulties, with some studies reporting more difficulties among non-Hispanic White (vs. non-Hispanic Black) youth. It is unknown if these disparities exist among adolescent military-dependents, or between civilian and military-dependent youth. Methods Non-Hispanic Black (187 civilian, 38 military-dependent) and non-Hispanic White (205 civilian, 84 military-dependent) adolescents with overweight/obesity (14.7 ± 1.6 years; 73.9% girls; body mass index adjusted for age and sex 1.9 ± 0.5) completed a disordered-eating interview; parents completed a measure assessing their child’s internalizing and externalizing difficulties. Multiple linear regressions examined parental military-status as a moderator of the relationship of participant race with eating, internalizing, and externalizing difficulties. Results White civilian youth with overweight/obesity reported significantly greater disordered-eating than their Black peers (p < .001); there were no other significant racial differences. In all regressions, parental military-status significantly moderated the association between race and each dependent variable (ps < .047). Black military-dependents (vs. civilians) reported more disordered-eating and internalizing difficulties (ps = .01). White military-dependents (vs. civilians) reported fewer externalizing difficulties (p = .01). Conclusions Black adolescent military-dependents with overweight/obesity may experience more eating and internalizing difficulties (vs. civilians), a pattern not observed among White participants. Future work should examine if being a military-dependent and a historically marginalized racial group member accounts for these findings. Such data may inform providers of youth with intersecting minority identities.

Introduction. Atrial Fibrillation and Atrial Flutter (AF/AFL), the most common atrial arrhythmias, have never been examined in combat casualties. In this study, we investigated the impact of traumatic injury on AF/AFL among service members with deployment history. Methods. Sampled from the Department of Defense (DoD) Trauma Registry (n=10,000), each injured patient in this retrospective cohort study was matched with a non-injured service member drawn from the Veterans Affairs/DoD Identity Repository. The primary outcome was AF/AFL diagnosis identified using ICD-9-CM and ICD-10-CM codes. Competing risk regressions based on Fine and Gray subdistribution hazards model with were utilized to assess the association between injury and AF/AFL. Results. There were 130 reported AF/AFL cases, 90 of whom were injured and 40 were non-injured. The estimated cumulative incidence rates of AF/AFL for injured was higher compared to non-injured patients (HR = 2.04; 95% CI = 1.44, 2.87). After adjustment demographics and tobacco use, the association did not appreciably decrease (HR = 1.90; 95% CI = 1.23, 2.93). Additional adjustment for obesity, hypertension, diabetes, and vascular disorders, the association between injury and AF/AFL was no longer statistically significant (HR: 1.51; 95% CI = 0.99, 2.52). Conclusion. Higher AF/AFL incidence rate was observed among deployed service members with combat injury compared to servicemembers without injury. The association did not remain significant after adjustment for cardiovascular-related covariates. These findings highlight the need for combat casualties surveillance to further understand the AF/AFL risk within the military population and to elucidate the potential underlying pathophysiologic mechanisms.

Background Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain a challenging problem in patients with implantable cardioverter-defibrillators (ICDs). Objectives This study aimed to determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD. Methods This was double-blind, placebo-controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized to 1,000 mg ranolazine twice a day or placebo. The primary endpoint was VT or VF requiring appropriate ICD therapy or death, whichever occurred first. Pre-specified secondary endpoints included ICD shock for VT, VF, or death and recurrent VT or VF requiring ICD therapy. Results Among 1,012 ICD patients (510 randomized to ranolazine and 502 to placebo) the mean age was 64 ± 10 years and 18% were women. During 28 ± 16 months of follow-up there were 372 (37%) patients with primary endpoint, 270 (27%) patients with VT or VF, and 148 (15%) deaths. The blinded study drug was discontinued in 199 (39.6%) patients receiving placebo and in 253 (49.6%) patients receiving ranolazine (p = 0.001). The hazard ratio for ranolazine versus placebo was 0.84 (95% confidence interval: 0.67 to 1.05; p = 0.117) for VT, VF, or death. In a pre-specified secondary analysis, patients randomized to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51 to 0.96; p = 0.028). There were no other significant treatment effects in other pre-specified secondary analyses, which included individual components of the primary endpoint, inappropriate shocks, cardiac hospitalizations, and quality of life. Conclusions In high-risk ICD patients, treatment with ranolazine did not significantly reduce the incidence of the first VT or VF, or death. However, the study was underpowered to detect a difference in the primary endpoint. In prespecified secondary endpoint analyses, ranolazine administration was associated with a significant reduction in recurrent VT or VF requiring ICD therapy without evidence for increased mortality. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253)

To determine the frequency and risk factors for non-home discharge (NHD) and its association with clinical outcomes and quality of life (QOL) at 1 year following cardiac surgery in patients with ischemic mitral regurgitation (IMR).Discharge disposition was evaluated in 552 patients enrolled in trials of severe or moderate IMR. Patient and in-hospital factors associated with NHD were identified using logistic regression. Subsequently, association of NHD with 1-year mortality, serious adverse events (SAEs), and QOL was assessed.NHD was observed in 30% (154/522) with 25% (n = 71/289) in moderate and 36% (n = 83/233) in patients with severe IMR (unadjusted P = .006), a difference not significant after including age (5-year change: adjusted odds ratio [adjOR], 1.52; 95% confidence interval [CI], 1.35-1.72; P .001), diabetes (adjOR, 1.94; 95% CI, 1.27-2.94; P = .002), and previous heart failure (adjOR, 1.64; 95% CI, 1.06-2.52; P = .03). Odds of NHD were increased for patients with postoperative SAEs (adjOR, 1.85; 95% CI, 1.19-2.86; P = .01) but not based on type of cardiac surgery. Greater rates of death and SAEs were observed in NHD patients at 1 year: adjusted hazard ratio, 4.29 (95% CI, 2.14-8.59; P .001) and adjusted rate ratio, 1.45 (95% CI, 1.03-2.02; P = .03), respectively. QOL did not differ significantly between groups.NHD is common following surgery for IMR, influenced by older age, diabetes, previous heart failure, and postoperative SAEs. These patients may be at greater risk of death and subsequent SAEs after discharge. Discussion of NHD with patients may have important implications for decision-making and guiding expectations following cardiac surgery.

Objective The Cardiothoracic Surgical Trials Network reported that left ventricular reverse remodeling at 2 years did not differ between patients with moderate ischemic mitral regurgitation randomized to coronary artery bypass grafting plus mitral valve repair (n = 150) or coronary artery bypass grafting alone (n = 151). To address health resource use implications, we compared costs and quality-adjusted survival. Methods We used individual patient data from the Cardiothoracic Surgical Trials Network trial on survival, hospitalizations, quality of life, and US hospitalization costs to estimate cumulative costs and quality-adjusted life years. A microsimulation model was developed to extrapolate to 10 years. Bootstrap and deterministic sensitivity analyses were performed to address uncertainty. Results In-hospital costs were $59,745 for coronary artery bypass grafting plus mitral valve repair versus $51,326 for coronary artery bypass grafting alone (difference $8419; 95% uncertainty interval, 2259-18,757). Two-year costs were $81,263 versus $67,341 (difference 13,922 [2370 to 28,888]), and quality-adjusted life years were 1.35 versus 1.30 (difference 0.05; −0.04 to 0.14), resulting in an incremental cost-effectiveness ratio of $308,343/quality-adjusted life year for coronary artery bypass grafting plus mitral valve repair. At 10 years, its costs remained higher ($107,733 vs $88,583, difference 19,150 [−3866 to 56,826]) and quality-adjusted life years showed no difference (−0.92 to 0.87), with 5.08 versus 5.08. The likelihood that coronary artery bypass grafting plus mitral valve repair would be considered cost-effective at 10 years based on a cost-effectiveness threshold of $100K/quality-adjusted life year did not exceed 37%. Only when this procedure reduces the death rate by a relative 5% will the incremental cost-effectiveness ratio fall below $100K/quality-adjusted life year. Conclusions: The addition of mitral valve repair to coronary artery bypass grafting for patients with moderate ischemic mitral regurgitation is unlikely to be cost-effective. Only if late mortality benefits can be demonstrated will it meet commonly used cost-effectiveness criteria.

The aim of this study was to determine the in vitro electrophysiological properties of loperamide. The authors' hypothesis was that loperamide is a potent blocker of the current carried by the human ether-à-go-go-related gene (hERG) potassium channel.Loperamide is a peripherally-acting μ-opioid agonist available worldwide as an over-the-counter treatment for diarrhea. Like most opioids, it is not currently known to be proarrhythmic. Recent cases of torsade de pointes in association with high-dose loperamide raise concern given its structural similarity to methadone, another synthetic opioid with an established arrhythmia risk.Effects of loperamide on blockade of the hERG potassium channel ion current were assessed in Chinese Hamster Ovary (CHO) cells stably expressing hERG to elucidate current amplitude and kinetics. The concentration required to produce 50% inhibition of hERG current was assessed from the amplitude of tail currents and the impact on action potential duration was assessed in isolated swine ventricular cardiomyocytes.The 50% inhibitory concentration for loperamide inhibition of hERG ionic tail currents was approximately 40 nmol/l. In current-voltage measurements, loperamide reduced steady and tail currents and shifted the current activation to more negative potentials. Loperamide (10 nmol/l) also increased the action potential duration, assessed at 90% of repolarization, in ventricular myocytes by 16.4 ± 1.7% (n = 6; p 0.004). The maximum rate of rise of phase 0 of the action potential, however, was not significantly altered at any tested concentration of loperamide.Loperamide is a potent hERG channel blocker. It significantly prolongs the action potential duration and suggests a causal association between loperamide and recent clinical cases of torsade de pointes.

Cardiomyocytes can be differentiated from human pluripotent stem cells (hPSCs) in defined conditions, but efficient and consistent cardiomyocyte differentiation often requires expensive reagents such as B27 supplement or recombinant albumin. Using a chemically defined albumin-free (E8 basal) medium, we identified heparin as a novel factor that significantly promotes cardiomyocyte differentiation efficiency, and developed an efficient method to differentiate hPSCs into cardiomyocytes. The treatment with heparin helped cardiomyocyte differentiation consistently reach at least 80% purity (up to 95%) from more than 10 different hPSC lines in chemically defined Dulbecco's modified Eagle's medium/F-12-based medium on either Matrigel or defined matrices like vitronectin and Synthemax. One of heparin's main functions was to act as a Wnt modulator that helped promote robust and consistent cardiomyocyte production. Our study provides an efficient, reliable, and cost-effective method for cardiomyocyte derivation from hPSCs that can be used for potential large-scale drug screening, disease modeling, and future cellular therapies.

Background The incidence of permanent pacemaker (PPM) implantation is higher following mitral valve surgery (MVS) with ablation for atrial fibrillation (AF) compared with MVS alone. Objectives This study identified risk factors and outcomes associated with PPM implantation in a randomized trial that evaluated ablation for AF in patients who underwent MVS. Methods A total of 243 patients with AF and without previous PPM placement were randomly assigned to MVS alone (n = 117) or MVS + ablation (n = 126). Patients in the ablation group were further randomized to pulmonary vein isolation (PVI) (n = 62) or the biatrial maze procedure (n = 64). Using competing risk models, this study examined the association among PPM and baseline and operative risk factors, and the effect of PPM on time to discharge, readmissions, and 1-year mortality. Results Thirty-five patients received a PPM within the first year (14.4%), 29 (83%) underwent implantation during the index hospitalization. The frequency of PPM implantation was 7.7% in patients randomized to MVS alone, 16.1% in MVS + PVI, and 25% in MVS + biatrial maze. The indications for PPM were similar among patients who underwent MVS with and without ablation. Ablation, multivalve surgery, and New York Heart Association functional (NYHA) functional class III/IV were independent risk factors for PPM implantation. Length of stay post-surgery was longer in patients who received PPMs, but it was not significant when adjusted for randomization assignment (MVS vs. ablation) and age (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.61 to 1.08; p = 0.14). PPM implantation did not increase 30-day readmission rate (HR: 1.43; 95% CI: 0.50 to 4.05; p = 0.50). The need for PPM was associated with a higher risk of 1-year mortality (HR: 3.21; 95% CI: 1.01 to 10.17; p = 0.05) after adjustment for randomization assignment, age, and NYHA functional class. Conclusions AF ablation, multivalve surgery, and NYHA functional class III/IV were associated with an increased risk for permanent pacing. PPM implantation following MVS was associated with a significant increase in 1-year mortality. (Surgical Ablation Versus No Surgical Ablation for Patients With Atrial Fibrillation Undergoing Mitral Valve Surgery; NCT00903370)

Aim To assess the relative frequency of reporting of adverse events involving ventricular arrhythmia, cardiac arrest, QTc prolongation, or torsade de pointes to the US Food and Drug Administration (FDA) between buprenorphine and methadone.

[Figure][1] The Heart Research Follow-up Program at the University of Rochester Medical Center has an ongoing record of successfully carrying out large-scale clinical cardiovascular studies and randomized clinical trials for >35 years, and nearly all of the original executive committee

OBJECTIVE: To analyze patient risk factors and processes of care associated with secondary surgical site infection (SSI) after coronary artery bypass grafting (CABG). METHODS: Data were collected prospectively between February and October 2010 for consenting adult patients undergoing CABG with saphenous vein graft (SVG) conduits. Patients who developed a deep or superficial SSI of the leg or groin within 65 days of CABG were compared to those who did not develop a secondary SSI. RESULTS: Among 2,174 patients identified, 65 (3.0%) developed a secondary SSI. Median time to diagnosis was 16 days (interquartile range [IQR]: 11 - 29) with the majority (86%) diagnosed after discharge. Gram-positive bacteria were most common. Readmission was more common in patients with a secondary SSI (34% vs 17%, p < 0.01). After adjustment, an open SVG harvest approach was associated with an increased risk of secondary SSI (adjusted hazard ratio [HR]: 2.12, 95% confidence interval [CI]: 1.28, 3.48). Increased body mass index (BMI) (adjusted HR: 1.08, 95% CI: 1.04, 1.12) and packed red blood cell (PRBC) transfusions (adjusted HR: 1.13, 95% CI: 1.05, 1.22) were associated with a higher risk of secondary SSI. Antibiotic type, antibiotic duration, and post-operative hyperglycemia were not associated with risk of secondary SSI. CONCLUSIONS: Secondary SSI following CABG continues to be an important source of morbidity. This serious complication often occurs after discharge and is associated with open SVG harvesting, larger BMI, and blood transfusions. Patients with a secondary SSI have longer lengths of stay and are readmitted more frequently.

Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain a challenging problem in patients with implantable cardioverter-defibrillators (ICDs).This study aimed to determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD.This was double-blind, placebo-controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized to 1,000 mg ranolazine twice a day or placebo. The primary endpoint was VT or VF requiring appropriate ICD therapy or death, whichever occurred first. Pre-specified secondary endpoints included ICD shock for VT, VF, or death and recurrent VT or VF requiring ICD therapy.Among 1,012 ICD patients (510 randomized to ranolazine and 502 to placebo) the mean age was 64 ± 10 years and 18% were women. During 28 ± 16 months of follow-up there were 372 (37%) patients with primary endpoint, 270 (27%) patients with VT or VF, and 148 (15%) deaths. The blinded study drug was discontinued in 199 (39.6%) patients receiving placebo and in 253 (49.6%) patients receiving ranolazine (p = 0.001). The hazard ratio for ranolazine versus placebo was 0.84 (95% confidence interval: 0.67 to 1.05; p = 0.117) for VT, VF, or death. In a pre-specified secondary analysis, patients randomized to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51 to 0.96; p = 0.028). There were no other significant treatment effects in other pre-specified secondary analyses, which included individual components of the primary endpoint, inappropriate shocks, cardiac hospitalizations, and quality of life.In high-risk ICD patients, treatment with ranolazine did not significantly reduce the incidence of the first VT or VF, or death. However, the study was underpowered to detect a difference in the primary endpoint. In prespecified secondary endpoint analyses, ranolazine administration was associated with a significant reduction in recurrent VT or VF requiring ICD therapy without evidence for increased mortality. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253).

Breathing is a critical component of cardiopulmonary function, but few tools exist to evaluate respiration in ambulatory patients. Holter monitoring allows accurate diagnosis of a host of cardiac issues, and several investigators have demonstrated the ability to detect respiratory effort on the electrocardiogram. In this study we introduce a myogram signal derived from 12-lead, high frequency Holter as a means of detecting respiratory effort. Using the combined myogram and ECG signal, four novel variables were created: total number of Cheyne-Stokes episodes; the BWRatio, the ratio of power (above baseline) measured one second after peak-to-peak respiratory power, an assessment of the "shape" of the respiratory effort; DRR, the change in RR interval centering around peak inspiration; and minutes of synchronized breathing, a fixed ratio of heart beats to respiratory cycles. These variables were assessed in 24-hour recordings from three cohorts: healthy volunteers (n=33), heart failure subjects from the GISSI HF trial (n=383), and subjects receiving implantable defibrillators with severely depressed left ventricular function enrolled in the M2Risk trial (n=470). We observed a statistically significant 6-fold increase in the number of Cheyne-Stokes episodes (p=0.01 by ANOVA), decreases in BWRatio (p0.001), as well as decrease in DRR in heart failure subjects; only minutes of synchronized breathing was not significantly decreased in heart failure. This study provides "proof of concept" that novel variables incorporating Holter-derived respiration can distinguish healthy subjects from heart failure. The utility of these variables for predicting heart failure, arrhythmia, and death risk in prospective studies needs to be assessed.

Background Electrocardiogram (ECG) with preparticipation evaluation (PPE) for athletes remains controversial in the United States and diagnostic accuracy of clinician ECG interpretation is unclear. This study aimed to assess reliability and validity of clinician ECG interpretation using expert-validated ECGs according to the 2010 European Society of Cardiology (ESC) interpretation criteria. Methods This is a blinded, prospective study of diagnostic accuracy of clinician ECG interpretation. Anonymized ECGs were validated for normal and abnormal patterns by blinded expert interpreters according to the ESC interpretation criteria from October 2011 through March 2012. Six pairs of clinician interpreters were recruited from relevant clinical specialties in an academic medical center in March 2012. Each clinician interpreted 85 ECGs according to the ESC interpretation guidelines. Cohen and Fleiss’ kappa, sensitivity, and specificity were calculated within specialties and across primary care and cardiology specialty groups. Results Experts interpreted 189 ECGs yielding a kappa of 0.63, demonstrating “substantial” inter-rater agreement. A total of 85 validated ECGs, including 26 abnormals, were selected for clinician interpretation. The kappa across cardiology specialists was “substantial” and “moderate” across primary care (0.69 vs 0.52, respectively, P < 0.001). Sensitivity and specificity to detect abnormal patterns were similar between cardiology and primary care groups (sensitivity 93.3% vs 81.3%, respectively, P = 0.31; specificity 88.8% vs 89.8%, respectively, P = 0.91). Conclusions Clinician ECG interpretation according to the ESC interpretation criteria appears to demonstrate limited reliability and validity. Before widespread adoption of ECG for PPE of U.S. athletes, further research of training focused on improved reliability and validity of clinician ECG interpretation is warranted.

Background The failing heart exhibits an increased arrhythmia susceptibility that is often attributed to action potential (AP) prolongation due to significant ion channel remodeling. The inwardly rectifying K + current (I K1 ) has been reported to be reduced, but its contribution to shaping the AP waveform and cell excitability in the failing heart remains unclear. Objective The purpose of this study was to define the effect of I K1 suppression on the cardiac AP and excitability in the normal and failing hearts. Methods We used electrophysiological and pharmacological approaches to investigate I K1 function in a swine tachy-pacing model of heart failure (HF). Results Terminal repolarization of the AP (TRAP; the time constant of the exponential fit to terminal repolarization) was markedly prolonged in both myocytes and arterially perfused wedges from animals with HF. TRAP was increased by 54.1% in HF myocytes ( P P = .014). The increase in TRAP was recapitulated by the potent and specific I K1 inhibitor, PA-6 (pentamidine analog 6), indicating that I K1 is the primary determinant of the final phase of repolarization. Moreover, we find that I K1 suppression reduced the ratio of effective refractory period to AP duration at 90% of repolarization, permitting re-excitation before full repolarization, reduction of AP upstroke velocity, and likely promotion of slow conduction. Conclusion Using an objective measure of terminal repolarization, we conclude that I K1 is the major determinant of the terminal repolarization time course. Moreover, suppression of I K1 prolongs repolarization and reduces postrepolarization refractoriness without marked effects on the overall AP duration. Collectively, these findings demonstrate how I K1 suppression may contribute to arrhythmogenesis in the failing heart.

Objective To use novel statistical methods for analyzing the effect of lesion set on (long-standing) persistent atrial fibrillation (AF) in the Cardiothoracic Surgical Trials Network trial of surgical ablation during mitral valve surgery (MVS). Methods Two hundred sixty such patients were randomized to MVS + surgical ablation or MVS alone. Ablation was randomized between pulmonary vein isolation and biatrial maze. During 12 months postsurgery, 228 patients (88%) submitted 7949 transtelephonic monitoring (TTM) recordings, analyzed for AF, atrial flutter (AFL), or atrial tachycardia (AT). As previously reported, more ablation than MVS-alone patients were free of AF or AF/AFL at 6 and 12 months (63% vs 29%; P Results Estimated freedom from AF/AFL/AT on any transmission trended higher after biatrial maze than pulmonary vein isolation (odds ratio, 2.31; 95% confidence interval, 0.95-5.65; P = .07) 3 to 12 months postsurgery; estimated AF/AFL/AT load (ie, proportion of TTM strips recording AF/AFL/AT) was similar (odds ratio, 0.90; 95% confidence interval, 0.57-1.43; P = .6). Within 12 months, estimated prevalence of AF/AFL/AT by TTM was 58% after MVS alone, and 36% versus 23% after pulmonary vein isolation versus biatrial maze (P Conclusions Statistical modeling using TTM recordings after MVS in patients with (long-standing) persistent AF suggests that a biatrial maze is associated with lower AF/AFL/AT prevalence, but not a lower load, compared with pulmonary vein isolation. The discrepancy between AF/AFL/AT prevalence assessed at 2 time points by Holter monitoring versus weekly TTM suggests the need for a confirmatory trial, reassessment of definitions for failure after ablation, and validation of statistical methods for assessing atrial rhythms longitudinally.

Histone deacetylase inhibitors (HDIs) are under investigation for the treatment of a number of human health problems. HDIs have proven therapeutic value in refractory cases of cutaneous T-cell lymphoma,. Electrocardiographic ST segment morphological changes associated with HDIs were observed during development. Because ST segment morphology is typically linked to changes in ATP sensitive potassium (KATP) channel activity, we tested the hypothesis that HDIs affect cardiac KATP channel subunit expression. Two different HDIs, romidepsin and trichostatin A, caused ~20 fold increase in SUR2 (Abcc9) subunit mRNA expression in HL-1 cardiomyocytes. The effect was specific for the SUR2 subunit as neither compound causes a marked change in SUR1 (Abcc8) expression. Moreover, the effect was cell specific as neither HDI markedly altered KATP subunit expression in MIN6 pancreatic β-cells. We observe significant enrichment of the H3K9Ac histone mark specifically at the SUR2 promoter consistent with the conclusion that chromatin remodeling at this locus plays a role in increasing SUR2 gene expression. Unexpectedly, however, we also discovered that HDI-dependent depletion of cellular cholesterol is required for the observed effects on SUR2 expression. Taken together, the data in the present study demonstrate that KATP subunit expression can be epigenetically regulated in cardiomyocytes, defines a role for cholesterol homeostasis in mediating epigenetic regulation and suggests a potential molecular basis for the cardiac effects of the HDIs.

BACKGROUND: Electrocardiogram (ECG) with preparticipation evaluation (PPE) for athletes remains controversial in the United States and diagnostic accuracy of clinician ECG interpretation is unclear. This study aimed to assess reliability and validity of clinician ECG interpretation using expert‐validated ECGs according to the 2010 European Society of Cardiology (ESC) interpretation criteria. METHODS: This is a blinded, prospective study of diagnostic accuracy of clinician ECG interpretation. Anonymized ECGs were validated for normal and abnormal patterns by blinded expert interpreters according to the ESC interpretation criteria from October 2011 through March 2012. Six pairs of clinician interpreters were recruited from relevant clinical specialties in an academic medical center in March 2012. Each clinician interpreted 85 ECGs according to the ESC interpretation guidelines. Cohen and Fleiss’ kappa, sensitivity, and specificity were calculated within specialties and across primary care and cardiology specialty groups. RESULTS: Experts interpreted 189 ECGs yielding a kappa of 0.63, demonstrating “substantial” inter‐rater agreement. A total of 85 validated ECGs, including 26 abnormals, were selected for clinician interpretation. The kappa across cardiology specialists was “substantial” and “moderate” across primary care (0.69 vs 0.52, respectively, P < 0.001). Sensitivity and specificity to detect abnormal patterns were similar between cardiology and primary care groups (sensitivity 93.3% vs 81.3%, respectively, P = 0.31; specificity 88.8% vs 89.8%, respectively, P = 0.91). CONCLUSIONS: Clinician ECG interpretation according to the ESC interpretation criteria appears to demonstrate limited reliability and validity. Before widespread adoption of ECG for PPE of U.S. athletes, further research of training focused on improved reliability and validity of clinician ECG interpretation is warranted.

Hospitalization for worsening heart failure (HF) is known to increase mortality and morbidity risk and has been frequently used as an endpoint in randomized clinical trials. Whether outpatient management of HF exacerbation carries similar prognostic and therapeutic information is less well known, but could be important for the design of trials that use HF hospitalization as an endpoint.MADIT-CRT randomized patients with mild HF symptoms to resynchronization therapy vs. control with an average follow-up of 3.3 years and a total of 191 deaths. HF events were centrally adjudicated for receiving i.v. decongestive therapy in an outpatient setting, or an augmented HF regimen during a hospital stay. Patients were compared according to whether their first HF was an out- or inpatient event. The first primary event was non-fatal outpatient HF, non-fatal inpatient HF, and death in 52, 331, and 78 patients, respectively. Patients with inpatient HF tended to be older and more likely to have HF of ischaemic aetiology than subjects who developed outpatient HF events. The risk of death following either type of non-fatal HF events was extremely high [hazard ratio (HR) 12.4, 95% confidence interval (CI) 9.1-16.9 for inpatient HF; HR 10.7, 95% CI 6.1-18.7 for outpatient HF] compared with subjects without non-fatal HF events. Allocation to CRT-D was associated with significant reduction in both types of HF.Outpatient management of worsening HF portends a high risk of death, similar to inpatient HF events, and may be equally sensitive to the effects of therapy. These findings suggest that outpatient HF events should be considered in publicly reported outcomes measures and future HF clinical trials.NCT01294449.

The QT Variability Index (QTVI) is a non-invasive measure of repolarization lability that has been applied to a wide variety of subjects with cardiovascular disease. It is a ratio of normalized QT variability to normalized heart rate variability, and therefore includes an assessment of autonomic nervous system tone. The approach assesses beat-to-beat variability in the duration of the QT and U wave in conventional surface electrocardiographic recordings, as well as determines the heart rate variability (HRV) from the same recording. As opposed to T wave alternans, QTVI assesses variance in repolarization at all frequencies. Nineteen studies have published data on QTVI in healthy individuals, while 20 have evaluated its performance in cohorts with cardiovascular disease. Six studies have assessed the utility of QTVI in predicting VT/VF, cardiac arrest, or cardiovascular death. A prospective study utilizing QTVI to determine therapy allocation has not been performed, and therefore the final determination of the value of the metric awaits definitive exploration.

Electrolyte balance is a critical issue in managing comorbid conditions in both diseased and elderly patients. Patients with hypertension and diabetes need careful regulation of their calcium and magnesium levels, whereas in patients with congestive heart failure, sodium and potassium levels also are critical. Herein we report the outcome of a round table discussion at which issues of renal magnesium clearance, magnesium and arrhythmic risk, ion balance in heart failure, diabetes, ischemic stress, oxidative stress in the cardiomyopathy of magnesium deficiency, roles of magnesium and potassium in bone metabolism and the aging population, and the role of electrolyte balance in hypertension have been discussed. In all these issues the maintaining homeostasis of potassium and magnesium is critical and the various therapies that impact on retaining these ions were discussed. Hallmark studies, i.e., Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial and Studies of Left Ventricular Dysfunction, have provided insight into treatment of patients with cardiovascular and progressive heart failure. These studies and the availability of potassium- and magnesium-sparing diuretics for use in these disorders provide relevant perspectives for treatment.