Associations of social and cognitive-behavioral variables with disinhibited eating and anxiety: An ecological momentary assessment study.

OBJECTIVE: Among adolescents, disinhibited eating and anxiety commonly co-occur. Precision intervention approaches targeting unique mechanistic vulnerabilities that contribute to disinhibited eating and anxiety may therefore be helpful. However, the effectiveness of such interventions hinges on knowledge of between- and within-person associations related to disinhibited eating, anxiety, and related processes. METHOD: A sample of 39 adolescent females (12-17 years) with elevated anxiety and above-average weight (BMI %ile ≥ 75th) completed measures of theoretically driven social and cognitive-behavioral variables, disinhibited eating, and anxiety via ecological momentary assessment over 7 days. Data were analyzed using mixed-effects models. RESULTS: Between-person differences in social stressors were linked to emotional eating, eating in the absence of hunger, and anxiety, whereas between-person differences in negative thoughts were associated with all disinhibited eating variables and anxiety. Between-person differences in avoidance were not related to any outcome. Additionally, between-person differences in social stressors and negative thoughts-as well as within-person deviations (from person-average levels) of social stressors, negative thoughts, and avoidance-were associated with anxiety. In turn, between-person differences in anxiety predicted eating in the absence of hunger and emotional eating, and within-person deviations in anxiety were associated with emotional eating at any given time point. DISCUSSION: Findings support elements of both the interpersonal and cognitive-behavioral models of disinhibited eating. Differential trigger effects on anxiety, both at the between- and within-person levels, and significant associations between anxiety and all eating-related outcomes, highlight the potential utility of interventions targeting individual differences in sensitivity to anxiety triggers. PUBLIC SIGNIFICANCE: Findings provide support for the interpersonal and cognitive-behavioral models of disinhibited eating, highlighting anxiety as a salient vulnerability and potential mechanistic factor underlying disinhibited eating. Social, cognitive, and behavioral variables were differentially related to anxiety across participants, suggesting potential for future intervention tailoring and intervention selection based on adolescents' sensitivity to anxiety as a trigger for disinhibited eating behavior.

Emotional dysregulation moderates the relation between perceived stress and emotional eating in adolescent military dependents.

OBJECTIVE: Adolescent children of US service members (i.e., military-dependent youth) face unique stressors that increase risk for various forms of disinhibited eating, including emotional eating. Difficulties with adaptively responding to stress and aversive emotions may play an important role in emotional eating. This study examined emotion dysregulation as a potential moderator of the association between perceived stress and emotional eating in adolescent military dependents. METHOD: Participants were military-dependent youth (N = 163, 57.7% female, Mage = 14.5 ± 1.6, MBMI-z = 1.9 ± 0.4) at risk for adult binge-eating disorder and high weight enrolled in a randomized controlled prevention trial. Prior to intervention, participants completed questionnaires assessing perceived stress and emotional eating. Parents completed a questionnaire assessing their adolescent's emotion dysregulation. Moderation analyses were conducted using the PROCESS macro in SPSS and adjusted for theoretically relevant sociodemographic covariates. RESULTS: The interaction between adolescent perceived stress and emotion dysregulation (parent-reported about the adolescent) in relation to adolescent emotional eating was found to be significant, such that higher emotion dysregulation magnified the association between perceived stress and emotional eating (p = .010). Examination of simple slopes indicated that associations between perceived stress and emotional eating were strongest for youth with above-average emotion dysregulation, and non-significant for youth with average or below-average emotion dysregulation. DISCUSSION: Findings suggest that greater emotion dysregulation may increase risk for emotional eating in response to stress among military-dependent youth at risk for binge-eating disorder or high weight. Improving emotion regulation skills may be a useful target for eating disorder prevention among youth who are at risk for emotional eating. PUBLIC SIGNIFICANCE: Prior research has shown that adolescent military dependents are at increased risk for eating disorders and high weight. The current study found that emotion dysregulation moderated the relationship between perceived stress and emotional eating among military-dependent youth. There may be clinical utility in intervening on emotion regulation for adolescent dependents at particular risk for emotional eating and subsequent eating disorders.

Autonomic indices and loss-of-control eating in adolescents: an ecological momentary assessment study.

BACKGROUND: Loss-of-control (LOC) eating commonly develops during adolescence, and it predicts full-syndrome eating disorders and excess weight gain. Although negative emotions and emotion dysregulation are hypothesized to precede and predict LOC eating, they are rarely examined outside the self-report domain. Autonomic indices, including heart rate (HR) and heart rate variability (HRV), may provide information about stress and capacity for emotion regulation in response to stress. METHODS: We studied whether autonomic indices predict LOC eating in real-time in adolescents with LOC eating and body mass index (BMI) ⩾70th percentile. Twenty-four adolescents aged 12-18 (67% female; BMI percentile mean ± standard deviation = 92.6 ± 9.4) who reported at least twice-monthly LOC episodes wore biosensors to monitor HR, HRV, and physical activity for 1 week. They reported their degree of LOC after all eating episodes on a visual analog scale (0-100) using a smartphone. RESULTS: Adjusting for physical activity and time of day, higher HR and lower HRV predicted higher self-reported LOC after eating. Parsing between- and within-subjects effects, there was a significant, positive, within-subjects association between pre-meal HR and post-meal LOC rating. However, there was no significant within-subjects effect for HRV, nor were there between-subjects effects for either electrophysiologic variable. CONCLUSIONS: Findings suggest that autonomic indices may either be a marker of risk for subsequent LOC eating or contribute to LOC eating. Linking physiological markers with behavior in the natural environment can improve knowledge of illness mechanisms and provide new avenues for intervention.

A health systems assessment of genetic counseling in cardiovascular care in a large health system: Adherence to genetics recommendations in the Military Health System.

Genetic counseling and genetic testing are important tools for diagnosis, screening, and employment of effective medical management strategies for hereditary cardiovascular diseases. Despite widespread recognition of the benefits of genetic counseling and testing in cardiovascular care, little is published regarding their use in large healthcare systems. We conducted a retrospective cross-sectional study using administrative claims data in the US Military Health System to assess the state of recommended genomic counseling in clinical cardiovascular care. Logistic regression models were used to examine associations of genetic counseling among beneficiaries with hereditary cardiovascular conditions. Approximately 0.44% of beneficiaries in fiscal year 2018 had a diagnosis of a hereditary cardiovascular condition. Among the 23,364 patients with a diagnosis of hereditary cardiovascular disease, only 175 (0.75%) had documented genetic counseling and 196 (0.84%) had documented genetic testing. Genetic counseling did not differ by race, sex, service, or diagnosis. Age group, Active Duty status, rank as a proxy for socioeconomic status, and geographic location contributed significantly to the likelihood of receiving genetic counseling. These findings suggest that genetic counseling is underutilized in clinical cardiovascular care in the Military Health System and may be more broadly, despite expert consensus recommendations for its use and potential life-saving benefits. Unlike previous studies in the US civilian health sector, there did not appear to be disparities in genetic counseling by race or sex in the Military Health System. Strategies to improve care for cardiovascular disease should address the underutilization of recommended genetics evaluations for heritable diagnoses and the challenges of assessing use in large health systems studies.

Exertional-Related Sudden Cardiac Death in a Young, Presumed Healthy, and Medically Screened Population: A Military Case Series.

ABSTRACT: Sudden cardiac death (SCD) is defined as death from cardiac causes with loss of consciousness occurring within 1 hour of a change in cardiovascular status. As subset, SCD associated with physical exertion (SCD/E) can be defined as a cardiac event whose symptoms start during or within 1 hour of physical exertion. The US military represents a unique opportunity for studying SCD/E because of medical screening at recruitment, mandatory physical training, an active surveillance system, and centralized autopsy services. Because of medical screening, recruits are presumed healthy, but significant conditions can go undetected. We present 4 diverse cases of SCD/E in the military setting. Sudden cardiac death associated with physical exertion is often the first indication of a serious occult cardiac pathology. Postmortem genetic testing revealed a causative pathogenic mutation in 1 of 4 cases, enabling genetic testing of family members to prevent similar catastrophic loss of life, underscoring the importance of postmortem evaluation including genetic testing. Further investigations will help direct screening and prevention to capture those at risk for SCD. The cases presented in this series are a sample of the diverse etiologies and contexts surrounding SCD/E in the military setting that have been captured by Armed Forces Medical Examiner System.

The Relationship Between Anxiety, Coping, and Disordered-Eating Attitudes in Adolescent Military-Dependents at High-Risk for Excess Weight Gain.

Adolescent military-dependents are an understudied population who face unique stressors due to their parents' careers. Research suggests that 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 ≥ 85th 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, non-specific 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.

Examination of the Interaction between Parental Military-Status and Race among Non-Hispanic Black and Non-Hispanic White Adolescents with Overweight/Obesity.

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.

Associations among alexithymia, disordered eating, and depressive symptoms in treatment-seeking adolescent military dependents at risk for adult binge-eating disorder and obesity.

PURPOSE: Evidence suggests that difficulties identifying and describing one's feelings, core components of alexithymia, are 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.

Traumatic injury and atrial fibrillation among deployed service members.

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 (hazards ratio [HR] = 2.04; 95% confidence interval [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 casualty surveillance to further understand the AF/AFL risk within the military population and to elucidate the potential underlying pathophysiologic mechanisms.

Psychological factors and cardiac repolarization instability during anger in implantable cardioverter defibrillator patients.

BACKGROUND: Evidence indicates that emotions such as anger are associated with increased incidence of sudden cardiac death, but the biological mechanisms remain unclear. We tested the hypothesis that, in patients with sudden death vulnerability, anger would be associated with arrhythmic vulnerability, indexed by cardiac repolarization instability. METHODS: Patients with coronary artery disease (CAD) and an implantable cardioverter defibrillator (ICD; n = 41) and healthy controls (n = 26) gave an anger-inducing speech (anger recall), rated their current (state) anger, and completed measures of trait (chronic) levels of Anger and Hostility. Repolarization instability was measured using QT Variability Index (QTVI) at resting baseline and during anger recall using continuous ECG. RESULTS: ICD patients had significantly higher QTVI at baseline and during anger recall compared with controls, indicating greater arrhythmic vulnerability overall. QTVI increased from baseline to anger recall to a similar extent in both groups. In ICD patients but not controls, during anger recall, self-rated anger was related to QTVI (r = .44, p = .007). Trait (chronic) Anger Expression (r = .26, p = .04), Anger Control (r = -.26, p = .04), and Hostility (r = .25, p = .05) were each associated with the change in QTVI from baseline to anger recall (ΔQTVI). Moderation analyses evaluated whether psychological trait associations with ΔQTVI were specific to the ICD group. Results indicated that Hostility scores predicted ΔQTVI from baseline to anger recall in ICD patients (ß = 0.07, p = .01), but not in controls. CONCLUSIONS: Anger increases repolarization lability, but in patients with CAD and arrhythmic vulnerability, chronic and acute anger interact to trigger cardiac repolarization lability associated with susceptibility to malignant arrhythmias.

Hemodynamic Effects of Late Sodium Current Inhibitors in a Swine Model of Heart Failure.

OBJECTIVES: To evaluate possible treatment-related hemodynamic changes, we administered ranolazine or mexiletine to swine with heart failure (HF) and to controls. BACKGROUND: Ranolazine and mexiletine potently inhibit depolarizing late Na+ current (INa,late) and Na+ entry into cardiomyocytes. Blocking Na+ entry may increase forward-mode Na/Ca exchange and reduce cellular Ca+2 load, further compromising systolic contraction during HF. METHODS AND RESULTS: Anesthetized tachypaced HF swine received ranolazine (n = 9) or mexiletine (n = 7) as boluses, then as infusions; the same experiments were performed in 10 nonpaced controls. The swine with HF had characteristic elevated left ventricular end-diastolic pressure (LVEDP) and reduced maximal left ventricular pressure rise (+dP/dtmax) and left ventricular peak systolic pressure (LVSP). No significant change occurred after ranolazine dosing for any parameter: LVEDP, +dP/dtmax, LVSP, heart rate, maximal LV pressure fall rate (-dP/dtmax), or time constant for isovolumic relaxation. Similar results seen in additional swine with HF: 7 were given mexiletine, and 7 others were given ranolazine after a 27% rate decrement to maximize INa,late. Patch-clamped HF cardiomyocytes confirmed drug-induced INa,late blockade. CONCLUSIONS: Ranolazine or mexiletine blocking INa,late neither worsened nor improved hemodynamics during advanced HF. Although results must be clinically confirmed, they suggest inhibition of INa,late by ranolazine or mexiletine may not exacerbate HF in patients.

Detection of sleep-disordered breathing with ambulatory Holter monitoring.

PURPOSE: Obstructive sleep apnea (OSA) syndrome is a common condition that can impact clinical outcomes among patients with cardiovascular disease. Screening all subjects with heart disease via polysomnography (PSG) is costly and resource-limited. We sought to compare a Holter monitor-based algorithm to detect OSA to in-laboratory polysomnography (PSG). METHODS: Prospective cohort study of patients undergoing in-laboratory attended PSG for the evaluation of OSA. A standard 12-lead Holter monitor was attached to patients at the initiation of PSG. Holter-derived respiratory disturbance index (HDRDI) was extracted from the respiratory myogram, based on detecting skeletal muscle "noise" detected on the baseline. Apneic and hypopneic episodes were identified by comparing sudden changes in the myogram to abrupt increases in heart rate. The HDRDI was compared with the PSG-derived apnea-hypopnea index (PDAHI). RESULTS: Thirty patients underwent simultaneous Holter monitoring and overnight diagnostic PSG. An ROC curve for peak HDRDI was 0.79 (95% CI 0.61, 0.97) for OSA, with sensitivity of 94.4% and specificity of 54.5%. A cutoff value of HDRDI < 10 appeared to identify those individuals without clinically significant sleep-disordered breathing. CONCLUSION: Holter-derived respiration detected OSA comparable to PSG. Further study is warranted to determine its utility for screening and diagnosing OSA in appropriately selected patients.

Piperaquine Population Pharmacokinetics and Cardiac Safety in Cambodia.

Despite the rising rates of resistance to dihydroartemisinin-piperaquine (DP), DP remains a first-line therapy for uncomplicated malaria in many parts of Cambodia. While DP is generally well tolerated as a 3-day DP (3DP) regimen, compressed 2-day DP (2DP) regimens were associated with treatment-limiting cardiac repolarization effects in a recent clinical trial. To better estimate the risks of piperaquine on QT interval prolongation, we pooled data from three randomized clinical trials conducted between 2010 and 2014 in northern Cambodia. A population pharmacokinetic model was developed to compare exposure-response relationships between the 2DP and 3DP regimens while accounting for differences in regimen and sample collection times between studies. A 2-compartment model with first-order absorption and elimination without covariates best fit the data. The linear slope-intercept model predicted a 0.05-ms QT prolongation per ng/ml of piperaquine (5 ms per 100 ng/ml) in this largely male population. Though the plasma half-life was similar in both regimens, peak and total piperaquine exposures were higher in those treated with the 2DP regimen. Furthermore, the correlation between the plasma piperaquine concentration and the QT interval prolongation was stronger in the population receiving the 2DP regimen. Neither the time since the previous meal nor the baseline serum magnesium or potassium levels had additive effects on QT interval prolongation. As electrocardiographic monitoring is often nonexistent in areas where malaria is endemic, 2DP regimens should be avoided and the 3DP regimen should be carefully considered in settings where viable alternative therapies exist. When DP is employed, the risk of cardiotoxicity can be mitigated by combining a 3-day regimen, enforcing a 3-h fast before and after administration, and avoiding the concomitant use of QT interval-prolonging medications. (This study used data from three clinical trials that are registered at ClinicalTrials.gov under identifiers NCT01280162, NCT01624337, and NCT01849640.).

Real-time assessment of heart rate variability and loss of control eating in adolescent girls: A pilot study.

OBJECTIVE: Studying physiologic underpinnings of loss-of-control (LOC) eating may inform its etiology and contribute to intervention efforts. We therefore examined temporal relationships between autonomic indices [heart rate (HR), heart rate variability (HRV)] and LOC-eating in the natural environment. METHOD: For two days, adolescents (n = 17, 14.77 ± 1.55 years, BMI-Z 2.17 ± 0.48) with LOC-eating reported on LOC using an electronic device while HR and HRV were assessed continuously using Holter monitoring. RESULTS: Higher HR and lower HRV in the 30-minutes before eating were significantly associated with LOC-eating overall (p's < 0.001) and at the within-participants level (p's < 0.001), but not at the between-participants level (p's > 0.44). Examined categorically, HR was significantly higher, and HRV significantly lower, prior to high-LOC compared to low-LOC episodes (p's < 0.001). DISCUSSION: This pilot study suggests that LOC-eating may involve physiologic underpinnings. Additional research with larger samples is needed to further investigate this phenomenon.

Risk factors and the effect of cardiac resynchronization therapy on cardiac and non-cardiac mortality in MADIT-CRT.

AIMS: To understand modes of death and factors associated with the risk for cardiac and non-cardiac deaths in patients with cardiac resynchronization therapy with implantable cardioverter-defibrillator (CRT-D) vs. implantable cardioverter-defibrillator (ICD) therapy, which may help clarify the action and limitations of cardiac resynchronization therapy (CRT) in relieving myocardial dysfunction. METHODS AND RESULTS: In Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT), during 4 years of follow-up, 169 (9.3%) of 1820 patients died of known causes, 108 (63.9%) deemed cardiac, and 61 (36.1%) non-cardiac. In multivariate analysis, increased baseline creatinine was significantly associated with both cardiac and non-cardiac deaths [hazard ratio (HR) 2.97, P < 0.001; HR 1.80, P = 0.035, respectively], as was diabetes (HR 1.79, P = 0.006; HR 1.73, P = 0.038, respectively), and the worst New York Heart Association Class > II more than 3 months prior to enrolment (HR 1.90, P = 0.012; HR 2.46, P = 0.010, respectively). Baseline left atrial volume index was significantly associated only with cardiac mortality (HR 1.28 per 5 unit increase, P < 0.001). Ischaemic cardiomyopathy was associated only with non-cardiac death (HR 3.54, P = 0.001). CRT-D vs. an ICD-only was associated with a reduced risk for cardiac death in patients with left bundle branch block (LBBB) (HR 0.56, P = 0.029) but was associated with an increased risk for non-cardiac death in non-LBBB patients (HR 3.48, P = 0.048). CONCLUSIONS: In MADIT-CRT, two-thirds of the deaths were cardiac and one-third non-cardiac. Many of the same risk factors were associated with both cardiac and non-cardiac mortalities. CRT-D was associated with a reduced risk for cardiac death in LBBB but an increased risk for non-cardiac death in non-LBBB. CLINICAL TRIAL REGISTRATION: Information for the MADIT-CRT main study http://www.clinicaltrials.gov, NCT00180271.

Randomized, double-blind, placebo-controlled clinical trial of a two-day regimen of dihydroartemisinin-piperaquine for malaria prevention halted for concern over prolonged corrected QT interval.

Dihydroartemisinin-piperaquine, the current first-line drug for uncomplicated malaria caused by Plasmodium falciparum and Plasmodium vivax in Cambodia, was previously shown to be of benefit as malaria chemoprophylaxis when administered as a monthly 3-day regimen. We sought to evaluate the protective efficacy of a compressed monthly 2-day treatment course in the Royal Cambodian Armed Forces. The safety and efficacy of a monthly 2-day dosing regimen of dihydroartemisinin-piperaquine were evaluated in a two-arm, randomized, double-blind, placebo-controlled cohort study with 2:1 treatment allocation. Healthy military volunteers in areas along the Thai-Cambodian border where there is a high risk of malaria were administered two consecutive daily doses of 180 mg dihydroartemisinin and 1,440 mg piperaquine within 30 min to 3 h of a meal once per month for a planned 4-month period with periodic electrocardiographic and pharmacokinetic assessment. The study was halted after only 6 weeks (69 of 231 projected volunteers enrolled) when four volunteers met a prespecified cardiac safety endpoint of QTcF (Fridericia's formula for correct QT interval) prolongation of >500 ms. The pharmacodynamic effect on the surface electrocardiogram (ECG) peaked approximately 4 h after piperaquine dosing and lasted 4 to 8 h. Unblinded review by the data safety monitoring board revealed mean QTcF prolongation of 46 ms over placebo at the maximum concentration of drug in serum (Cmax) on day 2. Given that dihydroartemisinin-piperaquine is one of the few remaining effective antimalarial agents in Cambodia, compressed 2-day treatment courses of dihydroartemisinin-piperaquine are best avoided until the clinical significance of these findings are more thoroughly evaluated. Because ECG monitoring is often unavailable in areas where malaria is endemic, repolarization risk could be mitigated by using conventional 3-day regimens, fasting, and avoidance of repeated dosing or coadministration with other QT-prolonging medications. (This study has been registered at ClinicalTrials.gov under registration no. NCT01624337.).

Ranolazine for the suppression of ventricular arrhythmia: a case series.

BACKGROUND: Premature ventricular complexes (PVCs) and ventricular tachycardia (VT) are associated with persistent symptoms and ventricular dysfunction. Approved medical therapies have undesirable side effects and proarrhythmic liability. Ranolazine is a novel antianginal that preferentially blocks the late sodium current. This current is enhanced among patients with cardiomyopathy; a promising target population for ranolazine. The utility of ranolazine, however, for ventricular arrhythmia suppression has not been well characterized. OBJECTIVES: We sought to determine the effectiveness of ranolazine for suppression of ventricular ectopy, particularly in the setting of ventricular dysfunction where enhanced efficacy might be expected. METHODS: We retrospectively evaluated eight patients (six with >10% PVC burden and two with incessant VT) treated with ranolazine. Arrhythmia frequency was evaluated by continuous monitoring before and after ranolazine initiation and the correlation between ventricular function and reduction in PVC burden was assessed. RESULTS: Among six patients with PVCs, ranolazine resulted in a median decrease in PVC burden of 60.2% (P = 0.06). In two cases of apparent PVC-induced cardiomyopathy, normalization of ventricular function was observed. A significant, inverse correlation between baseline ejection fraction and percentage reduction in PVCs was observed (rho = -0.89, P = 0.02). In two patients treated for incessant VT despite Class III antiarrhythmic therapy, ranolazine eliminated VT and prevented recurrent defibrillator therapy. CONCLUSIONS: Although not approved for this indication, ranolazine appears effective for symptomatic ventricular arrhythmias. The reduction in PVC burden was greatest among individuals with reduced ventricular function, perhaps due to enhanced late sodium current associated with cardiomyopathy. A confirmatory prospective trial seems warranted.