Search

Background:Significant clinical similarities have been observed between the recently Described ‘Long-Haul’ COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, “brain-fog”, and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms.Methods/Design:A detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction. A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction. Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights.Discussion:Optimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade.Trial registration:ClinicalTrials.gov, ID:NCT05481177Registered on 29 July 2022.

Supplementary Figure 3 - PDF file 62K, Changes in mean heart rate during cycles 1 when patients taking betablockers were excluded

Supplementary Figure 4 - PDF file 314K, Changes in mean heart rate during cycles 1 when patients taking betablockers were excluded

Supplementary Figure 6 - PDF file 60K, Changes in heart rate observed for each patient in the NIH cohort during cycle 2 days 1, 8 and 15, excluding the patients taking beta-blockers

Supplementary Figure Legends - PDF file 25K, Legends describing supplementary figures

Supplemental Tables - PDF file 76K, Table S1. Diplotype arrangements of the ABCB1 SNPs calculated using Haploview. (Reproduced with authors' permission, Sissung et al, 2011(13); Table S2. Analysis of reported cardiovascular events for all 131 patients in NCI 1312; Table S3. Statistical Analyzes of Albumin, Potassium & Magnesium Data; Table S4. Analysis of variance to examine the relationship between albumin, potassium and magnesium levels in patients treated on NCI 1312; table legends

Supplementary Figure 5 - PDF file 60K, Changes in heart rate observed for patients in the NIH cohort during cycle 2 days 1, 8 and 15

Supplementary Figure 2 - PDF file 260K, Changes in mean heart rate occurring during cycle 1 days 1, 8 and 15 grouped by baseline heart rate

Supplementary Figure 7 - PDF file 317K, Changes in mean heart rate occurring during cycle 1 days 1, 8 and 15 grouped by baseline heart rate

Supplementary Figure 1 - PDF file 69K, Changes in heart rate observed for patients in the NIH cohort during cycle 1 days 1, 8 and 15

Supplementary Figure 8 - PDF file 299K, Changes in mean heart rate during cycles 2 when patients taking betablockers were excluded

BACKGROUND: Sleep-disordered breathing (SDB) is associated with an increased risk of cardiac arrhythmias, sudden cardiac death, and all-cause mortality. This study investigates the mechanisms underlying this association by examining the effects of prevalent and incident SDB and intermittent hypoxia on ventricular repolarization lability. METHODS: Electrocardiographic recordings from three cohorts were used for this study: (1) a cross-sectional sample of 61 participants with severe SDB and a matched group without SDB; (2) a longitudinal sample of 26 participants without SDB at baseline who developed SDB after a 5-year follow-up, and a matched group without SDB; and (3) a cohort of 19 healthy adults exposed to intermittent hypoxia or ambient air. Mean heart rate, heart rate variability (SDNN), and QT variability index (QTVI), a measure of ventricular repolarization lability, were calculated from one-lead ECG recordings. RESULTS: In the cross-sectional sample, participants with severe SDB had larger QTVI ( P = 0.027), heart rate ( P = 0.028), SDNN ( P = 0.018), and hypoxemia burden as assessed by the total sleep time with oxygen saturation less than 90% (TST (90) ; P < 0.001) than those without SDB. TST (90) , but not the frequency of arousals, was an independent predictor of QTVI ( P = 0.017). Both heart rate and QTVI were predictive of all-cause mortality. In the longitudinal sample with incident SDB, QTVI increased from -1.23 ± 0.15 to -0.86 ± 0.14 ( P = 0.017) over the 5-year follow-up period. Finally, in the cohort of healthy adults, 4 hours of exposure to intermittent hypoxia increased heart rate ( P = 0.001) and QTVI ( P = 0.016). CONCLUSIONS: Prevalent and incident SDB are associated with increased ventricular repolarization instability which predisposes to ventricular arrhythmias and sudden cardiac death. Intermittent hypoxemia can destabilize ventricular repolarization and is a likely mediator of increased mortality in SDB. CLINICAL PERSPECTIVE: WHAT IS NEW? Sleep-disordered breathing, a prevalent condition in the general population, is associated with unstable ventricular repolarization. Incident sleep-disordered breathing destabilizes ventricular repolarization, likely due to the effects of intermittent hypoxemia. Acute exposure to intermittent hypoxia destabilizes ventricular repolarization in healthy adults indicating a causal effect of sleep-disordered breathing on ventricular repolarization and increased mortality risk. WHAT ARE THE CLINICAL IMPLICATIONS? Identifying and treating sleep-disordered breathing in patients at risk for sudden cardiac death, such as those with congestive heart failure, can improve clinical outcomes.

Tactical athletes are individuals in the military, law enforcement, and other professions whose occupations have significant physical fitness requirements coupled with the potential for exposure to life-threatening situations. Such exposures can have varied hemodynamic effects on the cardiovascular system. It is crucial that their clinical evaluation is inclusive of specific occupational requirements. Safety protocols regarding medical clearance are relatively more stringent for this population than for competitive athletes due to the increased impact to the tactical athlete, their team, and the population they aim to serve and protect should they experience a cardiovascular event on the job.

Methadone, a widely-prescribed medication for chronic pain and opioid addiction, is associated with respiratory depression and increased predisposition for torsades de pointes, a potentially fatal arrhythmia. Most methadone-related deaths occur during sleep. The objective of this study was to determine whether methadone’s arrhythmogenic effects increase during sleep, with a focus on cardiac repolarization instability using QT variability index (QTVI), a measure shown to predict arrhythmias and mortality. Sleep study data of 24 patients on chronic methadone therapy referred to a tertiary clinic for overnight polysomnography were compared with two matched groups not on methadone: 24 patients referred for overnight polysomnography to the same clinic (Clinic group), and 24 volunteers who had overnight polysomnography at home (Community group). Despite similar values for heart rate, heart rate variability, corrected QT interval, QTVI and oxygen saturation (SpO(2)) when awake, patients on methadone had larger QTVI (p=0.015 vs Clinic, p1000 premature beats per median sleep period), a precursor for torsades de pointes, was uncommon but more frequent in patients on methadone (p=0.039). This study demonstrates that chronic methadone use is associated with increased cardiac repolarization instability. Methadone’s pro-arrhythmic impact may be mediated by sleep-related hypoxemia which could explain the increased nocturnal mortality associated with this opioid.

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.

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.

Background Methadone is associated with a disproportionate risk of sudden death and ventricular tachyarrhythmia despite only modest inhibition of delayed rectifier K + current ( I Kr ) , the principal mechanism of drug‐associated arrhythmia. Congenital defects of inward rectifier K + current ( I K1 ) have been linked to increased U‐wave amplitude on ECG and fatal arrhythmia. We hypothesized that methadone may also be a potent inhibitor of I K1 , contributing to delayed repolarization and manifesting on surface ECGs as augmented U‐wave integrals. Methods and Results Using a whole‐cell voltage clamp, methadone inhibited both recombinant and native I K1 with a half‐maximal inhibitory concentration IC50) of 1.5 μmol/L, similar to that observed for I Kr block (half‐maximal inhibitory concentration of 2.9 μmol/L). Methadone modestly increased the action potential duration at 90% repolarization and slowed terminal repolarization at low concentrations. At higher concentrations, action potential duration at 90% repolarization lengthening was abolished, but its effect on terminal repolarization rose steadily and correlated with increased fluctuations of diastolic membrane potential. In parallel, patient ECGs were analyzed before and after methadone initiation, with 68% of patients having a markedly increased U‐wave integral compared with premethadone (lead V3; mean +38%±15%, P =0.016), along with increased QT and T Peak to T End intervals, likely reflective of I Kr block. Conclusions Methadone is a potent I K1 inhibitor that causes augmentation of U waves on surface ECG. We propose that increased membrane instability resulting from I K1 block may better explain methadone’s arrhythmia risk beyond I Kr inhibition alone. Drug‐induced augmentation of U waves may represent evidence of blockade of multiple repolarizing ion channels, and evaluation of the effect of that agent on I K1 may be warranted.

Background: Among adults, weight stigma is associated with markers of poor cardiometabolic health. Although weight-based teasing (WBT) is common among youth with high body weight, few studies have examined its associations with cardiometabolic markers. Owing to unique stressors (e.g., parental deployment and frequent moves), military-dependent youth may be at particularly high risk for obesity, WBT, and poor cardiometabolic health. We, therefore, assessed associations between WBT and cardiometabolic health markers among adolescent military dependents presenting for a weight gain prevention trial. Methods: Participants underwent fasting phlebotomy; had fasting weight, height, and waist circumference measured; and completed assessments of WBT, anxiety, and loss-of-control eating. Multivariate analysis of covariance, adjusting for relevant covariates including demographics and body composition, was used to examine differences in metabolic syndrome (MetS) components (waist circumference, systolic and diastolic blood pressure, high-density lipoprotein cholesterol, triglycerides, and glucose) between youth reporting WBT and youth reporting no WBT. Bootstrapped models examined whether WBT mediated the relationship between BMIz and MetS components. Results: Data from 142 youth (57.7% female; 14.4 ± 1.6 years; 51.2% non-Hispanic White, 20.9% non-Hispanic Black; BMIz: 1.9 ± 0.4) were analyzed. WBT was not significantly associated with any MetS component. Relationships were observed between BMIz and all MetS components (except systolic blood pressure and glucose), although WBT did not significantly mediate these relationships (p's > 0.05). Conclusions: This study did not find support for a relationship between WBT and MetS components in adolescent military dependents at risk for adult obesity. Prospective research is needed to determine whether associations between WBT and adverse cardiometabolic outcomes emerge primarily in adulthood.

Opioids are the most potent of all analgesics. Although traditionally used solely for acute self-limited conditions and palliation of severe cancer-associated pain, a movement to promote subjective pain (scale, 0 to 10) to the status of a "fifth vital sign" bolstered widespread prescribing for chronic, noncancer pain. This, coupled with rising misuse, initiated a surge in unintentional deaths, increased drug-associated acute coronary syndrome, and endocarditis. In response, the American College of Cardiology issued a call to action for cardiovascular care teams. Opioid toxicity is primarily mediated via potent μ-receptor agonism resulting in ventilatory depression. However, both overdose and opioid withdrawal can trigger major adverse cardiovascular events resulting from hemodynamic, vascular, and proarrhythmic/electrophysiological consequences. Although natural opioid analogues are devoid of repolarization effects, synthetic agents may be proarrhythmic. This perspective explores cardiovascular consequences of opioids, the contributions of off-target electrophysiologic properties to mortality, and provides practical safety recommendations.

Background: Heart disease is the leading cause of death in the United States (US) and deaths due to heart failure (HF) are increasing, while disparities are widening. The military community is pertinent to the study of the epidemiology of HF for several reasons: the 9.6 million individuals receiving care through the Military Health System (MHS) are representative of the working age US population and the MHS is the closest model to universal healthcare in the US. Hence, this environment is conducive to evaluate health disparities as access to care is uncoupled from race, sex, and ethnicity. Further, persons who serve have numerous risk factors (hypertension, smoking, PTSD, anxiety), HF is a leading cause of death among veterans and for those on active duty presents challenges to military readiness. Methods: We conducted a cross-sectional study of MHS beneficiaries aged 18 to 64 years to measure the prevalence of HF in 2018-19 overall and by sex, race, and other sociodemographic characteristics. HF was defined by International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes. Results: Among 6,375,086 MHS beneficiaries aged 18 to 64 years, 142,201 (2.23%) were diagnosed with HF. Beneficiaries with HF were mainly men (60%), age 50 to 59 (41%), retired from military service (52%), with a Senior Enlisted rank (proxy for lower socio-economic status based on salary) (79%) and serving in the US Army (39%). In logistic regression, male sex, older age, Black race, and lower rank were associated with higher relative odds of HF. After multivariable adjustment, Black race and lower rank were independently associated with large increases in prevalent HF (Table). Conclusion: Among MHS beneficiaries of working age, the prevalence of HF is high and substantial disparities exist. The large excess odds of HF among Black beneficiaries and among lower rank individuals underscores the urgent need to understand and address the determinants of these disparities.

IntroductionHigh levels of aerobic exercise in individuals who have a gene mutation associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) are associated with clinical disease progression. Guidelines consequently restrict patients from competitive athletics. However, there is minimal literature to guide the safe dosing of physical activity outside of the setting of competitive athletics. Patients may be physically active pursuant to a variety of careers, including military service. This study aimed to define a therapeutic window for exercise for ARVC gene-positive individuals that are compatible with continuing military service and general health while maintaining a level of exercise below that which risks disease progression.Materials and MethodsUsing standard metabolic equations, we calculated the minimum VO2 max (amount of oxygen utilized at peak exercise capacity) required to pass the physical fitness tests for each branch. We then developed a sample exercise prescription to maintain this level of fitness. We compared the prescribed exercise load with the physical activity levels associated with non-inferior clinical outcomes in ARVC gene-positive individuals. Additionally, we determined the physical activity exposure sustained by service members based on self-report data and compared these values with the upper limit of safe exercise exposure.ResultsBased on a review of the currently available literature, aerobic exercise exposure less than 700 to 1,100 MET-hours/year (metabolic equivalent-hours per year) is not associated with inferior clinical outcomes for gene-positive individuals. A military service member needs 600 to 700 MET-hours/year to minimally pass the physical fitness test. However, many military members are exercising in excess of this minimum, with typical exposures between 900 and 2,400 MET-hours/year.ConclusionsA therapeutic window of aerobic exercise may exist for ARVC gene-positive individuals which would allow continuation of military service while maintaining levels of exercise restriction associated with non-inferior clinical outcomes.

Pheochromocytomas, arising from chromaffin cells, produce catecholamines, epinephrine and norepinephrine. The tumor biochemical phenotype is defined by which of these exerts the greatest influence on the cardiovascular system when released into circulation in high amounts. Action on the heart and vasculature can cause potentially lethal arrhythmias, often in the setting of comorbid blood pressure derangements. In a review of electrocardiograms obtained on pheochromocytoma patients (n = 650) treated at our institution over the last decade, severe and refractory sinus tachycardia, atrial fibrillation, and ventricular tachycardia were found to be the most common or life-threatening catecholamine-induced tachyarrhythmias. These arrhythmias, arising from catecholamine excess rather than from a primary electrophysiologic substrate, require special considerations for treatment and complication avoidance. Understanding the synthesis and release of catecholamines, the adrenoceptors catecholamines bind to, and the cardiac and vascular response to epinephrine and norepinephrine underlies optimal management in catecholamine-induced tachyarrhythmias.

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.

In the outpatient setting, ambulatory electrocardiography is the most frequently used diagnostic modality for the evaluation of patients in whom cardiac arrhythmias or conduction abnormalities are suspected. Proper selection of the device type and monitoring duration is critical for optimizing diagnostic yield and cost-effective resource utilization. However, despite guidance from major professional societies, the lack of systematic guidance for proper test selection in many institutions results in the need for repeat testing, which leads to not only increased resource utilization and cost of care, but also suboptimal patient care. To address this unmet need at our own institution, we formed a multidisciplinary panel to develop a concise, yet comprehensive algorithm, incorporating the most common indications for ambulatory electrocardiography, to efficiently guide clinicians to the most appropriate test option for a given clinical scenario, with the goal of maximizing diagnostic yield and optimizing resource utilization. The algorithm was designed as a single-page, color-coded flowchart to be utilized both as a rapid reference guide in printed form, and a decision support tool embedded within the electronic medical records system at the point of order entry. We believe that systematic adoption of this algorithm will optimize diagnostic efficiency, resource utilization, and importantly, patient care and satisfaction.

Many volatile chemicals inhaled for a recreational high have a chemical structure similar to chloroform and may lead to Ikr blockade and subsequent torsades de pointes. This is one potential mechanism of action for huffing‐associated sudden death.

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 (Delta QTVI). Moderation analyses evaluated whether psychological trait associations with Delta QTVI were specific to the ICD group. Results indicated that Hostility scores predicted Delta QTVI from baseline to anger recall in ICD patients (beta = 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.

Objective Military-dependent youth appear to be at greater risk for disordered-eating than their civilian counterparts. Permanent change of station moves (PCS-moves), typically occurring every 2–3 years, are commonly experienced by adolescent military-dependents. However, the links between PCS-moves and disordered-eating in this population have not been explored. We hypothesized that stress arising from PCS-moves may contribute to the development and/or exacerbation of disordered-eating. Methods One-hundred-forty-nine adolescent military-dependents with overweight or obesity (59.7% female; 46.3% non-Hispanic White; 14.4±1.5 years; BMI-z: 1.9±0.4) completed measures before commencing an adulthood obesity and binge-eating disorder prevention trial for adolescents at-risk for both conditions due to BMI percentile ≥85th and loss-of-control (LOC)-eating and/or elevated anxiety symptoms. Disordered-eating attitudes and LOC-eating were assessed by semi-structured interview, and emotional eating was self-reported. Adjusting for relevant covariates, multiple linear regressions examined the unique association of PCS-move frequency with disordered-eating attitudes and disinhibited-eating behaviors. Results PCS-move frequency was not significantly associated with either LOC-eating frequency (β = 0.09, p = .27) or emotional eating (β = −0.04, p = .62). However, PCS-move frequency was positively associated with disordered-eating attitudes (β = 0.17, p = .04), which appeared to be primarily driven by shape concerns (β = 0.21, p = .01). Discussion Findings indicate that frequency of PCS-moves is related to disordered-eating attitudes, but not behaviors. Longitudinal research is needed to understand if PCS-moves prospectively relate to the onset and/or exacerbation of disordered-eating, and the relevance of disordered-eating attitudes as opposed to disinhibited-eating behaviors.

We recently discovered that the histone deacetylase inhibitor, trichostatin A (TSA), increases expression of the sulfonylurea receptor 2 (SUR2; Abcc9) subunit of the ATP‐sensitive K+ (KATP) channel in HL‐1 cardiomyocytes. Interestingly, the increase in SUR2 was abolished with exogenous cholesterol, suggesting that cholesterol may regulate channel expression. In the present study, we tested the hypothesis that TSA increases SUR2 by depleting cholesterol and activating the sterol response element binding protein (SREBP) family of transcription factors. Treatment of HL‐1 cardiomyocytes with TSA (30 ng/ml) caused a time‐dependent increase in SUR2 mRNA expression that correlates with the time course of cholesterol depletion assessed by filipin staining. Consistent with the cholesterol‐dependent regulation of SREBP increasing SUR2 mRNA expression, we observe a significant increase in SREBP cleavage and translocation to the nucleus following TSA treatment that is inhibited by exogenous cholesterol. Further supporting the role of SREBP in mediating the effect of TSA on KATP subunit expression, SREBP1 significantly increased luciferase reporter gene expression driven by the upstream SUR2 promoter. Lastly, HL‐1 cardiomyocytes treated with the SREBP inhibitor PF429242 significantly suppresses the effect of TSA on SUR2 gene expression. These results demonstrate that SREBP is an important regulator of KATP channel expression and suggest a novel method by which hypercholesterolemia may exert negative effects on the cardiovascular system, namely, by suppressing expression of the KATP channel., The ATP‐sensitive potassium (KATP) channel can protect the heart during metabolic challenges. Our study shows that SREBP is a regulator of cardiac KATP channel expression and suggests a novel method by which hypercholesterolemia may exert negative effects on the cardiovascular system, namely, by suppressing expression of the KATP channel.

Introduction: Methadone is the second most frequently reported cause of drug-induced cardiac arrest in pharmacovigilance databases, yet the mechanism of its pro-arrhythmia is unclear. Methadone-induced QTU wave prolongation has been repeatedly observed and attributed to inhibition of the delayed rectifier hERG current, but QTU fusion suggests the inwardly rectifying K + current (IK1) might also be affected by methadone. Hypothesis: Methadone pro-arrhythmia is associated with potent block of the IK1 current responsible for rapid terminal repolarization of the cardiac action potential (AP). Methods: Human Kir2.2, encoding the IK1 current, was transiently expressed in COS cells. hERG1a was stably expressed in CHO cells. Cardiac myocytes from swine were obtained by ventricular enzymatic dissociation. Ionic current and APs were measured using patch-clamp methods. Methadone HCl (R+S racemates) was dissolved in Tyrode solution. Results: Methadone suppressed IK1 current with an IC 50 of 1.47 uM (Fig 1A). Methadone also suppressed outward IK1 (-60 mV) measured in swine myocytes (Ba 2+ -sensitive current) with an IC 50 of 1.52 μM. Methadone suppressed hERG currents with an IC 50 of 2.1 μM. APs measured in swine myocytes exhibited significant prolongation (13 ± 4 % increase of APD 90 , p Conclusions: Methadone is an equipotent blocker of IK1 and hERG. The effect of IK1 block coupled with modest hERG block has a synergistic effect on terminal repolarization that may partially explain the pro-arrhythmic impact of methadone. Moreover, this observation may be generalized to other drugs where unsuspected IK1 blockade may contribute to pro-arrhythmia and torsade de pointes.

Introduction: Although frequently used in heart failure (HF), long-term furosemide exacerbates HF in a swine model. This paradoxical phenomenon may reflect furosemide-induced alterations in signaling proteins of the extracellular matrix (ECM) to increase fibrosis. Examination of the ECM may clarify how treatments like furosemide enhance the progression of HF. Hypothesis: The administration of furosemide increased inflammation and fibrosis of the heart, leading to accelerated HF deterioration in a swine model. Methods: After Institutional Animal Care and Use Committee (IACUC) approval, Yorkshire swine (N=10, 5 = furosemide, 5 = saline) were paced 3 to 5 weeks at 200 beats per minute to induce HF (left ventricular fractional shortening Results: The overall increase in ECM fibrosis in HF was clearly demonstrated on Masson’s trichrome histology associated with significant, uniform increase in signaling pathways leading to fibrosis associated with furosemide use. SMAD 2-HF Furosemide to Control (p Conclusions: Histologic and biochemical analysis showed worsening HF in furosemide-treated paced swine was associated with consistent increases in fibrosis and indices of adverse ECM remodeling. The diuretic intended to reduce water retention during HF appeared to enhance myocardial fibrosis, paradoxically accelerating pathological processes responsible for HF.

Introduction In 2010, the U.S. Coast Guard (USCG) led a clean-up response to the Deepwater Horizon (DWH) oil spill. Human studies evaluating acute and longer-term cardiovascular conditions associated with oil spill-related exposures are sparse. Thus, we aimed to investigate prevalent and incident cardiovascular symptoms/conditions in the DHW Oil Spill Coast Guard Cohort. Methods Self-reported oil spill exposures and cardiovascular symptoms were ascertained from post-deployment surveys (n = 4,885). For all active-duty cohort members (n = 45,193), prospective cardiovascular outcomes were classified via International Classification of Diseases, 9th Edition from military health encounter records up to 5.5 years post-DWH. We used log-binomial regression to calculate adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs) in the cross-sectional analyses and Cox Proportional Hazards regression to calculate adjusted hazard ratios (aHR) and 95% CIs for incident cardiovascular diagnoses during 2010-2015 and stratifying by earlier (2010-2012) and later (2013-2015) time periods. Results Prevalence of chest pain was associated with increasing levels of crude oil exposure via inhalation (aPRhigh vs. none = 2.00, 95% CI = 1.16-3.42, p-trend = 0.03) and direct skin contact (aPRhigh vs. none = 2.72, 95% CI = 1.30-5.16, p-trend = 0.03). Similar associations were observed for sudden heartbeat changes and for being in the vicinity of burning oil exposure. In prospective analyses, responders (vs. non-responders) had an elevated risk for mitral valve disorders during 2013-2015 (aHR = 2.12, 95% CI = 1.15-3.90). Responders reporting ever (vs. never) crude oil inhalation exposure were at increased risk for essential hypertension, particularly benign essential hypertension during 2010-2012 (aHR = 2.00, 95% CI = 1.08-3.69). Responders with crude oil inhalation exposure also had an elevated risk for palpitations during 2013-2015 (aHR = 2.54, 95% CI = 1.36-4.74). Cardiovascular symptoms/conditions aPR and aHR estimates were generally stronger among responders reporting exposure to both crude oil and oil dispersants than among those reporting neither. Conclusions In this large study of the DWH oil spill USCG responders, self-reported spill clean-up exposures were associated with acute and longer-term cardiovascular symptoms/conditions.

A patient presented with torsade de pointes after inhaling tetrafluoroethane, a volatile gas propellant used to clean keyboards. She had a prior hospitalization for cardiac arrest without rhythm documentation after inhaling a similar product. Urine toxicology revealed methamphetamine. We are unaware of previous descriptions of torsade de pointes associated with volatile hydrocarbon inhalation or “huffing.” Although sudden death is associated with “huffing,” an arrhythmic mechanism has not been elucidated. Tetrafluoroethane, however, is chemically similar to chlorophorm (trichloromethane), which blocks the delayed rectifier potassium ion current (Ikr). Thus, we postulate that delayed repolarization with methamphetamine triggering may account for this arrhythmia.