Search

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 Methadone is associated with a disproportionate risk of sudden death and ventricular tachyarrhythmia despite only modest inhibition of delayed rectifier K

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.

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.

(1) Background: Standard-of-care lifestyle interventions show insufficient effectiveness for the prevention and treatment of excess weight and its associated cardiometabolic health concerns in adolescents, necessitating more targeted preventative approaches. Anxiety symptoms are common among adolescents, especially girls at risk for excess weight gain, and have been implicated in the onset and maintenance of disinhibited eating. Thus, decreasing elevated anxiety in this subset of adolescent girls may offer a targeted approach to mitigating disinhibited eating and excess weight gain to prevent future cardiometabolic health problems. (2) Methods: The current paper describes the protocol for a multisite pilot and feasibility randomized controlled trial of group cognitive behavioral therapy (CBT) and group interpersonal psychotherapy (IPT) in N = 40 adolescent girls (age 12–17 years) with elevated anxiety symptoms and body mass index (BMI; kg/m2) ≥ 75th percentile for age/sex. (3) Results: Primary outcomes are multisite feasibility of recruitment, protocol procedures, and data collection, intervention fidelity, retention at follow-ups, and acceptability of interventions and study participation. (4) Conclusions: Findings will inform the protocol for a future fully-powered multisite randomized controlled trial to compare CBT and IPT efficacy for reducing excess weight gain and preventing adverse cardiometabolic trajectories, as well as to evaluate theoretically-informed treatment moderators and mediators.

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.

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 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.

Background Metabolic syndrome in adolescence has been associated with adverse cardiometabolic outcomes in adulthood. Preliminary data suggest that boys may have worsened metabolic syndrome components compared to girls. Yet, little is known about the physical health of military dependents, a potentially at-risk population. Objective Examine sex differences in metabolic syndrome components in a sample of adolescent military dependents. Methods Participants were adolescents (N = 139; 14.4 ± 1.6 years; 45.3% male; 41.0% non-Hispanic White, 19.4% non-Hispanic Black; BMI-z: 1.9 ± 0.4) 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. A multivariate analysis of covariance was conducted to compare objectively measured metabolic syndrome components across boys and girls. Covariates were age, race, loss-of-control eating status, anxiety symptoms, and BMI-z. Results Metabolic syndrome components differed by sex (P = .01). Boys had higher systolic blood pressure (P = .049), lower high-density lipoprotein cholesterol (P = .01), and higher glucose (P = .001) than girls. Waist circumference, diastolic blood pressure, and triglycerides did not differ between boys and girls (P > .05). Conclusions Future research should prospectively examine these relationships into adulthood. If the current findings are supported, prevention programs should consider targeting cardiometabolic health particularly among male adolescent military dependents.

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.

Cognitive load is a key mediator of cognitive processing that may impact clinical reasoning performance. The purpose of this study was to gather biologic validity evidence for correlates of different types of self-reported cognitive load, and to explore the association of self-reported cognitive load and physiologic measures with clinical reasoning performance. We hypothesized that increased cognitive load would manifest evidence of elevated sympathetic tone and would be associated with lower clinical reasoning performance scores. Fifteen medical students wore Holter monitors and watched three videos depicting medical encounters before completing a post-encounter form and standard measures of cognitive load. Correlation analysis was used to investigate the relationship between cardiac measures (mean heart rate, heart rate variability and QT interval variability) and self-reported measures of cognitive load, and their association with clinical reasoning performance scores. Despite the low number of participants, strong positive correlations were found between measures of intrinsic cognitive load and heart rate variability. Performance was negatively correlated with mean heart rate, as well as single-item cognitive load measures. Our data signify a possible role for using physiologic monitoring for identifying individuals experiencing high cognitive load and those at risk for performing poorly during clinical reasoning tasks.

Introduction The US Department of Defense (DoD) has adopted a model concept of the warrior athlete. Identifying latent disease that could compromise the military operator is critical to the warrior athlete concept. Cardiovascular complaints are the important problem recognized in service members evacuated from combat zones, and the incidence of sudden cardiac death in U.S. military recruits is comparable to or greater than that among National Collegiate Athletic Association Athletes. Nevertheless, the mandatory electrocardiogram (ECG) was removed from official U.S. military accession screening policy in 2002. Inclusion of ECG screening in high risk athletics is increasingly recognized as appropriate by professional organizations such as the American Heart Association and American Medical Society for Sports Medicine, though neither recommends ECG for generalized screening in large, low-risk populations. Materials and Methods The appropriate DoD instructions were reviewed in the context of recent literature regarding the sensitivity and specificity of ECG screening for prevention of sudden cardiac arrest or debilitating arrhythmias. Results Challenges to implementation of ECG as a screening modality in U.S. military accessions include clinician interpretation validity and reliability. Modern interpretation criteria and new interpretation technology each serve to mitigate these recognized limitations. Outside experience with implementation of modern ECG suggest potential benefits are significant in the highest risk military groups. Conclusion Prospective study of ECG screening is needed to determine the impact on cardiovascular outcomes in U.S. military populations.

Background The widespread use of opioids has resulted in sharp rise of associated complications, particularly opioid-induced constipation (OIC). Opioid receptor antagonists have been proposed to treat OIC, but could precipitate rapid opioid withdrawal. As cardiovascular safety data are lacking, we assessed disproportionate reporting of adverse cardiac events associated with naloxone across large, international pharmacovigilance systems. Methods Post-marketing data from the World Health Organization (WHO) and FDA Adverse Events Reporting System (FAERS) were evaluated for naloxone and the synthetic opioids oxycodone and tilidine. The proportional reporting ratio (PRR), a measure of reporting frequency analogous to an odds ratio, was assessed. The primary outcome was reporting frequency of the MedDRA System Organ Class (SOC) ‘Cardiac Disorders' for naloxone alone and in fixed-dose combination with opioids. Opioid mono-preparations served as quasi-experimental controls. A PRR greater than 2.0 was considered significant. Results In total, 14,827,374 million adverse drug event reports were reviewed. In WHO, there were 1757 reports of SOC cardiac disorders among 10,866 total reports for oxycodone (PRR 2.38 [95% CI 2.28–2.49, χ 2 =1504]). For oxycodone-naloxone, there were 43/453 reports of SOC cardiac disorders (PRR 1.45 [95% CI 1.09–1.92, χ 2 =6.4]). For the synthetic opioid tilidine there were 13/179 reports (PRR 1.13 [95% CI 0.67–1.91, χ 2 =0.2]) and for tilidine-naloxone, 30/505 reports (PRR 0.92 [95% CI 0.65–1.31, χ 2 =0.2]). In FAERS, the PRR for SOC cardiac disorders was 0.95 [95% CI 0.89–1.01, χ 2 =2.1] for naloxone (all administration routes) and 1.16 [95% CI 0.93–1.45, χ 2 =1.3] for naloxone (oral only). In comparison, the PRR was 1.66 [95% CI 1.63–1.69, χ 2 =4278] for oxycodone and 1.52 [CI 1.28–1.80, χ 2 =1500] for oxycodone-naloxone. Conclusions Available pharmacovigilance data do not suggest disproportionate reporting of adverse cardiovascular events for opioid antagonists used to treat OIC.

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 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 , [NCT00180271][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00180271&atom=%2Feuropace%2F17%2F12%2F1816.atom

Brugada syndrome (BrS) is a common occult cause of sudden cardiac arrest in otherwise healthy-appearing adults. The pathognomonic electrocardiographic pattern may be unmasked only by certain medications, many of which are unknown. We report a case of a depressed but otherwise healthy man with an asymptomatic right bundle branch block on electrocardiography who experienced antidepressant-induced BrS and ultimately recovered with transcranial magnetic stimulation (TMS). After an initial trial of nortriptyline, the patient's depressive symptoms improved; however, he experienced a syncopal event and was subsequently diagnosed as having BrS. Cross titration to bupropion, which had not previously been known to exacerbate BrS, was followed by another cardiac event. As a result, the patient was referred for TMS as a substitute for pharmacotherapy. After 31 TMS sessions over 8 weeks, the patient demonstrated significant improvement by subjective report and objective reduction in his Patient Health Questionnaire-9 scores from 10 (moderate) to 1 (minimal). Transcranial magnetic stimulation is a Food and Drug Administration-approved nonpharmacologic treatment for depression. Given the potential lethality of BrS with known and unknown psychopharmacologic agents, providers should consider TMS as first-line therapy in this patient population. Bupropion should be added to the list of agents known to exacerbate this disease.

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 ( C max ) 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.)

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). 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). 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

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.)

Background Identifying which patients might benefit the most from ICD therapy remains challenging. We hypothesize that increased T-wave alternans (TWA) and QT variability (QTV) provide complementary information for predicting appropriate ICD therapy in patients with previous myocardial infarction and reduced ejection fraction. Methods We analyzed 10-min resting ECGs from MADIT-II patients with baseline heart rate > 80 beats/min. TWA indices IAA and IAA 90 were computed with the multilead Laplacian Likelihood ratio method. QTV indices QTVN and QTVI were measured using a standard approach. Cox proportional hazard models were adjusted considering appropriate ICD therapy and sudden cardiac death (SCD) as endpoints. Results TWA and QTV were measured in 175 patients. Neither QTV nor TWA predicted SCD. Appropriate ICD therapy was predicted by combining IAA 90 and QTVN after adjusting for relevant correlates. Conclusion Increased TWA and QTV are independent predictors of appropriate ICD therapy in MADIT-II patients with elevated heart rate at baseline.

The finding of QTc prolongation often sounds the death knell for a new molecule, but investigators have long suspected that QTc prolongation alone may be an indifferent predictor of risk. Premature or inappropriate rejection of promising molecules deprives clinicians of new therapies and depletes industry resources. Could it be that the conventional electrocardiogram contains information that might prevent us from relegating "virtuous" compounds to a fate they do not deserve?

Background Long-term mortality data after cardiac resynchronization therapy with implanted defibrillator (CRT-D) in minimally symptomatic patients are limited. Objective To clarify influences on long-term mortality after CRT-D, we assessed MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial—Cardiac Resynchronization Therapy) patient outcomes by baseline conduction abnormality and 1-year posttreatment remodeling. Methods MADIT-CRT followed 1820 patients assigned to CRT-D or implanted cardioverter-defibrillator (ICD) only. Using Cox proportional hazards regression analysis, treatment effects (CRT-D vs ICD only) on mortality were evaluated in patients with left bundle branch block (LBBB) and non-LBBB. Among 1196 patients with echocardiography repeated at 1 year, effect of CRT-D on later mortality (landmark analysis) was analyzed by baseline conduction and 1-year change in left ventricular end-systolic volume (LVESV). Results Overall mortality was not reduced by CRT-D (hazard ratio [HR] for CRT-D/ICD only 0.94; P = .72). Among 761 patients with LBBB and CRT-D, mortality trended lower (HR 0.71; P = .10) after adjustment for clinical covariates. The effect of CRT-D on mortality was further evaluated in patients who did (responders) and did not (hypo-responders) have reduction in LVESV by≥30%. LBBB responders (n = 323) had significantly reduced mortality with CRT-D (HR 0.36; P = .027), and LBBB hypo-responders (n = 182) did not (HR 0.99). By contrast, non-LBBB responders (n = 89) trended toward more deaths with CRT-D (HR 2.11; P = .22). Non-LBBB hypo-responders (n = 118) had significantly worsened mortality (HR 3.72; P =.011). Conclusions In MADIT-CRT, late mortality with CRT-D varied markedly with baseline conduction defect and remodeling response. Patients with both LBBB and substantially reduced LVESV had improved mortality. Those with non-LBBB or with LBBB and less-reduced LVESV had unchanged or worsened mortality after CRT-D.

Anorexia nervosa (AN) is a complex psychiatric disorder that can have devastating cardiovascular complications. Its lesser-known association with pericardial effusion has been recently described in the literature. We present the case of a 45 year-old female who presented with a recurrent small bowel obstruction requiring lysis of adhesions and who was found to have a large pericardial effusion that progressed to cardiac tamponade necessitating surgical intervention. The patient had a body mass index of 14.8 kg/m2 (i.e. 71% of ideal body weight) and a long-standing history of food aversion, extreme exercise habits, and weight obsession consistent with AN. To the best of our knowledge, this is the first case of AN-associated cardiac tamponade in the United States, and the first requiring surgical intervention. In conclusion, with this and current data regarding AN-associated pericardial effusions, we recommend a low threshold for performing pre-operative echocardiography for those in whom AN is suspected.

The most feared drug-induced complication is fatal cardiac arrest. Torsades de pointes (TdP) is a polymorphic ventricular tachycardia occurring in the setting of a QT interval prolongation and is the most frequent type of drug-induced pro-arrhythmia. The most common mechanism of QT prolongation and TdP is blockade of the rapid component of the delayed rectifier repolarizing potassium conductance IKr. Anesthesiologists have extensive experience with QT prolonging drugs, but there are relatively few reports of TdP occurring in the perioperative setting. Nevertheless, regulatory concern regarding the drug droperidol resulted in a significant reduction in its use. Concern regarding two other agents that potently block IKr, i.e., sevoflurane and methadone, has grown, and practitioners are worried that these valuable agents may meet the same fate. In this review, the data regarding the TdP risk of droperidol, sevoflurane, and methadone are compared with particular emphasis on the different settings in which they are employed. While the three drugs are potent IKr inhibitors, little evidence exists to suggest that droperidol or sevoflurane are associated with significant proarrhythmia in the perioperative setting. Due to factors such as inhibition of the parasympathetic nervous system, prevention of hypoxia and hypercarbia, and attention to serum electrolytes, TdP is a very rare occurrence in the perioperative environment. Methadone, however, is typically given to outpatients, over long periods, and in combination with agents that inhibit its metabolism or are QT prolonging in their own right. Thus, pre- and post-drug electrocardiograms may be appropriate when prescribing methadone for outpatients, while the much lower risk for TdP (and the difficulties inherent in QT measurement in the perioperative period) render this approach unfruitful and worthy of reevaluation.

In this edition of the Journal, the Center for Substance Abuse Treatment (CSAT) publishes the recommendations of its expert panel regarding QT interval screening in methadone maintenance treatment ...

Background Increased temporal variability of repolarization, as reflected by QT interval variability measured over 10–15 minutes, predicted spontaneous ventricular arrhythmias and death in implantable cardioverter-defibrillator patients in mild to moderate heart failure (HF). Objective The purpose of this study was to test our hypothesis that increased mean QT variability over 24 hours would be associated with increased cardiovascular (CV) mortality in a heterogeneous HF population. Methods The Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure trial prospectively enrolled subjects with HF of any cause. Twenty-four-hour Holter recordings from 268 subjects were analyzed using a template-matching, semiautomatic algorithm to measure QT and heart rate time series in sequential 5-minute epochs over 24 hours. The QT variability index (QTVI) was expressed as the log ratio of the normalized QT variance over normalized heart rate variance. Total and CV mortality were assessed as a function of continuous and dichotomous QTVI (>−0.84) in univariate and multivariable Cox proportional hazards models, adjusting for significant clinical predictors. Results After a median of 47 months, there were 53 deaths, of which 44 were from CV causes. A significant association with the outcome was found for QTVI both as continuous and dichotomous variables after adjustment for clinical covariates (age >70, New York Heart Association class III–IV, left ventricular ejection fraction, nonsustained ventricular tachycardia, creatinine): QTVI hazard ratio (HR) 4.0 (confidence interval [CI] 1.8–88; P = .008) for total and 4.4 (CI 1.9–10.1; P = .0006) for CV mortality; QTVI >−0.84 HR 2.0 (CI 1.1–3.6; P = .02) for total and 2.1 (CI 1.1–3.8; P = .02) for CV mortality. Conclusion Increased repolarization lability, as reflected in QTVI measured over 24 hours, is associated with increased risk for total and CV mortality in a heterogeneous population with chronic HF.

Previous studies have shown that increased temporal variability of repolarization, as reflected by QT interval variability measured for 10 minutes, predicted spontaneous ventricular arrhythmias in implantable cardioverter defribrillator patients, but it is unclear how these measures perform in 24-hour recordings.Twenty-four-hour digital Holter recordings from 372 subjects with chronic heart failure enrolled in Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca, (GISSI) Heart Failure study were analyzed using a template-matching, semiautomatic algorithm to measure QT and heart rate time series in sequential 5-minute epochs for 24 hours. QT variability was expressed as normalized QT variance (QTVN) or as the log ratio of the QTVN over normalized heart rate variance (QT variability index, or QTVI).A pronounced diurnal variation was seen in both QTVI and QTVN. Both were lowest in the midnight to 6 am time frame and increased throughout the day, peaking at noon to 6 pm, then decreasing 6 pm to midnight. For QTVI, all 4 time points were significantly different (P.0001). QT variability index correlated with heart rate (r = 0.38, P.0001) and was significantly higher for those in higher New York Heart Association (NYHA) classes (r = 0.22, P = .0003). Normalized QT variance did not correlate with heart rate or NYHA but correlated negatively with serum potassium (r = -0.22, P = .0002) and manifested the greatest increase during midmorning hours.Repolarization lability as reflected in QT variability has a pronounced diurnal variation and increases significantly after 6 am, the time of greatest arrhythmic risk. QT variability for 24 hours might improve risk prediction in chronic heart failure patients and should be tested in appropriate trials.

Background Healthy women have longer QT intervals and more drug-induced proarrhythmia compared to men, yet those given implantable cardioverter-difibrillators (ICDs) for ischemic cardiomyopathy have fewer episodes of ventricular tachycardia/ventricular fibrillation (VT/VF) than men. The role of repolarization duration and stability in arrhythmogenesis in men and women with structural heart disease has not been explored. Objectives The purpose of this study was to analyze repolarization differences between men and women and their relation to the risk of VT/VF. Methods Multicenter Automatic Defibrillator Trial II study patients underwent 10-minute, resting digitized recordings at study entry. QT and heart rate were measured for each beat with a semiautomated method. QT variance was normalized for mean QT (QTVN) or for heart rate variance (QTVI). Spectral analysis of heart rate and QT time series was performed; coherence was indexed to quantify consistency of heart rate and QT power spectra. The incidence of VT/VF was determined by ICD interrogation. Results There were 805 usable recordings (142 females); 463 received ICDs (86 females). There was no gender difference in mean or median QT, QTc, or heart rate. QTVN and QTVI were slightly (but significantly) higher, and the mean coherence was lower in women. In a Cox multivariate analysis, increased QTVN or QTVI (top quartile) was associated with a significantly higher risk for VT/VF in men (QTVN hazard ratio (HR) 2.2; confidence interval [CI] 1.4–3.4; P = .001; QTVI HR 1.9; CI 1.2–3.0; P = .006) but not in women, while reduced coherence (bottom quartile) predicted VT/VF in women (HR 3.3; CI 1.2–9.0; P = .021) but not in men. Conclusions In post–myocardial infarcation patients with depressed ejection fraction, both women and men manifest increased temporal variability in the QT interval. In men, QT variability by itself raised arrhythmic risk. In women, however, QT variability dissociated from HR variability (low coherence) appeared to be a uniquely significant predictor of arrhythmic events.

Clinical trials suggest females experience less heart failure (HF) progression, mortality, and arrhythmia frequency. HF increases Na/Ca exchanger (NCX) expression and activity contributing to both depressed contractility and ventricular arrhythmias, but whether gender modifies this effect is unknown. Left ventricular myocytes were isolated from control and from tachycardic pacing-induced failing swine hearts of both sexes. The Ni-sensitive NCX current (I(NCX)) was measured in voltage clamp after blocking other channels. In control myocytes there is no difference in basal I(NCX) and beta-adrenergic responsiveness between male and female animals. HF greatly increased I(NCX) and reduced beta-adrenergic responsiveness in males compared to females, an effect that was eliminated by PP1. Diuretic therapy (furosemide, 1 mg/kg/day) further enhanced I(NCX) and reduced beta-adrenergic responsiveness in females and eliminated the gender difference. Gender-specific differences in calcium handling may contribute to improved survival of females in HF.

The appropriate initial treatment of a middle-aged individual with symptomatic paroxysms of atrial fibrillation, diabetes, and hypertension should focus on eliminating the underlying causes of disease to safely reduce morbidity and prolong life. An initial strategy using ablation temporarily reduces arrhythmia symptoms and exposes the individual to potentially needless risk and repeat procedures. Randomized trials have not established the superiority of ablation to antiarrhythmic drugs with respect to prolonging life or reducing serious morbidity. It is appropriate to treat modestly symptomatic individuals with antiarrhythmic drugs while performing aggressive risk factor modification.

Cardiac-related clinical practice guidelines have become an integral part of the practice of cardiology. Unfortunately, these guidelines are often long, complex, and difficult for practicing cardiologists to use. Guidelines should be condensed and their format upgraded, so that the key messages are easier to comprehend and can be applied more readily by those involved in patient care. After presenting the historical background and describing the guideline structure, we make several recommendations to make clinical practice guidelines more user-friendly for clinical cardiologists. Our most important recommendations are that the clinical cardiology guidelines should focus exclusively on (1) class I recommendations with established benefits that are supported by randomized clinical trials and (2) class III recommendations for diagnostic or therapeutic approaches in which quality studies show no benefit or possible harm. Class II recommendations are not evidence based but reflect expert opinions related to published clinical studies, with potential for personal bias by members of the guideline committee. Class II recommendations should be published separately as "Expert Consensus Statements" or "Task Force Committee Opinions," so that both majority and minority expert opinions can be presented in a less dogmatic form than the way these recommendations currently appear in clinical practice guidelines.

Synthetic opioid agents have been used in modern medicine for over a century and for opioid addiction treatment for over a half-century. Liberal use of opioids in the United States has been attended by an extraordinary increase in opioid-related mortality, with over 16,000 deaths in 2012. As there have been advances in opioid agents for pain and addiction, so have there been advances in our understanding of the cardiac effects of these agents. In the last 10 years, significant data regarding electrophysiologic effects of these agents have been collected. We aim in this review to discuss the effects on cardiac electrophysiology of the various opioid agents currently in use and the evidence that these effects are contributing to the rise in opioid-related mortality.

The decision to undergo pericardectomy for symptomatic pericardial constriction is usually dictated by an image of an abnormal pericardium. We report a case of symptomatic pericardial constriction despite radiographic and pathological evidence of a normal pericardium. The patient was successfully treated with a pericardectomy, with resolution of constrictive hemodynamics and symptoms. Our report suggests that a normal pericardium by computed tomography and biopsy should not preclude pericardectomy for patients who have refractory symptoms, physical findings, and intracardiac pressures diagnostic of constrictive pericarditis.

The Food and Drug Administration recently banned the sale of ephedra alkaloids because of their association with arrhythmic sudden death, myocardial infarction, and stroke. This has resulted in the emergence of formulations marketed for weight loss and performance enhancement that are "ephedra free" but contain other sympathomimetic substances, the safety of which has not been established. We report a case of exercise-induced syncope in a healthy 22-year-old woman that occurred 1 hour after she took the second dose of Xenadrine EFX, an ephedra-free weight-loss supplement. Electrocardiography revealed prolongation of the QT interval (corrected QT, 516 milliseconds); this resolved in 24 hours. Results of echocardiography and exercise stress testing were normal. Nine months of monitoring with an implanted loop recorder revealed no arrhythmias in the absence of Xenadrine EFX. Although this product contains a number of compounds whose pharmacologic effect is poorly characterized, notable quantities of phenylephrine are present, and the proarrhythmic potential of this compound in the setting of exercise is discussed.

Objectives We sought to determine whether non–potassium-sparing diuretics (PSDs) in the absence of a PSD may result in progressive heart failure (HF). Background Angiotensin-converting enzyme (ACE) inhibitors incompletely suppress ACE activity in HF patients. Furthermore, non-PSDs are activators of aldosterone secretion. We reasoned that non-PSDs, in the absence of a PSD, might result in progressive HF. Methods In the 6,797 patients in the Studies Of Left Ventricular Dysfunction (SOLVD), we compared the risk of hospitalization for, or death from, HF between those taking a PSD and those who were not, adjusting for known covariates. Results The risk of hospitalization from worsening HF in those taking a PSD relative to those taking only a non-PSD was 0.74 (95% confidence interval [CI] 0.55 to 0.99; p = 0.047). The relative risk for cardiovascular death was 0.74 (95% CI 0.59 to 0.93; p = 0.011), for death from all causes 0.73 (95% CI 0.59 to 0.90; p = 0.004), and for hospitalization for, or death from, HF 0.75 (95% CI 0.58 to 0.97; p = 0.030). Compared with patients not taking any diuretic, the risk of hospitalization or death due to worsening HF in patients taking non-PSDs alone was significantly increased (risk ratio [RR] = 1.31, 95% CI 1.09 to 1.57; p = 0.0004); this was not observed in patients taking PSDs with or without a non-PSD (RR = 0.99, 95% CI 0.76 to 1.30; p = 0.95). Conclusions The use of PSDs in HF patients is associated with a reduced risk of death from, or hospitalization for, progressive HF or all-cause or cardiovascular death, compared with patients taking only a non-PSD.

c t r b ( p Sudden cardiac arrest remains a leading cause of death, the underlying cause typically being ventricular tachycardia or ventricular fibrillation (VT/VF). The mechanism for VT/VF is thought to be reentry in most cases, but our inadequate understanding of how reentry is initiated hampers our ability both to identify those at greatest risk and to design preventive strategies. The theory of repolarization alternans has been proposed as an explanation of how reentry is induced in the absence of identifiable anatomic obstacles. The induction of reentrant VT/VF requires heterogeneous excitability leading to conduction block (“wave break”) of a premature stimulus at an area of temporary refractoriness while conduction persists in adjoining tissue. The resulting wave of depolarization can lead to further wave break and propagation of daughter waves, resulting in meandering, multiwave fibrillation. While Antzelevitch et al have shown that significant transmural gradients of reolarization heterogeneity exist even in normal ventricles, ource-sink mismatch prevents the induction of reentry by ypical premature foci. Under stressful conditions, that is, high stimulation rates, drugs that alter ion channel kinetics, or sympathetic stimulation, spatially differential variability in repolarization may occur transiently, increasing the risk for wave break in the presence of a premature stimulus. When the duration of the action potential alternately shortens and prolongs in a fixed short-long-short-long pattern, repolarization alternans exists. If repolarization alternans occurs in a consistent manner across a region of the ventricular wall, it is considered spatially concordant alternans. If, however, an area of myocardium manifests action potential prolongation and shortening while an adjacent area manifests alternans in the opposite phase, that is, long-short in one area and short-long in another, it is referred to as spatially discordant alternans. Discordant alternans have

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.

Abstract Studies in animal models and humans suggest that myocardium may adapt to chronic or intermittent prolonged episodes of reduced coronary perfusion. Stable maintenance of partial flow reduction is difficult to achieve in experimental models; thus, in vitro cellular models may be useful for establishing the mechanisms of adaptation. Since moderate hypoxia is likely to be an important component of the low-flow state, isolated adult rat cardiac myocytes were exposed to 1% O 2 for 48 hours to study chronic hypoxic adaptation. Hypoxic culture did not reduce cell viability relative to normoxic controls but did enhance glucose utilization and lactate production, which is consistent with an anaerobic pattern of metabolism. Lactate production remained transiently increased after restoration of normal O 2 tension. Myocyte contractility was reduced (video-edge analysis), as was the amplitude of the intracellular Ca 2+ transient (indo 1 fluorescence) in hypoxic cells. Relaxation was slowed and was accompanied by a slowed decay of the Ca 2+ transient. These changes were not due to alterations in the action potential. Tolerance to subsequent acute severe hypoxia occurred in cells cultured in 1% O 2 and was manifested as a delay in the time to full ATP-depletion rigor contracture during severe hypoxia and enhanced morphological recovery of myocytes at reoxygenation. The latter was still seen after normalization of the data for the prolonged time to rigor, suggesting a multifactorial basis for tolerance. An intervening period of normoxic exposure before subsequent acute severe hypoxia did not result in loss of tolerance but rather increased the delay to subsequent ATP depletion rigor. Cellular glycogen was preserved during chronic hypoxic exposure and increased after the restoration of normal O 2 tension. As mitochondrial cytochromes should be fully oxygenated at levels well below 1% O 2 , hypoxic adaptation may be mediated by a low-affinity O 2 -sensing process. Thus, adaptations that occur during prolonged periods of moderate hypoxia are proposed to poise the myocyte in a better position to tolerate impending episodes of severe O 2 deprivation.

An increasing number of academic senior physicians are approaching their potential retirement in good health with accumulated clinical and research experience that can be a valuable asset to an academic institution. Considering the need to let the next generation ascend to leadership roles, when and how should a medical career be brought to a close? We explore the roles for academic medical faculty as they move into their senior years and approach various retirement options. The individual and institutional considerations require a frank dialogue among the interested parties to optimize the benefits while minimizing the risks for both. In the United States there is no fixed age for retirement as there is in Europe, but European physicians are initiating changes. What is certain is that careful planning, innovative thinking, and the incorporation of new patterns of medical practice are all part of this complex transition and timing of senior academic physicians into retirement.

Purpose: Romidepsin is a histone deacetylase inhibitor (HDI) approved for the treatment of both cutaneous and peripheral T-cell lymphoma (CTCL and PTCL). During development, a thorough assessment of cardiac toxicity was conducted. Experimental Design: A phase II single-agent nonrandomized study of romidepsin was conducted in patients with CTCL or PTCL who had progressed after at least 1 prior systemic therapy. Results: Results for the first 42 patients enrolled on the NCI 1312 phase II study of romidepsin in CTCL or PTCL showed no cardiac toxicity based on serial electrocardiograms (ECG), troponins, and MUGA scans/echocardiograms. The cardiac assessments reported herein confirm the safety of romidepsin among 131 enrolled patients, while supporting a role for electrolyte replacement. Heart rate increased an average 11 bpm following romidepsin infusion; there was no evidence of increased arrhythmia. Criteria for potassium/magnesium replacement were met before 55% of 1365 romidepsin doses; an association with hypoalbuminemia was confirmed. We propose a mechanism for ST segment flattening and depression, the most common ECG abnormalities observed: HDI-induced alteration of the activity or expression of KATP channels. In addition, examination of the variants of the active transporter of romidepsin, ABCB1, showed a trend toward smaller heart rate changes in the peri-infusion period among wild-type than variant diplotypes. Conclusions: We conclude that in the context of appropriate attention to electrolyte levels, the data support the cardiac safety of romidepsin. Clin Cancer Res; 19(11); 3095–104. ©2013 AACR.

Background Intracellular magnesium ([Mg] i ) plays an important role in the regulation of myocardial metabolism, contractility, and the maintenance of transsarcolemmal and intracellular ionic gradients. An understanding of the role of magnesium in the clinical setting, however, is hampered by the lack of an assay of intracellular tissue magnesium levels. Methods and Results We used energy-dispersive x-ray analysis to measure [Mg] i in sublingual epithelial cells and to correlate the level with those in atrial biopsy specimens from the same patients during cardiopulmonary bypass. Levels were also measured in acute myocardial infarction (AMI) patients before and after intravenous magnesium sulfate administration and compared with those from intensive care unit (ICU) patients and healthy individuals. A strong correlation between sublingual epithelial cell (mean, 32.1±0.3 mEq/L) and atrial tissue (mean, 32.1±0.3 mEq/L) [Mg] i was present in 18 cardiac surgery patients ( r =.68, P i levels were lower than in healthy individuals (33.7±0.5 mEq/L, P i in 22 AMI patients was 30.7±0.4 mEq/L, which was significantly lower than in 21 ICU patients and 15 healthy individuals (35.0±0.5 mEq/L and 34.5±0.7 mEq/L, respectively, P i rose significantly in the AMI patients over the first 24 hours, and the magnitude of the increase was greater in those who received higher doses of intravenous magnesium sulfate. Conclusions Sublingual epithelial cell [Mg] i correlates well with atrial [Mg] i but not with serum magnesium. [Mg] i levels are low in patients undergoing cardiac surgery and those with AMI. Intravenous magnesium sulfate corrects low [Mg] i levels in AMI patients. Energy-dispersive x-ray analysis determination of sublingual cell [Mg] i may expedite the investigation of the role of magnesium deficiency in heart disease.

Intense exercise requires a significant increase in cardiac output in order to meet the needs of the skeletal muscles for oxygenated blood. In order to improve cardiac performance, the autonomic nervous system increases sympathetic tone primarily through release of norepinephrine from postganglionic receptors to stimulate the β-adrenergic receptors of the nodal and muscle tissue of the heart. This event initiates a signaling cascade focused on increasing the amount of calcium available to the contractile myofilaments in the cardiac cell. Failure of the myocytes to counterbalance the increase in inward ion flow or adequately sequester cytosolic calcium during diastole leads to potentially catastrophic electrical instability. In this review, the relationship between the cellular events initiated by exercise and the induction of arrhythmias associated with the long QT, Brugada, and Wolff-Parkinson-White syndromes; catecholaminergic polymorphic ventricular tachycardia; and the heritable cardiomyopathies are explored.

We recently demonstrated local voltage potentials indicating conduction impairment and block in the sinus beats preceding ventricular premature beats (VPBs) originating in the ventricular outflow tracts.The purpose of this study was to test the hypothesis that impairment of impulse conduction would also lead to changes in the contractile performance of sinus beats preceding ventricular ectopy using Tissue Doppler echocardiography.Twenty-three consecutive patients with VPBs were examined in the apical 4-chamber view with a frame rate of 150 Hz (GE VIVID VII). Eleven patients had no structural heart disease, 5 had dilated cardiomyopathy, 4 had ischemic heart disease, 2 had arrhythmogenic right ventricular dysplasia, and 1 had aortic stenosis. The ectopy originated in the ventricular outflow tracts in 15 patients and in the left ventricle 8. Eleven of the patients underwent radiofrequency ablation of the VPBs.Tissue Doppler imaging demonstrated a highly statistically significant decrease in myocardial performance in the last sinus beat before the VPB compared to earlier sinus beats. Thus, ejection time (time to peak end-systolic contraction) and peak systolic velocity shortened significantly (P.001 for both) with a subsequent reduction in systolic shortening (end-systolic displacement; P.001).Ventricular ectopy is preceded by a significant decrease in myocardial performance in the last sinus beat preceding VPBs as observed in consecutive patients with a broad variety of heart conditions pointing to a mutual underlying electrical mechanism (ie, localized conduction block confined to an area surrounding the ectopic pacemaker).