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The exact medical complications, leading to the well-known high risk of death in patients with anorexia nervosa (AN), remain elusive. Such deaths are often abrupt with no satisfactory explanation. Suspected causes include cardiac QTc prolongation and, in turn, torsade de pointes (TdP). Psychotropic medications often prescribed to these patients are linked to QTc prolongation. AN is also presumed to cause heart failure due to malnutrition with increased susceptibility to QTc prolongation, and TdP, resulting in sudden cardiac death. Recent literature, however, is conflicting, and the likely cause of death may involve other cardiac abnormalities, such as low heart rate, abnormal heart rate variability, or increased QT dispersion. With an ongoing gap in research explaining the high mortality rate in AN, a compelling need to define the exact proximate causes of death in these patients remains. Because low serum potassium is the most common trigger for TdP, we postulate the early signal of sudden cardiac death, especially in patients with AN who purge, is hypokalemia. We also speculate that hypoglycemia could be a major factor in the sudden death of patients with AN as well as bradycardia or sinus arrest. A path forward to elucidate potential causes is offered.

Ascertainment of the left ventricular ejection fraction is the primary reason for ordering echocardiography in the acute care setting; however, this parameter does not provide information regarding a patient's volume status. As such, it cannot be reliably used to inform decisions regarding intravenous fluid resuscitation or diuresis, particularly in undifferentiated dyspnea and hypotension. This is relevant given a national quality improvement exhortation to provide aggressive fluid resuscitation as part of a "sepsis bundle." This initiative must be tempered by the well-established increase in hospital mortality from providing intravenous fluid to patients with unrecognized heart failure, which may occur if sepsis is misdiagnosed. We describe herein, what is to our knowledge, the first description of a critically elevated Doppler ratio of mitral inflow peak E-wave velocity to the mean mitral annular velocity as a harbinger of sudden death from pulmonary edema in a patient treated with aggressive intravenous fluids as part of the "sepsis bundle." This is utilized as a springboard for proposing a clinical algorithm focused on expedited echocardiography. It emphasized the potential value of advancing markedly the diastolic assessment of filling pressure (ratio of mitral inflow peak E-wave velocity to the mean mitral annular velocity) in the acute care setting to a level of import comparable to the left ventricular ejection fraction.

Aims In this secondary analysis of the VOYAGER trial, rivaroxaban 2.5 mg twice/day plus aspirin 100 mg/day was assessed in older adults. Advanced age is associated with elevated bleeding risk and unfavourable net benefit for dual antiplatelet therapy in chronic coronary artery disease. The risk–benefit of low-dose rivaroxaban in patients ≥75 years with peripheral artery disease (PAD) after lower extremity revascularization (LER) has not been described. Methods and results The primary endpoint was a composite of acute limb ischaemia, major amputation, myocardial infarction, ischaemic stroke, or cardiovascular death. The principal safety outcome was thrombolysis in myocardial infarction (TIMI) major bleeding analysed by the pre-specified age cut-off of 75 years. Of 6564 patients randomized, 1330 (20%) were >75 years. Absolute 3-year Kaplan–Meier cumulative incidence rates for primary efficacy (23.4% vs. 19.0%) and safety (3.5% vs. 1.5%) endpoints were higher in elderly vs. non-elderly patients. Efficacy of rivaroxaban (P-interaction 0.83) and safety (P-interaction 0.38) was consistent irrespective of age. The combination of intracranial and fatal bleeding was not increased in patients >75 years (2 rivaroxaban vs. 8 placebo). Overall, benefits (absolute risk reduction 3.8%, number needed to treat 26 for the primary endpoint) exceeded risks (absolute risk increase 0.81%, number needed to harm 123 for TIMI major bleeding). Conclusion Patients ≥75 years with PAD are at both heightened ischaemic and bleeding risk after LER. No excess harm with respect to major, intracranial or fatal bleeding was seen in older patients yet numerically greater absolute benefits were observed. This suggests that low-dose rivaroxaban combined with aspirin should be considered in PAD after LER regardless of age.

Hispanics in the United States have worse cardiovascular disease (CVD) risk factor profiles than non-Hispanic Whites. Cardiovascular health literacy is important for health promotion but is not well characterized among monolingual Spanish-speaking Hispanics outside of health care settings. We recruited Hispanic participants (N=235) from a community-based health fair in Denver, Colorado. A total of 182 participants (77%) completed a subsequent language-congruent telephone survey to assess CVD risk-factor knowledge. Of these, 174 self-identified as monolingual Spanish-speaking, and constituted the analysis cohort. Cardiovascular disease risk knowledge score was defined as the number of established risk factors an individual participant could name (out of 10 pre-specified), and multivariable regression analyses were conducted to determine factors independently associated with knowledge. The mean knowledge score for the cohort was 2.2 ± 1.1 out of 10. This suggests an unmet need for tailored educational interventions beyond simple screening events.

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.

Atraumatic chest pain is a common emergency department (ED) presentation and the American College of Cardiology and American Heart Association recommends stress testing within 72 hours. The HEART score predicts major adverse cardiac events (MACE) in ED populations and does not require universal stress testing. An evaluation based solely on history, electrocardiography, and biomarkers, therefore, is an attractive approach to risk stratification in resource-limited settings. The HEART score has not been previously evaluated in a safety net hospital setting. We therefore implemented an interdisciplinary clinical care guideline utilizing the HEART score to stratify patients presenting to our inner-city hospital. During a 6-month study period, 1170 patients were evaluated (521 before and 649 after implementation). Among the 998 patients with confirmed follow-up 6-weeks after the index ED encounter, the prevalence of MACE (all-cause mortality, acute myocardial infarction, or coronary revascularization) was 0% [95% confidence interval (CI), 0%-1%] for low, 9% (95% CI, 7%-12%) for moderate, and 52% (95% CI, 39%-65%) for high-risk groups. Guideline implementation significantly increased admissions (+12%, 95% CI, 7%-17%) primarily in the moderate risk group (+38%, 95% CI, 29%-47%), but significantly decreased median ED length of stay (-37 minutes, 95% CI, 17-58). It also led to an increase in stress testing among moderate and high-risk patients (+10%, 95% CI, 0%-19%). In conclusion, the HEART score effectively stratified risk of MACE in a safety net population, improved evaluation consistency, and decreased ED length of stay. However, implementation was associated with an increase in hospitalizations and stress testing. Although the American Heart Association/American College of Cardiology guideline regarding atraumatic chest pain in the ED recommends universal noninvasive testing, the value of this approach, particularly in conjunction with the HEART score is uncertain in safety net hospitals. Further evaluation of the costs and clinical advantages of this approach are warranted.

Anorexia nervosa is a mental illness characterized by self-starvation, marked weight loss, and malnutrition. As the illness worsens, numerous medical complications develop throughout the body. Some of these resolve with effective nutritional rehabilitation and weight gain, whereas others can lead to permanent damage.

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.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are antihyperglycemic medications with cardiovascular disease and renal protective properties. While clinical trials supporting their efficacy, the utility among safety-net health system patients with low health literacy has not been evaluated. We sought to assess appropriate monitoring, safety and effectiveness of GLT2i initiation at a safety-net hospital. From May 2017 to July 2020, 150 patients were newly initiated on an SGLT2i therapy. We evaluated appropriate initiation, laboratory monitoring, impact on urine microalbumin, mean hemoglobin A1c (HbA1c), and systolic blood pressure (SBP). We also analyzed primary care versus subspecialty prescriber patterns. All patients did not have prohibitive renal dysfunction based on Food and Drug Administration labeling and the majority (N = 101, 67%) had renal function testing completed before initiation. Improvement in cardiovascular disease surrogate markers including SBP (mean, -3.12 mm Hg), albuminuria (mean, -3.98 mg/dL), and HbA1c (mean, -1.06%) were observed. A total of 94% of the cohort had serum chemistry panels drawn, yet only 4% were performed within the protocol-specified (14-day) period. Primary care and cardiology providers were the sole prescribers; despite the known renoprotective properties, no patients were initiated on SGLT2i therapy by a nephrologist. In conclusion, the benefits of SGLT2i drugs reducing SBP, albuminuria, and HbA1c observed in clinical trials were duplicated in our safety-net population. Therefore, ongoing education and promotion to providers to ensure broadened utilization and timely renal function monitoring appear warranted.

Bradycardia is common among patients with severe anorexia nervosa (AN). Though generally reversible,1 marked bradycardia may be worrisome to clinicians with limited experience treating eating disorders. While most patients are asymptomatic, a significant minority present with presyncope, lightheadedness, fatigue, and exercise intolerance that could be construed as concordant with current guidelines for permanent pacemaker (PPM) implantation.2 However, symptoms may not reflect bradycardia per se, but rather extreme malnutrition, deconditioning, and hypovolemia associated with restricted caloric intake and purging. Guidelines on the evaluation and management of patients with bradycardia enumerate many potentially reversible causes of sinus node dysfunction, but do not mention severe AN, nor do they proscribe PPM among eating disorder populations.2 The degree of bradycardia can be extreme, with junctional escape rhythms as low as 20 beats per minute (bpm) and may be an indication for hospitalization.3 In a prior inpatient case series the mean heart rate was 44 bpm, with 69% of patients less than 50 bpm.4 Several mechanisms have been postulated to explain bradycardia: increased parasympathetic tone, decreased intracardiac glycogen stores, and myocardial atrophy with resultant structural changes, including fibrosis, on gadolinium-enhanced magnetic resonance imaging.5, 6, 7, 8, 9 Despite functional and structural myocardial changes, bradycardia may principally reflect reduced metabolic demand and cardiac output as a compensatory response to starvation. Weight restoration, therefore, is the mainstay of treatment, with normalization of heart rate upon achieving 85%–90% of ideal body weight (IBW).10 Despite this natural history, profound bradycardia is often distressing to caregivers and may lead to unnecessary PPM placement and attendant iatrogenic morbidity, including exacerbation of existing distorted body self-image. Given this background, we present 4 AN patients transferred to our medical stabilization unit with marked bradycardia, all of whom had manifestations typical of “symptomatic bradycardia.” Two were initially referred by outside facilities for PPM, and 2 had recent pacemaker implants, which we ultimately extracted. Our analysis received exemption from the Colorado Multiple Institutional Review Board (Protocol 19-0547).

Background The cost-effectiveness of community health worker (CHW)-based cardiovascular disease (CVD) risk-reduction interventions is not well established. Colorado Heart Healthy Solutions is a CHW-based intervention designed to reduce modifiable CVD risk factors. This program has previously demonstrated success, but the cost-effectiveness is unknown. CHW-based interventions are potentially attractive complements to healthcare delivery because laypersons implement the intervention at a lower cost relative to medical care and may be attractive in rural settings with limited clinical resources. Methods CHWs performed screenings and provided ongoing participant support within predominantly rural communities. A point-of-service software tool was used to generate 10-year Framingham CVD risk scores and assist CHWs to make medical referrals and provide ongoing individualized support for lifestyle changes. A sample of program participants returned for reassessment of risk factors. We calculated quality-adjusted life years (QALYs) gained and program costs using a Markov model. Transition probabilities were calculated using Framingham risk equations or derived from the literature using the observed mean reduction in 10-year CVD risk score over of 37- months follow-up. Program cost-effectiveness was calculated for both at-risk (abnormal baseline CVD risk factors) and overall program populations. Results The base-case scenario evaluating a 52-year-old male participant revealed an incremental cost savings of $3576 and a gain of 0.16 QALYs associated with the intervention. Cost savings were greater in at-risk populations. The economic dominance of the model was robust in multiple sensitivity analyses. Conclusions A community-based CVD intervention demonstrated to reduce CVD risk is cost-effective. This suggests that population-based public health programs may have the potential to complement primary care preventative services to improve health and reduce the burden of traditional medical care.

The statewide Colorado Healthy Heart Solutions (CHHS) program provides cardiovascular disease (CVD) risk factor screening and education to the medically underserved and has been shown to improve CVD risk profiles. We aimed to enhance its effectiveness through addition of a mobile health (mHealth) intervention using SMS messaging (termed Cardio SMS). We conducted a prospective, non-randomized controlled pilot trial of this intervention implemented at 5 rural program sites (number of participants N = 204) compared with a contemporaneous propensity-score matched control group from 14 CHHS sites not receiving the intervention (N = 408) between 2012 and 2014. All participants were free of CVD at baseline, and follow-up time was 12-months. The primary outcome was program engagement, defined as the number of completed interactions with the program during the entire follow-up period. Secondary outcomes were program retention, defined as any interaction during the last two months of the study; change in self-reported healthy behaviors (physical activity, weight loss, smoking cessation, fat intake); and change in CVD risk factors. There were trends for differences between groups across multiple outcomes, but most did not reach statistical significance, except for a greater decrease in self-reported fat intake in the intervention vs. control groups (26.3% vs 10.6%, P = 0.001). In addition, a subset of surveyed participants who viewed the SMS messages as motivating showed greater program retention (P = 0.03). Given the relative ease and scalability of SMS interventions in rural underserved communities, further study of SMS as part of multicomponent strategies for CVD prevention is warranted. Keywords: Mobile health, Cardiovascular disease, Primary prevention

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.

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.

Drugs of abuse often have important effects on the cardiovascular system, some of which are life threatening. An understanding of the intersection between addictive and cardiovascular disorders is increasingly relevant to general practitioners, emergency physicians, and psychiatrists. The effects of these drugs vary depending upon the agent, dose, route of administration, and potential interactions with other medications. Cardiovascular consequences can range from innocuous side effects, such as mild tachycardia and hypertension, to life-threatening ventricular arrhythmias and myocardial infarction. Hemodynamic alterations are common with both active drug abuse and withdrawal and are frequently mediated by the autonomic nervous system.

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.

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.

A primigravida 26‐year‐old woman who had developed pre‐eclampsia with malignant hypertension at 30 weeks of gestation suffered acute myocardial infarction two days postpartum. Electrocardiogram demonstrated diffuse ST‐segment depression suggestive of subendocardial ischemia. Echocardiography demonstrated focal asymmetric left ventricular hypertrophy, with a characteristic “basal septal bulge”, and a left ventricular mid‐cavitary gradient of 51 mmHg. Coronary angiography revealed normal coronary arteries and vascular flow. Peripartum acute myocardial infarction is rare and portends a high mortality. However, to date, only one case of acute myocardial infarction associated with asymmetric left ventricular hypertrophy and pre‐eclampsia has been described in the literature.

Ultrasound contrast-enhanced stress echocardiography improves endocardial visualization, but diagnostic test rates versus stress myocardial perfusion imaging (MPI) have not been studied. A prospective randomized trial was performed between April 2012 and October 2014 at a single-center, safety net hospital. Hospitalized patients referred for noninvasive stress imaging were randomized 1:1 to stress echocardiography or stress MPI. The primary outcome was diagnostic test rate defined as interpretable images and achievement of >85% of age-predicted maximal heart rate (for dobutamine and exercise). Rates were assessed among those completing testing and then based solely on image interpretability. Charges and length of stay were secondary outcomes. A total of 240 patients were randomized, and 229 completed testing. Diagnostic test rates were similar for stress echocardiography versus MPI {89.4% [95% confidence interval (CI), 82.2-94.4] vs. 94.8% [95% CI, 89.1-98.1], P = 0.13} and did not differ with multivariable adjustment. Modalities requiring a diagnostic heart rate criteria were more frequently ordered with stress echocardiography (100% vs. 26%; P < 0.001). Therefore, an imaging-based analysis without the 12 individuals who failed to achieve target heart rate (n = 217) was evaluated with diagnostic test rates of 100% versus 94.8% (95% CI, 89.1%-98.1%; P = 0.03) for stress echocardiography and MPI, respectively. Median length of stay did not differ. Median (interquartile range) test-related charges were lower with stress echocardiography: $2,424 ($2400-$2508) versus $3619 ($3584-$3728), P < 0.0001. Overall, tests were positive for ischemia in 8% of patients. In conclusion, contrast-enhanced stress echocardiography provides comparable diagnostic test rates to MPI with lower associated charges.

Eating disorders are unique in that they inherently have much medical comorbidity both as a part of restricting-type eating disorders and those characterized by purging behaviors. Over the last three decades, remarkable progress has been made in the understanding and treatment of the medical complications of eating disorders. Yet, unfortunately, there is much research that is sorely needed to bridge the gap between current medical knowledge and more effective and evidence-based medical treatment knowledge. These gaps exist in many different clinical areas including cardiology, electrolytes, gastrointestinal and bone disease. In this paper, we discuss some of the knowledge gap areas, which if bridged would help develop more effective medical intervention for this population of patients.

Introduction Community Heart Health Actions for Latinos at Risk is a community health worker–led cardiovascular disease risk reduction program targeting low-income urban Latinos. The impact of community programs linked with clinical care has not been well characterized. Methods Community Heart Health Actions for Latinos at Risk provided 12 weeks of lifestyle education. Changes in risk factors were assessed before and after completion. Univariate, bivariate, and multivariate analyses were used to determine factors associated with changes in risk factors. Results From 2009 to 2013, a total of 1,099 participants were recruited and 768 had risk factors measured at baseline and 12 weeks. All analyses were performed in 2016. In participants with abnormal baseline risk factors, significant (all p n =244); low-density lipoprotein cholesterol (–14 mg/dL, n =201); glucose (–8 mg/dL, n =454); triglycerides (–57 mg/dL, n =242); and Framingham risk score (–2.3%, n =301) were observed. Program completion (eight of 12 classes) was associated with the reduction in low-density lipoprotein cholesterol ( p =0.03) and systolic blood pressure ( p =0.01). After adjustment, low-density lipoprotein cholesterol reduction was greatest in participants newly prescribed lipid-lowering drugs (–30%, 95% CI= –48, –15). Conclusions A community health worker–led intervention lowered cardiovascular disease risk among vulnerable Latinos. Integration with primary care services was an essential program component.

Computer‐generated Bazett‐corrected QT (QTcB) algorithms are common in clinical practice and can rapidly identify repolarization abnormalities, but accuracy is variable. This report highlights marked rate‐corrected QT (QTc) interval prolongation not detected by the computer algorithm. A 26‐year‐old woman with anorexia nervosa was admitted with severe hypokalemia and ventricular ectopy. Computer‐generated QTcB was 485 ms, while manual adjudication yielded a QTcB of 657 ms and a Fridericia‐corrected QT (QTcF) interval of 626 ms using digital calipers. Computer‐generated QTc intervals may aid in clinical decision‐making. However, accuracy is variable, particularly in the setting of ectopy, and requires manual verification.

BACKGROUND Anorexia nervosa (AN) is associated with autonomic dysfunction and carries a high risk of sudden death, putatively attributed to ventricular tachyarrhythmias. To date, long-term cardiac monitoring has not been performed to confirm this speculation. METHODS AND RESULTS We assessed the safety and acceptability of an insertable cardiac monitor (ICM) in patients with severe AN with markedly reduced body mass index (BMI), and investigated heart rate (HR) and rhythm before and after weight restoration. Autonomic function was assessed as HR response to a standardized activity protocol at baseline and four additional visits over 360 days. The Florida Patient Acceptance Survey (FPAS) was used to measure ICM acceptability. During a mean follow-up of 10 months, no ICM-related complications occurred and ICM was well-accepted by the 11 study participants (nine women, aged 19-59 years, baseline BMI = 12.7 ± 1.6 kg/m2 ). Both resting and peak HR increased with weight restoration and were directly associated with BMI (both P

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

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.

Vascular markers such as pulse-wave velocity and carotid intima-media thickness (CIMT) might improve the prediction of incident cardiovascular disease beyond traditional risk factors. These vascular markers have not been well characterized in minority populations and might be more useful than inflammatory biomarkers. We conducted a prospective, longitudinal cohort study among hypertensive patients in an urban safety-net hospital. We evaluated inflammatory biomarkers, arterial pulse-wave velocity, and carotid intima-media thickness at baseline, 1 year, and 2 years. The primary outcome variable was CIMT. Generalized linear mixed-effects models were used to evaluate associations between CIMT and predictive variables accounting for the correlation of multiple measurements within subjects over time. For our secondary outcome, we used administrative and National Death Index data to determine all-cause death, and univariate relationships were evaluated. Among 175 subjects, 117 were Latino (67%) and 117 were female (67%). Pulse-wave velocity and CIMT regressed over time (both P

Background Patients with hypertrophic cardiomyopathy (HCM) are at a fourfold to sixfold higher risk of developing atrial fibrillation (AF) compared to the general population, though incidence rates among patients undergoing alcohol septal ablation (ASA) are not well characterized. The purpose of this study was to evaluate atrial fibrillation incidence following ASA. Methods We studied 132 consecutive HCM patients without comorbid AF that underwent 154 ASA procedures. The incidence of AF in follow-up was assessed through chart abstraction including electrocardiography. Survival free of AF was estimated using Kaplan-Meier methodology. Results Over a mean follow-up of 3.6 ± 2.7 years (maximum 11.3 years), 10 (7.6%) patients developed new-onset AF. Of those who developed AF, both resting and provoked left ventricular outflow tract (LVOT) gradients had improved significantly (difference –79.78 mm Hg, P ≤ 0.005). Severity of mitral regurgitation improved in 7 (70%) patients. Survival free of AF was estimated to be 99.1%, 93.7%, and 91.7% at 1, 3, and 5 years. Conclusions Despite relieving LVOT obstruction and improving mitral regurgitation severity via ASA, new-onset AF remained a common complication of hypertrophic cardiomyopathy.

Background Anorexia nervosa is associated with a markedly increased risk of sudden cardiac death, but the mechanism has not been elucidated. Whether QT prolongation is an intrinsic feature of eating disorders is uncertain because previous studies are limited by small sample size, and extrinsic factors associated with QT prolongation were inconsistently reported. This study set to determine population-mean heart-rate–corrected QT interval (QTc) in an unselected cohort of patients with eating disorders. Methods Electrocardiogram (ECG) data from 1026 consecutive adults admitted into residential treatment were stratified by subtype: anorexia nervosa (caloric restriction only), anorexia nervosa binge-purge, and bulimia nervosa. Eating disorders not otherwise specified were excluded. Population-mean Fridericia-corrected QTc and categorical QTc threshold analysis were performed. Multivariable regression, controlling for age sex, duration of illness, body mass index (BMI), hypokalemia, QTc-prolonging drugs, purging behaviors, and laxatives was assessed. Results Among 906 patients, population-mean QTc (424 ± 25 standard deviation [SD]) was normal and lowest among patients with anorexia nervosa (417.3 ± 22.3, P 500 ms); all 11 patients had hypokalemia and were receiving QTc-prolonging medications or laxatives. After controlling for clinically relevant covariates, differences in mean QTc across eating disorder subtypes diminished yet persisted (P = 0.048). Conclusions In the largest study of patients with eating disorders, population-mean QTc was normal and varied by subtype. Marked QTc prolongation occurred solely in the presence of extrinsic factors, suggesting that QTc prolongation is not intrinsic to eating disorders. Therefore, further study is needed to define the etiology of sudden death in patients with eating disorders.

Coronary artery aneurysms (CAA) are a rare cause of acute coronary syndrome and there is little consensus as to the optimal treatment. Based on case series as well as expert opinion, surgery has been suggested as the optimal treatment for a giant CAA. Here, we present the case of a patient with recurrent myocardial infarction and severe angina due to a giant CAA, who was deemed a poor surgical candidate due to his multiple medical comorbidities. Given his intractable anginal symptoms despite medical therapy, he chose to pursue percutaneous intervention. However, the aneurysm was larger than available covered coronary stents and the patient had significant atherosclerotic disease proximal and distal to the aneurysm itself. Our approach used a long drug-eluting stent as a scaffold to overlap covered coronary stents to successfully exclude the aneurysm. The patient’s angina resolved and had no complications or readmissions after nearly 1 year of follow-up.

Anorexia nervosa and bulimia nervosa are serious psychiatric illnesses related to disordered eating and distorted body images. They both have significant medical complications associated with the weight loss and malnutrition of anorexia nervosa, as well as from the purging behaviors that characterize bulimia nervosa. No body system is spared from the adverse sequelae of these illnesses, especially as anorexia nervosa and bulimia nervosa become more severe and chronic. We review the medical complications that are associated with anorexia nervosa and bulimia nervosa, as well as the treatment for the complications. We also discuss the epidemiology and psychiatric comorbidities of these eating disorders.

Objective Anorexia nervosa portends the highest mortality among psychiatric diseases, despite primarily being a disease of adolescents and younger adults. Although some of this mortality risk is attributable to suicide, many deaths are likely cardiovascular in etiology. Recent studies suggest that adverse myocardial structural changes occur in this condition, which could underlie the increased mortality. Given limited prevalence of severe anorexia there is a paucity of clinical and autopsy data to discern an exact cause of death. Methods Given this background we conducted a systematic review of the medical literature to provide a contemporary summary of the pathobiologic sequelae of severe anorexia nervosa on the cardiovascular system. We sought to elucidate the impact of anorexia nervosa in four cardiovascular domains: structural, repolarization/conduction, hemodynamic, and peripheral vascular. Results A number of cardiac abnormalities associated with anorexia nervosa have been described in the literature, including pericardial and valvular pathology, changes in left ventricular mass and function, conduction abnormalities, bradycardia, hypotension, and dysregulation in peripheral vascular contractility. Despite the prevalent theory that malignant arrhythmias are implicated as a cause of sudden death in this disorder, data to support this causal relationship are lacking. Discussion It is reasonable to obtain routine electrocardiography and measurements of orthostatic vital signs in patients presenting with anorexia nervosa. Echocardiography is generally not indicated unless prompted by clinical signs of disease. Admission to an inpatient unit with telemetry monitoring is recommended for patients with severe sinus bradycardia or junction rhythm, marked prolongation of the corrected QT interval, or syncope.

Hereditary long QT syndrome (LQTS) is a genetic disorder resulting in delayed ventricular repolarization manifesting as a prolonged QT interval on the electrocardiogram and an increased propensity for polymorphic ventricular tachycardia (torsade de pointes), syncope, and sudden arrhythmic death in young adults without structural abnormalities. Originally described as Romano–Ward and Jervell and Lange‐Nielsen syndromes, breakthroughs in genetic and molecular analyses have allowed for more specific descriptions of a similar disease phenotype 1. Point mutations on five genes primarily affecting the function of the cardiac potassium current: KCNQ1 (LQTS1), KCNH2 (LQTS2), SCN5A (LQTS3), minK (LQTS5), and MiRP1 (LQTS6) have been implicated. Mutations in the KCNQ1 gene have been reported in 39–62% of patients with autosomal‐dominant LQTS where sudden cardiac death is often triggered by physical activity 2. The clinical triad of atrial fibrillation, cardiomyopathy, and sudden cardiac death in association with LQTS has not been previously described. We report a case of cardiac arrest with vigorous exercise, paroxysmal atrial fibrillation, and development of cardiomyopathy where subsequent genetic analysis identified a novel mutation in the KCNQ1 gene and LQTS1.

People with type 1 diabetes mellitus manifest a greater burden of both periodontal disease and coronary artery disease (CAD); however, little is known about their interrelation. Coronary artery calcium (CAC) measures subclinical atherosclerosis and predicts major adverse coronary events. The relation between periodontal disease and CAC progression in individuals with type 1 diabetes has not been previously described. We determined the prevalence and progression of CAC in relation to self-reported periodontal disease. Multivariate logistic and tobit regression models were used to examine the relation between periodontal disease duration and CAC progression and whether this relation differs by diabetes status after controlling for age, gender, total and high-density lipoprotein cholesterol, hypertension, smoking, body mass index (BMI), duration of diabetes, and baseline CAC. A total of 473 patients with type 1 diabetes and 548 without diabetes were followed for a mean of 6.1 years. At baseline, the prevalence and duration of periodontal disease did not differ between subjects with and without diabetes (14.5% vs 13.4%, p = 0.60; 6 vs 9 years, p = 0.18). Duration of periodontal disease was not significantly associated with baseline CAC prevalence. In patients with type 1 diabetes, periodontal disease duration was significantly related to CAC progression (p = 0.004) but not in subjects without diabetes (p = 0.63). In conclusion, this study suggests that periodontal disease is an independent predictor of long-term progression of CAC in patients with type 1 diabetes.

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

Background Electrocardiographic (ECG) safety evaluation is a required element of drug development. Performance characteristics of ECG measurement methodologies have rarely been studied prospectively. Methods We conducted a randomized, placebo-controlled, crossover study in 24 subjects to evaluate effects of moxifloxacin on the Fridericia rate-corrected QT (QTcF) interval. Five ECG replicates were obtained at 30 time points. Change from baseline QTcF (ΔQTcF) was fit by mixed-model analysis of variance to evaluate residual standard deviation. Precision was defined as intrasubject QTcF variance. Two core lab approaches were compared: QTinno, fully automated, 5 replicates and HeartSignals, computer-assisted manual, 3 replicates. Core lab values were then compared to an automated commercial algorithm (VERITAS). Results Twenty-three subjects provided 3450 ECGs potentially available for analysis. QTinno QTcF values were based upon 3419 ECGs, HeartSignals data on 2028 ECGs. Variance was similar between the QTinno and HeartSignals approaches (41.5 and 44 ms2). After excluding VERITAS QTcF measurements that deviated by >40 ms on visual review, variance in a set of 1907 common ECGs was lowest for HeartSignal, followed by QTinno and VERITAS (43.8, 52.6, 89.4 ms2) P = 0.02 HeartSignals versus QTinno, P < 0.0001 for both HeartSignals and QTinno versus VERITAS. Conclusions A fully automated core lab approach using 5 replicates and a computer-assisted manual approach using 3 replicates were equally precise. When an identical number of ECGs were compared, the computer-assisted manual method was most precise, while the commercial algorithm was relatively imprecise. Although suitable for clinical assessment the standard commercial algorithm cannot be recommended for regulated safety research.

Objectives This study was designed to identify the incidence of late complete heart block (CHB) first identified at least 48 hours post alcohol septal ablation (ASA). Background Septal reduction with ASA is a therapeutic option for patients with symptomatic hypertrophic obstructive cardiomyopathy (HCM). CHB, resulting from the septal infarct, is a known complication with a reported incidence of 9–22%. The incidence of CHB more than 48 hours post-procedure is unknown. Methods Consecutive patients who underwent ASA were analyzed and clinical characteristics associated with late CHB were assessed. Late CHB was defined as first identification of CHB more than 48 hours after ASA. Results From 2002–2013, 145 subjects underwent 168 ASA procedures and were followed for a mean of 3.2 +/− 2.3 years. The incidence of late CHB was 8.9% (15/168 ASA procedures). Heart block occurred from 48 hours to 3-years post-procedure. In a multivariable model, patients with any CHB were more likely to have had multiple ASA procedures (OR 4.14; 95% CI: 1.24, 13.9; P