Myocardial mechanics and cardiac biomarkers in adults with severe anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is associated with left ventricular (LV) atrophy and unexplained sudden death. Myocardial mechanics have not been well studied in adults with AN. Whether LV mass or illness duration, markers of AN severity, correlate with abnormal strain imaging is unknown. METHODS: We performed a prospective study among patients hospitalized with severe AN (n = 29) [body mass index (BMI) < 14.5 kg/m2] and sex/age-matched controls (n = 16) (BMI > 18.5 kg/m2). LV ejection fraction (LVEF) was calculated via modified-biplane method and LV mass was derived using the truncated ellipsoid formula. Apical 2-, 3-, and 4-chamber images were used to generate regional strain mapping and global longitudinal strain (GLS). N-terminal brain natriuretic peptide (NT-proBNP) levels were measured and linear regression was used to determine independent predictors of strain. RESULTS: Mean LVEF did not differ (65% ± 6.0 vs. 62% ± 4.4, p = 0.06), but LV mass was substantially reduced (61.6 ± 16.8 vs. 97.6 ± 19.1 g, p < .0001). GLS was similar (- 20.6 ± 3.8 vs. - 20.9 ± 2.8, p = 0.82), however, the basal strain was worse (-18.7 ± 4.8 vs. -21.9 ± 4.1, p = 0.03). Lower LV mass was associated with worsening GLS (r = - 0.40, p = 0.003), but not among controls (p = 0.89). Median (IQR) NT-proBNP (pg/ml) was higher in patients with AN [141 (59-257) vs. 35.5 (21-56.5) p = 0.0007]. Both increasing NT-proBNP and illness duration were associated with worsening strain patterns in AN (both p = .001). CONCLUSIONS: While LVEF and GLS did not differ, regional strain variation was noted among patients with AN. Elevated NT-proBNP may reflect increased wall tension from LV atrophy. Whether strain heterogeneity can identify patients with AN, at risk for sudden death, requires further study.

Ventricular Arrhythmias Associated With Over-the-Counter and Recreational Opioids.

BACKGROUND: Epidemic increases in opioid deaths prompted policies limiting access to prescription opioids in North America. Consequently, the over-the-counter opioids loperamide (Imodium A-D) and mitragynine, the herbal ingredient in kratom, are increasingly used to avert withdrawal or induce euphoria. Arrhythmia events related to these nonscheduled drugs have not been systematically studied. OBJECTIVES: In this study, we sought to explore opioid-associated arrhythmia reporting in North America. METHODS: The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS), and Canada Vigilance Adverse Reaction (CVAR) databases were searched (2015-2021). Reports involving nonprescription drugs (loperamide, mitragynine) and diphenoxylate/atropine (Lomotil) were identified. Methadone, a prescription opioid (full agonist), served as a positive control owing to its established arrhythmia risk. Buprenorphine (partial agonist) and naltrexone (pure antagonist), served as negative controls. Reports were classified according to Medical Dictionary for Regulatory Activities terminology. Significant disproportionate reporting required a proportional reporting ratio (PRR) of ≥2, ≥3 cases, and chi-square ≥4. Primary analysis used FAERS data, whereas CAERS and CVAR data were confirmatory. RESULTS: Methadone was disproportionately associated with ventricular arrhythmia reports (PRR: 6.6; 95% CI: 6.2-7.0; n = 1,163; chi-square = 5,456), including 852 (73%) fatalities. Loperamide was also significantly associated with arrhythmia (PRR: 3.2; 95% CI: 3.0-3.4; n = 1,008; chi-square = 1,537), including 371 (37%) deaths. Mitragynine demonstrated the highest signal (PRR: 8.9; 95% CI: 6.7-11.7; n = 46; chi-square = 315), with 42 (91%) deaths. Buprenorphine, diphenoxylate, and naltrexone were not associated with arrhythmia. Signals were similar in CVAR and CAERS. CONCLUSIONS: The nonprescription drugs loperamide and mitragynine are associated with disproportionate reports of life-threatening ventricular arrhythmia in North America.

Modeling community COVID-19 transmission risk associated with U.S. universities.

The ongoing COVID-19 pandemic is among the worst in recent history, resulting in excess of 520,000,000 cases and 6,200,000 deaths worldwide. The United States (U.S.) has recently surpassed 1,000,000 deaths. Individuals who are elderly and/or immunocompromised are the most susceptible to serious sequelae. Rising sentiment often implicates younger, less-vulnerable populations as primary introducers of COVID-19 to communities, particularly around colleges and universities. Adjusting for more than 32 key socio-demographic, economic, and epidemiologic variables, we (1) implemented regressions to determine the overall community-level, age-adjusted COVID-19 case and mortality rate within each American county, and (2) performed a subgroup analysis among a sample of U.S. colleges and universities to identify any significant preliminary mitigation measures implemented during the fall 2020 semester. From January 1, 2020 through March 31, 2021, a total of 22,385,335 cases and 374,130 deaths were reported to the CDC. Overall, counties with increasing numbers of university enrollment showed significantly lower case rates and marginal decreases in mortality rates. County-level population demographics, and not university level mitigation measures, were the most significant predictor of adjusted COVID-19 case rates. Contrary to common sentiment, our findings demonstrate that counties with high university enrollments may be more adherent to public safety measures and vaccinations, likely contributing to safer communities.

Impact of transitioning to virtual delivery of a cardiovascular health improvement program for Latinos during the COVID-19 pandemic.

BACKGROUND: Community Heart Health Actions for Latinos at Risk (CHARLAR) is a promotora-led cardiovascular disease (CVD) risk-reduction program for socio-demographically disadvantaged Latinos and consists of 11 skill-building sessions. The COVID-19 pandemic has led to worsening health status in U.S. adults and necessitated transition to virtual implementation of the CHARLAR program. METHODS: A mixed-methods approach was used to evaluate virtual delivery of CHARLAR. Changes in health behaviors were assessed through a pre/post program survey. Results from virtual and historical (in-person delivery) were compared. Key informant interviews were conducted with promotoras and randomly selected participants and then coded and analyzed using a thematic approach. RESULTS: An increase in days of exercise per week (+ 1.52), daily servings of fruit (+ 0.60) and vegetables (+ 0.56), and self-reported general health (+ 0.38), were observed in the virtual cohort [all p < 0.05]. A numeric decrease in PHQ-8 (-1.07 p = 0.067) was also noted. The historical cohort showed similar improvements from baseline in days of exercise per week (+ 0.91), daily servings of fruit (+ 0.244) and vegetables (+ 0.282), and PHQ-8 (-1.89) [all p < 0.05]. Qualitative interviews revealed that the online format provided valuable tools supporting positive behavior change. Despite initial discomfort and technical challenges, promotoras and participants adapted and deepened valued relationships through additional virtual support. CONCLUSION: Improved health behaviors and CVD risk factors were successfully maintained through virtual delivery of the CHARLAR program. Optimization of virtual health programs like CHARLAR has the potential to increase reach and improve CVD risk among Latinos.

Methadone Blockade of Cardiac Inward Rectifier K+ Current Augments Membrane Instability and Amplifies U Waves on Surface ECGs: A Translational Study.

Background Methadone is associated with a disproportionate risk of sudden death and ventricular tachyarrhythmia despite only modest inhibition of delayed rectifier K+ current (IKr), the principal mechanism of drug-associated arrhythmia. Congenital defects of inward rectifier K+ current (IK1) have been linked to increased U-wave amplitude on ECG and fatal arrhythmia. We hypothesized that methadone may also be a potent inhibitor of IK1, contributing to delayed repolarization and manifesting on surface ECGs as augmented U-wave integrals. Methods and Results Using a whole-cell voltage clamp, methadone inhibited both recombinant and native IK1 with a half-maximal inhibitory concentration IC50) of 1.5 µmol/L, similar to that observed for IKr block (half-maximal inhibitory concentration of 2.9 µmol/L). Methadone modestly increased the action potential duration at 90% repolarization and slowed terminal repolarization at low concentrations. At higher concentrations, action potential duration at 90% repolarization lengthening was abolished, but its effect on terminal repolarization rose steadily and correlated with increased fluctuations of diastolic membrane potential. In parallel, patient ECGs were analyzed before and after methadone initiation, with 68% of patients having a markedly increased U-wave integral compared with premethadone (lead V3; mean +38%±15%, P=0.016), along with increased QT and TPeak to TEnd intervals, likely reflective of IKr block. Conclusions Methadone is a potent IK1 inhibitor that causes augmentation of U waves on surface ECG. We propose that increased membrane instability resulting from IK1 block may better explain methadone's arrhythmia risk beyond IKr inhibition alone. Drug-induced augmentation of U waves may represent evidence of blockade of multiple repolarizing ion channels, and evaluation of the effect of that agent on IK1 may be warranted.

The E/e' Ratio: As "Critical" As the Left Ventricular Ejection Fraction?

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.

What accounts for the high mortality of anorexia nervosa?

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.

Impact of Sodium-glucose Cotransporter-2 Inhibitor Initiation in a Safety-net Hospital.

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.

Huffing and twist: Fatal Torsade de pointes associated with Tetrafluoroethane Inhalation and amphetamine use.

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.

V3-Loop genotypes do not predict maraviroc susceptibility of CCR5-tropic virus or clinical response through week 48 in HIV-1-infected, treatment-experienced persons receiving optimized background regimens.

Viruses from 15 of 35 maraviroc-treated participants with virologic failure and CCR5-tropic (R5) virus in the MOTIVATE studies at Week 24 had reduced maraviroc susceptibility. On-treatment amino acid changes were observed in the viral envelope glycoprotein 120 third variable (V3)-loop stems and tips and differed between viruses. No amino acid change reliably predicted reduced susceptibility, indicating that resistance was genetic context-dependent. Through Week 24, poor adherence was associated with maraviroc-susceptible virologic failure, whereas reduced maraviroc susceptibility was associated with suboptimal background regimen activity, highlighting the importance of overall regimen activity and good adherence. Predictive values of pretreatment V3-loop sequences containing these Week 24 mutations or other variants present at >3% in pretreatment viruses of participants with virologic failure at Week 48 were retrospectively assessed. Week 48 clinical outcomes were evaluated for correlates with pretreatment V3-loop CCR5-tropic sequences from 704 participants (366 responders; 338 virologic failures [83 with R5 virus with maraviroc susceptibility assessment]). Seventy-five amino acid variants with >3% prevalence were identified among 23 V3-loop residues. Previously identified variants associated with resistance in individual isolates were represented, but none were associated reliably with virologic failure alone or in combination. Univariate analysis showed virologic-failure associations with variants 4L, 11R, and 19S (P < 0.05). However, 11R is a marker for CXCR4 tropism, whereas neither 4L nor 19S was reliably associated with reduced maraviroc susceptibility in R5 failure. These findings from a large study of V3-loop sequences confirm lack of correlation between V3-loop genotype and clinical outcome in participants treated with maraviroc.Clinical trial registration numbers (ClinicalTrials.gov): NCT00098306 and NCT00098722.

Low-dose rivaroxaban plus aspirin in older patients with peripheral artery disease undergoing acute limb revascularization: insights from the VOYAGER PAD trial.

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.

Cardiovascular Risk Factor Knowledge among Monolingual Hispanics.

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.

A Point-of-Care Algorithm to Guide Proper Device Selection for Ambulatory Electrocardiography.

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.

Cardiovascular Complications of Opioid Use: JACC State-of-the-Art Review.

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.

Subendocardial stress in pre-eclampsia.

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.

Improving Atraumatic Chest Pain Evaluation in an Urban, Safety-net Hospital Through Incorporation of a Modified HEART Score.

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.