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1.  QT Interval Screening in Methadone Maintenance Treatment: Report of a SAMHSA Expert Panel 
Journal of addictive diseases  2011;30(4):283-306.
In an effort to enhance patient safety in Opioid Treatment Programs (OTPs), the Substance Abuse and Mental Health Services Administration (SAMHSA) convened a multi-disciplinary Expert Panel on the Cardiac Effects of Methadone. Panel members reviewed the literature, regulatory actions, professional guidances, and OTPs’ experiences regarding adverse cardiac events associated with methadone.
The Panel concluded that, to the extent possible, every OTP should have a universal Cardiac Risk Management Plan (incorporating clinical assessment, ECG assessment, risk stratification, and prevention of drug interactions) for all patients, and should strongly consider patient-specific risk minimization strategies (such as careful patient monitoring, obtaining ECGs as indicated by a particular patient’s risk profile, and adjusting the methadone dose as needed) for patients with identified risk factors for adverse cardiac events. The Panel also suggested specific modifications to informed consent documents, patient education, staff education, and methadone protocols.
doi:10.1080/10550887.2011.610710
PMCID: PMC4078896  PMID: 22026519
2.  Trends in Reporting Methadone-Associated Cardiac Arrhythmia, 1997–2011 
Annals of internal medicine  2013;158(10):735-740.
Background:
Long-acting opioids are a leading cause of accidental death in the United States, and methadone is associated with greater mortality rates. Whether this increase is related to the proarrhythmic properties of methadone is unclear.
Objective:
To describe methadone-associated arrhythmia events reported in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS).
Design:
Description of national adverse event registry data before and after publication of a 2002 report describing an association between methadone and arrhythmia.
Setting:
FAERS, November 1997 and June 2011.
Patients:
Adults with QTc prolongation or torsade de pointes and ventricular arrhythmia or cardiac arrest.
Measurements:
FAERS reports before and after the 2002 report.
Results:
1646 cases of ventricular arrhythmia or cardiac arrest and 379 cases of QTc prolongation or torsade de pointes were associated with methadone. Monthly reports of QTc prolongation or torsade de pointes increased from a mean of 0.3 (95% CI, 0.1 to 0.5) before the 2002 publication to a mean of 3.5 (CI, 2.5 to 4.8) after it. After 2000, methadone was the second-most common primary suspect in cases of QTc prolongation or torsade de pointes after dofetilide (a known proarrhythmic drug) and was associated with disproportionate reporting similar to that of antiarrhythmic agents known to promote torsade de pointes. Antiretroviral drugs for HIV were the most common coadministered drugs.
Limitation:
Reports to FAERs are voluntary and selective, and incidence rates cannot be determined from spontaneously reported data.
Conclusion:
Since 2002, reports to FAERS of methadone-associated arrhythmia have increased substantially and are disproportionately represented relative to other events with the drug. Coadministration of methadone with antiretrovirals in patients with HIV may pose particular risk.
Primary Funding Source:
Colorado Clinical and Translational Sciences Institute, National Institutes of Health, and Agency for Healthcare Research and Quality.
doi:10.7326/0003-4819-158-10-201305210-00008
PMCID: PMC3793842  PMID: 23689766
3.  Proarrhythmic Potential of Dronedarone: Emerging Evidence from Spontaneous Adverse Event Reporting 
Pharmacotherapy  2012;32(8):767-771.
Context
Dronedarone has not been previously associated with a major risk for ventricular arrhythmia, but increased fatal arrhythmias among patients with permanent atrial fibrillation in a recent randomized trial. The mechanism of this adverse safety signal leading to trial discontinuation is unknown.
Study Objective
To characterize cardiac events, including torsade de pointes, associated with dronedarone and its structural analogue, amiodarone, outside of the clinical trial setting.
Design
Publicly available extracts from the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) system were screened for events occurring from 7/1/2009, the time of dronedarone approval, through 6/30/2011.
Data extraction
Cardiac events were defined as serious if they involved death, disability, hospitalization, required intervention, or were life-threatening. Active ingredients were identified using the Drugs@FDA Database, and the Medical Dictionary for Regulatory Activities (MedDRA) was used to aggregate related adverse events. To avoid redundant counting, all statistics were generated in reference to unique case identifiers.
Results
Dronedarone was associated with more adverse cardiovascular event reports than amiodarone (810 vs. 493)during the evaluation period. Dronedarone was the leading reported culprit for torsade de pointes in the US (37 cases) followed by amiodarone (29 cases). Dronedarone was also associated with more cases of ventricular arrhythmias and cardiac arrest than amiodarone (138 vs. 113) as well a heart failure events (179 vs. 126).
Limitations
AERS data is subject to reporting biases and cannot generate actual incidence rates.
Conclusion
Dronedarone is associated with reports of ventricular arrhythmia and torsade de pointes in clinical practice. Whether this observation accounts for the increased risk of fatal arrhythmia observed in a recent prospective trial requires further investigation.
doi:10.1002/j.1875-9114.2012.01118.x
PMCID: PMC3463717  PMID: 22744806
4.  A Case of Swallow Syncope 
Texas Heart Institute Journal  2013;40(5):606-607.
Swallow syncope, also called deglutition syncope, is a rare disorder triggered by oral intake. Patients often have underlying esophageal or structural heart disease. In some cases, the condition can be treated conservatively by eliminating predisposing factors. We describe the case of a 65-year-old woman without cardiovascular or esophageal disease who presented after a motor vehicle accident that was attributed to syncope while driving and eating. In the hospital, the patient suddenly lost consciousness while eating solid food; complete heart block without ventricular escape was documented on continuous electrocardiographic monitoring. A dual-chamber permanent pacemaker was placed and completely resolved the symptoms. This case illustrates a high-risk manifestation of swallow syncope: asystole resulting from an exaggerated vago–glossopharyngeal reflex.
PMCID: PMC3853827  PMID: 24391337
Deglutition/physiology; deglutition disorders; eating/physiology; heart block/complications/diagnosis/physiopathology; syncope, vasovagal/diagnosis/etiology/therapy; treatment outcome
5.  Characteristics and Outcomes Among Heart Failure Patients With Anemia and Renal Insufficiency With and Without Blood Transfusions (Public Discharge Data from California 2000–2006) 
The American journal of cardiology  2011;107(1):10.1016/j.amjcard.2010.08.046.
Renal insufficiency and anemia are increasingly recognized as predictors of adverse events in heart failure. The impact of blood transfusion on mortality in patients with heart failure has not been previously characterized. We examined temporal changes in admissions and in-hospital mortality using public discharge data from California (2000 to 2006) and then evaluated the impact of renal insufficiency, anemia, and transfusion on in-hospital mortality in univariate and multivariate analyses. In total 596,456 unique patient admissions for heart failure were recorded. Renal insufficiency and anemia were common co-morbidities (27.4% and 27.1%, respectively) and 6.2% of patients received a transfusion of red blood cells. Renal insufficiency and anemia were associated with increased mortality (unadjusted odds ratio [OR] 2.45, 95% confidence interval [CI] 2.39 to 2.52, and 1.27, 95% CI 1.24 to 1.30, respectively). After adjustment, renal insufficiency (OR 2.54, 95% CI 2.46 to 2.62) and anemia (OR 1.12 95% CI 1.07 to 1.17) remained significant; however, transfusion emerged as the strongest single predictor (OR 3.81, 95% CI 3.51 to 4.13) of mortality. In conclusion, these data suggest that anemia and renal insufficiency are independently associated with mortality in an unselected heart failure population. This is the first study to demonstrate that transfusion magnifies this effect and is associated with a particularly poor prognosis.
doi:10.1016/j.amjcard.2010.08.046
PMCID: PMC3835688  PMID: 21146689
6.  Electrocardiographic Effects of Lofexidine and Methadone Co-administration: Secondary Findings from a Safety Study 
Pharmacotherapy  2009;29(5):495-502.
Study Objective
To determine the electrocardiographic (ECG) effects of co-administration of lofexidine and methadone.
Design
Prospective, double-blind study.
Subjects
Fourteen participants with physical dependence on opioids at an outpatient drug treatment research clinic.
Methods
Participants were stabilized on methadone maintenance therapy (80 mg/day), then received escalating doses of lofexidine for eight weeks. ECGs were performed during peak plasma lofexidine levels. Pre-specified outcome measures were mean and maximal changes in heart rate, PR, QRS, and QTc intervals (1) when stabilized on methadone and (2) after lofexidine (0.4 mg) co-administration.
Main Results
Repeated-measures regression showed no changes in HR, PR, QRS, or QTc after methadone stabilization, but a significant decrease in mean HR (mean change −8.0 ± 7.3 bpm, p=0.0006) after initiating lofexidine. When data were analyzed using maximal ECG response, again, there were no significant changes during methadone induction compared to pretreatment, but there were significant changes in all four ECG parameters when lofexidine was coadministered: decreased HR (−9.6 ± 5.8 bpm, p<0.0001) and increased PR interval (+11.1 ± 19.8 ms, p=0.026), QRS interval (+3.7 ± 4.3 ms, p=0.002), and QTc interval (+21.9 ± 40.8 ms, p=0.018). In three participants, the QTc prolongation was clinically significant (> 40 ms).
Conclusion
Pending larger studies, our data suggest that coadministration of lofexidine and methadone should be prescribed cautiously, preferably with ECG monitoring.
doi:10.1592/phco.29.5.495
PMCID: PMC3150470  PMID: 19397459
Methadone; Lofexidine; ECG; QTc interval
7.  Circulating adiponectin levels are lower in Latino versus non-Latino white patients at risk for cardiovascular disease, independent of adiposity measures 
Background
Latinos in the United States have a higher prevalence of type 2 diabetes than non-Latino whites, even after controlling for adiposity. Decreased adiponectin is associated with insulin resistance and predicts T2DM, and therefore may mediate this ethnic difference. We compared total and high-molecular-weight (HMW) adiponectin in Latino versus white individuals, identified factors associated with adiponectin in each ethnic group, and measured the contribution of adiponectin to ethnic differences in insulin resistance.
Methods
We utilized cross-sectional data from subjects in the Latinos Using Cardio Health Actions to reduce Risk study. Participants were Latino (n = 119) and non-Latino white (n = 60) men and women with hypertension and at least one other risk factor for CVD (age 61 ± 10 yrs, 49% with T2DM), seen at an integrated community health and hospital system in Denver, Colorado. Total and HMW adiponectin was measured by RIA and ELISA respectively. Fasting glucose and insulin were used to calculate the homeostasis model insulin resistance index (HOMA-IR). Variables independently associated with adiponectin levels were identified by linear regression analyses. Adiponectin's contribution to ethnic differences in insulin resistance was assessed in multivariate linear regression models of Latino ethnicity, with logHOMA-IR as a dependent variable, adjusting for possible confounders including age, gender, adiposity, and renal function.
Results
Mean adiponectin levels were lower in Latino than white patients (beta estimates: -4.5 (-6.4, -2.5), p < 0.001 and -1.6 (-2.7, -0.5), p < 0.005 for total and HMW adiponectin), independent of age, gender, BMI/waist circumference, thiazolidinedione use, diabetes status, and renal function. An expected negative association between adiponectin and waist circumference was seen among women and non-Latino white men, but no relationship between these two variables was observed among Latino men. Ethnic differences in logHOMA-IR were no longer observed after controlling for adiponectin levels.
Conclusions
Among patients with CVD risk, total and HMW adiponectin is lower in Latinos, independent of adiposity and other known regulators of adiponectin. Ethnic differences in adiponectin regulation may exist and future research in this area is warranted. Adiponectin levels accounted for the observed variability in insulin resistance, suggesting a contribution of decreased adiponectin to insulin resistance in Latino populations.
doi:10.1186/1472-6823-11-13
PMCID: PMC3141565  PMID: 21736747
8.  Pulse wave velocity and carotid atherosclerosis in White and Latino patients with hypertension 
Background
Preventive cardiology has expanded beyond coronary heart disease towards prevention of a broader spectrum of cardiovascular diseases. Ethnic minorities are at proportionately greater risk for developing extracoronary vascular disease including heart failure and cerebrovascular disease.
Methods
We performed a cross sectional study of Latino and White hypertension patients in a safety-net healthcare system. Framingham risk factors, markers of inflammation (hsCRP, LPpLA2), arterial stiffness (Pulse wave velocity, augmentation index, and central aortic pressure), and endothelial function (brachial artery flow-mediated dilatation) were measured. Univariate and multivariable associations between these parameters and an index of extracoronary atherosclerosis (carotid intima media thickness) was performed.
Results
Among 177 subjects, mean age was 62 years, 67% were female, and 67% were Latino. In univariate analysis, markers associated with carotid intima media thickness (IMT) at p < 0.25 included pulse wave velocity (PWV), augmentation index (AIx), central aortic pressure (cAP), and LpPLA2 activity rank. However, AIx, cAP, and LpPLA2 activity were not significantly associated with carotid IMT after adjusting for Framingham risk factors (all p > .10). Only PWV retained a significant association with carotid IMT independent of the Framingham general risk profile parameters (p = .016). No statistically significant interactions between Framingham and other independent variables with ethnicity (all p > .05) were observed.
Conclusion
In this safety net cohort, PWV is a potentially useful adjunctive atherosclerotic risk marker independent of traditional risk factors and irrespective of ethnicity.
doi:10.1186/1471-2261-11-15
PMCID: PMC3080337  PMID: 21481252
Pulse wave velocity; hypertension; atherosclerosis; carotid intima media thickness; Latino; inflammatory markers; augmentation index; central aortic pressure; C-reactive protein
9.  Flip-Flop Heart 
Mayo Clinic Proceedings  2010;85(1):103.
doi:10.4065/mcp.2009.0627
PMCID: PMC2800286  PMID: 20042568
10.  Left Ventricular Hypertrophy and Cardiovascular Mortality by Race and Ethnicity 
The American journal of medicine  2008;121(10):870-875.
Background
Left ventricular hypertrophy is a major independent risk factor for cardiovascular mortality. The contribution of left ventricular hypertrophy to racial and ethnic differences in cardiovascular mortality is poorly understood.
Methods
We used data from the Third National Health and Nutrition Examination Survey and from the National Death Index to compare mortality for those with an electrocardiographic (ECG) diagnosis of left ventricular hypertrophy to those without left ventricular hypertrophy separately for whites, African Americans, and Latinos. We used Cox proportional hazards regression to control for other known prognostic factors.
Results
ECG left ventricular hypertrophy was significantly associated with ten-year cardiovascular mortality in all three racial/ethnic groups, both unadjusted and adjusted for other known prognostic factors. The hazard ratio for this association was significantly greater for African Americans (2.31, 95% CI 1.55–3.42) than for whites and Latinos (1.32, 95% CI 1.14–1.76 and 2.11, 95% CI 1.35–3.30 respectively) independent of systolic blood pressure.
Conclusions
ECG left ventricular hypertrophy contributes more to the risk of cardiovascular mortality in African Americans than it does in Whites. Using regression of ECG left ventricular hypertrophy as a goal of therapy might be a means to reduce racial differences in cardiovascular mortality; prospective validation is required.
doi:10.1016/j.amjmed.2008.05.034
PMCID: PMC2574427  PMID: 18823858
left ventricular hypertrophy; electrocardiography; cardiovascular risk assessment; racial/ethnic differences
11.  Thresholds in the Relationship between Mortality and Left Ventricular Hypertrophy Defined by Electrocardiography 
Journal of electrocardiology  2008;41(4):342-350.
Background
Electrocardiographic criteria for the diagnosis of left ventricular hypertrophy in current use were defined using autopsy results or echocardiography; criteria defined using mortality might be more clinically meaningful.
Methods
Using data from NHANES III, we selected electrocardiographic measures that best differentiated those surviving at five years from those who did not. We identified voltage thresholds using regression techniques, and then compared survival for subjects above and below the thresholds.
Results
Cornell voltage, Cornell product, and Novacode estimate of left ventricular mass index were discriminative for mortality and had identifiable thresholds present in their relationships with mortality. Independent of systolic blood pressure, there were significant associations with five-year mortality for Novacode index above threshold; hazard ratios were 1.58 for women and 1.27 for men, and for five-year cardiovascular mortality were 1.78 for women and 2.34 for men.
Conclusions
Electrocardiographic criteria for left ventricular hypertrophy validated against mortality might be clinically useful.
doi:10.1016/j.jelectrocard.2007.11.006
PMCID: PMC2556300  PMID: 18342879
12.  Impact of prescription size on statin adherence and cholesterol levels 
Background
Therapy with 3-Hydroxy-3-methylglutaryl Co-enzyme A reductase inhibitors (statins) improve outcomes in a broad spectrum of patients with hyperlipidemia. However, effective therapy requires ongoing medication adherence; restrictive pharmacy policies may represent a barrier to successful adherence, particularly among vulnerable patients. In this study we sought to assess the relationship between the quantity of statin dispensed by the pharmacy with patient adherence and total cholesterol.
Methods
We analyzed a cohort of 3,386 patients receiving more than one fill of statin medications through an integrated, inner-city health care system between January 1, 2000 and December 31, 2002. Our measure of adherence was days of drug acquisition divided by days in the study for each patient, with adequate adherence defined as ≥ 80%. Log-binomial regression was used to determine the relative risk of various factors, including prescription size, on adherence. We also assessed the relationship between adherence and total cholesterol using multiple linear regression.
Results
After controlling for age, gender, race, co-payment, comorbidities, and insurance status, patients who obtained a majority of fills as 60-day supply compared with 30-day supply were more likely to be adherent to their statin medications (RR 1.41, 95% CI 1.28–1.55, P < 0.01). We found that statin non-adherence less than 80% was predictive of higher total serum cholesterol by 17.23 ± 1.64 mg/dL (0.45 ± 0.04 mmol/L).
Conclusion
In a healthcare system serving predominantly indigent patients, the provision of a greater quantity of statin medication at each prescription fill contributes to improved adherence and greater drug effectiveness.
doi:10.1186/1472-6963-7-175
PMCID: PMC2174936  PMID: 17961256
13.  Resting tachycardia, a warning sign in anorexia nervosa: case report 
Background
Among psychiatric disorders, anorexia nervosa has the highest mortality rate. During an exacerbation of this illness, patients frequently present with nonspecific symptoms. Upon hospitalization, anorexia nervosa patients are often markedly bradycardic, which may be an adaptive response to progressive weight loss and negative energy balance. When anorexia nervosa patients manifest tachycardia, even heart rates in the 80–90 bpm range, a supervening acute illness should be suspected.
Case presentation
A 52-year old woman with longstanding anorexia nervosa was hospitalized due to progressive leg pain, weakness, and fatigue accompanied by marked weight loss. On physical examination she was cachectic but in no apparent distress. She had fine lanugo-type hair over her face and arms with an erythematous rash noted on her palms and left lower extremity. Her blood pressure was 96/50 mm Hg and resting heart rate was 106 bpm though she appeared euvolemic. Laboratory tests revealed anemia, mild leukocytosis, and hypoalbuminemia. She was initially treated with enteral feedings for an exacerbation of anorexia nervosa, but increasing leukocytosis without fever and worsening left leg pain prompted the diagnosis of an indolent left lower extremity cellulitis. With antibiotic therapy her heart rate decreased to 45 bpm despite minimal restoration of body weight.
Conclusions
Bradycardia is a characteristic feature of anorexia nervosa particularly with significant weight loss. When anorexia nervosa patients present with nonspecific symptoms, resting tachycardia should prompt a search for potentially life-threatening conditions.
doi:10.1186/1471-2261-4-10
PMCID: PMC503388  PMID: 15257758
anorexia nervosa; bradycardia; tachycardia; malnutrition

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