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.

A controlled trial of mobile short message service among participants in a rural cardiovascular disease prevention program.

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.

Potent Inhibition of hERG Channels by the Over-the-Counter Antidiarrheal Agent Loperamide.

OBJECTIVES: 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. BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Cardiovascular complications of anorexia nervosa: A systematic review.

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.

Comparison of Frequency and Duration of Periodontal Disease With Progression of Coronary Artery Calcium in Patients With and Without Type 1 Diabetes Mellitus.

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.

Syncope and cardiac arrest during strenuous exercise associated with a novel mutation in LQTS1.

Exercise-induced syncope should alert clinicians to the possibility of LQTS and must be distinguished from other malignant causes of syncope such as hypertrophic cardiomyopathy, catecholaminergic ventricular tachycardia, and arrhythmogenic right ventricular cardiomyopathy. Emerging genotype-phenotype links have connected mutations resulting in LQTS with risk of developing atrial fibrillation and cardiomyopathy.

Cardiovascular disease is associated with COPD severity and reduced functional status and quality of life.

INTRODUCTION: Smoking is a major risk factor for both cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD). More individuals with COPD die from CVD than respiratory causes and the risk of developing CVD appears to be independent of smoking burden. Although CVD is a common comorbid condition within COPD, the nature of its relationships to COPD affection status and severity, and functional status is not well understood. METHODS: The first 2,500 members of the COPDGene cohort were evaluated. Subjects were current and former smokers with a minimum 10 pack-year history of cigarette smoking. COPD was defined by spirometry as an FEV1/FVC < lower limit of normal (LLN) with further identification of severity by FEV1 percent of predicted (GOLD stages 2, 3, and 4) for the main analysis. The presence of physician-diagnosed self-reported CVD was determined from a medical history questionnaire administered by a trained staff member. RESULTS: A total of 384 (15%) had pre-existing CVD. Self-reported CVD was independently related to COPD (Odds Ratio = 1.61, 95% CI = 1.18-2.20, p = 0.01) after adjustment for covariates with CHF having the greatest association with COPD. Within subjects with COPD, pre-existing self-reported CVD placed subjects at greater risk of hospitalization due to exacerbation, higher BODE index, and greater St. George's questionnaire score. The presence of self-reported CVD was associated with a shorter six-minute walk distance in those with COPD (p < 0.05). CONCLUSIONS: Self-reported CVD was independently related to COPD with presence of both self-reported CVD and COPD associated with a markedly reduced functional status and reduced quality of life. Identification of CVD in those with COPD is an important consideration in determining functional status.

The effect of a statewide smoking ordinance on acute myocardial infarction rates.

BACKGROUND: Public smoking ordinances may reduce acute myocardial infarction events. Most studies assessed small communities with reported reductions as high as 40%. No reduction or smaller reductions were found in countrywide studies; less is known about the impact of statewide ordinances. We previously demonstrated identical 27% reductions in acute myocardial infarction hospitalizations in 2 Colorado communities after enactment of strict smoking ordinances. Subsequently, on July 1, 2006, a statewide ordinance went into effect. We sought to determine the impact of this legislation on acute myocardial infarction hospitalization rates. METHODS: Hospital admissions for a primary acute myocardial infarction diagnosis were examined from 2000 to 2008. Poisson regression models were fit to the monthly events from January 1, 2000, to March 31, 2008. The final model included a quadratic trend over time, harmonic terms, and a post-ordinance effect. The model was adjusted temporally for population changes, using population estimates as an offset variable. RESULTS: A total of 58,399 unique acute myocardial infarctions were recorded during the study period. No significant reduction in acute myocardial infarction rates was observed post-ordinance (relative risk, 1.059; 95% confidence interval, 0.993-1.131). However, a steep decline in acute myocardial infarction rates was noted from 2000 to 2005 just before enactment. There were 11 strict, local smoking ordinances in effect within Colorado before enactment of the statewide ordinance. After excluding these communities, the findings were similar (relative risk, 1.038; 95% confidence interval, 0.971-1.11). CONCLUSIONS: Although local smoking ordinances in Colorado previously suggested a reduction in acute myocardial infarction hospitalizations, no significant impact of smoke-free legislation was demonstrated at the state level, even after accounting for preexisting ordinances.

An ECG-based cardiac safety initiative is well received by opioid treatment program staff: results from a qualitative assessment.

Registry data on methadone reveal that QTc-prolongation is reported more often among opioid-dependent patients than chronic pain patients. This suggests that opioid treatment programs may be an important venue for implementing arrhythmia risk-reduction strategies. An electrocardiography-based strategy in the opioid treatment program setting demonstrated a reduction in the QTc-interval among patients with marked QTc-prolongation. However, the feasibility of program implementation remains uncertain. Therefore, we performed qualitative interviews among opioid treatment program staff to determine the barriers and benefits of implementation. Overall, the program was well received by staff; however, a need for training and algorithms was identified. No patient was denied access to care.

QTc interval screening in an opioid treatment program.

Methadone is highly effective for opioid dependency, but it is associated with Torsade de pointes. Although electrocardiography (ECG) has been proposed, its utility is uncertain, because an ECG-based intervention has not been described. An ECG-based cardiac safety program in methadone maintenance patients was evaluated in a single opioid treatment program from September 1, 2009, to August 31, 2011, in the United States. Time from pretreatment to repeat ECG in new entrants was assessed. The proportion with marked rate-corrected QT (QTc) interval prolongation (>500 ms) and the effect of the intervention on the QTc interval in this group were evaluated. Multivariate predictors of QTc interval change were assessed using a mixed-effects model. Of 531 new entrants, 436 (82%) underwent ≥1 electrocardiographic assessment, and 186 (35%) underwent pretreatment ECG. Median time to follow-up ECG was 43 days but decreased over time (p <0.0001). In 21 patients with QTc intervals >500 ms, the mean QTc interval from peak to final ECG decreased significantly (-55.5 ms, 95% confidence interval -77.0 to -33.9, p = 0.001), and 12 of 21 (57.1%) decreased to lower than the 500-ms threshold. In new entrants with serial ECG, only methadone dose (p = 0.009) and pretreatment QTc interval (p <0.0001) were associated with the magnitude of QTc interval change. In conclusion, this study suggests that the implementation of an ECG-based intervention in methadone maintenance can decrease the QTc interval in high-risk patients; clinical characteristics alone were inadequate to identify patients in need of electrocardiographic screening.

A case of swallow syncope.

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.

Effectiveness of a community health worker cardiovascular risk reduction program in public health and health care settings.

OBJECTIVES: We evaluated whether a program to prevent coronary heart disease (CHD) with community health workers (CHWs) would improve CHD risk in public health and health care settings. METHODS: The CHWs provided point-of-service screening, education, and care coordination to residents in 34 primarily rural Colorado counties. The CHWs utilized motivational interviewing and navigated those at risk for CHD into medical care and lifestyle resources. A software application generated a real-time 10-year Framingham Risk Score (FRS) and guideline-based health recommendations while supporting longitudinal caseload tracking. We used multiple linear regression analysis to determine factors associated with changes in FRS. RESULTS: From 2010 to 2011, among 4743 participants at risk for CHD, 53.5% received medical or lifestyle referrals and 698 were retested 3 or more months after screening. We observed statistically significant improvements in diet, weight, blood pressure, lipids, and FRS with the greatest effects among those with uncontrolled risk factors. Successful phone interaction by the CHW led to lower FRS at retests (P = .04). CONCLUSIONS: A CHW-based program within public health and health care settings improved CHD risk. Further exploration of factors related to improved outcomes is needed.

Reduction in acute myocardial infarction hospitalization after implementation of a smoking ordinance.

BACKGROUND: Smoking ordinances have been associated with reduced acute myocardial infarction rates, but nearly all studies lack patient-level data. OBJECTIVE: We determined whether a smoking ordinance was associated with a reduction in hospitalizations for acute myocardial infarction, irrespective of smoking status and infarct presentation (ST elevation vs. non-ST elevation). METHODS: Detailed chart abstraction of biomarkers to confirm first acute myocardial infarction events was performed from the single community hospital serving Greeley, Colorado and adjacent zip codes, 17 months before and 31 months after implementing a public smoking ordinance. Poisson regression analysis, adjusted for population growth, was used to assess changes in mean incidence rates. RESULTS: A total of 706 hospitalizations were identified from July 2002 through June 2006: 482 among Greeley city residents and 224 within adjacent zip code areas. A postordinance reduction in hospitalizations was observed in Greeley (relative risk [RR] 0.73; 95% confidence interval [CI], 0.59-0.90). A smaller, nonsignificant decrease was noted in the area immediately surrounding Greeley (RR 0.83; 95% CI, 0.61-1.14). However, the comparison of relative risk reductions between Greeley and the surrounding area was not significant (P=.48). The reduction in Greeley was more pronounced among smokers (RR 0.44; 95% CI, 0.29-0.65) than nonsmokers (RR 0.86; 95% CI, 0.67-1.09) and did not differ by acute myocardial infarction presentation (P=.38). CONCLUSIONS: A smoking ordinance was associated with a decrease in acute myocardial infarction hospitalizations of a magnitude similar to previous reports, but could not be distinguished from the adjacent geographic area. Reductions were greatest among smokers, despite previous studies suggesting that benefits accrue primarily among nonsmokers. Smoke-free policy may therefore exert a beneficial effect among smokers, who are disproportionately exposed to direct and sidestream smoke.

Quality of care and in-hospital outcomes in patients with coronary heart disease in rural and urban hospitals (from Get With the Guidelines-Coronary Artery Disease Program).

Previous studies have suggested that patients with coronary artery disease (CAD) in rural areas may have worse outcomes due to limited availability of specialists, fewer resources, and less institutional funding. Data were collected from hospitals participating in the Get With the Guidelines-Coronary Artery Disease Program (GWTG-CAD) from January 2000 to December 2008. In-hospital outcomes and quality of care were stratified by care at rural versus urban hospitals. Multivariate logistic regression analysis was used to determine the association of rural locale with in-hospital mortality, length of stay, and compliance with the GWTG-CAD performance measurements including (1) early aspirin use, (2) smoking cessation counseling and discharge prescriptions of (3) aspirin, (4) angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers for left ventricular systolic dysfunction, (5) beta-blockers, and (6) lipid-lowering therapy and a composite of all 6 measurements. Data were collected from 22,096 patients at 71 rural centers and 329,938 patients at 477 urban centers. Unadjusted rates of compliance with performance measurements were lower in rural (range 82.4% to 90.5%) compared to urban (range 81.3% to 95.0%) hospitals including the composite (74.7% vs 80.6%, p <0.0001). In multivariate analysis, rural status was not independently associated with lower compliance with any of the performance measurements. Unadjusted mortality rates were higher in rural versus urban hospitals (5.7% vs 4.4%, p <0.0001), but this was not significant in multivariate analysis (odds ratio 1.05, 95% confidence interval 0.87 to 1.26). In conclusion, within the GWTG-CAD quality improvement initiative, patients with CAD treated at rural hospitals receive similar quality of care and have similar outcomes as those at urban centers.

Impact of a nurse telephone intervention among high-cardiovascular-risk, health fair participants.

BACKGROUND AND OBJECTIVES: Cardiovascular disease (CVD) is the leading cause of death in the United States, yet most individuals remain unaware of their risk. Current health fair models assess individual risk factors but miss the opportunity to assess, counsel, and follow-up with participants regarding global CVD risk. Objectives of this nurse telephone intervention were to (1) describe high-CVD-risk participants' healthcare-seeking behavior after the health fair and following a nurse telephone intervention and (2) describe CVD risk-reducing therapies provided to high-risk participants after the health fair and following a nurse telephone intervention. SUBJECTS AND METHODS: Five hundred twenty-nine of 4,489 health fair participants who completed an interactive Framingham risk assessment in 2006 were identified with high CVD risk. These participants received a nurse telephone intervention approximately 1 month after the health fair, during which the risk message was reinforced, principles of motivational interviewing were applied, and follow-up care was assessed. We evaluated the proportion of high-CVD-risk participants who obtained healthcare before and after intervention, and we compared the care received before and after intervention. RESULTS AND CONCLUSION: Among 447 contacted high-CVD-risk participants, 59% (n = 262) saw a healthcare provider, and 86% of those discussed CVD risk at their healthcare visit. A greater proportion of participants were started on a cardioprotective drug (41% vs 20%; P < .01), and more participants discussed "heart health" (96% vs 75%; P < .001) after receiving the nurse telephone intervention. Our findings suggest that a nurse intervention may improve individuals' CVD risk awareness as well as activate providers to implement CVD risk reduction strategies.

Methadone-induced mortality in the treatment of chronic pain: role of QT prolongation.

Methadone is increasingly prescribed for chronic pain, yet the associated mortality appears to be rising disproportionately relative to other opioid analgesics. We review the available evidence on methadone-associated mortality, and explore potential pharmacokinetic and pharmacodynamic explanations for its greater apparent lethality. While methadone shares properties of central nervous system and respiratory depression with other opioids, methadone is unique as a potent blocker of the delayed rectifier potassium ion channel (IKr). This results in QT-prolongation and torsade de pointes (TdP) in susceptible individuals. In some individuals with low serum protein binding of methadone, the extent of blockade is roughly comparable to that of sotalol, a potent QT-prolonging drug. Predicting an individual's propensity for methadone-induced TdP is difficult at present given the inherent limitations of the QT interval as a risk-stratifier combined with the multifactorial nature of the arrhythmia. Consensus recommendations have recently been published to mitigate the risk of TdP until further studies better define the arrhythmia risk factors for methadone. Studies are needed to provide insights into the clinical covariates most likely to result in methadone-associated arrhythmia and to assess the feasibility of current risk mitigation strategies.

QTc interval screening in methadone treatment.

DESCRIPTION: An independent panel developed cardiac safety recommendations for physicians prescribing methadone. METHODS: Expert panel members reviewed and discussed the following sources regarding methadone: pertinent English-language literature identified from MEDLINE and EMBASE searches (1966 to June 2008), national substance abuse guidelines from the United States and other countries, information from regulatory authorities, and physician awareness of adverse cardiac effects. RECOMMENDATION 1 (DISCLOSURE): Clinicians should inform patients of arrhythmia risk when they prescribe methadone. RECOMMENDATION 2 (CLINICAL HISTORY): Clinicians should ask patients about any history of structural heart disease, arrhythmia, and syncope. RECOMMENDATION 3 (SCREENING): Obtain a pretreatment electrocardiogram for all patients to measure the QTc interval and a follow-up electrocardiogram within 30 days and annually. Additional electrocardiography is recommended if the methadone dosage exceeds 100 mg/d or if patients have unexplained syncope or seizures. RECOMMENDATION 4 (RISK STRATIFICATION): If the QTc interval is greater than 450 ms but less than 500 ms, discuss the potential risks and benefits with patients and monitor them more frequently. If the QTc interval exceeds 500 ms, consider discontinuing or reducing the methadone dose; eliminating contributing factors, such as drugs that promote hypokalemia; or using an alternative therapy. RECOMMENDATION 5 (DRUG INTERACTIONS): Clinicians should be aware of interactions between methadone and other drugs that possess QT interval-prolonging properties or slow the elimination of methadone.