Prevalence and Predictors of Mitral Annular Disjunction and Ventricular Ectopy in Mitral Valve Prolapse.

BACKGROUND: Mitral annular disjunction (MAD) is associated with ventricular arrhythmia in mitral valve prolapse (MVP). The proportional risk from MAD and other predictors of ventricular arrhythmia in MVP have not been well characterized. OBJECTIVE: To identify predictors of complex or frequent ventricular ectopy (cfVE) in MVP and quantify risk of cfVE and mortality in MVP with MAD. METHODS: We studied 632 adult patients with MVP on transthoracic echocardiography at the University of North Carolina Medical Center from 2016-2019 (median age [IQR] 64 [52-74] years; 52.7% female; 16.3% African American). Resting and ambulatory electrocardiograms were used to identify cfVE. RESULTS: MAD was present in 94 (14.9%) patients. Independent associations of MAD were bileaflet prolapse (OR [95% CI] 4.25 [2.47-7.33], p<0.0001), myxomatous valve (2.17 [1.27-3.71], p=0.005), absence of hypertension (2.00 [1.21-3.32], p=0.007), electrocardiogram inferior or lateral lead T-wave inversion (TWI, 2.07 [1.23-3.48], p=0.006), and female sex (1.99 [1.21-3.25], p=0.006). cfVE was frequent with MAD (39 [41.5%] vs 93 [17.3%] without, p<0.0001). Independent cfVE predictors were MAD (HR [95% CI] 2.23 [1.47-3.36], p=0.0001), bileaflet prolapse (1.86 [1.25-2.76], p=0.002), heart failure (1.79 [1.16-2.77], p=0.009), lower LV ejection fraction (0.14 [0.03-0.61], p=0.009), coronary artery disease (1.60 [1.05-2.43], p=0.03), and TWI (1.51 [1.03-2.22], p=0.03). After median 40 (33-48) months, there was increased mortality with MAD (p=0.04). CONCLUSION: MAD in MVP is associated with bileaflet or myxomatous MVP, absence of hypertension, T-wave inversion, and female sex. There is increased complex and frequent ventricular ectopy and mortality with MAD, highlighting the need for closer follow-up in these patients.

Fine particulate matter-sudden death association modified by ventricular hypertrophy and inflammation: a case-crossover study.

Background: Sudden death accounts for approximately 10% of deaths among working-age adults and is associated with poor air quality. Objectives: To identify high-risk groups and potential modifiers and mediators of risk, we explored previously established associations between fine particulate matter (PM2.5) and sudden death stratified by potential risk factors. Methods: Sudden death victims in Wake County, NC, from 1 March 2013 to 28 February 2015 were identified by screening Emergency Medical Systems reports and adjudicated (n = 399). Daily PM2.5 concentrations for Wake County from the Air Quality Data Mart were linked to event and control periods. Potential modifiers included greenspace metrics, clinical conditions, left ventricular hypertrophy (LVH), and neutrophil-to-lymphocyte ratio (NLR). Using a case-crossover design, conditional logistic regression estimated the OR (95%CI) for sudden death for a 5 µg/m3 increase in PM2.5 with a 1-day lag, adjusted for temperature and humidity, across risk factor strata. Results: Individuals having LVH or an NLR above 2.5 had PM2.5 associations of greater magnitude than those without [with LVH OR: 1.90 (1.04, 3.50); NLR > 2.5: 1.25 (0.89, 1.76)]. PM2.5 was generally less impactful for individuals living in areas with higher levels of greenspace. Conclusion: LVH and inflammation may be the final step in the causal pathway whereby poor air quality and traditional risk factors trigger arrhythmia or myocardial ischemia and sudden death. The combination of statistical evidence with clinical knowledge can inform medical providers of underlying risks for their patients generally, while our findings here may help guide interventions to mitigate the incidence of sudden death.

Characteristics of sudden death by clinical criteria.

Sudden death is a leading cause of deaths nationally. Definitions of sudden death vary greatly, resulting in imprecise estimates of its frequency and incomplete knowledge of its risk factors. The degree to which time-based and coronary artery disease (CAD) criteria impacts estimates of sudden death frequency and risk factors is unknown. Here, we apply these criteria to a registry of all-cause sudden death to assess its impact on sudden death frequency and risk factors. The sudden unexpected death in North Carolina (SUDDEN) project is a registry of out of-hospital, adjudicated, sudden unexpected deaths attended by Emergency Medical Services. Deaths were not excluded by time since last seen or alive or by prior symptoms or diagnosis of CAD. Common criteria for sudden death based on time since last seen alive (both 24 hours and 1 hour) and prior diagnosis of CAD were applied to the SUDDEN case registry. The proportion of cases satisfying each of the 4 criteria was calculated. Characteristics of victims within each restrictive set of criteria were measured and compared to the SUDDEN registry. There were 296 qualifying sudden deaths. Application of 24 hour and 1 hour timing criteria compared to no timing criteria reduced cases by 25.0% and 69.6%, respectively. Addition of CAD criteria to each timing criterion further reduced qualifying cases, for a total reduction of 81.8% and 90.5%, respectively. However, characteristics among victims meeting restrictive criteria remained similar to the unrestricted population. Timing and CAD criteria dramatically reduces estimates of the number of sudden deaths without significantly impacting victim characteristics.

Social Disparities among Sudden Death victims with HIV.

Although cardiovascular death is a growing source of mortality for people living with human immunodeficiency virus (HIV), the risk factors and circumstances surrounding sudden death in this population are poorly understood. We compared 399 adult sudden death victims reported by Emergency Medical Services in North Carolina to 1,114 controls. Sudden death was more common among HIV-positive than HIV-negative individuals (OR: 2.59, 95% CI: 1.15-5.83). In a multivariable model of sudden death victims including Black race, BMI, and history of divorce, incarceration, substance abuse, and respiratory disease, HIV-positive individuals were more likely to be Black (adjusted OR [aOR]: 6.04, 95% CI: 1.08-33.7) or divorced (aOR: 4.71, 95% CI: 1.04-21.3), adjusted for all other variables in the model. Compared to controls with HIV, sudden death victims with HIV were more likely to have a history of incarceration, divorce, respiratory disease, alcohol abuse, or dyslipidemia. A qualitative assessment of victims suggested that many died in isolation, suffering from past and current substance abuse and depression. HIV infection appears to be an important risk factor for sudden death, and incarceration history, social isolation, and medical comorbidities contribute to sudden death risk for HIV-positive individuals.

Questionnaire-based exposome-wide association studies (ExWAS) reveal expected and novel risk factors associated with cardiovascular outcomes in the Personalized Environment and Genes Study.

While multiple factors are associated with cardiovascular disease (CVD), many environmental exposures that may contribute to CVD have not been examined. To understand environmental effects on cardiovascular health, we performed an exposome-wide association study (ExWAS), a hypothesis-free approach, using survey data on endogenous and exogenous exposures at home and work and data from health and medical histories from the North Carolina-based Personalized Environment and Genes Study (PEGS) (n = 5015). We performed ExWAS analyses separately on six cardiovascular outcomes (cardiac arrhythmia, congestive heart failure, coronary artery disease, heart attack, stroke, and a combined atherogenic-related outcome comprising angina, angioplasty, atherosclerosis, coronary artery disease, heart attack, and stroke) using logistic regression and a false discovery rate of 5%. For each CVD outcome, we tested 502 single exposures and built multi-exposure models using the deletion-substitution-addition (DSA) algorithm. To evaluate complex nonlinear relationships, we employed the knockoff boosted tree (KOBT) algorithm. We adjusted all analyses for age, sex, race, BMI, and annual household income. ExWAS analyses revealed novel associations that include blood type A (Rh-) with heart attack (OR[95%CI] = 8.2[2.2:29.7]); paint exposures with stroke (paint related chemicals: 6.1[2.2:16.0], acrylic paint: 8.1[2.6:22.9], primer: 6.7[2.2:18.6]); biohazardous materials exposure with arrhythmia (1.8[1.5:2.3]); and higher paternal education level with reduced risk of multiple CVD outcomes (stroke, heart attack, coronary artery disease, and combined atherogenic outcome). In multi-exposure models, trouble sleeping and smoking remained important risk factors. KOBT identified significant nonlinear effects of sleep disorder, regular intake of grapefruit, and a family history of blood clotting problems for multiple CVD outcomes (combined atherogenic outcome, congestive heart failure, and coronary artery disease). In conclusion, using statistics and machine learning, these findings identify novel potential risk factors for CVD, enable hypothesis generation, provide insights into the complex relationships between risk factors and CVD, and highlight the importance of considering multiple exposures when examining CVD outcomes.

Serious Cardiovascular Adverse Events Associated with Hydroxychloroquine/Chloroquine Alone or with Azithromycin in Patients with COVID-19: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: The use of hydroxychloroquine or chloroquine (HCQ/CQ) as monotherapy or combined with azithromycin for the treatment of coronavirus disease 2019 (COVID-19) may increase the risk of serious cardiovascular adverse events (SCAEs). OBJECTIVE: Our objective was to describe and evaluate the risk of SCAEs with HCQ/CQ as monotherapy or combined with azithromycin compared with that for therapeutic alternatives. METHODS: We performed a disproportionality analysis and descriptive case series using the US FDA Adverse Event Reporting System. RESULTS: Compared with remdesivir, HCQ/CQ was associated with increased reporting of SCAEs (reporting odds ratio [ROR] 2.1; 95% confidence interval [CI] 1.8-2.5), torsade de pointes (TdP)/QTc prolongation (ROR 35.4; 95% CI 19.4-64.5), and ventricular arrhythmia (ROR 2.5; 95% CI 1.6-3.9); similar results were found in comparison with other therapeutic alternatives. Compared with lopinavir/ritonavir, HCQ/CQ was associated with increased reporting of ventricular arrhythmia (ROR 10.5; 95% CI 3.3-33.4); RORs were larger when HCQ/CQ was used in combination with azithromycin. In 2020, 312 of the 575 reports of SCAEs listed concomitant use of HCQ/CQ and azithromycin, including QTc prolongation (61.4%), ventricular arrhythmia (12.0%), atrial fibrillation (8.2%), TdP (4.9%), and cardiac arrest (4.4%); 88 (15.3%) cases resulted in hospitalization and 79 (13.7%) resulted in death. In total, 122 fatal QTc prolongation-related cardiovascular reports were associated with 1.4 times higher odds of reported death than those induced by SCAEs; 87 patients received more than one QTc-prolonging agent. CONCLUSIONS: Patients treated with HCQ/CQ monotherapy or HCQ/CQ + azithromycin may be at increased risk of SCAEs, TdP/QTc prolongation, and ventricular arrhythmia. Cardiovascular risks need to be considered when evaluating the benefit/harm balance of treatment with HCQ/CQ, especially with the concurrent use of QTc-prolonging agents and cytochrome P450 3A4 inhibitors when treating COVID-19.

Symptoms prior to sudden death.

BACKGROUND: Sudden death accounts for up to 15% of all deaths among working age adults. A better understanding of victims' medical care and symptoms reported at their last medical encounter may identify opportunities for interventions to prevent sudden deaths. METHODS: From 2013-15, all out-of-hospital deaths, ages 18-64 reported by Emergency Medical Services (EMS) in Wake County, North Carolina were screened and adjudicated to identify 399 victims of sudden death, 264 of whom had available medical records. Demographic and clinical characteristics and prescribed medications were compared between victims with versus without a medical encounter within one month preceding death with chi-square tests and t-tests, as appropriate. Symptoms reported in medical encounters within one month preceding death were analyzed. RESULTS: Among the 264 victims with available medical records, 73 (27.7%) had at least one encounter within a month preceding death. These victims were older and more likely to have multiple chronic illnesses, yet most were not prescribed evidence-based medicines. Of these 73 victims, 30 (41.1%) reported cardiac symptoms including dyspnea, edema, and chest pain. CONCLUSIONS: Many victims seek medical care and report cardiac symptoms in the month prior to sudden death. However, medications that might prevent sudden death are under prescribed. These findings suggest that there are opportunities for intervention to prevent sudden death.

Missed Opportunities for Prevention of Sudden Death.

BACKGROUND: We assessed patterns of health care utilization to further characterize chronic comorbidities prior to sudden death. METHOD: From March 1, 2013, through February 28, 2015, all out-of-hospital deaths aged 18-64 reported by emergency medical services in Wake County, North Carolina, were screened to adjudicate 399 sudden death victims. Retrospective analysis of clinical records on victims determined health care utilization. Health care utilization frequency was assessed by latent growth curve analysis. RESULTS: Medical records were available for 264 victims (aged 53.5 ± 9.2) who were predominantly male (65%) and white (64%). Of these, 210 (80%) victims had at least one visit within two years of death and 73 (28%) had a visit within one month of death. Over the two years prior to death, there was an increasing frequency of doctor visits (P < .001). Victims averaged 3.7 ± 4.6 yearly visits and were categorized into low (0.4 visits/year), medium (3.3 visits/year), and high (11.4 visits/year) tiers of visit frequency. The high visit tier had a greater prevalence of coronary artery disease (38%), hypertension (80%), diabetes (58%), depression (74%), anxiety (64%), and substance misuse (46%) (P < .001). LIMITATIONS: Those who were non-free-living, minors, without formal medical records, and adults aged 65 and older were excluded from the analysis. CONCLUSIONS: A majority of sudden death victims utilized health care within two years prior to death and had comorbidities that may have contributed to their unexpected death. The increasing frequency of visits prior to death provided an opportunity for health care providers to address potential victims' chronic medical conditions to potentially prevent death.

High Prevalence of Diabetes Mellitus and Mental Illness Among Victims of Sudden Death.

OBJECTIVES: Diabetes mellitus (DM) increases the risk of cardiovascular disease and is associated with sudden death. Mental illness among individuals with DM may confound medical care. This study assessed the association of mental illness with DM and poorly controlled DM in sudden death victims. METHODS: We screened out-of-hospital deaths ages 18 to 64 years in Wake County, North Carolina from 2013 to 2015 to adjudicate sudden deaths. We abstracted demographics and clinical characteristics from health records. Mental illness included anxiety, schizophrenia, bipolar disorder, or depression. Poorly controlled DM was defined as a hemoglobin A1c >8 or taking ≥3 medications for glycemic control. Logistic regression assessed the association between DM and mental illness. RESULTS: Among victims with available records, 109 (29.4%) had DM. Of those, 62 (56.9%) had mental illness. Mental illness was present in 53.42% and 63.89% of victims with mild and poorly controlled DM, respectively. Mental illness was associated with DM (adjusted odds ratio 2.46, 95% confidence interval 1.57-3.91). Victims with poorly controlled DM were more likely to have mental illness (adjusted odds ratio 2.66, 95% confidence interval 1.14-6.18). CONCLUSIONS: DM is a common comorbid condition in sudden death victims. Among victims, mental illness is associated with the control of DM. Early management of comorbid mental illnesses may improve the care of patients with DM and reduce the incidence of sudden death.

Mental Disorders, Substance Use Disorders, and Psychotropic Medication Use Among Sudden-Death Victims.

OBJECTIVE: The authors sought to estimate the prevalence of mental and substance use disorders and psychotropic medication prescriptions among working-age sudden-death victims. METHODS: Using a written protocol, the authors screened for sudden deaths attended by emergency medical services (EMS) in a large metropolitan county in North Carolina from March 1, 2013, to February 28, 2015. Sudden-death cases were adjudicated by three cardiologists. Mental health and chronic disease diagnoses and treatments were abstracted from EMS, medical examiner, toxicology, and autopsy reports and from clinical records for the past 5 years before death. RESULTS: Sudden death was identified for 399 adults ages 18-64 years, 270 of whom had available medical records. Most sudden-death victims were White (63%) and male (65%), had a comorbid condition such as hypertension or respiratory disease, and had a mean±SD age of death of 53.6±8.8 years. Most victims (59%) had at least one mental health or substance use disorder documented in a recent medical record; 76%-78% of victims with a mental disorder had a documented psychotropic medication prescription. However, fewer than one-half (41%) had a documented referral to a mental health professional. The most common diagnostic categories were depressive, anxiety, and alcohol-related disorders. Almost one-half (46%) of the victims had a recent psychotropic prescription, most commonly antidepressants (29%) and benzodiazepines (19%). CONCLUSIONS: Mental illness, substance use disorders, and psychotropic medication prescriptions were prevalent among sudden-death victims. The health care needs of these individuals may be better addressed by collaborative care for general medical and mental disorders.

Variations in blood pressure control by medical comorbidities prior to sudden death.

Patients with hypertension have increased risk of sudden death, but the impact of blood pressure control in sudden death is not clear. To better understand potential opportunities to prevent sudden, we assessed blood pressure control, comorbidities, and the number of recent medical encounters among all-cause sudden death victims. Less than 40% of sudden death victims with hypertension had controlled blood pressure prior to death. Furthermore, increased frequency of medical visits and number of comorbidities were associated with better blood pressure control Strategies to address clinical inertia in hypertension treatment particularly for patients with fewer comorbidities may attenuate the risk of sudden death.

College of American Pathologists Cancer Protocols: From Optimizing Cancer Patient Care to Facilitating Interoperable Reporting and Downstream Data Use.

The College of American Pathologists Cancer Protocols have offered guidance to pathologists for standard cancer pathology reporting for more than 35 years. The adoption of computer readable versions of these protocols by electronic health record and laboratory information system (LIS) vendors has provided a mechanism for pathologists to report within their LIS workflow, in addition to enabling standardized structured data capture and reporting to downstream consumers of these data such as the cancer surveillance community. This paper reviews the history of the Cancer Protocols and electronic Cancer Checklists, outlines the current use of these critically important cancer case reporting tools, and examines future directions, including plans to help improve the integration of the Cancer Protocols into clinical, public health, research, and other workflows.

Reweighting Oranges to Apples: Transported RE-LY Trial Versus Nonexperimental Effect Estimates of Anticoagulation in Atrial Fibrillation.

BACKGROUND: Results from trials and nonexperimental studies are often directly compared, with little attention paid to differences between study populations. When target and trial population data are available, accounting for these differences through transporting trial results to target populations of interest provides useful perspective. We aimed to compare two-year risk differences (RDs) for ischemic stroke, mortality, and gastrointestinal bleeding in older adults with atrial fibrillation initiating dabigatran and warfarin when using trial transport methods versus nonexperimental methods. METHODS: We identified Medicare beneficiaries who initiated warfarin or dabigatran from a 20% nationwide sample. To transport treatment effects observed in the randomized evaluation of long-term anticoagulation trial, we applied inverse odds weights to standardize estimates to two Medicare target populations of interest, initiators of: (1) dabigatran and (2) warfarin. Separately, we conducted a nonexperimental study in the Medicare populations using standardized morbidity ratio weighting to control measured confounding. RESULTS: Comparing dabigatran to warfarin, estimated two-year RDs for ischemic stroke were similar with trial transport and nonexperimental methods. However, two-year mortality RDs were closer to the null when using trial transport versus nonexperimental methods for the dabigatran target population (transported RD: -0.57%; nonexperimental RD: -1.9%). Estimated gastrointestinal bleeding RDs from trial transport (dabigatran initiator RD: 1.8%; warfarin initiator RD: 1.9%) appeared more harmful than nonexperimental results (dabigatran initiator RD: 0.14%; warfarin initiator RD: 0.57%). CONCLUSIONS: Differences in study populations can and should be considered quantitatively to ensure results are relevant to populations of interest, particularly when comparing trial with nonexperimental findings. See video abstract: http://links.lww.com/EDE/B703.

Real-world on-treatment and initial treatment absolute risk differences for dabigatran vs warfarin in older US adults.

PURPOSE: Trials and past observational work compared dabigatran and warfarin in patients with atrial fibrillation, but few reported estimates of absolute harm and benefit under real-world adherence patterns, particularly in older adults that may have differing benefit-harm profiles. We aimed to estimate risk differences for ischemic stroke, death, and gastrointestinal bleeding after initiating dabigatran and warfarin in older adults (a) when patients adhere to treatment and (b) under real-world adherence patterns. METHODS: In a 20% sample of nationwide Medicare claims from 2010 to 2015, we identified beneficiaries aged 66 years and older initiating warfarin and dabigatran. We followed individuals from initiation until death or October 2015 (initial treatment, IT) and separately censored individuals' follow-up after drug switches and gaps in supply (on-treatment, OT). We applied inverse probability of treatment and standardized morbidity ratio weights, as well as inverse probability of censoring weights, to estimate two-year risk differences (RDs) for dabigatran vs warfarin. RESULTS: We identified 10,717 dabigatran and 74,891 warfarin initiators. Weighted OT RDs suggested decreased ischemic stroke risk for dabigatran vs warfarin; IT RDs indicated increased or no change in ischemic stroke risk. Regardless of follow-up approach and weighting strategy, risk of death appeared lower and risk of gastrointestinal bleeding appeared higher when comparing dabigatran vs warfarin. CONCLUSIONS: Dabigatran use was associated with lower risks of mortality and ischemic stroke in routine care when older adults stayed on treatment. IT analyses suggested that these benefits may be diminished under real-world patterns of switching and discontinuation.