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Background: Molecular testing with gene-expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) is increasingly used in the surveillance for acute cellular rejection (ACR) after heart transplant. However, the performance of dual testing over each test individually has not been established. Further, the impact of dual noninvasive surveillance on clinical decision-making has not been widely investigated., Methods: We evaluated 2,077 subjects from the Surveillance HeartCare Outcomes Registry registry who were enrolled between 2018 and 2021 and had verified biopsy data and were categorized as dual negative, GEP positive/dd-cfDNA negative, GEP negative/dd-cfDNA positive, or dual positive. The incidence of ACR and follow-up testing rates for each group were evaluated. Positive likelihood ratios (LRs+) were calculated, and biopsy rates over time were analyzed., Results: The incidence of ACR was 1.5% for dual negative, 1.9% for GEP positive/dd-cfDNA negative, 4.3% for GEP negative/dd-cfDNA positive, and 9.2% for dual-positive groups. Follow-up biopsies were performed after 8.8% for dual negative, 14.2% for GEP positive/dd-cfDNA negative, 22.8% for GEP negative/dd-cfDNA positive, and 35.4% for dual-positive results. The LR+ for ACR was 1.37, 2.91, and 3.90 for GEP positive, dd-cfDNA positive, and dual-positive testing, respectively. From 2018 to 2021, biopsies performed between 2 and 12-months post-transplant declined from 5.9 to 5.3 biopsies/patient, and second-year biopsy rates declined from 1.5 to 0.9 biopsies/patient. At 2 years, survival was 94.9%, and only 2.7% had graft dysfunction., Conclusions: Dual molecular testing demonstrated improved performance for ACR surveillance compared to single molecular testing. The use of dual noninvasive testing was associated with lower biopsy rates over time, excellent survival, and low incidence of graft dysfunction., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Exposure to air pollution is a major risk factor for cardiovascular disease, disease risk factors, and mortality. Specifically, particulate matter (PM), and to some extent ozone, are contributors to these effects. In addition, exposures to these pollutants may be especially dangerous for susceptible populations. In this repeated-visit panel study, cardiovascular markers were collected from thirteen male participants with stable coronary artery disease. For 0-4 days prior to the health measurement collections, daily concentrations of fine PM (PM 2.5 ) and ozone were obtained from local central monitoring stations located near the participant's homes. Then, single (PM 2.5 ) and two-pollutant (PM 2.5 and ozone) models were used to assess whether there were short-term changes in cardiovascular health markers. Per interquartile range increase in PM 2.5 , there were decrements in several heart rate variability metrics, including the standard deviation of the normal-to-normal intervals (lag 3, -5.8%, 95% confidence interval (CI) = -11.5, 0.3) and root-mean squared of successive differences (five day moving average, -8.1%, 95% CI = -15.0, -0.7). In addition, increases in PM 2.5 were also associated with changes in P complexity (lag 1, 4.4%, 95% CI = 0.5, 8.5), QRS complexity (lag 1, 4.9%, 95% CI = 1.4, 8.5), total cholesterol (five day moving average, -2.1%, 95% CI = -4.1, -0.1), and high-density lipoprotein cholesterol (lag 2, -1.6%, 95% CI = -3.1, -0.1). Comparisons to our previously published work on ozone were conducted. We found that ozone affected inflammation and endothelial function, whereas PM 2.5 influenced heart rate variability, repolarization, and lipids. All the health changes from these two studies were found at concentrations below the United States Environmental Protection Agency's National Ambient Air Quality Standards. Our results imply clear differences in the cardiovascular outcomes observed with exposure to the two ubiquitous air pollutants PM 2.5 and ozone; this observation suggests different mechanisms of toxicity for these exposures., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Longstanding racial/ethnic inequalities in morbidity and mortality persist in the United States. Although the determinants of health inequalities are complex, social and structural factors produced by inequitable and racialized systems are recognized as contributing sources. Social epigenetics is an emerging area of research that aims to uncover biological pathways through which social experiences affect health outcomes. A growing body of literature links adverse social exposures to epigenetic mechanisms, namely DNA methylation, offering a plausible pathway through which health inequalities may arise. This review provides an overview of social epigenetics and highlights existing literature linking social exposures-i.e., psychosocial stressors, racism, discrimination, socioeconomic position, and neighborhood social environment-to DNA methylation in humans. We conclude with a discussion of social epigenetics as a mechanistic link to health inequalities and provide suggestions for future social epigenetics research on health inequalities.

Importance: Unexplained sudden cardiac death (SCD) describes SCD with no cause identified. Genetic testing helps to diagnose inherited cardiac diseases in unexplained SCD; however, the associations between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies (CMs) and arrhythmia syndromes and the risk of unexplained SCD in both White and African American adults living the United States has never been systematically examined., Objective: To investigate cases of unexplained SCD to determine the frequency of P/LP genetic variants of inherited CMs and arrhythmia syndromes., Design, Setting, and Participants: This genetic association study included 683 African American and White adults who died of unexplained SCD and were included in an autopsy registry. Overall, 413 individuals had DNA of acceptable quality for genetic sequencing. Data were collected from January 1995 to December 2015. A total of 30 CM genes and 38 arrhythmia genes were sequenced, and variants in these genes, curated as P/LP, were examined to study their frequency. Data analysis was performed from June 2018 to March 2021., Main Outcomes and Measures: The frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD., Results: The median (interquartile range) age at death of the 413 included individuals was 41 (29-48) years, 259 (62.7%) were men, and 208 (50.4%) were African American adults. A total of 76 patients (18.4%) with unexplained SCD carried variants considered P/LP for CM and arrhythmia genes. In total, 52 patients (12.6%) had 49 P/LP variants for CM, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both CM and arrhythmia. Overall, 41 P/LP variants for hypertrophic CM were found in 45 patients (10.9%), 9 P/LP variants for dilated CM were found in 11 patients (2.7%), and 10 P/LP variants for long QT syndrome were found in 11 patients (2.7%). No significant difference was found in clinical and heart characteristics between individuals with or without P/LP variants. African American and White patients were equally likely to harbor P/LP variants., Conclusions and Relevance: In this large genetic association study of community cases of unexplained SCD, nearly 20% of patients carried P/LP variants, suggesting that genetics may contribute to a significant number of cases of unexplained SCD. Our findings regarding both the association of unexplained SCD with CM genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.

Background It is unclear whether the recent increase in the number of heart transplants performed annually in the United States is only because of higher availability of donors and if it affected recipients' survival. Methods and Results We examined characteristics of donors and recipients from 2008 to 2012 (n=11 654) and 2013 to 2017 (n=14 556) and compared them with 2003 to 2007 (n=10 869). Cox models examined 30-day and 1-year risk of recipients' death post transplant. From 2013 to 2017, there was an increase in the number of transplanted hearts and number of donor offers but an overall decline in the ratio of hearts transplanted to available donors. Donors between 2013 and 2017 were older, heavier, more hypertensive, diabetic, and likely to have abused illicit drugs compared with previous years. Drug overdose and hepatitis C positive donors were additional contributors to donor risk in recent years. In Cox models, risk of death post transplant between 2013 and 2017 was 15% lower at 30 days (hazard ratio [HR] 0.85; 95% CI, 0.74-0.98) and 21% lower at 1 year (HR, 0.79; 95% CI, 0.73-0.87) and between 2008 and 2012 was 9% lower at 30 days (HR, 0.91; 95% CI, 0.79-1.05) and 14% lower at 1 year (HR, 0.86; 95% CI, 0.79-0.94) compared with 2003 to 2007. Conclusions Despite a substantial increase in heart donor offers in recent years, the ratio of transplants performed to available donors has decreased. Even though hearts from donors who are older, more hypertensive, and have diabetes mellitus are being used, overall recipient survival continues to improve. Broader acceptance of drug overdose and hepatitis C positive donors may increase the number and percentage of heart transplants further without jeopardizing short-term outcomes.

Aims: End-stage heart failure patients often present with severe kidney failure and have limited treatment options. We compared the clinical characteristics and outcomes among end-stage heart and kidney failure patients who underwent combined heart and kidney transplant (HKTx) with those who underwent kidney transplant after heart transplant (KAH)., Methods and Results: All patients from 2007-2016 who underwent combined HKTx (n = 715) and those who underwent KAH (n = 130) using the United Network for Organ Sharing database were included. Kaplan-Meier curves and Cox models compared survivals and identified predictors of death. Number of combined HKTx performed annually in United States increased from 59 in 2007 to 146 in 2016 whereas KAH decreased from 34 in 2007 to 6 in 2016. Among KAH patients, average wait time for kidney transplant was 3.0 years, time to dialysis or to kidney transplant after heart transplant did not differ with varying severity of kidney disease at baseline (P for both >0.05). Upon follow-up (mean 3.5 ± 2.7 years), 151 patients died. In multivariable models, patients who underwent combined HKTx had 4.7-fold greater risk of death [95% confidence interval (CI) 2.4-9.4) than KAH patients upon follow up. A secondary analysis using calculation of survival only after kidney transplant for KAH patients still conferred higher risk for combined HKTx patients [hazard ratio (HR) 2.6 95% CI 1.33-5.15]. In subgroup analyses after excluding patients on dialysis (HR 3.99 95% CI 1.98-8.04) and analysis after propensity matching for age, gender, and glomerular filtration rate (HR 3.01 95% CI 1.40-6.43) showed similar and significantly higher risk for combined HKTx patients compared with KAH patients. Lastly, these results also remained unchanged after excluding transplant centres who performed only one type of procedure preferentially, i.e. HKTx or KAH (HR 4.70 95% CI 2.35-9.42)., Conclusions: National registry data show continual increase in combined HKTx performed annually in the United States but inferior survival compared with KAH patients. Differences in patient characteristics or level of kidney dysfunction at baseline do not explain these poor outcomes among HKTx patients compared with KAH patients. Consensus guidelines are greatly needed to identify patients who may benefit more from dual organ transplants., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Contaminated produce causes approximately 1 million cases of foodborne illness and 1 billion dollars in damages to the U.S. economy annually. The environmental conditions, especially weather, that influence the inoculation, proliferation, and dispersal of microbial load on produce are not well understood. Using a mixed models approach, we examined the relationship of temperature and precipitation to microbial indicators of contamination on fresh produce on the farm over a week-long period prior to harvest. Between 2000 and 2002, we assayed for four microbial indicators of contamination (aerobic plate count, Enterococcus, total coliforms, and Escherichia coli) on 10 produce types in 15 fields in the southern United States. The sample collection times varied, with most occurring between January and May. We collected hourly weather data for the corresponding time period and location. Our results indicated that there was a significant association between the average daily temperature (20°C) and both log aerobic plate count (e.g., an increase of 0.074 log CFU/g [standard error {SE}, 0.023] per °C increase in weekly average temperature) and log Enterococcus (e.g., an increase of 0.15 log CFU/g [SE, 0.031] per °C increase in weekly average temperature) for approximately 5 days prior to sample collection. Daily total precipitation was significantly associated with log coliforms on 2 days (∼0.11 log CFU/g [SE, 0.06] per mm of precipitation) during the week-long lag period prior to harvest. Our results suggest that microbial indicator concentrations may increase as the temperature increases. Precipitation may have a positive but complex relationship with microbial indicators, as precipitation may create moist conditions conducive to bacterial growth, spread contamination onto the field, or wash contamination off of the plant.

Extrapolating landscape regression models for use in assessing vector-borne disease risk and other applications requires thoughtful evaluation of fundamental model choice issues. To examine implications of such choices, an analysis was conducted to explore the extent to which disparate landscape models agree in their epidemiological and entomological risk predictions when extrapolated to new regions. Agreement between six literature-drawn landscape models was examined by comparing predicted county-level distributions of either Lyme disease or Ixodes scapularis vector using Spearman ranked correlation. AUC analyses and multinomial logistic regression were used to assess the ability of these extrapolated landscape models to predict observed national data. Three models based on measures of vegetation, habitat patch characteristics, and herbaceous landcover emerged as effective predictors of observed disease and vector distribution. An ensemble model containing these three models improved precision and predictive ability over individual models. A priori assessment of qualitative model characteristics effectively identified models that subsequently emerged as better predictors in quantitative analysis. Both a methodology for quantitative model comparison and a checklist for qualitative assessment of candidate models for extrapolation are provided; both tools aim to improve collaboration between those producing models and those interested in applying them to new areas and research questions.

Background: Trihalomethanes (THMs) are water disinfection by-products that have been associated with bladder cancer and adverse birth outcomes. Four THMs (bromoform, chloroform, bromodichloromethane, dibromochloromethane) were measured in blood and tap water of U.S. adults in the National Health and Nutrition Examination Survey (NHANES) 1999-2006. THMs are metabolized to potentially toxic/mutagenic intermediates by cytochrome p450 (CYP) 2D6 and CYP2E1 enzymes., Objectives: We conducted exploratory analyses of blood THMs, including factors affecting CYP2D6 and CYP2E1 activity., Methods: We used weighted multivariable regressions to evaluate associations between blood THMs and water concentrations, survey year, and other factors potentially affecting THM exposure or metabolism (e.g., prescription medications, cruciferous vegetables, diabetes, fasting, pregnancy, swimming)., Results: From 1999 to 2006, geometric mean blood and water THM levels dropped in parallel, with decreases of 32%-76% in blood and 38%-52% in water, likely resulting, in part, from the lowering of the total THM drinking water standard in 2002-2004. The strongest predictors of blood THM levels were survey year and water concentration (n = 4,232 total THM; n = 4,080 bromoform; n = 4,582 chloroform; n = 4,374 bromodichloromethane; n = 4,464 dibromochloromethane). We detected statistically significant inverse associations with diabetes and eating cruciferous vegetables in all but the bromoform model. Medications did not consistently predict blood levels. Afternoon/evening blood samples had lower THM concentrations than morning samples. In a subsample (n = 230), air chloroform better predicted blood chloroform than water chloroform, suggesting showering/bathing was a more important source than drinking., Conclusions: We identified several factors associated with blood THMs that may affect their metabolism. The potential health implications require further study.

Prevalence of diabetes and heart failure are increasing exponentially worldwide. Diabetes is well-known to increase the risk of heart failure independent of other traditional risk factors and ischemia. Current evidence indicates the presence of several biochemical and molecular changes associated with diabetes that lead to diastolic dysfunction or American Heart Association stage B heart failure. Some, if not all, changes may also predate the development of frank diabetes. In this review, the authors present some of the epidemiologic evidence and a brief description of major mechanistic pathways that favor the development of heart failure in prediabetic and diabetic states., (2012 Elsevier Inc. All rights reserved.)

Background: The relations between chronic kidney disease (CKD) and incident heart failure remain unclear., Methods and Results: We related CKD to incident nonfatal heart failure and cardiovascular (CVD) death (as separate and combined end points) in 10 181 male participants (mean age, 67 years). Kidney function was assessed by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease equation in clinically relevant categories of <60 and ≥60 mL · min(-1) · 1.73 m(-2) (referent) and <45, 45 to 60, 60 to 90, and ≥90 mL · min(-1) · 1.73 m(-2) (referent). During follow-up (mean, 10.1 years; range, 0.03 to 12.2), 439 developed heart failure and 832 had CVD death/heart failure. In multivariable models, men with eGFR <60 mL · min(-1) · 1.73 m(-2) had a 2-fold risk of heart failure (95% confidence interval, 1.62 to 2.56, P<0.0001) compared with referent category. The hazard ratio (with corresponding 95% confidence interval) for development of heart failure according to eGFR categories of 60 to 90, 45 to 60, and <45 mL · min(-1) · 1.73 m(-2) compared with referent category were 1.24 (0.98 to 1.56), 2.58 (1.91 to 3.49), and 1.52 (0.92 to 2.76), respectively. In the analyses restricted to subgroup of nondiabetic individuals and normotensive individuals at baseline (n=7545), men with eGFR <60 mL · min(-1) · 1.73 m(-2) had a 2.2-fold risk of heart failure (95% confidence interval, 1.66 to 2.95), compared with men with eGFR ≥60 mL · min(-1) · 1.73 m(-2). Additionally, risk of heart failure or CVD death was >2.5-fold higher among individuals with eGFR 45 to 60 and <45 mL · min(-1) · 1.73 m(-2), compared with referent category., Conclusions: Moderate level of CKD, even in absence of diabetes and hypertension at baseline, is associated with a higher risk of development of heart failure and CVD death/heart failure in men.

Background: It is uncertain to what extent high C-reactive protein (CRP) concentrations reflect the presence of inflammatory conditions in the community., Methods: We evaluated 3782 Framingham Offspring Study participants (mean age 55 years; 52% women) free of baseline cardiovascular disease. Logistic regression models examined the prevalence of common inflammatory conditions by CRP categories, while a separate matched case-referent analysis evaluated the prevalence of uncommon inflammatory conditions. Cox models were used to assess the influence of common inflammatory conditions on relations between CRP and incident cardiovascular disease., Results: Common inflammatory conditions were reported by nearly half of the participants; these individuals were more likely to have markedly high CRP concentrations (>10 mg/L, P for trend=.001). In multivariable models, there were increased odds of having at least one common inflammatory condition with CRP concentrations of 1-3.0, 3.01-10, and >10 mg/L, compared with the referent category (<1 mg/L); the respective odds ratios with 95% confidence intervals were 1.41 (1.07-1.86), 1.45 (1.07-1.98), and 1.64 (1.09-2.47) in men, and 1.08 (0.82-1.43), 1.07 (0.80-1.44), and 1.38 (0.97-1.96) in women. In case-referent analyses, uncommon inflammatory conditions were more common in individuals with CRP >10 mg/L compared with those with CRP <1 mg/L (12.1% vs 6.6%; P=.0001). In multivariable models, higher CRP categories were not associated with incident cardiovascular disease, and with additional adjustment for inflammatory conditions, results remained unchanged., Conclusion: There is high prevalence of common and uncommon inflammatory conditions in individuals with high CRP concentrations. Higher CRP concentrations should be interpreted with caution in cardiovascular disease risk assessment.