The study of epigenomics has advanced in recent years to span the regulation of a single genetic locus to the structure and orientation of entire chromosomes within the nucleus. In this review, we focus on the challenges and opportunities of clinical epigenomics in cardiovascular disease. As an integrator of genetic and environmental inputs, and because of advances in measurement techniques that are highly reproducible and provide sequence information, the epigenome is a rich source of potential biosignatures of cardiovascular health and disease. Most of the studies to date have focused on the latter, and herein we discuss observations on epigenomic changes in human cardiovascular disease, examining the role of protein modifiers of chromatin, noncoding RNAs and DNA modification. We provide an overview of cardiovascular epigenomics, discussing the challenges of data sovereignty, data analysis, doctor-patient ethics and innovations necessary to implement precision health.

Objective

To report our use of persuasion to treat patients with functional vision loss and to place them in the context of both Joseph Babinski's theories on hysteria and the current literature on management of functional vision loss.

Background

Conversion disorders, such as functional vision loss, can develop in response to a traumatic event. Recent functional imaging studies have found that, rather than being malingerers, patients with conversion disorders show changes within neuromodulatory pathways, suggesting organic dysfunction rather than a purely psychological disorder.

Methods

We conducted a retrospective analysis of 8 consecutive patients (7 female, 1 male; mean age 16 years) who had presented to a university-based neuro-ophthalmology clinic with vision loss from a conversion disorder. The patients had been given a lengthy visual task to perform at home, with the suggestion that their vision would improve by the time they completed the task.

Results

All 8 patients had evidence of a dissociation between real and perceived visual acuity and fields. All the patients performed the assigned visual task at home, and all either reported improvement or showed improved visual function at follow-up.

Conclusions

A century after Joseph Babinski proposed using persuasion in managing patients with vision loss from a conversion disorder, we report that his method remains a viable and pathophysiologically sound option. Future case-controlled studies that include functional magnetic resonance imaging, other neurophysiologic imaging, and neuroradiographic evaluation may strengthen the correlation between persuasion therapy and recovery of normal vision.

OBJECTIVES: The aim of this study was to examine the effect of implementation of the Affordable Care Acts Medicaid expansion on access to and outcomes after coronary artery bypass grafting (CABG) surgery. METHODS: Retrospective observational study utilizing the Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample (NIS) from 2011 to 2016. The southern region of the USA was used as a control and the western region as the implementation group. Univariate regression models and interrupted time series models were created to evaluate and assess the impact of the Affordable Care Acts Medicaid expansion on mortality after CABG with respect to patient race. RESULTS: From 2011 to 2016, a total of 117,819 isolated CABG operations were identified in the specified regions using the HCUP NIS. Of these, 89,918 were performed in the southern region, and the remainder were performed in the western region. The proportion of African American patients with Medicaid increased significantly in the western region after the ACA Medicaid expansion, from 13.1 to 17.6%, p = 0.034. There was no significant increase seen in the number of African American patients with Medicaid in the southern region. We found that overall, Black patients had higher mortality after CABG as compared to white patients (OR 1.15, p = 0.02); however, when broken down by region we found higher mortality among African American patients in the southern region only, with no statistically significant difference in mortality between white and Black patients in the western region. CONCLUSIONS: Implementation of the Affordable Care Act increased access to Medicaid among Black Americans but did not necessarily decrease the disparity in access to CABG or mortality after CABG between Black and white patients. When it comes to racial disparities in mortality after CABG, there are significant regional and geographic variations which have not been previously described. This finding has important implications for the development of policy and other strategies that aim to reduce these disparities.

Background: Postoperative atrial fibrillation (POAF) and acute kidney injury (AKI) are common yet significant complications after cardiac surgery, with incidences of up to 40% for each. Here, we assessed plasma nitrite and serum interleukin-6 (IL-6) levels before and after cardiac surgery to quantify the extent to which oxidative stress and inflammation contribute to POAF and AKI occurrence. Methods: We prospectively enrolled 206 cardiac surgical patients. Plasma nitrite and serum IL-6 levels were determined preoperatively and at 24 h, 48 h and 72 h postoperatively. The patients had continuous EKG monitoring for occurrence of POAF, while daily serum creatinine was measured for determination of stage 1 + AKI. Results: Postoperatively, 78 (38%) patients experienced AF, and 47 (23%) patients experienced stage 1 + AKI. POAF analysis: Age, ACE-inhibitor use, valve surgery and percent change in baseline plasma nitrite at 24 h postoperatively were associated with POAF in multiple logistic regression analysis. The inclusion of this new biomarker significantly improved the POAF prediction model (AUC 0.77 for clinical risk factors alone, to AUC 0.81). AKI analysis: A history of diabetes mellitus was associated with AKI in multiple logistic regression analysis, and the addition of preoperative IL-6 levels improved the prediction model for AKI occurrence (AUC 0.69 to AUC 0.74). Conclusions: We previously observed selective upregulation of NADPH oxidase isoform 4 (NOX4) in patients with AF, a critical causal role of NOX4 for AF in zebrafish and a robust inhibitory effect of nitric oxide (NO) on NOX4. Our data innovatively demonstrate that a reduction in circulating nitrite levels, likely implicative of elevated NOX4-mediated oxidative stress, independently associates with POAF and improves POAF prediction, whereas the inclusion of circulating IL-6 levels improves the prediction model for AKI. Therefore, therapeutic strategies to mitigate these pathophysiological sequalae of surgical stress may reduce the incidence of severe postoperative complications of POAF and AKI.

Background

Cardiac surgery and cardiopulmonary bypass induce a substantial immune and inflammatory response, the overactivation of which is associated with significant pulmonary, cardiovascular, and neurologic complications. Commensurate with the immune and inflammatory response are changes in the heart and vasculature itself, which together drive postoperative complications through mechanisms that are poorly understood. Longitudinal DNA methylation profiling has the potential to identify changes in gene regulatory mechanisms that are secondary to surgery and to identify molecular processes that predict and/or cause postoperative complications. In this study, we measure DNA methylation in preoperative and postoperative whole blood samples from 96 patients undergoing cardiac surgery on cardiopulmonary bypass.

Results

While the vast majority of DNA methylation is unchanged by surgery after accounting for changes in cell-type composition, we identify several loci with statistically significant postoperative changes in methylation. Additionally, two of these loci are associated with new-onset postoperative atrial fibrillation, a significant complication after cardiac surgery. Paired statistical analysis, use of FACS data to support sufficient control of cell-type heterogeneity, and measurement of IL6 levels in a subset of patients add rigor to this analysis, allowing us to distinguish cell-type variability from actual changes in methylation.

Conclusions

This study identifies significant changes in DNA methylation that occur immediately after cardiac surgery and demonstrates that these acute alterations in DNA methylation have the granularity to identify processes associated with major postoperative complications. This research also establishes methods for controlling for cell-type variability in a large human cohort that may be useful to deploy in other longitudinal studies of epigenetic marks in the setting of acute and chronic disease.

Background

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and post-operative atrial fibrillation (POAF) is a major healthcare burden, contributing to an increased risk of stroke, kidney failure, heart attack and death. Genetic studies have identified associations with AF, but no molecular diagnostic exists to predict POAF based on pre-operative measurements. Such a tool would be of great value for perioperative planning to improve patient care and reduce healthcare costs. In this pilot study of epigenetic precision medicine in the perioperative period, we carried out bisulfite sequencing to measure DNA methylation status in blood collected from patients prior to cardiac surgery to identify biosignatures of POAF.

Methods

We enrolled 221 patients undergoing cardiac surgery in this prospective observational study. DNA methylation measurements were obtained from blood samples drawn from awake patients prior to surgery. After controlling for clinical and methylation covariates, we analyzed DNA methylation loci in the discovery cohort of 110 patients for association with POAF. We also constructed predictive models for POAF using clinical and DNA methylation data. We subsequently performed targeted analyses of a separate cohort of 101 cardiac surgical patients to measure the methylation status solely of significant methylation loci in the discovery cohort.

Results

A total of 47 patients in the discovery cohort (42.7%) and 43 patients in the validation cohort (42.6%) developed POAF. We identified 12 CpGs that were statistically significant in the discovery cohort after correcting for multiple hypothesis testing. Of these sites, 6 were amenable to targeted bisulfite sequencing and chr16:24640902 was statistically significant in the validation cohort. In addition, the methylation POAF prediction model had an AUC of 0.79 in the validation cohort.

Conclusions

We have identified DNA methylation biomarkers that can predict future occurrence of POAF associated with cardiac surgery. This research demonstrates the use of precision medicine to develop models combining epigenomic and clinical data to predict disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.