Regional differences in mitochondrial DNA methylation in human post-mortem brain tissue

Background: DNA methylation is an important epigenetic mechanism involved in gene regulation, with alterations in DNA methylation in the nuclear genome being linked to numerous complex diseases. Mitochondrial DNA methylation is a phenomenon that is receiving ever-increasing interest, particularly in diseases characterized by mitochondrial dysfunction; however, most studies have been limited to the investigation of specific target regions. Analyses spanning the entire mitochondrial genome have been limited, potentially due to the amount of input DNA required. Further, mitochondrial genetic studies have been previously confounded by nuclear-mitochondrial pseudogenes. Methylated DNA Immunoprecipitation Sequencing is a technique widely used to profile DNA methylation across the nuclear genome; however, reads mapped to mitochondrial DNA are often discarded. Here, we have developed an approach to control for nuclear-mitochondrial pseudogenes within Methylated DNA Immunoprecipitation Sequencing data. We highlight the utility of this approach in identifying differences in mitochondrial DNA methylation across regions of the human brain and pre-mortem blood. Results: We were able to correlate mitochondrial DNA methylation patterns between the cortex, cerebellum and blood. We identified 74 nominally significant differentially methylated regions (p < 0.05) in the mitochondrial genome, between anatomically separate cortical regions and the cerebellum in matched samples (N = 3 matched donors). Further analysis identified eight significant differentially methylated regions between the total cortex and cerebellum after correcting for multiple testing. Using unsupervised hierarchical clustering analysis of the mitochondrial DNA methylome, we were able to identify tissue-specific patterns of mitochondrial DNA methylation between blood, cerebellum and cortex. Conclusions: Our study represents a comprehensive analysis of the mitochondrial methylome using pre-existing Methylated DNA Immunoprecipitation Sequencing data to identify brain region-specific patterns of mitochondrial DNA methylation

DNA methylation and the epigenetic clock in relation to physical frailty in older people:The Lothian Birth Cohort 1936

Background: The biological mechanisms underlying frailty in older people are poorly understood. There is some evidence to suggest that DNA methylation patterns may be altered in frail individuals. Methods: Participants were 791 people aged 70 years from the Lothian Birth Cohort 1936. DNA methylation was measured in whole blood. Biological age was estimated using two measures of DNA methylation-based age acceleration - extrinsic and intrinsic epigenetic age acceleration. We carried out an epigenome-wide association study of physical frailty, as defined by the Fried phenotype. Multinomial logistic regression was used to calculate relative risk ratios for being physically frail or pre-frail according to epigenetic age acceleration. Results: There was a single significant (P=1.16x10-7) association in the epigenome-wide association study comparing frail versus not frail. The same CpG was not significant when comparing pre-frail versus not frail. Greater extrinsic epigenetic age acceleration was associated with an increased risk of being physically frail, but not of being pre-frail. For a year increase in extrinsic epigenetic age acceleration, age- and sex-adjusted relative risk ratios (95% CI) for being physically frail or pre-frail were 1.06 (1.02, 1.10) and 1.02 (1.00, 1.04) respectively. After further adjustment for smoking and chronic disease, the association with physical frailty remained significant. Intrinsic epigenetic age acceleration was not associated with physical frailty status.Conclusions: People who are biologically older, as indexed by greater extrinsic epigenetic age acceleration, are more likely to be physically frail. Future research will need to investigate whether epigenetic age acceleration plays a causal role in the onset of physical frailty

The European System for Cardiac Operative Risk Evaluation (EuroSCORE) is not appropriate for withholding surgery in high-risk patients with aortic stenosis: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>The European System for Cardiac Operative Risk Evaluation (EuroSCORE) is a widely used risk assessment tool in patients with severe aortic stenosis to determine operability and to select patients for alternative therapies such as transcatheter aortic valve implantation. The objective of this study was to determine the accuracy of the EuroSCORE in predicting mortality following aortic valve replacement (AVR).</p> <p>Methods</p> <p>The logistic EuroSCORE was determined for all consecutive patients that underwent conventional AVR between 1995 and 2005 at our institution. Provincial Vital Statistics were used to determine all-cause mortality. The accuracy of the prognostic risk prediction provided by logistic EuroSCORE was assessed by comparing observed and expected operative mortality.</p> <p>Results</p> <p>During the study period, a total of 1,421 patients underwent AVR including 237 patients (16.7%) that had a logistic EuroSCORE > 20. Among these patients, the mean predicted operative mortality was 38.7% (SD = 18.1). The actual mortality of these patients was significantly lower than that predicted by EuroSCORE (11.4% vs. 38.7%, observed/expected ratio 0.29, 95% CI 0.15–0.52, P < 0.05). The EuroSCORE overestimated mortality within all strata of predicted risk. Although medium-term mortality is significantly higher among patients with EuroSCORE > 20 (log rank P = 0.0001), approximately 60% are alive at five years.</p> <p>Conclusion</p> <p>Actual operative mortality in patients undergoing AVR is significantly lower than that predicted by the logistic EuroSCORE. Additionally, medium-term survival following AVR is acceptable in high-risk patients with EuroSCORE > 20. More accurate risk prediction models are needed for risk-stratifying patients with severe aortic stenosis.</p

Cerebrovascular events after stentless aortic valve replacement during a 9-year follow-up period

BACKGROUND: One major advantage of biologic aortic valve prostheses is their low thrombogenicity compared with mechanical prostheses. The purpose of this study was to evaluate the incidence of cerebrovascular events during long-term follow-up after stentless aortic valve replacement. METHODS: Between 1996 and 2005, 1,014 patients (mean age, 73 years; range, 20 to 90 years) received stentless aortic valve replacement (Freestyle; Medtronic, Minneapolis, MN) and were included into the systematic follow-up that was closed in 2006 with a completeness of 94.7% and a mean follow-up interval of 3 years (range, 0.5 to 9.8 years). Predictors for freedom from cerebrovascular events were identified by Cox regression. RESULTS: Overall survival was 53% +/- 5% after 8 years (mean, 6.8 +/- 0.2 years). Permanent atrial fibrillation at time of surgery was a strong predictor of impaired survival during follow-up. Freedom from cerebrovascular events during follow-up was 68% +/- 5% at 9 years of follow-up. Multivariate regression analysis revealed previous stroke, age at implant, diabetes mellitus, and carotid lesions as significant risk factors. Especially age older than 75 years was a strong risk factor for cerebrovascular events during follow-up (p = 0.004). Atrial fibrillation was not an independent risk factor for cerebrovascular events (p = 0.26) but was a strong predictor of poor survival (p > 0.001) during follow-up. There was no influence of technique of implantation (subcoronary versus full root; p = 0.41), sex (p = 0.35), additional bypass grafting (p = 0.65), and the size of the implanted prosthesis (p = 0.47). CONCLUSIONS: The risk of cerebrovascular events during follow-up after stentless aortic valve replacement is related to the individual risk factors of the patients rather than to the valve prosthesis itself. Without additional risk factors, patients with these aortic valve prostheses showed an incidence of cerebrovascular events similar to those reported for a healthy population adjusted for age