Pharmacoepigenetics in Heart Failure

Epigenetics studies inheritable changes of genes and gene expression that do not concern DNA nucleotide variation. Such modifications include DNA methylation, several forms of histone modification, and microRNAs. From recent studies, we know not only that genetic changes account for heritable phenotypic variation, but that epigenetic changes also play an important role in the variation of predisposition to disease and to drug response. In this review, we discuss recent evidence of epigenetic changes that play an important role in the development of cardiac hypertrophy and heart failure and may dictate response to therapy

Active Tobacco Smoking Impairs Cardiac Systolic Function

Tobacco smoking is a well-established risk factor for cardiovascular disease, but its direct effect on myocardial structure and function remains unclear. This study investigated the effects of smoking using a nested matched case-control study design. 5,668 participants of the UK Biobank study who underwent cardiovascular magnetic resonance imaging were screened for inclusion. 102 smokers (56 males) with a median age of 56 years were matched to non-smokers based on sex, age, and body surface area. Manual post-processing and feature tracking analyses were performed to determine left ventricular (LV) and right ventricular (RV) structure and function measures. Linear regression analyses were performed to determine the effect of tobacco smoking on imaging measures. Tobacco smoking was associated with increased LV and RV end-systolic volume (4.98 +/- 2.08mL, 5.19 +/- 2.62mL, P=0.018, 0.049 respectively), reduced LV and RV ejection fraction (beta: -2.21 +/- 0.82%, -2.06 +/- 0.87%, P=0.007, 0.019 respectively), and reduced absolute measures of LV peak global longitudinal, radial, and circumferential strain (beta: 0.86 +/- 0.30%, -2.52 +/- 0.99%, 1.05 +/- 0.32%, P=0.004, 0.011, 0.001 respectively). Effect sizes were larger in daily smokers compared to occasional smokers. In a general Caucasian population without known clinical cardiovascular disease, active tobacco smoking was dose dependently associated with impaired cardiac systolic function

Peroxiredoxin 4, a novel circulating biomarker for oxidative stress and the risk of incident cardiovascular disease and all-cause mortality

BACKGROUND: Oxidative stress has been suggested to play a key role in the development of cardiovascular disease (CVD). The aim of our study was to investigate the associations of serum peroxiredoxin 4 (Prx4), a hydrogen peroxide-degrading peroxidase, with incident CVD and all-cause mortality. We subsequently examined the incremental value of Prx4 for the risk prediction of CVD compared with the Framingham risk score (FRS). METHODS AND RESULTS: We performed Cox regression analyses in 8141 participants without history of CVD (aged 28 to 75 years; women 52.6%) from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study in Groningen, The Netherlands. Serum Prx4 was measured by an immunoluminometric assay in baseline samples. Main outcomes were: (1) incident CVD events or CVD mortality and (2) all-cause mortality during a median follow-up of 10.5 years. In total, 708 participants (7.8%) developed CVD events or CVD mortality, and 517 participants (6.3%) died. Baseline serum Prx4 levels were significantly higher in participants with incident CVD events or CVD mortality and in those who died than in participants who remained free of outcomes (both P<0.001). In multivariable models with adjustment for Framingham risk factors, hazard ratios were 1.16 (95% CI 1.06 to 1.27, P<0.001) for incident CVD events or CVD mortality and 1.17 (95% CI 1.06 to 1.29, P=0.003) for all-cause mortality per doubling of Prx4 levels. After the addition of Prx4 to the FRS, the net reclassification improvement was 2.7% (P=0.01) using 10-year risk categories of CVD. CONCLUSIONS: Elevated serum Prx4 levels are associated with a significantly higher risk of incident CVD events or CVD mortality and all-cause mortality after adjustment for clinical risk factors. The addition of Prx4 to the FRS marginally improved risk prediction of future CVD

PROMISE:effect of protein supplementation on fat-free mass preservation after bariatric surgery, a randomized double-blind placebo-controlled trial

Introduction: Protein malnutrition after bariatric surgery is a severe complication and leads to significant morbidity. Previous studies have shown that protein intake and physical activity are the most important factors in the preservation of fat-free mass during weight loss. Low protein intake is very common in patients undergoing bariatric surgery despite dietary counseling. Protein powder supplements might help patients to achieve the protein intake recommendations after bariatric surgery and could therefore contribute to preserve fat-free mass. This double-blind randomized placebo-controlled intervention study aims to assess the effect of a daily consumed clear protein powder shake during the first 6 months after bariatric surgery on fat-free mass loss in the first 12 months after laparoscopic Roux-en-Y gastric bypass (LRYGB). Methods and analysis:Inclusion will take place at the outpatient clinic of the bariatric expertise center for obesity of the Maasstad Hospital. Patients will be randomly assigned to either the intervention or control group before surgery. The intervention group will receive a clear protein powder shake of 200 ml containing 20 g of whey protein dissolved in water which should be taken daily during the first 6 months after LRYGB on top of their normal postoperative diet. The control group will receive an isocaloric, clear, placebo shake containing maltodextrine. Postoperative rehabilitation and physiotherapeutical guidance will be standardized and similar in both groups. Also, both groups will receive the same dietary advice from specialized dieticians. The main study parameter is the percentage of fat-free mass loss 6 months after surgery, assessed by multi-frequency bioelectrical impedance analysis (MF-BIA). Ethics and dissemination: The protocol, version 2 (February 20, 2022) has been approved by the Medical Research Ethics Committees United (MEC-U) (NL 80414.100.22). The results of this study will be submitted to peer-reviewed journals. Trial registration: ClinicalTrials.gov NCT05570474. Registered on October 5, 2022.</p

A portable isometric knee extensor strength testing device:test-retest reliability and minimal detectable change scores of the Q-Force II in healthy adults

Abstract Background Although knee extensors are essential in daily activities (e.g. walking, climbing stairs), knee extensor strength is often not measured in clinical settings. Existing devices to test muscle strength are not always suitable to accurately measure the high forces of this muscle group. Therefore, a device to test muscle strength that is convenient, feasible, reliable, and valid in clinical settings is required. This study evaluated the reliability, responsiveness, and level of discomfort of the newly developed Q-Force ӀӀ (i.e. a portable device to measure isometric knee extensor strength) in healthy middle-aged and elderly adults. Methods Participants (n = 22) conducted two standardized test sessions on the Q-Force ӀӀ (five to ten days apart). Each session consisted of one familiarisation trial followed by three trials of peak isometric knee extension per each leg. Per trial, peak and mean knee extension force (N) and torque (Nm) were measured at 90° flexion. The level of discomfort was determined using a visual analog scale (VAS: 0-100). Intra Class Correlation (ICC, model: two-way mixed with absolute agreement), Standard Error of Measurement (SEM), and minimal detectable change (MDC) were determined. A repeated measures ANOVA was used to determine between-test variation. Results Excellent test-retest (ICC > 0.95) and inter-trial (ICC > 0.91) reliability for both legs were shown. No significant differences were found in peak and mean knee forces and torques between test and retest of both legs, indicating good test-retest reliability (P-value range: 0.360-0.538; F(1,21) range: 0.4-0.9). The SEM of the peak and mean forces and torques ranged from 28.0 to 30.4 N (6.0-6.8%) and from 9.2 to 10.4 Nm (6.4-7.7%), respectively. The MDC for these outcomes ranged respectively from 77.6 to 84.1 N (16.5-18.8%) and from 25.5 to 28.9 Nm (17.6-21.4%). The level of discomfort was low (median range: 7-10, IQR: 4-18). Conclusion The portable Q-Force ӀӀ is a comfortable, responsive, and relatively cheap device with excellent test-retest reliability. This device would be potentially suitable to measure isometric knee extensor strength in clinical settings

Infrared fixed point in quantum Einstein gravity

We performed the renormalization group analysis of the quantum Einstein gravity in the deep infrared regime for different types of extensions of the model. It is shown that an attractive infrared point exists in the broken symmetric phase of the model. It is also shown that due to the Gaussian fixed point the IR critical exponent $\nu$ of the correlation length is 1/2. However, there exists a certain extension of the model which gives finite correlation length in the broken symmetric phase. It typically appears in case of models possessing a first order phase transitions as is demonstrated on the example of the scalar field theory with a Coleman-Weinberg potential.Comment: 9 pages, 7 figures, final version, to appear in JHE

Temporal course of plasma trimethylamine n-oxide (Tmao) levels in st-elevation myocardial infarction

The gut metabolite trimethylamine N-oxide (TMAO) at admission has a prognostic value in ST-elevation myocardial infarction (STEMI) patients. However, its sequential changes and relationship with long-term infarct-related outcomes after primary percutaneous coronary intervention (PCI) remain elusive. We delineated the temporal course of TMAO and its relationship with infarct size and left ventricular ejection fraction (LVEF) post-PCI, adjusting for the estimated glomerular filtration rate (eGFR). We measured TMAO levels at admission, 24 h and 4 months post-PCI in 379 STEMI patients. Infarct size and LVEF were determined by cardiac magnetic resonance 4 months after PCI. TMAO levels decreased from admission (4.13 ± 4.37 μM) to 24 h (3.41 ± 5.84 μM, p = 0.001) and increased from 24 h to 4 months (3.70 ± 3.86 μM, p = 0.026). Higher TMAO values at 24 h were correlated to smaller infarct sizes (rho = −0.16, p = 0.024). Larger declines between admission and 4 months suggestively correlated with smaller infarct size, and larger TMAO increases between 24 h and 4 months were associated with larger infarct size (rho = −0.19, p = 0.008 and rho = −0.18, p = 0.019, respectively). Upon eGFR stratification using 90 mL/min/1.73 m(2) as a cut-off, significant associations between TMAO and infarct size were only noted in subjects with impaired renal function. In conclusion, TMAO levels in post-PCI STEMI patients are prone to fluctuations, and these fluctuations could be prognostic for infarct size, particularly in patients with impaired renal function

Polygenic risk score and coronary artery disease:A meta-analysis of 979,286 participant data

BACKGROUND AND AIMS: Coronary artery disease (CAD) is a complex disease with a strong genetic basis. While previous studies have combined common single-nucleotide polymorphisms (SNPs) into a polygenic risk score (PRS) to predict CAD risk, this association is poorly characterised. We performed a meta-analysis to estimate the effect of PRS on the risk of CAD. METHODS: Online databases were searched for studies reporting PRS and CAD. PRS computation was based on log-odds (PRSLN), pruning or clumping and thresholding (PRSP/C + T), Lassosum regression (PRSLassosum), LDpred (PRSLDpred), or metaGRS (PRSmetaGRS). The reported odds ratio (OR), hazard ratio (HR), C-indexes and their corresponding 95% confidence interval (95% CI) were pooled in a random-effects meta-analysis. RESULTS: Forty-nine studies were included (979,286 individuals). There was a significant association between 1-standard deviation [SD] increment in PRS and adjusted risks of both incident and prevalent CAD (OR [95% CI]: 1.67 [1.57-1.77] for PRSmetaGRS, 1.46 [1.26-1.68] for PRSLDpred). The risk of incident CAD was highest for PRSP/C + T (HR [95% CI]: 1.49 [1.26-1.78]), PRSmetaGRS (1.37 [1.27-1.47]), and PRSLDpred (1.36 [1.31-1.42]). Analysis of model performance demonstrated that PRS predicted incident CAD with C-index of up to 0.71. Importantly, addition of PRS to clinical risk scores resulted in modest but statistically significant improvements in CAD risk prediction, with 1.5% observed for PRSP/C + T (p < 0.001) and 1.6% for PRSLDpred (p < 0.001). CONCLUSIONS: Polygenic risk score is strongly associated with increased risks of CAD. Future prospective studies should explore the usefulness of polygenic risk scores for identifying individuals at a high risk of developing CAD