Aims: Low plasma testosterone levels have been shown to predict worse outcome in men with severe atherosclerotic disease. We hypothesized that a low plasma testosterone level affects disease risk through changes in gene expression in atherosclerotic plaques. Therefore, we studied plasma testosterone levels in relation to gene expression levels in atherosclerotic plaque tissue of men with advanced atherosclerotic disease. Methods: Plasma testosterone levels were measured in 203 men undergoing carotid endarterectomy. The corresponding atherosclerotic plaque tissue was used for RNA sequencing. First, we assessed how often the androgen receptor gene was expressed in the plaque. Second, correlations between plasma testosterone levels and pre-selected testosterone-sensitive genes were assessed. Finally, differences within the RNA expression profile of the plaque as a whole, characterized into gene regulatory networks and at individual gene level were assessed in relation to testosterone levels. Results: Testosterone plasma levels were low with a median of 11.6 nmol/L (IQR: 8.6-13.8). RNA-seq of the plaque resulted in reliable expression data for 18,850 genes to be analyzed. Within the RNA seq data, the androgen-receptor gene was expressed in 189 out of 203 (93%) atherosclerotic plaques of men undergoing carotid endarterectomy. The androgen receptor gene expression was not associated with testosterone plasma levels. There were no significant differences in gene expression of atherosclerotic plaques between different endogenous testosterone levels. This remained true for known testosterone-sensitive genes, the complete transcriptomic profile, male-specific gene co-expression modules as well as for individual genes. Conclusion: In men with severe atherosclerotic disease the androgen receptor is highly expressed in plaque tissue. However, plasma testosterone levels were neither associated with pre-selected testosterone sensitive genes, gene expression profiles nor gene regulatory networks in late-stage atherosclerotic plaques. The effect of testosterone on gene expression of the late-stage atherosclerotic plaque appears limited, suggesting that alternate mechanisms explain its effect on clinical outcomes.

Background: Electrocardiographic features are well-known for heart failure with reduced ejection fraction (HFrEF), but not for left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF). As ECG features could help to identify high-risk individuals in primary care, we systematically reviewed the literature for ECG features diagnosing women and men suspected of LVDD and HFpEF. Methods and Results: Among the 7,127 records identified, only 10 studies reported diagnostic measures, of which 9 studied LVDD. For LVDD, the most promising features were T-end-P/(PQ*age), which is the electrocardiographic equivalent of the passive-to-active filling (AUC: 0.91-0.96), and repolarization times (QTc interval ≥ 350 ms, AUC: 0.85). For HFpEF, the Cornell product ≥ 1,800 mm*ms showed poor sensitivity of 40% (AUC: 0.62). No studies presented results stratified by sex. Conclusion: Electrocardiographic features are not widely evaluated in diagnostic studies for LVDD and HFpEF. Only for LVDD, two ECG features related to the diastolic interval, and repolarization measures showed diagnostic potential. To improve diagnosis and care for women and men suspected of heart failure, reporting of sex-specific data on ECG features is encouraged.

Background: The prognosis of women and men with persistent anginal complaints and non-obstructed coronary arteries is impaired as compared with asymptomatic women and men. The increased healthcare burden in the hospital due to repeated coronary angiography in these women and men has been documented, yet little is known about the percentage of women and men who remain symptomatic and under care of the general practitioner in the years following a coronary angiographic outcome of non-obstructed coronary arteries. Methods: From the Utrecht Coronary Biobank study, including individuals who underwent a coronary angiography from 2011 to 2015 (N = 2,546, 27% women), we selected women and men with non-obstructed coronary arteries (N = 687, 39% women). This population was linked to the Julius General Practitioners Network (JGPN); a database with routine care data of general practitioners. For every individual with non-obstructed coronary arteries, we selected an asymptomatic non-referred age-, sex-, and general practitioner-matched individual from the JGPN. We compared the healthcare consumption of men and women with non-obstructed coronary arteries to these matched individuals. The McNemar's test was used for pairwise comparison, and sex differences were assessed using stratified analyses. Results: The prevalence of non-obstructed coronary arteries was higher in women as compared with men (39 vs. 23%). During a median follow-up of 7 years [IQR 6.4-8.0], 89% of the individuals with non-obstructed coronary arteries (91% women and 87% men) visited their general practitioner for one or more cardiovascular consultations. This was compared to 34% of the matched individuals (89 vs. 34%, p < 0.001). The consultations were most often for angina (equivalents) (57 vs. 11%, p < 0.001) and heart failure (10 vs. 2%, p = 0.015). In addition, they more often consulted the general practitioner for psychosocial complaints (31 vs. 15%, p = 0.005). Findings were similar for women and men. Conclusions: A coronary angiographic outcome of non-obstructed coronary arteries is more common in women than in men. In the years following the coronary angiography, the majority of the population remains symptomatic. Both women and men with non-obstructed coronary arteries had higher health needs for angina, heart failure, and psychosocial complaints than matched asymptomatic individuals.