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Background: Exercise training improves VO2peak in heart failure with reduced ejection fraction (HFrEF), but the effect is highly variable as it is dependent on peripheral adaptations. We evaluated changes in plasma-derived miRNAs by acute and chronic exercise to investigate whether these can mechanistically be involved in the variability of exercise-induced adaptations.Methods: Twenty-five male HFrEF patients (left ventricular ejection fraction < 40%, New York Heart Association class ≥ II) participated in a 15-week combined strength and aerobic training program. The effect of training on plasma miRNA levels was compared to 21 male age-matched sedentary HFrEF controls. Additionally, the effect of a single acute exercise bout on plasma miRNA levels was assessed. Levels of 5 miRNAs involved in pathways relevant for exercise adaptation (miR-23a, miR-140, miR-146a, miR-191, and miR-210) were quantified using RT-qPCR and correlated with cardiopulmonary exercise test (CPET), echocardiographic, vascular function, and muscle strength variables.Results: Expression levels of miR-146a decreased with training compared to controls. Acute exercise resulted in a decrease in miR-191 before, but not after training. Baseline miR-23a predicted change in VO2peak independent of age and left ventricular ejection fraction (LVEF). Baseline miR-140 was independently correlated with change in load at the respiratory compensation point and change in body mass index, and baseline miR-146a with change in left ventricular mass index.Conclusion: Plasma-derived miRNAs may reflect the underlying mechanisms of exercise-induced adaptation. In HFrEF patients, baseline miR-23a predicted VO2peak response to training. Several miRNAs were influenced by acute or repeated exercise. These findings warrant exploration in larger patient populations and further mechanistic in vitro studies on their molecular involvement.

OBJECTIVES: Overwhelming clinical evidence exists on disturbed vascular and endothelial function in the pathophysiology of preeclampsia (PE). In a non-pregnant (NP) population, L-FMC (low-flow mediated constriction) provides insight in the 'resting' endothelial capacity in contrast to the gold standard of flow mediated dilatation (FMD), reflecting endothelial nitric oxide bioavailability.STUDY DESIGN: Longitudinal follow-up of 100 healthy pregnant (HP) women, 33 PE women and 16 NP controls with non-invasive vascular assessments. HP women were evaluated at 12 and 35 weeks of gestation and at 6 months postpartum. PE patients were assessed at diagnosis (mean 30 weeks) and 6 months postpartum.MAIN OUTCOME MEASURES: Endothelial function (L-FMC, FMD, peripheral arterial tonometry (PAT)) and arterial stiffness (pulse wave velocity (PWV) and analysis (PWA)) were measured at the different visits and compared between groups.RESULTS: Overall endothelial dysfunction is present in PE (FMD HP 9.09 ± 4.20 vs PE 5.21 ± 4.47, p = 0.0004; L-FMC HP -1.90 ± 2.66 vs PE -0.40 ± 2.09, p = 0.03). L-FMC gradually elevates during the course of a HP (1st trim -0.31 ± 1.75 vs 3rd trim -1.97 ± 3.02, p 0.05).CONCLUSION: PE is characterized by dysfunction of both resting and recruitable endothelial capacity. This study offers new insights in different aspects of endothelial function in pregnancy, since L-FMC reflects an adaptation in HP that is absent in PE.

Endothelial function and arterial stiffness are known to be altered in preeclamptic pregnancies. Previous studies have shown conflicting results regarding the best technique for assessing vascular function in pregnancy. In this study, we made a comprehensive evaluation of in vivo vascular function [including flow-mediated dilatation (FMD), peripheral arterial tonometry (PAT), and arterial stiffness] in preeclamptic patients and compared them with normal pregnancies. In addition, we assessed the relation between vascular function and systemic inflammation. Fourteen patients with preeclampsia (PE) and 14 healthy pregnant controls were included. Endothelial function was determined by FMD and PAT and arterial stiffness by carotid-femoral pulse-wave velocity and augmentation index. Systemic inflammation was assessed using mean platelet volume (MPV) and neutrophil-lymphocyte ratio (NLR). The reactive hyperemia index, assessed using PAT, is decreased at the third trimester compared with the first trimester in a normal, uncomplicated pregnancy ( P = 0.001). Arterial stiffness is significantly higher in PE versus normal pregnancy ( P < 0.001). Endothelial function, obtained by FMD, is deteriorated in PE versus normal pregnancy ( P = 0.015), whereas endothelial function assessment by PAT is improved in PE versus normal pregnancy ( P = 0.001). Systemic inflammation (MPV and NLR) increases during normal pregnancy. FMD and PAT are disturbed in PE. Endothelial function, assessed by FMD and PAT, shows distinct results. This may indicate that measurements with FMD and PAT reflect different aspects of endothelial function and that PAT should not be used as a substitute for FMD as a measure of endothelial function in pregnancy.

Phenotypical heterogeneity among patients could be a reason why prognosis of heart failure with preserved ejection fraction (HFpEF) has not been improved in clinical trials. Vascular dysfunction is considered a central mediator in HFpEF pathophysiology, but its clinical detection has shown mixed

Background Exercise training improves peak oxygen uptake (VO2) in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms are unknown. In other cardiovascular diseases, exercise training improves vascular function and increases levels of circulating endothelium-repairing cells. We aimed to investigate the effects of moderate continuous training (MCT) and high intensity interval training (HIIT) on vascular function and cellular endothelial repair in HFpEF. Methods This was a prespecified subanalysis of the Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure randomized trial. HFpEF patients (n=180) were randomized to HIIT, MCT or attention control. At baseline and after 12 weeks, we measured peak VO2, fingertip arterial tonometry (n=109), brachial artery flow-mediated dilation (n=59), aortic pulse wave velocity (n=94), and flow cytometry (n=136) for endothelial progenitor cells (CD45dimCD34+VEGFR2+) and angiogenic T cells (CD3+CD31+CD184+). Changes in these parameters were compared between groups using linear mixed models. Parameters were correlated using Spearman's rho. Results At 3 months, we did not observe significant differences between HIIT, MCT and control group regarding changes in vascular function throughout the vascular tree (fingertip arterial tonometry, brachial artery flow-mediated dilation and central arterial stiffness, Table 1) or levels of circulating endothelium-repairing cells (endothelial progenitor cells and angiogenic T cells, Table 1). Results were similar at 12 months and when restricting analysis to patients with at least 70% adherence to training sessions. Patients with higher peak VO2 at baseline had lower numbers of circulating endothelial progenitor cells (rho=−0.22, p=0.011). Conclusions In patients with HFpEF, exercise training did not change vascular function or levels of endothelium-repairing cells. Thus, improved vascular function likely does not contribute to the change in peak VO2 after training. These findings are in contrast with the benefits of exercise on vascular function in heart failure with reduced ejection fraction and coronary artery disease. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): EU Framework Programme 7 Table 1