FA supplementation does not reduce intracellular concentrations of Hcy or any of its closely related substances. Rather, FA may disturb physiological regulation of intracellular 1C metabolism by interfering with SAM's inhibitory effect on MTHFR activity.

Background:Adequate folate status supports endothelial structure and function. Folic acid (FA), an oxidized synthetic folate, which is present in the plasma of patients consuming fortified food or FA supplements, may impair cellular uptake of physiological, reduced folates. We studied the effect of FA on uptake of the dominant circulatory folate, 5-methyltetrahydrofolate (5MTHF) in endothelial cells.Methods and Results:For short-term effects of FA, primary human umbilical vein endothelial cells (HUVECs) were maintained in growth medium containing 200 nM 5MTHF and preincubated with 20 nM FA 10 minutes before the 5MTHF uptake assessment. For long-term effects, HUVECs were cultured for 3 passages in growth medium containing either 200 nM 5MTHF, or a combination of 100 nM 5MTHF and 100 nM FA. 5MTHF uptake was assessed after exposing cells to 200 nM [13C5]-5MTHF, after which intracellular [13C5]-5MTHF was quantified using liquid chromatography/tandem mass spectrometry. Acute FA exposure caused a 57% reduction in 5MTHF uptake compared with control conditions (51 ± 12 vs. 22 ± 7 fmol·min−1·mg−1 protein; P = 0.01). Long-term exposure to FA reduced 5MTHF uptake by 41% (51 ± 12 vs. 30 ± 11 fmol·min−1·mg−1 protein; P = 0.05) and reduced total cellular 5MTHF levels by 47 ± 21% in HUVEC (P = 0.02).Conclusion:Unmetabolized FA, which appears in the plasma after consumption of fortified food or FA supplements, may impair uptake of 5MTHF, the dominant bioactive form of folate, in HUVEC.

Objective: The mechanisms underlying obesity-related hypertension are incompletely understood. Microvascular dysfunction might play a role by increasing peripheral vascular resistance (PVR). Metabolic and microvascular effects of insulin are impaired in obesity, but how these impairments contribute to disturbed blood pressure homeostasis is unclear. Specifically, it is unknown whether local microvascular vasoactive effects of insulin play a role in determining systemic vascular resistance. The aim of this study was to investigate the association between PVR and local microvascular effects of insulin. Design and Methods: Thirty-seven healthy, overweight subjects (age 25-55 years, BMI 25-30 kg/m 2 ) were cross-sectionally studied. Local insulin-mediated vasodilation was measured using skin laser Doppler fluxmetry combined with transcutaneous iontophoresis of insulin. For comparison, local vasodilatory effects of acetylcholine and sodium nitroprusside were measured. PVR was calculated from mean arterial pressure and cardiac output, assessed by pulse-dye densitometry. Results: PVR was inversely correlated with insulin-mediated vasodilation (r ¼ À0.50; P < 0.01). This finding was maintained after adjustment for age, sex, blood pressure, and smoking. PVR was not associated with local microvascular effects of acetylcholine. Conclusions: Our study in overweight subjects suggests that insulin's role in the microvasculature may contribute to blood pressure control.

In men, higher homocysteine levels are associated with a reduction in basal perfusion of skin capillaries. This finding provides a novel potential explanation for how homocysteine influences cardiovascular disease risk.

Background Heart failure (HF) is a cardiovascular disease that is increasing by epidemic proportions, largely due to an aging society and therapeutic advances in disease management. Because heart failure is largely a cardiogeriatric syndrome, age-related syndromes such as frailty and cognitive impairment are common in heart failure patients. Purpose To assess the prevalence and determinants of frailty and cognitive impairment in a HF population ≥60 years of age. Methods Data from n=236 patients with HF (77±9 years; 43% female) visiting the heart-brain clinic in Amsterdam in 2018–2019. HF severity was evaluated by NT-proBNP and NYHA-classification. Frailty was assessed using Fried's frailty criteria, cognition using the Montreal cognitive assessment (MoCa). Logistic regression analyses were performed to evaluate which variables were associated with frailty and cognitive impairment. Results Median (IQR) NT-proBNP was 2000 (876–3469) pmol/L, 38% of patients had NYHA III-IV. 51% of patients were pre-frail and 28% frail. 77% of the patients were (mildly) cognitive impaired. Age, NYHA-classification III-IV, NT-proBNP>2000 pmol/L and use of ≥10 drugs were associated with frailty; HR (95% CI): 2.0 (1.4–3.0) per 10 years, 3.4 (1.9–6.2), 1.8 (1.0–3.2) and 1.8 (1.4–3.3) respectively. Age was associated with cognitive impairment; HR (95% CI) 2.2 (1.4–3.6) per 10 years. Figure 1 Conclusion(s) Frailty affects almost a third of the patients with HF and is more prevalent in older patients and those with more severe HF. Screening for frailty and cognitive impairment should be part of the standard workup in older HF patients as frail and/or cognitively impaired HF patients are less likely to adhere to their HF treatment and more likely to be (re)admitted to hospital for HF.