Given the ongoing strain that the obesity epidemic has placed on public health outcomes, new and effective approaches to weight control are needed. One approach to improving weight and metabolic outcomes is intermittent fasting, which consists of multiple different timing schedules for temporary food avoidance, including alternate-day fasting, other similar full-day fasting patterns, and time-restricted feeding (where the day’s food is consumed over a 6-h period, allowing for 18 h of fasting). These feeding schedules have favorable metabolic effects by intermittently inducing the metabolism of fatty acids to ketones. The regimens overall lead to a decrease in weight and have been linked to improvements in dyslipidemia and blood pressure. While more research is needed on longer-term outcomes and this approach should be avoided in particular health conditions, intermittent fasting should be considered as an option for individuals who have a pattern of unhealthy weight gain using standard eating patterns.

BackgroundStable plasma nitric oxide (NO) metabolites (NOM), composed predominantly of nitrate and nitrite, are attractive biomarkers of NO bioavailability. NOM levels integrate the influence of NO‐synthase‐derived NO production/metabolism, dietary intake of inorganic nitrate/nitrite, and clearance of NOM. Furthermore, nitrate and nitrite, the most abundant NOM, can be reduced to NO via the nitrate‐nitrite‐NO pathway.Methods and ResultsWe compared serum NOM among subjects without heart failure (n=126), subjects with heart failure and preserved ejection fraction (HFpEF; n=43), and subjects with heart failure and reduced ejection fraction (HFrEF; n=32). LV mass and extracellular volume fraction were measured with cardiac MRI. Plasma NOM levels were measured after reduction to NO via reaction with vanadium (III)/hydrochloric acid. Subjects with HFpEF demonstrated significantly lower unadjusted levels of NOM (8.0 μmol/L; 95% CI 6.2–10.4 μmol/L; ANOVA P=0.013) than subjects without HF (12.0 μmol/L; 95% CI 10.4–13.9 μmol/L) or those with HFrEF (13.5 μmol/L; 95% CI 9.7–18.9 μmol/L). There were no significant differences in NOM between subjects with HFrEF and subjects without HF. In a multivariable model that adjusted for age, sex, race, diabetes mellitus, body mass index, current smoking, systolic blood pressure, and glomerular filtration rate, HFpEF remained a predictor of lower NOM (β=−0.43; P=0.013). NOM did not correlate with LV mass, or LV diffuse fibrosis.Conclusions HFpEF, but not HFrEF, is associated with reduced plasma NOM, suggesting greater endothelial dysfunction, enhanced clearance, or deficient dietary ingestion of inorganic nitrate. Our findings may underlie the salutary effects of inorganic nitrate supplementation demonstrated in recent clinical trials in HFpEF.

Aims To assess the hemodynamic effects of organic vs. inorganic nitrate administration among patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We assessed carotid and aortic pressure-flow relations non-invasively before and after the administration of 0.4 mg of sublingual-nitroglycerin (NTG; n=26), and in a separate sub-study, in response to 12.9 mmol of inorganic nitrate (n=16). NTG did not consistently reduce wave reflections arriving at the proximal aorta (change in real part of reflection coefficient, 1st harmonic:-0.09; P=0.01; 2nd harmonic:-0.045, P=0.16; 3rd harmonic:+0.087; P=0.05), but produced profound vasodilation in the carotid territory, with a significant reduction in systolic blood pressure (133.6 vs 120.5 mmHg; P=0.011) and a marked reduction in carotid bed vascular resistance (19580 vs. 13078 dynes·s/cm5; P=0.001) and carotid characteristic impedance (3440 vs. 1923 dynes·s/cm5; P=0.002). Inorganic nitrate, in contrast, consistently reduced wave reflections across the first 3 harmonics (change in real part of reflection coefficient, 1st harmonic: -0.12; P=0.03; 2nd harmonic:-0.11, P=0.01; 3rd harmonic:-0.087; P=0.09) and did not reduce blood pressure, carotid bed vascular resistance or carotid characteristic impedance (P=NS). Conclusions NTG produces marked vasodilation in the carotid circulation, with a pronounced reduction in blood pressure and inconsistent effects on central wave reflections. Inorganic nitrate, in contrast, produces consistent reductions in wave reflections, and unlike NTG, it does so without significant hypotension or cerebrovascular dilatation. These hemodynamic differences may underlie the different effects on exercise capacity and side effect profile of inorganic vs. organic nitrate in HFpEF.

In our cross-sectional analysis, circulating dp-ucMGP was independently associated with CF-PWV in type 2 diabetes. This suggests that deficient vitamin K-dependent activation of MGP may lead to large artery stiffening and could be targeted with vitamin K supplementation in the patients with diabetes.

Large artery stiffening contributes to the pathophysiology of heart failure (HF) and associated comorbidities. MGP (matrix Gla-protein) is a potent inhibitor of vascular calcification. MGP activation is vitamin K–dependent. We aimed (1) to compare dp-ucMGP (dephospho-uncarboxylated MGP) levels between subjects with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) and subjects without HF; (2) to assess the relationship between dp-ucMGP levels and arterial stiffness; and (3) to assess the relationship between warfarin use, dp-ucMGP levels, and arterial stiffness in HF. We enrolled 348 subjects with HFpEF (n=96), HFrEF (n=53), or no HF (n=199). Carotid-femoral pulse wave velocity, a measure of large artery stiffness, was measured with arterial tonometry. Dp-ucMGP was measured with ELISA. Dp-ucMGP levels were greater in both HFrEF (582 pmol/L; 95% CI, 444–721 pmol/L) and HFpEF (549 pmol/L; 95% CI, 455–643 pmol/L) compared with controls (426 pmol/L; 95% CI, 377–475 pmol/L; ANCOVA P =0.0067). Levels of dp-ucMGP were positively associated with carotid-femoral pulse wave velocity (standardized β, 0.31; 95% CI, 0.19–0.42; P <0.0001), which was also true in analyses restricted to patients with HF (standardized β, 0.34; 95% CI, 0.16–0.52; P =0.0002). Warfarin use was significantly associated with carotid-femoral pulse wave velocity (standardized β, 0.13; 95% CI, 0.004–0.26; P =0.043), but this relationship was eliminated after adjustment for dp-ucMGP. In conclusion, levels of dp-ucMGP are increased in HFpEF and HFrEF and are independently associated with arterial stiffness. Future studies should investigate whether vitamin K supplementation represents a suitable therapeutic strategy to prevent or reduce arterial stiffness in HFpEF and HFrEF.

Although idiopathic hypereosinophilic syndrome (HES) is uncommon, we studied the clinical characteristics of this disorder in patients with cutaneous involvement. We chronicle the case of a patient with diffuse skin rash due to idiopathic HES from our clinical experience. Furthermore, a systematic literature search of the medical databases PubMed and Google Scholar was conducted. A total of 32 cases fulfilled the inclusion criteria. The data on patients’ characteristics, epidemiology, clinical features, diagnosis, treatment and outcome were collected and analysed. This review illustrates that physicians should maintain a high index of clinical suspicion for idiopathic HES in patients presenting with dermatological lesions and hypereosinophilia, without an obvious cause. Randomised clinical trials are warranted to outline a generalised and efficient therapeutic approach in these patients. Additionally, this paper highlights the need for population-based studies to delineate the magnitude and scope of this association.

Vascular calcification leads to increased large artery stiffness. Matrix gla-protein (MGP) is a vitamin K-dependent protein that inhibits arterial calcification. Aldosterone promotes vascular calcification and stiffness, but the relationships between aldosterone, MGP, and arterial stiffness are unknown. We studied 199 adults (predominantly older men) with hypertension. We assessed the relationship between levels of dephospho-uncarboxylated MGP (dp-ucMGP), aldosterone, and carotid-femoral pulse wave velocity (CF-PWV) using standard regression and mediation analyses. Plasma aldosterone was measured in a subgroup of subjects (n = 106). Aldosterone was strongly associated with dp-ucMGP (standardized β = 0.50, P < .001), which was independent of potential confounders (β = 0.37, P < .001). Levels of dp-ucMGP were significantly associated with CF-PWV (β = 0.30; P < .001), which persisted after adjustment for potential confounders (β = 0.25; P = .004). Plasma aldosterone was also significantly associated with CF-PWV (standardized β = 0.21; P = .035). However, in a model that included aldosterone and dp-ucMGP, only the latter was associated with CF-PWV. Mediation analyses demonstrated a significant dp-ucMGP-mediated effect of aldosterone on CF-PWV, without a significant direct (dp-ucMGP independent) effect. Our study demonstrates a novel independent association between high aldosterone levels and dp-ucMGP, suggesting that aldosterone may influence the MGP pathway. This relationship appears to underlie the previously documented relationship between aldosterone and increased arterial stiffness.

Organic nitrates, but not inorganic nitrates, increase the amount of hydraulic energy transmitted into the carotid artery in subjects with HFpEF. These findings may have implications for the adverse effect profiles of these agents (such as the differential incidence of headaches) and for the pulsatile hemodynamic stress of the brain microvasculature in this patient population.