Associations Between Depressive Symptoms and HFpEF-Related Outcomes.

OBJECTIVES: This study analyzed changes in depressive symptoms in patients with heart failure and preserved ejection fraction (HFpEF) who were enrolled in the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial. BACKGROUND: There are limited longitudinal data for depressive symptoms in patients with HFpEF. METHODS: In patients enrolled in the United States and Canada (n = 1,431), depressive symptoms were measured using Patient Health Questionnaire-9 (PHQ-9). Clinically meaningful changes in PHQ-9 scores were defined as worse (≥3-point increase) or better (≥3-point decrease). Multivariate models were used to identify predictors of change in depressive symptoms. Cox proportional hazard models were used to determine the impact of symptom changes from baseline on subsequent incident cardiovascular events. RESULTS: At 12 months, 19% of patients experienced clinically worsening depressive symptoms, 31% better, and 49% unchanged. Independent predictors of clinically meaningful improvement in depressive symptoms included higher baseline PHQ-9 scores, male sex, lack of chronic obstructive pulmonary disease, and randomization to spironolactone. After data were adjusted for cardiovascular comorbidities, higher baseline PHQ-9 was associated with all-cause mortality (hazard ratio [HR]: 1.09; 95% confidence interval [CI]: 1.02 to 1.16; p = 0.011), whereas worsening depressive symptoms at 12 months were associated with cardiovascular death (HR: 2.47; 95% CI: 1.32 to 4.63; p = 0.005) and all-cause mortality (HR: 1.82; 95% CI: 1.13 to 2.93; p = 0.014). Randomization to spironolactone was associated with modest but statistically significant reduction in depressive symptoms over the course of the trial (p = 0.014). CONCLUSIONS: Higher baseline depressive symptoms and worsening depressive symptoms were associated with all-cause mortality. Randomization to spironolactone was associated with modest reduction in depressive symptoms. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302).

The short-chain fatty acid propionate increases glucagon and FABP4 production, impairing insulin action in mice and humans.

The short-chain fatty acid propionate is a potent inhibitor of molds that is widely used as a food preservative and endogenously produced by gut microbiota. Although generally recognized as safe by the U.S. Food and Drug Administration, the metabolic effects of propionate consumption in humans are unclear. Here, we report that propionate stimulates glycogenolysis and hyperglycemia in mice by increasing plasma concentrations of glucagon and fatty acid-binding protein 4 (FABP4). Fabp4-deficient mice and mice lacking liver glucagon receptor were protected from the effects of propionate. Although propionate did not directly promote glucagon or FABP4 secretion in ex vivo rodent pancreatic islets and adipose tissue models, respectively, it activated the sympathetic nervous system in mice, leading to secretion of these hormones in vivo. This effect could be blocked by the pharmacological inhibition of norepinephrine, which prevented propionate-induced hyperglycemia in mice. In a randomized, double-blind, placebo-controlled study in humans, consumption of a propionate-containing mixed meal resulted in a postprandial increase in plasma glucagon, FABP4, and norepinephrine, leading to insulin resistance and compensatory hyperinsulinemia. Chronic exposure of mice to a propionate dose equivalent to that used for food preservation resulted in gradual weight gain. In humans, plasma propionate decreased with weight loss in the Dietary Intervention Randomized Controlled Trial (DIRECT) and served as an independent predictor of improved insulin sensitivity. Thus, propionate may activate a catecholamine-mediated increase in insulin counter-regulatory signals, leading to insulin resistance and hyperinsulinemia, which, over time, may promote adiposity and metabolic abnormalities. Further evaluation of the metabolic consequences of propionate consumption is warranted.