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Aims: Medication adherence in patients with heart failure with preserved ejection fraction (HFpEF) is unclear. This study sought to evaluate treatment adherence in the Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction (PIROUETTE) trial, identify factors that predict adherence, and understand the impact of missed medication doses on treatment efficacy.Methods: Adherence was evaluated at each study visit through pill counts and diary cards. Univariable and multivariable regression models were used to assess the relationship between adherence and baseline characteristics. Instrumental variable regression was used to estimate the causal effect of pirfenidone treatment duration on myocardial fibrosis, measured using cardiovascular magnetic resonance extracellular volume.Results: Complete adherence data was available in 54 of 80 participants completing the trial. Mean adherence with study medication was 94.7% and 96.9% in the pirfenidone and placebo groups respectively. Each additional day of treatment with pirfenidone resulted in a significant decrease in myocardial extracellular volume (–0.004%; 95% confidence interval: -0.007% to -0.001%; p=0.007). Associations with adherence included older age, higher symptom burden, lower body weight and smaller right ventricular size. Limitations of adherence assessments were highlighted. Conclusion: Adherence with study medication in the PIROUETTE trial was very high among patients for whom complete adherence data was available. Importantly, each additional day of treatment reduced myocardial fibrosis. Potential predictors of adherence were identified. Implementation of improved methods for assessing adherence is required.Keywords: Heart failure with preserved ejection fraction, adherence, efficacy, myocardial fibrosis

ObjectivesThe aim of this study was to investigate the effects of bariatric surgery on small artery function and the mechanisms underlying this.BackgroundIn lean healthy humans, perivascular adipose tissue (PVAT) exerts an anticontractile effect on adjacent small arteries, but this is lost in obesity-associated conditions such as the metabolic syndrome and type II diabetes where there is evidence of adipocyte inflammation and increased oxidative stress.MethodsSegments of small subcutaneous artery and perivascular fat were harvested from severely obese individuals before (n = 20) and 6 months after bariatric surgery (n = 15). Small artery contractile function was examined in vitro with wire myography, and perivascular adipose tissue (PVAT) morphology was assessed with immunohistochemistry.ResultsThe anticontractile activity of PVAT was lost in obese patients before surgery when compared with healthy volunteers and was restored 6 months after bariatric surgery. In vitro protocols with superoxide dismutase and catalase rescued PVAT anticontractile function in tissue from obese individuals before surgery. The improvement in anticontractile function after surgery was accompanied by improvements in insulin sensitivity, serum glycemic indexes, inflammatory cytokines, adipokine profile, and systolic blood pressure together with increased PVAT adiponectin and nitric oxide bioavailability and reduced macrophage infiltration and inflammation. These changes were observed despite the patients remaining severely obese.ConclusionsBariatric surgery and its attendant improvements in weight, blood pressure, inflammation, and metabolism collectively reverse the obesity-induced alteration to PVAT anticontractile function. This reversal is attributable to reductions in local adipose inflammation and oxidative stress with improved adiponectin and nitric oxide bioavailability.