August 2020 at a Glance: Focus on Neurohormonal Antagonists and Electrolytes

Heart failure (HF) has a worldwide diffusion with high mortality and morbidity.1-3 Groenewegen et al.4 provide an updated overview of the epidemiology of HF. MicroRNAs (miRNAs) are small non-coding RNAs potentially useful for the diagnosis and prognosis of HF.5-7 They may also be useful for better understanding HF pathophysiology. Garg et al.8 investigated the mechanisms of aldosterone-induced cardiac remodelling. After screening 2555 miRNAs, miR-181 was found to be a potential regulator of the aldosterone–mineralocorticoid receptor pathway with potential therapeutic implications. Cooper et al.9 showed a U-shaped association between serum potassium levels and mortality risk in 13 015 patients with HF and reduced ejection fraction (HFrEF) from the Swedish HF Registry. A potassium value of 4.2 mmol/L was associated with the lowest risk of death at 30 days, 12 months, and at long term. Hyperkalaemia is a major cause of underuse of renin–angiotensin–aldosterone system inhibitors (RAASi).10, 11 An analysis from the European Society of Cardiology (ESC)–HF Association (HFA) EURObservational Registry Programme (EORP) HF Long-Term Registry confirmed that hyperkalaemia is associated with mineralocorticoid receptor antagonist (MRA) non-prescription or discontinuation and poorer survival. At multivariable analyses, adjusting for RAASi discontinuation, RAASi discontinuation itself, but not hyperkalaemia, was an independent predictor of poorer outcomes. This suggests that the relation with outcomes of hyperkalaemia is mediated by RASSi discontinuation.12 Rossignol et al.13 developed updated risk models for prediction of cardiovascular death, HF hospitalizations and all-cause death in HFrEF patients. In addition to traditional clinical variables, these models included time-dependent variables such as serum potassium, glomerular filtration rate and anaemia, as well as treatment with diuretics, MRA and beta-blockers. The addition of these variables, namely potassium and MRA treatment, improved risk prediction compared with the Meta-Analysis Global Group in Chronic HF (MAGGIC) score.13 Selenium deficiency may lead to oxidative stress, which is an important pathophysiological pathway in HF.14 HF patients with selenium deficiency showed poorer outcomes and impaired exercise tolerance.15 Diuretic treatment was reviewed in a recent HFA position statement.16 Data from the ESC-HFA EORP HF Long-Term Registry showed that diuretic dose increase (vs. no change) was associated with HF death, while a decrease had a trend for better outcomes. Predictors of successful down-titration of loop diuretics were higher systolic blood pressure, the absence of sleep apnoea, peripheral congestion and significant mitral regurgitation.17 In patients hospitalized for acute HF, diuretic response may be monitored by urinary sodium assessment.16 In a prospective cohort of 175 acute HF patients, urinary sodium excretion at 6 h predicted 24 h urine volume and all-cause mortality, but not HF rehospitalization.18 The Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in HF (ATHENA-HF) trial failed to show beneficial effects of high dose spironolactone compared to low dose or placebo.19 These results may be explained by low concentrations of the spironolactone active metabolite for at least 48 h after start of treatment as shown by de Denus et al.20 Novel potassium-lowering agents may be considered to manage hyperkalaemia.21 A pre-specified subgroup analysis of HF patients enrolled in the patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER) trial showed that patiromer allows a more persistent use of spironolactone through a reduction in hyperkalaemia.22 Adherence to guideline-directed medical therapy is associated with better outcome in HFrEF patients.23, 24 Ouwerkerk et al.25 analysed the effects of combined up-titration of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs) and β-blockers with all-cause mortality and hospitalization for HF in patients enrolled in the BIOlogy Study to TAilored Treatment in Chronic HF (BIOSTAT-CHF) and Asian Sudden Cardiac Death in HF (ASIAN-HF) registries. The best outcomes were observed in patients achieving the guideline-recommended target doses for both ACEi/ARBs and β-blockers (hazard ratio 0.32, 95% confidence interval 0.26–0.39).25