Determinants of anti-fibrotic response to mineralocorticoid receptor antagonist therapy: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) and Early Eplerenone Treatment in Patients with Acute ST-elevation Myocardial Infarction without Heart Failure (REMINDER) trials.

Introduction: After myocardial infarction complicated by heart failure or diabetes, eplerenone (compared to placebo) significantly decreases amino-terminal propeptide of type III procollagen (PIIINP). Determining the subset of patients who are more prone to have a decrease in PIIINP and those who may respond better to the anti-fibrotic effects of mineralocorticoid receptor antagonists (MRA) therapy may be relevant for a personalized treatment approach. The aim of this study is to identify predictors of a PIIINP decrease and assess potential subgroups of "responders" to eplerenone.

Utility of the Cardiovascular Physical Examination and Impact of Spironolactone in Heart Failure With Preserved Ejection Fraction.

Background: The prognostic value of physical examination, its relation to quality of life, and influence of therapy in heart failure with preserved ejection fraction is not well known.

Methods And Results: We studied participants from the Americas with available physical examination (jugular venous distention, rales, and edema) at baseline in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist). The association of the number of signs of congestion with the primary outcome (cardiovascular death or heart failure hospitalization), its individual components, and all-cause mortality was assessed using time-updated, multivariable-adjusted Cox regression analyses.

Mean BMI, visit-to-visit BMI variability and BMI changes during follow-up in patients with acute myocardial infarction with systolic dysfunction and/or heart failure: insights from the High-Risk Myocardial Infarction Initiative.

Background: In patients with acute myocardial infarction (MI), BMI < 18.5 kg/m and a decrease in BMI during follow-up have been associated with poor prognosis. For BMI ≥ 25 kg/m, an "obesity paradox" has been suggested.

N-Terminal Pro-B-Type Natriuretic Peptide Levels for Risk Prediction in Patients With Heart Failure and Preserved Ejection Fraction According to Atrial Fibrillation Status.

Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is useful in diagnosis and prognostication in heart failure (HF). We examined the relationship between NT-proBNP and outcomes in patients with HF and preserved ejection fraction, with and without atrial fibrillation (AF). Methods and Results Among 3835 HF with preserved ejection fraction patients enrolled in the I-Preserve (Irbesartan in Heart Failure With Preserved Systolic Function trial) or TOPCAT trial (Treatment of Preserved Cardiac Function in Heart Failure With an Aldosterone Antagonist), 719 (19%) patients had AF on their baseline ECG.

Potassium binders for the prevention of hyperkalaemia in heart failure patients: implementation issues and future developments.

New therapeutic options to treat hyperkalaemia, such as potassium binders, have been suggested as potentially beneficial by allowing the maintenance (or increase) of the dose of medications that improve outcomes in several cardiovascular conditions, but which have in common the propensity for raising serum potassium. However, potassium binding drugs have yet to prove their causal association with improvements in patients' prognosis before their widespread use can be recommended. In this review we provided an up-to-dare appraisal on potassium binders, their potential clinical applications and directions for future research.

The renin-angiotensin-aldosterone system and its suppression.

Chronic activation of the renin-angiotensin-aldosterone system (RAAS) promotes and perpetuates the syndromes of congestive heart failure, systemic hypertension, and chronic kidney disease. Excessive circulating and tissue angiotensin II (AngII) and aldosterone levels lead to a pro-fibrotic, -inflammatory, and -hypertrophic milieu that causes remodeling and dysfunction in cardiovascular and renal tissues. Understanding of the role of the RAAS in this abnormal pathologic remodeling has grown over the past few decades and numerous medical therapies aimed at suppressing the RAAS have been developed.

IL-33-mediated IL-13 secretion by ST2+ Tregs controls inflammation after lung injury.

Acute respiratory distress syndrome is an often fatal disease that develops after acute lung injury and trauma. How released tissue damage signals, or alarmins, orchestrate early inflammatory events is poorly understood. Herein we reveal that IL-33, an alarmin sequestered in the lung epithelium, is required to limit inflammation after injury due to an unappreciated capacity to mediate Foxp3+ Treg control of local cytokines and myeloid populations.

Renal function stratified dose comparisons of eplerenone versus placebo in the EMPHASIS-HF trial.

Background: Current heart failure guidelines recommend target eplerenone dose of 50 mg/day. We have examined the effect of different eplerenone doses based on pre-specified renal function stratification in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF).

Methods And Results: In EMPHASIS-HF, the target dose of eplerenone/placebo was stratified at randomization according to estimated glomerular filtration rate (eGFR): 50 mg/day if eGFR ≥ 50 mL/min/1.

Non‑canonical Wnt signaling contributes to ventilator‑induced lung injury through upregulation of WISP1 expression.

Mechanical ventilation may cause ventilator‑induced lung injury (VILI). Canonical Wnt signaling has been reported to serve an important role in the pathogenesis of VILI. Bioinformatics analysis revealed that canonical and non‑canonical Wnt signaling pathways were activated in VILI.

Comparison of Outcomes in Patients With Diabetes Mellitus Treated With Versus Without Insulin + Heart Failure With Preserved Left Ventricular Ejection Fraction (from the TOPCAT Study).

We aimed to evaluate the impact of diabetes mellitus (DM) and insulin treatment on clinical outcomes in patients with heart failure and preserved left ventricular ejection fraction enrolled in the TOPCAT study. We investigated the influence of DM status (insulin-treated [ITDM], non-insulin treated [NITDM], and no diabetes [non-DM]) at baseline on time to development of the primary end point, a composite of cardiovascular (CV) mortality, heart failure hospitalization, and aborted cardiac arrest. Secondary end points included the individual components of the primary end point, myocardial infarction, stroke, all-cause mortality, hyperkalemia, and worsened renal function.

Efficacy and Safety of Spironolactone in Patients With HFpEF and Chronic Kidney Disease.

Objectives: This study investigated the association between baseline renal function and the net benefit of spironolactone in patients with heart failure (HF) with a preserved ejection fraction (HFpEF).

Background: Guidelines recommend consideration of spironolactone to reduce HF hospitalization in HFpEF. However, spironolactone may increase risk for hyperkalemia and worsening renal function, particularly in patients with chronic kidney disease.

Impact of eplerenone on major cardiovascular outcomes in patients with systolic heart failure according to baseline heart rate.

Background: Increased resting heart rate is a risk factor for cardiovascular mortality and morbidity. Mineralocorticoid receptor antagonists (MRAs) have been shown to improve cardiac sympathetic nerve activity, reduce heart rate and attenuate left ventricular remodelling. Whether or not the beneficial effects of MRA are affected by heart rate in heart failure patients with reduced ejection fraction (HFREF) is unclear.

Cardiac Troponin I and Risk of Cardiac Events in Patients With Heart Failure and Preserved Ejection Fraction.

Background: Levels of cTn (cardiac troponin) are frequently elevated in patients with heart failure (HF) and reduced ejection fraction (EF) and correlate with the risk for mortality. However, factors associated with high cTn concentrations and the association with cardiovascular events in patients with HF and preserved EF are unclear.

Methods And Results: Of 1767 subjects with symptomatic HF with preserved EF from the Americas part of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial), 236 underwent baseline measurements of high-sensitivity (hs) cTnI using the Abbott Architect STAT assay.

Prognostic Value of Albuminuria and Influence of Spironolactone in Heart Failure With Preserved Ejection Fraction.

Background: Albuminuria predicts adverse events in heart failure with preserved ejection fraction. No therapies to date have reduced albuminuria in heart failure with preserved ejection fraction.

Methods And Results: We analyzed 1175 participants from the Americas from the TOPCAT study (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) with urinary albumin:creatinine ratio (UACR) measurements at baseline.

Incidence, Predictors, and Outcome Associations of Dyskalemia in Heart Failure With Preserved, Mid-Range, and Reduced Ejection Fraction.

Objectives: This study investigated 1-year incidence and predictors of dyskalemia (dysK) and its outcome associations in heart failure with preserved ejection fraction (HFpEF), HF with mid-range EF (HFmrEF), and HF with reduced EF (HFrEF).

Background: DysK in real-world HF is insufficiently characterized. Fear of dyskalemia may lead to underuse or underdosing of renin-angiotensin-aldosterone system inhibitors.

Canrenone on cardiovascular mortality in congestive heart failure: CanrenOne eFFects on cardiovascular mortality in patiEnts with congEstIve hearT failure: The COFFEE-IT study.

Aim: To evaluate canrenone effects compared to other therapies on cardiovascular mortality in patients with chronic heart failure (CHF) and preserved systolic function after 10 years of evaluation.

Methods: We enrolled 532 patients with CHF and preserved systolic function. Patients were followed with a mean follow-up of 10 years: 166 patients were in therapy with canrenone, while 336 patients were in conventional therapy.

Mechanical ventilation enhances extrapulmonary sepsis-induced lung injury: role of WISP1-αvβ5 integrin pathway in TLR4-mediated inflammation and injury.

Background: High tidal volume ventilation of healthy lungs or exacerbation of existing acute lung injury (ALI) by more moderate mechanical ventilation (MTV) produces ventilator-induced lung injury. It is less clear whether extrapulmonary sepsis sensitizes the lung to MTV.

Methods: We used a two-hit model of cecal ligation and puncture (CLP) followed 12 h later by MTV (10 ml/kg; 6 h) to determine whether otherwise noninjurious MTV enhances CLP-induced ALI by contrasting wildtype and TLR4 mice with respect to: alveolar-capillary permeability, histopathology and intrapulmonary levels of WNT-inducible secreted protein 1 (WISP1) and integrin β5; plasma levels of cytokines and chemokines (TNF-α, IL-6, MIP-2, MCP-1) and intrapulmonary neutrophil infiltration; and other inflammatory signaling via intrapulmonary activation of JNK, p38 and ERK.

Beware of on-treatment safety analyses.

Introduction: Assessing safety is important to evaluating new medications. In many randomized clinical trials, assessment of safety relies on so-called on-treatment analysis, where data on adverse events are collected only while the participant is taking study medication and perhaps for a few (7, 14, or 30) days after stopping. This article discusses the consequence of such failure to use intent-to-treat analyses in assessing safety.

Association between renin-angiotensin system inhibitor use and mortality/morbidity in elderly patients with heart failure with reduced ejection fraction: a prospective propensity score-matched cohort study.

Aims: In heart failure with reduced ejection fraction (HFrEF), renin-angiotensin system inhibitors (RASi) improve morbidity and mortality. However, patients aged >80 years constituted a small minority in trials. We assessed the association between RASi use and mortality/morbidity in HFrEF patients aged >80 years.

Impact of mineralocorticoid receptor antagonists on the risk of sudden cardiac death in patients with heart failure and left-ventricular systolic dysfunction: an individual patient-level meta-analysis of three randomized-controlled trials.

Background: Sudden cardiac death (SCD) is an important cause of death in patients with left-ventricular systolic dysfunction (LVSD). Mineralocorticoid receptor antagonists (MRAs) may attenuate this risk. We aimed to assess the impact of MRAs on SCD in patients with LVSD.

Editor's Choice- Impact of insulin-treated diabetes on cardiovascular outcomes following high-risk myocardial infarction.

Background: Diabetes is associated with poor cardiovascular outcomes, and insulin-treated patients usually have a worse prognosis than non-insulin-treated subjects. The relationship between insulin treatment and outcomes in high-risk myocardial infarction patients has not been described in a large dataset.

Methods: To investigate the association between insulin-treated diabetes and long-term cardiovascular outcomes in patients with high-risk myocardial infarction, we used adjusted Cox models to compare cardiovascular mortality and hospitalisation among 28,771 patients grouped by diabetes status and insulin treatment from four randomised clinical trials (VALIANT, EPHESUS, OPTIMAAL, CAPRICORN) of acute myocardial infarction complicated by heart failure and/or left ventricular systolic dysfunction.