European Journal of Heart Failure最新文献

Aims

Non-ischaemic cardiomyopathy (NICMP), an incurable disease terminating in systolic heart failure (heart failure with reduced ejection fraction [HFrEF]), causes immune activation, however anti-inflammatory treatment strategies so far have failed to alter the course of this disease. Myeloperoxidase (MPO), the principal enzyme in neutrophils, has cytotoxic, pro-fibrotic and nitric oxide oxidizing effects. Whether MPO inhibition ameliorates the phenotype in NICMP remains elusive.

Methods and results

Prognostic information from MPO was derived from proteomic data of a large human cardiovascular health cohort (n = 3289). In a murine model of NICMP, we studied the mechanisms of MPO in this disease. In a case series, the MPO inhibitor was also evaluated in NICMP patients. Individuals with increased MPO revealed higher long-term mortality and worsening of heart failure, with impaired prognosis when MPO increased during follow-up. MPO infusion attenuated left ventricular ejection fraction (LVEF) in mice with NICMP, whereas genetic ablation or inhibition of MPO decreased systemic vascular resistance (SVR, 9.4 ± 0.7 mmHg*min/ml in NICMP vs. 6.7 ± 0.8 mmHg*min/ml in NICMP/Mpo^−/−mice, n = 8, p = 0.006, data expressed as mean ± standard error of the mean) and improved left ventricular function (LVEF 30.3 ± 2.2% in NICMP vs. 40.7 ± 1.1% in NICMP/Mpo^−/− mice, n = 16, p < 0.0001). Four patients diagnosed with NICMP and treated with an MPO inhibitor over 12 weeks showed increase in LVEF, decline in natriuretic peptides and improved 6-min walking distance. MPO inhibitor-related changes in the proteome of NICMP patients predicted reduced mortality when related to the changes in the proteome of the above referenced cardiovascular health cohort.

Conclusions

Myeloperoxidase predicts long-term outcome in HFrEF and its inhibition elicits systemic anti-inflammatory and vasodilating effects which translate into improved left ventricular function. MPO inhibition deserves further evaluation as a novel, complementary treatment strategy for HFrEF.

Aims

Digoxin is the oldest drug in cardiovascular (CV) medicine, and one trial conducted >25 years ago showed a reduction in heart failure (HF) hospitalizations but no effect on mortality. However, later studies suggested that the dose of digoxin used in that trial (and other studies) may have been too high. The DECISION (Digoxin Evaluation in Chronic heart failure: Investigational Study In Outpatients in the Netherlands) trial will examine the efficacy and safety of low-dose digoxin in HF patients with reduced or mildly reduced left ventricular ejection fraction (LVEF) with a background of contemporary HF treatment.

Methods

The DECISION trial is a randomized, double-blind, parallel-group, placebo-controlled event-driven outcome trial which will investigate the efficacy and safety of low-dose digoxin in patients with chronic HF and LVEF <50%. Both patients with sinus rhythm and atrial fibrillation will be enrolled and will be randomized (1:1) to low-dose digoxin or matching placebo. To maintain a target serum digoxin concentration of 0.5–0.9 ng/ml, dose adjustments are made throughout follow-up based on serum digoxin measurements with dummy values for the placebo group. The primary endpoint is a composite of CV mortality and total HF hospitalizations or total urgent hospital visits for worsening HF, and all endpoints are adjudicated blindly by a Clinical Event Committee. The estimated sample size was 982 patients who will be followed for a median of 3 years, and in December 2023 enrolment was completed after 1002 patients.

Conclusions

The DECISION trial will provide important evidence regarding the effect of (low-dose) digoxin on CV mortality and total HF hospitalizations and urgent hospital visits when added to contemporary HF treatment of patients with reduced or mildly reduced LVEF.

Clinical Trial Registration: ClinicalTrials.gov identifier: NCT03783429.

Aims

There is a lack of therapies able to prevent anthracycline cardiotoxicity (AC). Remote ischaemic conditioning (RIC) has shown beneficial effects in preclinical models of AC.

Methods

REmote iSchemic condItioning in Lymphoma PatIents REceiving ANthraCyclinEs (RESILIENCE) is a multinational, prospective, phase II, double-blind, sham-controlled, randomized clinical trial that evaluates the efficacy and safety of RIC in lymphoma patients receiving anthracyclines. Patients scheduled to undergo ≥5 chemotherapy cycles including anthracyclines and with ≥1 AC-associated risk factors will be randomized to weekly RIC or sham throughout the chemotherapy period. Patients will undergo three multiparametric cardiac magnetic resonance (CMR) studies, at baseline, after the third cycle (intermediate CMR), and 2 months after the end of chemotherapy. Thereafter, patients will be followed up for clinical events over an anticipated median of ≥24 months. The primary endpoint is the absolute change from baseline in CMR-based left ventricular ejection fraction (LVEF). The main secondary outcome is the incidence of AC events, defined as (1) a drop in CMR-based LVEF of ≥10 absolute points, or (2) a drop in CMR-based LVEF of ≥5 and <10 absolute points to a value <50%. Intermediate CMR will test the ability of T2 mapping to predict AC versus classical markers (left ventricular strain and cardiac injury biomarkers). A novel CMR sequence allowing ultrafast cine acquisition will be validated in this vulnerable population.

Conclusions

The RESILIENCE trial will test RIC (a novel non-invasive intervention to prevent AC) in a cohort of high-risk patients. The trial will also test candidate markers for their capacity to predict AC and will validate a novel CMR sequence reducing acquisition time in a vulnerable population.