Purpose Approximately 30% of patients with atrial fibrillation (AF) develop heart failure (HF), but the underlying mechanisms and their impact on the left ventricle (LV) remain unclear. Fibrosis and inflammation are suspected contributors. This study aimed to investigate LV tissue characteristics in patients with and without AF using cardiac magnetic resonance imaging (CMR). Methods Patients from a single-center CMR registry were categorized by AF status, adjudicated by two blinded investigators. LV fibrosis was assessed by native T1 and extracellular volume (ECV), while T2 indicated inflammation. Results were adjusted for LV ejection fraction (LVEF), end-systolic volume index (ESVi), and late gadolinium enhancement mass (LGEmass). Prognostic value was tested with multivariable Cox regression, using all-cause mortality or HF hospitalization at one year as the endpoint. Results Of 2,879 patients with one-year follow-up, 590 had AF. They showed lower LVEF and higher ESVi and LGEmass. After adjustment, AF was linked to higher T1 (p = 0.006), T2 (p = 0.01), and ECV (p < 0.001). Eighty-five patients reached the endpoint. In multivariable analysis, only T1 independently predicted outcome. Kaplan-Meier analysis showed patients with T1 above the median (1125 ms) had worse outcomes than those below, even without AF. The combination of AF and elevated T1 carried the poorest prognosis (p = 0.001). Conclusion AF is closely associated with LV fibrosis and inflammation, with T1 emerging as an independent predictor of outcome. These findings suggest a mechanistic pathway with important prognostic implications. Prospective studies are warranted to confirm these associations and explore their role in patient stratification and management.
BACKGROUND:The therapeutic efficacy of the cardiac glycoside digitoxin in patients with heart failure and reduced ejection fraction is not established. METHODS:In this international, double-blind, placebo-controlled trial, we randomly assigned patients with chronic heart failure who had a left ventricular ejection fraction of 40% or less and a New York Heart Association (NYHA) functional class of III or IV or a left ventricular ejection fraction of 30% or less and an NYHA functional class of II in a 1:1 ratio to receive digitoxin (at a starting dose of 0.07 mg once daily) or matching placebo in addition to guideline-directed medical therapy. The primary outcome was a composite of death from any cause or hospital admission for worsening heart failure, whichever occurred first. RESULTS:Among 1240 patients who underwent randomization, 1212 fulfilled the criteria for inclusion in the modified intention-to-treat population: 613 patients in the digitoxin group and 599 in the placebo group. Over a median follow-up of 36 months, a primary-outcome event occurred in 242 patients (39.5%) in the digitoxin group and 264 (44.1%) in the placebo group (hazard ratio for death or first hospital admission for worsening heart failure, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P = 0.03). Death from any cause occurred in 167 patients (27.2%) in the digitoxin group and 177 (29.5%) in the placebo group (hazard ratio, 0.86; 95% CI, 0.69 to 1.07). A first hospital admission for worsening heart failure occurred in 172 patients (28.1%) in the digitoxin group and 182 (30.4%) in the placebo group (hazard ratio, 0.85; 95% CI, 0.69 to 1.05). At least one serious adverse event occurred in 29 patients (4.7%) in the digitoxin group and 17 (2.8%) in the placebo group. CONCLUSIONS:Treatment with digitoxin led to a lower combined risk of death from any cause or hospital admission for worsening heart failure than placebo among patients with heart failure and reduced ejection fraction who received guideline-directed medical therapy. (Funded by the German Federal Ministry of Research, Technology, and Space and others; DIGIT-HF EudraCT number, 2013-005326-38.).
AIMS:This report presents the baseline characteristics of patients enrolled in the DIGIT-HF trial and compares them with participants from recent trials with improved outcomes in patients with heart failure (HF) and a reduced ejection fraction (HFrEF). METHODS AND RESULTS:DIGIT-HF, a randomized, double-blind, placebo-controlled, multicentre trial enrolling patients with symptomatic HFrEF (New York Heart Association [NYHA] functional class II and left ventricular ejection fraction [LVEF] ≤30%, or NYHA class III-IV and LVEF ≤40%), compares the efficacy and safety of digitoxin versus placebo in addition to standard treatment. Most baseline characteristics of the intention-to-treat population (1212 patients, mean age 66 ± 11 years, 20% women, mean LVEF 29 ± 7%) were similar to those in recent HFrEF trials. The distribution of NYHA class II, III, and IV was 30%, 66% and 4%, respectively, and indicates that the patients were sicker than in comparator HFrEF trials. Less patients had atrial fibrillation (27%) than those in recent HFrEF trials, but prescription rates of background therapy with beta-blockers (96%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (95%), mineralocorticoid receptor antagonists (76%), and diuretics (87%) were high and similar. Overall, 40% of patients were on angiotensin receptor-neprilysin inhibitors, 19% on sodium-glucose cotransporter 2 inhibitors, and 9% on ivabradine. Rates of implantable cardioverter-defibrillator (ICD, 64%) and cardiac resynchronization therapy (CRT, 25%) devices were much higher than in recent HFrEF trials. CONCLUSIONS:Patients included in DIGIT-HF display a more severe HF symptom burden and higher rates of ICD/CRT implants compared to participants in recent HFrEF trials, while pharmacotherapy was largely similar. CLINICAL TRIAL REGISTRATION:EudraCT (2013-005326-38).
