Cardiovascular magnetic resonance assessment of coronary flow reserve improves risk stratification in heart failure with preserved ejection fraction

Background Coronary microvascular dysfunction (CMD) has been proposed as a novel mechanism for the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). Recent studies have suggested the potential utility of coronary flow reserve (CFR) as a marker of CMD in patients with HFpEF. Phase contrast (PC) cine cardiovascular magnetic resonance (CMR) of the coronary sinus has emerged as a non-invasive method to quantify CFR. We aimed to investigate the prognostic value of CMR-derived CFR in patients with HFpEF. Methods Data from 163 HFpEF patients (73 ± 9 years; 86 [53%] female) were retrospectively analyzed. Coronary sinus blood flow was measured in all patients, and myocardial blood flow was calculated as coronary sinus blood flow divided by left ventricular mass. CFR was calculated as the myocardial blood flow during adenosine triphosphate infusion divided by that at rest. Adverse events were defined as all-cause death and hospitalization due to HF exacerbation. Event-free survival stratified according to CFR < 2.0 was estimated with Kaplan–Meier survival methods and Log-rank test. Results During a median follow-up of 4.1 years, 26 patients (16%) experienced adverse events. CMR-derived CFR was significantly lower in HFpEF with adverse events compared with those without (1.93 ± 0.38 vs. 2.67 ± 0.52, p < 0.001). On a Kaplan Meier curve, the rates of adverse events were significantly higher in HFpEF patients with CFR < 2.0 compared with HFpEF with CFR ≥ 2.0 (p < 0.001). The area under the curve of CFR for predicting adverse events was significantly higher than that of LGE (0.881 vs. 0.768, p = 0.037) and GLS (0.881 vs. 0.747, p = 0.036). Conclusions CFR assessed using coronary sinus PC cine CMR may be useful as a non-invasive prognostic marker for HFpEF patients.

Activation of TGF-β1/α-SMA/Col I Profibrotic Pathway in Fibroblasts by Galectin-3 Contributes to Atrial Fibrosis in Experimental Models and Patients

Background/Aims: This study aimed to evaluate whether galectin-3 (Gal-3) contributes actively to atrial fibrosis both in patients and experimental atrial fibrillation (AF) models. Methods: Mouse HL-1 cardiomyocytes were subjected to rapid electrical stimulation (RES) to explore Gal-3 expression and secretion levels by western blotting (WB) and enzyme linked immunosorbent assay (ELISA). Neonatal rat cardiac fibroblasts were treated with conditioned culture medium and recombinant human Gal-3 to evaluate the activation of the transforming growth factor (TGF)-β1/α-smooth muscle actin (SMA)/collagen I (Col I) profibrotic pathway (WB) and fibroblast proliferation with a Cell Counting Kit-8 (CCK-8). Furthermore, in the rapid atrial pacing (RAP) rabbit AF model, atrial Gal-3 expression and its effects on the profibrotic pathway were evaluated (WB and Masson’s trichrome staining). Moreover, 44 consecutive patients who underwent single mitral valve repair/replacement were included, consisting of 28 patients with persistent AF (PeAF) and 16 with sinus rhythm (SR). Coronary sinus blood was also sampled to test circulating Gal-3 levels (ELISA), and atrial myocardium Gal-3 and its downstream TGF-β1/α-SMA pathway were also measured by WB and immunohistochemical staining. Results: Gal-3 expression in HL-1 cells and its secretion level in culture medium were greatly increased after 24 h RES. Treatment of neonatal rat cardiac fibroblasts with conditioned media collected from the RES group or recombinant human Gal-3 protein (10 and 30 µg/mL) for 72 h induced the activation of the TGF-β1/α-SMA/Col I profibrotic pathway. RAP increased Gal-3 levels and activated the TGF-β1/α-SMA/Col I pathway in rabbit left atria, while the Gal-3 inhibitor N-acetyllactosamine, injected at 4.5 mg/kg every 3 days, mitigated these adverse changes. Furthermore, Gal-3 levels in coronary sinus blood samples and myocardial Gal-3 expression levels were higher in the PeAF patients than in the SR patients, and higher level profibrotic pathway activation was also confirmed. Conclusions: Activation of Gal-3 expression in the atria can subsequently activate the TGF-β1/α-SMA/Col I pathway in cardiac fibroblasts, which may enhance atrial fibrosis.