BACKGROUND: Fibroblast growth factor 21 (FGF21) levels are often elevated in heart failure (HF), although this has not been assessed using a longitudinal study design. Therefore, we investigated the association between baseline plasma FGF21 levels and incident HF in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: A total of 5408 participants, free of clinically apparent cardiovascular disease, were included in the analysis, of which 342 developed HF over a median follow-up period of 16.7 years. Multivariable Cox regression analysis was performed and the additive value of FGF21 in the performance of risk prediction over other well-established cardiovascular biomarkers was assessed. RESULTS: The mean age of the participants was 62.6 years with 47.6 % male. Regression spline analysis demonstrated a significant association of FGF21 levels with incident HF among participants with FGF21 levels ≥239.0 pg/mL (hazard ratio = 1.84 [95 % confidence interval 1.21, 2.80] per SD increase in ln-transformed levels) after adjustment for traditional cardiovascular risk factors and biomarkers, but not in participants with FGF21 levels <239.0 pg/mL (p for heterogeneity = 0.004). Among participants with FGF21 levels ≥239.0 pg/mL, FGF21 levels were associated with HF with preserved ejection fraction (HR [95 % CI] = 2.57 [1.51, 4.37]), but not HF with reduced ejection fraction. CONCLUSIONS: The present study suggests baseline FGF21 levels could predict the development of incident HF with preserved ejection fraction, among participants with elevated FGF21 levels at baseline. This study may suggest a pathophysiological role of FGF21 resistance in HF with preserved ejection fraction.

Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G>A mutation in the MT-ND4 gene being the most common disease-causing mtDNA variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G>A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary end point was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary end point). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (P < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (P < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G>A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.