High-density lipoprotein (HDL) and its main protein component apolipoprotein A-I (ApoA-I) have immunomodulatory properties, which pose an interesting target in patients with HFpEF [
77]. Experimentally, increased ApoA-I/HDL levels showed a protective effect on vascular function by downregulation of the angiotensin-1 receptor [
78]. More recently, infusion of recombinant HDL in a TAC model protected against oxidative stress and apoptosis, improving diastolic function compared with sham animals [
79], and decreased hypertrophy, fibrosis, and adverse remodeling in murine model of T2DM-induced diabetic cardiomyopathy and HFpEF [
80,
81]. The presence of ApoA-I immune complexes, illustrating the presence of autoantibodies, were associated with an increased risk of cardiovascular events [
82]. In the MILANO-PILOT trial, recombinant HDL showed no relevant adverse events although the effect on plaque progression was neutral and further drug development was halted. Furthermore, in a large cohort of HF patients, HDL particle analysis showed an association between derangement in small HDL particle concentration and adverse outcome in HFrEF (most pronounced) and HFpEF [
83]. To our knowledge, a randomized trial investigating ApoA-I administration or a way to enhance HDL directly has not been performed. In this perspective, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors might come into play, which are safe and seem to increase long-term ApoA-I levels [
84].