Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of the current pandemic of coronavirus disease 2019 (COVID-19). SARS-CoV-2 is a positive-sense single-stranded RNA betacoronavirus sharing genetic similarities with the severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and the Middle East respiratory syndrome-related coronavirus (MERS-CoV).¹ SARS-CoV-2 enters the cells mainly through angiotensin-converting enzyme 2 (ACE2), and triggers an intense inflammatory host response, sometimes leading to a life-threatening acute respiratory distress syndrome (ARDS).¹ Several randomized controlled trials (RCTs) are investigating the safety and efficacy of various antiviral and immunosuppressive agents. Still, many of these drugs have serious adverse effects, and may not be readily available in some healthcare settings, such as in low-income countries.

Galectin-3 (Gal-3) is involved in inflammation, fibrogenesis, and cardiac remodeling. Previous evidence shows that Gal-3 interacts with aldosterone in promoting macrophage infiltration and vascular fibrosis and that Gal-3 genetic and pharmacological inhibition prevents remodeling in a pressure-overload animal model of heart failure. We aimed to explore the contribution of Gal-3 and aldosterone in mechanisms leading to heart failure in a murine model. Male mice with cardiac-specific hyperaldosteronism underwent isoproterenol subcutaneous injections, to be then randomized to receive placebo, a Gal-3 inhibitor (modified citrus pectin [MCP]), an aldosterone antagonist (potassium canrenoate), or MCP+canrenoate for 14 days. Isoproterenol induced a rapid and persistent decrease in left ventricular fractional shortening (−20% at day 14); this was markedly improved by treatment with either MCP or canrenoate (both P <0.001 versus placebo). MCP and canrenoate also reduced cardiac hypertrophy and fibrosis and the expression of genes involved in fibrogenesis ( Coll-1 and Coll-3 ) and macrophage infiltration ( CD-68 and MCP-1 ). After isoproterenol, Gal-3 gene expression ( P <0.05 versus placebo) and protein levels (−61% and −69% versus placebo) were decreased by both canrenoate and MCP. The combined use of antagonists of Gal-3 and aldosterone resulted in more pronounced effects on cardiac hypertrophy, inflammation, and fibrosis, when compared with either MCP or canrenoate alone. Inhibition of Gal-3 and aldosterone can reverse isoproterenol-induced left ventricular dysfunction, by reducing myocardial inflammation and fibrogenesis. Gal-3 likely participates in mechanisms of aldosterone-mediated myocardial damage in a heart failure murine model with cardiac hyperaldosteronism. Gal-3 inhibition may represent a new promising therapeutic option in heart failure.

Transthyretin (TTR) is a homotetrameric protein mainly synthesised by the liver and the choroid plexus whose function is to carry the thyroid hormone thyroxine and the retinol-binding protein bound to retinol in plasma and cerebrospinal fluid. When the stability of the tetrameric structure is lost, it breaks down, paving the way for the aggregation of TTR monomers into insoluble fibrils leading to transthyretin (ATTR) amyloidosis, a progressive disorder mainly affecting the heart and nervous system. Several TTR gene mutations have been characterised as destabilisers of TTR structure and are associated with hereditary forms of ATTR amyloidosis. The reason why also the wild-type TTR is intrinsically amyloidogenic in some subjects is largely unknown. The aim of the review is to give an overview of the TTR biological life cycle which is largely unknown. For this purpose, the current knowledge on TTR physiological metabolism, from its synthesis to its catabolism, is described. Furthermore, a large section of the review is dedicated to examining in depth the role of mutations and physiological ligands on the stability of TTR tetramers.