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© The author(s)., The origin and functions of mast cells (MCs) have been debated since their description by Paul Ehrlich in 1879. MCs have long been considered 'reactive bystanders' and 'amplifiers' in inflammatory processes, allergic reactions, and host responses to infectious diseases. However, knowledge about the origin, phenotypes and functions of MCs has increased substantially over the past 50 years. MCs are now known to be derived from multipotent hematopoietic progenitors, which, through a process of differentiation and maturation, form a unique hematopoietic lineage residing in multiple organs. In particular, MCs are distinguishable from basophils and other hematopoietic cells by their unique phenotype, origin(s), and spectrum of functions, both in innate and adaptive immune responses and in other settings. The concept of a unique MC lineage is further supported by the development of a distinct group of neoplasms, collectively referred to as mastocytosis, in which MC precursors expand as clonal cells. The clinical consequences of the expansion and/or activation of MCs are best established in mastocytosis and in allergic inflammation. However, MCs have also been implicated as important participants in a number of additional pathologic conditions and physiological processes. In this article, we review concepts regarding MC development, factors controlling MC expansion and activation, and some of the fundamental roles MCs may play in both health and disease. We also discuss new concepts for suppressing MC expansion and/or activation using molecularly-targeted drugs., P.V. was supported by the Austrian Science Fund (FWF), grants F4701-B28, F4704-B28 and P32470-B. DDM is supported by the Division of Intramural Research, NIAID. SJG's research is supported by the NIH, USA, the US-Israel Binational Foundation, and the Department of Pathology and the Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Stanford, CA.

Mast cells are multifarious immune cells with complex roles in tissue homeostasis and disease. They produce a plethora of mediators that play roles in inflammation, angiogenesis, lymphangiogenesis, and tissue remodeling. Recent insights into the heterogeneity of cardiac mast cell (CMC) subpopulations have renewed interest in their functional diversity in homeostasis and disease. They are located within the human heart in the myocardium, in atherosclerotic plaques, in the aortic valve, and in close proximity to nerves. Their plasticity enables different and even opposite functions in response to changing tissue contexts. These characteristics render CMCs intriguing, with a dichotomous role in protecting against, or accelerating, cardiovascular diseases. Future work should aim to identify CMC subsets, which could reveal novel therapeutic opportunities for cardiovascular disorders.

SARS-CoV-2 infection continues to cause increased morbidity and mortality, and due to the slow pace of vaccination COVID-19 will probably remain a global burden to health systems for a long time. Unfortunately, the necessary prevention and treatment strategies of COVID-19 have led to restriction measures that are hampering the routine care of common chronic metabolic conditions like hypercholesterolemia. It is of particular concern that during the acute phase of COVID-19, the control of pre-existing metabolic diseases tends to get worse which again increases the risk for complications and a poor outcome in these patients. A significant contributor to these complications is endothelial dysfunction which is associated with COVID-19. This Commentary will discuss the impact of COVID-19 on endothelial function particularly in patients with familial hypercholesterolemia (FH), a metabolic inherited disease known to in itself adversely affect endothelial function. There should be no hesitation to continue with statin therapy in severe hypercholesterolemic patients with COVID-19. We argue that in FH patients with COVID-19 the clinicians need even consider intensifying statin therapy as well as the addition of other lipid-lowering agents, such as proprotein convertase subtilisin/kexin type 9(PCSK9) inhibitors. In contrast to statins, the PCSK9 inhibitors lower lipoprotein(a) [Lp(a)] level, and, accordingly, these latter drugs need to be considered particularly in FH patients with an elevated level of Lp(a). This call applies to the in-hospital stay and also beyond. When considering that the vasculopathic effects of COVID-19 may persist, a long-term follow-up of individualized therapies in FH patients is warranted.

Tiivistelmä Ateroskleroottiset valtimotaudit aiheuttavat maailmassa yhä eniten kuolemia. Pienentämällä LDL-kolesterolipitoisuutta valtimotautitapahtumien riski vähenee. Ruokavalion muutos on keskeinen LDL-kolesterolipitoisuuden pienentämisessä. Kasvistanoli rasvahappoesterinä vähentää kolesterolin imeytymistä ja pienentää LDL-kolesterolipitoisuutta. FINRISKI-laskurin mukaan ruokavalion rasvan laadun muutos yhdistettynä kasvistanoliesterituotteiden käyttöön vähentäisi sepelvaltimotaudin ilmaantuvuutta 23 %. Abstract Atherosclerotic cardiovascular diseases (ASCVDs) cause more deaths than any other disease group worldwide. However, it is possible to prevent the progression of atherosclerosis and the risk of ASCVD events by reducing the circulating concentrations of low-density-lipoprotein cholesterol (LDL-C). Large meta-analyses have demonstrated that decreasing the dietary intake of saturated fat and cholesterol can reduce the risk of ASCVD events. Here, we discuss the recent information regarding the prevention of subclinical atherosclerosis, ASCVD, and the risk of ASCVD events with a focus on dietary means. Plant stanols as fatty-acid esters were developed as a dietary adjunct to reduce LDL-C levels as part of a heart-healthy diet. They reduce cholesterol absorption so that less cholesterol is transported to the liver, the expression of LDL receptors is upregulated, and LDL-C concentrations are reduced on average by 0.40 mmol/L (12%) by consuming 3 g of plant stanols as esters/day. Using the equations of Keys, Anderson, and Grande, and the FINRISKI-counter equation, we also demonstrate that a heart-healthy diet combined with plant stanol ester consumption plausibly reduces the risk of coronary artery disease events by 23%. Thus, plant stanol esters as part of a heart-healthy diet seem to offer an effective means to reduce the risk of ASCVD events both at a population level and for subjects with different risk levels of ASCVD, when needed, in combination with statins.

Vuorio A, Watts GF, Schneider WJ, Tsimikas S, Kovanen PT (Mehilainen Airport Health Centre, Vantaa; University of Helsinki, Helsinki, Finland; University of Western Australia, Perth, Australia; Royal Perth Hospital, Perth, Australia; Medical University of Vienna, Vienna, Austria; University of California San Diego, La Jolla, CA, USA; Wihuri Research Institute, Helsinki, Finland). Familial hypercholesterolemia and elevated lipoprotein(a): double heritable risk and new therapeutic opportunities (Review). J Intern Med 2020; 287: 2-18. There is compelling evidence that the elevated plasma lipoprotein(a) [Lp(a)] levels increase the risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. Like low-density lipoprotein (LDL) particles, Lp(a) particles contain cholesterol and promote atherosclerosis. In addition, Lp(a) particles contain strongly proinflammatory oxidized phospholipids and a unique apoprotein, apo(a), which promotes the growth of an arterial thrombus. At least one in 250 individuals worldwide suffer from the heterozygous form of familial hypercholesterolemia (HeFH), a condition in which LDL-cholesterol (LDL-C) is significantly elevated since birth. FH-causing mutations in the LDL receptor gene demonstrate a clear gene-dosage effect on Lp(a) plasma concentrations and elevated Lp(a) levels are present in 30-50% of patients with HeFH. The cumulative burden of two genetically determined pro-atherogenic lipoproteins, LDL and Lp(a), is a potent driver of ASCVD in HeFH patients. Statins are the cornerstone of treatment of HeFH, but they do not lower the plasma concentrations of Lp(a). Emerging therapies effectively lower Lp(a) by as much as 90% using RNA-based approaches that target the transcriptional product of the LPA gene. We are now approaching the dawn of an era, in which permanent and significant lowering of the high cholesterol burden of HeFH patients can be achieved. If outcome trials of novel Lp(a)-lowering therapies prove to be safe and cost-effective, they will provide additional risk reduction needed to effectively treat HeFH and potentially lower the CVD risk in these high-risk patients even more than currently achieved with LDL-C lowering alone.

Atherosclerotic cardiovascular diseases (ASCVDs) cause every fifth death worldwide. However, it is possible to prevent the progression of ASCVDs by reducing circulating concentrations of low-density lipoprotein cholesterol (LDL-C). Recent large meta-analyses demonstrated that by reducing the dietary intake of saturated fat and cholesterol, it is possible to reduce the risk of ASCVD events. Plant stanols, as fatty-acid esters, were developed as a dietary adjunct to reduce LDL-C levels as part of a heart-healthy diet. They reduce cholesterol absorption so that less cholesterol is transported to the liver, and the expression of LDL receptors is upregulated. Ultimately, LDL-C concentrations are reduced on average by 9–12% by consuming 2–3 g of plant stanol esters per day. In this review, we discuss recent information regarding the prevention of ASCVDs with a focus on dietary means. We also present new estimates on the effect of plant stanol ester consumption on LDL-C levels and the risk of ASCVD events. Plant stanol esters as part of a heart-healthy diet plausibly offer a means to reduce the risk of ASCVD events at a population level. This approach is not only appropriate for subjects with a high risk of ASCVD, but also for subjects at an apparently lower risk to prevent subclinical atherosclerosis.