Gianni Biolo

Cardiovascular disease (CVD) is still a leading cause of morbidity and mortality, despite all the progress achieved as regards to both prevention and treatment. Having high levels of lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease that operates independently. It can increase the risk of developing cardiovascular disease even when LDL cholesterol (LDL-C) levels are within the recommended range, which is referred to as residual cardiovascular risk. Lp(a) is an LDL-like particle present in human plasma, in which a large plasminogen-like glycoprotein, apolipoprotein(a) [Apo(a)], is covalently bound to Apo B100 via one disulfide bridge. Apo(a) contains one plasminogen-like kringle V structure, a variable number of plasminogen-like kringle IV structures (types 1–10), and one inactive protease region. There is a large inter-individual variation of plasma concentrations of Lp(a), mainly ascribable to genetic variants in the Lp(a) gene: in the general po-pulation, Lp(a) levels can range from <1 mg/dL to >1000 mg/dL. Concentrations also vary between different ethnicities. Lp(a) has been established as one of the risk factors that play an important role in the development of atherosclerotic plaque. Indeed, high concentrations of Lp(a) have been related to a greater risk of ischemic CVD, aortic valve stenosis, and heart failure. The threshold value has been set at 50 mg/dL, but the risk may increase already at levels above 30 mg/dL. Although there is a well-established and strong link between high Lp(a) levels and coronary as well as cerebrovascular disease, the evidence regarding incident peripheral arterial disease and carotid atherosclerosis is not as conclusive. Because lifestyle changes and standard lipid-lowering treatments, such as statins, niacin, and cholesteryl ester transfer protein inhibitors, are not highly effective in reducing Lp(a) levels, there is increased interest in developing new drugs that can address this issue. PCSK9 inhibitors seem to be capable of reducing Lp(a) levels by 25–30%. Mipomersen decreases Lp(a) levels by 25–40%, but its use is burdened with important side effects. At the current time, the most effective and tolerated treatment for patients with a high Lp(a) plasma level is apheresis, while antisense oligonucleotides, small interfering RNAs, and microRNAs, which reduce Lp(a) levels by targeting RNA molecules and regulating gene expression as well as protein production levels, are the most widely explored and promising perspectives. The aim of this review is to provide an update on the current state of the art with regard to Lp(a) pathophysiological mechanisms, focusing on the most effective strategies for lowering Lp(a), including new emerging alternative therapies. The purpose of this manuscript is to improve the management of hyperlipoproteinemia(a) in order to achieve better control of the residual cardiovascular risk, which remains unacceptably high.

Physical inactivity increases cardiometabolic risk through a variety of mechanisms, among which alterations of immunological, metabolic, and autonomic control systems may play a pivotal role. Physical inactivity is frequently associated with other factors that may further worsen prognosis. The association between physical inactivity and hypoxia is particularly interesting and characterizes several conditions—whether physiological (e.g., residing or trekking at high altitude and space flights) or pathological (e.g., chronic cardiopulmonary diseases and COVID-19). In this randomized intervention study, we investigated the combined effects of physical inactivity and hypoxia on autonomic control in eleven healthy and physically active male volunteers, both at baseline (ambulatory) conditions and, in a randomized order, hypoxic ambulatory, hypoxic bedrest, and normoxic bedrest (i.e., a simple experimental model of physical inactivity). Autoregressive spectral analysis of cardiovascular variabilities was employed to assess cardiac autonomic control. Notably, we found hypoxia to be associated with an impairment of cardiac autonomic control, especially when combined with bedrest. In particular, we observed an impairment of indices of baroreflex control, a reduction in the marker of prevalent vagal control to the SA node, and an increase in the marker of sympathetic control to vasculature.