Proprotein convertase subtilisin/kexin type 9 (PCSK9) has a crucial role in lipid metabolism, particularly due to its function in low‐density lipoprotein receptor degradation. Gain‐of‐function ...genetic mutations of PCSK9 result in autosomal dominant familial hypercholesterolemia, characterized by high levels of low‐density lipoprotein cholesterol (LDL‐C) and clinical signs of early atherosclerosis. In recent years, PCSK9 has become an important therapeutic target for cholesterol‐lowering therapy. Particularly, its inhibition with monoclonal antibodies has shown excellent efficacy in decreasing LDL‐C and reducing cardiovascular events. However, PCSK9, first identified in the brain, seems to be a ubiquitous protein with different tissue‐specific functions also independent of cholesterol metabolism. Accordingly, it appears to be involved in the immune response, haemostasis, glucose metabolism, neuronal survival, and several other biological functions. This review provides a comprehensive overview of the genetics, biochemical structure, expression, and function of PCSK9 and discusses the potential implications of its long‐term pharmacological inhibition.
Lipoprotein(a) Lp(a) is an established cardiovascular risk factor, and growing evidence indicates its causal association with atherosclerotic disease because of the proatherogenic low-density ...lipoprotein (LDL)-like properties and the prothrombotic plasminogen-like activity of apolipoprotein(a) apo(a). As genetics significantly influences its plasma concentration, Lp(a) is considered an inherited risk factor of atherosclerotic cardiovascular disease (ASCVD), especially in young individuals. Moreover, it has been suggested that elevated Lp(a) may significantly contribute to residual cardiovascular risk in patients with coronary artery disease and optimal LDL-C levels. Nonetheless, the fascinating hypothesis that lowering Lp(a) could reduce the risk of cardiovascular events - in primary or secondary prevention - still needs to be demonstrated by randomized clinical trials. To date, no specific Lp(a)-lowering agent has been approved for reducing the lipoprotein levels, and current lipid-lowering drugs have limited effects. In the future, emerging therapies targeting Lp(a) may offer the possibility to further investigate the relation between Lp(a) levels and cardiovascular outcomes in randomized controlled trials, ultimately leading to a new era in cardiovascular prevention. In this review, we aim to provide an updated overview of current evidence on Lp(a) as well as currently investigated therapeutic strategies that specifically address the reduction of the lipoprotein.
Desmosomes in heart and skin: friends or foes? Caiazzo, Giuseppina; De Simone, Rosa Redenta; Monda, Emanuele ...
Journal of translational medicine,
04/2024, Volume:
22, Issue:
1
Journal Article
Cardiomyopathies (CMPs) represent a diverse group of heart muscle diseases, grouped into specific morphological and functional phenotypes. CMPs are associated with mutations in sarcomeric and ...non-sarcomeric genes, with several suspected epigenetic and environmental mechanisms involved in determining penetrance and expressivity. The understanding of the underlying molecular mechanisms of myocardial diseases is fundamental to achieving a proper management and treatment of these disorders. Among these, inflammation seems to play an important role in the pathogenesis of CMPs. The aim of the present study is to review the current knowledge on the role of inflammation and the immune system activation in the pathogenesis of CMPs and to identify potential molecular targets for a tailored anti-inflammatory treatment.
Hypertrophic cardiomyopathy (HCM) is a myocardial disorder characterized by left ventricular (LV) hypertrophy, which cannot be entirely attributed to loading conditions such as valve or congenital ...heart disease or hypertension ...
Sudden cardiac death (SCD) is a devastating event which can also affect people in apparent good health, such as young athletes. It is known that intense and continuous exercise along with a genetic ...background that predisposes a person to the risk of fatal arrhythmias is a trigger for SCD. Therefore, knowledge of the athlete's genetic conditions underlying the onset of SCD must be extended, in order to develop new effective prevention and/or therapeutic strategies. Arrhythmic features occur across a broad spectrum of cardiac diseases, sometimes presenting with overlapping phenotypes. The genetic basis of arrhythmogenic disorders has been greatly highlighted in the last 30 years, and has shown marked heterogeneity. The advent of next-generation sequencing has constantly updated our understanding of the genetic basis of arrhythmogenic diseases and is laying the foundation for precision medicine. With the exception of a few clinical cases involving a single athlete showing a highly suspected phenotype for the presence of a heart disease, there are few studies to date that analysed the applicability of genetic testing on cohorts of athletes. This evidence shows that genetic testing can contribute to the diagnosis of up to 13% of athletes; however, the presence of clinical markers is essential. This review aims to provide a reference collection on current knowledge of the genetic basis of sudden cardiac death in athletes and to review updated evidence on the effectiveness of genetic testing in early identification of athletes at risk for SCD.
Cardiomyopathies are mostly determined by genetic mutations affecting either cardiac muscle cell structure or function. Nevertheless, cardiomyopathies may also be part of complex clinical phenotypes ...in the spectrum of neuromuscular (NMD) or mitochondrial diseases (MD). The aim of this study is to describe the clinical, molecular, and histological characteristics of a consecutive cohort of patients with cardiomyopathy associated with NMDs or MDs referred to a tertiary cardiomyopathy clinic. Consecutive patients with a definitive diagnosis of NMDs and MDs presenting with a cardiomyopathy phenotype were described. Seven patients were identified: two patients with ACAD9 deficiency (
carried the c.1240C>T (p.Arg414Cys) homozygous variant in
;
carried the c.1240C>T (p.Arg414Cys) and the c.1646G>A (p.Ar549Gln) variants in
); two patients with
-related myopathy (
carried the c.1325G>A (p.Arg442His) variant in
;
carried the c.1357C>T (p.Arg453Cys) variant in
); one patient with desminopathy (
carried the c.46C>T (p.Arg16Cys) variant in
); two patients with mitochondrial myopathy (
carried the m.3243A>G variant in
;
carried the c.253G>A (p.Gly85Arg) and the c.1055C>T (p.Thr352Met) variants in
). All patients underwent a comprehensive cardiovascular and neuromuscular evaluation, including muscle biopsy and genetic testing. This study described the clinical phenotype of rare NMDs and MDs presenting as cardiomyopathies. A multidisciplinary evaluation, combined with genetic testing, plays a main role in the diagnosis of these rare diseases, and provides information about clinical expectations, and guides management.
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