Introduction Although novel drugs have successfully entered the clinical arena of heart failure with reduced ejection fraction (HFrEF), such as the PARADIGM-HF-derived angiotensin receptor neprilysin inhibitor (ARNI), disease-modifying therapies with a prognostic impact for patients affected by heart failure with preserved ejection fraction (HFpEF) are still lacking.15 HF is a complex and highly prevalent syndrome for which the heart undergoes a substantial structural remodeling in patients at risk for major cardiovascular diseases (CVDs) (Figure 1).16 Geneenvironment interactions can be mediated by specific patterns of epigenetic-sensitive changes (mainly DNA methylation and histone modifications) which may modulate the individual responsiveness to HF development.614 This complex molecular circuit seems to trigger early cardiomyocyte loss, cardiac-remodeling, and micro- and macrovascular damage contributing to the development of major CVDs which may lead to differential HF clinical phenotypes.614 Of note, the reversible nature of epigenetic-sensitive changes has been translated in the clinical management of specific hematological malignancies with the approval by the Food and Drug Administration (FDA) of some epidrugs, such as decitabine (Dacogen) and azacitidine (Vidaza), as DNA methylation inhibitors, as well as vorinostat (Zolinza), belinostat (Beleodaq), romidepsin (Istodax), and panobinostat (Farydak), as histone deacetylase inhibitors (HDACi).15 Epidrugs are now providing a novel vision for personalized therapy of HF and heart transplantation, opening up novel options for management of the affected patients.1518 At molecular level, we can classify the epidrugs in: direct epidrugs [eg, the bromodomain and extra-terminal (BET) protein inhibitor apabetalone]; and repurposed drugs with potential, indirect (non-classical) epigenetic-oriented interference by which they may exert cardioprotective functions [eg, hydralazine, metformin, statins, and sodium-glucose co-transporter-2 inhibitors (SGLT2i)] or nutraceutical compounds [eg, omega-3 polyunsaturated fatty acids (PUFAs)]. Encouraging results are coming from large randomized trials evaluating the putative beneficial effects of combining epidrugs with the conventional therapy in patients with HF.1422 Our goal is to update on the emerging epigenetic-based strategies which may be useful in the prevention and treatment of HFrEF and HFpEF (Figure 1). Continue reading →

In this week's column we will address a vexing cause of death and recommend ways for individuals to assess their risks and that of their immediate family members, and take steps to mitigate those risks. Sudden death is a worrisome event that leaves families devasted and confused, especially when this occurs in otherwise healthy young individuals. While many causes of sudden death are yet to be properly understood, common causes are often cardiovascular in origin and measures exist that can be taken to identify individuals at increased risk and steps taken to reduce such risks for these individuals. Continue reading →

Introduction Diabetes mellitus (DM) is an immunological disease characterized by metabolic dysregulation and chronic inflammation.1 However, hyperglycemia is commonly associated with the generation of ROS and the formation of AGEs.24 Chronic and low-grade inflammation has been related to hyperglycemia in diabetes. Programmed cell death plays a significant role in the hosts advancement and survival in the bodys defensive mechanism against several microbial infections.58 Apoptosis, necrosis, pyroptosis, ferroptosis, autophagy, and efferocytosis are the most common cell death mechanisms.914 Apoptosis is the most widely studied, while the research of pyroptosis is neither comprehensive nor concrete. Apoptosis-mediated cell death regulates multicellular organism development.9 Notably, the apoptosis-mediated cell death mechanism predominantly impairs single cells and appears without any inflammatory responses.15 Apoptosis is induced by the cell surface death-receptor stimulation, exogenous, mitochondrial, and ER stress-regulated signaling pathways facilitating caspases initiation.1619 In apoptosis-mediated cell death, cells shrink and are fragmented into apoptotic bodies engulfed by surrounding macrophages, leading to cell deaths non-inflammatory nature.20 Inhibiting the apoptotic caspase-8 due to pro-apoptotic stimulus initiates necroptosis-regulated cell death through the receptor-interacting serine/threonine-protein kinase 1 (RIPK1)RIPK3-mixed lineage kinase domain-like (MLKL) axis.21 Mounting evidence shows that RIPK3-phosphorylated MLKL changes to the membrane to accomplish membrane rupture, promoting cell swelling as well as lysis.2225 Pyroptosis is programmed necrosis, which regulates a common innate immune effector mechanism in invertebrates.26,27 Significantly, the innate immune response depends on PRRs to sense and recognize several microbial products or endogenous danger signals.28 Stimulating cytokine transcription and inducing PRRs cause pyroptosis to promote inflammatory response.29 Pyroptosiss immune defense functions are increased by disrupting the pathogen replication niche and directly invading intracellular bacteria through pore-stimulated intracellular traps.30,31 For a long time, pyroptosis has been described as a caspase-1-dependent monocyte cell death mechanism.32 Caspase-1 belongs to the inflammatory caspase family group, which processes pro-IL-1 and IL-18 into mature IL-1 and IL-18 pro-inflammatory factors.33,34 These pro-inflammatory factors nature discriminate pyroptosis from apoptosis despite the dependency on caspases.35,36 Indeed, pyroptosis is lytic, attributing cell rupture and swelling and many bubbles blowing on the plasma membrane.28,37,38 Our narrative review highlights the current understanding and knowledge of the molecular mechanism of pyroptosis-mediated cell death and the potential role of inflammasome and pyroptosis in diabetes mellitus and its complications Continue reading →