Search Results (460)

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, with hypercholesterolemia identified as a major, but modifiable risk factor. This review serves as the second part of a comprehensive analysis of dyslipidemia management. The first installment laid the groundwork by detailing the key pathophysiological mechanisms of lipid metabolism, the development of atherosclerosis, major complications of hyperlipidemia, and the importance of cardiovascular risk assessment in therapeutic decision-making. It also examined non-pharmacological interventions and conventional therapies, with a detailed focus on statins and ezetimibe. Building upon that foundation, the present article focuses exclusively on emerging pharmacological therapies designed to overcome limitations of standard treatment. It explores the mechanisms, clinical applications, safety profiles, and pharmacogenetic aspects of novel agents such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (alirocumab, evolocumab), small interfering RNA (siRNA) therapy (inclisiran), adenosine triphosphate–citrate lyase (ACL) inhibitor (bempedoic acid), microsomal triglyceride transfer protein (MTP) inhibitor (lomitapide), and angiopoietin-like protein 3 (ANGPTL3) inhibitor (evinacumab). These agents offer targeted strategies for patients with high residual cardiovascular risk, familial hypercholesterolemia (FH), or statin intolerance. By integrating the latest advances in precision medicine, this review underscores the expanding therapeutic landscape in dyslipidemia management and the evolving potential for individualized care. Full article

Background: Aortic stenosis (AS) has long been considered a degenerative disease and is typically diagnosed in older men at an advanced stage. However, accumulating evidence has highlighted the similarities between AS and atherosclerosis, particularly regarding shared risk factors and overlapping pathophysiological mechanisms. This connection has led to a paradigm shift, suggesting that AS may be preventable in its early stages. Methods: This narrative review synthesizes the existing literature exploring the parallels between AS and atherosclerosis, focusing on common risk factors, pathogenic pathways, and evolving therapeutic strategies. Clinical trials and translational studies were examined to assess the effectiveness of atherosclerosis-based treatments for AS. Results: Multiple studies have confirmed the shared inflammatory, lipid-mediated, and calcific mechanisms of AS and atherosclerosis. Despite these similarities, therapeutic strategies effective in atherosclerosis, such as statin therapy, have not consistently shown benefits in AS. New medical approaches aim to delay aortic valve replacement and reduce the associated morbidity. The partially overlapping pathogenesis continues to guide future research. Conclusions: While AS and atherosclerosis share several pathogenic features, their clinical courses and treatment responses diverge. Understanding the limits and potential of their overlap may inform future preventive and therapeutic strategies. Earlier detection and targeted intervention in AS remain key goals, drawing on insights from cardiovascular disease management. Full article

Background: TGF-β is an immunosuppressive cytokine. Its signaling pathway plays a role in anti-inflammatory responses. Coronary artery disease (CAD) is a clinical consequence of atherosclerosis, which manifests as chronic inflammation and involves platelet mediators, including TGF-β. The aim of this study is to validate the diagnostic utility of TGF-β levels in relation to classical and molecular risk factors for CAD. Methods: The study group included 25 women and 75 men, all aged up to 55 and 50 years, respectively, who had been diagnosed with early-onset CAD. Fasting blood samples were taken to measure plasma levels of TGF-β, sCD36, PCSK9, TNF, VEGF, IL-6, and E-selectin using the ELISA method. Furthermore, a full lipid profile, apolipoproteins (Lp(a), ApoA1, and ApoB), C-reactive protein (hsCRP), and blood morphology were analyzed at the Central Hospital Laboratory. A physical examination was also performed. Results: Positive associations were observed between TGF-β concentration and TNF, platelet count, PTC, and triglyceride levels. TNF and platelet concentration were significant independent predictors of increased plasma TGF-β levels. None of the clinical parameters showed statistically significant associations with plasma TGF-β concentration. Conclusions: Our research has demonstrated that TGF-β levels, including circulating TNF, triglycerides, and platelets, are linked to specific biochemical risk factors in early-onset CAD cases. Full article

Background: Proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) has been reported to exhibit anti-neoplasm effects. However, the specific impacts remain uncertain. This study aims to evaluate the association between PCSK9i and the risk of neoplasm. Methods: Randomized controlled trials (RCTs) comparing PCSK9i with other lipid-lowering drugs or placebo in patients, which reported neoplasm events, were included. Data were sourced from PubMed, Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and the Clinicaltrial.gov website from the inception to June 2024. The primary endpoint was the association between PCSK9i and the risk of overall neoplasm events. Results: A total of 37 RCTs with 108,430 participants were included. PCSK9i treatment was associated with a lower risk of neoplasm compared to non-users (RR = 0.92, 95% CI, 0.85 to 0.99, I² = 0%). Subgroup analysis revealed a more prominent risk reduction of overall neoplasm in studies with female-dominant populations (male percentage < 50%, RR = 0.47, 95% CI, 0.27 to 0.82, I² = 0%), with a significant subgroup differences (p = 0.02). Meta-regression analysis also suggested that the lower percentage of males was associated with a decreased risk of neoplasms (β = 0.018, 95% CI, 0.0063, 0.031, p = 0.002). Meanwhile, the decreased risk of neoplasms was independent of LDL-c reduction. Conclusions: PCSK9i therapy was associated with reduced risk of overall neoplasm, especially in female-dominant populations. The benefits for lower risk of neoplasm with PCSK9i treatment were independent of LDL-c reduction. Full article

Background/Objectives: Cardiovascular diseases are a global health issue with an increasing burden and are exacerbated by hypertension. High blood pressure is partly attributed to genetic variants that are generally not well understood or extensively studied in sub-Saharan African populations. Variants linked to blood pressure have been found through genome-wide association studies (GWASs), which were mostly conducted among European ancestry populations; however, limited research has been undertaken in Africa. The current study evaluated single-nucleotide polymorphisms (SNPs) of PCSK9, ABCA1, LPL, and PON1 in relation to blood pressure measurements of 1839 Ghanaian adults. Methods: Genotypes were extracted from data generated by the H3Africa SNP array. After adjusting for sex, age, smoking, and body mass index (BMI), inferential statistics were used to investigate the relationships between SNPs and blood pressure (BP) indices. Additionally, Bonferroni correction was used to adjust for multiple testing. Results: Diastolic blood pressure (DBP) and the minor allele T of the PCSK9 variant (rs17111557) were positively associated at p = 0.006 after covariate adjustments. Although this novel DBP-associated variant is located in the 3′ untranslated region (3′ UTR) of the PCSK9 gene, in silico functional prediction suggests it is an expression quantitative trait locus (eQTL) that may change the binding site of transcription factors, potentially altering the rate of transcription and impacting DBP in this Ghanaian population. Conclusions: Our findings highlight the role of genetics in hypertension risk and the potential of discovering new therapies targeting isolated diastolic blood pressure in this rural African population. Full article

Kallmann syndrome (KS) is a form of hypogonadotropic hypogonadism (HH) characterized by gonadotropin-releasing hormone (GnRH) deficiency and anosmia due to defective neuronal migration. While traditionally considered irreversible, cases of spontaneous improvement of HH have been reported, suggesting residual GnRH neuronal function in some individuals. We present a case of a 29-year-old man with KS who exhibited spontaneous recovery of endogenous testosterone production following the cessation of long-term androgen therapy without the use of alternative hormonal agents. After ceasing testosterone therapy for several months, the patient’s total testosterone levels normalized (407–424 ng/dL), accompanied by increased secondary sexual characteristics, stable gonadotropin levels, and normal testicular volume. Persistent anosmia was noted, suggesting that restoration of reproductive endocrine function can occur independently of olfactory recovery. Genetic testing identified heterozygous mutations in PCSK1 and HS6ST1, genes implicated in GnRH regulation and KS pathogenesis. This case highlights the potential role of genetic variation in spontaneous HH improvement and underscores the need for individualized management strategies, including periodic reassessment of gonadal function and fertility potential. Further research is needed to elucidate the mechanisms driving spontaneous HH improvement, identify predictive biomarkers of reversibility, and explore therapeutic strategies that may promote endogenous GnRH activity in select patients with KS. Full article

Atherosclerosis is a complex disease characterized by pathological thickening of the arterial intima. The mechanisms underlying the induction and progression of atherosclerosis are convoluted and remain under active investigation, with key components such as lipid accumulation and local inflammation being identified. Several risk factors (e.g., metabolic disorders, genetic background, diet, infections) have been shown to exacerbate disease progression, but their roles as clinically relevant markers remain to be established. Despite the growing body of evidence on the molecular pathogenesis of atherosclerosis, there is no effective preventive treatment against the development of this disease. In this review, we focus on gene targets for gene therapy as a novel potential approach to cure and prevent atherosclerosis. We critically review recent research demonstrating the therapeutic potential of viral vector-based (adeno-associated virus (AAV) and lentivirus) gene therapy for the treatment of atherosclerosis. We also summarize alternative gene targets and approaches (e.g., non-coding RNA (ncRNA), micro RNA (miRNA), small interfering RNA (siRNA), antisense oligonucleotide (ASO), CRISPR/Cas9) that aim to limit disease progression. We highlight the importance of local inflammation in the pathogenesis of atherosclerosis and propose gene targets with anti-inflammatory activity to inhibit the pathological inflammatory response. In addition, we provide perspectives on the future development of gene therapeutics and their potential applications. We anticipate that recent advances in gene therapy will help to identify new and effective targets to prevent atherosclerosis. Full article

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of global morbidity and mortality, prompting significant interest in individualized prevention and treatment strategies. This review synthesizes recent advances in genomic and precision medicine approaches relevant to ASCVD, with a focus on genetic risk scores, lipid metabolism genes, and emerging gene editing techniques. A structured literature search was conducted across PubMed, Scopus, and Web of Science databases to identify key publications from the last decade addressing genomic mechanisms, therapeutic targets, and computational tools in ASCVD. Notable findings include the identification of causal genetic variants such as PCSK9 and LDLR, the development of polygenic risk scores for early prediction, and the use of deep learning algorithms for integrative multi-omics analysis. In addition, we highlight current and future therapeutic applications including PCSK9 inhibitors, RNA-based therapies, and CRISPR-based genome editing. Collectively, these advances underscore the promise of precision medicine in tailoring ASCVD prevention and treatment to individual genetic and molecular profiles. Full article

The design of small-molecule inhibitors targeting proprotein convertase subtilisin/Kein type 9 (PCSK9) remains a forefront challenge in combating atherosclerosis. While various monoclonal antibodies have achieved clinical success, small-molecule inhibitors are hindered by the unique structural features of the PCSK9 binding interface. In this study, a potential small-molecule inhibitor was identified through virtual screening, followed by molecular dynamics (MD) simulations to explore the binding mechanisms between the inhibitor and the PCSK9 protein. Binding free energies were calculated using molecular mechanics/Generalized Born surface area (MM/GBSA) with the interaction entropy (IE) method, and critical hot-spot residues were identified via alanine scanning analysis. Key residues, including ARG237, ILE369, ARG194 and PHE379, were revealed to form critical interactions with inhibitor and play dominant roles during the inhibitor’s binding. In addition, the polarization effect was shown to significantly influence PCSK9–ligand binding. The identified inhibitor exhibited highly similar binding patterns with two known active compounds, providing valuable insights for the rational design and optimization of small-molecule inhibitors targeting PCSK9. This work contributes to the development of more effective treatments for hyperlipidemia and associated cardiovascular diseases. Full article

High-density lipoprotein (HDL) and small dense low-density lipoprotein (sdLDL) represent two critical yet contrasting components in lipid metabolism and cardiovascular risk modulation. While HDL has traditionally been viewed as cardioprotective due to its role in reverse cholesterol transport and anti-inflammatory effects, emerging evidence emphasizes that HDL functionality—rather than concentration alone—is pivotal in atheroprotection. Conversely, sdLDL particles are increasingly recognized as highly atherogenic due to their enhanced arterial penetration, oxidative susceptibility, and prolonged plasma residence time. This review critically examined the physiological roles, pathological implications, and therapeutic interventions targeting HDL function and sdLDL burden. Lifestyle modifications, pharmacologic agents including statins, fibrates, PCSK9 inhibitors, and novel therapies such as icosapent ethyl were discussed in the context of their effects on HDL quality and sdLDL reduction. Additionally, current clinical guidelines were analyzed, highlighting a paradigm shift away from targeting HDL-C levels toward apoB-driven risk reduction. Although HDL-targeted therapies remain under investigation, the consensus supports focusing on lowering apoB-containing lipoproteins while leveraging lifestyle strategies to improve HDL functionality. In the setting of heart failure, particularly with preserved ejection fraction (HFpEF), alterations in HDL composition and elevated sdLDL levels have been linked to endothelial dysfunction and systemic inflammation, further underscoring their relevance beyond atherosclerosis. A comprehensive understanding of HDL and sdLDL dynamics is essential for optimizing cardiovascular prevention strategies. Full article

Cardiotoxicity related to anthracyclines and trastuzumab represents a significant clinical challenge in cancer therapy, often limiting treatment efficacy and patient survival. The underlying mechanisms of cardiotoxicity involve the activation of NLRP3 and the MyD88-dependent signaling pathway. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), such as inclisiran, are known for their lipid-lowering effects, but emerging data indicate that they may also exert pleiotropic benefits beyond cholesterol reduction. This study investigates whether inclisiran can mitigate the cardiotoxic effects of anthracyclines and trastuzumab through reduction of NLRP3 activation and MyD88 signaling, independently of its effects on dyslipidemia. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were exposed to subclinical concentrations of doxorubicin (1 µM) and trastuzumab in sequential therapy (200 nM), alone or in combination with inclisiran (100 nM) for 24 h. After the incubation period, we performed the following tests: determination of cardiomyocytes apoptosis, analysis of intracellular reactive oxygen species, lipid peroxidation products (including malondialdehyde and 4-hydroxynonenal), intracellular mitofusin-2 and Ca⁺⁺ levels. Troponin and BNP were quantified through selective ELISA methods. A confocal laser scanning microscope was used to study cardiomyocyte morphology and F-actin staining after treatments. Moreover, pro-inflammatory studies were also performed, including the intracellular expression of NLRP-3, MyD-88 and twelve cytokines/growth factors involved in cardiotoxicity (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IFN-γ, TNF-α, G-CSF, GM-CSF). Inclisiran co-incubated with doxorubicin and trastuzumab exerts significant cardioprotective effects, enhancing cell viability by 88.9% compared to only DOXO/TRA treated cells (p < 0.001 for all). Significant reduction of oxidative stress, and intracellular levels of NLRP-3, MyD88, IL-1α, IL-1β, IL-6, IL-12, IL17-α, TNF-α, G-CSF were seen in the inclisiran group vs. only DOXO/TRA (p < 0.001). For the first time, PCSK9i inclisiran has been shown to exert significant anti-inflammatory effects to reduce anthracycline-HER-2 blocking agent-mediated cardiotoxicity through NLRP-3 and Myd-88 related pathways. The overall conclusions of the study warrant further investigation of the use of PCSK9i in primary prevention of CTRCD in cancer patients, independently from dyslipidemia. Full article

Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more consecutive pregnancy losses before 20 weeks of gestation, encompassing both embryonic and fetal losses. Although previous studies have provided substantial insights into RPL, the causes in many cases remain unexplained. This lack of information has prompted continued investigation into various risk factors, including those identified through next-generation sequencing (NGS). In the present study, whole-exome sequencing (WES) was used to identify genes potentially associated with RPL and infertility, which may serve as novel biomarkers. Confirmation of the association between these genetic variants and RPL may help to develop functional biomarkers for early diagnosis. The findings revealed that the PCSK5 rs1110222 G > A polymorphism was significantly associated with a reduced risk of RPL. In contrast, the MUC2 rs10902088 C > T polymorphism was associated with an increased risk of RPL among women with more than four pregnancy losses. Notably, the A-T allele combination of PCSK5 rs1110222 G > A and MUC2 rs10902088 C > T showed a significant association with a decreased risk of RPL relative to the G-C combination. In conclusion, this study confirms that the PCSK5 rs1110222 G > A and MUC2 rs10902088 C > T polymorphisms are genetically associated with the prevalence of RPL in Korean women. Full article

Earthworms are valued as a dietary protein source in many regions. Earthworm protein can yield bioactive peptides, but enzymatic hydrolysis is inefficient by commercial proteases, and bioactivity development is still inadequate. This study developed a novel efficient method for degrading earthworm protein and investigated the lipid-lowering activity and mechanism of earthworm peptides. It was found that combining autolysis and alcalase exhibited a higher hydrolysis degree of earthworm protein of 43.64 ± 0.78% compared to using autolysis or alcalase only. The hydrolysate significantly reduced lipid accumulation in steatotic hepatocytes. LC-MS/MS results showed that the primary lipid-lowering peptides (EWPs) in the hydrolysate were small molecule peptides with molecular weights of 500–1000 Da and chain lengths of 4–7 amino acid residues. Western blot results demonstrated that EWP regulated the expression of lipid metabolism-related proteins, including APOC3, HMGCR, PCSK9, SREBP1, C/EBP-α, NPC1L1, PPAR-γ, and CYP7A1. Transcriptomic analysis and validation experiments indicated that the lipid-lowering activity of EWP was associated with its suppression of inflammatory factors, such as IL-6. This study presents an efficient enzymatic hydrolysis strategy for earthworm protein utilization, laying the foundation for its application in functional foods such as protein supplements, nutraceutical capsules, hypoallergenic infant formulas, and sports nutrition products. Full article

Background: The advent of newer pharmacological agents, particularly proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors, in combination with conventional lipid-lowering treatments, has allowed for the significant lowering of low-density lipoprotein cholesterol (LDL-C). However, it is unclear if very low LDL-C levels achieved with the use of PCSK-9 inhibitors are associated with increased adverse events that may outweigh potential benefits. Methods: A systematic search of PubMed, Medline, and Cochrane databases was conducted from their inception to 21 February 2025, for randomized controlled trials (RCTs) reporting clinical outcomes with intensive lipid-lowering treatment with PCSK-9 inhibitors leading to very low (<40 mg/dL) LDL-C levels vs. a control group with higher LDL-C levels. The outcomes of interest included the incidence of major adverse cardiovascular events (MACEs), neurocognitive disorders, diabetes mellitus, muscle disorders, any adverse events, events leading to drug discontinuation, cataract, hepatobiliary disorders, and cancer. Random effects meta-analysis models were used to calculate the pooled incidence and odds ratio (OR) with 95% confidence intervals (Cis). Results: A total of six RCTs with 52,951 patients (11,209 very low LDL-C, and 41,742 control) met the inclusion criteria. Compared with patients in the control arm, very low LDL-C was associated with a reduction in MACEs (OR = 0.76, 95% CI: 0.64, 0.89; p < 0.01; I² = 44.8%). The incidence of most safety outcomes including neurocognitive disorders, diabetes mellitus, muscle disorders, any adverse events, events leading to drug discontinuation, cataract, hepatobiliary disorders, and cancer were comparable between the very low LDL-C and control groups. Conclusions: Very low LDL-C values following intensive lipid-lowering with PCSK-9 inhibitors are associated with a major reduction in cardiovascular events without any significant increase in serious side effects. Full article

Coronary atherosclerosis (CAS) is a major cause of cardiovascular morbidity worldwide. The understanding of atherosclerosis has shifted from a cholesterol deposition disorder to an inflammation-driven disease, with anti-inflammatory therapies demonstrating clinical efficacy. Identifying inflammatory protein targets is crucial for developing targeted therapies. A proteome-wide Mendelian randomization (MR) analysis was performed to explore therapeutic targets for CAS by integrating inflammatory proteomics data from the UK-PPP (54,219 participants, 2923 proteins) and Iceland cohorts (35,559 participants, 4907 proteins) as exposures and outcome data for CAS, atherosclerosis, and carotid atherosclerosis from FinnGen. Replication MR employed meta-analysis of six proteomics datasets and CAS data from three sources, while the impact of the identified proteins on four cardiovascular diseases was also investigated. Colocalization analysis (PPH₄ > 0.9), reverse MR, and SMR were used to ensure robust causal inference. Proteome-wide MR identified 11 proteins significantly associated with CAS (p < 3.52 × 10⁻⁵), with all but CD4 linked to cardiovascular disease risk. Notably, colocalization confirmed the causal roles of PCSK9, IL6R, CELSR2, FN1, and SPARCL1 in CAS, and single-cell RNA-seq analysis revealed that five genes (TGFB1, SPARCL1, IL6R, FN1, and CELSR2) were exclusively expressed in smooth muscle cells of either coronary plaques or healthy vasculature. Druggability assessments were subsequently conducted for these targets. The three most promising targets (CELSR2, FN1, and SPARCL1), along with the other identified proteins and their biological functions, exhibit robust causal associations with CAS. FN1 and TGFB1 have the potential for drug repurposing in atherosclerosis treatment. Full article