👤 Michael V Zaragoza

A significant proportion of patients continue to experience cardiovascular (CV) events despite achieving recommended low-density lipoprotein cholesterol (LDL-C) targets, a phenomenon referred to as residual CV risk. Clinical evidence from large outcome trials highlights the impact of residual risk on cardiovascular disease (CVD) burden, underscoring the need for therapeutic strategies beyond LDL-C lowering. Residual CV risk arises from diverse mechanisms, including persistent atherogenic dyslipidaemia [elevated triglyceride-rich lipoproteins (TRL), high triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C) levels and increased apolipoprotein B (ApoB), Lipoprotein(a) (Lp[a]) and non-HDL-C], chronic inflammation, metabolic disorders and a prothrombotic state. These abnormalities continue to drive atherosclerotic progression in optimally treated patients, underscoring that managing residual CV risk requires a multifaceted approach. Lifestyle and dietary interventions remain foundational, targeting weight reduction, smoking cessation or adoption of a Mediterranean diet. Pharmacological options include statins (as first-line therapy), or the use of ezetimibe, or bempedoic acid since they both have complementary effects to LDL-C lowering. Emerging therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein C-III (ApoC3) and angiopoietin-like 3 (ANGPTL3) inhibitors, demonstrate potential efficacy in favourably modulating lipid profiles and targeting specific components of atherogenic dyslipidaemia (AD). Combination therapies tailored to individual lipid profiles show promise to reduce residual CV risk. The following review aims to provide a comprehensive overview of the latest evidence on the factors driving residual CV risk and the therapeutic interventions available to treat atherogenic dyslipidaemia beyond LDL-C reduction. Show less

(1) Background: Early response after acute myocardial infarction (AMI) prevents extensive cardiac necrosis, in which inflammation resolution, including expression of anti-inflammatory interleukin-10 (IL-10), may play a key role. (2) Methods: We synthesized NIL10, a micelle-based nanoparticle, to target IL-10 receptor in mice and pigs subjected to AMI. (3) Results: Administration of NIL10 induced cardiac protection of wild-type and IL-10 knockout mice and pigs subjected to AMI. Cardiac protection was not induced in IL-10-receptor null mice, as shown by a significant recovery of cardiac function, in which inflammatory foci and fibrosis were strongly reduced, together with the finding that resolving M2-like macrophage populations were increased after day 3 of reperfusion. In addition, anti-inflammatory cytokines, including IL-4, IL-7, IL-10, IL-13, IL-16, and IL-27 were also elevated. Mechanistically, NIL10 induced activation of the IL-10 receptor/STAT-3 signaling pathway, and STAT3-dependent inhibition of nuclear translocation of pro-inflammatory NF-ĸB transcription factor. (4) Conclusions: Taken together, we propose using NIL10 as a novel therapeutic tool against AMI-induced cardiac damage. Show less

Toll-like receptor 4 (TLR4) contributes to the pathogenesis of coronary ischemia/reperfusion (IR). To test whether the new TLR4 antagonist, ApTOLL, may prevent coronary IR damage, we administered 0.078 mg/kg ApTOLL or Placebo in pigs subjected to IR, analyzing the levels of cardiac troponins, matrix metalloproteinases, pro-, and anti-inflammatory cytokines, heart function, and tissue integrity over a period of 7 days after IR. Our results show that ApTOLL reduced cardiac troponin-1 24 h after administration, improving heart function, as detected by a significant recovery of the left ventricle ejection fraction (LVEF) and the shortening fraction (FS) cardiac parameters. The extension of necrotic and fibrotic areas was also reduced, as detected by Evans blue/2,3,5-triphenyltetrazolium chloride (TTC) staining, Hematoxylin/Eosine, and Masson Trichrome staining of heart sections, together with a significant reduction in the expression of the extracellular matrix-degrading, matrix metalloproteinase 9. Finally, the expression of the following cytokines, CCL1, CCL2, MIP1-A-B, CCL5, CD40L, C5/C5A, CXCL1, CXCL10, CXCL11, CXCL12, G-CSF, GM-CSF, ICAM-1, INF-g, IL1-a, ILI-b, IL-1Ra, IL2, IL4, IL5, IL6, IL8, IL10, IL12, IL13, IL16, IL17-A, IL17- E, IL18, IL21, IL27, IL32, MIF, SERPIN-E1, TNF-a, and TREM-1, were also assayed, detecting a pronounced decrease of pro-inflammatory cytokines after 7 days of treatment with ApTOLL. Altogether, our results show that ApTOLL is a promising new tool for the treatment of acute myocardial infarction (AMI). Show less

The goals are to understand the primary genetic mechanisms that cause Sick Sinus Syndrome and to identify potential modifiers that may result in intrafamilial variability within a multigenerational family. The proband is a 63-year-old male with a family history of individuals (>10) with sinus node dysfunction, ventricular arrhythmia, cardiomyopathy, heart failure, and sudden death. We used exome sequencing of a single individual to identify a novel LMNA mutation and demonstrated the importance of Sanger validation and family studies when evaluating candidates. After initial single-gene studies were negative, we conducted exome sequencing for the proband which produced 9 gigabases of sequencing data. Bioinformatics analysis showed 94% of the reads mapped to the reference and identified 128,563 unique variants with 108,795 (85%) located in 16,319 genes of 19,056 target genes. We discovered multiple variants in known arrhythmia, cardiomyopathy, or ion channel associated genes that may serve as potential modifiers in disease expression. To identify candidate mutations, we focused on ~2,000 variants located in 237 genes of 283 known arrhythmia, cardiomyopathy, or ion channel associated genes. We filtered the candidates to 41 variants in 33 genes using zygosity, protein impact, database searches, and clinical association. Only 21 of 41 (51%) variants were validated by Sanger sequencing. We selected nine confirmed variants with minor allele frequencies <1% for family studies. The results identified LMNA c.357-2A>G, a novel heterozygous splice-site mutation as the primary mutation with rare or novel variants in HCN4, MYBPC3, PKP4, TMPO, TTN, DMPK and KCNJ10 as potential modifiers and a mechanism consistent with haploinsufficiency. Show less

Noncompaction of the left ventricle is a descriptive anatomical term and recently recognized primary cardiomyopathy. Cardiac imaging now allows for prompt detection. The specific etiology remains poorly understood, however, and the major genetic determinants are unknown. This review describes recent data showing the genetic heterogeneity and overlap with other cardiomyopathies. Understanding the genetics may depend on clarifying the distinctive diagnostic features and investigating the contribution of all known cardiomyopathy-causing genes with overlapping morphology. Adding to the known genes (TAZ, DTNA, LDB3 and LMNA), recent work has identified SCN5A, MYH7 and MYBPC3 as associated loci. LDB3 may also be a genetic modifier. Case reports and linkage studies suggest additional loci at 1p36, 1q43 and 11p15. Aside from Barth syndrome, other genetic and metabolic syndromes with noncompaction have been described. Despite this, large studies have failed to identify the etiology in the majority of patients. Despite advances in detection, comprehensive clinical, pathological, genetic, and family studies are necessary to define the phenotypic overlap with other cardiomyopathies. Without a more precise understanding of its etiology, the answers to the questions regarding the clinical relevance and management of patients with noncompaction of the left ventricle will remain elusive. Show less