Daily Cardiology Research Analysis

BACKGROUND: Conventional statistical approaches are not designed to compare highly correlated variables such as low-density lipoprotein cholesterol (LDL-C), non-high density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (apoB). Discordance analysis was designed to overcome this limitation by creating groups in which the predictions of 2 markers differ. OBJECTIVE: This systematic review compiled all discordance studies that compare the predictive powers of LDL-C and non-HDL-C vs LDL particle number (LDL P) or apoB as markers of atherosclerotic disease risk to determine which is the most accurate marker of cardiovascular risk. METHODS: A PubMed search completed September 30, 2024, identified 15 studies involving 593,354 participants. These studies encompassed diverse populations, and included patients with and without statin therapy. Several variations of discordance analysis were used including median-based, percentile-based, residual-based, and variance-based approaches. RESULTS: ApoB outperformed LDL-C in 9 of 9 studies whereas LDL P was superior to LDL-C in 2 of 3 comparisons. In 1 study, non-HDL-C was superior to apoB, in 1 study apoB and non-HDL-C were equivalent, whereas in 7 studies, apoB, overall, was a significantly more accurate marker of atherosclerotic cardiovascular disease risk than non-HDL-C. CONCLUSION: Discordance analysis provides robust evidence that apoB is a more accurate marker of cardiovascular risk than either LDL-C or non-HDL-C, notwithstanding these variables are highly intercorrelated. Thus, neither LDL-C nor non-HDL-C are adequate clinical surrogates for apoB. Accordingly, apoB should be the primary measure in clinical care to estimate the cardiovascular risk attributable to the apoB lipoproteins and the adequacy of lipid-lowering therapy to reduce this risk.

BACKGROUND: Nexilin (NEXN)-related cardiomyopathies (CMPs) are largely unexplored. OBJECTIVES: This study investigated the causative role of NEXN in CMPs, examining its phenotypic expression and prognostic profile. METHODS: Twelve referral centers collected phenotypic/genotypic data of patients with NEXN variants. Variant rarity was determined according to gnomAD allele frequency in CMPs. Burden enrichment tested rare NEXN variants in hypertrophic (HCM) and dilated cardiomyopathy (DCM)/nondilated left ventricular cardiomyopathy (NDLVC) CMPs against gnomAD non-Finnish Europeans (NFE). Outcomes of validated variants were detailed, with prognostic comparisons to Titin (TTN)- and Filamin C (FLNC)-related CMP cohorts. RESULTS: Involving 60 NEXN carriers with rare, protein-altering variants, a significant enrichment of NEXN-truncating variants (tvs) was found in the DCM/NDLVC cohort (0.39% vs 0.09% in gnomAD NFE; P = 0.0001), whereas no association was observed with HCM. Patients with DCM/NDLVC with NEXNtv (n = 17; median age: 45 years [Q1-Q3: 36-55 years], 88% probands, 53% male) showed mild left ventricular dilatation (indexed end-diastolic volume 69 mL [Q1-Q3: 46-87 mL]), mildly reduced left ventricular ejection fraction (44% [Q1-Q3: 31%-53%]), and myocardial fibrosis (64%). NYHA functional class I was common (71%). During a 45-month median follow-up (Q1-Q3: 11-130 months), 53% of patients were implanted with an implantable cardioverter-defibrillator and 25% had malignant ventricular arrhythmias (MVAs). Compared with TTN-CMP, NEXN-CMP exhibited earlier and more frequent MVAs at higher ejection fractions, and no significant differences were found against FLNC-CMP. CONCLUSIONS: NEXNtvs were significantly associated with DCM/NDLVC, characterized by mild cardiac abnormalities, infrequent heart failure, common fibrosis, and arrhythmias. This largest NEXN variant carrier cohort to date contributes to defining the causative role of this rare genotype and its associated phenotype.

BACKGROUND: Aging is associated with adipose tissue alterations, oxidative stress, and fibrosis and the onset of cardiometabolic complications. While it has been shown that perivascular adipose tissue (PVAT) contributes to vascular damage, the involvement of subcutaneous adipose tissue (SCAT) - particularly through its secretory activity - in vascular aging remains poorly understood. Previously, we have demonstrated that human adipose-derived stromal cells (ASCs) from the SCAT of aged women display senescence and oxidative stress. We hypothesized that the ASC secretome contributes to the onset of endothelial dysfunction, an early stage of vascular aging. METHODS: We prepared conditioned media from ASCs isolated from SCAT of healthy young (< 25y) or aged (> 60y) women. The ASCs secretome was analyzed and added on human coronary artery endothelial cells (HCAECs). Using clinical cohorts, we evaluated the expression of C-C-chemokine-ligand-5 (CCL5)/Regulated upon-Activation-Normally-T-expressed-and-secreted (RANTES) in adipose tissue of individuals with coronary heart disease. RESULTS: The secretome of aged-donor ASCs induced endothelial cell dysfunction in HCAEC, as evidenced by lower nitric oxide production, higher oxidative stress, senescence, and a pro-adherent phenotype. Aged-donor ASCs also favored the endothelial-to-mesenchymal transition, characterized by the higher expression of mesenchymal markers, a pro-migratory profile and angiogenesis. We showed that the higher secretion of CCL5/RANTES in the secretome of aged- vs. young-donor ASCs and was responsible for these effects. Accordingly, CCL5/RANTES expression in SCAT, but not in epicardial adipose tissue, was associated with blood pressure in patients with coronary heart diseases, thus confirming the important role of SCAT in the onset of cardiometabolic disorders. CCL5’s ability to induce endothelial cell dysfunction and senescence was confirmed using a recombinant CCL5 and a CCL5/RANTES neutralizing antibody. Furthermore, we demonstrated that the CCL5/RANTES receptor antagonist drug maraviroc prevented the deleterious impact of CCL5/RANTES in both HCAECs and human cohorts. Thus, CCL5/RANTES secreted from SCAT during aging could contribute to endothelial dysfunction by exerting both local and systemic effects. CONCLUSIONS: Our results highlighted the ability of the CCL5/RANTES released from aging SCAT and, specifically, from adipose stromal cells, to induce endothelial dysfunction and senescence - both of which are early steps in vascular aging - as well as a potential link between these phenomena and hypertension in particular. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12933-025-02815-4.