European Heart Journal最新文献

Background and aims: Baseline cardiovascular toxicity risk stratification is critical in cardio-oncology. The Heart Failure Association (HFA) and International Cardio-Oncology Society (ICOS) score aims to assess this risk but lacks real-life validation. This study validates the HFA-ICOS score for anthracycline-induced cardiovascular toxicity.

Methods: Anthracycline-treated patients in the CARDIOTOX registry (NCT02039622) were stratified by the HFA-ICOS score. The primary endpoint was symptomatic or moderate to severe asymptomatic cancer therapy-related cardiac dysfunction (CTRCD), with all-cause mortality and cardiovascular mortality as secondary endpoints.

Results: The analysis included 1066 patients (mean age 54 ± 14 years; 81.9% women; 24.5% ≥65 years). According to the HFA-ICOS criteria, 571 patients (53.6%) were classified as low risk, 333 (31.2%) as moderate risk, 152 (14.3%) as high risk, and 10 (0.9%) as very high risk. Median follow-up was 54.8 months (interquartile range 24.6-81.8). A total of 197 patients (18.4%) died, and 718 (67.3%) developed CTRCD (symptomatic: n = 45; moderate to severe asymptomatic: n = 24; and mild asymptomatic: n = 649). Incidence rates of symptomatic or moderate to severe symptomatic CTRCD and all-cause mortality significantly increased with HFA-ICOS score [hazard ratio 28.74, 95% confidence interval (CI) 9.33-88.5; P < .001, and hazard ratio 7.43, 95% CI 3.21-17.2; P < .001) for very high-risk patients. The predictive model demonstrated good calibration (Brier score 0.04, 95% CI 0.03-0.05) and discrimination (area under the curve 0.78, 95% CI 0.70-0.82; Uno's C-statistic 0.78, 95% CI 0.71-0.84) for predicting symptomatic or severe/moderate asymptomatic CTRCD at 12 months.

Conclusions: The HFA-ICOS score effectively categorizes patients by cardiovascular toxicity risk and demonstrates strong predictive ability for high-risk anthracycline-related cardiovascular toxicity and all-cause mortality.

Background and aims: The role of vascular smooth muscle cells (SMCs) in atherosclerosis has evolved to indicate causal genetic links with the disease. Single cell RNA sequencing (scRNAseq) studies have identified multiple cell populations of mesenchymal origin within atherosclerotic lesions, including various SMC sub-phenotypes, but it is unknown how they relate to patient clinical parameters and genetics. Here, mesenchymal cell populations in atherosclerotic plaques were correlated with major coronary artery disease (CAD) genetic variants and functional analyses performed to identify SMC markers involved in the disease.

Methods: Bioinformatic deconvolution was done on bulk microarrays from carotid plaques in the Biobank of Karolinska Endarterectomies (BiKE, n = 125) using public plaque scRNAseq data and associated with patient clinical data and follow-up information. BiKE patients were clustered based on the deconvoluted cell fractions. Quantitative trait loci (QTLs) analyses were performed to predict the effect of CAD associated genetic variants on mesenchymal cell fractions (cfQTLs) and gene expression (eQTLs) in plaques.

Results: Lesions from symptomatic patients had higher fractions of Type 1 macrophages and pericytes, but lower fractions of classical and modulated SMCs compared with asymptomatic ones, particularly females. Presence of diabetes or statin treatment did not affect the cell fraction distribution. Clustering based on plaque cell fractions, revealed three patient groups, with relative differences in their stability profiles and associations to stroke, even during long-term follow-up. Several single nucleotide polymorphisms associated with plaque mesenchymal cell fractions, upstream of the circadian rhythm gene ARNTL were identified. In vitro silencing of ARNTL in human carotid SMCs increased the expression of contractile markers and attenuated cell proliferation.

Conclusions: This study shows the potential of combining scRNAseq data with vertically integrated clinical, genetic, and transcriptomic data from a large biobank of human plaques, for refinement of patient vulnerability and risk prediction stratification. The study revealed novel CAD-associated variants that may be functionally linked to SMCs in atherosclerotic plaques. Specifically, variants in the ARNTL gene may influence SMC ratios and function, and its role as a regulator of SMC proliferation should be further investigated.