The impact of myocardial fibrosis biomarkers in a heart failure population with atrial fibrillation—The HARVEST-Malmö study

Abstract

BackgroundSeveral studies suggest that circulating biomarkers of myocardial fibrosis are associated with worse prognosis in subjects with atrial fibrillation (AF). Here, we aimed to explore associations between fibrosis biomarkers, prevalent AF, and left atrial volume (LAV) enlargement in subjects with heart failure (HF). Additionally, we evaluated the prognostic impact of fibrotic biomarkers in HF with co-existing AF.Materials and methodsPatients hospitalized for HF (n = 316, mean age 75 years; 30% women) were screened for AF. Seven proteins previously associated with myocardial fibrosis [metalloproteinase inhibitor 4 (TIMP-4), suppression of tumorigenicity 2 (ST-2), galectin-3 (GAL-3), growth/differentiation factor-15 (GDF-15), and matrix metalloproteinase 2, 3, and 9 (MMP-3, MMP-3, and MMP-9, respectively)] were analyzed using a proximity extension assay. Proteins with significant Bonferroni-corrected associations with mortality and re-hospitalization risk were taken forward to multivariable Cox regression analyses. Further, Bonferroni-corrected multivariable logistic regression models were used to study associations between protein plasma levels, prevalent AF, and severely enlarged left atrial volume index (LAVI ≥ 48 ml/m2).ResultsPrevalent AF was observed in 194 patients at the hospitalization of whom 178 (92%) were re-hospitalized and 111 (57%) died during the follow-up period. In multivariable logistic regression models, increased plasma levels of TIMP-4, GDF-15, and ST-2 were associated with the prevalence of AF, whereas none of the seven proteins showed any significant association with severely enlarged LAVI. Increased plasma levels of five proteins yielded significant associations with all-cause mortality in patients with co-existing AF; TIMP-4 (HR 1.33; CI95% 1.07–1.66; p = 0.010), GDF-15 (HR 1.30; CI95% 1.05–1.62; p = 0.017), GAL-3 (HR 1.29; CI95% 1.03–1.61; p = 0.029), ST-2 (HR 1.48; CI95% 1.18–1.85; p < 0.001), and MMP-3 (HR 1.33; CI95% 1.09–1.63; p = 0.006). None of the proteins showed any significant association with re-hospitalization risk.ConclusionIn this study, we were able to demonstrate that elevated levels of three plasma proteins previously linked to myocardial fibrosis are associated with prevalent AF in a HF population. Additionally, higher levels of five plasma proteins yielded an increased risk of mortality in the HF population with or without co-existing AF.

Predictive value of soluble suppression of tumorigenicity 2 in atrial fibrillation: a systematic review and meta-analysis

“…A total of 12 studies were analyzed with 11,961 participants (including 1,707 AF patients and 10,254 controls). The pooled analysis of 10 studies ( 12 , 21 , 24 , 25 , 27 , 28 , 32 , 34 , 36 , 37 ) as a continuous variable indicated that sST2 was associated with the risk of AF occurrence (HR:1.04, 95% CI: 1.02–1.07, P < 0.01; I 2 = 67.8% Figure 2 ). Sensitivity analyses showed that the outcomes were stable ( Supplementary Figure S2A ).…”

“…After reading the full text, 14 studies were further excluded because 3 were reviews, 5 were irrelevant findings, and the other 6 were inadequate data. Finally, 24 studies ( 12 – 14 , 17 – 37 ) were included.…”

“…Table 1 displayed the baseline characteristics of 24 included studies from 2015 to 2022, comprising 14 prospective studies ( 14 , 17 – 23 , 26 , 29 – 31 , 33 , 37 ), 4 retrospective studies ( 24 , 25 , 27 , 32 ), 4 cross-sectional studies ( 12 , 13 , 34 , 35 ), and 2 case-control studies ( 28 , 36 ). Eleven studies were conducted in Asia (China, Thailand, Singapore), 10 studies in Europe (Germany, Poland, Finland, France, Norway, Spain, Sweden, Turkey), and 3 study in America (The united states).…”

“…The included studies used various sources of sST2 reagents and adopted diverse detection strategies (e.g., 15 studies used ELISA to detect sST2, 2 used aspect plus assay, 1 used plasma samples assay, and 1 used duoset immunoassay assay). Concerning the purpose of these studies, 12 studies ( 12 , 13 , 21 , 24 , 25 , 27 , 28 , 32 , 34 – 37 ) evaluated the predictive value of sST2 in occurrence of AF, while 8 studies ( 14 , 19 , 20 , 22 , 26 , 29 , 31 , 33 ) evaluated AF recurrence, 5 studies ( 17 , 18 , 23 , 30 , 37 ) evaluated MACEs following AF.…”

“…Table 4 diaplayed the characteristics of the included studies for predictive value of sST2 in MACEs following AF. Five studies ( 17 , 18 , 23 , 30 , 37 ) with 1,614 AF patients examined the relationship between sST2 and the risk of MACEs following AF. The pooled analysis of the estimates as a continuous variable indicated that sST2 was significantly associated with the risk of MACEs (HR:1.60, 95% CI: 1.13–2.27, P < 0.01; I 2 = 82.0% Figure 6 ).…”