Prognostic biomarker soluble ST2 exhibits diurnal variation in chronic heart failure patients

Abstract

Aim Soluble suppression of tumorigenicity‐2 (sST2) is a strong prognostic biomarker in heart failure. The emerging understanding of circadian biology in cardiovascular disease may lead to novel applications in prognosis and diagnosis and may provide insight into mechanistic aspects of the disease–biomarker interaction. So far, it is unknown whether sST2 exhibits a diurnal rhythm. Repeated measurements of sST2 may aid in clinical decision making. The goal of this study was to investigate whether sST2 exhibits diurnal variation in patients with heart failure with reduced ejection fraction (HFrEF) and in control subjects, thereby enhancing its diagnostic and prognostic values. Methods and results The study comprised 32 subjects: 16 HFrEF patients and 16 controls. Blood was collected at seven subsequent time points during a 24 h time period. sST2, N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), melatonin, and cortisol were measured from serum. Peak values of sST2 clustered at daytime (modal value: 5 p.m.) in 87.6% of all subjects (81.3% of patients, P = 0.021; 93.8% of controls, P = 0.001), and minimum concentrations at night‐time (modal value: 5 a.m.) in 84.4% (87.5% of patients, P = 0.004 81.3% of controls, P = 0.021). A cosinor analysis of mean normalized sST2 values revealed significant cosine shaped 24 h oscillations of patients (P = 0.026) and controls (P = 0.037). NT‐proBNP in contrast did not show a diurnal rhythm, while melatonin and cortisol patterns were intact in all subjects. Conclusions sST2 exhibits a diurnal rhythm with lower values in the morning than in the late afternoon. This new insight could lead to refinement of its diagnostic and prognostic values through specified and consistent sampling times with repeated measurements. For example, by measuring sST2 during the afternoon, when levels are at their highest, false negatives on prognosis prediction could be avoided.

Melatonin’s Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease

“…In the field of cardiovascular effects, melatonin protects against ischemia/reperfusion injury (IRI) [ 62 , 117 , 118 , 119 , 120 , 121 ] and hypertension [ 122 , 123 , 124 ], as an endogenous effect, nutritional supplement, or acute parenteral administration [ 125 , 126 ]. In addition, it appears that other promising effects such as anti-apoptotic, anti-inflammatory [ 127 ], preconditioning [ 118 , 128 ], myocardial infarction [ 129 , 130 , 131 ], and even an implication in heart failure [ 132 , 133 , 134 , 135 ] have been documented. However, it seems than in some conditions, melatonin can have deleterious effects, as exaggerated collagen and glycosaminoglycans deposition and increased size in post-myocardial infarction scar have also been reported [ 136 , 137 ].…”

Diagnostic Value of sST2 in Cardiovascular Diseases: A Systematic Review and Meta-Analysis

“…The Framingham Heart Study found that age and sex are important determinants of normal sST2 levels (41). Specifically, sex has a potentially crucial influence on sST2, in that female sST2 levels are lower than those of males at corresponding ages (42), which may be influenced by sex hormones (43). In addition, sST2 secretion follows a diurnal rhythm, with lower values in the morning, a peak in the afternoon, and lowest levels at night (43).…”

“…Specifically, sex has a potentially crucial influence on sST2, in that female sST2 levels are lower than those of males at corresponding ages (42), which may be influenced by sex hormones (43). In addition, sST2 secretion follows a diurnal rhythm, with lower values in the morning, a peak in the afternoon, and lowest levels at night (43). Understanding the diurnal rhythm and sex differences affecting sST2 expression can help avoid false negatives in prognostic prediction.…”

“…According to the AUC values obtained in the present meta-analysis, the potential diagnostic value of sST2 in HF is considerable. However, as mentioned above, sex and diurnal rhythm (41)(42)(43) should be considered when setting the cutoff value for diagnosis during clinical application.…”

The Diagnostic Value of Soluble ST2 in Heart Failure: A Meta-Analysis

“…Soluble suppression of tumorigenicity 2 (sST2), a marker associated with cardiomyocyte traction, is a potential pathophysiological mediator of myocardial hypertrophy and myocardial fibrosis and an important biomarker of HF (5). Several trials have now confirmed that sST2 levels are significantly elevated in patients with HF and that the elevated levels of sST2 correlate significantly with the degree of HF (6,7). In recent years, more studies have been reported on the diagnosis of HF using sST2, but the results of these studies vary significantly.…”