Biomarkers: Their potential in the diagnosis and treatment of heart failure

Biomarkers of inflammation and fibrosis: Soluble ST2 and galectin-3

Inflammation has long been associated with HF, and clinically available markers of inflammation such as high-sensitivity C-reactive protein (CRP)^30,31 and myeloperoxidase³² have consistently tracked with prognosis. The search for a stable biomarker of inflammation has been challenging because inflammation is a dynamic process and because of the lack of treatment options for heightened inflammation.

A promising new protein biomarker, ST2 (suppression of tumorigenicity-2), has been identified in a soluble form (sST2) that binds to interleukin 33 (IL-33) to antagonize the maladaptive response of the myocardium to overload states.³³ The levels of sST2 inversely correlate with the ejection fraction and have a positive association with increasing New York Heart Association class, worsening symptoms, and indicators of HF severity, such as norepinephrine levels, diastolic filling pressures, CRP, and natriuretic peptide levels.³⁴ Unlike natriuretic peptides, levels of sST2 are not significantly affected by age, sex, body mass index, and valve disease,³⁴ although recent observations have challenged its cardiac associations.³⁵ In patients with chronic HF, elevated levels of sST2 (especially >35 ng/mL) have been associated with poorer clinical outcomes³⁶ and increased risk of sudden cardiac death in HF.³⁷ In addition, persistently elevated sST2 levels consistently confer poor long-term prognosis. Several studies have also demonstrated the prognostic value of elevated sST2 in predicting long-term risk of death in acute HF, either at baseline^38,39 or on serial testing.⁴⁰

Another new biomarker, galectin-3, has been implicated in fibrosis and in structural and pathophysiologic changes seen in HF.⁴¹ Studies have shown that higher levels of galectin-3 in patients with acute HF and chronic HF were associated with more severe cardiac fibrosis and with an increase in left ventricular remodeling.^42–44 Serial measurements also confer prognostic information.⁴⁵ However, many of these studies did not fully account for renal dysfunction as a major confounder, and the relationship between circulating galectin-3 and estimated GFR is strong.^46,47 Meanwhile, head-to-head comparisons among galectin-3 and other clinically available biomarkers also revealed that the prognostic value of galectin-3 can be attenuated in the presence of sST2 and NT-proBNP.^48,49 Furthermore, careful evaluation of diastolic parameters only showed a modest relationship with galectin-3 levels, especially in those with HF with preserved ejection fraction.^50,51

In animal infarction models, disruption of the galectin-3 and IL-33/ST2 pathway with pharmacologic therapy such as mineralocorticoid receptor antagonists may attenuate cardiac remodeling.^52,53 It is conceivable that these biomarkers may have mechanistic links with therapeutic benefits. However, the practical uses of galectin-3 and sST2 are still debated (Class 2b recommendation by the latest guidelines²) despite strong statistical associations between biomarker levels and adverse outcomes. The majority of biomarker substudies from clinical trials have suggested that improvements following drug or device therapy were largely confined to patients with lower rather than higher biomarker levels.^54,55 Furthermore, validation studies have challenged the incremental prognostic value of these markers when natriuretic peptide levels are available.^54,56–58 Thus, more clinical experience and research are warranted, and current clinical applications may be restricted to patient subsets.

BIOMARKERS IN EARLY STAGES OF HEART FAILURE

The potential benefit of biomarker testing may reside in the earlier end of the HF spectrum, especially in patients at risk of but not yet diagnosed with HF (so-called stage A). In the HealthABC study, the future risk of HF in elderly patients can be predicted with a combination of clinical risk factors (age, sex, left ventricular hypertrophy, systolic blood pressure, heart rate, smoking), as well as biochemical risk factors such as albumin, creatinine, and glucose.⁵⁹ Patients with elevated natriuretic peptide levels are more likely to have underlying cardiac abnormalities and to have poorer long-term outcomes.⁶⁰ In a recent prospective, randomized controlled trial, participants with a BNP-guided transition to HF therapies (when BNP >50 pg/mL) had a lower incidence of HF than participants without knowledge of BNP levels.⁶¹ Elevated levels of clinically available biomarkers of inflammation, such as myeloperoxidase,^29,62 ceruloplasmin,⁶³ and CRP,⁶⁴ have also been associated with an increased risk of future HF. These findings support the notion that biomarkers, especially when combined with clinical risk factors, can serve as indicators of HF vulnerability. If independently confirmed, this will be an important therapeutic approach to the prevention of HF.

PRACTICAL CONSIDERATIONS

An important perspective often overlooked concerns the variability of a biomarker level as it is utilized in clinical practice (Table 4). In general, point-of-care assays are often more variable than the same tests done in clinical laboratories. Sample collection, handling, and processing also introduce a degree of variability. The biologic variability of specific measurements can significantly affect the precision of the measurement. In the case of HF, the biologic variability (as measured in stable patients over time) of natriuretic peptides and galectin-3 are significantly higher than those observed in cardiac troponins or sST2 (> 130% vs approximately 30%).⁶⁵ Nevertheless because of their relative cardiac specificity, natriuretic peptides have maintained their clinical utility.