Good afternoon, dear distinctive judges

Today I will present my literature review about Soluble Suppression of Tumorigenicity 2 (sST2) as a
Novel Predictor for Sudden Cardiac Death in Heart Failure.

Sudden cardiac death (SCD) is a leading cause of mortality and responsible for approximately half of all
deaths from cardiovascular disease. The prediction and prevention of SCD remains a major challenge in
the management of patients with chronic HF. Only a limited number of biomarkers have been identified
for SCD and thus far, none of these are in clinical use for risk stratification. Recent studies have shown
that IL-33/ST2L signaling mechanism had cardioprotective capabilities that are mediated through
binding sST2 with IL-33 and sST2 act as a decoy receptor to inhibit those mechanism. Therefore, in this
review, we will highlight the current evidence-based literature regarding the role of sST2 to predict
Sudden Cardiac Death in Heart Failure Patients.

Our current risk factor and predictor for SCD in cardiac disease consist of traditional risk factors such as
• diabetes
• obesity
• dyslipidemia
• hypertension.
• prolonged QT-interval
• Left Ventricular Ejection Fraction (LVEF)
At present, LVEF is the most common clinically utilized risk predictor of SCD, with LVEF below 35%
indicating the need for ICD implantation.
We also have biomarkers to predict cardiovascular mortality such as, galectin-3 as a marker for cardiac
fibrosis, Growth differentiation factor-15 (GDF-15), as a marker of multiple stress pathways in the heart,
N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of myocardial stretch, C-reactive protein
(CRP) and Interleukin-6 (IL-6), as a marker of systemic vascular inflammation, highly sensitive Troponin-T
(hs-TnT), as a marker of cardiac myocyte necrosis.
Among them, only NT-pro BNP that were associated with a greater risk of SCD of HF patients in most of
the study, and also been established in the guideline, as a marker for prognosis and treatment monitoring,
regarding the course of disease.
But all of them, have their own limited effectiveness. Effective risk stratification will require the availability
of tools that can be employed at an early stage in the natural history of the condition.

Now we move on to soluble st2 as a potential biomarker to predict SCD in HF patients

From the pathobiology, we know that
ST2 is an interleukin-1 receptor family member with transmembrane (ST2L) and soluble isoforms (sST2).
ST2L is a membrane bound receptor, and interleukin-33 (IL-33) is the functional ligand for ST2L. In
principle, IL-33 functions as a danger signal by signaling the presence of tissue damage to local immune
cells after exposure to pathogens, injury-induced stress, or death by necrosis. sST2, a soluble truncated
form of ST2L, is secreted into the circulation and is believed to function as a “decoy” receptor for IL-33,
inhibiting the effects of IL-33/ST2L signaling. IL-33/ST2 signaling protects the myocardium under
mechanical strain and acts as a biomechanically activated fibroblast-cardiomyocyte paracrine system that
prevents cardiac hypertrophy and fibrosis. sST2 protein abrogates this adaptative response in a dose-
dependent manner by binding IL-33 and preventing signaling through ST2L. sST2 modulates extracellular
matrix remodeling and regulates inflammatory and electrical signals between cardiac cells types that may
facilitate lethal cardiac arrhythmias or other cardiac events ultimately leading to SCD.

The role of soluble ST2 in predicting SCD itself have been documented in several trials and studies.
For instance, from the music study, a prospective, multicentre, longitudinal study designed to assess risk
predictors of cardiac mortality and sudden cardiac death in ambulatory patients with CHF. We know that
declined serum sST2 (<0.23 ng/mL) was able to predict lowered risk of sudden death. Another study by
Domingo et al, also shows that increased serum levels of sST2, were predictive of SCD in ambulatory
patients with mild-to-moderate chronic HF and left ventricular systolic dysfunction.
Changes in sST2 with therapy were linearly correlated with the risk of the primary outcome,
hospitalizations for HF, and cardiovascular death, according to paradigm HF trial which compare ARNI
and ACE I treatment in global mortality of the heart.
And not just predicting SCDs, soluble ST2, also can be used as a biomarker in an ambulatory setting to
target pharmacotherapy for optimal, more personalized medical management of patients with HF,
according to the study by Berezin et al, in his research comparing the clinical outcome of patients who has
been treated in relation to different concentration of ST2.
As we all know, one of the established biomarkers for prognosis in HF patients according to AHA guidelines
is NT pro BNP. And so what is the difference between soluble ST2 and NT pro BNP. According to the study
by chang et al, he concluded that sST2 is superior for prediction of long-term HF-related outcomes,
whereas NPs were most optimal for prediction of hospital length of stay and re-admission.
Another advantage of ST2 is that sST2 levels seem not to be influenced by confounders such as age or
renal function, with lower biologic and analytic variability than NPs. Moreover, it has an ability to predict
clinical outcomes in patients with different phenotype of HF, according to the study by Laqqan et al.
Despite the situation, sST2 is also a potent marker of risk in chronic heart failure and when used in
combination with NT-proBNP. A cohort study by Bonnie et al, shows that the addition of ST2 and NT-
proBNP to the Seattle Heart Failure Model reclassified 14.9% of patients into more appropriate risk
categories, beyond clinical risk scores.

These initial results were confirmed in the Barcelona Study, and in a multivariable cox proportional
hazards model by antoni et al, shows that the individual inclusion of sST2 and NTproBNP in the model
with established mortality risk factors significantly improved the C statistic for predicting death.

As we can see from this Kaplan meier survival curve, when neither st2 nor NT pro BNP reaches its cutoff,
the survival rate of the patients is still high. When one of them reaches the cutoff, the survival rate
becomes lower for both soluble st2 and NT pro BNP. But when both of them reaches the cut off point,
the survival rate is significantly lower than the other.

Also from the other study, from this graph we can also draw the same conclusion that the incidence of
SCDs is the highest when both biomarkers reaches its cutoff.

So, what I’m trying to say from this review is that, sST2 is potentially strong biomarker to predict not
only sudden cardiac death in heart failure patients, but also overall mortality and personified treatment
for cardiac failure patient populations.

It can also be used as a complementary biomarker in conjunction with NT-pro BNP or other clinical risk
scores to accurately improves the risk stratification for death in heart failure patients.

That is all for my presentation. Thank you for your attention.