ST2-Based Precision Medicine in Device Management: the Next Frontier Beyond MADIT-CRT?
On January 20, 2015, President Obama announced the Precision Medicine Initiative (PMI) in his State of the Union address. Through advances in research, technology, and policies that empower patients, the PMI aims to enable a new era of medicine in which researchers, providers, and patients work together to develop individualized care (https://www.whitehouse.gov/precision-medicine). The cancer-focused component of this initiative will be designed to address some of the obstacles that have already been encountered in “precision oncology”: unexplained drug resistance, genomic heterogeneity of tumors, insufficient means for monitoring responses and tumor recurrence, and limited knowledge about the use of drug combinations .
Heart disease, killer number 1 in western countries and one of the most serious emerging threats in developing countries, cannot afford sitting and waiting to follow the path of cancer, but instead, the cardiovascular field needs to be audacious to promote specific cardiovascular precision medicine programs. The challenge is enormous, but the benefits greatly outweigh inactivity. In the past three decades, cardiovascular research has been the driving force behind the lengthened life expectancy. Indeed, from 1980 to 2009, life expectancy at birth in Spain increased by more than 6 years for both sexes. The contribution of the decrease in cardiovascular mortality to the total increase in life expectancy at birth was 63 % among women and 53 % among men. Among the ≥65-year-old age group, this contribution was 93 % among women and 87 % among men . If this was achieved with imprecision medicine, the potential of cardiovascular research in the era of precision medicine has no limits.
Biomarkers now have an established role in aiding with diagnosis and prognostication in a number of cardiovascular diseases; nevertheless, their role in patient monitoring and personalized care is at present ill-defined. Although a large number of candidate biomarkers have been evaluated to help fill this gap, few have survived the rigorous studies that are a prerequisite to translation into the clinical realm. ST2 is recently emerging as a bona fide biomarker for patient care.
ST2 is a member of the IL-1 receptor-like family of proteins. Through alternative splicing, ST2 is found in multiple isoforms, including a transmembrane form (ST2 ligand or ST2L) and a soluble, circulating form (sST2). In response to mechanical stress, cardiomyocytes and fibroblasts express both ST2L and sST2 (hereafter referred to simply as “ST2”). Soluble ST2 is thought to act as a decoy receptor for IL-33. The presence of high levels of ST2 blocks the favorable effects of IL-33 by limiting activation of the cascade triggered by the IL-33/ST2L interaction. Higher levels of ST2 are thereby associated with increased myocardial fibrosis, adverse cardiac remodeling, and worse cardiovascular outcomes .
Whether ST2 may be valuable in predicting sudden death and arrhythmia is uncertain. Indeed, the prediction and prevention of sudden death remains a major challenge in the management of patients with chronic heart failure (HF). Sudden death is the cause of 50 % of all HF deaths, mainly affecting patients with mild-to-moderate symptoms, and the number of patients with HF at risk is increasing. The challenge lies in identifying patients with HF who are at significant risk of sudden death. Severe left ventricular systolic dysfunction has long been recognized as a risk factor for sudden death, yet left ventricular ejection fraction (LVEF) lacks enough sensitivity and specificity by itself.
In the present study, Skali et al  provide data on a biomarker substudy of the MADIT-CRT Trial. The authors report that both baseline and serial elevated ST2 levels (≥35 ng/mL) were predictive of an increasing risk of death, HF, or ventricular arrhythmic events. This study shows that for every 10 % increase in ST2 levels at 1 year, there was an increased risk of ventricular arrhythmias or death during follow-up regardless of randomization arm in MADIT-CRT.
Previously, Pascual-Figal et al found, in an ambulatory HF population, that elevation of ST2 and NT-proBNP above the cutoff values was associated with a very high rate (71 %) of sudden death, and interestingly, a very low rate (4 %) of sudden death existed when both markers were below the cutoff thresholds . Given the increased risk of sudden death and ventricular arrhythmias found in these two studies in HF patients with elevated ST2, it is conceivable that action should be taken at the individual patient level.
We have been quite successful in the past decades using imprecise medicine. Incorporation of precision medicine tools will likely be beneficial for our patients, and moreover, it will make us better doctors. Biomarkers such as ST2 and other (i.e., natriuretic peptides, troponins) are already FDA/CE approved and are ready for incorporation in personalized decision algorithms.
- 4.Skali, H., Gerwien, R., Meyer, T. E., Snider, J. V., Solomon, S. D., Stolen, C. M. (2016). Soluble ST2 and risk of arrhythmias, heart failure or death in patients with mildly symptomatic heart failure: results from MADIT-CRT. Journal of Cardiovascular Translational Research. doi: 10.1007/s12265-016-9713-1.
- 5.Pascual-Figal, D. A., Ordoñez-Llanos, J., Tornel, P. L., Vázquez, R., Puig, T., Valdés, M., Cinca, J., de Luna, A. B., Bayes-Genis, A., & MUSIC Investigators. (2009). Soluble ST2 for predicting sudden cardiac death in patients with chronic heart failure and left ventricular systolic dysfunction. Journal of the American College of Cardiology, 54, 2174–2179.CrossRefPubMedGoogle Scholar