Biomarkers of Sudden Cardiac Death: From Troponins to Circulating microRNAs View PDF

SCD remains a significant global health challenge, often presenting without warning and resulting in rapid mortality [1-6]. Early and accurate diagnosis of underlying cardiac conditions is crucial for risk stratification and preventative intervention. Biomarkers play a pivotal role in identifying individuals at risk and guiding clinical decisionmaking. Traditionally, cTn have been the gold standard for detecting myocardial injury, but emerging research suggests the potential of circulating miRNAs and other novel biomarkers to enhance diagnostic accuracy and predictive power for SCD [7-12]. This article will explore the evolution of biomarkers in SCD, focusing on the utility of Tn and the promise of miRNAs, while also considering other relevant markers and diagnostic strategies.

The quest for reliable biomarkers to predict and diagnose SCD has garnered significant attention in recent years, driven by the need for early detection and improved forensic and clinical outcomes [13- 17]. Traditional biomarkers such as cTn have long been established in clinical practice, yet emerging molecular markers like circulating miRNAs are increasingly recognized for their potential to enhance diagnostic accuracy and prognostic assessment. Initial investigations into myocardial biomarkers have primarily focused on enzymatic and protein markers detectable postmortem or in clinical settings [18-23]. Sacco et al. [24] conducted a comprehensive analysis of five cardiac markers—creatine kinase-MB (CK-MB), myoglobin, TnI, B-type natriuretic peptide (BNP), and D-dimer—in peripheral blood samples from autopsied cadavers. Their study distinguished between SCD cases and controls, demonstrating the utility of these markers in postmortem analysis. Notably, TnI emerged as a significant indicator, aligning with its established role in detecting myocardial injury [24].

Building upon this foundation, the development of non-invasive, rapid detection methods has gained momentum. Wu et al. [25] introduced a printed immunosensing photonic crystal biochip (PCB) capable of detecting cTnT from a single drop of saliva or urine within 10 min. This innovative approach underscores the potential for point-ofcare testing, facilitating timely diagnosis of acute myocardial infarction (AMI) and, by extension, SCD risk assessment [25]. Such advancements highlight the transition from traditional blood-based assays to more accessible, non-invasive platforms. While Tn remain central to current diagnostic paradigms, recent research emphasizes the importance of circulating miRNAs as novel biomarkers. MiRNAs are small, noncoding RNA molecules involved in post-transcriptional regulation of gene expression, and their stability in peripheral blood makes them attractive candidates for biomarker development. Emerging evidence suggests that specific circulating miRNAs are associated with various cardiac pathologies, including heart failure, MI, and SCD [26].

The genetic underpinnings of SCD further reinforce the significance of molecular biomarkers [27-30]. Variants in genes such as TNNT2, MYH7, and MYBPC3 have been linked to increased susceptibility to SCD, with TNNT2 encoding cTnT being particularly noteworthy. The gene result for TNNT2 highlights its role as a postmortem biomarker for AMI, emphasizing its relevance in forensic investigations of SCD [31]. These genetic associations suggest that integrating genetic and molecular biomarker data could improve risk stratification. In clinical practice, the inclusion of hs-cTn assays (hs-TnT/I) has revolutionized early detection of myocardial injury. Advancements in assay sensitivity allow for the detection of minute elevations in Tn levels, which can precede overt clinical symptoms. This has significant implications for identifying individuals at imminent risk of SCD, especially in populations with subclinical cardiac disease [13]. Moreover, the combination of circulating miRNAs with traditional peptide biomarkers enhances prognostic accuracy. For instance, combined assays of miRNAs and hs-cTn have demonstrated improved predictive power for adverse cardiac events, including SCD [32].

The potential of circulating miRNAs extends beyond diagnosis to prognostication [33-38]. Wang et al. [39] has demonstrated that specific miRNA profiles can predict cardiac death post-discharge in patients with acute coronary syndromes. These miRNAs are involved in pathways related to myocardial stress, apoptosis, and remodeling, which are critical processes in the pathogenesis of SCD [39]. The stability of miRNAs in blood and their disease-specific expression patterns make them promising candidates for routine clinical and forensic use. Further research explores the integration of epigeneticsensitive biomarkers, including miRNAs, for personalized therapy and risk assessment. For example, miRNA-210 has been identified as a biomarker for congestive heart failure, a condition that predisposes to SCD. Such findings suggest that miRNAs could serve as both diagnostic and therapeutic targets, offering a more nuanced understanding of individual risk profiles [40].

In the context of acute coronary syndrome, circulating miRNAs have been extensively reviewed as diagnostic markers. Their expression patterns correlate with myocardial injury severity and can complement Tn measurements, providing a more comprehensive assessment of cardiac risk [41]. The combined use of miRNAs and Tn enhances the sensitivity and specificity of SCD prediction models, which is crucial for timely intervention. The paradigm shift from solely relying on traditional biomarkers like Tn to incorporating circulating miRNAs reflects a broader trend toward molecular precision medicine. MiRNAs not only serve as indicators of ongoing myocardial injury but also offer insights into the underlying pathophysiological mechanisms leading to SCD. Their role in forensic investigations is also gaining recognition, with studies demonstrating their utility in postmortem body fluid analysis for identifying cardiac events [42].

Overall, the landscape of biomarkers for SCD is evolving from conventional protein markers such as Tn to sophisticated molecular signatures like circulating miRNAs. While Tn remain integral to early detection and clinical management, miRNAs provide additional layers of diagnostic and prognostic information, especially in complex or ambiguous cases. The integration of genetic, proteomic, and miRNA data holds promise for more accurate risk stratification, personalized therapy, and forensic diagnosis of SCD. Continued research into these biomarkers will likely refine our understanding and improve outcomes in patients at risk of SCD