Influence of Cardiac Markers in Pediatric Laboratory Medicine: A Critical Review

Abstract

Cardiac biomarkers play a crucial role in the diagnosis and management of various cardiovascular conditions in adults. However, their application in pediatric populations presents unique challenges due to physiological differences, varying disease presentations, and limited data. This comprehensive review examines the role of cardiac biomarkers in pediatric laboratory medicine, focusing on their clinical utility, limitations, and future directions. We discuss the key cardiac biomarkers, including cardiac troponins, natriuretic peptides, myoglobin, and creatine kinase-MB, and their relevance in specific pediatric conditions such as myocarditis, cardiomyopathy, sepsis, and Kawasaki disease. We also address the challenges associated with interpreting cardiac biomarker results in children, including age-related variations, the impact of physiological stress, and the lack of standardized reference ranges. This review aims to provide a critical appraisal of the current state of knowledge regarding cardiac biomarkers in pediatric populations and guide future research to improve their clinical utility in this vulnerable patient group.

Introduction

Pediatric cardiology presents unique challenges in the diagnosis and management of cardiovascular diseases. Unlike adults, children exhibit significant physiological differences in cardiac structure and function throughout growth and development. This necessitates a nuanced approach to the evaluation of cardiac health, where traditional clinical assessments may not always suffice. Cardiac biomarkers, reflecting the presence and extent of cardiac injury or stress, have emerged as valuable tools in adult cardiology. However, their application in pediatric populations presents several unique considerations. This review comprehensively examines the role of cardiac biomarkers in pediatric laboratory medicine, focusing on their clinical utility, limitations, and future directions.

Key Cardiac Biomarkers

• Cardiac Troponins:

  • Troponin I and Troponin T: Highly specific and sensitive proteins within cardiac muscle.

    • Released into the bloodstream following myocardial injury, such as myocardial infarction, myocarditis, or cardiomyopathy.

    • Represent the gold standard for diagnosing myocardial injury in adults.

  • In pediatrics:

    • Troponin elevations are observed in various conditions beyond acute myocardial infarction, including myocarditis, Kawasaki disease, sepsis, and after cardiac surgery.

    • Defining clinically significant elevations in children remains challenging due to:

      • Age-dependent reference ranges: Troponin levels vary significantly with age and pubertal status.

      • Limited data on physiological variations: Normal ranges can be influenced by factors such as exercise, inflammation, and renal function, which require further investigation in pediatric populations.

      • Lack of standardized assays and methodologies: Variations in assay sensitivity and specificity can significantly impact results.

• Natriuretic Peptides:

  • Brain Natriuretic Peptide (BNP) and N-terminal pro-BNP (NT-proBNP):

    • Hormones primarily secreted by the ventricles in response to myocardial stretch and increased pressure.

    • Reflect cardiac workload and ventricular function.

    • Used in adults for the diagnosis and risk stratification of heart failure.

  • In pediatrics:

    • Elevated BNP levels are observed in various conditions, including heart failure, myocarditis, sepsis, and renal dysfunction.

    • Age-related variations: BNP levels vary significantly with age, with higher levels observed in neonates and infants.

    • Physiological influences: Factors such as exercise, obesity, and renal dysfunction can also significantly influence BNP levels.

    • Clinical utility:

      • BNP can be helpful in differentiating dyspnea of cardiac origin from other causes in children.

      • It may also be useful in assessing the severity of heart failure and guiding treatment decisions.

• Myoglobin:

  • A small protein found in cardiac and skeletal muscle.

  • Released into the bloodstream early after myocardial injury.

  • Less specific than troponin, as it can also be elevated in skeletal muscle injury (e.g., rhabdomyolysis).

  • Limited clinical utility in the diagnosis of myocardial infarction in children.

• Creatine Kinase-MB (CK-MB):

  • An enzyme found predominantly in the heart muscle.

  • Elevated CK-MB levels can indicate myocardial injury.

  • However, CK-MB lacks the specificity and sensitivity of troponin for the diagnosis of myocardial infarction in children.

Clinical Applications of Cardiac Biomarkers in Pediatric Populations

• Myocarditis:

  • Diagnosis:

    • Elevated troponin levels, often in conjunction with clinical and echocardiographic findings, support the diagnosis of myocarditis.

    • However, the diagnosis of myocarditis remains challenging and often requires a combination of clinical, laboratory, and imaging data.

  • Risk stratification:

    • Serial troponin measurements may help assess the severity of myocarditis and predict the risk of adverse outcomes.

• Cardiomyopathy:

  • Diagnosis:

    • Elevated BNP levels can support the diagnosis of heart failure in children with cardiomyopathy.

    • Troponin levels may be elevated in certain types of cardiomyopathies, such as myocarditis-associated cardiomyopathy.

  • Prognosis:

    • BNP levels may help to assess the severity of heart failure and predict the risk of adverse events in children with cardiomyopathy.

• Sepsis:

  • Assessment of myocardial injury:

    • Sepsis can lead to myocardial dysfunction and elevated troponin levels.

    • Monitoring troponin levels can help assess the severity of myocardial injury and guide treatment decisions.

  • Prognostication:

    • Elevated troponin levels in sepsis may be associated with increased risk of adverse outcomes, such as organ dysfunction and mortality.

• Kawasaki disease:

  • Assessment of myocardial involvement:

    • Myocardial involvement is a common complication of Kawasaki disease.

    • Elevated troponin levels can be observed in children with Kawasaki disease, particularly those with coronary artery aneurysms.

    • Serial troponin measurements may help to monitor for the development of myocardial injury and assess the response to treatment.

• Post-cardiac surgery:

  • Monitoring for myocardial injury:

    • Elevated troponin levels after cardiac surgery may indicate myocardial ischemia, reperfusion injury, or other complications.

    • Serial troponin measurements can help to monitor the course of myocardial recovery and identify patients at increased risk for adverse outcomes.

  • Risk stratification:

    • Elevated troponin levels may be associated with increased risk of postoperative complications, such as prolonged hospital stay and the need for mechanical circulatory support.

Challenges and Limitations

• Age-related variations:

  • Establishing accurate age- and sex-specific reference ranges for cardiac biomarkers in children is crucial.

  • These reference ranges must account for physiological changes that occur throughout childhood and adolescence.

• Physiological influences:

  • Factors such as exercise, stress, inflammation, and renal dysfunction can significantly influence the release and clearance of cardiac biomarkers.

  • It is important to carefully consider these factors when interpreting biomarker results.

• Lack of standardized protocols:

  • Variations in sample collection, processing, and assay methods can significantly impact biomarker results.

  • Standardization of laboratory procedures is crucial for accurate and reliable biomarker measurements.

• Limited data:

  • Compared to adults, there is limited data available on the use of cardiac biomarkers in pediatric populations.

  • Large-scale, well-designed studies are needed to establish the clinical utility of cardiac biomarkers in various pediatric conditions.

• Ethical considerations:

  • The potential for overdiagnosis and overtreatment based on elevated biomarker levels must be carefully considered.

  • The potential impact of repeated blood draws on children should also be taken into account.

Future Directions

• Development of age- and sex-specific reference ranges:

  • Ongoing research is focused on establishing accurate and comprehensive age- and sex-specific reference ranges for cardiac biomarkers in children.

• Investigation of novel biomarkers:

  • Research is ongoing to identify novel biomarkers that may be more specific and sensitive for the diagnosis and prognosis of pediatric cardiac diseases.

  • Examples include:

    • Growth differentiation factor 15 (GDF-15): A member of the TGF-beta superfamily that has been shown to be elevated in heart failure and other cardiovascular conditions.

    • Soluble suppression of tumorigenicity 2 (sST2): A protein involved in cardiac remodeling that may be a useful biomarker for the risk stratification of heart failure.

    • MicroRNAs: Small non-coding RNAs that play a role in various cellular processes, including cardiac remodeling.

• Development of predictive models:

  • The development of predictive models that incorporate cardiac biomarker data with other clinical and imaging data can improve risk stratification and guide treatment decisions.

• Integration of biomarkers into clinical practice guidelines:

  • The development of evidence-based guidelines for the use of cardiac biomarkers in pediatric populations is crucial for optimizing their clinical utility.

• Ethical considerations:

  • Careful consideration of the ethical implications of biomarker testing in children, including the potential for overdiagnosis and the impact on healthcare cost.

Conclusion

Cardiac biomarkers play an important role in the evaluation and management of various cardiovascular conditions in adults. However, their application in pediatric populations presents unique challenges.

Continued research is necessary to:

• Establish accurate age- and sex-specific reference ranges:

  • Ongoing research is focused on establishing accurate and comprehensive age- and sex-specific reference ranges for cardiac biomarkers in children. This requires large-scale, well-characterized cohorts to generate robust data.

  • Longitudinal studies are crucial to understand how biomarker levels change with age and pubertal development.

• Investigate the role of novel biomarkers:

  • Explore the potential of novel biomarkers, such as growth differentiation factor 15 (GDF-15), soluble suppression of tumorigenicity 2 (sST2), and microRNAs, in the diagnosis and prognosis of pediatric cardiac diseases.

  • Evaluate their sensitivity, specificity, and clinical utility in comparison to established biomarkers.

• Develop and validate predictive models:

  • Develop and validate predictive models that incorporate cardiac biomarker data with other clinical and imaging data (e.g., echocardiography, electrocardiography) to improve risk stratification and guide treatment decisions.

  • These models can help identify children at high risk for adverse outcomes and guide the intensity of monitoring and treatment.

• Integrate biomarkers into clinical practice guidelines:

  • Develop evidence-based guidelines for the appropriate use of cardiac biomarkers in pediatric populations.

  • These guidelines should address indications for biomarker testing, interpretation of results, and the integration of biomarker data into clinical decision-making.

• Address ethical considerations:

  • Carefully consider the ethical implications of biomarker testing in children, including:

    • The potential for overdiagnosis and overtreatment.

    • The impact on healthcare costs.

    • The potential for psychological distress associated with abnormal test results.

  • Ensure that biomarker testing is used judiciously and that results are interpreted and communicated appropriately to families.

Future Perspectives

The field of pediatric cardiac biomarker research is rapidly evolving. Continued advancements in technology, such as high-throughput genomics and proteomics, will facilitate the discovery and validation of novel biomarkers. Furthermore, the integration of artificial intelligence (AI) and machine learning algorithms has the potential to revolutionize the analysis and interpretation of biomarker data, enabling more accurate and personalized risk stratification.

Ultimately, the goal is to utilize cardiac biomarkers to improve the diagnosis, management, and prognosis of cardiovascular diseases in children. By addressing the unique challenges and limitations associated with the use of biomarkers in this population, we can enhance the quality of care for children with cardiac conditions and improve their long-term outcomes.