How Much Is Too Much? Cardiac Biomarkers After Cardiac Surgery: A Debate With No End in Sight?

In this issue of the Journal of the American Heart Association (JAHA), Koechilin et al ¹ present a detailed analysis of the clinical impact of using the main cardiac biomarkers (cardiac troponins T and I [cTnT and cTnI]) after coronary artery bypass grafting. It demonstrates that the different types of biomarkers show markedly different postoperative concentrations after coronary artery bypass grafting, which should affect the classification of perioperative myocardial infarction (PMI).

Core of the Study

In details, the authors showed that, in a cohort of 258 patients (median age, 69 years) undergoing uneventful isolated coronary artery bypass grafting surgery, the postoperative median peak values of cTnT and cTnI were 349 ng/L and 1517 ng/L, respectively, for the average patient on postoperative day 1. Moreover, cTnI exceeded established biomarker thresholds for PMI far more often than cTnT across all major definitions. For instance, according to the Universal Definition of Myocardial Infarction, elevated cutoff values were met in 60.0% of patients for cTnT compared with 72.4% for cTnI, while the Academic Research Consortium‐2 criteria were fulfilled in 30.0% versus 69.2% of patients, respectively (all P<0.001). Even when echocardiographic and electrocardiographic findings were incorporated, the discrepancy between markers persisted.

This striking variability clearly illustrates how heavily PMI diagnosis depends on the selected troponin assay, carrying significant implications for clinical decision making, for postoperative assessment, and mainly for the interpretation of outcomes in clinical trials. ² , ³ , ⁴

Interpretations With No End in Sight

While the direct comparison of the 2 troponins, provided by the authors in this elegant study, is new, the discussion of PMI definitions and cutoffs is not. ⁵ , ⁶ , ⁷ These questions arise: How we will proceed in this field? How will we define PMI in the future? Should we just use the cutoff that has been published most recently and maybe distinguish even further among the different biomarkers, with no end in sight?

We had already taken a mechanistic perspective on this issue ⁸ and would like to review some of our points. A first point addresses the question on what the release of biomarkers (troponins in this case) means. The basis for using biomarker release in definitions of myocardial infarctions (specifically in the ones using biomarkers only) is the assumption that troponin release reflects irreversible cell damage (ie, cell death). This assumption should result in release rates for 2 different, but considered equally suitable, troponins that are related to each other. Since a direct relationship of the 2 parameters has not been provided by the authors, the available data suggest that such a correlation does not exist.

We showed that biomarkers used for PMI definitions (cTnT, cTnI, and creatine kinase MB) can be released in the complete absence of cell death. ⁸ Endurance athletes, animal models exposed to brief inotropic stimulation, and in vitro systems subjected to transient flow changes all demonstrate substantial biomarker elevations without true myocardial necrosis (Table1). ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ In cardiac surgery, additional procedural factors such as atrial manipulation during cannulation or concomitant valve interventions contribute further to biomarker release that does not reflect ventricular ischemia. These non–cell‐death mechanisms may explain the poor correlation between postoperative enzyme levels and long‐term outcomes seen across recent clinical trials. ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶

Table 1.

Detailed Causes of Cardiac Biomarker Elevation Without Myocardial Necrosis

Category	Details
1. Noncardiac critical illness	Sepsis/septic shock
	Severe anemia
	Hypotension or shock of any cause
	Hypoxia or respiratory failure
	Pulmonary embolism
	Stroke/subarachnoid hemorrhage/intracerebral hemorrhage
	Severe burns
2. Renal‐related causes	Dialysis (chronic or acute)
	Uremia
3. High physiological stress	Extreme physical exertion (marathon, triathlon, military training)
	Catecholamine surge (stress response)
	Tachyarrhythmias
4. Cardiac causes	Heart failure (acute or chronic)
	Takotsubo cardiomyopathy
	Myocarditis (nonnecrotic inflammatory injury)
	Pericarditis
	Cardioversion or defibrillation
	Postablation procedures
	Right ventricular strain (eg, pulmonary hypertension)
	Amyloidosis
	Hypertrophic cardiomyopathy
	Infiltrative storage diseases
5. Toxins and drugs	Chemotherapy drugs (eg, anthracyclines)
	Cocaine or amphetamines (catecholamine toxicity)
	Carbon monoxide poisoning
6. Endocrine/metabolic	Thyroid disorders (especially thyrotoxicosis)
	Diabetic ketoacidosis
	Extreme hypoglycemia
7. Procedures/trauma	Noncardiac major surgery
	Electrical injury
	Blunt chest trauma

Although the authors do not discuss this point, these non–cell‐death mechanisms of biomarker release may also explain why they arrive at the high rates of myocardial infarctions with any of the available definitions in their patients who did not show any sign of an adverse event in the clinical course. If one accepts the current perception of the meaning of troponin release also for the surgical setting, one would have to conclude that heart operations cause major cell death and may therefore pose an unknown additional risk. Thus, the main question that arises is what these biomarker releases actually mean in the context of cardiac surgery. Answering this question would put an end to the discussion of how we define myocardial infarction during and after cardiac surgery but would require us to correlate the amounts and dynamics of biomarker release with the amount of actual cell death/myocardial injury.

Light at the End of the Tunnel

Our current approach to interpreting myocardial injury using biomarkers after cardiac surgery reminded us of an old psychological test (the Rorschach test), where a blob of ink is dropped on a page that is folded and the erratic distribution of ink on the reopened page is then interpreted by a person, allowing us to assess the emotional status or the way this person thinks. ¹⁷

We therefore started the RORSCHACH (Cardiac Biomarkers for the Quantification of Myocardial Damage After Cardiac Surgery; NCT06066970) trial, ¹⁸ a multicenter prospective, observational assessment of biomarker release that will be correlated to the amount of myocardial cell death visualized by cardiac magnetic resonance imaging performed immediately before and 5 days after surgery. There are 5 different participating sites in Germany that are currently initiated. Presently, 40% of the recruitment is already done, and the preliminary results are expected by the end of 2026.

The outcomes will answer the key question on the meaning of biomarker release in cardiac surgery. In the meantime, it may be reasonable to question the value of biomarkers in the current definitions of myocardial infarction. If the currently possible conclusion of significant myocardial injury induced by cardiac surgery using cardiopulmonary bypass were true, it would be difficult to explain the repeatedly observed survival advantage found for coronary artery bypass grafting compared with both medical and interventional treatment of chronic coronary artery disease. ¹⁹ , ²⁰ , ²¹ In any case, the field is one that is in desperate need of new, mechanistically driven evidence because only if we know “why” things happen in our hands will we be able to stop the endless discussions on the outcomes of our doing.

Disclosures

None.