Cardiac Biomarkers in Dyspnea Hospitalizations – Still Breathing Not Predictively

Abstract

Since the first report of cardiac biomarker in 1954 [1], where a rise in blood aspartate aminotransferase was noted in acute myocardial infarction patient, we have witnessed a rapid evolution of biomarkers that have emerged as a critical tool for diagnosis, risk stratification, and therapeutic decision-making in the practice of cardiovascular (CV) medicine (Fig. 1). Dyspnea is a multidimensional symptom resulting from a complex interaction of signals arising from the central nervous system, CV and respiratory systems, and skeletal muscles. The freedom from dyspnea has been termed equivalent to human rights issue [2]. Dyspnea poses significant burden on healthcare system [3], but importantly is one of the most feared symptoms for patients with a broad range of clinical diagnoses, including cardiac, respiratory, neuromuscular, endocrine, and hematologic diseases and cancer. Among broad differential diagnoses of dyspnea, awareness to excluding and/or diagnosing in a timely manner life-threatening diseases in emergency department such as acute heart failure (HF), acute coronary syndrome, and pulmonary embolism has led to serum biomarker testing of cardiac troponin T (cTnT) and NT-proBNP in dyspnea patients as a standard of care. HF and acute coronary syndrome are the leading causes of hospital admissions with effects not limited to cardiology but also among other noncardiac global health problems such as diabetes, chronic lung disease, and cancer patients [4–9]. Several different risk scores and guidelines recommend use of cardiac troponins and natriuretic peptides to guide management and escalation of invasive interventions [10–13]. Fig. 1. Evolution of biomarker development in cardiology. AST, aspartate aminotransferase; LDH, lactate dehydrogenase; CK, creatine kinase; CK-MB, myocardial creatine kinase isoenzyme; BNP, brain natriuretic peptide; hsCRP, high-sensitivity C-reactive protein; Hs-troponin, high-sensitivity troponin; sST2, soluble suppression of tumorigenesis-2. In this issue of Cardiology, Bhatnagar et al. [14] studied and compared the properties of cTnT and NT-proBNP for predicting short-term prognosis (all-cause in-hospital or 30-day mortality and 30-day readmissions) in unselected patients coming to emergency department with acute dyspnea. They aimed to determine the better prognostic biomarker for patients with acute dyspnea to improve risk assessment, reduce readmission rates, and ultimately reduce the cost associated with readmissions. The plasma levels of cTnT and NT-proBNP (collected within 24 h of emergency department presentation with acute dyspnea) were measured at a core laboratory as a single batch in 314 patients at Akershus University Hospital from June 2009 to November 2010. Given acute dyspnea is a complex and challenging presentation that can encompass both cardiac and noncardiac conditions, 2 senior physicians independently reviewed the patient’s electronic health records to adjudicate HF as a primary cause of hospital admission (n = 143/314, 45.5%; HF with reduced ejection fraction [HFrEF] n = 91/143, 6.4%; HF with preserved ejection fraction [HFpEF] n = 52/143, 36.4%). They found that patients who died (n = 12/314, 3.8%) or readmitted (n = 71/314, 22.6%) within 30 days of discharge had a higher cTnT (median: 32.6, Q1–Q3: 18.4–74.2 ng/L vs. median: 19.4, Q1–Q3: 8.4–36.1 ng/L; p for comparison <0.001) and NT-proBNP (median: 1,753.6, Q1–Q3: 464.2–6,862.0 ng/L vs. median 984, Q1–Q3: 201–3,600 ng/L; for comparison p = 0.027) concentrations compared to patients who survived and were not readmitted. The group with higher concentration of cTnT was associated with 30-day outcomes of readmission or all-cause death in total cohort (adjusted hazard ratio [aHR]: 1.64, 95% confidence interval [CI]: 1.30–2.05), those with adjudicated diagnosis of HF (aHR: 1.58, 95% CI: 1.14–2.18), HFpEF (aHR: 2.04, 95% CI: 1.08–3.87), and those with non-HF cause of dyspnea (aHR: 1.74, 95% CI: 1.09–2.79). The concentrations of cTnT did not associate with outcomes in HFrEF subgroup (aHR: 1.52, 95% CI: 0.97–2.38). NT-proBNP was not associated with higher likelihood of short-term adverse events in overall cohort with acute dyspnea (aHR: 1.10, 95% CI: 0.94–1.30), those with adjudicated diagnosis of HF (aHR: 1.06, 95% CI: 0.80–1.40), HFrEF (aHR: 1.52 [0.97–2.38]), HFpEF (aHR: 2.04, 95% CI: [1.08–3.87]), and those with non-HF cause of dyspnea (aHR: 1.02, 95% CI: 0.80–1.32). They conclude that cTnT concentrations are associated with higher 30-day readmissions or all-cause death in patients hospitalized with acute dyspnea irrespective of cause, as well as in those patients with adjudicated diagnosis of HF and HFpEF but not in HFrEF. These results are generally consistent with existing literature showing importance of cardiac troponins for predicting outcomes but contrast with previous studies on showing prognostic importance of cardiac troponin in HFrEF subset [15]. Surprisingly, NT-proBNP measured at the time of hospital admissions failed to predict outcomes in both HF and non-HF patients, despite having higher absolute values in patients with adverse outcomes. This study has several important strengths. First, it shows that cTnT measurements during initial phase of hospitalization can predict short-term outcomes, irrespective of the cause of dyspnea. Such early identification can potentially identify patients who are at high risk for readmissions and death during hospitalization or after discharge. Second, it provides additional evidence that cTnT can prognosticate patients with and without cardiac problems, reflecting its ability to capture complex extracardiac pathophysiology leading to myocardial injury and myonecrosis. Given that the elevation of cTnT is driven by the balance of myocardial oxygen demand (systolic wall tension, contractility, heart rate) and myocardial oxygen supply (coronary blood flow, oxygen carrying capacity), it captures disequilibrium between multiorgan systems including extracardiac factors [16]. Data from TIMI group and TRITON-TIMI 38 trial provided robust evidence that myonecrosis identified using abnormal cardiac troponin levels even in the absence of atherosclerotic plaque rupture was associated with poor prognosis [17]. Third, authors show the significant association of abnormal cTnT with all-cause mortality and 30-day all-cause readmissions, supporting the role of cTnT particular for overall outcomes (CV and non-CV) [18, 19]. While data on cardiac troponin I are not available in current study, high-sensitivity cTnT has been suggested to have stronger association with non-CV comorbidities in head-to-head comparisons even with high-sensitivity troponin I [20]. The ability of cTnT to reflect abnormalities at the level of diseased skeletal muscle [21] might also contribute to these adverse all-cause and non-CV outcomes, given that skeletal muscle dysfunction is prevalent in patients with dyspnea [22]. Robust evidence exists supporting role of cardiac troponins as prognostic markers of mortality and readmissions in both HFpEF and HFrEF patients [15, 23]. The current study aligns with previous data in HFpEF subgroup as discussed by authors highlighting cTnT’s ability to capture predictors of adverse outcomes such as new ischemic events, structural changes in the left ventricle, increased filing pressures, endothelial dysfunction, and chronic inflammation. In contrast, the outcomes of HFrEF group were not predicted by the cTnT measurements. NT-proBNP to a greater surprise failed to show any significant association with outcomes in overall dyspnea group and even in HF patients unlike published literature [24–27]. Such findings can plausibly be due to lack of sample size (type II error), selection bias, single center, short-term follow-up, and collection of biomarkers posttreatment. As authors note that NT-proBNP fluctuate depending on changes in the volume status and with changes in hemodynamic parameters such as heart rate or blood pressure; hence, whether single-sample emergency room (ER) measurement of natriuretic peptides for prognosis purposes is appropriate versus serial testing during hospitalization versus prior to discharge remains unknown [28]. O'Brien et al. found that pre-discharge, but not admission, levels of NT-proBNP predict adverse prognosis following acute HF [28]. The current study relies on the values at a single point in time and does not contain serial measurements that are needed for identification of high-risk phenotype and optimal management of patients [29, 30]. The study lacks details regarding the baseline medications or those used during ER/hospital stay/discharge, acuity, or duration of dyspnea prior to ER visit and pulmonary vascular disease. The outcomes are limited to 30-day events and association with long-term outcomes remains unknown [26, 28]. Also, other key details related to major adverse CV events, and reasons for readmissions were not captured. The study data are more than a decade old and how does such data apply to the current practice after lifesaving and threatening events for dyspnea patients such as introduction of angiotensin receptor/neprilysin inhibitor, sodium-glucose cotransporter-2 inhibitors, COVID-19 pandemic needs further exploration. We are grateful to Bhatnagar and colleagues for addressing an issue at the heart of patients suffering with dyspnea. There remains room to improve and identify the best prognostication strategy, single biomarker or multistage adaptive biomarker, or comprehensive risk model incorporating serum, clinical and genetics information. Looking to the future, as we develop better understanding of the biomarkers, focus should be on individualized approach to medicine. This needs to occur hand in hand with the technological advancements that have opened doors to omics application for integrative personalized medicine. There is an urgent need to pursue innovative studies and trials to demonstrate the utility of existing and new biomarkers in sync with multi-omics risk profile models to create a unique biosignature for improving the outcomes of our patients with dyspnea. Conflict of Interest Statement M.A. and W.M.: none. J.B.: J.B. is a consultant to Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronic, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, PharmaIN, Roche, Sequana, SQ Innovation, 3live, and Vifor. Funding Sources No funding was received relevant to this study, preparation of data or the manuscript. Author Contributions Manyoo A. Agarwal, Wael AlMahmeed, and Javed Butler drafted, reviewed, and revised the manuscript.