A patient arrives at hospital with chest pain. Doctors suspect heart attack and rapid diagnosis is important, but the tests to confirm it can be invasive and it could easily be something else. Could a simple blood test help to non-invasively rule heart attack in or out?
A new study in open access journal Frontiers in Cardiovascular Medicine certainly suggests so. The study identified telltale markers in the blood of heart attack patients that distinguished them from patients suffering chest pain with other causes. The researchers hope that the results will lead to new diagnostic tests for heart attacks.
If you have ever suffered chest pain, the possibility of a heart attack may have popped into your head. While chest pain is an important symptom for heart attacks, there are a variety of other conditions that can cause similar symptoms, and many of them are not serious.
If a patient presents with chest pain at hospital, doctors need to quickly determine if a heart attack is the culprit. Early treatment is important in limiting the damage that occurs.
At present, this may involve coronary angiography, where a catheter is placed into the blood vessels of the heart. While effective, angiography is invasive, and not something you would like to undergo if unnecessary. In addition, in busy or poorly resourced hospitals, angiography may not always be available in time.
Another test involves taking a blood sample to check for proteins that indicate damage to the heart muscle. However, these markers are sometimes unreliable, and can be elevated by other conditions.
These issues inspired these researchers to look for new markers in the blood that form a unique fingerprint for a heart attack. They turned to small molecules called metabolites that are produced during biochemical processes within our bodies.
“We analyzed circulating metabolites in blood plasma samples from cardiac chest pain patients, including heart attack cases and other cardiac chest pain cases, to identify potential markers for heart attack diagnosis and early warning,” explained Dr. Xiangqing Kong of the First Affiliated Hospital of Nanjing Medical University, corresponding author on the paper.
“Such markers could be helpful in confirming heart attack in a timely manner when angiography is unavailable.”
The researchers collected blood samples from 146 patients who presented at hospital with chest pain and 84 healthy volunteers. Of the 146 chest pain patients, 85 were later confirmed to have suffered a heart attack and the remainder had chest pain from other causes.
Strikingly, on analyzing the samples, the researchers found an array of metabolites that were present in different amounts, and the differences were significant enough that they could successfully distinguish between the samples from heart attack patients, those with non-heart attack-related chest pain and the healthy volunteers. Three metabolites showed particular promise as diagnostic markers.
“Even after accounting for other cardiac risk factors such as hypertension, smoking and diabetes history, the metabolites deoxyuridine, homoserine and methionine scored highly as potential diagnostic and risk markers of heart attack,” explained Dr. Jiye Aa of the China Pharmaceutical University, another author on the paper.
In reality, a suspected heart attack patient will likely undergo various tests before a heart attack is confirmed, but expanding the available arsenal of reliable tests will be useful for doctors in narrowing things down quickly. The researchers plan to conduct further research to assess why and how these biomarkers are involved in heart attacks.
According to the World Health Organization (WHO), cardiovascular disease (CVD) is the number one cause of death globally and is responsible for 45% of all deaths, equating to >4 million deaths per year in Europe . Its high morbidity, mortality, and high rate of rehospitalization have forced a number of researchers to search for the best way to diagnose, stratify risk, and manage patients with suspected cardiovascular diseases, among which acute coronary syndrome (ACS) and heart failure (HF) are most commonly studied.
Acute coronary syndrome, usually caused by decreased coronary artery perfusion due to stenosis or distal embolization of the thrombus  and sudden total occlusion of a coronary artery by thrombosis, typically presents with the main symptoms of acute chest pain and persistent ST-segment elevation in an electrocardiogram (ECG).
However, there are a small number of patients without obvious symptoms or changes in the ECG. Thus, the measurement of a number of cardiac biomarkers is urgently needed to help with early diagnosis, risk stratification, and management of acute coronary syndrome. Heart failure is the terminal stage of a wide range of cardiovascular diseases that result in the decompensation of the heart’s ability to contract or relax, also defined as a clinical condition with typical symptoms and signs .
The pathophysiological process involves the release of a series of factors, hormones, and proteins into the bloodstream, which could subsequently be used as diagnostic biomarkers.
Classically, biomarkers, such as cardiac troponin and the natriuretic peptides (NPs), associated with acute coronary syndromes and heart failure, respectively, play an important role in routine clinical practice. The ideal biomarker for detecting myocardial injury needs to be expressed at relatively high levels within cardiac tissue, with high clinical sensitivity and specificity that is detectable in the blood early after the onset of symptoms, such as chest pain .
As there are numerous cardiac biomarkers, it is useful to classify biomarkers into various pathophysiologic groups, such as myocardial ischemia or necrosis, inflammation, hemodynamics, angiogenesis, atherosclerosis, or plaque instability . Cardiac troponin (cTn), expressed as three similar isoforms (I, C, and T), is the biomarker of choice for the diagnosis of myocardial necrosis because it is the most sensitive and specific biochemical marker of myocardial ischemia/necrosis available .
It has been demonstrated that plasma cTn content is elevated in many cardiovascular diseases other than acute myocardial infarction, including acute or chronic heart failure, aortic dissection, myocarditis, takotsubo cardiomyopathy, atrial fibrillation, and stroke .
The mechanisms underlying the release of cTn into the bloodstream are believed to include cell turnover, myocyte apoptosis, necrosis and reversible injury, increased cell membrane permeability, and release of cardiac troponin degeneration products [7, 8]. Studies have also shown that membranous blebs enable the release of cardiac troponin in response to ischemia without necrosis .
Among the isoforms, the most specific markers for acute coronary syndromes are cardiac troponin I (cTnI) and cardiac troponin T (cTnT), the elevations of which have become a predominant indicator for acute myocardial infarction (AMI)  and are considered the “gold standard” in AMI diagnosis.
Natriuretic peptides (NPs), composed of three structurally similar peptides, that is, atrial natriuretic peptide (ANP), B-type (or brain) natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), play an important role in cardiovascular disease  and are elevated to a large extent in response to increased wall stretching due to volume or load stress in HF. BNPs play a critical role in maintaining homeostasis in the cardiovascular system, serving as counterregulatory hormones for volume and pressure overload .
The levels of blood BNP and the N-terminal pro-B-type natriuretic peptide (NT-proBNP) are widely measured in clinical applications for the diagnosis, risk stratification, and management of patients with heart failure, as they are the closest to optimal biomarker standards for clinical implications in HF . Higher natriuretic peptide levels increase the likelihood that the etiology of dyspnea is due to HF .
We performed PubMed and Web of Science searches for original studies and screened reference lists to identify possible relevant studies by searching the literature from 2003 to 2019. Search terms were “biomarker,” “new biomarker,” “B-type natriuretic peptide,” “cardiac troponin,” “C-reactive protein,” “copeptin,” “endothelial cell-specific molecule 1,” “interleukin-6,” “inflammatory medium,” “cardiac myosin-binding protein C,” “gene expression biomarkers,” “heart-type fatty acid binding protein,” “platelet related biomarkers,” “transmembrane and soluble isoforms,” “cystatin C,” “microRNA,” “acute coronary disease,” “coronary artery disease,” “heart failure,” “non–ST-elevation acute coronary syndrome,” etc. Studies were included if they were prospective, retrospective, randomized controlled trials or animal models.
This article will provide an overview of cardiac biomarkers, mainly focusing on the recent studies of the role and applications of cTn and NPs in the diagnosis, risk stratification, and management of patients with acute coronary syndromes and heart failure. Additionally, this article reviews some biomarkers related to acute coronary syndromes and heart failure that may have potential clinical value in the future.
The Most Popular and Effective Biomarkers
The cTn complex is one of the components of the thin filament and it plays a significant role in the regulation of muscle contraction. This complex is composed of three isoforms, namely, cTnC, which binds Ca2+, cTnI, which inhibits the ATPase activity of actomyosin, and cTnT, which interacts with actomyosin. cTn mediates the interaction between actin and myosin and thereby regulates cardiomyocyte contraction .
cTnI and cTnT are the two isoforms expressed in the cardiac muscle only (cTnC is also expressed in the skeletal muscle), and they have been verified to be specific and sensitive biomarkers of myocardial damage [16–18], which is particularly important in asymptomatic patients, when combined with other biomarkers and examinations . Many researches have proved that cTn is a more sensitive and specific marker of cardiomyocyte injury than creatine kinase (CK), its MB isoenzyme (CK-MB), and myoglobin .
In clinical practice, high-sensitivity cTn (hs-cTn) assays are recommended over sensitive cTn or traditional cTn [16–18, 20] because they enable accurate quantification of troponin in most healthy people . In addition, the hs-cTn assay presents a superior prognostic performance in the non–ST-elevation acute coronary syndrome (NSTE-ACS), compared to the commercial fourth-generation cTnT assay [22, 23].
cTn is an integral criterion in the diagnosis of AMI. According to the 2015 European Society of Cardiology (ESC) guidelines for NSTE-ACS, the measurement of a biomarker of cardiomyocyte injury, preferably hs-cTn, was mandatory in all patients with suspected NSTE-ACS .
This can serve to confirm the diagnosis in symptomatic patients with diagnostic electrocardiographic changes . An undetectable level of hs-cTn at presentation has a high negative predictive value and allows the rapid rule-out of AMI in patients with acute chest pain . The elevation of hs-cTn usually occurs within 3–12 hours and persists for 5–14 days after the onset of symptoms in patients with AMI .
Data from several large multicenter studies have consistently shown that hs-cTn assays increased the accuracy of the AMI diagnosis at the time of presentation to the emergency department (ED) [16, 20, 26]. Blood levels of hs-cTn must be evaluated at the time when patients come into ED with the complaint of chest pain. If the level is over the upper limit of normal (ULN) or the pain persists no more than 6 hours, especially without typical changes in ECG, hs-cTn should be retested .
When the initial level is above ULN or the retest level is increased accompanied by typical changes in the ECG, the patient should be treated as soon as possible because the diagnosis of AMI is highly suspected. However, if the initial level of hs-cTn is normal, the time interval to the second cardiac troponin assessment remains controversial. For rapid rule-out in AMI patients with hs-cTn, two alternative approaches using the 0 h/1 h algorithm or 0 h/3 h algorithm have been adequately validated and may be considered .
It has been confirmed that the addition of the 1h-hs-cTn measurement significantly promotes the diagnostic accuracy in the patients with mild cTn elevation . The ESC recommended that the rule-in using the 0 h/3 h algorithm has a high positive predictive value, while the sensitivity remains too low for clinical use . However, increasing age reduces the rule-in accuracy of the 0 h/1 h algorithm, and therefore, a modest increase in the cut-off point is recommended which can still maintain the rule-out safety .
With regard to the gender factor, researches have demonstrated that the gender-specific hs-cTnT cut-off point only has modest influence compared to the age factor . Another study showed that the downward adjustment of hs-cTn thresholds in women may be warranted to reduce the underdiagnosis of acute myocardial infarction in women . It was also confirmed that revised cut-offs for hs-cTnT based on age and gender only improve the diagnostic performance rather than the prognostic risk prediction for death or other adverse events .
One report has shown that while hs-cTnT and hs-cTnI seem to have comparable diagnostic accuracies, hs-cTnI had greater early diagnostic accuracy . That suggests that hs-cTnI can be examined separately to rule-in or rule-out patients in time if possible in the advanced analytical technique.
Additionally, another study showed that the hs-cTnT blood concentration exhibited a diurnal rhythm, characterized by gradually decreasing concentrations throughout the daytime, rising concentrations during nighttime, and peak concentrations in the morning . The rhythm does not seem to affect the diagnostic accuracy for AMI, except for screening purposes. hs-TnI does not seem to express the same rhythm, it demonstrates high diagnostic accuracy for AMI, and it does not differ with time of presentation .
Beyond diagnostic utility, cTn levels provide prognostic information in predicting short- and long-term outcomes based on clinical and ECG variables. Numerous studies have demonstrated a strong independent relationship between cTn and prognosis . Meta-analysis indicated that in patients with NSTE-ACS the short-term odds of death were increased three- to eightfold for patients with an abnormal troponin test, and in patients with suspected ACS, those who had a negative troponin test had an overall mortality between 0.7% (troponin I, cohort studies) and 2.1% (troponin I, trial studies) .
However, unlike in the diagnosis of AMI, frequent and serial measurements are not necessary, because an isolated measurement on the first postoperative day is enough to identify high-risk subgroups, and changes of hs-cTn do not seem to further improve risk stratification beyond initial presentation values . In the study by Shah et al., almost two-thirds of the patients with suspected ACS could have been discharged with very few cardiac events, using the standard of cTn concentration of less than 5 ng/L .
However, for those who are well within the normal reference interval, increasing cTn concentrations is positively associated with adverse cardiovascular outcomes in primary prevention populations . Both hs-cTnI and hs-cTnT were predictive for all-cause mortality. Notably, hs-cTnT measurement showed superior prognostic performance in predicting long-term all-cause mortality compared with hs-cTnI .
BNP or NT-proBNP
BNP is synthesized and released by cardiac ventricular cells in response to volume or pressure overload . Both active BNP and inactive NT-proBNP are generated from the cleavage of proBNP and therefore they are secreted into the bloodstream in equal concentrations . While ANP is stored as the preform in the intracellular granules, BNP is predominantly synthesized when triggered by extracellular stimuli. After secretion into the bloodstream, the BNP will then bind to NP receptors (NPRs) and subsequently activate the intracellular cGMP signaling cascades to reduce the volume or pressure overload. BNP is primarily cleared through the degradation by neutral endopeptidases and partially through the uptake by NPR and renal excretion . BNP and NT-proBNP, the two most commonly used natriuretic peptides, play a diagnostic role in the assessment of heart failure .
They may be increased due to systolic and/or diastolic dysfunction, left ventricular hypertrophy, valvular heart disease, ischemia, or a combination of these factors . In multiple logistic-regression analyses, the measurements of B-type natriuretic peptide added significant independent predictive power to other clinical variables in models predicting which patients had congestive heart failure, with an odds ratio of 29.60.
It is suggested that BNP is the best single predictor of a final diagnosis of HF, compared to individual history, physical examination, chest X-ray, and laboratory findings . Furthermore, the BNP level in the bloodstream has a predictive role for cardiovascular risk in the general population and BNP itself could serve as a therapeutic target for cardiovascular diseases, including hypertension, heart failure, and myocardial infarction .
Guidelines recommend the use of BNP or NT-proBNP in the diagnostic algorithm for HF, especially for the patients whose echocardiography was not found to have an important cardiac abnormality , with higher levels indicating a higher likelihood for AHF to be the main cause of acute dyspnea . These tests help doctors rule out heart failure quickly and identify those who would benefit from additional confirmatory tests, typically echocardiography, or making echocardiography unnecessary [3, 48].
As the 2016 European Society of Cardiology guidelines for HF recommend, the upper limit of normal in the nonacute setting for BNP is 35 pg/mL and for NT-proBNP it is 125 pg/mL; in the acute setting, higher values should be used (BNP, 100 pg/mL, NT-proBNP, 300 pg/mL, and mid-regional pro-A-type natriuretic peptide (MR-proANP), 120 pmol/L) . However, a cut-point of BNP ≤ 54 pg/mL is recommended for ruling out CHF in severely obese patients (BMI ≥ 35) [49, 50], which indicates that the cut-off points varied among different populations, including the elderly, obese patients, patients with renal disease, and even nonacute patients.
According to the 2016 European Society of Cardiology guidelines for HF, when a patient comes into the ED with nonspecific symptoms and signs, such as breathlessness, ankle swelling, and fatigue, there are two alternative paths for clinicians, either echocardiography first or BNP/NT-proBNP first. Because both BNP/NT-proBNP and echocardiography have limitations and the guidelines recommend using them in different situations, it was still worthy of scientific research to explore the association between them Roberts et al. concluded that there was no statistical difference between the diagnostic accuracy of plasma BNP and NT-proBNP, though NT-proBNP had a longer half-life than BNP, and that the measurement of MRproANP may also be a valuable rule-out test for HF [44, 51], which is rarely measured in the current clinical practice. The reason may be that the measurement of ANP in plasma is hampered by marked instability of the hormones, reminding us that biochemical research into detecting the proANP-derived peptides is still worthy of attention .
In addition to their utility in HF diagnosis, the levels of BNP or NT-proBNP are remarkably useful for risk stratification and management of patients with suspected HF. In HF management, the trend of decreasing levels of natriuretic peptide indicates effective management strategies .
Recently, Troughton et al. reported that for patients aged <75 years with chronic heart failure (CHF), with or without impaired left ventricular systolic function, NP-guided treatment can decrease the all-cause mortality and readmission rate compared with clinically guided therapy, even with its potential to unexpectedly induce or exacerbate concomitant disorders . Across the wide range of HF, even at-risk patients, concentrations of BNP and NT-proBNP also have prognostic value .
NT-proBNP can improve the prediction of heart failure in patients with type 2 diabetes . In Piercarlo Ballo’s study, the author measured 1012 asymptomatic subjects with systemic hypertension and/or type 2 diabetes with no clinical evidence of HF and concluded that NT-proBNP measurement could provide more information for the prediction of clinical outcome in asymptomatic, stage A-B HF hypertensive and diabetic patients .
Furthermore, several studies have established that BNP or NT-proBNP also had strong associations with adverse cardiovascular outcomes in a variety of primary prevention and general populations . In addition, assessment of risk stratification is particularly important in planning end-of-life care for patients and when making the decision to undergo surgery (including transplantation) .
Previous meta-analyses have suggested that a single elevated preoperative NP measurement was highly predictive of serious cardiovascular complications after noncardiac surgery , and a recent study has indicated that the addition of a postoperative NP measurement significantly improved the prediction of the mortality or nonfatal MI within 30 days or ≥180 days after noncardiac surgery . All these potential functions for the detection of BNP/NT-proBNP levels still need large randomized multicenter trials to better explore this personalized approach to care.
Combined Use of cTn and BNP/NT-proBNP
Both cTn and BNP are quantitative markers of cardiac damage and widely applied in clinical diagnosis, risk stratification, and management of patients with or without cardiovascular diseases. BNP, widely used for the diagnosis and risk stratification of patients presenting with suspected heart failure, may sometimes be measured after an ACS in order to identify patients at high risk and low risk of adverse outcomes . In patients with NSTE-ACS, NT-proBNP has good and comparable predictive value for 30-day mortality .
In James and his coworkers’ research, they measured BNP in samples obtained three days after the onset of ischemic symptoms in 2525 patients and found that BNP could provide predictive information for use in risk stratification across the spectrum of acute coronary syndromes, such as the risk of new or recurrent myocardial infarction .
CTn, commonly used for the diagnosis and risk stratification in patients presenting with suspected ACS, is sometimes measured to help in determining the etiology or trigger of acute HF (AHF). However, there is considerable overlap in cTn levels from AHF without AMI versus AHF with AMI . Age, renal function, diabetes, hypertension, and a history of heart failure have all been reported as determinants of circulating cTnT concentrations [19, 59, 60].
One report has suggested that the levels of NT-proBNP and hs-cTnT may be useful adjuncts to clinical assessment and that both provide much more prognostic information than the total cholesterol or high-sensitivity C-reactive protein levels in this cohort of patients with type 2 diabetes . The prognostic accuracy of the Global Registry of Acute Coronary Events (GRACE) score was improved when combined with three individual biomarkers including hsTnT, NT-proBNP, and high-sensitivity C-reactive protein (hs-CRP) in patients with acute coronary syndrome . However, another study suggested that a dual-biomarker strategy combining the detection of cTn and BNP does not promote the diagnostic accuracy of inducible cardiac ischemia .
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988690/
More information: Plasma metabolites alert patients with chest pain to occurrence of myocardial infarction, Frontiers in Cardiovascular Medicine, DOI: 10.3389/fcvm.2021.652746 , www.frontiersin.org/articles/1 … 2021.652746/abstract