Non-Cardiovascular Etiologies of Troponin Elevation

Epidemiology

As Tn assays have become more sensitive, the presence of Tn circulating in the serum has been found to be more common in the general population—including in healthy individuals—than previously thought. Of the 3557 individuals enrolled in the Dallas Heart Study to study subclinical cardiovascular disease, conventional TnT was detectable in 0.7% using a conventional assay with a detection limit of <0.01 μg/L [35]. The rate of detectable Tn is significantly higher using an hs-Tn assay, which has a lower limit of detection. For instance, in the Atherosclerosis Risk in Communities (ARIC) study, which included 9593 individuals without preexisting cardiovascular disease, hs-TnT was detectable (≥3 ng/L) in 59% and elevated (>99th percentile URL) in 7% of the study population [36]. When the ARIC study sample was narrowed only to patients with ideal cardiovascular health (including controlled cholesterol, blood pressure, and blood glucose, goal levels of physical activity, and nonsmoking status, with full criteria detailed in the 2010 American Heart Association statement) [37], the prevalence of detectable hs-TnT dropped from 59% to 44% [36]. The Scottish Family Health Study of 19,501 participants yielded similar findings, with detectable hs-TnT (>3 ng/L) found in 53.3% of individuals. This study also measured the levels of hs-TnI, with a lower limit of detection of <1.2 ng/L, and found the prevalence of detectable hs-TnI to be 74.8%, although patients with a history of cardiovascular disease were not excluded on enrollment [38].

Hypothesized Mechanism

The etiology of Tn elevation above the lower limit of detection but below the 99th percentile of normal in asymptomatic individuals has not been fully elucidated. Hs-Tn levels in asymptomatic individuals have positive associations with male sex, age, body mass index, systolic blood pressure (SBP), LV mass, and indices of LV systolic and diastolic function [39]. Minimal hs-Tn levels are further associated with the presence of cardiovascular risk factors, including hypertension, diabetes, and obesity [36,39]. Detectable Tn levels may also be explained by some amount of natural cardiomyocyte turnover. A study examining hearts obtained from the autopsies of 106 men and women found that while myocardial mass is preserved in women, about 1 g of mass is lost per year through the physiological loss of myocardium by necrosis and apoptosis in the normal male heart [40]. Subtle structural abnormalities, such as diastolic dysfunction, resulting from advancing age and the coexistence of cardiovascular risk factors may also contribute to Tn release in asymptomatic individuals [41].

Moreover, a study of hourly measurement of hs-TnT demonstrated that Tn levels exhibit diurnal variation, peaking in the morning (17.1 ± 2.9 ng/L at 8:30 AM), decreasing throughout the day (1.9 ± 1.6 ng/L at 8:30 PM), and then rising again overnight [42]. However, it is unclear whether these fluctuations represent a disease-specific mechanism (e.g., ischemia) or a physiological mechanism (e.g., protein turnover) associated with normal circadian rhythm patterns. Finally, extreme exercise has also been shown to cause Tn elevation in the general population, as discussed in a subsequent section.

Prognostic Implications

Even minimally elevated Tn in asymptomatic patients may be associated with adverse outcomes. In a meta-analysis of 28 trials measuring hs-Tn (variable assays) in 154,052 asymptomatic individuals, the levels of hs-TnI and hs-TnT at the upper limit of the normal range were predictive of cardiovascular mortality [43]. In another study including individual data from 10 prospective population-based studies and 74,738 participants, hs-TnI levels exhibited strong associations with cardiovascular mortality, first cardiovascular events, and overall mortality [44]. In each of the sections that follow, the association between minimally elevated Tn and adverse outcomes will be a recurrent theme. However, at this time, there is no consensus or guideline on how to approach mildly elevated troponins in the setting of acute illness, as clinical management does not necessarily change in the setting of acute illness. The decision on whether an ischemic evaluation is warranted should involve an individualized approach that takes into consideration all clinical data, including the nature of the acute illness and the overall patient prognosis.

Epidemiology

The prevalence of Tn elevation is high in acute respiratory distress syndrome (ARDS). In a study of the Fluids and Catheters Treatment Trial (FACTT) and the Assessment of Low tidal Volume and elevated End-expiratory volume to Obviate Lung Injury (ALVEOLI) trial, which together enrolled 1057 patients with ARDS without signs or symptoms of acute cardiac ischemia, 94% of ARDS patients had detectable hs-TnI levels, and 56% had hs-TnI levels above the 99th percentile of a healthy reference population [156].

Hypothesized Mechanism

In the aforementioned study, the mechanism of Tn elevation in ARDS was surmised to include myocyte necrosis in the setting of critical illness and/or cellular changes in myocytes without necrosis, including increased myocyte permeability, cell membrane changes, and the cellular release of Tn degradation products [156]. It should be noted that in both the FACTT and ALVEOLI trials, patients were excluded from enrollment if they had signs or symptoms of acute cardiac ischemia. This suggests that the Tn elevation in these patients with ARDS occurred via myocardial injury rather than myocardial infarction.

Prognostic Implications

Elevated hs-Tn may be associated with increased morbidity and mortality in ARDS patients [157]. In the study of the FACTT and ALVEOLI trials, increased hs-Tn levels in ARDS were also associated with markers of other organ dysfunction, such as elevated serum creatinine, the Sequential Organ Failure Assessment (SOFA) score, ventilation indices like pH and pCO2, vital signs such as heart rate and body temperature, and abnormal findings on echocardiography including tricuspid regurgitation and regional wall motion abnormalities. However, after adjusting for clinical factors like the SOFA score, heart rate, and vasopressor use, hs-Tn was no longer independently associated with mortality, suggesting that the degree of Tn elevation may simply be a reflection of the underlying stressors of critical illness rather than an active player in the pathogenesis of deterioration [156].

Epidemiology

Tn elevation is common in chronic obstructive pulmonary disease (COPD). Patients with COPD tend to have modestly higher hs-Tn levels at baseline (hs-TnT of 7.75 ng/L) compared to patients without COPD (3.01 ng/L). Additionally, hs-TnT levels tend to be higher in acute COPD exacerbations compared to stable disease, and hs-TnT levels are higher with increasing classes of COPD [158].

Hypothesized Mechanism

Elevated Tn levels in COPD may be a result of hypoxemic pulmonary vasoconstriction, which leads to elevated pulmonary pressure and, consequently, increased RV stretch, strain, and possible myocardial necrosis. This dysfunction is similar to the pathophysiology that occurs secondary to PE [159,160].

Prognostic Implications

Elevated hs-Tn is associated with increased mortality in patients with COPD. In a study of 2741 patients with COPD, elevated hs-TnI levels were an independent prognostic factor for mortality after discharge, regardless of the data analysis methodology and general cardiovascular risk [160]. A cohort study of 1599 patients with COPD further demonstrated a positive association between hs-TnI levels and the risk of cardiovascular events and death [161]. Furthermore, a cohort study of 99 patients hospitalized for COPD exacerbation showed that this association was modified by the heart rate at admission, with a stronger association demonstrated between mortality and hs-TnT in patients with tachycardia [162].

Epidemiology

Persistently elevated Tn is common in patients with end-stage kidney disease (ESKD), even when there is no suspected myocardial ischemia. The prevalence of Tn elevations in ESKD depends on the Tn assay used. For example, in patients with ESKD and no clinical or reported evidence of cardiovascular disease, conventional TnT elevations can be found in up to 53% of patients, and hs-TnT may be detectable in up to 81–99% of patients, while conventional TnI and hs-TnI elevations are less common, found is as few as 6% and 34% of patients, respectively [163–166].

Hypothesized Mechanism

Both increased cardiac release and decreased clearance have been implicated as possible mechanisms for increased Tn in ESKD. A study examining the clearance of conventional TnT in rats and humans found that at high concentrations of TnT (e.g., as occurs after a large MI), the extrarenal clearance of TnT dominates, while at low concentrations of TnT (e.g., in patients with chronic kidney disease [CKD]), renal clearance also contributes to TnT clearance [167]. In addition, increased cardiac release of Tn may occur due to cardiac abnormalities resulting from ESKD, such as increased ventricular pressures, small-vessel coronary obstruction, anemia, hypotension, and direct toxic effects on the myocardium from uremia [1].

Prognostic Implications

Because increased Tn is likely reflective of myocardial injury, it can be an important prognostic indicator. Several early studies, including a meta-analysis of 28 studies and a retrospective study of 733 ESKD patients, showed that elevated conventional TnT (≥0.1 μg/L) is associated with increased cardiovascular and all-cause mortality [168,169]. Similarly, several studies have shown that elevated hs-TnT and hs-TnI are associated with increased risk for long-term major adverse cardiovascular events (MACE), and hs-TnT is associated with increased mortality [170–172].

Diagnosing acute MI in patients with CKD and ESKD can be challenging due to the persistently elevated nature of Tn in these patients. Studies have found that static cutoffs for hs-TnI and hs-TnT have low specificity in detecting NSTEMI in CKD and ESKD patients, in whom Tn can be chronically elevated even without acute myocardial injury. Instead, serial Tn measurements can be used in these patients for higher diagnostic accuracy of acute MI, and changes in ECG or imaging and clinical judgment must be considered for diagnosis. It is important to remember that a lack of increase in serial Tn levels may make acute MI less likely but does not indicate the absence of baseline CAD, as renal dysfunction and CAD are correlated [5,173].

Epidemiology

Elevated Tn may be seen in patients with acute kidney injury (AKI) alone, without other conditions known to cause elevated Tn. In a cohort study of 19 patients with AKI (excluding patients with concomitant multi-organ failure, acute MI, myocarditis, pericarditis, infiltrative cardiac disease, arrhythmia, PE, congestive HF, and sepsis), elevated conventional TnT and TnI were found in 30% of patients. These elevations were more common in certain scenarios, including older age, a history of ischemic heart disease, and abnormal ECG [174].

Hypothesized Mechanism

Tn elevation in patients with AKI but no cardiac disease may be due to the decreased renal clearance of normally released Tn [174,175]. In patients with comorbid conditions, it is likely that factors that precipitate AKI also precipitate myocardial injury, leading to Tn release. Of note, kidney function decreases during AKI and increases during the recovery phase, leading to a rise-and-fall pattern in Tn that may mimic acute MI [176].

Prognostic Implications

The significance of elevated Tn in AKI without confounding comorbidities is not well studied.

Epidemiology

Tn elevations may be seen in all types of stroke, including ischemic stroke and intracerebral or subarachnoid hemorrhage. Tn elevations are found in 30–60% of patients with acute ischemic stroke (hs-Tn) [177–180], 11–52% of patients with subarachnoid hemorrhage (conventional Tn) [181,182], and 41% of intracerebral hemorrhages (conventional TnI) [183]. Several comorbidities increase the risk of hs-TnT elevation after stroke, including older age, structural or coronary heart disease, and impaired renal function [179,184,185].

Hypothesized Mechanism

It is thought that Tn elevations in stroke are a result of the activation of the sympathoadrenal system and increased catecholamine release, which can lead to direct myocardial toxicity, demand ischemia, LV dysfunction, arrhythmias, possible plaque instability causing MI, and neurogenic sudden cardiac death [177,186–188].

Prognostic Implications

Elevations in Tn increase the risk of adverse outcomes after stroke. In ischemic stroke, hsTnT and TnI elevations are associated with s decline in cognitive function and an increased risk of cardiac complications, including reduced LV function, arrhythmias, and MACE [178,186,189,190]. In subarachnoid hemorrhage, several meta-analyses showed that conventional Tn elevations were associated with increased mortality, more delayed cerebral ischemia, and worse neurologic status [181,182,187]. Adverse outcomes of Tn elevations in intracerebral hemorrhage are not as well studied but may be associated with worse functional status and increased mortality [191,192].

Epidemiology

Tn elevations are common in critically ill patients, including patients with sepsis and septic shock. It is estimated that 31–80% of patients with systemic inflammatory response syndrome (SIRS; the study was conducted prior to the phasing out of the SIRS definition), sepsis, or septic shock have elevated conventional TnT and TnI levels [193]. Using hs-Tn assays, one study found elevated hs-TnI in 60% of patients (excluding patients with other apparent causes of Tn elevation) [194], and another found hs-TnI elevations in 47% of patients (excluding post-cardiac arrest patients) [195].

Hypothesized Mechanism

The mechanism of Tn elevation in sepsis and septic shock in the absence of ACS is not fully understood but may be related to a myocardial oxygen demand–supply mismatch, microvascular dysfunction, increased myocardial cell membrane permeability, and the presence of myocardial depressive factors like inflammatory mediators [193].

Prognostic Implications

Tn elevations in sepsis and septic shock are associated with an increased risk of cardiovascular complications, even in patients without preexisting cardiovascular disease. In a retrospective study of over 14,000 patients with sepsis and no CAD, elevated conventional TnI was found to be associated with an increased risk for the development of atherosclerotic cardiovascular disease, atrial fibrillation, and HF [196]. Furthermore, several studies have found associations between elevated Tn (conventional Tn and hs-TnI) in sepsis and mortality [194,197,198].

Epidemiology

Exercise-induced Tn elevation is a known phenomenon. For example, in a systematic review of 16 studies (936 participants), 0.6% of participants had detectable conventional Tn prior to running a marathon, while 62% of post-marathon participants were found to have detectable Tn, and 15% were found to have Tn above the myocardial necrosis threshold [199]. Two recent studies using hs-TnT and hs-TnI found that all marathon runners had detectable levels after a race [200,201].

Hypothesized Mechanism

A proposed etiology for the Tn increase in exercise is increased myocyte cell membrane permeability, likely due to transient wounding of the sarcolemma or stress-mediated integrin-stimulated Tn release [202].

Prognostic Implications

The clinical relevance of Tn elevation after exercise is not clear [203]. Many studies have found no association between elevated post-exercise Tn (in both healthy patients and patients with angina) and an increased risk of adverse outcomes [204–207]. One recent study found an association between detectable conventional Tn after long-distance walking and an increased risk of long-term MACE, although the sample consisted of middle-aged adults, making the findings inapplicable to younger athletes [208]. Because of the unclear significance of elevated Tn after exercise, it is suggested that patients seeking care after exercise who are found to have elevated Tn be evaluated for ACS using the standard protocol [202].

Epidemiology

The reported incidence of cardiac injury following blunt chest trauma is variable, largely due to a lack of standardized diagnostic criteria. Therefore, Tn elevations are also variable based on the classification of the trauma. Using conventional Tn assays, various studies have found detectable levels of TnI in 44–50% and elevated levels of TnI and/or TnT in 23–43% of patients with blunt chest trauma [209,210]. Using high-sensitivity assays, a study of 82 patients with blunt chest trauma found detectable levels of hs-TnT in 34% and elevated levels in 66% of patients [211].

Hypothesized Mechanism

Six potential mechanisms have been suggested for blunt cardiac injury: direct (the most common), indirect, bidirectional, deceleration, blast, crush, concussive, or combined [212]. The most common cardiac injuries from blunt trauma resulting in death are due to transmural cardiac chamber rupture, venous–atrial confluence tears, or coronary artery tears or dissection [213].

Direct trauma and damage to cardiac structures can result in the loss of integrity of cardiac myocytes, resulting in Tn release. Tn release may also happen more indirectly through increases in intracardiac pressure. Indirect increases in cardiac preload from the abdominal or extremity veins cause a sharp increase in intracardiac pressure and subsequent myocardial injury. This type of injury is most likely at the end of diastole, when the ventricles are already maximally dilated [214]. This suggests that an increase in intracardiac pressure through these multiple mechanisms is another etiology of Tn release, which is consistent with multiple studies showing that Tn release is associated with increased wall stress and myocyte stretch [63–65].

Furthermore, sequelae of trauma, including shock, hypoxia, thermal injury, and sepsis, can contribute to Tn release [215]. In fact, in a large series of 1081 patients, the degree of TnI elevation was more strongly related to the degree of overall injury and physiological stress than to mechanical chest trauma itself [216].

Prognostic Implications

Higher Tn levels are associated with significantly higher injury severity scores, the need for pressors, and mortality [216,217]. Multiple studies have shown that in patients with normal ECG findings and serial measurements of conventional TnI within the reference interval, there was no development of significant blunt thoracic trauma (defined as cardiogenic shock, arrhythmias requiring treatment, structural cardiac abnormalities directly related to the cardiac trauma) [209,210]. In one study of 115 patients with blunt chest trauma, ECG and conventional TnI had positive predictive values of 28% and 48% and negative predictive values of 95% and 93%, respectively, for significant blunt cardiac injury. However, when both tests were concordant (both abnormal or both normal), the positive and negative predictive values increased to 62% and 100%, respectively [209]. Using hs-Tn assays, elevated hs-TnT is associated with higher in-hospital mortality, a higher number of ventilator days, and lower Glasgow Outcome Scale scores on discharge [211]. Therefore, in the absence of other injuries or hemodynamic instability, patients with normal ECG and Tn can be discharged, whereas increased Tn may serve to identify patients at increased risk of mortality.

Epidemiology

Patients presenting with rhabdomyolysis may have elevated conventional TnI levels in 11–30% of cases [218–220]. In one study using hs-Tn assays, hsTnT and hsTnI levels were elevated in 63.5% and 41.6% of patients with rhabdomyolysis, respectively (although this study did not exclude patients with preexisting cardiac disease) [221].

Hypothesized Mechanism

In patients without ACS, the etiology of Tn elevation in rhabdomyolysis is unclear. Proposed mechanisms include direct injury from free radicals, acidemia, or cytokines; hypotension; and myocardial stretch from aggressive fluid resuscitation [219]. Others propose that these are false-positive elevations that may represent minor cardiac injury or cross-reactivity with skeletal forms of Tn [218].

Prognostic Implications

Studies on the risks of elevated conventional Tn in rhabdomyolysis show mixed results regarding the increased risk of mortality, although a large study of 404,369 patients with rhabdomyolysis showed an increased risk of mortality and a higher hospital cost in patients with elevated Tn [219,222]. Treatment with fluid resuscitation has been found to reduce measured serum Tn levels to baseline, but patients at risk for CAD should undergo evaluation after the resolution of rhabdomyolysis [155,221].

Epidemiology

Many patients with hereditary or acquired skeletal myopathy have elevated Tn on testing. In two studies of patients with various types of skeletal myopathy and no known cardiac disease, elevations in hs-TnT were common (68% and 69%) [223,224]. On the other hand, the percentage of hs-TnI elevation is less common and tends to be similar to that of the general population [223,225].

Hypothesized Mechanism

Discussion is still ongoing regarding the etiology of elevated Tn in myopathy. Some suggest that cardiac Tn is re-expressed in skeletal muscles after injury and is released into the bloodstream, while others posit that skeletal TnT can cross-react with cardiac TnT and lead to false-positive Tn elevation [223,226]. In skeletal myopathies without cardiac involvement, the source of elevated TnT is skeletal rather than cardiac and is therefore less likely to be indicative of cardiac involvement in the absence of a change in serial Tn measurements [223,227]. On the other hand, isoforms of skeletal and cardiac TnI are unique, and TnI is rarely elevated in patients with skeletal myopathy and no known cardiac disease. Therefore, TnI elevations are typically seen in myopathies that tend to have cardiac involvement and can reflect myocardial fibrosis, myocardial inflammation, and recurrent, focal microvascular ischemia [223,228].

Prognostic Implications

The prognostic implications of elevated Tn in skeletal myopathy are not well studied. One study of 142 patients with idiopathic inflammatory myopathy (IIM) found that elevated levels of hs-TnI in IIM patients were associated with cardiac involvement. On the other hand, increased levels of TnT were associated with weakness and reduced daily living function but not cardiac involvement [229].

Epidemiology

Tn can become elevated in patients receiving various chemotherapy drugs for cancer treatment, most commonly anthracyclines, trastuzumab, immune checkpoint inhibitors, and vascular endothelial growth factor (VEGF) inhibitors. In a large early study of patients receiving chemotherapy, conventional TnI elevations were seen in 30% of patients on anthracyclines and 14% of patients on trastuzumab [230]. A recent large prospective study found hs-TnI elevations in 11.2% of patients on immune checkpoint inhibitors [231]. Data on Tn elevations in patients on VEGF therapy are scarce, despite the known association between VEGF and LV dysfunction [232].

Hypothesized Mechanism

Tn elevations in patients receiving chemotherapy are often reflective of myocardial injury, which can occur through direct toxic effects on the myocardium (anthracyclines), indirect effects that lead to a decline in cardiac function (trastuzumab and VEGF inhibitors), or inflammatory cell infiltration in the myocardium (checkpoint inhibitors) [232].

Prognostic Implications

Tn assays are an important screening tool for the early assessment of chemotherapy-related cardiac injury. For example, multiple studies found that hs-TnT and hs-TnI elevations were predictive of LV dysfunction in patients on anthracyclines and/or trastuzumab [233–236]. In patients on immune checkpoint inhibitors, elevated conventional Tn was associated with myocarditis and the risk of MACE, including cardiovascular death, cardiogenic shock, cardiac arrest, or complete heart block [237]. Because Tn elevations can be detected prior to echocardiographic changes, the assay can allow clinicians to identify patients who require cardiotoxicity prevention or treatment and to monitor the response to therapy in patients who have developed cardiotoxicity [232,238].

Epidemiology

Patients presenting with acute gastrointestinal bleeds (GIBs) may have elevations in Tn, an important finding given that cardiovascular-related deaths account for 30% of deaths in patients with acute GIB who survive the initial bleeding episode [239]. The prevalence of conventional TnI elevation in acute GIB is 10–19%, depending on the study. However, these studies did not control for risk factors and comorbid conditions like chronic kidney disease and coronary artery disease, which were more likely to be found in the TnI-positive group [239–241].

Hypothesized Mechanism

The mechanism of Tn elevation in GIB is multifactorial and may include decreased oxygen supply due to anemia, increased oxygen demand due to tachycardia, and, in patients who develop sepsis, cytokine release, leading to increased myocyte permeability [241,242]. Another possible mechanism is that patients with elevated hs-TnT may also have subclinically elevated venous filling pressures, which may increase gastrointestinal mucosal congestion and subsequently increase the likelihood of GIB. Additionally, since studies have found associations between hs-TnT and microvascular disease, an increased incidence of microvascular disease may be contributing to fragile, poorly healing, and injury-prone vessels in the gastrointestinal tract [243].

Prognostic Implications

In patients admitted for GIB, elevated conventional Tn levels are associated with higher mortality, though this may be confounded by the higher prevalence of CKD, CAD, HF, and hypertension in this group [239–241]. In one study that adjusted for GIB severity and baseline characteristics, elevated Tn was associated with increased long-term mortality but not increased 30-day mortality [242].