Cardiovascular Etiologies of Troponin Elevation

Epidemiology

The prevalence of Tn elevation in the setting of tachyarrhythmia is generally estimated to be between 30% and 50%. In one study of 100 patients with supraventricular tachyarrhythmias (atrial fibrillation [AF], atrial flutter [AFL], and reentrant tachycardia), 44.2% of initial hs-TnT testing and 50.7% of repeat testing were positive [45]. In another study of 73 patients with tachyarrhythmia, 32.9% had abnormal conventional TnT values, and the magnitude of Tn elevation was associated with the degree of tachycardia [46]. Similarly, a study utilizing conventional TnI assays found that 37.2% of 78 patients with supraventricular tachycardia had elevated TnI [47]. On average, Tn release in the case of tachyarrhythmia is not as high as in NSTEMI [48].

Hypothesized Mechanism

Tn elevation in the setting of tachyarrhythmia is often an indicator of myocardial injury and a supply–demand mismatch from increased energy demands rather than coronary artery obstruction or myocardial necrosis [49]. Several studies have demonstrated that many patients with Tn elevation in the setting of tachyarrhythmia have unobstructed coronary arteries on invasive coronary angiography [46,50]. In a study of 10 patients undergoing rapid atrial pacing during diagnostic angiography, rapid atrial pacing was found to increase hs-TnT levels even in patients without CAD or evidence of myocardial ischemia [51]. Another possible mechanism is a shortened duration of diastole, leading to reduced coronary perfusion and subsequent subendocardial ischemia [52].

Prognostic Implications

The presence of elevated Tn with supraventricular tachycardia (SVT) has been associated with worse outcomes across multiple retrospective studies. For instance, one study examining 78 patients who had SVT found that even mild elevations in conventional TnI were associated with an increased risk of the composite outcome of death, myocardial infarction, or cardiovascular rehospitalization [47]. Although a more recent single-center study found no significant correlation between hs-TnI and mortality, their findings were limited by a small sample size, the presence of a nearby unaffiliated cardiology center, and an extremely low event rate (one instance of mortality from non-cardiac causes over the study period) [53]. There is increasing evidence that Tn may have higher prognostic importance in certain subsets of patients with SVT. For instance, one study demonstrated that while elevations in conventional TnI > 99th percentile URL at admission or 4 h after the onset of SVT were predictive of a composite of MI, new-onset heart failure, or sudden cardiac death, this effect was more pronounced for patients with a rate <85% of their age-predicted maximum compared to those with rates above this threshold [54]. Similarly, another retrospective trial found that over a mean follow-up period of nearly 2 years, elevated TnI on admission independently predicted a composite outcome of death, MI, or PCI only in patients with known CAD (hazard ratio = 3.3, p = 0.05) [55].

Epidemiology

Both acutely decompensated and chronic heart failure (HF) are associated with elevated TnI [56], regardless of the presence of coronary artery disease [57]. Elevated conventional Tn has been found in 15–29% of patients with chronic HF [57–59]. Mean conventional TnI levels are significantly higher in HF patients than in healthy controls and are negatively correlated with LV ejection fraction values in HF patients [58,59]. In a meta-analysis of 10 studies including 9289 patients with chronic HF (mostly HF with reduced ejection fraction), the median hs-TnT was 15 ng/L, 18 ng/L, and 22 ng/L in the <40%, 40–49%, and ≥50% LV ejection fraction groups, respectively [60].

Hypothesized Mechanism

Various nonischemic and ischemic mechanisms have been proposed to explain elevated Tn levels in HF. Tn can be elevated by increased ventricular preload in the absence of coronary ischemia or coronary disease [57,61]. Some studies suggest that even brief periods of pressure overload begin to manifest biochemical and histopathologic signs of myocardial damage. For instance, a study using porcine hearts showed that 1 h of phenylephrine-induced elevations in SBP and LV end-diastolic pressure caused TnI elevations above the URL for over 24 h, as well as transient myocardial apoptosis without ischemic disturbances on imaging [62]. Pressure and volume overload increase myocardial wall stress, which can directly cause Tn release independent of ischemia [56,63,64]. It has also been hypothesized that the stimulation of stretch-responsive integrins in the overloaded state may result in Tn release [65].

Tn elevation in chronic HF may also be linked to ventricular remodeling and progressive myocyte loss from necrosis, apoptosis, and autophagy [56,66]. TnI elevation has been found to be independently correlated with LV wall thickness due to increased LV mass [67]. The increased wall stress caused by pressure and volume overload also predisposes the ventricular wall to hypertrophy and fibrosis. A thickened myocardium is thus susceptible to a myocardial demand–supply mismatch, impairing subendocardial microvascular perfusion and worsening ischemia [67–69]. Notably, Tn levels tend to be higher in patients with ischemic cardiomyopathies compared to those with dilated cardiomyopathies [70].

Prognostic Implications

Tn elevations are associated with impaired hemodynamic profiles in patients with HF, including lower ejection fractions, lower cardiac indices, higher systolic pulmonary artery pressures, higher wedge pressures, higher B-Type Natriuretic Peptide (BNP) levels, and a higher clinical grading of HF [56]. In light of these multifactorial insults, a meta-analysis showed that elevated hs-TnT in chronic HF is independently associated with all-cause mortality, cardiovascular mortality, and cardiovascular hospitalization [60], and other studies showed that both conventional TnT and hs-TnT are associated with mortality and combined adverse cardiovascular outcomes [71,72].

Epidemiology

Historical studies estimate that one-third of patients with myocarditis have abnormal values of conventional Tn. In a study including 53 patients with a histological diagnosis of myocarditis, conventional TnI was elevated in 34% of patients with myocarditis [73]. In another study of 80 patients with clinically suspected myocarditis, TnT was detected in 28 (35%) of serum samples [74]. However, these studies are several decades old. The prevalence of elevated Tn in milder cases of myocarditis is likely higher in the present day with the widespread use of hs-Tn. In a study of the transition from conventional to hs-Tn at a single center, the transition from using conventional to hs-Tn was associated with a two-fold increase in the diagnosis rate [75].

Hypothesized Mechanism

Elevated Tn can be found in patients with myocarditis in whom CAD has been excluded [76,77]. It has been postulated that this is due, at least in part, to transient ischemia caused by coronary vasospasm [78]. Given that Tn elevation can be seen in the absence of LV dysfunction in cases of myocarditis, it is thought that Tn release is more likely due to transiently increased membrane permeability of myocyte membranes rather than true cell necrosis [79]. It has been postulated that this increased permeability and subsequent Tn release is the result of the direct cytotoxic effects of infectious agents (viruses, bacteria, etc.), exogenous toxins, and autoantibodies directed against cardiomyocytes [80].

Tn elevation can also be seen in cases of pericarditis. The prevalence of Tn elevation in pericarditis has been described as 32% [76], 49% [77], and 71% [81] in different studies prior to the introduction of hs-Tn. Notably, although Tn elevation is reported in cases of pericarditis, Tn is not found in the pericardium itself [69,81]. Therefore, Tn elevation in pericarditis likely represents the concurrent involvement of the myocardium (e.g., inflammatory involvement of subepicardial myocytes), and the presentation is better characterized as myopericarditis or perimyocarditis, with similar mechanisms of Tn release to those in myocarditis.

Prognostic Implications

Patients with myocarditis and Tn elevation typically have similar features and outcomes to those of their counterparts without Tn elevation. In a study of 80 patients with clinically suspected myocarditis with and without elevated values in conventional TnT assays, the frequency of clinical symptoms was equal in both groups, with no differences in the frequency of AF, premature supraventricular beats, premature ventricular beats, bundle branch block, or ST-segment alterations. Hemodynamic variables at rest measured by ventriculography (ejection fraction, end-diastolic volume, end-systolic volume, stroke volume) also did not differ by Tn elevation status. The only difference was that patients with elevated TnT had more frequent pericardial effusions (p = 0.024) [74].

Outcomes are also similar for patients with and without Tn elevation in pericarditis and myopericarditis. In a study of 69 patients with acute pericarditis, Tn elevation was associated with increased rates of ST elevation at the time of illness; however, no differences in symptom intensity, disease severity, or the initial length of hospital stay were observed based on conventional Tn levels [77]. Furthermore, long-term outcomes are similar in patients with pericarditis with and without Tn elevation, with one study of 118 patients with acute pericarditis showing no cases of cardiac tamponade or residual LV dysfunction in either group [76]. In myopericarditis, while Tn elevation is believed to be associated with the extent of myocardial inflammatory involvement, it has not been associated with an adverse prognosis. In a study of 486 patients with acute pericarditis or myocarditis, the majority of patients with and without conventional Tn elevation had normalized findings on echocardiogram, ECG, and treadmill testing at 36 months [82].

Epidemiology

The prevalence of elevated Tn in the setting of endocarditis is relatively high and has been observed to be between 57% and 84% [83–86].

Hypothesized Mechanism

Endocardial myocytes do not contain Tn. As previously discussed in cases of pericarditis, it has been hypothesized that serum Tn elevations in endocarditis occur due to inflammation of the surrounding myocardial tissue [80].

Prognostic Implications

In a meta-analysis of nine observational studies, conventional and hs-Tn elevation in endocarditis was associated with a significantly increased risk of in-hospital mortality and the need for surgery or valve replacement [86]. Additionally, patients with Tn elevation experienced significantly higher rates of cardiac abscesses and ischemic or hemorrhagic cerebral events [86]. However, it is important to consider that the findings of this meta-analysis could have been confounded by the relationship between Tn release and greater degrees of acute illness, as the constituent studies did not systematically account for the presence of cardiogenic shock, severe HF, or other comorbidities that could affect the prognosis.

Epidemiology

Elevations in Tn are frequently encountered in patients with a hypertensive emergency. One study of 467 patients presenting to the emergency department with hypertensive urgency or emergency found detectable Tn using conventional assays in 35% of patients. However, myocardial injury, as defined by elevation above the 99th URL, occurred in fewer than half of this subset of patients, and even fewer patients experienced dynamic changes in troponin values suggestive of an acute process [87]. On the other hand, the prevalence of Tn elevation may be higher in the inpatient setting. A prospective study of 205 adults admitted for hypertensive emergencies at a single center found that 49.8% had elevated conventional TnI. However, those with elevated troponins also had markedly higher serum creatinine values (0.89 mg/dL vs. 2.07 mg/dL, p < 0.001), making decreased renal function a possible confounding factor in this study [88].

Hypothesized Mechanism

The mechanisms of Tn release in a hypertensive emergency are incompletely understood and often confounded by comorbidities such as HF or chronic kidney disease [87,88]. The precise mechanism of Tn release likely varies due to the diversity of pathophysiologic conditions that fulfill the criteria for a diagnosis of a hypertensive emergency. For instance, in patients experiencing hypertension-related cardiac manifestations such as an ACS or type 2 MI, elevations in serum Tn may be the direct result of endomyocardial necrosis [89]. In the setting of HF, a common end-organ manifestation of a hypertensive emergency, increased intraventricular pressures and resultant rises in wall stress are known to lead to the release of Tn, even in the absence of coronary disease [57,62]. Hypertension-induced endothelial dysfunction may play a role, as it has been hypothesized to cause Tn release through various proinflammatory, thrombotic, and ischemic downstream effects [90,91]. Although our understanding of the cause of endothelial dysfunction during episodes of severe hypotension is limited, it may be partially mediated by increased renin–angiotensin–aldosterone (RAAS) system activity [89,92].

Prognostic Implications

In multiple studies, elevations of both conventional and hs-TnI have been found to be associated with worse outcomes, including higher rates of pulmonary edema, intubation, and mortality [88,93,94]. Patients with higher hs-TnI levels were observed to have higher initial presenting SBP, more abnormal laboratory findings (including creatinine, BNP, D-dimer, and hemoglobin), and higher rates of admission, revisit, and readmission [93]. In a prospective study of 918 consecutive patients who presented to the emergency department with a hypertensive emergency and without ACS, elevated hs-TnI was found to have a strong association with mortality independent of age, sex, comorbidity burden, and clinical markers of adverse physiology [94]. In a retrospective analysis of 171 patients presenting to the ED with a hypertensive emergency or urgency, higher conventional TnI levels were also found to be associated with a substantially increased risk of major adverse cardiac and cerebrovascular events (hazard ratio = 2.77, p < 0.001) [95].

Epidemiology

In a meta-analysis of four studies and 496 patients with acute aortic dissection (AAD), predominantly type A, elevated Tn measured by conventional assays was present in 26.8% of patients with AAD and ranged between 23% and 33% in individual studies [96]. Meanwhile, in a study that made use of hs-Tn assays, elevated hs-TnT was seen in 61.2% of patients who presented with type A aortic dissection [97].

Hypothesized Mechanism

The aortic wall contains the calcium-binding protein calponin but not Tn [98,99], suggesting that the mechanism of Tn release in AAD is likely multifactorial and may include coronary artery obstruction, acute LV pressure overload, and shock. A study of 398 patients with AAD found that the presence of Tn elevation (both conventional and hs-Tn) during AAD was frequently associated with ACS-like ECG abnormalities, with 13% of patients with abnormal Tn presenting with classic ST elevation [100]. Among 10 patients who underwent transesophageal echocardiograms, 4 had an anatomic obstruction of at least one coronary artery due to coronary dissection or diastolic apposition of the flap to the ostium, illustrating at least one mechanism of myocardial ischemia and likely consequent Tn release [100].

Prognostic Implications

The association of elevated Tn with mortality in aortic dissection is unclear. In the aforementioned study, the combination of Tn elevation and ACS-like ECG findings was associated with a two-fold increased risk of in-hospital diagnostic delay and a significantly increased risk of the composite endpoint of coronary angiography, antithrombotic therapy, or in-hospital diagnostic delay. Nevertheless, the in-hospital diagnostic delay did not influence mortality [100]. In contrast, a meta-analysis of five studies and 711 patients and a study of 103 patients with type-A AAD showed an association between Tn elevation (conventional or hs-Tn) and short-term mortality [96,97].

Epidemiology

Most patients with stress (takotsubo) cardiomyopathy have a modest rise in Tn [101,102]. In a study of 59 patients with stress cardiomyopathy, 95% of patients had elevations in conventional TnT [103]. Patients with stress cardiomyopathy can have chest pain similar to ischemic chest pain and ST-segment and T-wave changes on ECG, which can make the condition difficult to differentiate from ACS. However, the magnitude of the increase in serum Tn is not as pronounced as that observed in ACS. For example, in a study of 136 patients with stress cardiomyopathy using conventional Tn, median TnT was 3.88 ng/mL in patients with left anterior descending artery occlusions and 0.64 ng/mL in patients with stress cardiomyopathy [103]. In another study of 41 patients with ACS and 51 patients with suspected stress cardiomyopathy, median hs-TnT was 564.3 pg/mL in patients with ACS and 162.0 pg/mL in patients with stress cardiomyopathy [104].

Hypothesized Mechanism

The pathophysiology of Tn release in stress cardiomyopathy is not well understood. Proposed mechanisms include catecholamine-induced myocardial stunning, coronary vasospasm-induced ischemia, and focal myocarditis [105]. It is well known that stress cardiomyopathy is mediated by supraphysiologic levels of plasma catecholamines and stress-related neuropeptides [106]. The apical myocardium may have increased responsiveness to sympathetic stimulation, while there is a relative sparing of the basal segments. An alternative hypothesis is ischemia-mediated stunning due to coronary vasospasm. Microvascular dysfunction is present in at least two-thirds of patients at the time of presentation, and its severity correlates with the magnitude of Tn elevation and ECG abnormalities [107]. Others have noted that the degree of Tn elevation in stress cardiomyopathy is disproportionately low compared to the large territory of dysfunctional myocardium on echocardiography, suggesting that mechanisms other than myocyte necrosis are involved in Tn release [102]. This hypothesis is supported by the absence of late gadolinium enhancement on cardiac MRI both during the acute phase and on follow-up imaging, in contradistinction to ischemia or myocarditis [102].

Prognostic Implications

Studies have shown that Tn elevation in stress cardiomyopathy has an independent association with long-term adverse outcomes, including increased mortality [108,109]. Additionally, in a study of 1750 patients with stress cardiomyopathy, elevations in a combination of conventional TnI, conventional TnT, and hs-TnT more than 10 times the 99% percentile URL were significantly associated with an increase in the composite endpoint of in-hospital complications, which included catecholamine use, cardiogenic shock, invasive or noninvasive ventilation, cardiopulmonary resuscitation, and death [110].

Epidemiology

Persistently elevated Tn levels are frequently found in amyloidosis, including both primary/light chain (AL) and transthyretin (TTR) amyloidosis. In a study of 117 patients with cardiac amyloidosis, 64.1% had detectable conventional TnI, defined as ≥0.06 ng/mL [111]. In another study of 102 patients with cardiac amyloidosis, 88.23% had an elevated hs-TnT of >14 ng/L, with the lower limit of detection being 1 ng/L [112]. In another study comparing 96 patients with cardiac amyloidosis (AL, wild-type TTR, and mutant TTR amyloidosis) and 91 patients with non-amyloid causes of cardiac hypertrophy, hs-TnT levels were significantly higher in the cardiac amyloidosis group than in the other hypertrophy group [113].

The degree of elevation may also relate to organ involvement. In a study of 163 patients with AL amyloidosis, hs-TnT was highest in patients with apparent cardiac involvement, followed by patients with suspected cardiac involvement, followed by patients with no apparent cardiac involvement. However, even in AL amyloidosis patients with no apparent cardiac involvement, median hs-TnT levels were above the 99th percentile, underscoring the high prevalence of elevated Tn in amyloidosis [114].

Hypothesized Mechanism

The mechanism of Tn release in patients with cardiac amyloidosis is thought to be multifactorial. Proposed mechanisms include microvascular ischemia due to luminal stenosis and extrinsic compression of microvasculature in the setting of amyloid deposits [115,116]. In a study of 96 patients with cardiac amyloidosis, 66% had obstructive coronary amyloidosis, and microscopic changes of myocardial ischemia were more common in patients with intramural coronary amyloidosis [116]. Additionally, amyloid protein and its precursor can have direct proinflammatory or toxic effects that can lead to myocardial cell damage, membrane leakage, and Tn release [117,118]. Finally, increased LV filling pressure and wall stress due to diastolic dysfunction in amyloidosis likely also contribute to Tn release, which has been demonstrated in multiple studies [56,63,64].

Prognostic Implications

The degree of Tn elevation in amyloidosis may be associated with higher mortality. Using conventional assays, a study of 98 patients with AL amyloidosis undergoing peripheral blood stem cell transplantation found that elevations in TnI, but not TnT, were associated with poorer survival in the 90 days post-transplant [119]. Using hs-Tn assays, a study of 163 patients with AL amyloidosis found that hs-TnT > 50 ng/L was associated with poorer survival but that the survival of patients with hs-TnT of 14–50 ng/L did not differ from that of patients with hs-TnT of 3–14 ng/L. The association between hs-TnT and mortality persisted after the exclusion of patients with impaired renal function [114].

Epidemiology

Tn elevation occurs in virtually all patients in the post-heart transplant period. In one study of 110 patients who received a heart transplant, all patients had elevated conventional TnI levels during the first month after transplant, and in 51% of patients, TnI remained persistently elevated after 12 months [120]. More recently, in a study of 170 cardiac transplant recipients who underwent hs-TnI measurement serially 10–12 times within the first year after transplant, detectable hs-TnI levels were found in all samples, and 82% of the samples had hs-TnI levels above the normal range [121].

Hypothesized Mechanism

In the immediate post-transplant period, myocytes are commonly subject to ischemic injury and reperfusion injury, leading to coagulative myocyte necrosis [120]. However, many patients have persistent cardiac Tn elevation lasting over a month. However, because the half-life of TnT is 2 h, the persistence of Tn elevation suggests the existence of processes other than perioperative ischemic damage, such as host immunity against the transplanted heart, that continue to injure myocytes [122].

Prognostic Implications

Post-transplant Tn levels have been shown to be associated with short-term and long-term mortality. In a study of 212 heart transplant recipients, elevations in hs-TnT measured 48 h postoperatively were associated with increased all-cause mortality at 1 year [123]. In another study of 156 heart transplant recipients, elevations in hs-TnI measured a median of 10 months post-transplant were associated with increased long-term all-cause mortality at a median follow-up of 10 years [124].

The role of post-transplant Tn levels in assessing the presence of cardiac transplant rejection is less clear. In a recent meta-analysis of 27 studies with 1684 heart transplant recipients, patients with acute rejection had a statistically significant late elevation in Tn measurements taken at least 1 month postoperatively (the analysis included both conventional and hs-Tn assays and both TnI and TnT assays) [125]. However, the pooled diagnostic accuracy was poor, with a sensitivity of 41% and specificity of 76%, suggesting that Tn is insufficient for use as a stand-alone diagnostic tool. In a study of 110 heart transplant recipients, the presence of persistent conventional TnI elevation measured at 12 months was associated with the presence of fibrin deposits in the microvasculature and cardiomyocytes [120]. Patients with persistently elevated levels of conventional TnI had an increased risk for the development of CAD and graft failure [121]. In the aforementioned recent study of 170 patients who underwent routine surveillance endomyocardial biopsy, there was no association between hs-TnI and the presence of acute cellular rejection on endomyocardial biopsy [121]. Taken together, the current literature suggests that Tn elevation has limited reliability as a criterion for assessing transplant rejection.

Epidemiology

Unsurprisingly, Tn elevation has been seen in the majority of patients undergoing cardiac ablation. In a study of 60 patients undergoing radiofrequency (RF) ablation by pulmonary vein isolation for AF who had no underlying structural heart disease and baseline normal conventional TnT, all patients were found to have increased post-procedure Tn, with all measurements exceeding the diagnostic threshold for MI [126]. In a study of 51 patients undergoing RF ablation for different indications using conventional TnI assays, the lowest release of TnI was found in ablation for atrioventricular nodal reentrant tachycardia, and the highest release of TnI was found in ablation for AF or AFL [127]. In another study of patients undergoing ablation for ventricular tachycardia (VT) (19 patients) and AF (24 patients), the release of hs-TnT was seen in both groups but reached higher values in VT, though levels equalized after 24 h [128].

Surprisingly, Tn elevation in elective external cardioversion is less common. Many older studies found no significant increase in conventional Tn levels after cardioversion, and in the few patients who had a Tn increase post-cardioversion, the increase was usually mild [129–133]. More recently, a study of hs-TnT in 120 patients who underwent elective external cardioversion for AF or AFL [134] and a study of hs-TnI in 171 patients who underwent elective external cardioversion for AF [135] found that although Tn was detectable in most patients using an hs-Tn assay, it was within the normal range (under 99th percentile), and there was no significant difference between pre- and post-cardioversion hs-TnT.

Hypothesized Mechanism

It is hypothesized that RF catheter ablation creates a small area of localized necrosis, causing Tn release through direct myocardial damage from the procedure itself [127]. Since external cardioversion is not associated with Tn elevation, no mechanism is provided.

Prognostic Implications

In a study of patients who underwent AF ablation, the degree of conventional TnT elevation was not related to the number of RF lesions, RF time, procedure time, or associated external cardioversion [126]. Interestingly, the degree of Tn elevation after RF catheter ablation is associated with favorable outcomes, greater reversal of structural remodeling, a lower likelihood of the need for repeat RF ablation, and an increased reduction in the left atrial volume index at 6 months. These findings may be due to elevated TnT being reflective of the successful ablation of the offending arrhythmia-inducing cardiomyocytes [136]. On the other hand, the less common, mild elevation in Tn after cardioversion has not been shown to have any prognostic significance, with no association between hs-TnI levels and AF recurrence after cardioversion [135].

Epidemiology

Pulmonary embolism (PE) has been reported to be the most common non-cardiac cause of increased Tn [137], with an estimated 10–50% of patients with PE presenting with elevated conventional Tn [138,139]. Studies investigating the release kinetics of conventional TnT have shown that peak TnT in PE tends to be lower and persists for a shorter time compared to ACS [140]. Using hs-Tn assays, one study of 834 patients with hemodynamically stable PE found the prevalence of hs-TnI to be 31.7% [141], and another study of 4611 patients with PE found the prevalence of hs-TnT to be 76.5% (though this study did not exclude patients with preexisting cardiac conditions) [142].

Hypothesized Mechanism

The mechanism of Tn elevation in PE is thought to be related to acute right ventricular (RV) strain and myocardial ischemia secondary to an increase in pulmonary artery resistance [143,144]. This elevation is typically modest, but it typically reflects the amount of myocardium injured by ischemia [138].

Prognostic Implications

Conventional Tn elevations in PE are associated with an increased risk of a complicated in-hospital course, including prolonged hypotension, cardiogenic shock, the need for resuscitation, and death [139–142] [145–148]. In a meta-analysis of 20 studies of acute PE, patients with elevated conventional TnT or TnI had a 5-fold increase in mortality compared to patients without elevated Tn (19.7% vs. 3.7%) [147]. Additionally, RV dysfunction increases the risk for adverse clinical outcomes in all patients, but this risk is 10-fold higher in the presence of elevated conventional TnT (>0.4 ng/mL). Some have suggested that this increased risk may warrant more aggressive treatment approaches, such as thrombolysis or embolectomy, in patients with PE and elevated TnT [149]. Using hs-Tn assays, hsTnT has been found to be associated with both short-term and long-term mortality [142], though studies show mixed results on the prognostic effects of elevated hsTnI [141,150].

Epidemiology

Tn elevations can be found in patients with pulmonary hypertension (PH). In a cohort study of 55 patients with mixed classes of PH, elevated Tn was seen in approximately 27% and 90% of patients using hs-TnT and hs-TnI assays, respectively, and in 27% and 11% of patients using fourth-generation TnT and TnI assays, respectively [151].

Hypothesized Mechanism

Tn elevation in PH is likely secondary to RV injury. Elevated pulmonary vascular resistance leads to increased RV tension, which may cause RV injury and ischemia [152]. In fact, right chamber dilation was more common in patients with PH and detectable conventional Tn levels. Furthermore, correlations between conventional TnI and C-reactive protein (CRP) have been reported, suggesting a possible inflammatory component in TnI elevation [152].

Prognostic Implications

Elevated Tn in PH is associated with adverse outcomes. Specifically, in a cohort study of 68 patients with group 1 PH, patients with detectable conventional TnI had worse functional class, lower 6 min walking distance, more evidence of right heart strain on an echocardiogram, higher levels of BNP, and worse lung-transplant-free survival compared to patients with undetectable TnI [153]. Similar findings were seen in studies evaluating conventional TnT and hs-TnT in patients with mixed classes of PH. Specifically, patients with detectable conventional TnT or hs-TnT had higher heart rates, higher BNP levels, shorter 6 min walk tests, more right heart strain, and worse 2-year cumulative survival (29% vs. 81%) [151,152]. In a meta-analysis of eight studies with 739 patients, elevated conventional Tn in general conferred a higher mortality risk, with TnI predicting mortality better than TnT [154].