A 47 year-old man was previously being managed for hypertension but stopped taking his medications in favor of a “homeopathic” regimen. There was periodic exertional dyspnea but no chest pain, lightheadedness, orthopenea, or peripheral edema. While driving one day he became acutely short of breath. Paramedics found him severely dyspnic with tachycardia, basilar rails, and a blood pressure of 250/155mmHg. He denied chest pain, heaviness, neck, back, or arm discomfort. An EKG was acquired. ST elevation was noted in contiguous precordial leads accompanied by a late anterior transition zone. There was also ST depression in the inferior and lateral leads. The appearance of LVH was severe but the S/ST proportions were difficult to assess due to the paper size. On arrival at the hospital another two EKGs were captured. This appeared slightly more benign, however a positive troponin assay was returned at 2.24ng/mL.
Physical exam at this time was notable for positive hepatojugular reflux, a pronounced S4 gallop, and crackles throughout the lung fields. There was no JVD or peripheral edema. The BUN was 40, Creatinine 2.2, ALT and AST of 51 and 57. The LDL was >200. No BNP was recorded. Detailed history revealed one prior episode of hypertensive crisis but no established CAD or CHF. He had quit smoking but continued to drink somewhat heavily as per his wife. His father suffered from both HTN and CHF and was no longer living.
The patient was admitted to ICU with hypertensive crisis and heart failure. Ejection fraction by echo was estimated at 30% with LVH and global systolic dysfunction. Cardiac catheterization on the third hospital day revealed a right dominant coronary system with severe triple vessel disease constituted by multiple complex lesions and several well-formed collaterals. Recommendation was for CABG evaluation.
The troponin peaked slightly above 4.0.
Elevation of cardiac troponins in the absence of acute coronary occlusion is not uncommon. This is particularly true of the severely ill. In the absence of a diagnostic electrocardiogram, low and even moderate level elevations should not overly persuade the clinician of an acute thrombotic coronary etiology.
On the molecular scale, muscle contraction results from a ratchet like interaction between actin and myosin microfilaments. The myosin “thick” filaments repeatedly attach, pull, and release from the actin “thin” filaments. As the two filaments slide along one another this telescoping is transmitted to the boundaries of the cell to produce a unified cellular contraction.
Retrieved from: http://www.pathologyoutlines.com/topic/stainsactin.html
In order to regulate and coordinate the contraction of filaments, an inhibitory protein, tropomyosin, lies along the length of each actin strand and occludes the actin-myosin attachment sites. When membrane depolarization occurs, calcium ions are released from the sarcoplasmic reticulum and bind to tropomyosin, shifting it out of the way and disinhibiting the contractile interaction of myosin and actin.
Tropomyosin effects its inhibitory activity at the active site through the troponin regulatory complex. This complex is a trimer consisting of troponin I (cTnI), troponin C (cTnC), and troponin T (cTnT). The cross-bridge active sites are occluded by the inhibitory “I” tropoin subunit. When the myocyte depolarizes, calcium ions are released from the sarcoplasmic reticulum and bind to the troponin C subunit. This produces a conformational change in the complex which retracts troponin I and unblocks the binding site for cross-bridge between actin and myosin.
Serum immunoassays for the proteins troponin I and troponin T have shown high sensitivity for cardiac myocyte injury and necrosis. The aggregate of these proteins is structurally bound to tropomyosin, however some free cytosolic troponin I and T is known to exist. The mechanisms where by these proteins are liberated into the blood serum remain incompletely characterized.
Retrieved from: http://acb.rsmjournals.com/content/45/4/349.abstract
Significant elevations of serum troponins regularly occur in the absence of acute thrombotic coronary occlusion. Thygesen and collegues have described three categories of non-ACS related troponin elevation:
Mechanisms potentially responsible for troponin elevation in this case include:
- Heart Failure
- Malignant Hypertension
- Ischemic Cardiomyopathy
- Alcoholic Cardiomyopathy
- Renal Failure
- Tachycardia with demand ischemia due to stable coronary leisions
- Unlikely but possible PE or significant Pulmonary Hypertension
The literature addressing non-ACS related troponin elevation is extensive; below are excerpts touching on some of the most common etiologies.
Regarding troponin elevation in heart failure:
“Release of TnI from cytosolic pool as a result of myocardial cell membrane injury without damage of structurally bound TnI has been reported. However, cytosolic TnI has been estimated to account for < 2% of total intracellular TnI. It is perhaps more likely that detectable troponin in HF reflects ongoing degradation of contractile protein and cellular injury. An increased level of neurohormonal factors, oxidative stress, and a number of cytokines are universal in HF. Each of these factors is known to promote cardiac cell death; therefore, they may be responsible for the elevation of troponin in HF.” (3)
“…Elevation of troponin in acute pericarditis is believed to represent injury of the epicardial layer of myocardium adjacent to visceral pericardium where the active inflammation occurs…” (3)
“Bonnefoy et al reported that approximately one half of their 69 consecutive patients (49%) with acute idiopathic pericarditis had troponin I (TnI) levels > 0.5 ng/mL. Twenty-two percent had TnI levels > 1.5 ng/mL, their cut-off level for acute MI. The average TnI level was 8 ± 12 ng/mL (range, 0 to 48 ng/mL). The median level was, however, only 1 ng/mL.” (3)
Regarding troponin elevation in sepsis:
“…there are several potential mechanisms, other than acute MI, for troponin release in septic patients. First, it is well known that a number of local and circulating mediators (eg, cytokines or reactive oxygen species) possess direct cardiac myocytoxic properties. Secondly, myocardial injury from the effect of bacterial endotoxins has been demonstrated. Finally, dysfunction of the microcirculation has been described in sepsis. This microvascular dysfunction can lead to ischemia and reperfusion injury of the myocardial cell.” (3)
Regarding troponin elevation in PE:
“Right ventricular dilation and strain from sudden increase in pulmonary arterial resistance is believed to be the cause of troponin release in acute PE.” (3)
“Giannitis et al, reported the incidence and prognostic significance of troponin T (TnT) elevation in patients with confirmed acute PE. Of the 56 patients, 32% had elevated TnT levels (≥ 0.1 ng/mL). In contrast, only 7% had CK levels above twice the upper limit of normal. Using a clinical grading system adapted from Goldhaber, 23%, 46%, and 30% of the patients were classified as having small PE, moderate-to-large PE, and massive PE, respectively. Elevated TnT was only observed in patients with either moderate-to-large PE or massive PE. None of those with small PE had increased TnT. TnT-positive patients were more likely to have right ventricular dysfunction, severe hypoxemia, prolonged hypotension, or cardiogenic shock. They also more often required inotropic therapy or mechanical ventilation than those with negative TnT. Complete or incomplete right bundle-branch block or ST-T changes on ECG were also more prevalent in TnT-positive subgroup. More importantly, TnT positivity was associated with approximately 30-fold increased risk of in-hospital mortality. In addition, TnT level was found to be an independent predictor of the 30-day outcome. Survival rates at 30 days were 60% and 95%, respectively, for those with and without TnT elevation.” (3)
Regarding troponin elevation in renal disease:
“In patients with severe renal dysfunction troponin T as well as troponin I, elevations are found that cannot be linked to myocardial injury. The reasons for these elevations are not yet convincingly explained. Reexpression of cardiac isoforms in skeletal muscles has been excluded by different analyses and investigators.13,14 Loss of membrane integrity and constant outflow from the free cytosolic troponin pool as well as amplified elevation of normal low levels because of impaired renal excretion are more likely. The higher unbound cytosolic pool and higher molecular weight may explain why troponin T is more frequently found elevated than troponin I.” (2)
As a final note, in 2011 Afonso et al retrospectively reviewed 567 patients admitted with a diagnosis of “hypertensive emergency.” Of these, 186 (32%) had cTnI elevation with the mean peak level at 4.06. They conclude, “Predictors of cTnI were age, history of hypercholesterolemia, blood urea nitrogen level, pulmonary edema, and requirement for mechanical ventilation. … Neither the presence nor the extent of cTnI elevation was associated with mortality, while age, history of coronary artery disease, and blood urea nitrogen level were predictive of mortality.” (1)
- Afonso L, et al. Prevalence, determinants, and clinical significance of cardiac troponin-I elevation in individuals admitted for a hypertensive emergency. J Clin Hypertens (Greenwich). 2011 Aug;13(8):551-6. doi: 10.1111/j.1751-7176.2011.00476.x. Epub 2011 Jun 27.
- Hamm, CW, Giannitsis, E, Katus, HA Cardiac troponin elevations in patients without acute coronary syndrome. Circulation 2002; 106, 2871-2872
- Roongsritong C, Warraich I, Bradley C. Common Causes Of Troponin Elevations In The Absence Of Acute Myocardial Infarction: Incidence And Clinical Significance. CHEST. 2004;125(5):1877-1884.
- Thygesen K, Mair J, Katus H, et al. Recommendations for the use of cardiac troponin measurement in acute cardiac care. Eur Heart J 2010; 31:2197
- Gibson, M. et al. Elevated cardiac troponin concentration in the absence of an acute coronary syndrome. UpToDate. July 11, 2012.