A 60-year-old man with end-stage renal disease on chronic hemodialysis, coronary artery disease with a history of coronary artery bypass surgery, ischemic cardiomyopathy, diabetes, obesity, and obstructive sleep apnea is admitted after experiencing sudden-onset diaphoresis, nausea, and vomiting while having a bowel movement. These symptoms resolved prior to his arrival to the ED, where serial electrocardiograms (EKGs) did not show ischemic changes and his initial cardiac troponin I level was elevated to 0.048 mcg/L (reference range, <0.030 mcg/L). During a previous admission, after a surgical procedure, his cardiac troponin levels had been elevated to a peak of 0.147 mcg/L. Upon physical exam, the patient is resting comfortably in bed and reports no chest pain, shortness of breath, nausea, or other acute concerns. Serial troponin levels are measured overnight with a peak of 0.084 mcg/L before decreasing to 0.055 mcg/L the following morning.
Acute coronary syndrome (ACS) accounts for many deaths, hospitalizations, and 30-day rehospitalizations in the United States every year, and patients with chronic kidney disease (CKD) face higher rates of both mortality and rehospitalization from ACS than those with normal kidney function (11. Khawaja FJ, Shah ND, Lennon RJ, et al. Factors associated with 30-day readmission rates after percutaneous coronary intervention. Arch Intern Med. 2012;172:112-7. [PMID: 22123752]). Their overall one-year mortality rate following an acute myocardial infarction (MI) can reach up to 60% (22. Herzog CA, Ma JZ, Collins AJ. Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med. 1998;339:799-805. [PMID: 9738087]). Unfortunately, the fact that many patients with CKD have chronically elevated levels of cardiac troponin has led to physician uncertainty, cognitive dissonance, and inaccurate diagnoses.
Cardiac enzymes have been employed since the 1960s in the detection of ACS. However, as these biomarkers have become more sensitive and specific in detecting damage to cardiac myocytes, there has been increasing recognition that a wide variety of conditions, including sepsis, pulmonary embolism, and malignant hypertension, can elevate troponin levels to within the pathologic range (33. Kelley WE, Januzzi JL, Christenson RH. Increases of cardiac troponin in conditions other than acute coronary syndrome and heart failure. Clin Chem. 2009;55:2098-112. [PMID: 19815610]).
Particularly notable in this subset are patients with CKD or end-stage renal disease (ESRD), who often exhibit a persistent elevation of cardiac troponin levels. In one study, 44% of asymptomatic patients with CKD who were not on hemodialysis had a detectable cardiac troponin T level (44. McMurray JJ, Uno H, Jarolim P, et al. Predictors of fatal and nonfatal cardiovascular events in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia: an analysis of the Trial to Reduce cardiovascular Events with Aranesp (darbepoetin-alfa) Therapy (TREAT). Am Heart J. 2011;162:748-755.e3. [PMID: 21982669]). While this has at times been variously dismissed by clinicians as “troponin leak,” “troponemia,” or “troponinitis,” it is important to remember that even minor elevation of cardiac troponin levels above the 99th percentile of the upper reference limit (URL) of the lab assay is abnormal and represents pathologic myocardial injury. This applies not only to the commonly used fourth-generation troponin assay, but to the new gender-specific fifth-generation high-sensitivity troponin assays as well. While patients with CKD and ESRD often do have chronic myocardial necrosis, cardiac causes of death are the most common in patients with CKD stage 3 or greater (estimated glomerular filtration rate less than 60 mL/min/1.73 m2), making accurate diagnosis of ACS imperative (22. Herzog CA, Ma JZ, Collins AJ. Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med. 1998;339:799-805. [PMID: 9738087]).
The pathophysiology of chronic myocardial injury in patients with renal dysfunction is not well understood, although there is a strong association between CKD and coronary artery disease (CAD) (55. Manjunath G, Tighiouart H, Ibrahim H, et al. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol. 2003;41:47-55. [PMID: 12570944]). This association is even stronger in patients undergoing chronic hemodialysis, who have thrice-weekly exposure to high-calcium dialysate solutions. One study using postmortem analyses found diffuse calcific deposits in the hearts of 62% of patients on chronic hemodialysis (66. Roberts WC, Taylor MA, Shirani J. Cardiac findings at necropsy in patients with chronic kidney disease maintained on chronic hemodialysis. Medicine (Baltimore). 2012;91:165-78. [PMID: 22549132]). Other proposed mechanisms of chronic myocardial injury include stretch-induced apoptosis of the myocardium, inflammation-induced cellular toxicity, stress-induced release of troponin subunits, and even disruptions in the gut microbiome.
Patients with CKD and ESRD are also more likely to present with atypical symptoms of ACS than the general population. One study demonstrated that only 44% of patients on chronic hemodialysis being admitted with ACS presented with chest pain (as opposed to 68% of nondialysis patients) (77. Herzog CA, Littrell K, Arko C, et al. Clinical characteristics of dialysis patients with acute myocardial infarction in the United States: a collaborative project of the United States Renal Data System and the National Registry of Myocardial Infarction. Circulation. 2007;116:1465-72. [PMID: 17785621]). Furthermore, this study revealed that EKG changes in patients with ESRD were similarly atypical; only 19% presented with ST-elevation MI, compared to 35% of nondialysis patients.
Next-generation and high-sensitivity troponin measurements are bringing ever-greater speed and precision to bear in the detection of myocardial necrosis, but the interpretation of these data in the setting of chronic troponin elevation lags behind. The Fourth Universal Definition of Myocardial Infarction, released in late 2018, has attempted to improve this situation (88. Thygesen K, Alpert JS, Jaffe AS, et al; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction. Fourth Universal Definition of Myocardial Infarction (2018). J Am Coll Cardiol. 2018;72:2231-64. [PMID: 30153967]).
Particularly relevant for hospitalists caring for patients with CKD is that the new definition makes clear the difference between myocardial injury and myocardial infarction, as well as distinguishing between “type 1” and “type 2” MI. Type 1 MI is defined as a rise or fall in cardiac troponin levels with a peak value above the 99th percentile of the URL, caused by either acute coronary thrombus or plaque rupture and accompanied by signs of ischemia, such as angina, ischemic EKG changes, or visible ischemia or wall-motion abnormalities on noninvasive testing (Table). Type 2 MI is a similar entity, defined as a rise or fall in cardiac troponin levels above the 99th percentile of the URL with similar signs of ischemia, but rather than acute thrombus or plaque rupture as the inciting mechanism, cell death is the result of inadequate perfusion of the myocardium, due to inordinate metabolic demand in the setting of chronic coronary stenosis, coronary vasospasm, or dissection.
In contrast, patients with troponin elevations above the 99th percentile of the URL but without signs of ischemia fall into the category of myocardial injury. If this is accompanied by a rise and/or fall of troponin levels, the injury is considered acute (e.g., due to acute heart failure), whereas if there is no rise/fall pattern, the injury is considered chronic, as is often seen in patients with CKD.
In patients presenting without baseline elevation of their troponin values above the 99th percentile of the URL, a single elevated value is enough to diagnose either acute MI or acute myocardial injury. However, in patients presenting with an initial troponin value above the 99th percentile of the URL, serial troponin values are essential in guiding diagnosis. The figure illustrates the proposed kinetics of troponin release (Figure), with an initial immediate release of “free” troponin from within the myocytes, followed by a longer, slower release of troponin subunits as dead myocytes slowly degrade (99. Starnberg K, Jeppsson A, Lindahl B, et al. Revision of the troponin T release mechanism from damaged human myocardium. Clin Chem. 2014;60:1098-104. [PMID: 24842954]). Depending on blood flow rates, this process can take hours to days, and the ability to appreciate a substantial rise or fall may depend on when within this cycle troponin levels are monitored. Numerous studies have looked at the optimal change (delta) in troponin values sufficient to diagnose acute MI. The Fourth Universal Definition of Myocardial Infarction recommends that a rise or fall of cardiac troponin levels greater than 20% is sufficient for the diagnosis of acute MI or injury.
Management strategies should vary by diagnosis, and since myocardial necrosis in and of itself is not associated with increased risk of arrhythmia, telemetry monitoring should be considered on a case-by-case basis depending on the chronicity of troponin elevation and other underlying risk factors (1010. Sandau KE, Funk M, Auerbach A, et al; American Heart Association Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Cardiovascular Disease in the Young. Update to Practice Standards for Electrocardiographic Monitoring in Hospital Settings: A Scientific Statement From the American Heart Association. Circulation. 2017;136:e273-e344. [PMID: 28974521]). In clear cases of chronic myocardial injury, patients should be treated for their presenting symptoms and considered for telemetry based on their underlying risk factors. For acute myocardial injury, treatment should be directed at the inciting insult and telemetry would be reasonable for at least the first 24 to 48 hours until signs of ischemia can be ruled out.
For type 1 and type 2 MI, the underlying mechanism must be carefully evaluated, keeping in mind the higher risk of cardiac death for patients with CKD. Potential empiric therapies for ACS (e.g., aspirin or heparin) must be considered. Troponin values should be monitored every four hours until clearly trending down or returned to baseline. Echocardiography may reveal new wall-motion abnormalities that could raise concern for coronary blockage.
In many cases, cardiology consultation with or without coronary angiography may be the only way to safely exclude type 1 MI (88. Thygesen K, Alpert JS, Jaffe AS, et al; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction. Fourth Universal Definition of Myocardial Infarction (2018). J Am Coll Cardiol. 2018;72:2231-64. [PMID: 30153967]). In non-emergent cases, nephrology consultation prior to administration of contrast dye may be prudent, especially in cases of advanced CKD. However, even in clear cases of type 2 MI, nonurgent consultation or referral to both cardiology and nephrology is reasonable, as mortality data suggest that outcomes for patients after type 2 MI can be just as severe—or even worse—than for patients with type 1 MI (1111. Bjurman C, Larsson M, Johanson P, et al. Small changes in troponin T levels are common in patients with non-ST-segment elevation myocardial infarction and are linked to higher mortality. J Am Coll Cardiol. 2013;62:1231-8. [PMID: 23933541]).
Back to the case
Cardiology consultation is obtained and a subsequent coronary angiogram reveals severe three-vessel disease with a 95% occlusion of the first-diagonal branch of the left anterior descending artery, consistent with a diagnosis of type 1 MI. A drug-eluting stent is successfully placed.
Summary and recommendations
Due to the high prevalence of coronary atherosclerosis in patients with CKD, as well as their high rates of mortality following acute MI, clinicians should have a high index of suspicion for ACS when patients with kidney disease present with elevated cardiac troponin levels. Serial troponin levels should be carefully monitored when the first troponin value is above the 99th percentile of the URL, with the understanding that a rise or fall greater than 20% may represent acute MI, necessitating further critical analysis, telemetry monitoring, or possible use of empiric medical therapies, noninvasive imaging, cardiology and/or nephrology consultation, or aggressive interventions.