Which Diagnostic Test Would You Choose For This 59-Year-Old Male with Continuous Chest Pain?
HPI: The patient is a 59-year-old male with the onset of continuous chest pain 2 hours prior to admission. The pain was described as severe mid-sternal pain (unable to characterize further) without radiation, with associated dyspnea, diaphoresis, and nausea. He never had similar pain before.
PMH: Hypertension and Diabetes
MEDS: ACE inhibitor, Diuretic, Insulin
PE: BP Right arm 160/90 mmHg, Left arm 155/88 mmHg, pulse-110 bpm, RR 18, O2 sat 96% on 2 L NC
Gen; appears uncomfortable and in moderate distress
Heart: tachycardic without murmur or gallop, JVP-nl
Lungs: bibasilar crackles
Extremities: no edema, all peripheral pulses normal
ECG: sinus tachycardia with LVH with ST-T changes
CXR: mild interstitial markings c/w possible early CHF
cTnI- 0.09 ng/ml (99th% 0.04 ng/ml)
BNP- 250 pg/ml ( normal < 100 pg/ml)
D-dimer- 2,241 ng/mL ( normal < 500 ng/ml)
Electrolytes and CBC are normal
The patient received ASA, beta-blocker, and IV morphine. Repeat TnI 3 hours later was 0.10 ng/ml
What would you choose for the next diagnostic test?
The correct answer is: 4. CT for aortic dissection
The patient had a CT scan of the chest performed that demonstrated a dissection in the ascending aorta. Cardiothoracic surgery was consulted and the patient underwent urgent surgery.
The diagnosis of Aortic Dissection (AD) is clinically challenging as historical and physical features are not highly sensitive, and there is a 1-2% per hour mortality rate early after symptom onset in the setting of an ascending AD.1 In the Emergency Department the 3 life threatening conditions of most concern in a patient with chest pain are acute coronary syndrome (ACS), pulmonary embolism, and AD. Multiple studies have demonstrated the utility of D-dimer for excluding pulmonary embolism and guidelines recommend its measurement to rule-out pulmonary embolism in low-risk patients.(2) ACS appeared less likely as there was no significant change in values on serial samples.3 Hypertension and Diabetes are associated with mild chronic elevations of cTn.4 Although our patient did have a mild elevation of BNP, BNP levels can be elevated in patients with hypertension.5 Although not as extensively studied as in ACS or pulmonary embolism, several studies have evaluated the utility of serum markers in the setting of AD.
D-dimer and smooth muscle myosin heavy chain (smMHC) have been the most studied. The protein smMHC is a major component of smooth muscle in the aorta, intestine, and uterus, and is released into the blood stream in the setting of AD. Suzuki measured smMHC at 12 hour intervals for the first 3 days in 27 patients with AD.6 The sensitivity at 12 and 24 hours was 90% and 85%, respectively. Importantly, patients with ACS did not show an increase in smMHC. Initial levels were the highest, with a rapid decrease within the first 24 hours. All AD patients with values below the cut-off value had a descending aorta AD, which may relate to deferential expression in different anatomic locations of the aorta. In a larger study Suzuki evaluated 95 patients with AD, 48 with AMI, and 131 healthy volunteers.7 Levels of smMHC were significantly higher for patients with AD compared to controls. Levels were significantly reduced within the first 3 hours, resulting in a significant decrease in sensitivity. The sensitivity at 3 hours, 6 hours and 9 hours was 91%, 72%, and 30%, respectively. This rapid decrease in levels is a significant limitation for smMHC and there are presently no commercial assays available.
Sodeck performed a meta-analysis of the use of D-dimer in AD that included 16 studies with 439 patients.8 The diagnostic cut-offs ranged from 100-900 ng/ml. There were 15/439 (3.4%) patients with AD that had a D-dimer level below the cut-off. The pooled sensitivity and specificity of D-dimer was 97% and 59%, with a an excellent negative liklelihood ratio of 0.06. Two smaller more recent meta-analyses showed similar results.9, 10 Marill found a similar sensitivity of 97% using a standard cut-off 500 ng/ml, which is the typical cut-point to exclude pulmonary embolism.9 Thus, there is a consistent finding that D-dimer is elevated in patients with AD and it potentially could be used to exclude AD.
The most recent large study to address the diagnostic utility of D-dimer for AD was performed as part of The International Registry of Acute Aortic Dissection.11 Of the 220 patients included, 87 were diagnosed with AD. Of the 133 non-AD cases there were 46, 37, 45, and 5 cases of AMI, angina, uncertain diagnosis, and pulmonary embolism, respectively. The mean values of D-dimer were 3,213 ng/ml for Type A AD, 3,574 ng/ml for Type B AD, 2,452 ng/ml for pulmonary embolism, 1,459 ng/ml for AMI, 760 ng/ml for angina, and 1,399 ng/ml for uncertain diagnosis. The sensitivity was 97% and the specificity was 47%. The negative likelihood ratio of 0.07 is remarkably similar to the meta-analysis by Sodeck.8 Using a higher cutoff of 1,684 ng/ml, the positive likelihood ratio was a very favorable 12.8.
Our patient had a very high D-dimer which made the diagnosis of AD or pulmonary embolism much more likely. The clinical suspicion was higher for AD than pulmonary embolism so a CT scan was ordered for aortic dissection evaluation.
The current AHA/ACC guidelines give a Class I recommendation to perform CTA, TEE or MRI when there is clinical suspicion for AD.12 These imaging tests are time-consuming, expensive, and not readily available in all hospitals. A blood test that could evaluate for possible AD would be extremely useful, particularly for identifying patients who present atypically. However, based on the limited data, ACC/AHA guidelines state "...the writing committee cannot recommend serum D-dimer screening for all patients being evaluated for AD."12
Despite promising data, there are several concerns about the routine use of D-dimer in the evaluation of patients with possible AD. Presently there is no standardization amongst D-dimer tests, resulting in different recommended cut-points.13, 14 Each assay would therefore need to be evaluated in a clinical trial. One must be aware that a multitude of conditions may lead to an elevated D-dimer such as sepsis, pregnancy, cancer, and pulmonary embolism. Many times, however, these conditions can be excluded based on history and clinical presentation. Intramural hematoma, when there is only bleeding within the aortic wall and has similar outcomes to classic AD, may not have elevation of D-dimer as there is no communication with the lumen of the aorta.15 Although further studies are needed for confirmation, if obtained, a very high level of D-dimer in a patient in the proper clinical context should prompt consideration of AD.
- Hirst AE, Jr., V.J. Johns, Jr., and S.W. Kime, Jr., Dissecting aneurysm of the aorta: a review of 505 cases. Medicine 1958; 37:217-79.
- Clinical policy: critical issues in the evaluation and management of adult patients presenting with suspected pulmonary embolism. Ann Emerg Med 2003; 41:257-70.
- Mueller M, et al., Absolute and relative kinetic changes of high-sensitivity cardiac troponin T in acute coronary syndrome and in patients with increased troponin in the absence of acute coronary syndrome. Clin Chem 2012; 58:209-18.
- de Lemos JA, et al., Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA 2010; 304:2503-12.
- Pahle AS, et al., Impact of systemic hypertension on the diagnostic performance of B-type natriuretic peptide in patients with acute dyspnea. Am J Cardiol 2009; 104:966-71.
- Suzuki T, et al., Novel biochemical diagnostic method for aortic dissection. Results of a prospective study using an immunoassay of smooth muscle myosin heavy chain. Circulation 1996; 93:1244-9.
- Suzuki T, et al., Diagnostic implications of elevated levels of smooth-muscle myosin heavy-chain protein in acute aortic dissection. The smooth muscle myosin heavy chain study. Ann Intern Med 2000; 133:537-41.
- Sodeck G, et al., D-dimer in ruling out acute aortic dissection: a systematic review and prospective cohort study. Eur Heart J 2007; 28:3067-75.
- Marill KA, Serum D-dimer is a sensitive test for the detection of acute aortic dissection: a pooled meta-analysis. J Emerg Med 2008; 34:367-76.
- Shimony A, et al., Meta-analysis of usefulness of d-dimer to diagnose acute aortic dissection. Am J Cardiol 2011; 107:1227-34.
- Suzuki T, et al., Diagnosis of acute aortic dissection by D-dimer: the International Registry of Acute Aortic Dissection Substudy on Biomarkers (IRAD-Bio) experience. Circulation 2009; 119:2702-7.
- Hiratzka LF, et al., 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology,American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons,and Society for Vascular Medicine. J Am Coll Cardiol 2010; 55:e27-e129.
- Dempfle, C.E., et al., The Fibrin Assay Comparison Trial (FACT): evaluation of 23 quantitative D-dimer assays as basis for the development of D-dimer calibrators. FACT study group. Thromb Haemost 2001; 85:671-8.
- Geersing GJ, et al., Diagnostic accuracy and user-friendliness of 5 point-of-care D-dimer tests for the exclusion of deep vein thrombosis. Clin Chem 2010; 56:1758-66.
- Evangelista A, et al., Acute intramural hematoma of the aorta: a mystery in evolution. Circulation 2005; 111:1063-70.