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(Circulation. 1996;93:1244-1249.)
© 1996 American Heart Association, Inc.

Articles

Novel Biochemical Diagnostic Method for Aortic Dissection

Results of a Prospective Study Using an Immunoassay of Smooth Muscle Myosin Heavy Chain

Toru Suzuki, MD; Hirohisa Katoh, PhD; Masafumi Watanabe, MD; Masahiko Kurabayashi, MD; Katsuhiko Hiramori, MD; Shingo Hori, MD; Masakiyo Nobuyoshi, MD; Hiromitsu Tanaka, MD; Kazuhisa Kodama, MD; Hikaru Sato, MD; Shin Suzuki, MD; Yasuhiro Tsuchio, MD; Yoshio Yazaki, MD; Ryozo Nagai, MD

From the Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo (T.S., M.W., M.K., Y.Y.); Immunology Laboratory, Diagnostics Division, Yamasa Corporation, Chiba (H.K.); Second Department of Internal Medicine, Iwate Medical University (K.H.); Department of Emergency Medicine, Keio University School of Medicine, Tokyo (S.H.); Department of Cardiology, Kokura Memorial Hospital, Fukuoka (M.N.); First Department of Internal Medicine, Faculty of Medicine, Kagoshima University (H.T.); Cardiovascular Division, Osaka Police Hospital (K.K.); Department of Cardiology, Hiroshima City Hospital (H.S.); Department of Cardiology, Sakakibara Heart Institute, Tokyo (S.S.); and Second Department of Internal Medicine, Gunma University School of Medicine (Y.T., R.N.), Japan.

	Abstract

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Background Aortic dissection is one of the most common aortic catastrophes. Although newer diagnostic methods as exemplified by image diagnostic techniques have greatly improved the diagnosis of aortic dissection, the diagnosis is still frequently missed today because the signs and symptoms of the disease are at times obscure. A reliable biochemical diagnostic method for aortic dissection would be beneficial.

Methods and Results A novel biochemical diagnostic method for diagnosis of aortic dissection was developed that uses an immunoassay of monoclonal antibodies to smooth muscle myosin heavy chain. A prospective study was conducted to ascertain the usefulness of the method in the diagnosis of aortic dissection. Twenty-seven patients with aortic dissection admitted within the first 24 hours after onset were enrolled. Serial assay of serum smooth muscle myosin heavy chain showed significant elevations within the first 24 hours after onset of aortic dissection, with levels exceeding 10 ng/mL, with subsequent rapid reductions. The sensitivity of the assay within the first 12 hours was 90%, with a specificity of 97%. Analysis of 65 patients with acute myocardial infarction showed that the method could accurately differentiate myocardial infarction from aortic dissection.

Conclusions The immunoassay of serum smooth muscle myosin heavy chain is a rapid and reliable biochemical method in the diagnosis of aortic dissection. The potential use of the method in clinical medicine is promising.

Key Words: aorta • myosin • muscle, smooth

	Introduction

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Aortic dissection is the one of the most common catastrophes of the aorta.¹ In the United States alone, it is estimated that 2000 new cases of aortic dissection are reported each year.^{2 3 4 5} The history of the management of the disease by modern medicine, however, is relatively new, dating back just over a quarter of a century.⁶ The surgical therapy of aortic dissection by DeBakey and colleagues in 1955⁷ revolutionized the management of the disease, making what was once thought to be a "no-win situation" into a potentially treatable disease. Introduction of medical management of aortic dissection by Wheat and colleagues in 1965⁸ provided a new aspect to the management of the disease. These revolutionary methods made way for the emergence of the modern approaches to aortic dissection. A critical factor supporting the evolving management process of aortic dissection is the recent advances in noninvasive and invasive diagnostic techniques.⁴ With the newer techniques, the diagnosis of aortic dissection has entered a new realm in which antemortem diagnosis of the disease can be established with certainty. The newer imaging devices (eg, magnetic resonance imaging, computed tomography, transesophageal and transthoracic echocardiography, and angiography), in particular, have greatly improved the diagnosis of aortic dissection.⁹

Still, even in an era of modern technology, the intuition of the physician remains the essential factor in the diagnosis of the disease. Because the clinical manifestations of aortic dissection are often diverse, the clinical presentation may mimic signs and symptoms of other diseases. A high level of suspicion maintained by the physician is therefore vital to definite diagnosis. The newer and preferred diagnostic methods (eg, magnetic resonance imaging, computed tomography, transesophageal and transthoracic echocardiography) are still limited by availability and technique. Also, the patients may be hemodynamically unstable, with diagnostic methods difficult to perform, and thus the diagnosis of the disease, even with available diagnostic equipment, may remain obscure. Unfortunately, the diagnosis is still frequently missed today.¹⁰

To further improve on the present levels of the clinical approach and management of aortic dissection, a simple, fast, and accurate method for diagnosis of aortic dissection would indeed be beneficial. Recently, we developed a novel biochemical method for diagnosis of aortic dissection that uses an immunoassay of smooth muscle myosin heavy chain levels in serum.¹¹ Preliminary studies have shown the potential role of the assay as a sensitive marker for diagnosis of aortic dissection.¹² In the present study, the results of a prospective study to determine the usefulness of the immunoassay in the diagnosis of aortic dissection are presented. Diagnosis of aortic dissection using the immunoassay of serum smooth muscle myosin heavy chain was effective in the differential diagnosis of the disease. The assay presented is a promising technique for clinical use in the future.

	Methods

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Patient Registry and Criteria
A prospective registry of patients admitted for acute aortic dissection was conducted between October 1994 and March 1995. All patients with suspected acute aortic dissection were eligible. Serum samples for testing smooth muscle heavy chain were obtained at 12-hour intervals for the first 3 days and at 24-hour intervals thereafter up to 7 days after administration. Serum samples were stored frozen at -20°C until testing.

Clinical Variables
Protocols for enrolled patients included documentation of patient characteristics. Clinical variables included the following: age; sex; time of onset; time of admission; diagnosis according to DeBakey and Stanford classifications; prehospital events; history of past illnesses; family history; underlying aortic disease, including Marfan's syndrome, aortic annuloectasia, trauma, and syphilis; physical examination at the time of admission; complications, defined as myocardial infarction, cardiac tamponade, shock, neurological symptoms, and/or aortic regurgitation; ECG findings; image diagnosis findings, including those from plain x-ray, ultrasonography, computed tomography, magnetic resonance imaging, and angiography; details of medical and/or surgical therapy; and time schedule of blood sampling. Complete blood count, erythrocyte sedimentation rate, the acute phase reactant C-reactive protein, and serum chemistry panels including aspartate transaminase, alanine transaminase, lactate dehydrogenase, total bilirubin, blood urea nitrogen, creatinine levels, and creatinine kinase and MB fraction were also measured serially.

Immunoassay of Serum Smooth Muscle Myosin Heavy Chain
A double monoclonal sandwich enzyme immunoassay was used to measure serum smooth muscle myosin heavy chain. The assay was developed by use of antibodies obtained by a hybridoma technique based on immunization of mice with smooth muscle myosin purified from the human uterus. The details of the immunoassay have been described elsewhere.¹¹

In brief, BALB/c mice were immunized at 2-week intervals. After six immunizations and an additional booster injection, splenocytes obtained from the mouse with the highest titer as assessed by ELISA¹³ were fused with mouse myeloma cells.¹⁴ The supernatant of the cultured hybridoma was screened for anti–smooth muscle myosin antibody production by ELISA, and the specific antibody–producing hybridoma cells were cloned by limiting dilution.

Monoclonal antibodies were produced in ascitic fluid of BALB/c mice primed with pristane and were purified by protein A affinity chromatography. Western blot analysis confirmed reactivity of the monoclonal antibodies with smooth muscle myosin heavy chain. The combination of paired antibodies with highest assay sensitivity was used for the double monoclonal antibody sandwich assay. Measurements could be completed within 5 hours.

The assay showed reliable detection of smooth muscle myosin heavy chain in human serum. The sensitivity of the assay was 0.4 ng/mL. Cross-reactivity with cardiac, skeletal, or platelet myosin was negligible at <0.1%, and the cross-reactivity with aortic myosin was 100%. The analytical recovery showed good agreement with theoretical values, and within- and between-run variation showed good reproducibility. Analysis of 75 healthy individuals showed smooth muscle myosin heavy chain levels in normal human sera to be 0.9±0.1 ng/mL.

Statistical Analysis
Results are presented as mean±SEM. Comparison between means of two independent samples was performed by the two-tailed unpaired t test. Analysis of multiple groups was performed with ANOVA as adjusted by the Bonferroni/Dunn method. Statistical significance was defined as P<.05. Statistical testing was performed with commercially available statistics software (StatView version 4.0, Abacus Concepts Inc).

	Results

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Patient Characteristics
The Table summarizes the demographic and clinical characteristics of the patients enrolled. A total of 27 patients (mean age, 67.6±2.0 years) with acute aortic dissection were enrolled in the study. Twenty men and 7 women 66.5±2.5 and 71.0±1.8 years old (P=NS), respectively, were enrolled. There were 16 and 11 cases of Stanford types A and B dissections, respectively. In terms of the DeBakey classification, 11 cases of type I, 5 cases of type II, and 11 cases of type III were found. All patients (27 of 27, 100%) showed symptoms of either chest or back pain. The diagnosis was confirmed by imaging in all cases, with 14 cases diagnosed by computed tomography. Angiography was conducted in 2 cases, and 3 cases were diagnosed by magnetic resonance imaging. Ultrasonography and transesophageal echocardiography were performed in 7 and 4 cases, respectively. Duration after onset until admission was 6.0±1.3 hours. The serum smooth muscle myosin heavy chain levels at admission were 30.8±13.9 ng/mL. The time course of serum smooth muscle myosin heavy chain levels in the patients with aortic dissection are shown in Fig 1. Underlying diseases included hypertension in 14 patients, 1 case of collagen-vascular disease in which chronic renal failure and hypertension were also present, and 1 case of prior cardiac catheterization that was the immediate cause of aortic dissection. Of the patients with Stanford type A dissections, 5 received surgical therapy, with all others (n=11) receiving medical therapy. Of the surgical cases, 3 were DeBakey type I aortic dissections and 2 were DeBakey type II. All patients with Stanford type B aortic dissections (n=11) received medical therapy. Circulatory shock as defined by systolic blood pressure <85 mm Hg and urine output <20 mL/h was found in 10 patients. Renal dysfunction as defined by serum creatinine levels of >1.5 mg/dL was found in 5 patients.

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics

View larger version (15K): [in this window] [in a new window]   Figure 1. Time course of serum smooth muscle myosin heavy chain levels in patients with aortic dissection (n=27). Note that peak levels are at onset. Rapid reductions in levels are found during the first 24 hours.

Statistical Analysis
The baseline patient characteristics of mean age and sex were not significant. Statistical analysis with the serum smooth muscle myosin heavy chain level as the reference parameter was performed. The results did not show significantly different levels for age, diagnosis, mode of therapy, presence of renal function, or past illness. However, significantly higher serum levels were demonstrated in patients in shock compared with hemodynamically stable patients (53.9±18.8 versus 11.0±2.9 ng/mL, P<.01). Analysis performed with groups separated for hemodynamically stable and unstable patients as defined by the previous criteria did not show statistical significance for any of the previously mentioned parameters.

At a cutoff value of 2.5 ng/mL, the assay showed a sensitivity of 90% during the first 12 hours after onset (18 of 20 patients), which was reduced to 85% at 24 hours (23 of 27 patients). All patients with values less than the cutoff value were patients with a diagnosis of distal Stanford type B or DeBakey type III lesions. The specificity of the assay was 97%.

The lesion site according to Stanford or DeBakey classification in relation to serum smooth muscle myosin heavy chain levels was analyzed. Significance was not found among groups for initial smooth muscle myosin heavy chain levels. Initial levels did not show a significant relationship with any other parameter, including age, sex, peak serum smooth muscle myosin heavy chain levels, mode of therapy, or presence of circulatory shock. However, as previously stated, at a cutoff value of 2.5 ng/mL, a number of patients with distal Stanford type B or DeBakey type III lesions were found to show levels below the cutoff point. Analysis of the difference in smooth muscle myosin heavy chain levels at initial presentation and at 12 hours after admission showed that DeBakey type II lesions showed greater reduction in levels compared with other lesions (DeBakey type I, 4.7±2.9 ng/mL [n=6]; type II, 39.2±19.6 ng/mL [n=3]; and type III, 3.9±2.7 ng/mL [n=8]; P<.05). Significance was not found between Stanford types. The significant reduction in levels according to DeBakey type did not show significant relation to type of therapy.

Analysis of smooth muscle myosin heavy chain levels with other biochemical parameters did not show a significant correlation between smooth muscle myosin heavy chain serum levels and leukocyte count, hematocrit, erythrocyte sedimentation rate, the acute phase reactant C-reactive protein, aspartate transaminase, alanine transaminase, lactate dehydrogenase, total bilirubin, blood urea nitrogen, creatinine levels, and creatinine kinase or MB fraction. Leukocyte count and C-reactive proteins were markedly elevated regardless of type of lesion according to either Stanford or DeBakey classification.

Differential Diagnosis of Myocardial Infarction
Diseases that present with similar symptoms of chest or back pain require differential diagnosis and should not show falsely elevated levels. In particular, the differential diagnosis of acute myocardial infarction is of utmost importance. To investigate, the levels of serum smooth muscle myosin heavy chain were compared with serum cardiac myosin light chain levels in patients with myocardial infarction. Cardiac myosin light chain, a biochemical index of myocardial infarction, shows elevated serum levels for up to 2 weeks in patients after initial elevation at 4 to 12 hours after onset of myocardial infarction.¹⁵ Serum smooth muscle myosin heavy chain and cardiac myosin light chain levels were serially measured in a total of 65 cases of myocardial infarction. Serial examination was conducted in 15 cases, and trivial time points within 1 week of onset were examined in 50 cases. None of the tested cases showed significantly elevated serum smooth muscle myosin heavy chain levels (Figs 2 and 3).

View larger version (14K): [in this window] [in a new window]   Figure 2. Comparison of serum smooth muscle myosin heavy chain levels and serum cardiac myosin light chain levels in patients with myocardial infarction. Serum smooth muscle myosin heavy chain levels are not falsely elevated in patients. Normal levels of serum cardiac myosin light chain, 0.24±0.07 ng/mL. Elevation >2.5 ng/mL is significant.

View larger version (16K): [in this window] [in a new window]   Figure 3. Serial measurements of serum smooth muscle myosin heavy chain (SMMHC) levels and serum cardiac (ventricular) myosin light chain levels (VMLC1) in a representative patient with myocardial infarction (MI).

	Discussion

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Advances in diagnostic methods in cardiovascular medicine have relied heavily on medical research and technology. Modern technology has made possible not only advances in physiological and image diagnostic methods but also equal advances in biochemical diagnosis. Great progress has been made in the past quarter century in the diagnostic biochemical testing of cardiovascular diseases. Beginning with the introduction of the serum transaminase assays,¹⁶ clinical application of assays of enzyme activity (eg, lactate dehydrogenase, creatinine kinase) followed that greatly improved the diagnosis of acute myocardial infarction,^{17 18} and recently assays of structural proteins (eg, cardiac myosin light chain and troponin)^{15 19 20 21 22} have established their roles in clinical medicine.

Biochemical assays for vascular diseases, however, have not been available, in part because of a lack of specific markers for vascular diseases. With the recent progress made in the field of vascular biology, markers specific to vascular components have become available. Characterization of smooth muscle myosin heavy chain, a structural protein found in smooth muscle cells, and its isoforms by the authors and by others in the past have shown that smooth muscle myosin heavy chain is specific to the smooth muscle lineage.^{23 24 25 26 27 28} With expectations that smooth muscle myosin heavy chain would be a specific biochemical index of smooth muscle diseases, the immunoassay of serum smooth muscle myosin heavy chain we present was developed.

Aortic dissection is a cardiovascular catastrophe characterized by disruption of the aortic media by blood entering through a laceration of the luminal vascular wall. The insult causes extensive damage to smooth muscle cells of the media, leading to release of structural proteins of the smooth muscle cells, including smooth muscle myosin heavy chain, into the circulation. The present study was undertaken to ascertain the clinical usefulness of the immunoassay of serum smooth muscle myosin heavy chain in the diagnosis of acute aortic dissection.

The results of the present study show that the immunoassay of smooth muscle myosin heavy chain is useful in the diagnosis of aortic dissection.

Accurate Diagnosis of Aortic Dissection During the First 24 Hours
The levels of serum smooth muscle myosin heavy chain in aortic dissection were 30.8±13.9 ng/mL at admission, with subsequent reduction in levels. The rate of reduction in serum levels was rapid, with reduction to within twofold elevations of the cutoff value (2.5 ng/mL) within the first 24 hours. A statistical relationship could not be demonstrated for initial serum smooth muscle myosin heavy chain levels with age, sex, diagnosis as defined by type of dissection according to the Stanford and/or DeBakey classifications, renal dysfunction, or mode of therapy (surgical or medical). Serum levels, being independent of renal function, allowed reliable measurements in patients with renal dysfunction, which is a not uncommon complication of or underlying disease in aortic dissection. Patients in circulatory shock showed significantly elevated levels compared with those not in shock (53.9±16.4 versus 13.2±3.3 ng/mL, P<.01). The reason for this characteristic is unknown. However, there may be factors other than aortic damage that affect the serum myosin heavy chain levels for patients in shock.

The patients were admitted at 6.0±1.3 hours after onset. Although reduction in serum smooth muscle myosin heavy chain levels was rapid, levels during this time period were significantly elevated to allow accurate diagnosis. Patients with DeBakey type II lesions showed significant reductions during the first 12 hours compared with types I and III regardless of therapy. This may suggest that type II lesions, which are the most localized lesions, with damage to only the proximal region of the aortic root, show a limited vascular process compared with the other types, and may suggest a semiquantitative role for the assay.

A number of patients with DeBakey type III aortic dissections did not show elevated levels. Since the abdominal aorta shows reduced expression of smooth muscle cells compared with the thoracic aorta (unpublished observation), perhaps a reduced extent in the damage to the vascular smooth muscle cells was responsible for the lack of elevation in serum levels. From a clinical standpoint, the patients with nonelevated levels were those who showed a noncomplicated course, with favorable response to medical therapy. However, further investigations will be necessary to clarify this characteristic.

Immunoassay Can Accurately Differentiate Acute Myocardial Infarction
The usefulness of the assay depends greatly on its ability to distinguish aortic dissection from other diseases of the chest that present with similar symptoms of chest or back pain. In particular, the differential diagnosis of acute myocardial infarction is of utmost importance.

During the first several hours after onset of acute myocardial infarction, patients in extremely early phases of the evolving myocardial infarction may not present with typical ST-segment elevation on the ECG and may show only the often-overlooked elevated T wave in the hyperacute period. In these early stages, the differentiation of acute myocardial infarction from other diseases, including aortic dissection, may present difficulties. Biochemical markers for acute myocardial infarction, which include elevated leukocyte count, creatinine kinase, aspartate transaminase, and lactate dehydrogenase, may not be elevated during the initial hours.^{29 30} Therefore, the differential diagnosis is of critical importance. Serial examination of blood levels in patients showed that there is little possibility of false elevation of smooth muscle myosin heavy chain in myocardial infarction. Although coronary involvement or cardiac tamponade associated with proximal aortic dissections may show confusing signs and symptoms, differentiation of primary or conventional myocardial infarction by use of this biochemical method should not pose any problems.

Limitations of Use
Smooth muscle myosin heavy chain is common to smooth muscle myosin also found abundantly in the intestine and uterus. It is theoretically possible that patients with diseases of other smooth muscle–containing organs might show elevated serum levels, although this is unlikely because the myosin proteins are not readily released into the circulation in abundance compared with vascular intrinsic diseases. Preliminary studies in other vascular diseases (eg, aortitis, aortic aneurysms) as well have not shown significant elevations. Further investigations will be necessary to address this issue. The possibility of elevations as well as clinical profile should always be considered in the interpretation of results.

The novel immunoassay showed a sensitivity of 90% within the first 12 hours after onset of aortic dissection and a specificity of 97%. Although the assay used in the present study showed performance at 5 hours, on-site testing would be most beneficial, because patients with suspected aortic dissection require immediate diagnosis. On-site testing with a performance time of <30 minutes is technically feasible and will become possible in the near future.

The assay shows tremendous clinical possibilities, providing an easy, fast, and accurate method for screening of aortic dissection. The biochemical method shows promise in the differential diagnosis as well, as exemplified by acute myocardial infarction. In the cardiovascular institution, as one parameter of the clinical assessment, the method may play an assistive role in the diagnosis, along with other available diagnostic methods. At facilities that do not have available diagnostic instruments (eg, computed tomography, transesophageal echocardiography), the biochemical method may provide a highly useful tool for screening of aortic dissection in patients presenting with chest pain and to aid in the clinical judgment of the assessment and management of such cases.

	Footnotes

 
Reprint requests to Ryozo Nagai, MD, Second Department of Internal Medicine, Gunma University School of Medicine, 3-39-15, Showa-machi, Maebashi, Gunma 371, Japan.

Received July 5, 1995; revision received November 9, 1995; accepted November 13, 1995.

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