Unveiling the Silence: Two cases of sST-2-negative Aortic Dissection with Diagnostic Implications

Unveiling the Silence: Two cases of sST-2-negative Aortic Dissection with Diagnostic Implications | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Unveiling the Silence: Two cases of sST-2-negative Aortic Dissection with Diagnostic Implications Mengmeng Wu, Yifan Wang, Xiaoqing Ming, Fen Ai This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7281580/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background Soluble ST2 (sST2) is a biomarker linked to myocardial stress and inflammation, demonstrating potential in the early diagnosis of acute aortic dissection (AAD), often surpassing traditional markers such as D-dimer. Nonetheless, its diagnostic efficacy in real-world settings remains insufficiently characterized. Case Summary: We present two uncommon cases of clinically confirmed AAD: one involving a Stanford type B intramural hematoma and the other an extensive DeBakey type I dissection, both exhibiting unexpectedly low sST2 levels (5.87 ng/mL and 15.94 ng/mL, respectively), significantly below the standard diagnostic threshold of 34.6 ng/mL. Both patients were hemodynamically stable and did not display elevated cardiac biomarkers. Despite the severity and extent of the disease, sST2 did not accurately indicate the presence of aortic pathology. Conclusion : Normal sST2 levels do not exclude the possibility of AAD. These cases highlight the necessity for caution when interpreting sST2 results in isolation and advocate for a comprehensive diagnostic approach that incorporates clinical assessment and imaging techniques. Further research is essential to clarify the diagnostic limitations of sST2 and to enhance biomarker strategies for the evaluation of acute chest pain. sST2 Aortic Dissection D-dimer Figures Figure 1 Figure 2 Figure 3 Background Growth stimulation expressed gene 2 (ST2) protein, a member of the interleukin-1 (IL-1) receptor family, is recognized as a specific biomarker associated with inflammation and autoimmune diseases. The ST2 gene is situated on the human chromosome 2q12 [ 1 ] . ST2 exists in two isoforms: the soluble form (sST2) and the transmembrane form (ST2L). It is ubiquitously expressed in various tissues, including myocardial and endothelial cells. Notably, sST2 has garnered significant attention as a novel biomarker for heart failure due to its strong association with myocardial inflammation and fibrosis, rendering it an important marker in the context of cardiovascular diseases. Elevated sST2 levels reflect ongoing inflammation and myocardial stress, often seen in conditions such as heart failure and aortic dissection [ 2 ] . Evidence suggests that sST2 exhibits superior diagnostic accuracy in distinguishing acute myocardial infarction, aortic dissection, and pulmonary embolism in patients presenting with acute chest pain, surpassing conventional biomarkers such as D-dimer and cardiac troponin I [ 2 ] . These findings underscore its potential utility as an adjunctive tool in early clinical evaluation [ 3 – 5 ] . When applying a cutoff value of 34.6 µg/L for sST2, the biomarker demonstrated a positive predictive value of 68.7%, a negative predictive value of 99.7%, and a negative likelihood ratio of 0.01 for diagnosing acute aortic dissection (AAD). Moreover, the study indicated that within 24 hours of symptom onset in patients presenting with acute chest pain, sST2 exhibited greater predictive utility for AAD than D-dimer [ 3 ] . Despite increasing evidence supporting the diagnostic utility of sST2 in AAD, its clinical application and reliability in real-world settings remain inadequately established. Prior to this report, there have been no documented instances of AAD presenting with negative sST2 levels, rendering these findings significant in assessing the limitations of sST2 as a diagnostic biomarker. This article presents two cases of AAD with negative sST2 results, highlighting the necessity for further research into the biomarker’s sensitivity and diagnostic limitations. Case reports Case 1 A 75-year-old male presented to the emergency department (ED) with a 12-hour history of chest pain. He had no prior history of chronic diseases. The blood pressure was 150/87 mmHg, the heart rate was 78 beats per minute, and the oxygen saturation (SpO₂) was 98% on room air. He was alert and oriented. Pulmonary auscultation revealed clear breath sounds bilaterally without rales. Cardiac examination showed a regular rhythm with no audible murmurs. The patient had a long history of smoking for 30 years and alcohol consumption for 30 years. Laboratory tests conducted in the ED revealed normal results for complete blood count, liver function, renal function, coagulation profile, myocardial enzyme profile, and electrolytes. D-dimer and high-sensitivity cardiac troponin I (hs-cTnI) were all negative. sST2 5.87 ng/ml (The normal range is < 35 ng/ml). The electrocardiogram (ECG) showed sinus rhythm with a normal waveform. Chest computerized tomography (CT) demonstrated heterogeneous density of the thoracic aorta, with areas of high and low attenuation (Fig. 1 ). Further assessment with aortic computer tomography angiography (CTA) revealed an aortic intramural hematoma (Stanford type B), accompanied by formation of a localized dissection in the mid-portion of the thoracic aorta, and multiple small ulcers in the aorta (Fig. 2). After blood pressure control and pain management in the ED, the patient was transferred to the Cardiothoracic Surgery Department for thoracic aortic stent implantation and was discharged following the procedure. After discharge, the patient was prescribed long-term medication, including Clopidogrel bisulfate 50mg Once daily and Rivaroxaban 7.5mg once daily. Case 2 A 44-year-old male presented to the ED with chest pain radiating for 2 hours. His medical history includes undergoing aortic valve replacement with a mechanical valve 10 years ago due to aortic stenosis, after which he has been on long-term warfarin therapy (4.5mg daily). The patient’s blood pressure was 154/92 mmHg, heart rate was 59 beats per minute, and SpO₂ was 100% on room air. He was alert and oriented. Pulmonary auscultation revealed clear breath sounds bilaterally without rales or wheezes. Cardiac examination showed a regular heart rhythm, and a mechanical valve click was audible at the apex, consistent with prior aortic valve replacement. He has a 20-year smoking history. Emergency laboratory results showed a white blood cell count of 16.29 × 10^9/L, normal liver function, normal renal function, normal electrolytes, normal myocardial enzyme profile, prothrombin time of 17.2 seconds, international normalized ratio (INR) of 1.44, fibrinogen level of 1.9 g/L, thrombin time of 17 seconds, and activated partial thromboplastin time of 27.2 seconds. hs-cTnI was normal, and D-dimer was 1.34 mg/L, sST2 was 15.94 ng/ml. Cardiac ultrasound revealed a high-echo membrane-like strip in the aorta, with dilation of the ascending aorta (5.7 cm), post-aortic valve replacement. No paravalvular leak was observed, and the ejection fraction was 60%. Chest and abdominal aortic CTA showed: Aortic dissection (DeBakey Type I), with an aneurysm formed in the ascending aorta, extending from the aortic root to the proximal level of the bilateral external iliac arteries, with involvement of the brachiocephalic trunk. The celiac trunk and superior mesenteric artery were bridged by a false lumen, with the right renal artery and inferior mesenteric artery originating from the false lumen, while the left subclavian artery, left common carotid artery, and left renal artery originated from the true lumen (Fig. 3 ). After blood pressure control and pain management in the ED, the patient underwent total aortic arch replacement with artificial graft, elephant trunk procedure, along with aortic valve and ascending aorta replacement, and coronary artery bypass grafting (Bentall procedure). Discussion The cases discussed in this report underscore an intriguing and potentially underrecognized dimension of aortic dissection diagnosis: the occurrence of negative soluble ST2 (sST2) levels in patients exhibiting clinically significant aortic pathology. While sST2 has been suggested as a promising biomarker for various cardiovascular conditions, including aortic dissection, the negative findings observed in these two cases necessitate further investigation and a critical assessment of its clinical utility. Elevated sST2 levels have been correlated with heightened systemic inflammation and myocardial stress, suggesting its theoretical relevance as a marker for acute cardiovascular events [ 6 ] . In both instances, sST2 levels remained within the normal range, thereby raising significant clinical questions about its sensitivity and diagnostic applicability. These observations necessitate further investigation into whether negative sST2 results might indicate alternative or less pronounced pathophysiological mechanisms in certain cases of aortic dissection, such as diminished inflammatory activation or myocardial involvement. Additionally, the timing of biomarker measurement warrants careful consideration, as prior studies have indicated that sST2 concentrations may vary depending on the phase of disease progression. This temporal variability could potentially restrict its diagnostic utility to particular stages of aortic dissection. In both cases described, sST2 levels were markedly below the commonly proposed diagnostic cutoff of 34.6 ng/mL, with values of 15.94 ng/mL and 5.87 ng/mL. The result in Case 2 is particularly notable, given the extensive nature of the dissection, which involved the entire aorta in a DeBakey type I pattern. Such a presentation is typically associated with significant vascular injury, hemodynamic stress, and systemic inflammation, all of which are mechanisms thought to promote sST2 elevation. The discordance between disease severity and biomarker levels observed here suggests that activation of the IL-33/ST2 signaling pathway may not be uniform across all presentations of acute aortic dissection and may be modulated by additional clinical or biological factors. One potential explanation for the low sST2 levels lies in the timing of measurement relative to symptom onset. Although sST2 is known to rise early in response to cardiovascular stress, its kinetic profile in the setting of aortic dissection remains poorly characterized. It is conceivable that, in cases where symptom onset is gradual or delayed, the peak expression window of sST2 may have passed by the time of sampling, thereby leading to false-negative results. This may have been a contributing factor in Case 1 , where the patient presented 12 hours after the onset of symptoms and was diagnosed with an intramural hematoma rather than a classic dissection. Intramural hematomas may produce less abrupt disruption of the aortic wall, resulting in attenuated systemic inflammatory and neurohumoral responses. Additionally, both patients were hemodynamically stable at presentation. Unlike in cases of cardiogenic shock or acute decompensated heart failure, where sST2 has been shown to correlate strongly with ventricular strain, aortic dissection in the setting of preserved hemodynamics may not provide sufficient stimulus to induce sST2 elevation. The presence of a mechanical aortic valve and chronic anticoagulation therapy in Case 2 adds further complexity. Long-term warfarin use may influence vascular reactivity or dampen inflammatory signaling, potentially contributing to lower-than-expected biomarker levels. At present, there is no research indicating the correlation between warfarin and sST2. These findings challenge the assumption that a low sST2 value can be used to reliably exclude aortic dissection reliably. The implications for clinical practice are significant, particularly concerning emergency triage protocols. Overreliance on sST2 as a rule-out test, especially in patients with atypical symptoms or normal vital signs, could lead to missed or delayed diagnoses and adverse outcomes. These cases reinforce the continued importance of imaging, particularly CTA, as a cornerstone of diagnostic assessment in patients presenting with chest pain and suspected aortic pathology [ 7 ] . From a research perspective, these observations underscore the heterogeneity of aortic dissection as a disease entity. Rather than representing a single pathological process, aortic dissection encompasses a spectrum that includes classic intimal tears, intramural hematomas, penetrating atherosclerotic ulcers, and various overlapping forms [ 8 ] . Each subtype may activate distinct pathophysiological pathways and exhibit different biomarker signatures. This variability suggests that a single-marker approach may be inadequate for comprehensive diagnostic evaluation. Instead, a multi-marker strategy that integrates sST2 with other biomarkers such as D-dimer, matrix metalloproteinases (MMPs), interleukin-6 (IL-6), or markers of vascular injury may provide more robust diagnostic performance [ 9 ] . In conclusion, while sST2 remains a promising biomarker in cardiovascular disease, these cases indicate that its diagnostic utility in acute aortic dissection may be more limited than previously thought. The presence of negative sST2 results in both patients challenges current assumptions about its sensitivity and raises important considerations regarding timing, disease subtype, hemodynamic status, and patient-specific factors. Clinicians should exercise caution in interpreting sST2 levels in isolation and instead employ a multimodal diagnostic approach that incorporates clinical evaluation, imaging, and complementary biomarkers. These findings highlight the complexity of aortic dissection pathophysiology and underscore the need for further studies to refine biomarker-based diagnostic strategies. Declarations Not applicable, as this manuscript does not contain any individual person’s data in any form (including images, videos, or other details). Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors. Contributors: MW conceived and designed this investigation. YW and XM collected the original data. MW and FA contributed to the writing of the paper. Ethics: The study was approved by the Medical Ethics Committee of the Central Hospital of Wuhan (WHZXKYL2024-156). This study adheres to the principles outlined in the Declaration of Helsinki. Acknowledgments: None Conflict of interest statements: None Clinical trial number: Not applicable. Consent for publication: Written informed consent for publication of the clinical details and images was obtained from the patient (or their legal guardian). Availability of data and materials: The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no competing interests. References Obradovic DM, Büttner P, Rommel K, et al. Soluble ST2 Receptor: Biomarker of Left Ventricular Impairment and Functional Status in Patients with Inflammatory Cardiomyopathy[J]. Cells. 2022;11(3):414. Agrawal V, Hardas S, Gujar H, et al. Correlation of serum ST2 levels with severity of diastolic dysfunction on echocardiography and findings on cardiac MRI in patients with heart failure with preserved ejection fraction[J]. Indian Heart J. 2022;74(3):229–34. Wang Y, Tan X, Gao H, et al. Magnitude of Soluble ST2 as a Novel Biomarker for Acute Aortic Dissection[J]. Circulation. 2018;137(3):259–69. Aleksova A, Paldino A, Beltrami AP et al. Cardiac Biomarkers in the Emergency Department: The Role of Soluble ST2 (sST2) in Acute Heart Failure and Acute Coronary Syndrome-There is Meat on the Bone[J]. J Clin Med, 2019,8(2). Jiang W, Wang X, Gao P, et al. Association of IL1R1 Coding Variant With Plasma-Level Soluble ST2 and Risk of Aortic Dissection[J]. Front Cardiovasc Med. 2021;8:710425. Geenen LW, Baggen V, Kauling RM et al. The Prognostic Value of Soluble ST2 in Adults with Pulmonary Hypertension[J]. J Clin Med, 2019,8(10). Hiratzka LF, Bakris GL, Beckman JA, American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery. 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 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]. Circulation, 2010,121(13):e266-e369. Zhu Q, Wang L, Dai C, et al. Diagnostic potential of soluble ST2 and D-dimer for Stanford Type B aortic dissection and intramural aortic hematoma[J]. Microvasc Res. 2024;151:104623. Chen H, Li Y, Li Z, et al. Diagnostic biomarkers and aortic dissection: a systematic review and meta-analysis[J]. BMC Cardiovasc Disord. 2023;23(1):497. Additional Declarations No competing interests reported. Supplementary Files CAREchecklistEnglish2013.pdf Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 05 Oct, 2025 Reviews received at journal 01 Oct, 2025 Reviewers agreed at journal 27 Sep, 2025 Reviewers agreed at journal 18 Sep, 2025 Reviewers invited by journal 18 Sep, 2025 Editor assigned by journal 15 Sep, 2025 Editor invited by journal 28 Aug, 2025 Submission checks completed at journal 28 Aug, 2025 First submitted to journal 28 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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2","display":"","copyAsset":false,"role":"figure","size":110993,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe aortic CTA of case 1\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7281580/v1/06bd152a9899cc71e2c64151.png"},{"id":92480094,"identity":"36927c1d-b40b-41b2-9bb6-c6548ea7acb9","added_by":"auto","created_at":"2025-09-30 07:39:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":273693,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe Chest and abdominal aortic CTA of Case 2\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7281580/v1/716be1e74bd07054d402af5b.png"},{"id":92480115,"identity":"51e11c34-8baf-422f-bfe7-0171862e0533","added_by":"auto","created_at":"2025-09-30 07:39:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":988799,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7281580/v1/ba8fe010-2c33-42d5-9432-620f20457fb3.pdf"},{"id":92475162,"identity":"683396d3-7479-48ad-9279-a04300b04a26","added_by":"auto","created_at":"2025-09-30 07:15:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":829941,"visible":true,"origin":"","legend":"","description":"","filename":"CAREchecklistEnglish2013.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7281580/v1/fe224ca708a79d9a2d195da5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Unveiling the Silence: Two cases of sST-2-negative Aortic Dissection with Diagnostic Implications","fulltext":[{"header":"Background","content":"\u003cp\u003eGrowth stimulation expressed gene 2 (ST2) protein, a member of the interleukin-1 (IL-1) receptor family, is recognized as a specific biomarker associated with inflammation and autoimmune diseases. The ST2 gene is situated on the human chromosome 2q12\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. ST2 exists in two isoforms: the soluble form (sST2) and the transmembrane form (ST2L). It is ubiquitously expressed in various tissues, including myocardial and endothelial cells. Notably, sST2 has garnered significant attention as a novel biomarker for heart failure due to its strong association with myocardial inflammation and fibrosis, rendering it an important marker in the context of cardiovascular diseases. Elevated sST2 levels reflect ongoing inflammation and myocardial stress, often seen in conditions such as heart failure and aortic dissection\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eEvidence suggests that sST2 exhibits superior diagnostic accuracy in distinguishing acute myocardial infarction, aortic dissection, and pulmonary embolism in patients presenting with acute chest pain, surpassing conventional biomarkers such as D-dimer and cardiac troponin I\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. These findings underscore its potential utility as an adjunctive tool in early clinical evaluation\u003csup\u003e[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. When applying a cutoff value of 34.6 \u0026micro;g/L for sST2, the biomarker demonstrated a positive predictive value of 68.7%, a negative predictive value of 99.7%, and a negative likelihood ratio of 0.01 for diagnosing acute aortic dissection (AAD). Moreover, the study indicated that within 24 hours of symptom onset in patients presenting with acute chest pain, sST2 exhibited greater predictive utility for AAD than D-dimer\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eDespite increasing evidence supporting the diagnostic utility of sST2 in AAD, its clinical application and reliability in real-world settings remain inadequately established. Prior to this report, there have been no documented instances of AAD presenting with negative sST2 levels, rendering these findings significant in assessing the limitations of sST2 as a diagnostic biomarker. This article presents two cases of AAD with negative sST2 results, highlighting the necessity for further research into the biomarker\u0026rsquo;s sensitivity and diagnostic limitations.\u003c/p\u003e"},{"header":"Case reports","content":"\u003cp\u003e\u003cstrong\u003eCase 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 75-year-old male presented to the emergency department (ED) with a 12-hour history of chest pain. He had no prior history of chronic diseases. The blood pressure was 150/87 mmHg, the heart rate was 78 beats per minute, and the oxygen saturation (SpO₂) was 98% on room air. He was alert and oriented. Pulmonary auscultation revealed clear breath sounds bilaterally without rales. Cardiac examination showed a regular rhythm with no audible murmurs. The patient had a long history of smoking for 30 years and alcohol consumption for 30 years. Laboratory tests conducted in the ED revealed normal results for complete blood count, liver function, renal function, coagulation profile, myocardial enzyme profile, and electrolytes. D-dimer and high-sensitivity cardiac troponin I (hs-cTnI) were all negative. sST2 5.87 ng/ml (The normal range is \u0026lt;\u0026thinsp;35 ng/ml). The electrocardiogram (ECG) showed sinus rhythm with a normal waveform. Chest computerized tomography (CT) demonstrated heterogeneous density of the thoracic aorta, with areas of high and low attenuation (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Further assessment with aortic computer tomography angiography (CTA) revealed an aortic intramural hematoma (Stanford type B), accompanied by formation of a localized dissection in the mid-portion of the thoracic aorta, and multiple small ulcers in the aorta (Fig. 2). After blood pressure control and pain management in the ED, the patient was transferred to the Cardiothoracic Surgery Department for thoracic aortic stent implantation and was discharged following the procedure. After discharge, the patient was prescribed long-term medication, including Clopidogrel bisulfate 50mg Once daily and Rivaroxaban 7.5mg once daily.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 44-year-old male presented to the ED with chest pain radiating for 2 hours. His medical history includes undergoing aortic valve replacement with a mechanical valve 10 years ago due to aortic stenosis, after which he has been on long-term warfarin therapy (4.5mg daily). The patient\u0026rsquo;s blood pressure was 154/92 mmHg, heart rate was 59 beats per minute, and SpO₂ was 100% on room air. He was alert and oriented. Pulmonary auscultation revealed clear breath sounds bilaterally without rales or wheezes. Cardiac examination showed a regular heart rhythm, and a mechanical valve click was audible at the apex, consistent with prior aortic valve replacement. He has a 20-year smoking history. Emergency laboratory results showed a white blood cell count of 16.29 \u0026times; 10^9/L, normal liver function, normal renal function, normal electrolytes, normal myocardial enzyme profile, prothrombin time of 17.2 seconds, international normalized ratio (INR) of 1.44, fibrinogen level of 1.9 g/L, thrombin time of 17 seconds, and activated partial thromboplastin time of 27.2 seconds. hs-cTnI was normal, and D-dimer was 1.34 mg/L, sST2 was 15.94 ng/ml. Cardiac ultrasound revealed a high-echo membrane-like strip in the aorta, with dilation of the ascending aorta (5.7 cm), post-aortic valve replacement. No paravalvular leak was observed, and the ejection fraction was 60%. Chest and abdominal aortic CTA showed: Aortic dissection (DeBakey Type I), with an aneurysm formed in the ascending aorta, extending from the aortic root to the proximal level of the bilateral external iliac arteries, with involvement of the brachiocephalic trunk. The celiac trunk and superior mesenteric artery were bridged by a false lumen, with the right renal artery and inferior mesenteric artery originating from the false lumen, while the left subclavian artery, left common carotid artery, and left renal artery originated from the true lumen (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). After blood pressure control and pain management in the ED, the patient underwent total aortic arch replacement with artificial graft, elephant trunk procedure, along with aortic valve and ascending aorta replacement, and coronary artery bypass grafting (Bentall procedure).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe cases discussed in this report underscore an intriguing and potentially underrecognized dimension of aortic dissection diagnosis: the occurrence of negative soluble ST2 (sST2) levels in patients exhibiting clinically significant aortic pathology. While sST2 has been suggested as a promising biomarker for various cardiovascular conditions, including aortic dissection, the negative findings observed in these two cases necessitate further investigation and a critical assessment of its clinical utility. Elevated sST2 levels have been correlated with heightened systemic inflammation and myocardial stress, suggesting its theoretical relevance as a marker for acute cardiovascular events\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. In both instances, sST2 levels remained within the normal range, thereby raising significant clinical questions about its sensitivity and diagnostic applicability. These observations necessitate further investigation into whether negative sST2 results might indicate alternative or less pronounced pathophysiological mechanisms in certain cases of aortic dissection, such as diminished inflammatory activation or myocardial involvement. Additionally, the timing of biomarker measurement warrants careful consideration, as prior studies have indicated that sST2 concentrations may vary depending on the phase of disease progression. This temporal variability could potentially restrict its diagnostic utility to particular stages of aortic dissection.\u003c/p\u003e\u003cp\u003eIn both cases described, sST2 levels were markedly below the commonly proposed diagnostic cutoff of 34.6 ng/mL, with values of 15.94 ng/mL and 5.87 ng/mL. The result in Case \u003cspan refid=\"FPar2\" class=\"InternalRef\"\u003e2\u003c/span\u003e is particularly notable, given the extensive nature of the dissection, which involved the entire aorta in a DeBakey type I pattern. Such a presentation is typically associated with significant vascular injury, hemodynamic stress, and systemic inflammation, all of which are mechanisms thought to promote sST2 elevation. The discordance between disease severity and biomarker levels observed here suggests that activation of the IL-33/ST2 signaling pathway may not be uniform across all presentations of acute aortic dissection and may be modulated by additional clinical or biological factors.\u003c/p\u003e\u003cp\u003eOne potential explanation for the low sST2 levels lies in the timing of measurement relative to symptom onset. Although sST2 is known to rise early in response to cardiovascular stress, its kinetic profile in the setting of aortic dissection remains poorly characterized. It is conceivable that, in cases where symptom onset is gradual or delayed, the peak expression window of sST2 may have passed by the time of sampling, thereby leading to false-negative results. This may have been a contributing factor in Case \u003cspan refid=\"FPar1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, where the patient presented 12 hours after the onset of symptoms and was diagnosed with an intramural hematoma rather than a classic dissection. Intramural hematomas may produce less abrupt disruption of the aortic wall, resulting in attenuated systemic inflammatory and neurohumoral responses.\u003c/p\u003e\u003cp\u003eAdditionally, both patients were hemodynamically stable at presentation. Unlike in cases of cardiogenic shock or acute decompensated heart failure, where sST2 has been shown to correlate strongly with ventricular strain, aortic dissection in the setting of preserved hemodynamics may not provide sufficient stimulus to induce sST2 elevation. The presence of a mechanical aortic valve and chronic anticoagulation therapy in Case \u003cspan refid=\"FPar2\" class=\"InternalRef\"\u003e2\u003c/span\u003e adds further complexity. Long-term warfarin use may influence vascular reactivity or dampen inflammatory signaling, potentially contributing to lower-than-expected biomarker levels. At present, there is no research indicating the correlation between warfarin and sST2.\u003c/p\u003e\u003cp\u003eThese findings challenge the assumption that a low sST2 value can be used to reliably exclude aortic dissection reliably. The implications for clinical practice are significant, particularly concerning emergency triage protocols. Overreliance on sST2 as a rule-out test, especially in patients with atypical symptoms or normal vital signs, could lead to missed or delayed diagnoses and adverse outcomes. These cases reinforce the continued importance of imaging, particularly CTA, as a cornerstone of diagnostic assessment in patients presenting with chest pain and suspected aortic pathology\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eFrom a research perspective, these observations underscore the heterogeneity of aortic dissection as a disease entity. Rather than representing a single pathological process, aortic dissection encompasses a spectrum that includes classic intimal tears, intramural hematomas, penetrating atherosclerotic ulcers, and various overlapping forms\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Each subtype may activate distinct pathophysiological pathways and exhibit different biomarker signatures. This variability suggests that a single-marker approach may be inadequate for comprehensive diagnostic evaluation. Instead, a multi-marker strategy that integrates sST2 with other biomarkers such as D-dimer, matrix metalloproteinases (MMPs), interleukin-6 (IL-6), or markers of vascular injury may provide more robust diagnostic performance\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn conclusion, while sST2 remains a promising biomarker in cardiovascular disease, these cases indicate that its diagnostic utility in acute aortic dissection may be more limited than previously thought. The presence of negative sST2 results in both patients challenges current assumptions about its sensitivity and raises important considerations regarding timing, disease subtype, hemodynamic status, and patient-specific factors. Clinicians should exercise caution in interpreting sST2 levels in isolation and instead employ a multimodal diagnostic approach that incorporates clinical evaluation, imaging, and complementary biomarkers. These findings highlight the complexity of aortic dissection pathophysiology and underscore the need for further studies to refine biomarker-based diagnostic strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eNot applicable, as this manuscript does not contain any individual person\u0026rsquo;s data in any form (including images, videos, or other details).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThe authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributors:\u0026nbsp;\u003c/strong\u003eMW conceived and designed this investigation. YW and XM collected the original data. MW and FA contributed to the writing of the paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics:\u0026nbsp;\u003c/strong\u003eThe study was approved by the Medical Ethics Committee of the Central Hospital of Wuhan (WHZXKYL2024-156). This study adheres to the principles outlined in the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest statements:\u0026nbsp;\u003c/strong\u003eNone\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u003c/strong\u003e Not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eWritten informed consent for publication of the clinical details and images was obtained from the patient (or their legal guardian).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eObradovic DM, B\u0026uuml;ttner P, Rommel K, et al. Soluble ST2 Receptor: Biomarker of Left Ventricular Impairment and Functional Status in Patients with Inflammatory Cardiomyopathy[J]. Cells. 2022;11(3):414.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAgrawal V, Hardas S, Gujar H, et al. Correlation of serum ST2 levels with severity of diastolic dysfunction on echocardiography and findings on cardiac MRI in patients with heart failure with preserved ejection fraction[J]. Indian Heart J. 2022;74(3):229\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang Y, Tan X, Gao H, et al. Magnitude of Soluble ST2 as a Novel Biomarker for Acute Aortic Dissection[J]. Circulation. 2018;137(3):259\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAleksova A, Paldino A, Beltrami AP et al. Cardiac Biomarkers in the Emergency Department: The Role of Soluble ST2 (sST2) in Acute Heart Failure and Acute Coronary Syndrome-There is Meat on the Bone[J]. J Clin Med, 2019,8(2).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJiang W, Wang X, Gao P, et al. Association of IL1R1 Coding Variant With Plasma-Level Soluble ST2 and Risk of Aortic Dissection[J]. Front Cardiovasc Med. 2021;8:710425.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGeenen LW, Baggen V, Kauling RM et al. The Prognostic Value of Soluble ST2 in Adults with Pulmonary Hypertension[J]. J Clin Med, 2019,8(10).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHiratzka LF, Bakris GL, Beckman JA, American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery. 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 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]. Circulation, 2010,121(13):e266-e369.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhu Q, Wang L, Dai C, et al. Diagnostic potential of soluble ST2 and D-dimer for Stanford Type B aortic dissection and intramural aortic hematoma[J]. Microvasc Res. 2024;151:104623.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen H, Li Y, Li Z, et al. Diagnostic biomarkers and aortic dissection: a systematic review and meta-analysis[J]. BMC Cardiovasc Disord. 2023;23(1):497.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"sST2, Aortic Dissection, D-dimer","lastPublishedDoi":"10.21203/rs.3.rs-7281580/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7281580/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSoluble ST2 (sST2) is a biomarker linked to myocardial stress and inflammation, demonstrating potential in the early diagnosis of acute aortic dissection (AAD), often surpassing traditional markers such as D-dimer. Nonetheless, its diagnostic efficacy in real-world settings remains insufficiently characterized.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Summary:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe present two uncommon cases of clinically confirmed AAD: one involving a Stanford type B intramural hematoma and the other an extensive DeBakey type I dissection, both exhibiting unexpectedly low sST2 levels (5.87 ng/mL and 15.94 ng/mL, respectively), significantly below the standard diagnostic threshold of 34.6 ng/mL. Both patients were hemodynamically stable and did not display elevated cardiac biomarkers. Despite the severity and extent of the disease, sST2 did not accurately indicate the presence of aortic pathology.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNormal sST2 levels do not exclude the possibility of AAD. These cases highlight the necessity for caution when interpreting sST2 results in isolation and advocate for a comprehensive diagnostic approach that incorporates clinical assessment and imaging techniques. Further research is essential to clarify the diagnostic limitations of sST2 and to enhance biomarker strategies for the evaluation of acute chest pain.\u003c/p\u003e","manuscriptTitle":"Unveiling the Silence: Two cases of sST-2-negative Aortic Dissection with Diagnostic Implications","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-30 07:15:38","doi":"10.21203/rs.3.rs-7281580/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-10-05T16:40:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-01T04:10:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"328668099804000099060719159328229734523","date":"2025-09-27T07:27:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"302057652997838131532408445407097328881","date":"2025-09-18T07:57:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-18T07:43:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-15T09:35:58+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-28T07:16:50+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-28T05:07:01+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cardiovascular Disorders","date":"2025-08-28T05:04:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"98c84d80-8d84-4a80-a7b5-5142662ccfcc","owner":[],"postedDate":"September 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-09-30T07:15:38+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-30 07:15:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7281580","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7281580","identity":"rs-7281580","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}