Identifying Smooth Muscle Cell Specific Proteins as Biomarkers for Early Diagnosis of Acute Aortic Dissection UMHS-PUHSC JOINT INSTITUTE

Transcription

1 Identifying Smooth Muscle Cell Specific Proteins as Biomarkers for Early Diagnosis of Acute Aortic Dissection

2 Background Story AAD was first described by Dr. Nicholls over 200 years ago. King George II 1

3 Composition of the Arterial Wall Adventitia Media Intima 2

4 What is AAD? AAD starts with a Primary Intimal Tear of the Aorta. 3

5 What is AAD? The media layer of the aortic wall is dissected along the aorta into two layers, forming a True Lumen and a False Lumen. 4

6 Classification of Aortic Dissections The Stanford Classification 5

7 Classification of Aortic Dissections 6

8 Acute Type A Dissection Highly Lethal Untreated Type A Dissection Mortality Rate Succumb Rapidly Mortality rate of 1-2% per hour after the onset of symptoms. Majority of patients succumb within 30 days. 7

9 Acute Type A Dissection Highly Lethal In Experienced Treatment Center as UMHC Survival Chance Avoid Complications Surgical repair can transform the high mortality risk to an 80-90% chance of survival. Avoid other common major complications: stroke, paraplegia, renal failure, necrotic bowel, liver and limbs. 8

10 Acute Type A Dissection Highly Lethal Survival chance The time from onset of symptoms to surgical treatment 9

11 Current Diagnosis Method Computer Tomography (CT) Magnetic Resonance Imaging(MRI) Transesophageal Echocardiography (TEE) Time consuming Incurs a further Logistical Delay in patient management 10

12 Management Delay In the United States, 50% of patients have a time to diagnosis of greater than 15 hours after the patients arrive at the hospital. 11

13 Management Delay In type A dissection, the time duration between presentation and definitive management is greater than 12 hours in the majority of patients, and has been reported as being greater than 24 hours in 20-50% in some cases. 12

14 Current Diagnosis Method The door remains open for the incorporation of Biochemical Tests to aid in detecting AAD. 13

15 Current Diagnosis Method Current Biomarkers: CRP (C-reactive protein) Elevated in AAD Very non-specific D-dimer Very high sensitivity (97%) Poor specificity (56%) Positive predictive value (69%) 14

16 Ideal Biomarkers High Sensitivity and Specificity Would be Easy to Use and Fast Their Release should be Temporally Related to the Presentation of an Event Widely Commercial Available and have an Acceptable Cost AMI TNI AAD 15

17 Ideal Biomarkers The media of the aortic wall is composed mainly of Smooth Muscle Cells (SMC) and there is Extensive SMC Injury during AAD Investigate SMC-specific Proteins (sm22α, smmhc, sm-calponin, H-Caldesmom, Smoothelin, and α-sma) for the Early Diagnosis of AAD. 16

18 Research Strategy Research Aims: Identify elevated proteins in the serum in patients of AAD using proteomics. Focusing on smooth muscle cell specific proteins, identify potential biomarkers for AAD. 17

19 Research Strategy Research Groups: Patients diagnosed with acute aortic dissection confirmed by imaging techniques. Patients diagnosed with acute coronary syndrome confirmed by elevated TNI and ECG. Healthy volunteers 18

20 Research Strategy Group A Group B Group C Blood samples (10 ml) are obtained within 12 hours of onset of chest pain Samples Samples Samples Identification and quantification of proteins by mass spectrometry Proteins Increase most significantly Proteins Candidate Biomarkers 19

21 Research Strategy Group A Group B Group C Blood samples (10 ml) are obtained within 12 hours of onset of chest pain Samples Samples Samples Blood samples (10 ml) are obtained within 24 hours of onset of chest pain Samples Samples Compare D-dimer and the SMC specific protein, including sm22a, smmhc, sm- Calponin, H-Caldesmom, Smoothelin, a-sma, and other proteins selected from aim 1 across each group to validate each biomarker s discriminative property Biomarkers 20

22 Research Strategy Timeline: YEAR 1 Obtain IRB approval for the submission which is currently in preparation Identification of candidate biomarkers with proteomics 20 subjects at the University of Michigan and 40 subjects at Peking University YEAR 2 Complete the tasks outlined in Specific Aim 2 Identification of the SMC-specific proteins as candidate biomarkers for acute aortic dissection (AAD) with a larger sample size with known diagnosis 125 subjects at the University of Michigan, and 325 subjects at Peking University YEAR 3-5 Future Study Once we identify the biomarker candidates, we plan to continue studying the half-life and kinetics of those candidates to identify the time points of serum peak level of the biomarker candidates With the preliminary data gathered from years 1 and 2, we will apply for an NIH (USA) grant and National Science Foundation (China) for a clinical study with a larger sample size (1,000 patients), including using the samples from GenTAC to validate the candidate biomarkers in prospective cohorts of patients presenting with chest pain 21

23 Thanks! 22