Sivabaskari Pasupathy

Dr Sivabaskari Pasupathy

Post Doctoral - Research Fellow

Adelaide Medical School

Faculty of Health and Medical Sciences

Eligible to supervise Masters and PhD (as Co-Supervisor) - email supervisor to discuss availability.


Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA)

Our understanding of heart attack acute myocardial infarction (AMI) has evolved considerably over the past 50 years, which has given rise to innovative therapies that have improved patient outcomes. Each year, 55,000 Australians suffer an AMI whereby treatment is centered around a prompt diagnosis of coronary artery blockages followed by coronary interventions to re-open the artery. However, in 10% of myocardial infarction patients (6,000 annually), a blockage is not identified and so the cause and management for patients are unclear. During my Ph.D., I generated the first landmark systematic review publication characterizing these patients (Circulation). These presentations are referred to as MINOCA and is now an established clinical entity. However, in clinical practice, the MINOCA diagnosis is often neglected as patients are considered to be “false positive infarcts”. Importantly, the management of these intriguing patients is predicated upon their initial recognition and subsequent evaluation to elucidate the pathophysiological processes responsible for their presentation.

WHAT is MINOCA? 

  1. AMI as per the “Fourth Universal definition of MI” Criteria.
  2. Nonobstructive coronary arteries on angiography: the absence of obstructive disease on angiography (ie, no coronary artery stenosis ≥50%) in any major epicardial vessel.
  3. No specific alternate diagnosis for the clinical presentation: Alternate diagnoses include but are not limited to non-ischemic causes such as sepsis, pulmonary embolism, and myocarditis.

Specific causes of MINOCA Presentations: Atherosclerotic vs Nonatherosclerotic Causes of Myocardial Necrosis

  • Plaque disruption: approximately 1/3 of MINOCA undergoing intravascular ultrasound testing.
  • Coronary Spasm: approximately 50% of MINOCA undergoing provocative spasm testing.
  • Microvascular Dysfunction: need to be studied in MINOCA population
  • Coronary embolism/Thrombosis: inherited hypercoagulable states in patients with MINOCA, especially in younger women
  • Spontaneous Coronary Artery Dissection: Rare and Should be suspected mainly in young women

WHY Diagnose MINOCA?

Because MINOCA is a new diagnostic syndrome, the question arises as to why it should be created. There are 3 key reasons for establishing this new clinical entity, which include (1) ensuring its clinical recognition, (2) prompting the evaluation of its underlying cause, and (3) the guarded prognosis.

  • Clinical Recognition Some clinicians consider coronary angiography as the gold standard test for establishing a diagnosis of AMI. For example, acute ST-elevation MI (STEMI) registry studies have labeled patients presenting with acute ST elevation and non-obstructive CAD on angiography as a “false-positive STEMI diagnosis”. In some cases this may be appropriate if the ECG is misinterpreted. However, if the patient exhibits new ST elevation with a significant troponin rise and non-obstructive CAD on angiography, they should be diagnosed as MINOCA. Labeling such patients as “false-positive” AMI will result in these patients being dismissed as having a cardiac event and therefore discharged without further evaluation or appropriate treatment. In contrast, a diagnosis of MINOCA should flag these patients as requiring further cardiac assessment.
  • Evaluating the Underlying Cause As listed above in the specific causes of MINOCA, a diagnosis of MINOCA should be a “working diagnosis”, flagging the necessity to evaluate the patient for the potential underlying cause of this presentation.
  • Guarded Prognosis The prognosis of patients with MINOCA is unclear and likely to be heterogeneous, considering the diverse mechanisms responsible for the syndrome. Pooled analysis of 8 studies that followed up patients with MINOCA suggests an in-hospital all-cause mortality of 0.9% (95% confidence interval (CI): 0.5%, 1.3%) and 4.7% (95% CI: 2.6%, 6.9%) at 12 months.  Analysis of AMI registries that compared patients with an AMI associated with obstructive CAD with those with MINOCA suggests that the latter have a more favorable prognosis. However, it is disconcerting that patients with stable chest pain (who have not experienced a recent AMI) in the absence of obstructive CAD, have an annual all-cause mortality of 0.3%. Moreover, in the prospectively conducted Korean MI Registry, the MINOCA patients had the equivalent 12-month all-cause mortality to those with an AMI associated with single- or double-vessel CAD. Hence patients with MINOCA should receive the same clinical attention as AMI patients who have single- or double-vessel disease and not merely dismissed as having an insignificant clinical condition.

 

MINOCA RESEARCH AT UNIVERSITY OF ADELAIDE 

1. MINOCA-BAT (MINOCA-Beta blockers and/or ACE-I/ARB Therapy) Trial (Recruitting): Stemming from AMI management guidelines, the European Society of Cardiology Position Paper on MINOCA recommended beta blockers, ACE inhibitors, dual antiplatelet agents and statins as empiric therapeutic strategies. Observational data from the SWEDEHEART Registry supports the use of ACEI/ARB and statins, with equivocal data for beta-blockers and no benefit from dual antiplatelet therapies. Given the inherent risk of residual confounding in observational studies, the results need to be prospectively validated in a randomised clinical trial. This led to the present pragmatic international multicentre MINOCA-BAT trial. In this trial, it is hypothesized that long-term treatment with ACEI/ARBs and/or beta-blockers will reduce the risk of all-cause death, myocardial infarction, stroke or heart failure in patients with MINOCA and preserved ejection fraction. The MINOCA-BAT Study is an investigator-initiated, registry-based, pragmatically-designed, international, multicentre, open-labelled, 2x2 factorial design, randomised controlled trial.

2. Post Infarct Angina in MINOCA Trial (Recruitting): over a quarter of MINOCA patients continue to experience chest pain (Post-Infarct Angina) over the next 12 months, with an initial prevalence higher than patients with MI and obstructive coronary artery disease (MI-CAD). Post Infarct angina in MINOCA aims to determine whether oral beta-blockade and/or ACEI/ARB in MINOCA patients with post-infarct angina impacts on post-infarct angina at 12 months, where angina frequency is assessed with the Seattle Angina Questionnaire (SAQ).

3. MINOCA CATH study (In Progress): The overall purpose of this project is to identify the prevalence of ischaemic mechanisms in patients with MINOCA. Identifying these ischaemic mechanisms requires invasive coronary assessment with the findings have major implications in affected patients. For example, those with inducible spasm require calcium channel blockers as a cornerstone therapy, patients with plaque disruption would benefit from statin therapy, those with coronary emboli should have anti-thrombotic therapy, and those with coronary microvascular dysfunction may benefit from therapies targeting the microcirculation. The project will specifically evaluate the following pathophysiological mechanisms based upon local experience and safety considerations: (i) coronary microvascular dysfunction, (ii) plaque disruption, and (iii) plaque associated thrombi.

4. MINOCA Health Status Assessments (In Progress): Coronary Angiogram Database of South Australua or CADOSA is a unique registry collects clinical details on all patients undergoing coronary angiographyat South Australian public hospitals with data collected by trained staff dedicated to this task. Since commencing in 2012, there are over 30,000 patient records, including patients MINOCA. The data collected includes detailed chest pain history, risk factors, past history, medications and angiographic findings. In addition, the SAQ-7, PHQ-9, and EQ5D are established and validated health status instruments that respectively document angina frequency (including the impact of angina on physical limitations and quality of life), depression, and generic quality of life. These are collected at baseline,1, and 12 months via CADOSA registry. 

 

Coronary Slow Flow Phenomenon (CSFP)

Coronary microvascular dysfunction is an ‘abnormal coronary microvascular resistance (either arteriolar or pre-arteriolar) that is clinically evident as an inappropriate coronary blood flow response, impaired myocardial perfusion and/or myocardial ischaemia that cannot be accounted for by abnormalities in the epicardial coronary arteries.’ Typically, it clinically manifests as angina but its diagnosis may be overlooked if the clinician is not vigilant to its potential presence. Coronary microvascular dysfunction (CMD) may occur in the context of myocardial disease (eg myocarditis or hypertrophic cardiomyopathy), epicardial coronary artery disease (eg atherosclerotic obstructive coronary artery disease or acute myocardial infarction), or associated with iatrogenic conditions (eg the no-reflow phenomenon, post-percutaneous coronary intervention angina). Moreover coronary microvascular dysfunction may occur in the absence of these conditions, such as the primary coronary microvascular disorders (syndrome X, microvascular angina, microvascular spasm and the coronary slow flow phenomenon). Although CMD is frequently encountered in clinical practice, its management is challenging since many conventional anti-anginal agents primarily target the large epicardial coronary vessels and thus have limited impact on CMD.

WHAT is coronary slow flow?

Nearly 50 years ago, Tambe and colleagues initially described this angiographic entity in patients with angina symptoms where they noted the injected contrast during coronary angiography moved very slowly through the coronary arteries, and aptly named “coronary slow flow phenomenon”. The prevalence is estimated at approximately 1-6% of elective angiograms. The condition was largely neglected until Professor John Beltrame identified the distinct clinical features associated with this intriguing entity and thus concluded the coronary slow flow phenomenon was a new coronary disorder rather than angiographic curiosity. Evidence suggests that the coronary slow flow phenomenon leads to clinical manifestations of ischemia, arrhythmias, acute coronary syndromes and even sudden cardiac death.

How is coronary slow flow diagnosed?

Coronary slow flow phenomenon is usually identified subjectively by visual judgment.

  • Thrombolysis in myocardial infarction (TIMI) flow grade reflects the speed and completeness of the passage of the injected contrast through the coronary tree. In the setting of coronary slow flow, diagnosis can be made on the basis of TIMI 2 flow grade (ie: requiring ≥ 3 beats to opacify the vessel).
  • Corrected TIMI frame count (CTFC) facilitates the standardization of TIMI flow grades and flow assessment. It represents the number of cine-frames required for contrast to first reach standard distal coronary landmarks. TIMI frame count > 27 frames have been frequently used to diagnose slow flow.

What is the medical management for coronary slow flow phenomenon?

Although coronary slow flow phenomenon patients have good overall prognosis, ongoing anginal episodes results in considerable impairment of their quality of life. Professor Beltrame has been long fighting the battle of identifying appropriate management for these patients, in particular, therapies that limiting the anginal episodes. His group has shown dipyridamole and mibefradil has some benefit in this setting, yet larger studies are required to confirm these findings. Currently available anti-anginal agents are of limited clinical value. To date, no large trial testing pharmacological approaches has been conducted, and the evidence available is derived from small studies, some with inhomogeneous inclusion criteria.

 

CSFP RESEARCH AT UNIVERSITY OF ADELAIDE 

1. Ticagrelor In Coronary microvascular dysfunction (TIC) Trial (Recruitting):  The CSFP is a primary coronary microvascular disorder that is frequently associated with recurrent chest pain and poorly controlled with conventional anti-anginal agents. Ticagrelor has potential anti-anginal benefits for patients with the CSFP since it may ameliorate the associated coronary microvascular dysfunction via its effects on endogenous adenosine levels. A previous study utilizing another agent that increased adenosine levels (dipyridamole), showed a trend towards improvement in the CSFP patients but the study was constrained by the poor tolerance of this agent due to headaches (an effect that is not problematic with ticagrelor). The primary objective of this trial is to assess the effect of ticagrelor 90mg bd on angina frequency in patients with the CSFP who experience angina at least 3 times/week.

2. Zibotentan in CSFP Trial (Recruitting): Studies conducted both at

the University and at other sites, have implicated ET-1, a potent microvascular vasoconstrictor) in the pathogenesis of the CSFP. Key supporting findings include: (i) intracoronary ET-1 infused in animal models reproduces the angiographic findings of the CSFP, (ii) ET-1 levels are elevated in patients with the CSFP, (iii) an endothelin gene mutation is strongly linked to the CSFP, (iv) intravenous ET-1 infusion in healthy humans replicates physiological parameters associated with the CSFP and (v) subcutaneous microvessels from CSFP patients exhibit a selective hyper-responsiveness to ET-1. Furthermore, our previously conducted randomised, double-blind, placebo-controlled, cross- over trial evaluating the anti-anginal benefits of bosentan (a combined ET-A/ET-B receptor blocker) in patients with the CSFP showed a nonsignificant trend for anti-anginal benefit compared to placebo. This finding may reflect (a) a type II error due to an insufficient sample size, and/or (b) use of a combined ET-A/B receptor blocker rather than a specific ET-A receptor blocker. Hence a sufficiently powered study using a specific ET-A blocker may produce more favourable results. Zibotentan is a potent ET-A receptor blocker with no effect on the ET-B receptor. Moreover, it will be the first study to confirm the anti-anginal benefits of selective endothelin receptor blockade and may have implications for broader coronary artery disease conditions. The primary objective is to assess the effect of Zibotentan 10mg once daily/mane on angina frequency in patients with the CSFP who experience angina at least 3 times/week.

 

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  • Journals

    Year Citation
    2019 Pasupathy, S., Tavella, R., & Beltrame, J. (2019). Myocardial Infarction with Non Obstructive Coronary Arteries (MINOCA): Are there ethnic differences?. International Journal of Cardiology, 287, 46-47.
    DOI
    2019 Hausvater, A., Pasupathy, S., Tornvall, P., Gandhi, H., Tavella, R., Beltrame, J., . . . Reynolds, H. (2019). ST-segment elevation and cardiac magnetic resonance imaging findings in myocardial infarction with non-obstructive coronary arteries. International Journal of Cardiology, 287, 128-131.
    DOI Scopus1 WoS2
    2019 Dreyer, R. P., Tavella, R., Curtis, J. P., Wang, Y., Pauspathy, S., Messenger, J., . . . Beltrame, J. F. (2019). Myocardial infarction with non-obstructive coronary arteries as compared with myocardial infarction and obstructive coronary disease: outcomes in a Medicare population.. European heart journal.
    DOI
    2018 Pasupathy, S., Tavella, R., & Beltrame, J. (2018). Response by Pasupathy et al to Letters Regarding Article, "early Use of N-acetylcysteine (NAC) with Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction Reduces Myocardial Infarct Size (The NACIAM Trial [N-Acetylcysteine in Acute Myocardial Infarction])". Circulation, 137(13), 1424-1425.
    DOI
    2018 Beltrame, J., Pasupathy, S., Tavella, R., & White, H. (2018). How Can You Have a Myocardial Infarction Without Significant Coronary Artery Disease?. Heart Lung and Circulation, 27(6), 649-651.
    DOI Scopus2 WoS1 Europe PMC1
    2018 Tavella, R., Pasupathy, S., & Beltrame, J. (2018). MINOCA – A personalised medicine approach. International Journal of Cardiology, 267, 54-55.
    DOI Scopus2 WoS3 Europe PMC1
    2018 Pasupathy, S., & Beltrame, J. (2018). Refining the diagnosis of myocardial infarction with nonobstructive coronary arteries. Coronary Artery Disease, 29(6), 528-529.
    DOI Scopus1 Europe PMC1
    2018 Pasupathy, S., Rodgers, S., Tavella, R., McRae, S., & Beltrame, J. (2018). Risk of Thrombosis in Patients Presenting with Myocardial Infarction with Nonobstructive Coronary Arteries (MINOCA). TH Open, 02(02), 167-172.
    DOI
    2017 Pasupathy, S., Tavella, R., Grover, S., Raman, B., Procter, N., Du, Y., . . . Beltrame, J. (2017). Early use of N-acetylcysteine with nitrate therapy in patients undergoing primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction reduces myocardial infarct size (the NACIAM trial [N-acetylcysteine in acute myocardial infarction]). Circulation, 136(10), 894-903.
    DOI Scopus30 WoS29 Europe PMC18
    2017 Pasupathy, S., Tavella, R., & Beltrame. (2017). Unravelling the Enigma of MI With Nonobstructive Coronary Arteries. American College of Cardiology.
    2017 Pasupathy, S., Tavella, R., & Beltrame, J. (2017). Myocardial Infarction with Nonobstructive Coronary Arteries (MINOCA): The Past, Present, and Future Management. Circulation, 135(16), 1490-1493.
    DOI Scopus32 WoS32 Europe PMC18
    2015 Pasupathy, S., Air, T., Dreyer, R., Tavella, R., & Beltrame, J. (2015). Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries. Circulation, 131(10), 861-870.
    DOI Scopus167 WoS171 Europe PMC95
    2015 Pasupathy, S., Air, T., Dreyer, R., Tavella, R., & Beltrame, J. (2015). Response to Letter Regarding Article, "Systematic Review of Patients Presenting With Suspected Myocardial Infarction and Nonobstructive Coronary Arteries". Circulation, 132(19), e232.
    DOI Scopus1 WoS2
    2015 Pasupathy, S., Tavella, R., & Beltrame, J. (2015). The what, when, who, why, how and where of myocardial infarction with non-obstructive coronary arteries (MINOCA). Circulation Journal, 80(1), 11-16.
    DOI Scopus26 WoS24 Europe PMC10
    2015 Pasupathy, S., Tavella, R., McRae, S., & Beltrame, J. (2015). Myocardial infarction with non-obstructive coronary arteries - Diagnosis and management. European Cardiology Review, 10(2), 79-82.
    DOI Scopus6 Europe PMC1
    2012 Du, Y., Pasupathy, S., Neil, C., & Beltrame, J. (2012). A comparison of ECG scores for area at risk. Heart, 98(16), 1257.
    DOI Scopus3 WoS3 Europe PMC1
  • Conference Items

    Year Citation
    2017 Reynolds, H., Pasupathy, S., Gandhi, H., Tavella, R., Axel, L., & Beltrame, J. (2017). ST-segment Elevation and cardiac magnetic resonance imaging findings in Myocardial Infarction with Non-Obstructive Coronary Arteries. Poster session presented at the meeting of JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY. Washington, DC: ELSEVIER SCIENCE INC.
    2017 Pasupathy, S., Tavella, R., Zeitz, C., Worthley, M., Sinhal, A., Arstall, M., & Beltrame, J. F. (2017). Abstract 19443: Utility of Clinical Assessments in Patients Presenting With Troponin Positive Non Obstructive Coronary Arteries (TP-NOCA). Poster session presented at the meeting of Circulation. American Heart Association, Inc..
    2017 Tavella, R., Pasupathy, S., Zeitz, C., Worthley, M., Sinhal, A., Arstall, M., & Beltrame, J. F. (2017). Abstract 19361: A Comprehensive Comparison Between Myocardial Infarction With Non Obstructive Coronaries (MINOCA) and Myocardial Infarct Patients With Coronary Artery Disease (MICAD). Poster session presented at the meeting of Circulation. American Heart Association, Inc..
    2017 Procter, N., Pasupathy, S., Stafford, I., Heresztyn, T., Liu, S., Selvanayagam, J., . . . Horowitz, J. (2017). Glycocalyx shedding in acute myocardial infarction: interactions with reperfusion and n-acetylcysteine therapy. Poster session presented at the meeting of EUROPEAN HEART JOURNAL. OXFORD UNIV PRESS.
    2017 Tavella, R., Pasupathy, S., Zeitz, C., Worthley, M., Sinhal, A., Arstall, M., & Beltrame, J. F. (2017). A Comprehensive Comparison Between Myocardial Infarction With Non Obstructive Coronaries (MINOCA) and Myocardial Infarct Patients With Coronary Artery Disease (MICAD). Poster session presented at the meeting of CIRCULATION. Anaheim, CA: LIPPINCOTT WILLIAMS & WILKINS.
    2017 Pasupathy, S., Tavella, R., Zeitz, C., Worthley, M., Sinhal, A., Arstall, M., & Beltrame, J. F. (2017). Utility of Clinical Assessments in Patients Presenting With Troponin Positive Non Obstructive Coronary Arteries (TP-NOCA). Poster session presented at the meeting of CIRCULATION. Anaheim, CA: LIPPINCOTT WILLIAMS & WILKINS.
    2016 Pasupathy, S., Tavella, R., Potamianos, R., Arstall, M., Chew, D., Worthley, M., . . . Beltrame, J. (2016). Diagnostic utility of Cardiac Magnetic Resonance Imaging (CMR) in Myocardial Infarction with Non Obstructive Coronary Arteries (MINOCA) patients. Poster session presented at the meeting of Abstracts of the 64th Annual Scientific Meeting of the Cardiac Society of Australia and New Zealand (CSANZ 2016), as published in Heart, Lung and Circulation. Adelaide, Australia: Elsevier.
    DOI
    2016 Tavella, R., Pasupathy, S., Lu, J., Arstall, M., Chew, D., Worthley, M., . . . Beltrame, J. (2016). One-year prognosis of patients with myocardial infarction and non-obstructive coronary artery disease (MINOCA). Poster session presented at the meeting of EUROPEAN HEART JOURNAL. Rome, ITALY: OXFORD UNIV PRESS.
    2016 Pasupathy, S., Rodgers, S., Tavella, R., Pope, S., McRae, S., & Beltrame, J. (2016). Risk of Thrombosis in Myocardial Infarction with Non Obstructive Coronary Arteries (MINOCA). Poster session presented at the meeting of Heart, Lung and Circulation.
    DOI
    2016 Pasupathy, S., Leow, K., Wu, S., Lee, A., Du, Y., Tavella, R., & Beltrame, J. (2016). Electrocardiographic-assessed Myocardial Area at Risk in Patients with Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA). Poster session presented at the meeting of Heart, Lung and Circulation.
    DOI
    2016 Pasupathy, S., Tavella, R., Arstall, M., Chew, D., Worthley, M., Zeitz, C., & Beltrame, J. (2016). Chest Pain Characteristics of Myocardial Infarction With Non-Obstructive Coronary Arteries (MINOCA) in Comparison to Myocardial Infarction With Coronary Artery Disease (MI-CAD). Poster session presented at the meeting of Circulation: Cardiovascular Quality and Outcomes.
    2015 Sheikh, A., Sidharta, S., Pasupathy, S., Worthley, M., & Beltrame, J. (2015). The importance of evaluating patients with MINOCA (Myocardial infarction with non-obstructive coronary arteries). Poster session presented at the meeting of Heart, Lung and Circulation.
    DOI
    2015 Pasupathy, S., Tavella, R., Arstall, M., Chew, D., Worthley, M., Zeitz, C., & Beltrame, J. F. (2015). Clinical profile of acute myocardial infarction patients in the absence of significant coronary artery disease. Poster session presented at the meeting of Heart, Lung and Circulation.
    DOI
    2015 Pasupathy, S., Tavella, R., Arstall, M., Chew, D., Worthley, M., Zeitz, C., & Beltrame, J. (2015). Abstract 273: Myocardial Infarction with Non Obstructive Coronary Artery Disease: Prevalence, Clinical Features and Outcomes. Poster session presented at the meeting of Circulation: Cardiovascular Quality and Outcomes.
    2014 Tavella, R., Pasupathy, S., Arstall, M., Chew, D., Worthley, M., Zeitz, C., & Beltrame, J. (2014). Abstract 19581: In-hospital Management and Outcomes in Patients with Myocardial Infarction and Non-obstructive Coronaries. Poster session presented at the meeting of Circulation.
    2014 Pasupathy, S., Tavella, R., Dreyer, R., & Betrame, J. (2014). PW059 Myocardial Infarction with Non Obstructive Coronary Arteries (MINOCA): A Systematic Review and Meta analysis. Poster session presented at the meeting of Global Heart.
    DOI
    2012 Pasupathy, S., Neil, C., & Beltrame, J. (2012). Measurement of Area at Risk by Cardiac Magnetic Resonance Imaging: Comparison of T2-Weighted Imaging with the Endocardial Surface Area Method. Poster session presented at the meeting of Heart, Lung and Circulation.
    DOI
    2012 Du, Y., Pasupathy, S., Neil, C., & Beltrame, J. (2012). Correlation of Electrocardiographic and Cardiac Magnetic Resonance Imaging Indices of Infarct Size in Acute St Elevation Myocardial Infarction. Poster session presented at the meeting of Heart, Lung and Circulation.
    DOI
  1. Tom Simpsons Fund: Heart Foundation of Australia

$15,000

2020

  1. External Partner Investigator: Research Themes Investment Scheme - Seed Funding

$ 39,657

2019

  • Position: Post Doctoral - Research Fellow
  • Phone: 82228685
  • Email: sivabaskari.pasupathy@adelaide.edu.au
  • Campus: North Terrace
  • Building: TQEH - Basil Hetzel Institute, floor 2
  • Org Unit: Adelaide Medical School

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